kuvempu universitykuls-ir.kuvempu.ac.in/1603/1/t-2922.pdf · 2017-04-05 · kuvempu university...

KUVEMPU UNIVERSITY

Title

“SYNTHETIC AND PHARMACOLOGICAL STUDIES OF

BENZOTHIOPHENE DERIVATIVES”

Thesis submitted to

KUVEMPU UNIVERSITY

For the Award of the Degree of

DOCTOR OF PHILOSOPHY

IN

CHEMISTRY

By

NAGESH. H.K Research Scholar

Department of Chemistry

Sahyadri Science College

Kuvempu University

Shimoga - 577 203

Guide

Dr. BASAVARAJ PADMASHALI Professor and Chairman

School of Basic Sciences: Chemistry

Rani Channamma University

NH-4, Belagavi-591 156

SEPTEMBER - 2014

130 00

't-2922

Dedicated

To

My Beloved Parents, Teachers and Friends

for everything…

KUVEMPU

Mr. Nagesh. H.K M.sc. Research Scholar

UNIVERSITY

Department of Chemistry Sahyadri Science College Shimoga - 577 203

DECLARATION

I hereby declare that the work presented in this thesis "SYNTHETIC

AND PHARMACOLOGICAL STUDIES OF BENZOTHIOPHENE

DERIVATIVES" is entirely original and was carried out by me under the

supervision of Dr. Basavaraj Padmashali, Professor and Chairman, School of

Basic Sciences: Chemistry, Rani Channamma University, Belagavi - 591 156.

I further declare that the results presented in the thesis or any part of the thesis has

not been submitted elsewhere for any other degree or diploma of similar title of

any other University.

M*(* KM (Mr. Nagesh. H.K)

F \NI CHANNAMMA * < £ > * UNIVERSITY, BELAGAVI

Dr. BASAVARAJ PADMASHALI M.SC PI,.D.

Professor and Chairman School of Basic Sciences : Chemistry Rani Channamma University Mobile: +91 9844218894 BeIagavi-591 156 Karnataka, INDIA E-mail: [email protected]

CERTIFICATE

This is to certify that the work reported in this thesis entitled "SYNTHETIC AND

PHARMACOLOGICAL STUDIES O F BENZOTHIOPHENE

DERIVATIVES" submitted by Mr. NAGESH. H.K to the Faculty of Science,

Km empu University,', for the award of Doctor of Philosophy in Chemistry, is a record of

the bonafide and original research work carried out by him under my guidance. The work

reported in this thesis has not formed the basis for the award of any degree, diploma or

any other similar title.

Date: *>s"/^/^^ Dr. Basava^ayPadmashali

Bclagavi Research Guide. - „ « . . . M 1 ,y , Dr. BASAVARAJ PADMASHALI

professor & Chair man Deptof. Strifes & Research in Chemistry

School cf Basic Sconces Ranichennamrna University

taAGAV*491156

mailto:[email protected]

A C K N O W L E D G E M E N T S

The research work embodied in this thesis has been carried out under the able

guidance of Dr. Basavaraj Padmashali, Professor and Chairman, School of Basic

Sciences: Chemistry, Rani Channamma University, Belagavi-591156. His guidance and

impressive understanding of the Chemical Sciences has helped my development as a

good researcher and chemist. It gives me immense pleasure to express profound sense of

gratitude to my beloved guide Dr. Basavaraj Padmashali, for his personal care,

stimulating discussion and inspiring guidance. He has been constant and consistent

source of strength throughout the pursuit of this research work. I also would like to thank

his wife Mrs. Divya B. Padmashali and Little Niyathi for her kind encouragement during

my thesis preparation.

I would like to thank Prof. S. A. Bari, Honorable Vice Chancellor, Kuvempu

University, for all the facilities provided for doing research work. I am grateful to the

authorities of Kuvempu University, for providing me the facilities to do this research

work.

It is my duty to express my pleasant thanks to faculty members of Department of

Chemistry, Dr. Y. Arthoba Naik, Chairman, Department of Chemistry, Dr. V.P. Vaidya,

Dr. J. Keshavayya, Dr. T.V. Venkatesha and Dr. K.M. Mahadevan for their

encouragement.

I express my deep sense of gratitude to Prof. Shakunthala, Principal, Sahyadri

Science College, and all the teaching and non teaching staff of Sahyadri Science College

(Autonomous) for their cooperation extended.

It is my duty to express my pleasant thanks to faculty members of Department of

Chemistry, Prof. Siddaramappa, Dr. H. Jayadevappa, Principal, Sahyadri Arts and

Commerce College, Dr. B.C. Goudar Shivannanavar, Chairman, Department of

Chemistry, Dr. Venugopala Reddy, Dr. H.M. Vagdevi, Dr. Vittal rao, Dr. Anitha,

Dr. G. Krishnamurthy, Dr. K.P. Latha, 'Sri. T.C.M. Yuvaraj, Sri. S.A. Srikanta,

p r p. Parameshwar Naik, Dr. Pramod and Sri. N.C. Arunakumar for their kind

encouragement.

J would )ike to express my sincere gratitude to our research group

Dr. R- Nag^ndra Rao, Dr. T.H. Suresh Kumar, Dr. G. Naganagowda,

Dr. H.S. Basavaraja, Dr. B.N. Chidananada, Mr. C. sandeep, Mr. M.B. Siddesh,

Mr. S.M. M^Hikarjuna, Mrs. Thriveni K.S, for their kind co-operation and

encouragement, '• .

I would like to express heartful thanks to faculty members of Department of

Chemistry and Industrial Chemistry, Mr. T.E. Musthurappa, Dr. G. Vinod,

Dr. S.V. Lokesh, Dr Raghavendra, for their valuable support and guidance.

I would like to express my heartfelt thanks to Dr. Sampath, Dr. Khaleel,

Dr. Shivarudrappa, Dr. N.D. Shashikumar, Dr. M. Chethan gowda, Mr. M.R. Lokesh,

Mr. K.V. HaHsh, Mr. shefi ahamed, Mr. Jithendra, Mr. Ravi, Mr. Venugopal,

Mr. Prashanth, and non teaching staff of chemistry department for their encouragement

and support,

J must %cknow)edge the outstanding contribution of my friends and we)) -wishers

Mr. Shashi(kulla) Mr. Sunil kumar, Mr. kahalandhar, Mr. Basavaraj bisthahalli, Mr.

Mohan, Mr Ravish, Mr George, Mr. Balakrishna, Mr. Bramhalingayya, Mr. Dhananjay<i,

Mr. Yashwanth, Mr. Harish, Mr. Rajashekar, Mr. veerabhadr achar, whose help in variety

of ways was exceptional.

I would like to extend my gratitude to my beloved friends Mr. G.C. Ravikumar.

Mr. Dushyanth, Mr. B. Kumar naik, Mr.Vinod, Mr. Musturappa, Mr. Lokesh,

Mr. D. Thippeswamy, Mr. Basappa bhovi, Mr. T.E. Rangaswamy, Mr. Chandrappa,

Mr. Danappa for their valuable support.

I would also like to thank, Indian Institute of Science, Bangalore, Punjab

University, Sapala Organics Hyderabad, and SJM College of Pharmacy, Chitradurga,

Pharmacy College, Dharwad, for providing spectral data, for their support in completing

this research work smoothly. I would also like to thank Harapanahalli College of

Pharmacy for helping to carryout biological activity. I would like to express my heartfelt

thanks to Mr. B.D. Shiva Kumar, Web World, Durgigudi, Shimoga,

I lovingly acknowledge the moral support of my father Sri. Kariyappa, my

mother Smt. Rudramma,.. my brothers Mr. H.K. Halesh, Mr. H.K. Yenkatesh,

Mr. Kariyappa(master) Mr. Siddappa(master) Mr. K. Thippeswamy, Mr. Halasiddappa,

Mr. Chandrappa, Mr. Halaswamy, Mr. Varadaswamy, Mr, marijanna, Mr. Basavaraj,

Mr. H.V. parameshwarappa, Mr. K. suresh, Mr. Lokesh, Mr. K. Dinesh, Mr. K. Nagaraj,

my sister H.K. Radha and family members and relatives whose inspiration and heartfelt

encouragement is responsible for me to attain this level.

Every completed task has got many hands to accomplish it. Mere mention of

them will not justify their true contribution. My acknowledgement are therefore many

more than what I have expressed here.

(Mr. NageskH.K)

Contents

Page No.

CHAPTER – I

Introduction

Introduction to benzothiophene 01-24

References 25-33

CHAPTER – II

The synthesis of methyl-3-amino-1-benzothiophene-2-carboxylate

substituted pyrazole and pyrazolone moieties.

Introduction 34-41

Present work 42-45

Experimental 46-53

References 54-57

CHAPTER – III

Synthesis of novel series of imidazole, oxadiazole and pyrazole containing

benzothiophene derivatives.

Introduction 58-64

Present work 65-69

Experimental 70-76

References 77-83

CHAPTER – IV

A convenient synthesis of methyl-3-amino-1-benzothiophene-2-carboxylate

substituted 1,3,4-oxadiazoles.

Introduction 84-88

Present Work 89-94

Experimental 95-107

References 108-111

CHAPTER – V

An overview on synthesis of benzothiophene substituted azetidinone and

thiazolidinone derivatives

Introduction 112-117

Present work 118-122

Experimental 123-130

References 131-136

CHAPTER –VI

A new approach to the synthesis of 3-amino-6-methoxy-benzothiophene-2-

carboxylate substituted pyrimidine derivatives.




References 158-162

CHAPTER –VII

Synthesis of benzothiophene linked triazolothiadiazole derivatives.




References 177-184

CHAPTER –VIII

Biological evaluation 185-218

References 219

Instrumentation and Methodology

Melting points

Melting points (in 0C) were determined in open capillary tubes and are uncorrected.

Infrared Spectra

IR spectra were recorded on Perkin-Elmer KBr Unicam FTIR 1000 and Shimadzu

Spectrophotometer using KBr pellets. Wave numbers are expressed in cm-1

.

NMR Spectra

1H NMR Spectra were recorded on Bruker AV (400 and 500 MHz) Spectrometer,

AVON series 400MHz supercon Bruker Germany and JEOL MODEL GSX 270 FT

NMR Spectrophotometer (NMR 300 MHz and 400 MHz) Supercon Spectrometer using

CDCl3 and DMSO-d6

as solvents and TMS as an internal standard reference. Chemical

shifts are expressed in values [ppm].

Mass Spectra

The mass spectra were recorded Mass spectra were performed on a Joel JMS-D 300

mass spectrometer operating at 70 ev and Triple Quadropole LC-MS with ESI source.

Mfg.SCIEX .

CHN: Elemental analysis was done by a Perkin-Elmer auto analyzer.

Purity

Purity of compounds was checked by TLC.

Biological Activity and Pharmacological Screening

Biological and pharmacological activities have been carried out at SCS College of

Pharmacy, Harapanahalli, SJM Pharmacy College, Chitradurga and Sahyadri Science

College, Shimoga.

CHAPTER - I

Introduction.

Chapter - I

Page No. 1

INTRODUCTION

Heterocyclic chemistry is one of the most complex and intriguing branch of

organic chemistry. Heterocyclic compounds constitute the largest and most varied

family of organic compounds. Many broader aspects of heterocyclic chemistry are

recognized as disciplines of general significance that impinge on almost all aspects of

modern organic chemistry, medicinal chemistry and biochemistry. Heterocyclic

compounds offer a high degree of structural diversity and have proven to be broadly

and economically useful as therapeutic agents.

Drugs are known to develop immunity in the organization gradually. Hence,

efficacy of the present drugs may decrease in the course of time. This needs the

replacement of existing drugs periodically by newer drugs. They can also be made

potent by structural alterations through chemical reactions. In addition to this, these

drugs are associated with some unwanted side effects. Attempts to improve the potency

of the drugs and to eliminate the unwanted side effects are being made continuously

throughout the world.

The word „drug‟ is derived from the French word „drogue‟ which means a dry

herb. According to “WHO” a drug may be defined as “any substance or product that is

used or intended to be used for modifying or exploring physiological system or

pathological system status for benefit of recipient”.

There are two main divisions of medicinal chemistry. The first chemotherapy,

concerns the treatment of infections, parasite or malignant disease by chemical agents,

usually substances that show selective toxicity towards the pathogens. The other

division relates to diseases of body dysfunction and the agents employed are mainly

compounds that effect the functioning of enzymes, the transmission of impulses or the

action of on hormone on receptors. Heterocyclic compounds are used for all these

Chapter - I

Page No. 2

purposes, because they have a specific chemical reactivity. The dissociation constants

of sulfa drugs or modify their pattern of absorption, metabolism or toxicity. During the

period of 1930-1950, there was an urgent need for new drug to treat diseases, which

had a high mortality rate, there was only limited appreciation of the hazard such drug

might present and toxicological studies before clinical trials were fairly rudimentary.

Proving the proverb necessity is the mother of invention, during the decade of 30 & 40s

a large number of drugs introduced. Therefore, this period is regarded as golden period

of new drug discovery.

Some specific examples representing new therapeutics are summarized here. In

1893, the first antibacterial drug prontosil leading to various sulfa drugs; 1940-

penicillin, antibiotic; 1945-chloroquin, antimalerial; 1950-methyldopa,

antihypertensive; 1958-coronary vasodilators; 1960-semisynthetic penicillin’s,

antibacterial; 1965-trimethoprim, antimicrobial; 1967-disodium chromoglycolate,

antiallergic; 1972-antagonist; 1981-captopril, antihypertensive. Drugs are known to

develop immunity in the organization gradually.

The chemical and biological potentials of five-membered heterocyclic

compounds fused with aromatic nuclei have attracted the attention of organic and

medicinal chemists for several years, because of the unsatisfactory status of present

drug side effects and the resistance by the infecting organisms to present drugs.

In particular, literature is well documented with sulphur containing

heterocycles are the active research in the pharmaceutical chemistry. Now a days

benzothiophene derivatives in combination with other ring systems have been used

extensively in pharmaceutical applications such as antiallergic, analgesic, anti-

inflammatory etc.

Chapter - I

Page No. 3

In view of these facts, the present study is focused on the development of new

potent heterocyclic moieties containing benzothiophene nucleus for enhancing better

biological and pharmacological properties.

This chapter starts with general introduction to the field of benzothiophene

derivatives. The introduction includes brief explanation for selecting benzothiophene

derivatives as research program. The chapter ends with the scope of the present work

taken for pursuing Ph.D. degree.

Benzothiophene derivatives

Benzothiophene is an organic compound with molecular formula C8H6S and an

odour similar to naphthalene (mothballs). It occurs naturally as a constituent of

petroleum-related deposits such as lignite tar. Benzothiophene has no household use. It

is used primarily in industry and research. Being heterocyclic compound,

benzothiophene finds use in research as starting material for the synthesis of larger,

usually bioactive structure. It is found within the chemical structure of pharmaceutical

drugs such as Raloxifene, Zileuton, and Sertacanazole. It is also used in the

manufacturing of dyes such as thioindigo1-9

.

Its aromaticity makes it relatively stable, although as a heterocycles, it has

reactive sites, which allow for functionalization. Benzothiophene is frequently referred

as the sulfur analogue of indole10

.

S

Molecular formula C8H6S

Molar mass 134.20g/mol

Appearance White solid

Melting point 32 C

Boiling point 221C

Chapter - I

Page No. 4

Methods of synthesis of benzothiophenes.

01. From 2-arylthio-aldehydes, ketones or-acids.

Cyclization of 2-arylthio-aldehydes, ketones or acids via intramolecular

electrophilic attack on the aromatic ring, with the loss of water, creates the heterocyclic

ring, this route is the commonest method for benzo[b]thiophenes11

.

SH

O-H2o

S

02. Preparation from 2-(orthothioxy)aryl)-acetaldehydes, ketones or acids.

Cyclodehydration of 2-(ortho-thioxyaryl)-acetaldehydes, ketones or acids give

the heterocycles.

H

OSH

- H2O

S

The employment of aryl 2-chloroprop-2-enyl-sulfides (or ethers) as Thio-

Claisen rearrangement substrates neatly eliminates the necessity for an oxidative step

thus providing a route to 2-methyl-benzo[b]thiophenes12

.

S

Cl

PhMe

S

heat

77 %

Cl

SH

HCl/90 0C

56 %

03. From ortho-acylarylthioacetic acids or esters or ketones.

Cyclising condensation of ortho-acylarylthioacetic acid (esters) or (ketones)

gives the bicyclic heterocycles.

SO

O

S O

- H2O

Chapter - I

Page No. 5

The intramolecular aldol/Perkin type condensation of ortho-formylaryl

thioacetic acid ester produces benzo[b]thiophene-2-ester13

.

I

F

LDA

THF, -780 C

then DMF

92 %

I

F

OHSCH2COOMe

NaH, DMSO

81 %

I

S

O

COOMe S O

OMe

I

The reaction depicted in scheme is an interesting event where the deprotonated

methyl ketone received the carbamoyl group and unmasked the thiophenol at the same

time, which then underwent an oxidative cyclization to give a benzothiophene along

with six-membered thiolactone14

.

O

S

NMe2O

Me NaH, DMF

SH

NMe2

S

OH

NMe2

O

Electrophiles (RCO-) for the sulfur methyl anion in include an amide to give a

3-hydroxy benzothiophene15

.

O

S

NMe2

ph S

OH

ph

t-BuOk.DMF

Carboxylic acid to give a 3-chlorobenzothiophene16

and most commonly, an

aldehyde to provide 3-unsubstituted derivatives17-22

.

COOH

S COOH S

Cl

COOH

POCl 3, DMF

SCOOH

N+

O-

O

O

Cl

N+

O-

O HSCH2COOMe

NaOMe, MeOH

Chapter - I

Page No. 6

Rhodium-catalyzed trimerization of alkynes has been successfully applied to the

synthesis of the unique benzobisthiophene23

.

S

S

Ph

Ph

Ph

Ph

O

O

Ph

Ph

S

S

Ph

Ph

O

O

1.RhCl(PPh3)3

Benzene

2. Acetylene

Several recent examples of using thionyl chloride mediated cyclization of

styrene derivatives have been reported. This reaction invariably afforded 3-chloro

benzothiophenes and works best for cinnamic acid derivatives24-28

.

COOH

SOCl 2 S

Cl

O

Cl

N

04. Synthesis which involve making the benzene ring.

6,7-Dihydrobenzo[b]thiophenes react as diens with alkynes, subsequent retro-

Diels-Alder elimination of ethene giving a benzo[b]thiophene, as illustrated29

.

S

phHC CCOOEt

PhMe, 1000 C

S

ph

OO

Thiophene is a five membered heterocyclic ring system containing sulphur

atom. The simple thiophenes are stable liquids, which closely resemble corresponding

benzene compounds in boiling points and in odour. They occur in coal tar distillates.

Discovery of thiophenes began with accidental discovery by Victor Meyer. In 1882,

during a lecture-demonstration, Victor Meyer before undergraduate students failed to

Chapter - I

Page No. 7

perform test for benzene. In early days, colour test of benzene involved production of

blue colour when heated with isatin. An inquiry revealed that lecture assistant had run

out of commercial benzene and had provided pure benzene, which was prepared by

decarboxylation of benzoic acid. It was thus clear that commercial benzene contained

impurity and that was this not the benzene which was responsible for the colour

reaction. On subsequent investigation Meyer isolated the impurity via sulphonic acid

derivative and showed that it to be the first representative of new ring system which

was named as “thiophene” the name derived from Greek word “theion” meaning

sulphur for sulphon and another Greek word “phaino” meaning “shining” a root first

used in phenic acid.

Aromatic thiophenes play no part in animal metabolism. Biotin 1 which is one

of the vitamins is a tetrahydrothiophene.

S

NH NH

O

HH

COOH

H

1

( + ) – Biotin

(Vitamin H)

Compounds containing thiophene moiety 2, 3 also have been isolated from

plants30

, crude oils and in pyrolysates of kerogens and asphaltenes31

.

Alpha-terthienyl

S

OH

S SS

SS

2

Chapter - I

Page No. 8

S

2-Hexadecyl-5-methylthiophene

S

2-Methyl-5-tridecylthiophene

S

2-Butyl-5-tridecylthiophene

3

Thiophene (thienyl) analogs are found as active constituents in plant kingdom.

These have been proven to possess several activities like anti-tumor32

, insecticide33

,

antiviral34

and anti-inflammatory activities35

. Roots of Echinops latifolius is known to

contain 5-(3-hydroxmethyl-3-isovaleroyloxyprop-1-ynyl)-2,2a-bithiophene36

. The

phytochemical investigations of Blumea obliqua afforded 5′-methyl-[5-(4-acetoxy-1-

butynyl)]-2,2′-bithiophene, 5′-methyl-[5-(4-hydroxy-1-butynyl)]-2,2′-bithiophene, 5′-

acetoxymethyl-5-(3-butene-1-ynyl)-2,2′-bithiophene and 5′-methyl-[5-(3-hydroxy-4-

isovaleroxy-1-butynyl)]-2,2′-bithiophene37

. Aerial parts of Blumea obliqua yielded a

novel dithienylacetylene, 5′-Methylene-bis-[5,3,1]-2,2′-bithiophene, along with 5′-

Hydroxymethyl5-(3-butene-1-ynyl)-2,2′-bithiophene and 5′-Carboxaldehyde-5-(3-

butene-1-ynyl)-2,2′-bithiophene which are acetylenic thiophene derivatives38

. The Z-

isomers of a dithiacyclohexadiene and a thiophene polyine were isolated and

identified from root cultures of Rudbeckia hirta39

. Ineupatoriol, a thiophene analogue

of ichthyothereol, was isolated from Inula eupatorioides40

. The roots of Echinops

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TH7-3VVD3GK-1P&_user=10&_coverDate=09%2F03%2F1998&_alid=864193929&_rdoc=21&_fmt=high&_orig=search&_cdi=5275&_sort=d&_docanchor=&view=c&_ct=133&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=83fab7de9e8ae5e2fcfe62d2ea42ac6e#b1



Chapter - I

Page No. 9

pappii contain 5-[but-3-en-1-ynyl]-2,2′-bithienyl,2,2′:5,2″-terthienyl, the cis-, and

trans-2-[pent-3-en-1-ynyl]-5-[4-hydroxybut-1-ynyl]- thiophenes, 2-[pent-1,3-diynyl]-

5-[4-hydroxy but-1-ynyl]- thiophene, santamarin, reynosin and β-amyrin palmitate41

.

Four polyacetylenes of thiophenes are reported from the roots of Leuzea

carthamoides42

. Roots, green parts and flower heads of Dahlia tubulata were examined

separately and nine polyacetylenes and five thiophenes of were isolated and

characterized43

. .Roots and green parts of 16 Echinops species were examined by GC-

MS for their content of thiophenes. Two thiophenes were detected from roots of E.

bannaticus and E. ritro, cardopatine and isocardopatine. These dimers have previously

been isolated from Cardopatium corymbosum, but are reported here from Echinops

species for the first time44, 45

.

Phototoxic activity of aqueous extracts of underground parts of Leuzea

carthamoides revealed the presence of an thienyl derivative, polyacetylene 4 (E)-1-[5-

(hept-5-en-1,3-diynyl)-2-thienyl]ethan-1,2-diol46,47

. The thiophene polyacetylene

showed apparent activity in comparison with xanthotoxin (standard). Later Jahodar et

al, showed that the same thienyl derivative exhibited antifungal activity48

.

S

CH3

OH

OH

4

1-{5-[5E)-hept-5-ene-1,3-diyn-1-yl]-2-thienyl}ethane-1,2-diol

In the latter half of the last century, the thieno compounds were introduced as

therapeutic agents. Janssen pharmaceuticals introduced tetramisole 5 which is racemic

mixture of (-) Levamisole and (+) Dextramisole and considered to be second modern

broad spectrum anthelmintic agent.

Chapter - I

Page No. 10

N

N

SH N

N

SH

+

5 (-) Levamisole (+) Dextramisole

This drug was reported to be fully effective against a wide range of

gastrointestinal nematodes in many species of animals and birds including tigers49,50

.

The discovery of tetramisole was due to the keen observation and strong desire

of Janssen pharmaceutical company to continue the efforts until successful, because

one of the earlier compound thiazothienol 6 in the primary screen in chickens was

found to possess good nematocidal properties.

6

S

N

N

CH3

CH3

However, the compound lacked activity in mice and rats. All the metabolites of

thiazothienol which were isolated and synthesized were inactive against nematodes

except thiazothielite 7. This compound was more potent than its precursor,

thiazothienol.

N

N S

S

7

Thiazothielite was also active in rodents but it was expensive and had limited

solubility in water. These results led the Janssen pharmaceutical company to develop a

close analog dl-2,3,5,6-tetrahydro-6-phenylimidazole[2,1-thiazole] 7 tetramisole.

Further investigations showed that most of anthelmintic activity of racemic tetramisole

reided in the levorotary isomer, levamisole. Since then tetramisole and levamsole have

Chapter - I

Page No. 11

been the most widely used anthelmintic agents against a broad range of nematodes in

humans, cattle, pigs, sheep and poultry51

.

In addition to anthelmintic activity, levamisole also has other interesting

biochemical properties. The discovery of anthelmintic activity in isouranium 8 led

Pfizer laboratories to initiate program on the synthesis of analogs of this compound.

Although this compound was active against experimental nematospiroides dubius

infection during rodent primary screening, it possessed little activity when administered

to sheep.

NH

N

S

S

8

The loss of activity when administered to sheep was due to rapid hydrolysis of

the compound to inactive products in this species. Further, efforts to synthesize

compounds that resist ready hydrolysis led to discovery of good anthelmintic activity in

cyclic amidines 9, which finally culminated in the discovery of pyrantel 10 and

morantel 11.

S

NH

N

( CH2)n

9, n = 0, 1

SN

N

CH3

SN

N

CH3

CH3

10

11

Chapter - I

Page No. 12

Pyrantel 10 and morantel 11 are the most valuable broad spectrum anthelmintic

agents52,53

. Pyrantel is effective against a wide range of gastrointestinal nematodes and

certainly one of the drug of choice for the treatment of human pinworm, hookworm and

ascaris infections54,55

.

Further work revealed that the following type of thieno compounds 12, 13 and

14 also possessed interesting anthelmintic activities56-58

.

S

N+

Br-

12

SX

N RNR 3

13

SX

SN

14

R= alkyl, substituted alkyl

With the advance in synthetic organic chemistry, many attempts were made to

fuse or link thiophene ring to various other homocyclic and heterocyclic rings. Thus

thiophenes which may have alkyl side chains or may be condensed with one or more

benzene or saturated ring(s) were discovered, resulting in the formation of

benzo[b]thiophenes, dibenzo[b]thiophenes, naphthothiophenes, benzonapthothio

phenes, 5,6-dihydro-4H-cyclopenta[b]thiophene 4,5,6,7-tetrahydro -1-benzothiophenes,

2,3-dimethylthiophenes, etc. These were used as synthons for synthesis of innumerous

derivatives59-61

.

Among bicyclic heteroaromatic compounds, benzo[b]thiophene and its

substituted derivatives occupy a unique place in organic chemistry62-64

. This class of

compounds has been known for a long time since their isolation from coal tar

distillates. Several synthetic methodologies have been developed in the intervening

years. On the other hand, the practical applications of benzothiophenes, especially as

pharmaceutical agents pale, when compared with their nitrogen cousins, i.e. indole

Chapter - I

Page No. 13

alkaloids. However, growing interests in this area, especially those of medicinal

applications, have rekindled research activities in this venerable field. This review will

focus on the most recent developments in the synthesis and medicinal applications of

benzo[b]thiophenes65-67

. Selected reactions unique to benzothiophene, that offers

previously unmet synthetic needs, will also be discussed. For a systematic coverage of

this heterocycle, including its chemical reactivity’s, physical properties, and reviews

that appeared in the last decade and earlier are available68-71

.

Benzo[b]thiophene, second in importance to thiophene among sulfur

heterocycles, has attracted scant attention at that time, apart from its industrial

application in dye industry. With the discovery of bioisosterism, organic chemists

started showing interest in benzo[b]thiophene since it is a bioisoster of indole. The

main area of activity in the chemistry of benzo[b]thiophene, in the 60’s and 70’s of the

last century, centered on the synthesis of its derivatives that are analogues of bioactive

indole derivatives including indole alkaloids. This line of work continues till date and

its literature up to 1980 has been reviewed.

S

Br

O

N

O

NH

NH

N

NH

O

S

Br

OH

NH

15

16

(+)-Discorhabdine A (-)-Makaluvamine F

Although alkylated benzo[h]thiophenes account for a large portion of the sulfur

content in coal tar distillates and crude petroleum72-75

their origin has not been clearly

elucidated and their presence in these products has largely been regarded as a nuisance

Chapter - I

Page No. 14

to product quality. The isolation of pure benzothiophene derivatives from these sources

posed a considerable technical challenge as many close analogs with similar physical

characteristics often coexist. While there was some earlier interest of thioindigo as a

dye, the commercial availability of benzothiophene and its derivatives has so far been

very limited. Whereas indole plays a key role in protein chemistry as part of the

essential amino acid L-tryptophan, and numerous natural products of important

biological activities containing that heterocycles have been identified, synthesized, and

commercialized, there is a relative scarcity of benzo[b]thiophene-containing

compounds isolated from living organisms. However, the recent discovery of a novel

class of antitumor and antimicrobial compounds from the latrunculia sponge species of

New Zealand is likely to elevate the interest level of benzothiophene in the natural

products arena, as represented by a hexahydrobenzothiophene, 15 (+)-discorhabdine A

(prianosin A, 2)76,77

. The benzothiophene moiety is better manifested in another

member of the marine natural product family as the dihydro derivative 16 (-)-

makaluvamine F 78-81

.

Undoubtedly, the major driving force behind advances in the chemistry of

benzothiophene has to be their biological applications. It is within this domain of highly

valued added products either as pharmaceuticals or agrochemicals, that costly multi-

step synthesis can be justified. Within the last two decades, benzothiophene has

increasingly been recognized as a pharmacophore that offers advantages including

superior chemical and pharmacological stability and low intrinsic toxicity82,83

. Most

importantly, a rich chemistry that enables medicinal chemists to explore molecular

diversity in a rapid fashion using tools that have been developed concurrently and are

recently gaining popularity, such as transition metal catalyzed carbon-carbon, and

carbon-hetero bond formation and combinatorial chemistry.

Chapter - I

Page No. 15

A large body of work related to benzothiophenes emerged with the development

and introduction of three new chemical entities (NCE) containing this heterocycle as

pharmaceuticals in recent years. Raloxifene 17 is a selective estrogen receptor

modulator84,85

(SERM) that mimics the beneficial effects of estrogen in the skeletal and

the cardiovascular systems, while lacking certain unpleasant side effects linked with

traditional estrogen replacement therapies in reproductive tissues. This drug has been

approved in the US and Europe for the prevention of osteoporosis in postmenopausal

women.

Zileutin, 18 is a 5-lipoxygenase inhibitor86,87

has been approved and is on the

market for anti-inflammatory indications. Sertaconale 19 has recently been introduced

to the market as a broad spectrum antifungal reagent88,89

. The strategy of isosteric

replacement of the indole nucleus by benzothiophene in medicinal chemistry has been

widely used in other areas as well, for example, in SAR studies of GABA modulators,

ergot alkaloids90,91

and opioid analgesics92

.

HCl

O O

N

SOH

OH

17

S

Me

N

OH

NH2

O

18

Raloxifene Zileutin

SCl

O

Cl

Cl

N

N

19

Sertaconazole

Chapter - I

Page No. 16

Several other molecular entities containing benzothiophene are at various stages

of development. They include T58893,94

20 a cognition enhancing agent with potential

application for treating Alzheimer’s dementia 21 LY3538195

another SERM from Lilly

22 AP52196

with potent 5HtlA receptor binding ability CI95997-99

an anti-inflammatory

agent and B428100

a urokinase inhibitor. Another structurally interesting compound is

24 PD 144795101-103

an endothelial cell activation inhibitor as a benzothiophene oxide.

S

ONEt2

OH

20

O O

N

SOMe

OH

HCl

21

T588 LY35381

S NH

NH

O

O

O

22

S

NH2

NH

23

AP521 B428

S

NH2

OO

OPrOMe

24

PD144795

In the late 1980’s, knowledge about physiological reasons behind various

diseases, novel methods of evaluating biological and pharmacological activities,

molecular mechanism behind drug action has also been advanced. This further

stimulated the research on synthesis and evaluation of various thiophenes for their

biological and pharmacological properties. Among these, benzo[b]thiophene is one of

the most exploited thiophene derivative104-107

.

Chapter - I

Page No. 17

Nonsteroidal anti-inflammatory drugs (NSAIDs) were introduced to overcome

severe side effects produced by steroidal inflammatory drugs. NSAID’s possess anti-

inflammatory, analgesic, and antipyretic activities and widely used in the treatment of

acute and subchronic inflammatory conditions. In early 1970s, it was reported that

NSAID’s show their action by inhibiting the functions of the enzymes which are

involved in arachidanoic acid cascade like cyclooxogenase (COX) and lipooxygenase

(LO)108,

. Svoboda et al, have reported the synthesis and COX inhibitory activity of 3-

substituted 1-benzo[b]thiophene-2-carboxanilides109

25-28.

S

R

O

NH

25-28

25 R = H 26 R = Cl 27 R = OCH3 28 R = OH

Some of benzothiophene derivatives were useful as antianxiety drugs, hypnotics

and antiepileptic drugs. Benzo[b]thiophene derivatives are known to act as excitatory

amino acid antagonists and used in the treatment of myocardial ischemia, hypertension,

fungal infection, as oral contraceptives and as hypoglycemic agent. Very recently, there

are reports on the anti-inflammatory, antiexudative, analgesic and antipsychotic

activities as well as their inhibitory action on protein tyrosin phosphatase and 5-

lypoxygenase enzymes110,111

.

It is reported that benzo[b]thiophene derivatives have exhibited anticancer

activities. Tamoxifen 29 is the archetypal selective estrogen receptor modulator

(SERM). Despite its side effects (endometrial cancer), tamoxifen has been the

treatment of choice in the endocrine treatment of all stages of hormone-dependent

breast cancer and in the primary and secondary chemoprevention of breast cancer112

.

Chapter - I

Page No. 18

ON

CH3

CH3

29

Arzoxifene 30 is a structural analogue of raloxifene in which the carbonyl hinge

has been replaced by an ether linkage and the 4-hydroxy group is methylated.

Arzoxifene is in late stage of clinical trials as a next generation SERM with promise of

substantial therapeutic benefits113

that are suggested to result from (a) increased

antiestrogenic potency and (b) improved bioavailability relative to raloxifene.

S

O

HO

ON

OCH3

30

Qin et al, have reported that regulation of estrogenic and antiestrogenic effects

of selective estrogen receptor modulators114

(SERMs) is thought to underlie their

clinical use. Most SERMs are polyaromatic phenols susceptible to oxidative

metabolism to quinoids, which are proposed to be genotoxic. Conversely, the redox

reactivity of SERMs may contribute to antioxidant and chemo preventive mechanisms,

providing a new approach to improve the therapeutic properties of SER modulators.

Mukherjee et al, have reported the chemistry and uses of

hydroxybenzo[b]thiophenes115

. The interest which this class of compounds has received

is principally due to their usefulness in the (a) synthesis of sulfur analogues of several

important bioactive indole derivatives, viz. serotonin, and (b) annulation of oxygenated

rings onto the benzo[b]thiophene core.

Chapter - I

Page No. 19

Benzo[b]thiophene derivatives have been shown to have anti-HIV1 effects by

blocking HIV-1 transcription in response to tumor necrosis factor, a stimulation of

promyelocytes116

. Gualberto et al, have studied the effects of PD 144795

117 (Parke-

Davis Pharmaceuticals) 31 on HIV-1 LTR-directed transcription in Jurkat T cells. The

expression of HIV-1 genes is controlled in part by the interaction of sequence-specific

transcription factors with the LTR region of the provirus.

S

O

Pr i

MeO

31

Apart from these, there are innumerous reports on various biological and

pharmacological activities of benzo(b)thiophenes like antifungal, analgesic,

anthelmintic, anti-arrhythmic, herbicidal, muscle relaxant and tranquilizing

activities118,119

.

Synthesis of thiophenes fused to saturated homocyclic systems like cyclopentanone,

cyclohexanone, cycloheptanones and polysubstituted systems began with revolutionary

discovery by Gewald120

. Gewald and coworkers in year 1961 synthesized

polysubstituted thiophenes from the multicomponent condensation of ketones or

aldehydes, activated nitriles and elemental sulfur.

Stanislav Radl and Iva Obadalova have modified Gewalds method and successfully

synthesized novel 32 3-amino-2-(1H-1,2,3-benzotriazol-1-yl) substituted benzofurans,

benzothiophenes and 1H-indoles121

.

X

N

H

O32

X=O, S, N

Chapter - I

Page No. 20

Gewald’s reaction can be successfully employed for the synthesis of following

different types of synthons 33, 34 and 35 using cyclopentanone, cyclohexanone,

cycloheptanones respectively as ketones.

S

R

NH2 S

R

NH2

S

R

NH2

33 3435

R = COOEt, CONH2, CN

These various substituted thiophenes have been extensively used for the

synthesis of innumerous compounds and evaluated for various biological and

pharmacological activities. Literature survey reveals that, thiophenes fused to

pyrimidines which are called thienopyrimidines122-125

have been extensively studied

due to their biological and pharmacological versatility. This made us to synthesize

novel thienopyrimidines for their biological significance126-131

.

Manhas et al, have synthesized and studied anti-inflammatory activities of some

substituted thiopyrimidines 36. Some of the compounds exhibited promising anti-

inflammatory activity132

.

S

N

N

O

R

CH3

36

R= phenyl, substituted phenyl

Antihyperlipaemic activity has been reported in few thieno(2,3-d)pyrimidine-2-

propanoic acids and some 2-mercapto(2,3-d)-pyrimin(4(3H)-ones133,134

. Shishoo et al,

have prepared novel thioneo(2,3-d)pyrimidines 37 and evaluated their biological

acitivities135

.

Chapter - I

Page No. 21

S

N

NHH

O

R

37


El-Gazzar et al, have synthesized thienopyrimido-1,2,4-triazoles 38 and

evaluated their biological activities136

.

El-Dean et al, have reported the synthesis of series of pyridothienopyridines 39,

40 and evaluated them for antibacterial and antifungal activities137

.

N S

S N

CH3

CH3 O

O

CH3

CH3

39

N SCH3

CH3 NH

CH3

NH

S

40

Shmeiss et al, have prepared series of tetrahydrobenzothieno[2,3-d]pyrimidine

derivatives 41, 42 and evaluated their antibacterial activity against gram positive and

gram negative pathogens. Some of the compounds exhibited anti-bacterial activity

equal to that of standard138

.

S

N

N S NH2

R

ArO

41

S

N

N

O

S

O

42


S N

N

NN

CH3

38

Chapter - I

Page No. 22

Enough literature is available on synthesis and biological evaluation of 4-

substituted thienopyrimidines. Bhaskar et al, have prepared series of 4-subsituted

thienopyrimidines 43 and evaluated their antimicrobial and anti-obesity activity. Some

of the tested compounds exhibited anti-obesity activity equal to that of standard drug

gemfibrogil139

.

S N

N

RR

1

43

R=R1=alkyl

Leishmaniasis is one of several parasitic diseases which contribute to the high

rate of mortality in developing countries. In addition, several hundreds of people are

now infected with HIV and leishmaniasis, making both infections harder to treat.

Leishmaniasis has also been an epidemic in countries such as Sudan, India and

Afghanistan. Current antileishmanial drugs have severe limitations such as toxicity, the

development of resistance and administration by injection. The severity of the disease

has led to many research groups to develop novel antileishmanial agents. Victoria

Tkacz and group has attempted the synthesis and of novel thiophenes 44 and screened

them for antileishmanial activity. Some of the synthesized compounds exhibited

promising antileishmanial activity140-143

.

S

N

N

R

R2

R3

R1

44

R=R1=alkyl R2=R

3= phenyl, substituted phenyl

Chapter - I

Page No. 23

H.S. Joshi et al, synthesis and antimicrobial activity of some new 45

benzo(b)thiophene incorporated dihydroquinolines144

. Sembian ruso jayaraman et al,

synthesized 46 3-methyl-4,5,6,7-tetrahydro-1-benzothiophene-2- carboxylic acid145

.

S

NHCl

O

45

S

O

OH

46

Arun M. Isloor et al, synthesis, characterization and biological activities of a

number of new 47 benzo[b]thiophene derivatives146

. Basavaraj Padmashali, et al,

synthesis of 48 3-substituted-2-methyl-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-

d]pyrimidin-4-(3H)-ones and their pharmacological efficacy147

.

S

Cl

O

N

N

R

Ar-

47

N

NS

O

N

S

RR1

48

Basavaraj Padmashali et al, synthesis and pharmacological investigation of 49

benzothiophene heterocycle148

. Peter Langer, et al, synthesis of 50 functionalized

benzothiophenes by two fold heck and subsequent 6 п -eletrocyclization reactions of 2,

3-dibromothiophene149

.

S

Cl

NH

O

N

O49

R

R2

S

50

Ming-Wei Wang et al, synthesis of 51 benzothieno [3,2-b] indole derivatives as

potent selective estrogen receptor modulators150

.

Chapter - I

Page No. 24

OZ

N

RSOH

51

Apart from this, there are many reports available on biological significance of

thienopyrimidines like anti-hypertensive, mollucidal, anticonvulsant and cholesterol

inhibition activities.

Keeping in view of biological importance of benzothiophene derivatives and

inspired by the scope of research in this field, we have carried out the research work on

the synthesis of benzothiophene derivatives to explore their biological profile.

Chapter - I

Page No. 25

REFERENCES

[1] S. Rollas and S.G. Küçükgüzel, Molecules., 2007, 1, 910.

[2] U.O. Ozdemir, F. Arslan, F. Hamurcu, Spectrochim Acta A Mol Biomol

Spectrums., 2010, 75(1), 121.

[3] T. Horiuchi, M. Nagata, K. Akahane and K. Uoto, Bioorg Med Chem., 2009,

17(23), 7850.

[4] V. Onnis, M.T. Cocco, R. Fadda and C. Congiu, Bioorg Med Chem., 2009,

17(17), 6158.

[5] F. Chimenti, B. Bizzarri, A. Bolasco, D. Secci, P. Chimenti, S. Carradori, D.

Rivanera, N. Frishberg, C. Bordón, and L. Jones-Brando, J Med Chem., 2009,

52(15), 4574.

[6] C. Unger, B. Häring, M. Medinger, J. Drevs, S. Steinbild, F. Kratz and K.

Mross, Clin Cancer Res., 2007, 13(16), 4858.

[7] J. Nawrot-Modranka, E. Nawrot and Graczyk, J. Eur J Med Chem., 2006,

41(11), 1301.

[8] S.E. Asís, M.I. Abasolo and A.M. Bruno, Pharmazie., 2003, 58(10), 690.

[9] E. Katja, H. Marijana, P. Ivo, C. Irena, J. Ivana P. Kreimir K. Marijeta and K.Z.

Grace, J. Med. Chem., 2009, 52 (8), 2482.

[10] B. Iddon and R.M. Scrowston, Adv. Heterocycl.Chem., 1970, 11, 177.

[11] B.D. Tilak, Tetrahedron., 1960, 9, 76.

[12] W.K. Anderson, E.J. La Voie and J.C. Bottaro, J. Chem. Soc., 1999, 14, 345.

[13] A.J. Bridges, A. Lee, E.C. Maduakor and C.E. Schwartz, Tetrahedron Lett.,

1976, 33, 7499.

[14] S.W. Wright and R.L. Corbett, Tetrahedron Lett., 1993. 34, 2875.

[15] A.J. Bridges and H. Zhou, J. Heterocycl. Chem., 1997. 34, 1163.

[16] H. Schaefer and K. Gewald, J. Prakt.Chem., 1985 327, 328.

[17] V.J. Majo and P.T. Perumal, J. Org. Chem., 1996 61, 6523.

Chapter - I

Page No. 26

[18] V.G. Matassa, F.J. Brown, P.R. Bernstein, H.S. Shapiro, T.P. Maduskuie, L.A.

Cronk, E.P. Vacek, Y.K. Yee, D.W. Snyder et al, J. Med. Chem., 1990,33, 262,

1.

[I9] A.J. Bridges, A. Lee, C.E. Schwartz, M.J. Towle and B.A. Littlefield, Bioorg.

Med. Chem., 1993, 1, 403.

[20] A.J. Bridges, A. Lee, E.C. Maduakor and C.E. Schwartz, Tetrahedron Lett.,

1992, 33, 7499.

[21] R.A. Zambias and M.L. Hammond, Synth. Commun., 1991, 21, 959.

[22] H. Osuga, H. Suzuki and K. Tanaka, Bull. Chem. SOCJ. pn., 1997, 70, 891.

[23] U. Dahlmann and R. Neidlein, Synthesis., 1997, 1027.

[24] J.G. Stuart, S. Khora, J.D. McKinney and R.N. Castle, J. Heterocycle., 1987.

[25] J.D. McKinney and R.N. Castle, J. Heterocycl.Chem., 1987, 24, 1103.

[26] T.N. Sidorenko and G.A. Terent’eva, Khim. Geterotsikl. Soedin., 1988, 33.

[27] J.K. Luo, S.L. Castle and R.N. Castle, J. Heterocycl. Chem., 1990, 27, 2047.

[28] S. Pakray and R.N. Castle, J. Heterocycl. Chem., 1986, 23, 1571.

[29] S.S. Labadie, Syn. Commun., 1988, 28, 2531.

[30] L.P. Christensen and J. Lam, Photochemistry., 1990, 29, 2753

[31] W.I.C. Sinninghe Damste, J.W. Rijpstra, De Leeuw, Schenck. Cosmochim.

Acta., 1989, 53, 1323.

[32] J.D. Lambert, G. Campbell and J. Majak, Can. J. Plant Sci., 1991, 71, 215.

[33] M. Nivsarkar, G.P. Kumar and M. Laloraya, Biochem. Physiol., 1991, 16, 249.

[34] R.J. Marles, J.B. Hudson, E.A. Graham and J.T. Arnason, Photochem.

Photobiol., 1992, 56, 479.

[35] Y.L. Lin, R.L. Huang, Y.H. Kuo, Hance Chin. Pharm., 1999, 51, 201.

[36] Y. Li, X. Meng, D.L. Li, Z.L. Zhang and P. Xu, Asian.Nat.Pro.Res., 2006, 7,

585.

[37] Viqar Uddin Ahmad and Naseer Alam, Phytomedicin., 1996, 42, 733.

Chapter - I

Page No. 27

[38] Viqar Uddin Ahmad, Naseer Alam and Mohammad Qaisar, Phytomedicin.,

1998, 49, 259.

[39] C. Peter Constabel, Felipe Balza and G.H. Neil Towers, Phytochemistry., 1988,

27(11), 3533.

[40] Robindra Baruah and P. Ram Sharma, Phytochemistry., 1982, 21(3), 665.

[41] M. Berhanu Abegaz, Phytochemistry., 1991, 30(3), 879.

[42] Kalman Szendrei, Johannes Reisch and Erzsebet Varga, Phytochemistry., 1984,

23(4), 901.

[43] Lars Christensen and Jorgen Lam, Phytochemistry., 1990, 29(10), 3153.

[44] Jørgen Lam, Lars P. Christensen and Tove Thomasen, Phytochemistry., 1991,

30(4), 1157.

[45] Wenrong Jin, Qiang Shi, Chengtao Hong, Yiyu Cheng, Zhongjun Ma, Haibin

Qu, Phytomedicin., 2008, 15 ,768.

[46] Ria Biswasa, P.K. Duttab, B. Acharib, Durba Bandyopadhyaya, Moumita

Mishraa, K.C. Pramanika, T.K. Chatterjee, Phytomedicin., 2007, 14 ,534.

[47] Naira Quintana, Tiffany Weir, Jiang Du, Phytochemistry., 2008, 69, 2572.

[48] Vladimir Chobot, Jitka Vytlacilova, Lenka Kubicova, Lubomír Opletal, Ludek

Jahodar and Pia Vuorela, Fitoterapia., 2006, 77, 194.

[49] V. Chobot, V. Buchta, H. Jahodarova, M. Pour, L. Opletal, L. Jahodar and P.

Harant, Fitoterapia., 2003, 74, 288.

[50] D. Thienpont, Nature., 1996, 209, 1084.

[51] A.H.M. Raeymaekers, J.Med. Chem., 1996, 9, 545.

[52] P.A.J. Janssen, Fostschr. Arzneimittelforsh., 1976, 20, 347.

[53] W.C. Austin, Nature, 1966, 212, 1273.

[54] J.W. Mc Ferland, J. Med. Chem., 1969, 12, 1066.

[55] M.J. Miller, Fortshar, Arzneimittelforsh., 1976, 20, 449.

Chapter - I

Page No. 28

[56] J.W. Ms Ferland, Arzneimittelforsh., 1972, 16, 157.

[57] L.P. Christensen and J. Lam, Photochemistry, 1990, 29, 2753.

[58] S. Sinninghe Damst´e, W.I.C. Rijpstra, J.W. De Leeuw and P.A. Schenck,

Cosmochim. Acta., 1989, 53, 1323.

[59] S. Rollas. and S.G. Küçükgüzel, Molecules., 2007, 12(8), 1910.

[60] U.O. Ozdemir, F. Arslan, F. Hamurcu, Spectrochim Acta A Mol Biomol

Spectrosc., 2010, 75(1), 121.

[61] T. Horiuchi M. Nagata K. Akahane and K. Uoto, Bioorg Med Chem., 2009,

17(23), 7850.

[62] H.M. Hassan, J.Serb.Chem.Soc., 1998, 63 (2), 117.

[63] S.J. Wood and S. Shadomy, Eur J. Clin. Microbiol., 1983, 2(3), 242.

[64] W.B. Wright, J.Heterocycl.Chem., 1972, 9, 879.

[65] M. Garcia-Valverde, T. Tomas, Molecules., 2005, 10, 318-320.

[67] D.L. Boger, Chem. Rev., 1986, 86, 781-793.

[68] M.J. Leach, M.S. Nobls, Eur. Pat. Appl-EP459, 829; Chem. Abstr., 1992, 116,

128970.

[69] S. Rajappa and M.V. Natekar, In Compr. Heterocycl. Chem., 1996, 11, 491.

[70] M. Szajda and J.N. Lam, In Comp. Heterocycl. Chem., 1996, 437.

[71] E. Campaigne, D.R. Knapp, E.S. Neiss and T.R. Bosin, Adv. Drug Res., 1970,

5, 1.

[72] F. Boberg, W. Bruns, R. Kaller and D. Musshoff, Phosphorus, Sulfur Silicon

Relat. Elem., 1992, 72, 33.

[73] F. Boberg, W. Bruns and D. Musshoff Phosphorus, Sulfur Silicon Relar. Elem.,

1992. 72, 13.

[74] F. Boberg, A. Jachiewicz and A. Garming, Phosphorus, Sulfur Silicon

Relar.Elem., 1992, 72, 1.

Chapter - I

Page No. 29

[75] C.D. Czogalla and F. Boberg, Phosphorus Sulfur., 1988, 35, 127.

[76] N.B. Perry, J.W. Blunt and M.H.G. Munro, Tetrahedron., 1988, 44, 1727.

[77] J.W. Blunt, M.H.G. Munro, C.N. Battershill, B.R. Copp, J.D. McCombs, N.B.

Perry, M. Prinsep and A.M. Thompson., New J. Chem., 1990, 14,761.

[78] L.R. Barrows, D.C. Radisky, B.R. Copp, D.S. Swaffar, R.A. Kramer, R.L.

Warters and C.M. Ireland Anti-Cancer Drug Des., 1993, 8, 333.

[79] J.R. Carney, P.J. Scheuer and M. Kelly-Borges, Tetrahedron., 1993, 49, 8483.

[80] M. Makosza, J. Stalewski and O.S. Maslennikova, Synthesis., 1997, 1131.

[81] D.C. Radisky, E.S. Radisky, L.R. Barrows, B.R. Copp, R.A. Kramer and C.M.

Ireland, J. Am. Chem. Soc., 1993, 115, 1632.

[82] T.A. Grese, J.P. Sluka, H.U. Bryant, G.J. Cullinan, A.L. Glasebrook, C.D.

Jones, K. Matsumoto, A.D. Palkowitz, M. Sato, J.D. Termine, M.A. Winter,

N.N. Yang and J.A. Dodge, Proc. Narf. Actid. Sci. U.S.A., 1997, 94, 14105.

[83] A.D. Palkowitz, A.L. Glasebrook, H.U. Bryant, K.J. Thrasher, L.L. Short, P.K.

Shelter, K.L. Hauser, D.L. Phillips, H.W. Cole et al, Book of Abstracts, 213th

ACS National Meeting, Sun Francisco, April 13-17, 1997, MEDI-204.

[84] C.D. Jones, M.G. Jevnikar, A.J. Pike, M.K. Peters, L.J. Black, A.R. Thompson,

J.F. Falcone and J.A. Clemens, J. Med. Chem., 1984, 27, 1057.

[85] H.U. Bryant and W.H. Dere, Proc. Soc. Exp. Biol. Med., 1998, 217, 45.

[86] A. Basha, J.D. Rdtajczyk and D.W. Brooks Tetrahedron Lett. 1991, 32, 3783.

[87] A.O. Stewart and D.W. Brooks, J. Org. Chem., 1992, 57, 5020.

[88] R. Thesen, Phann. Ztg., 1995,140, 44.

[89] M. Raga, C. Palacin, J.M. Castello, J.A. Ortiz, M.R. Cuberes and M. Moreno,

2005.

[90] T.P. Blackburn, D.T. Davies, I.T. Forbes, C.J. Hayward, C.N. Johnson, R.T.

Martin, D.C. Piper, D.R. Thomas, M. Thompson et al Bioorg. Med.Cheni. Lett.,

1995, 5, 2589.

Chapter - I

Page No. 30

[91] P.D. Clark and N.M. Irvine, Phosphorus, Sulfur Silicon Relat. Ele., 1996, 118,

61.

[92] C.R. Clark, P.R. Halfpenny, R.G. Hill, D.C. Horwell, J. Hughes, T.C. Jarvis,

D.C. Rees and D. Schofield, J. Med. Chem., 1988, 31, 831.

[93] A.M. Martel, J. Prous and J. Castaner-Prous Drug.s Future, 1997, 22, 386.

[94] H. Miyazaki. T. Murayama, S. Ono, H. Narita and Y. Nomura Biochem.

Phurmtrcol., 1997, 53, 1263.

[95] S. Ono, T. Yamafuji, H. Chaki, Y. Todo, M. Maekawa, K. Kitamura, T.

Kimurd, Y. Nakada, K. Mozumi and H. Narita Bid. Phurm. Bull., 1995, 18,

1779.

[96] A.D. Palkowitz, A.L. Glasehrook, K.J. Thrasher, K.L. Hauser, L.L. Short, D.L.

Phillips, B.S. Muehl. M. Sato, P.K. Shetler, G.J. Cullinan, T.R. Pel1 and H.U.

Bryant, J. Merl. Chem., 1997, 40, 1407.

[97] H. Kawakubo, S. Takagi, Y. Yamaura, S. Katoh, Y. Ishimoto, T. Nagatani, D.

Mochizuki, T. Kamata and Y. Sasaki, J. Med. Chem., 1993, 36, 3526.

[98] C.D. Wright, S.F. Stewart, P.J. Kuipers, M.D. Hoffman, L.J. Devall, J.A.

Kennedy, M.A. Ferin, D.O. Thueson and M.C. Conroy, J. Leukocp Biol., 1994,

55, 443.

[99] R.L. Adolphson, R.R. Schellenberg, D.O. Hudson and M.C. Conroy, Int.Arch.

Allergy Appl. Immunol., 1990, 93, 267.

[100] R.H. Xing, A. Mazar, J. Henkin and S.A. Rabbani, Cancer Res., 1997, 57, 3585.

[101] A. Gualberto, G. Marquez, M. Carballo, G.L. Youngblood, S.W. Hunt, A.S.

Baldwin and F. Sobrino, J. Bid. Chem., 1998, 273, 7088.

[102] S.T. Butera, B.D. Roberts, J.W. Critchfield, G. Fang, T. McQuade, S.J.

Gracheck and T.M. Folks, Mol. Med. (Cambridge, Mass.), 1995, 1, 758.

[103] D.H. Boschelli, J.B. Kramer, S.S. Khatana, R.J. Sorenson, D.T. Connor, M.A.

Ferin, C.D. Wright, M.E. Lesch, K. Imre et al, J Med. Chem.,1995, 38, 4597.

[104] I.C.F. Ferreira, R.C. Calhelha, L.M. Estevinho, M.J.R. Queiroz, Bioorg. Med.

Chem. Lett., 2004, 14, 5831.

Chapter - I

Page No. 31

[105] S. Shafeeque, S. Mohan, K.S. Manjunatha, Indian J. Hetero. Chem., 1999, 8(4),

297.

[106] U.V. Laddi, M.B. Talwar, S.R. Desai, Y.S. Somannavar, R.S. Bennur, S.C.

Bennur; Indian Drugs., 1998, 35(8) 509.

[107] C.F.R. Ferreira, R.P. Maria-Joao, M. Vilas-Boas, L.M. Estevinho, A. Begouin,

K. Gilbert, Bioorg.Med. Chem. Lett., 2006, 16, 1384.

[108] J.B. Smith and A.L. Willis, Nature (New Boil.).1971, 231, 235.

[109] Jiri Svoboda, Michal Stadler, Antonin Jandera, Vladimira Panajotova and

Miroslav Kuchar, Collect. Czech. Chem. Commun., 2000, 14, 65.

[110] T. Nakao, Y. Morimoto, S. Takehara and H. Tanaka, US Patent, 1992, 175, 162.

[111] V. Chobot, V. Buchta, H. Jahodárová, M. Pour, L. Opletal, L. Jahodá and P.

Harant, Fitoterapia., 2003, 74, 288.

[112] C. Jordan, Nat. Rev. Drug Disco., 2003, 2, 205.

[113] B.L. Flynn, P. Verdier-Pinard and E. Hamel, Org. Lett., 2001, 3, 651.

[114] Zhihui Qin, Irida Kastrati, R. Esala, P. Chandrasena, Hong Liu, Ping Yao, P.A.

Petukhov, J.L. Bolton and G.R.J. Thatcher, J. Med. Chem., 2007, 50, 2682.

[115] Chandrani Mukherjee and Asish De, J. Indian Inst. Sci., 2002, 81, 417.

[116] S.T. Butera, B.D. Roberts, J.W. Critchfield, G. Fang, T. McQuade, S.J.

Gracheck and T.M. Folks, Mol. Med., 1999, 1, 758.

[117] Antonio Gualberto, Gracia Marquez, Modesto Carballo, G.L. Youngbloodi,

S.W. Hunt III and Francisco Sobrino, Bioorg. Med. Chem., 1998, 12,273.

[118] J. Millard, M. Vincent, R. Morin, M. Benard, Chem. Abstr., 1962, 57, 15251.

[119] M. Najer, R. Giudcelli, C. Moral and M. Menin, Bull. Chem. Soc. France.,

1966, 34, 153.

[120] K. Gewald, E. Schinke, H. Bottcher, Chemische Berichte., 1965, 100, 99.

[121] Stanislav Radl and Iva Obadalová, Arkivoc, 2005, xv, 4.

Chapter - I

Page No. 32

[122] V.P. Litvinov. Rus. Chem. Bulletin., 2004, 53,487-16.

[123] V. Alagarsamy, S. Vijayakumar. Biomed. Pharmacotherapy., 2007, 61, 285-91.

[124] V. Alagarsamy, S. Meena, Eur. J.Med. Chem., 2006, 4, 1293-1300.

[125] T. Horiuchi, J. Chiba, K. Uoto, Bioorg. Med. Chem. Lett., 2009, 19, 305-08.

[126] G.D. Madding & M.D. Thompson, J Hetero Chem., 1987, 24, 581.

[127] A.P. Vinogradoff, patent no. EP 0234557.

[128] D.L. Temple, patent no.US 4054656.

[129] F.E. Janssens, J.L.G. Torremans J.F. Hens & T.T. VanOffenwert, patent no.EP

0144101.

[130] H.M. Eggenweiler & V. Eiermann, patent no.DE 10063223.

[131] E. Gillespie, K.W. Dungan, A.W. Gomol & R.J. Seidehamel, Int J Immuno

pharmacol., 1985, 655.

[132] Z.H. Khalil & A.A. Geies, Phosphorus, Sulfur, Silicon Relat Elem., 1991, 60,

223.

[133] M.S. Manhas, D. Sharma, S.G. Amin, J. Med.Chem., 1971, 15, 106.

[134] M. Wahab Khan, M. Jahangir Alam, M.A. Rashid and R. Chowdhury, Bioorg.

Med. Chem., 2005, 13, 4796.

[135] Kamal Dawood, Hassan Abdel-Gawad, A. Eman Rageb and Mohey Ellithey,

Bioorg. Med. Chem., 2006, 14, 3672.

[136] C.J. Shishoo, U.S. Pathak, K.S. Jain, I.T. Devani, and M.T. Chhabria, Ind. J.

Chem., 1994, 33B,436.

[137] A.B.A. El-Gazzar, M.I. Hegab, S.A. Swelam, and A.S. Aly, Phosphorus, Sulfur

and Silicon., 2002, 177:123.

[138] Maisa, Abdel Moneam and Adel M. Kamal El-Dean, Phosphorus, Sulfur, and

Silicon., 2003, 178,263.

Chapter - I

Page No. 33

[139] A.M. Sh. El-Sharief, J.A.A. Micky, N.A.M.M. Shmeiss and G. El-Gharieb,

Phosphorus Sulfur and Silicon., 2003, 178,439.

[140] V.H. Bhaskar, P. Pawan Kumar, B. Sangameshwaran, Asian J Chem., 2007, 19,

5187.

[141] R.K. Russel, J.B. Press, R.A. Rampula, J.J. Mcnally, J. Med .Chem., 1988, 31,

1786.

[142] H.M. Hosni, W.M. Basyoni, A.M. bayouki, J.Chem.Res(s) 1999, 646

.

[143] J.N. Hrib and J.G. Jureak, US Patent No. 4933453.

[144] D.A. Burnett, M.A. Caplen, H.R. Davis, J. Med. Chem., 1994, 37, 1733.

[145] H.S. joshi. K.M. thaker, B.L. dodiya, K.A. joshi, R.M .ghetiya, P.B .vekariya,

Indian journal of heterocyclic chemistry., 2010, 20, 21

[146] Sembian ruso jayaraman, Madhavan sridharan and Rajendiran nagappan,

Molbank journal., 2010, M648.

[147] Arun m.isloor. Balakrishna kalluraya, K. sridhar pai, European Journal of

medicinal Chemistry., 2009, 1.

[148] Gadada naganagowda and Basavaraj padmashali, Indian journal of heterocyclic

chemistry., 2009, 19, 9.

[149] Gadada naganagowda, Basavaraj padmashali and T.H. Suresha kumara, Indian

journal of heterocyclic chemistry., 2009, 19, 13.

[150] Manish dixit and Atul goe, Tetrahedron Letters., 2006, 47, 3557.

CHAPTER - II

The synthesis of methyl-3-amino-1-benzothiophene-2-carboxylate

substituted pyrazole and pyrazolone moieties.

Chapter -II

Page No. 34

INTRODUCTION

Pyrazoles play predominant role in medicinal chemistry and they have been

intensively used as scaffolds for drug development. The rapid assembly of molecular

diversity is an important goal of synthetic organic chemistry and is one of the key

paradigms of modern drug discovery. The synthesis of the pyrazole containing

heterocyclic systems occupies an important place in the realm of synthetic organic

chemistry, due to their therapeutic and pharmacological properties1-4

. They have

emerged as integral backbones of over number existing drugs5-7

.

The simple doubly unsaturated compound containing two nitrogen and three

carbon atoms in the ring, with the nitrogen atoms neighboring is known as pyrazole.

Pyrazole is the name given by “LUDWIG KNORR” to this class of compounds in

1883. Pyrazole is a colourless solid, having melting point 70C. This high value

(compared with 1-alkyl or aryl substituted pyrazoles) is due to intermolecular hydrogen

bonding which results in a dimmer. Pyrazole is a tautomeric substance; the existence of

tautomerism cannot be demonstrated in pyrazole itself, but it can be inferred by the

consideration of pyrazole derivatives.

Pyrazole are associated with wide range of biological properties. Pyrazole and

pyrazolone ring systems represent an important class of compounds not only for their

theoretical interest, but also for their anti-inflammatory, postmenopausal osteoporosis,

angiotensin, antagonists, and anti coagulant activities8-12

. Recently some aryl pyrazole

are reported to have non-nucleoside HIV-1 reverse transcriptase inhibitor activities13

.

Over the past two decades, pyrazole containing compounds have received considerable

attention owing to their diverse chemotherapeutic potentials including versatile

antineoplastic activities. Literature survey revealed that some pyrazoles have been

implemented as antileukemic14-16

, antitumor17-19

and antiproliferative agents20-22

,

Chapter -II

Page No. 35

besides their capability to exert remarkable anticancer effects23,24

through inhibiting

different types of enzymes that play important roles in cell division.

The synthesis of pyrazoles remains of great interest due to the wide applications

of such heterocycles in the pharmaceutical and agrochemical industry. Pyrazole

derivatives have a long history of application in agrochemicals and pharmaceutical

industry, as herbicides and active pharmaceuticals. A systematic investigation of this

class of heterocyclic lead revealed that, pyrazole containing pharmaco active agents

play important role in medicinal chemistry. The prevalence of pyrazole cores in

biologically active molecules has stimulated the need for elegant and efficient ways to

make these heterocyclic lead.

Among the family of heterocycles, nitrogen containing heterocycles especially

pyrazoles is an important class of heterocyclic compound and its derivatives are

reported to have the broad spectrum of biological activities such as anti-inflammatory25

,

herbicidal26

, antitumor and antiviral activities27

. Pyrazole derivatives also act as A3

adenosine receptor antagonists28

, neuropeptide YY5 receptor antagonists29

, and

hyperlipidemia and thrombo biotin mimetics30

. Very few pyrazole derivatives are

naturally occurring may be due to the difficulty of living organisms to construct the N-

N bond. Owing to the widespread applications, synthesis and biological activity

evaluation of pyrazoles and their derivatives has been a subject of intensive

investigations as revealed by enormous literature covering the subject.

Furthermore, pyrazoles represent a key motif in heterocyclic chemistry and

occupy a prime place in medicinal and pesticide chemistry due to their capability to

exhibit a wide range of bioactivities such as antimicrobial31-34

, anticancer

35, anti-

inflammatory36,37

, antidepressant38

, anticonvulsant39

, antipyretic40

and selective enzyme

inhibitory activities41

.

Chapter -II

Page No. 36

Zhang et al, synthesized a series of 1 novel pyrazolo[1,5-a]pyrazin-4(5H)-one

derivatives showed that the compounds could inhibit the growth of A549 cells in

dosage and time dependent manners42

.

N N N

OCl

1

Lian et al, synthesized a series of 2 novel 3-aryl-1-arylmethyl-1Hpyrazole-5-

carbohydrazide N-b-glycoside derivatives showed inhibitory effects on the growth of

A549 lung cancer cells43

.

Cl

N

N

NH

NH

NH2

2

Balbi et al, synthesized 3 thirty-six novel pyrazole derivatives and studied their

antiproliferative activity in human ovarian adenocarcinoma A2780 cells, human lung

carcinoma A549 cells, and murine P388 leukemia cells44

.

O

OH

N

N

N

3

Isloor et al, reported 4 the synthesis of Schiff and Mannich bases containing

pyrazole moiety. The newly synthesized compounds were screened for their

antibacterial and antifungal activity. Some of the compounds were found to exhibit

significant antimicrobial activity45

.

Chapter -II

Page No. 37

R1=Me, ethyl R

2=t-butyl, 4(chlorophenyl), cyclopropyl

In the 1800’s German dye industry was producing hundred of new dyes for

industrial and biological purpose. In industries, dyes were used for dyeing textiles and

other materials and in biology, it was used for identifying various types of pathogens

like bacteria, protozoa etc. Paul Ehrlich, who is considered as founder of modern

medicinal chemistry, chemotherapy and molecular pharmacology, was working on

biological properties of these dyes on blood cells, demonstrating the specific staining of

parts of certain leucocytes, the basis of hematology. In order to test the hypothesis that

it is possible to stain pathogens specifically and perhaps be killed without harming the

host, Ehrlich’s laboratory focused first on malaria protozoa using methylene blue and

related dyes. For five years, Ehrlich and his associates studied hundred of synthesized

dyes leading to the first synthetic antimalarial, 5 Tryphan red in 190446

.

N

N N

N

NH2NaO3S

NaO3S

NH2 SO3Na

SO3Na

NaO3S5

Tryphan

However, Typhan red did not have anti-malarial potency needed for an effective

human cure. Ehrlich thought that an introduction of heavy metal atoms such as arsenic

NH

N

N

N SR

N

R1

R2

R3

4

Chapter -II

Page No. 38

might improve its potency and he introduced arsenic into dye and discovered Atoxyl,

which was successful in treatment of malaria. However, since it contained arsenic, it’s

long term use lead to hepatotoxic effects and hence its use was discontinued. He then

shifted his research interest towards finding a drug for syphilis. Therefore, he modified

the structure of atoxyl and produced two important molecules namely salvarsan and

neosalvarsan in 1912, which were less toxic and highly effective against syphilis.

This stimulated many researchers to look towards dyes as possible drug

candidates. Fritz Mietzsch and Joseph Klarer of Bayer laboratories began systematic

synthesis of azo dyes as possible antimicrobials. Sulphonamide azo dyes were included

for the study as they were relatively easy to synthesize and had improved staining

properties. Gerhard Domagk was the Bayer pathologist who evaluated Mietzsch and

Klarer dyes for their antimicrobial activity. In 1932, Domagk began study of bright red

dye later to be named as Prontosil 6 and found that it caused remarkable cures of

Streptococcal infections of mice. However, prontosil was inactive on bacterial cultures.

He continued his work on prontosil and proved successfully the efficiency of prontosil

against Streptococcal infections47

. For his pioneering work in chemotherapy, Gerhard

Domagk was awarded the Nobel Prize.

N

N

NH2

S

O

O

NH2

NH2

6

Prontosil

Prontosil’s inactivity in vitro but excellent activity in vivo attracted much

attention. In 1935, through series of SAR studies, Trefouel reported that azo linkage of

prontosil was metabolically broken to release the active ingredient 7 sulphanilamide48

.

Chapter -II

Page No. 39

N

N

NH2

S

O

O

NH2

NH2

NH2 S

O

O

NH2

In-vivo metabolism

7 Prontosil Sulphanilamide

Research on toxicity studies of diazo compounds indicated that, due to in-vivo

transformation into amine group which binds to CYP enzyme, diazo compounds

produce toxicity. However, with the emergence of antibiotic resistant bacterial strains,

newer diseases, fresh attempts were made to use diazo functionality for discovery of

lead molecules. This has resulted in publication of many research papers where

considerable work has been done on the synthesis and biological and pharmacological

evaluation of novel compounds containing azo group.

Abasiekog et al, have synthesized novel diazo compounds 8 containing

naphthalene moiety and tested their biological activity against various pathogens and

found that some of the azo compounds exhibited significant activity49

.

NN

OH

R

8

R= SO2NH2, substituted amino

Ulcerous colitis is a serious chronic intestinal disease localized to large

intestine. Several novel azo dyes 9 are prepared and evaluated for their usefulness in

treatment of ulcerous colitis50

.

Chapter -II

Page No. 40

N

N

HOOC

OH

COOH

OH

9

In the beginning, Schiff’s bases were extensively used for their industrial

applications like metal chelating abilities and analytical purposes for estimation of

various metal ions51-53

. Later on, they were used as intermediates for the synthesis of

various biopotent heterocycles like β-lactums and thiazolidinones.

In the last half of the last century, the mechanism of action of some antibiotics

like streptomycin, aspergillic acid, usnic acid and tetracycline revealed that they exhibit

their antibacterial action due to their metal chelating properties54,55

. As the Schiff’s

bases were already used extensively for their metal chelating abilities, this finding

inspired several researchers to evaluate the antibacterial and other properties of Schiff’s

bases. This was a diversion from research on diazo compounds, as diazo compounds,

were proved to be toxic, azomethines were considered as alternatives to diazo

compounds in search for novel potent molecules. This has resulted in synthesis of

numerous Schiff’s bases for evaluating their biological activity.

Ramesh et al, have synthesized series of Schiff’s bases 10 which contain isatin

nucleus and evaluated their anti-inflammatory, analgesic and anti-pyretic activities. All

the tested compounds exhibited moderate pharmacological activities56

.

N

N R

O

R1

10 l R= substituted phenyl R

1= alkyl, substituted alkyl

Amir et al, have synthesized various substituted pyrazolones 11 and evaluated

their analgesic, ulcerogenic and antioxidant activities. Few of the synthesized

Chapter -II

Page No. 41

compounds exhibited analgesic activity equal to that of standard drug, diclofenac

sodium56-60

.

N N

O CH3

R

O

11 R=pyridyl, phenyl, substituted phenyl

There are reports that many pyrazolone derivatives possess antifungal activity.

Kidwai61

et al, have synthesized and evaluated the antifungal activity of 12 pyrazolone

derivatives.

NH

NH

O

NNO

O

CH3 CH3

12 Apart from these, pyrazolone derivatives are also known to possess anti-

tubercular, anti-cancer, anti-HIV, anthelmintic and CNS activities61-65

.

It is evident from the literature65-70

that, azo functionality, pyrazolone

derivatives are important pharmacophoric functionalities which are present in number

of compounds which are known to possess wide spectrum of biological activities.

Significance of benzothiophene as biopotent moiety is already discussed in detail in

introduction chapter. Hence, in this section, we have made an attempt to synthesize

compounds which contain benzothiophene moiety, azo functionality and pyrazolone

ring system.

In order to synthesize active molecules of widely different composition such as

combination of two heterocyclic frameworks to achieve good biological profile, it was

planned to synthesize some benzothiophene derivatives containing pyrazolone and

pyrazole moieties.

Chapter -II

Page No. 42

Present work

Since our aim was to synthesize compounds which contain all the three

pharmacophoric groups, i.e. azo functionality, pyrazolone moiety and benzothiophene

nucleus, we employed the method adopted by Parekh71

et al, which comply with our

requirement of synthesizing compounds containing all three moieties. In this method,

aromatic primary amine group containing compounds like various substituted anilines

were first diazotized and then treated with compounds which contain active methylene

group like ethyl acetoacetate, which results in the formation of hydrazono compounds.

The hydrazono compounds thus formed were refluxed with NH2-NH2 functionality

containing compounds resulting in formation of compounds which contain azo group,

pyrazolone moiety and the substituent, which is attached to NH2-NH2 functionality,

Different chalcones were prepared using different aromatic aldehydes these were made

to react with benzothiopene carbohydrazide in 1,4 dioxane which undego cyclization to

give different benzothiophene substituted pyrazoles.

Chapter -II

Page No. 43

S

NH2

O

O

NH

N

CH3

O

O

O

CH3

S

NH2

O

N

N

O

CH3

N

NH

N

Br

+ SHO

OCH3

KOH

O

S

NH2

O

N

N

1

3a-f 4a-f

R R

R

Scheme-1

R

S

NH2

NH

O

NH2

NH2NH2

2

Compounds R Compounds R

3a 4-OCH3 4a 4-Br

3b 2-OH 4b 4-NO2

3c 2-NO2 4c 2-NO2

3d 4-Cl 4d 4-Cl

3e 4-F 4e 4-OCH3

3f 4-CH3 4f 4-F

Chapter -II

Page No. 44

The intermediate carbohydrazide 2 was utilized for the synthesis of pyrazole

derivatives 3a-f as they are associated with wide biodynamic properties. To the hot

solution of chalcone in 1,4-dioxane, carbohydrazide 2 was added slowly, then catalytic

amount of acetic acid was added. The reaction mixture was refluxed for about 24 hours.

The formation of the pyrazole was monitored by TLC. After completion of the reaction,

the reaction mixture was cooled to room temperature and poured in to crushed ice with

stirring, solid that separated out was filtered and washed with water, dried and purified

by column chromatography using ethyl acetate and n-hexane (2:8) to get compound 3a

similarly compounds 3b-f were prepared and confirmed by spectral data.

S

NH2

NH

O

NH2

O

R

S

NH2

O

N

N

R

23a-f

In confirmation, 3a exhibited NH2 bands stretching at 3458, 3381 and carbonyl

group absorption band at 1665 cm-1

respectively in its IR spectrum. 1H NMR spectra

showed the multiplet in between at δ 8.34-6.48 for fourteen aromatic protons. NH2

group broad signal at 4.9 and three protons appeared in the region 3.7 for methoxy

group, an additional proof the mass spectrum of 3a indicated molecular ion peak at m/z

425. The isolated yield of the pyrazole derivatives were range of 40-60%. The low

yield of pyrazole is due to electron withdrawing carbonyl group, which lowers the

nucleophilicity of-NHNH2.

Chapter -II

Page No. 45

The synthesis of benzothiophene substituted pyrazolone derivatives 4a-f was

prepared by taking an equimolar mixture of 3-amino-1-benzothiophene-2-

carbohydrazide 2 and ethyl-(2Z)-3-oxo-2-(phenylhydrazinylidene) butanoate were

refluxed for 10-12 hours in glacial acetic acid to furnish to get compound 4a. The same

procedure was used to synthesize compounds 4b-f. And the prepared compound was

confirmed by spectral data.

S

NH2

NH

O

NH2

R

R

NH

N

O

O

O

S

NH2

O

N

N

O

N

NH

2 4a-f

The IR spectrum of the compound 4a exhibited broad peak corresponding to

NH2 group at 3461, 3385 cm-1

and peak at 3167 cm-1

which indicates the presence of

NH functionality. Further, C=O group at 1705. In addition, 1H NMR spectra showed

peak at δ 10.46 due to NH for one proton, the multiplet in between δ 8.26-6.94 for eight

aromatic protons. NH2 group at δ 4.37 and three protons of methyl group appeared in

the region δ 1.39. Further, the structure of 4a was confirmed by mass spectrum which

showed formation of compound 4a at m/z 456.

S

NH2

O

O

IR spectrum of 1

S

NH2

O

O

1H NMR spectrum of 1

S

NH2

O

O

Mass spectrum of 1

S

NH2

NH

O

NH2

IR spectrum of 2

S

NH2

NH

O

NH2


S

NH2

NH

O

NH2

Mass spectrum of 2

S

NH2

O

N

N

O

1H NMR spectrum of 3a

S

NH2

O

N

N

O

Mass spectrum of 3a

S

NH2

O

N

N

O

N

NH

Br

IR spectrum of 4a

S

NH2

O

N

N

O

N

NH

Br


S

NH2

O

N

N

O

N

NH

Br

Mass spectrum of 4a

Chapter -II

Page No. 46

EXPERIMENTAL

Preparation of methyl 3-amino-1-benzothiophene-2-carboxylate (1):

2-Bromobenzonitrile (5.46g, 0.03mol) was added to stirred solution of

methylthioglycolate (2.7ml, 0.03mol) and potassium hydroxide (4.12g, 0.075mol) in

DMF and refluxed at 75 C for 10 hours. The completion of the reaction was monitored

by TLC. After completion, the reaction mixture was cooled to room temperature and

poured in to crushed ice. The pale yellow solid were separated out was filtered and

washed with water, dried and purified by column chromatography using ethyl acetate

and n-hexane 8:2.

S

NH2

O

O

Solid (Crystalline); Yield (85%); IR (KBr) (νmax cm-1

): 3447, 3358 (NH2), 1684 (C=O);

1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 8.20-7.28 (4H, m, Ar-H), 4.91 (2H, bs),

3.78 (3H, s); Elemental analysis: Calculated (%) for C10H9NO2S: C, 57.95. H, 4.38. N,

6.75. S, 15.47 ; Found: C, 57.81. H, 4.35. N, 6.71. S, 15.44 ; LC-MS m/z: 207.2; M.P:

138-141 0C.

Preparation of 3-amino-1-benzothiophene-2-carbohydrazide (2):

To a stirred solution of methyl 3-amino-1-benzothiophene-2-carboxylate 1 (2.07g,

0.01mol) in absolute alcohol (50ml) was added hydrazine hydrate (0.3ml, 0.01mol) at

room temperature. Then the reaction mixture was refluxed on a water bath for 6 hours.

The completion of the reaction was monitored by TLC. After completion, the reaction

mixture was cooled to room temperature and poured into crushed ice. The pale yellow

solid separated was filtered, washed with water, dried and recrystallized with ethyl

acetate.

Chapter -II

Page No. 47

S

NH2

NH

O

NH2


): 3422, 3396 (NH2), 3130

(CONH), 1646 (C=O); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 8.94 (1H, bs), 8.01-

6.97 (4H, m, Ar-H), 5.51 (2H, bs), 4.49 (2H, bs).; Elemental analysis: Calculated (%)

for C9H9N3OS: C, 52.16. H, 4.34. N, 20.27. S, 15.47; Found: C, 52.13. H, 4.30. N,

20.24. S, 15.42 ; LC-MS m/z: 207.25 ; M.P: 174-177 0C.

3-Amino-1-benzothiophen-2-yl)[3-(2-hydroxyphenyl)-5-phenyl-2,3-dihydro-1H-

pyrazol-1-]methanone (3a):

Mixture of 1,3-diphenylprop-2-en-1-one (0.208g, 0.001mol) and catalytic

amount of acetic acid in 1,4-dioxane (40ml) was stirred for 15 minutes at 1010C and

then added 3-amino benzothiophene-2-carbohydrazide 2 (0.207g, 0.001mol). The

reaction mixture was refluxed for 28 hours. The completion of the reaction was

monitored by TLC. After completion, the reaction mixture was cooled and poured in to

crushed ice. The solid separated was filtered, washed with water, dried and purified by

column chromatography using ethyl acetate and n-hexane. Similarly, the compounds

3b-f were prepared.

S

NH2

O

N

N

O

Solid (Amorphous); Yield (52%); IR (KBr) (νmax cm-1

): 3458, 3381 (NH2), 1665 (C=O),

1625 (C=N); 1H-NMR: (400 MHz: CDCL3) δ (ppm): 8.34-6.48 (14H, m, Ar-H), 4.91

Chapter -II

Page No. 48

(2H, m, NH2), 3.70 (3H, s, OCH3); Elemental analysis: Calculated (%) for

C25H21N3O2S: C, 70.23. H, 4.95. N, 9.82. S, 7.50 ; Found: C,70.18. H, 4.91. N, 9.79. S,

7.47; LC-MS m/z: 425. ; M.P: 235-238 0C.

(3-Amino-1-benzothiophen-2-yl)[3-(2-hydroxyphenyl)-5-phenyl-2, 3-dihydro-1H-

pyrazol-1-yl]methanone (3b):

S

NH2

O

N

N

OH


): 3420, 3375 (NH2), 1660 (C=O)


(1H, s, OH), 4.90 (2H, bs, NH2); Elemental analysis: Calculated (%) for C24H19N3O2S:

C, 69.71. H, 4.63. N, 10.16. S,7.75; Found: C, 69.65. H, 4.59. N, 10.13. S, 7.72 ;.LC-

MS m/z: 413.49; M.P: 245-248 0C.

(3-Amino-1-benzothiophen-2-yl)[3-(2-nitrophenyl)-5-phenyl-2, 3-dihydro-1H-

pyrazol-1-yl]methanone (3c):

S

NH2

O

N

N

N+

O-

O


): 3410, 3365 (NH2), 1658 (C=O),


(2H, bs, NH2); Elemental analysis: Calculated (%) for C24H18N4O3S: C, 65.14. H, 4.10.

Chapter -II

Page No. 49

N, 12.66. S, 7.24; Found: C, 65.10. H, 4.07.N, 12.62. S, 7.20;. LC-MS m/z: 442.48;

M.P: 251-254 0C.

(3-Amino-1-benzothiophen-2-yl)[3-(4-chlorophenyl)-5-phenyl-2, 3-dihydro-1H-

pyrazol-1-yl]methanone (3d):

S

NH2

O

N

N

Cl


): 3408, 3360 (NH2), 1656 (C=O),


(2H, bs, NH2); Elemental analysis: Calculated (%) for C24H18ClN3OS: C, 66.73. H,

4.20. N, 9.72. S, 7.42; Found: C, 66.69. H, 4.17. N, 9.69. S, 7.39; LC-MS m/z: 431.93;

M.P: 263-267 0C.

(3-Amino-1-benzothiophen-2-yl)[3-(4-fluorophenyl)-5-phenyl-2, 3-dihydro-1H-

pyrazol-1-yl]methanone (3e):

S

NH2

O

N

N

F


): 3415, 3372 (NH2), 1657 (C=O),


(2H, bs, NH2). Elemental analysis: Calculated (%) for C24H18FN3OS: C, 69.37. H, 4.36.

Chapter -II

Page No. 50

N, 10.11. S, 7.71; Found: C, 69.33. H, 4.32. N, 10.05. S, 7.67; LC-MS m/z: 415.48;

M.P: 270-273 0C.

(3-Amino-1-benzothiophen-2-yl)[3-(4-methylphenyl)-5-phenyl-2, 3-dihydro-1H-

pyrazol-1-yl]methanone (3f):

S

NH2

O

N

N


): 3400, 3360 (NH2), 1648 (C=O),


(2H, bs, NH2). 2.20 (3H, s, CH3). Elemental analysis: Calculated (%) for C25H21N3OS:

C, 72.96. H, 5.14. N, 10.21. S, 7.71; Found: C, 72.92. H, 5.11. N, 10.17. S, 7.68 ; LC-

MS m/z: 411.51; M.P: 256-259 0C.

(4E)-2-[(3-Amino-1-benzothiophen-2-yl)carbonyl]-4-[2-(4-bromophenyl)hydraziny

lidene]-5-methyl-2,4-dihydro-3H-pyrazol-3-one (4a):

Mixture of 3-amino-benzothiophene-2-carbohydrazide (0.207g, 0.001mol) and ethyl-

(2Z)-3-oxo-2-(2-phenylhydrazinylidene)butanoate (0.234g, 0.001mol) in glacial acetic

acid (20ml) were refluxed for 10-12 hours. The reaction was monitored by TLC. After

completion, the reaction mixture was cooled and poured in to crushed ice. The solid

separated out was filtered, washed with water, dried and recrystallized by ethyl alcohol

to get compound 4a. The same procedure was used to synthesize compounds 4b-f.

Chapter -II

Page No. 51

S

NH2

O

N

N

O

CH3

N

NH

Br


): 3461, 3385 (NH2), 1705 (C=O),

1608 (C=N), 604 (C-Br); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 10.46 (1H, s, NH),

8.26-6.94 (8H, m, Ar-H), 4.37 (2H, s, NH2), 1.39 (3H, s); Elemental analysis:

Calculated (%) for C19H14BrN5O2S: C, 50.01. H, 3.09. N, 15.34. S, 7.02; Found: C,

49.95. H, 3.05. N, 15.31. S, 6.99 ;. LC-MS m/z: 456. 458; M.P: 239-241 0C.

(4E)-2-[(3-Amino-1-benzothiophen-2-yl)carbonyl]-5-methyl-4-[2-4(nitrophenyl)

hydrazinylidene]-2,4-dihydro-3H-pyrazol-3-one (4b):

S

NH2

O

N

N

O

CH3

N

NH

N+

O-

O


): 3455, 3349 (NH2), 1710 (C=O),

1612 (C=N); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 10.60 (1H, s, NH), 8.46-7.10

(8H, m, Ar-H), 4.58 (2H, s, NH2), 1.48 (3H, s, CH3); Elemental analysis: Calculated

(%) for C19H14N6O4S: C, 54.02. H, 3.34.N, 19.89. S, 7.59 ; Found: C, 53.98. H, 3.31.

N, 19.85. S, 7.56 ; LC-MS m/z: 422.41; M.P: 225-228 0C.

Chapter -II

Page No. 52

(4E)-2-[(3-Amino-1-benzothiophen-2-yl)carbonyl]-5-methyl-4-[2-(2-nitrophenyl)

hydrazinylidene]-2, 4-dihydro-3H-pyrazol-3-one (4c):

S

NH2

O

N

N

O

CH3

N

NH

N+ O

-

O


): 3456, 3350 (NH2), 1711 (C=O),



(%) for C19H14N6O4S: C, 54.02. H, 3.34. N, 19.89. S, 7.59; Found: C, 53.94. H, 3.29.

N, 19.86. S, 7.55 ; LC-MS m/z: 422.41; M.P: 235-238 0C.

(4E)-2-[(3-Amino-1-benzothiophen-2-yl)carbonyl]-4-[2-(4-chlorophenyl)hydrazin

ylidene]-5-methyl-2, 4-dihydro-3H-pyrazol-3-one (4d):

S

NH2

O

N

N

O

N

NH

Cl


): 3453, 3348 (NH2), 1708 (C=O),



(%) for C19H14ClN5O2S: C, 55.40. H, 3.42. N, 17.00. S, 7.78; Found: C, 55.35. H, 3.40.

N, 16.93. S, 7.75; LC-MS m/z: 411.86; M.P: 257-260 0C.

Chapter -II

Page No. 53

(4E)-2-[(3-Amino-1-benzothiophen-2-yl)carbonyl]-4-[2-(4-methoxyphenyl)hydrazi

nylidene]-5-methyl-2,4-dihydro-3H-pyrazol-3-one (4e):

S

NH2

O

N

N

O

N

NH

O


): 3460, 3355 (NH2), 1720 (C=O),


(8H, m, Ar-H), 4.40 (2H, s, NH2), 3.83 (3H, s, OCH3), 1.45 (3H, s, CH3); Elemental

analysis: Calculated (%) for C20H17N5O3S: C, 58.95. H, 4.20. N, 17.18. S, 7.86; Found:

C, 58.92. H, 4.15. N, 17.15. S, 7.83; LC-MS m/z: 407.44; M.P: 247-250 0C.

(4E)-2-[(3-Amino-1-benzothiophen-2-yl)carbonyl]-4-[2-(4-fluorophenyl)hydraziny

lidene]-5-methyl-2,4-dihydro-3H-pyrazol-3-one (4f):

S

NH2

O

N

N

O

N

NH

F


): 3455, 3350 (NH2), 1715 (C=O);



(%) for C19H14ClFN5O2S: C, 57.71. H, 3.56. N, 17.71. S, 8.10 ; Found: C, 53.10. H,

3.01. N, 16.23. S, 7.42; LC-MS m/z: 429.85; M.P: 274-277 0C.

Chapter -II

Page No. 54

REFERENCES

[1] S. Malladia, A.M. Isloor, S. Peethambar. K.B. Ganesh, B.M. Palusa,

SanathKumar Goud, Der Pharma Chemica., 2012, 4 (1), 43-52.

[2] T.J. Sultivan, J.J. Truglio, M.E. Boyne, P. Novichenok, X. Zhang, C.F. Stratton,

H.J. Li, T. Kaur, A. Amin, F. Johnson, R.A. Stayden, C. Kisker, P.J. Tonge,

ACS Chem. Biol., 2007, 1, 43.

[3] A.M. Gilbert, A. Failli, J. Shumsky, Y. Yang, A. Severin, G. Singh, W. Hu, D.

Keeney, P.J. Petersen, A.H. Katz, J. Med. Chem., 2006, 49, 6027.

[4] O. Prakash, R. Pundeer, P. Ranjan, K. Pannu, Y. Dhingra, K.R. Aneja, Indian.

J. Chem., 2009, 48B, 563.

[5] A.M. Isloor, B. Kalluraya, P. Shetty, Eur. J. Med. Chem., 2009, 44, 3784.

[6] I.V. Magedov, M. Manpadi, S.V. Slambrouck, W.F.A. Steelant, E. Rozhkova,

N.M. Przheval’skii, S. Rogelj, A. Kornienko, J. Med. Chem., 2007, 50, 5183.

[7] G. Szabo, J. Fischer, A. Kis-Varga, K. Gyires, J. Med. Chem., 2008, 51, 142.

[8] Seranthimata Samshuddina, Badiadka Narayanaa, Balladka Kunhanna

Sarojinib, Rajagopalan Srinivasana, Vinayachandrac and K.R. Chandrashekarc,

Der Pharma Chemica., 2012, 4 (2), 587-592.

[9] P. Francisco, A.M.O. de Retana & P.A. Jaiore, Tetrahedron., 1999, 551, 4451.

[10] K.Y. Lee, J.M. Kim & J.N. Kim, Tetrahedron Lett., 2003, 44, 6737.

[11] Z.J. Jia, Y. Wu, W. Hung, P. Zhang, Y. Song, J. Woolfrey, U. Sinha, A.E.

Arfsten, S.T. Edwards, A. Hutchaleelaha, S.J. Hollennbach, J.L. Lambing, R.M.

Scarborough & B.Y. Zhu, Bioorg med chemLett., 2004, 14, 1229.

[12] M.J. Genin, C. Biles, B.J. Keiser, S.M. poppe, S.M. Swaney, Tarpley, Y. Yogi

& D.L. Romero, J.med chem., 2003, 43, 1034.

[13] G. Daidone, B. Maggio, D. Raffa, S. Plescia, D. Schillaci, M.V. Raimondi, Il

Farmaco., 2004, 59, 413.

[14] L.C. Chou, L.J. Huang, J.S. Yang, F.Y. Lee. C.M. Teng, S.C. Kuo, Bioorg.

Med. Chem., 2007, 15, 1732.

[15] F. Manetti, C. Brullo, M. Magnani, F. Mosci, B. Chelli, E. Crespan, S.

Schenone, A. Naldini, O. Bruno, M.L. Trincavelli, G. Mag, M.F. Carraro, C.

Martini, F. Bondavalli, M. Botta, J.Med. Chem., 2008, 51, 1252.

[16] J. Li, Y.F. Zhao, X.L. Zhao, X.Y. Yuan, P. Gong, Arch. Pharm. Chem. Life Sci.,

2006, 339, 593.

Chapter -II

Page No. 55

[17] Y. Xia, Z.W. Dong, B.X. Zhao, X. Ge, N. Meng, D.S. Shin, J.Y. Miao, Bioorg.

Med.Chem., 2007, 15, 6893.

[18] Y. Xia, C.D. Fan. B.X. Zhao, J. Zhao, D.S. Shin, J.Y. Miao, Eur. J. Med.

Chem., 2008, 43, 2347.

[19] A.M. Farag, A.S. Mayhoub, S.E. Barakat, A.H. Bayomi, Bioorg. Med. Chem.,

2008, 16, 881.

[20] S. Schenone, O. Bruno, A. Ranise, F. Bondavalli, C. Brullo, P. Fossa, L. Mosti,

G. Menozzi, F. Carraro, A. Naldini, C. Bernini, F. Manettic, M. Botta, Bioorg.

Med.Chem.Lett., 2004, 14, 2511.

[21] G. Daidone, D. Raffa, B. Maggio, M.V. Raimondi, F. Plescia, D. Schillaci, Eur.

J. Med.Chem., 2004, 39, 219.

[22] N.C. Warshakoon, S. Wu, A. Boyer, R. Kawamoto, S. Renock, K. Xu. M.

Pokross, A.G. Evdokimov, S. Zhou, C. Winter, R. Walter, M. Mekel, Bioorg.

Med. Chem. Lett., 2006, 16, 5687.

[23] S. Huang, R. Lin, Y. Yu, Y. Lu, P.J. Connolly, G. Chiu, S. Li, S.L. Emanuel

S.A. Middleton, Bioorg. Med. Chem. Lett., 2007, 17, 1243.

[24] G.D. Zhu, J.V. Gong, B. Gandhi, K. Woods, Y. Luo, X. Liu, R. Guan, V.

Klinghofer, E.F. Johnson, V.S. Stoll, M. Mamo, Q. Li, S.H. Rosenberg, V.L.

Giranda, Bioorg. Med.Chem., 2007, 15, 2441.

[25] S.P. Singh, O. Prakash, R.K. Tomer, S.N. Sawhney, Indian J. Chem., 1978,

16B, 733-735.

[26] N. Kudo, S. Furuta, M. Taniguchi, T. Endo, K. Sato, Chem. Pharm. Bull., 1999,

47, 857-868.

[27] H.E. Skipper, R.K. Robins, J.R. Thompson, Society for Experimental Biology

and Medicine (New York, N.Y.), 1955, 594-596.

[28] P.G. Baraldi, A. Bovero, F. Fruttarolo, R. Romagnoli, M.A. Tabrizi, D. Preti, K.

Varani, P.A. Borea, A.R. Moorman, Bio.org. Med. Chem., 2003, 11, 4161-4169.

[29] A.W. Stamford and Y. Wu. “New Neuropeptide Y Y5 Receptor antagonists”

PCT Int. Appl. WO., 2004, 5262.

[30] D.A. Heerding, “Thrombopoietin mimetics” PCT Int. Appl. WO., 2003,103686.

[31] T.J. Sultivan, J.J. Truglio, M.E. Boyne, P. Novichenok, X. Zhang, C.F. Stratton,

H.J. Li, T. Kaur, A. Amin, F. Johnson, R.A. Stayden, C. Kisker, P.J. Tonge,

ACS Chem. Biol., 2007, 1, 43.

Chapter -II

Page No. 56

[32] A.M. Gilbert, A. Failli, J. Shumsky, Y. Yang, A. Severin, G. Singh, W. Hu, D.

Keeney, P.J. Petersen, A.H. Katz, J. Med. Chem. 2006, 49, 6027.

[33] O. Prakash, R. Pundeer, P. Ranjan, K. Pannu, Y. Dhingra, K.R. Aneja, Indian.

J. Chem., 2009, 48B, 563.


[35] I.V. Magedov, M. Manpadi, S.V. Slambrouck, W.F.A. Steelant, E. Rozhkova,

N.M. Przheval’skii, S. Rogelj, A. Kornienko, J. Med. Chem., 2007, 50, 5183.

[36] G. Szabo, J. Fischer, A. Kis-Varga, K. Gyires, J. Med. Chem., 2008, 51, 142.

[37] N. Benaamane, B. Nedjar-Kolli, Y. Bentarzi, L. Hammal, A. Geronikaki, P.

Eleftheriou, A. Langunin, Bioorg. Med. Chem., 2008, 16, 3059.

[38] Y.R. Prasad, A. Lakshmana Rao, L. Prasoona, K. Murali, K.P. Ravi, Bioorg.

Med. Chem. Lett., 2005, 15, 5030.

[39] Z. Ozdemir, H.B. Kandilici, B. Gumusel, U. Calis, A.A. Bilgin, Eur. J. Med.

Chem., 2007, 42, 373.

[40] A. Sener, M.K. Sener, I. Bildmci, R. Kasimogullari, Y. Akcamur, J. Heterocycl.

Chem., 2002, 39, 869.

[41] G.A. Wachter, R.W. Hartmann, T. Sergejew, G.L. Grun, D. Ledergerber, J.

Med. Chem., 1996, 39, 834.

[42] 1H-pyrazole-5-carboxylate. Bioorg Med Chem. Lett., 2006, 16, 6342-47.

[43] Y.S. Xie, X.H. Pan, B.X. Zhao, J.T. Liu, D.S. Shin, J.H. Zhang et al, J

Organometal Chem., 2008, 693, 1367-74.

[44] A.M. Isloor, B. Kalluraya, M.J. Rao, Saudi Chem. Soc., 2000, 4(3), 265-270.

[45] A.M. Isloor, B. Kalluraya, P. Shetty, Eur. J. Med.Chem., 2009, 44 (9), 3784-

3787.

[46] Williun Foye, Text book of Organic and Medicinal and Pharmacetical

chemistry, Eigth edition, J.B. Lippincott Company, Philadelphia, 1986, 1, 205.

[47] G. Domagk, Deut.Med. Wochenshr., 1935, 61,250.

[48] J. Trofouel and C.R. Sea, Pro. Soc. Biol., 1935, 45,459.

[49] G. Mkpeni, I.B. Ebong, B. Obot and B. Abasiekong, E. J. Chemistry., 2008, 5,

431.

[50] US Patent no.4556330.

Chapter -II

Page No. 57

[51] US Patent no.6387902 B1.

[52] www.wikepedia.com/hugoschiff.

[53] S.N. Pandeya, D. Sriram and G. Nath, Arzneim-Forsch., 2000, 50, 55.

[54] S.N. Pandeya, D. Sriram and G. Nath, Eur. J. Med. Chem., 2000, 35, 249.

[55] A.A. Jarrahpour, M. Motamedifar and K. Pakshir, Molecules., 2004, 9, 815.

[56] Mohd Amir and Shikha Kumar, Indian J. Chem., 2005, 44, 2532.

[57] M. Benigno, V. Marya and R. Inmaculada, J. Inorg. Biochem., 2001, 84, 163.

[58] Nurþen Sari, Seza arslan, Elif Loolu and Yffet Pakiyan, G.U.J of Sci., 2003, 16,

283.

[59] Seshaiah Krishnan, Sridhar and Atmakuru Ramesh, Biol. Pharm. Bull., 2001,

24(10), 1149.

[60] V.P. Lozitsky, G.L. Kamalov, R.N. Lozitskaya, A.I. Zheltvay, A.S. Fedtchouk

and D.N. Kryzhanovsky, Acta Bioche.Polanica., 2000, 47,867.

[61] Mazhar Kidwai and Richa Sharma, Indian .J. Chem., 2002, 41, 427.

[62] B.C. Ma, X. Ma, L.R. Yan and D. Yang, Xingyong-Huaxue., 2004, 21, 841.

[63] M.G. Thomas, C. Lawson, N. Allanson, B. Leslie, J.R Bottomley, A. McBride

and O.A. Olusanya, Bioorg. Med. Chem. Lett., 2003, 13, 423.

[64] K.N. Wadodkar, S.A. Wadhal and P.S. Pandey, Indian J. Heterocycl. Chem.,

2004, 14, 55.

[65] Z. Marija, T. Iztok and B. Peter, Chemica. Acta., 2001, 74, 61.

[66] T.L. Hullar and D.L. Failla, J. Med. Chem., 1969, 12, 420.

[67] P. Jimonet, A. Francois, M. Barreau and A. Boirean., J.Med. Chem., 1991, 42,

2828.

[68] U. Huseyin, K. Vanderpooten and J.P. Stables, J. Med. Chem., 1998, 41, 1138.

[69] N. Ranee, S. Hamilton, A. Luttick, G.Y. Kappner and D.B. Mcconnel, Bioorg.

Med. Chem. Lett., 2003, 13, 657.

[70] J.H. Hanke and B.A. Pollock, Inflammation Res., 1995, 44, 357.

[71] H.H. Parekh, P.P. Patel, A.M. Joshi and K.V. Ketan, Ore. J. Chem., 2003, 19,

435.

CHAPTER - III

Synthesis of novel series of imidazole, oxadiazole and pyrazole

containing benzothiophene derivatives.

Chapter - III

Page No. 58

INTRODUCTION

Medicinal chemistry concerns with the discovery, development, interpretation

and the identification of mechanism of action of biologically active compounds at the

molecular level1. Various biologically active synthetic compounds have five-membered

nitrogen-containing heterocyclic ring in their structures2. Structural frameworks have

been described as privileged structures and in particular, nitrogen containing polycyclic

structures has been reported to be associated with a wide range of biological activity.

Imidazole (1,3-diaza-2,4-cyclopentadiene) is a planar five-member ring system

with three carbon and two nitrogen atom in 1 and 3 positions. The simplest member of

the imidazole family is imidazole itself, a compound with molecular formulaC3H4N2. It

exists in two equivalent tautomeric forms because the hydrogen atom can be located on

either of the two nitrogen atoms. Imidazole is a highly polar compound, as evidenced

by a calculated dipole of 3.61D.

In the field of five membered heterocyclic structures, imidazole nucleus shows

various properties3-10

. The high therapeutic properties of the imidazole related drugs

have encouraged the medicinal chemists to synthesize a large number of novel

chemotherapeutic agents. Imidazole drugs have broadened scope in remedying various

dispositions in clinical medicines11-16

. Medicinal properties of imidazole include

anticancer, b-lactamase inhibitors, 20-HETE (20-Hydroxy-5,8,11,14-eicosatetraenoic

acid) synthase inhibitors, carboxypeptidase inhibitors, heme oxygenase inhibitors,

antiaging agents, anticoagulants, anti-inflammatory, antibacterial, antifungal, antiviral,

antitubercular, antidiabetic and antimalarial17-29

.

This group presents in azoles

antifungal which inhibit the accumulation of methylated sterols destroy the composition

of the lipid bilayer of membranes. Some imidazole drugs, at high concentrations, could

exert direct inhibitory action on membranes, without interference with sterols and sterol

Chapter - III

Page No. 59

esters30,31

. Infectious microbial disease causes worldwide problem, because microbes

have resisted prophylaxis or therapy longer than any other form of life. In recent

decades, problems of multidrug-resistant microorganisms have reached an alarming

level in many countries around the world. Resistance of anti-microbial agents such as

β-lactam antibiotics, macrolides, quinolones etc. In addition, different species of

bacteria causes increased important global problem32,33

. Imidazole and its derivatives

are reported to be physiologically and pharmacologically active and find applications in

the treatment of several diseases.

Imidazole is incorporated into many important biological molecules34-41

. The

most pervasive is the amino acid histidine, which has an imidazole side chain. Histidine

is present in many proteins and enzymes and plays a vital part in the structure and

binding functions of hemoglobin. Histidine can be decarboxylated to histamine, which

is also a common biological compound. One of the applications of imidazole is in the

purification of His tagged proteins in immobilized metal affinity chromatography

(IMAC). Imidazole has become an important part of many pharmaceuticals.

Imidazole was first reported in 1858, although various imidazole derivatives

had been discovered as early as the 1840s. Its synthesis as shown below used glyoxal

and formaldehyde in ammonia to form imidazole (or glyoxaline, as it was originally

named). This synthesis, while producing relatively low yields is still used for creating

C-substituted imidazoles.

O O

R2R3

+R1

O

NH N

R1

R2 R3

+ 2 NH3

- 2 H2O

1

http://en.wikipedia.org/wiki/Glyoxal

http://en.wikipedia.org/wiki/Formaldehyde

http://en.wikipedia.org/wiki/Ammonia

Chapter - III

Page No. 60

During the past decade, a large number of compounds containing imidazole ring

have been used clinically for various disorders like hypertension, hypersecretion of

gastric acid (as anti-ulcer agents), fungal infections and cancer.

NH N

NH

Cl

Cl

N

N

NH

CH3

OH

23

Clonidine (anti-hypertensive) Phentolamine (anti-hypertensive)

NNH

NH

NH

S

CH3

N

NCH3O2N

OH4

5 Cimetidine (anti-hypersecretory) Metronidazole (anti-protozoal)

Imidazolones have also been found to be associated with various biological

activities such as potassium channel opener, phosphodiesterase III/IV inhibition and

crop protection activities42-45

. Hence, this class of compounds has become a synthetic

target for organic and medicinal chemists.

Malla Reddy and G.V.S. Rama Sharma have synthesized novel imidazolines 6

which are coupled with benzoxazole ring and tested them for anti-histaminic activity46

.

N

O

N N

O

R

R1

6 R=R

1=pyridyl, pheny, substituted phenyl

Purohit and Shah have synthesized compounds 7 which contain imidazolines

ring coupled with quinazolone ring system and evaluated their antimicrobial activity.

Some of the tested compounds exhibited activity comparable to that of standard drugs

used was Ciproflaxacin47

.

Chapter - III

Page No. 61

N

N

O

NN

O

R

R1

7 R= phenyl, substituted phenyl R

1= Cl, NO2

Parekh et al, have utilized imidazolines moiety and synthesized compounds 8

and evaluated their anti-tubercular and anticancer activities. Some of the tested

compounds were found to active against lung, breast and brain cancer cell lines48

.

NH NH

S

N

N

O

R

OCH3

OCH3

8 R=phenyl, substituted phenyl

Apart from these, imidazolone ring system is known to be associated with wide

range of therapeutic activities such as anticonvulsant, sedative, hypnotic, fungicidal,

anti-inflammatory, mono amino oxidase inhibitory, anti-parkinson’s and

antihypertensive activities49

.

Inspite of therapeutic significance of imidazolinone ring system, there are

hardly few reports on synthesis and biological and pharmacological evaluation of

compounds which contain both benzothiophene and imidazolinone moiety. This

inspired us to take up the synthesis of novel compounds which contain both

benzothiophene and imidazolinone ring system and to evaluate their biological and

pharmacological profile.

Heterocyclic compounds are acquiring more importance in recent years because

of broad pharmacological activities. Pyrazolone is a five membered lactum ring

containing two nitrogens and one ketonic group in its structure. During the discovery of

Chapter - III

Page No. 62

pyrazolone, they were only known as NSAIDs but in recent time, they play versatile

role in several complications like cerebral ischaemia and cardiovascular diseases. The

chemistry of pyrazolone has gained increasing attention due to its diverse

pharmacological properties50-56

such as cytotoxic, anti-inflammatory, antimicrobial,

antioxidant, antifungal, antiviral, oral hypoglycemic activities57-63

. Pyrazolones are

believed to be involved in various biochemical and physiological reactions64-74

. Thus,

scientific research programs are continuously pouring in with respect to improvised

synthetic techniques to prepare numerous pyrazolone derivatives75-81

. From last decade,

a lot of work is going on the pyrazolone nucleus. Scientists have developed large

number of new compounds related to this moiety and screened them for their different

pharmacological activities to get a molecule of desired pharmacological activity82-93

.

Soon after the discovery of phenyl hydrazine 9 by Emil Fischer in 1883, Ludwig Knorr

(Fischer's assistant) attempted to synthesize a quinoline derivative. The product

however, isolated after methylation was found to be a pyrazolone derivative and was

named as antipyrine or phenazone 10 Because of its promising antipyretic and

analgesic activities antipyrine was launched by Hoechst Pharmaceuticals. For the next

20 years, antipyrine became the most widely used drug in the world, proving highly

successful for treating fever and flu like infections, until acetylsalicylic acid (aspirin)

began to outsell it.

NHNH2

NN

O NN

O

9 10 11 Phenyl hydrazine Antipyrine MCI-186

Recently, a new pyrazolone compound 11 edaravone (3-methyl-1-phenyl-2-

pyrazolin-5-one, also known as MCI-186,

Chapter - III

Page No. 63

G. Kuçukguze. et al, synthesized a series of 3-phenyl or pyridyl-5-pyrazolone

derivatives 12 and 13 which was useful in improving cardiac contractibility94

.

N

N

O

N

NN

O

12 13 3-phenyl-5-pyrazolone 3-pyridyl-5-pyrazolone

A.N. Evstropov et al, synthesized 4-iodo-1,5-dimethyl-2-phenyl-pyrazol-3-one

(iodoantipyrine) 14 was evaluated its antiviral activity against different varieties of

viruses95

. These derivatives had shown potent antiviral activity against tick borne

encephalitis virus, hantavirus, HBV or HCV, coxsackie A and B enteroviruses, Rift

valley fever viruses and influenza type A viruses.

N

N

I

O

14 4-Iodo-1,5-dimethyl-2-phenyl-pyrazol-3-one

Kumar Siva et al, synthesized a series of 5-amino-4-[2-(6-bromo-1,3-

benzothiazol-2-yl)hydrazinylidene]-2,4-dihydro-3H-pyrazol-3-one derivatives 15 and

were screened for their cytotoxic activity. These compounds had shown prominent

cytotoxic and antioxidant activities96

.

N

SBr

NH

NN

NH

O

NH2

15 (Z)-3-Amino-4-(2-(6-bromobenzo[d]thiazol-2-yl)hydrazono)-1H-pyrazol-5(4H)-one

Khan Rahat et al, synthesized brominated 5-methyl-2,4-dihydropyrazol-3-one

16 its derivatives. All of these derivatives had shown significant cytotoxic activity97

.

Chapter - III

Page No. 64

NH

N

O

16 5-methyl-2,4-dihydropyrazol-3-one

S. Sunitha et al synthesized N-phenyl[(methylphenyl-5 pyrazolyl)methylidene]

aniline compound 17. These compounds were screened for their in vitro antimicrobial

activity against various gram +ve and gram –ve bacteria and they had shown prominent

antimicrobial activity. In addition, these compounds had shown good anti-inflammatory

activity98

.

NHN

N

17 N-phenyl[(methylphenyl-5-pyrazolyl)methylidene]aniline

Oxadiazole nucleus is continuously drawing interest for development of newer

drug moiety. Due to its wide range of activities viz. anticancer, antibacterial, antifungal,

antimalarial, anticonvulsant, antiinflammatory, etc. a steady research is going on in

oxadiazole nucleus99-103

.

In recent years, a wide range of research has been done in the field of anticancer

drug development. Since oxadiazole nucleus has shown quite good response as an

anticancer agent, hence this nucleus has become an interest in the field of research.

Among different types of oxadiazole nucleus containing molecules, many 2,5-

disubstituted 1,3,4-oxadiazoles had shown better anticancer activities104-107

. One of

such compound of 2,5- disubstituted 1,3,4-oxadiazole class- A-204197 had been proven

useful for the treatment of neoplastic diseases in in vivo studies as an antimitotic agent.

Chapter - III

Page No. 65

Hence our prime target was to synthesize dimers of 2,5- disubstituted 1,3,4-oxadiazoles

for potent biological activity108-110

.

Present work

Among bicyclic heteroaromatic compounds, benzo[b]thiophene and its

substituted derivatives occupy a unique place in synthetic organic chemistry.

Benzo[b]thiophene derivatives constitute highly valuable heterocyclic motifs found in

the structure of many natural and synthetic products. Various literatures revealed that,

the constant and growing interest in the development of new efficient synthesis of

compounds incorporating imidazole, oxadiazole and pyrazolone moieties has been

attracting widespread attention due to their diverse pharmacological properties. By

considering these views, in this chapter, we demonstrated an efficient synthesis of

oxadiazole by using different acid chlorides, pyrazolone substituted benzothiophene

derivative by using ethyl acetoacetate and by using different oxazolones, we prepared

benzothiophene substituted imidazoles.

Chapter - III

Page No. 66

N

FF

+SH

O

O

Scheme-II

KOH/DMF

SF

NH2

O

O

S

Cl

Cl

O

S

Cl

NH

O

SF

NH2

NH

O

S

ClN

O

S

F

NH2 N

Ethylacetoacetate

SF

NH2

O

N

N

OSF

NH2

NH

O

NH2

NH2NH2

POCl3

O

N

O 1

2

3a-c

4a-c

5

6a-f

R

S

FNH2

NH

O

N

N

O

R


4a S

Cl

O

Cl 6a 2-OH

4b S

O

Cl

6b 3,4-OCH3

4c O

Cl

6c 4-OCH3

6d 4-NO2

6e 2-Cl

6f 4-Cl

Chapter - III

Page No. 67

The starting material methyl-3-amino-6-fluoro-benzothiophene-2-corboxylate 1

was prepare by reacting 2,4-difluorobenzonitrile with methylthioglycolate in the

presence of KOH produced in good yield which on treated with hydrazine hydrate to

gave 3-amino-6-fluorbenzothiophene-2-carbohydrazide 2.

The compound 2 was treated with different acid chlorides in dry acetone gave

substituted benzothiophene carbohydrazides 3a-c. The compound 3a was prepared by

refluxing 3-chloro-benzothiophene-2-carbonyl chloride with compound 2 in dry

acetone in the presence of K2CO3 for 4 hours. Excess of solvent is removed in vacuo

and the residue was stirred with water. The crude product was dried and recrystallized

from methanol to furnish compound 3a.Similarly 3b and 3c were prepared.

S

Cl

NH

O

SF

NH2

NH

O

SF

NH2

NH

O

NH2

S

NH2

O

Cl

23a-c

The 1H NMR spectra of 3a, showed peak at δ 8.03-6.64 due to seven aromatic

protons which appears as multiplet, a singlet at δ 4.9 due to two protons of NH2 group.

The formation of the compound 3a was further confirmed by recording its mass

spectrum, which exhibited a molecular ion peak at m/z 420.

The hydrazides 3a-c were underwent cyclization with POCl3 to gave

oxadiazoles 4a-c. POCl3 was taken in round bottom flask, to this compound 3a was

added slowly at 0 C and stirred for 1 hour, then refluxed for 10 hours on water bath.

Completion of the reaction was monitored by TLC. After completion, it was cooled and

poured on to crushed ice with stirring and neutralized with 2N sodium bicarbonate

solution. The solid that separated was filtered and washed with water, dried and

Chapter - III

Page No. 68

recrystallized from ethanol and further purified through column chromatography. using

ethyl acetate and n-hexane (3:7)

S

ClN

O

S

F

NH2 N

S

Cl

NH

O

SF

NH2

NH

O POCl 3

3a-c4a-c

In confirmation, 4a exhibited NH2 bands stretching at 3442, 3354 and C=N

stretching at 1628 cm-1

respectively in its IR spectrum. In addition, absence of NH

group confirms the formation of the 4a compound. 1H NMR spectra of the same

compound showed multiplet in the region 7.98-7.12 due to seven aromatic protons. A

singlet at 4.42 due to two protons of NH2 group. This was further confirmed by its

mass spectrum that showed molecular ion peak at m/z 402. Which corresponds

molecular weight of the compound. Similarly, compound 4b and 4c were prepared.

Compound 2 was allowed to react with ethylacetoacetate in absolute ethanol

and it was refluxed for 24 hours. The progress of the reaction was monitored by TLC.

After completion, the solid product that obtained was filtered, washed with water, dried

and recrystllized and further purified through column chromatography using ethyl

acetate and n-hexane (2:8) to get pure 5.

SF

NH2

NH

O

NH2

OO

O

SF

NH2

O

N

N

O

25

The compound 5 exhibited peaks at 3463, 3354 1625, 1723 cm-1

due to NH2,

C=N and pyrazolone C=O stretching frequencies in its IR spectrum. 1H NMR spectra

showed a multiplet in the region 8.19-7.28 due to three aromatic protons, and a

Chapter - III

Page No. 69

singlet at 4.75 due to two protons of NH2, the presence of three protons of CH3 group

at 1.2 respectively. As an additional proof, the mass spectrum of the compound 5

exhibited molecular ion peak at m/z 291.

Carbohydrazide 2 was converted in to imidazoles 6a-f, by using different

oxazolones. The compound 6a was prepared by refluxing mixture of 3-amino-6-fluoro-

benzothiophene-2-carbohydrazide 2 and (4Z)-4-(2-hydroxybenzylidene)-2-phenyl-1,3-

oxazol-5(4H)-one in glacial acetic acid for 12 hours. Progress of the reaction was

monitored by TLC. After completion of the reaction, it was cooled and poured on to

crushed ice. The solid that obtained was filtered, washed and purified by methanol to

get pure 3-Amino-N-[(4Z)-4-(2-hydroxybenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-

imidazol-1-yl]-6-fluoro 1-benzothiophene-2-carboxamide 6a.

SF

NH2

NH

O

NH2

O

N

O

OH

SF

NH2

NH

O

NN

O

OH

26a-f

In confirmation, the 1H NMR spectrum of compound 6a showed a singlet at δ

9.6 due to one proton of NH. And a multiplet in between δ 8.64-7.28 due to thirteen

protons in the aromatic region. Further, it was confirmed by its mass spectrum a

molecular ion peak at m/z 472 was in agreement with the structure. Similarly,

compound 6b-f were prepared.

S

Cl

NH

O

SF

NH2

NH

O


S

Cl

NH

O

SF

NH2

NH

O

Mass spectrum of 3a

S

ClN

O

S

F

NH2 N

IR spectrum of 4a

S

ClN

O

S

F

NH2 N


S

ClN

O

S

F

NH2 N

Mass spectrum of 4a

S

FNH2

NH

O

N

N

O

OH


S

FNH2

NH

O

N

N

O

OH

Mass spectrum of 6a

SF

NH2

O

N

N

O

IR spectrum of 5

SF

NH2

O

N

N

O


SF

NH2

O

N

N

O

Mass spectrum of 5

Chapter - III

Page No. 70

EXPERIMENTAL

Preparation of 3-amino-N-[(3-chloro-1-benzothiophen-2-yl)carbonyl]-6-fluoroben

zothiophene-2-carbohydrazide (3a):

To the compound 2 (0.225g, 0.001mol) was added 3-chloro-benzothiophene-2-carbonyl

chloride (0.231g 0.001mol) in dry acetone in the presence of K2CO3 and was refluxed

for about 4 hrs. Excess of solvent was removed in vacuo. The residue was washed with

water and then with NaHCO3. The crude product was dried and recrystallized with

suitable solvent. Similarly, compounds 3b-3c were prepared.

S

Cl

NH

O

SF

NH2

NH

O


): 3455, 3360 (NH2), 1656 (C=O);

1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 9.83 (1H, s, NH), 9.13 (1H, s, NH), 8.03-

6.64 (7H, m, Ar-H), 4.92 (2H, bs, NH2); Elemental analysis: Calculated (%) for

C18H11ClFN3O2S2: C, 51.48. H, 2.64. N, 10.01. S, 16.88; Found: C, 51.44. H, 2.61. N,

9.95. S, 16.85; LC-MS m/z: 420. 422; M.P: 256-259 0C.

3-Amino-6-fluoro-N'-(thiophen-2-ylcarbonyl)-1-benzothiophene-2-carbohydrazide

(3b):

SNH

O

SF

NH2

NH

O


): 3443, 3352 (NH2), 1648

(C=O); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 9.95 (1H, s, NH), 9.38 (1H, s, NH),

8.56-7.15 (6H, m, Ar-H), 4.79 (2H, bs, NH2).; Elemental analysis: Calculated (%) for

C14H10FN3O2S2: C, 50.13. H, 3.04. N, 12.52. S, 19.12 ; Found: C, 49.79. H, 3.52. N,

12.41. S, 18.97; LC-MS m/z: 335; M.P: 214-217 0C.

Chapter - III

Page No. 71

3-Amino-6-fluoro-N'-(phenylacetyl)-1-benzothiophene-2-carbohydrazide (3c):

NH O

SF

NH2

NH

O


): 3430, 3345 (NH2), 1642 (C=O);

1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 9.59 (1H, s, NH), 9.10 (1H, s, NH), 8.26-

7.25 (8H, m, Ar-H), 4.95 (2H, bs, NH2), 4.20 (2H, s, CH2); Elemental analysis:

Calculated (%) for C17H14FN3O2S: C, 59.46. H, 4.10. N, 12.23. S, 9.33; Found: C,

59.43. H, 4.08. N, 12.19. S, 9.30; LC-MS m/z: 343; M.P: 195-198 0C.

Preparation of 2-[5-chloro-1-benzothiophen-2-yl)-1,3,4-oxadiazol-2-yl]-6-fluoro-1-

benzothiophene-3-amine (4a):

POCl3 (25ml) was added to compound 3a (0.419g, 0.001mol) and the reaction mixture

was refluxed for 10 hrs on waster bath. After completion of the reaction, it was cooled,

poured in to crushed ice and neutralized with 2N sodium bicarbonate solution. The

solid thus separated was filtered, and washed with water, dried and recrystallized from

ethanol. It was purified by column chromatography. Similarly, compounds 4b-4c were

prepared.

S

ClN

O

S

F

NH2 N


): 3442, 3354 (NH2), 1628 (C=N),

663 (C-Cl); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 7.98-7.12 (7H, m, Ar-H), 4.42

(2H, bs, NH2); Elemental analysis: Calculated (%) for C18H9ClFN3OS2: C, 53.79. H,

2.26. N, 10.46. S, 15.95; Found: C, 53.75. H, 2.23. N, 10.42. S, 15.91; LC-MS m/z:

402. 404; M.P: 298-301 0C.

Chapter - III

Page No. 72

6-Fluoro-2-[5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl]-1-benzothiophen-3-amine (4b):

S

N

O

S

F

NH2 N


): 3435, 3345 (NH2), 1625 (C=N);

1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 8.29-6.98 (6H, m, Ar-H), 4.69 (2H, bs,

NH2); Elemental analysis: Calculated (%) for C14H8FN3OS2: C, 52.98. H, 2.54. N,

13.24. S, 20.19; Found: C, 52.59. H, 3.12. N, 13.11. S, 20.05; LC-MS m/z: 317.36;

M.P: 279-281 0C.

2-(5-Benzyl-1, 3, 4-oxadiazol-2-yl)-6-fluoro-1-benzothiophen-3-amine (4c):

N

O

S

F

NH2 N


): 3430, 3339 (NH2), 1620

(C=N); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 8.10-7.05 (8H, m, Ar-H), 4.90 (2H,

bs, NH2), 4.10 (2H, s, CH2); Elemental analysis: Calculated (%) for C17H12FN3OS: C,

62.75. H, 3.17. N, 12.91. S, 9.85; Found: C, 62.69. H, 3.14. N, 12.85. S, 9.81; LC-MS

m/z: 325.36; M.P: 262-264 0C.

Preparation of 2-[3-amino-6-fluoro-1-benzothiophen-2yl)carbonyl]-5-methyl-2-4-

dihydro-3H-pyrazol-3-one (5):

Ethyl acetate (0.21ml, 0.002mol) and compound 2 (0.45g, 0.002mol) were taken in

absolute ethanol (40ml) and refluxed for 24 hrs. After the completion of the reaction, it

was poured into ice-cold water and filtered it was then dried and purified.

Chapter - III

Page No. 73

SF

NH2

O

N

N

O


): 3463, 3354 (NH2), 1723 (C=O);

1H-NMR: (400 MHz: CDCL3) δ (ppm): 8.19-7.28 (3H, m, Ar-H), 4.75 (2H, bs, NH2),

3.09 (2H, s, CH2), 1.20 (3H, s, CH3); Elemental analysis: Calculated (%) for

C13H10FN3O2S: C, 53.60. H, 3.50. N, 14.42. S, 11.00; Found: C, 53.55. H, 3.46. N,

14.38. S, 10.97; LC-MS m/z: 291; M.P: 232-235 0C.

Preparation of 3-Amino-N-[(4Z)-4-(2-hydroxybenzylidene)-5-oxo-2-phenyl-4,5-

dihydro-1H-imidazol-1-yl]-6-fluoro 1-benzothiophene-2-carboxamide (6a):

An equimolar mixture of methyl-3-amino-6-fluoro-1-benzothiophene-2-carbohydrazide

2 (0.225g 0.001mol) and (4Z)-4-(2-hydroxybenzylidene)-2-phenyl-1,3-oxazol-5(4H)-

one (0.265g, 0.001mol) in glacial acetic acid (20ml) refluxed for 12 hrs. Completion of

the reaction was monitored through TLC. The reaction mixture was poured in to

crushed ice. The product that separated was collected by filtration, dried and

recrystallized from aqueous ethanol. Similarly, 6b-f were prepared.

SF

NH2

NH

O

NN

O

OH


): 3410, 3345 (NH2), 1706 (C=O);

1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 9.69 (1H, s, NH) 8.64 (1H, s), 7.98-7.28

(12H, m, Ar-H), 6.01 (1H, s, OH), 4.18 (2H, bs, NH2); Elemental analysis: Calculated

Chapter - III

Page No. 74

(%) for C25H17FN4O3S: C, 63.55. H, 3.62. N, 11.86. S, 6.78; Found: C, 63.52. H, 3.57.

N, 11.83. S, 6.74; LC-MS m/z: 472. ; M.P: 269-272 0C.

3-Amino-N-[(4Z)-4-(3,4,-dimethoxybenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-

imidazol-1-yl]6-fluoro-1-benzothiophene-2-carboxamide (6b):

SF

NH2

NH

O

NN

O O

O


): 3460, 3355 (NH2), 1722

(C=O); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 9.59 (1H, s, NH), 8.58 (1H, s), 7.88-

7.21 (11H, m, Ar-H), 4.38 (2H, bs, NH2), 3.88 (6H, s, OCH3); Elemental analysis:

Calculated (%) for C27H21FN4O4S: C, 62.78. H, 4.09. N, 10.85. S, 6.20; Found: C,

62.75. H, 4.05. N, 10.80. S, 6.17 ; LC-MS m/z: 516.54 ; M.P: 285-288 0C.

3-Amino-N-[(4Z)-4-(4-methoxybenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-

imidazol-1-yl] 6-fluoro-1-benzothiophene-2-carboxamide (6c):

SF

NH2

NH

O

NN

O

O


): 3455, 3352 (NH2), 1720 (C=O);

1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 9.55 (1H, s, NH), 8.54 (1H, s), 7.90-7.26

(12H, m, Ar-H), 4.45 (2H, bs, NH2), 3.86 (3H, s, OCH3); Elemental analysis:

Calculated (%) for C26H19FN4O3S: C, 64.19. H, 3.93. N, 11.51. S, 6.59 ; Found: C,

64.16. H, 3.87. N, 11.49. S, 6.56; LC-MS m/z: 486.51; M.P: 248-251 0C.

Chapter - III

Page No. 75

3-Amino-N-[(4Z)-4-(4-nitrobenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-

1-yl]6-fluoro -1-benzothiophene-2-carboxamide (6d):

SF

NH2

NH

O

NN

O

N+

O-

O


): 3395, 3335 (NH2), 1695 (C=O);

1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 9.69 (1H, bs, NH), 8.74 (1H, s), 7.92-7.64

(12H, m, Ar-H), 4.48 (2H, bs, NH2);. Elemental analysis: Calculated (%) for

C25H16FN5O4S: C, 59.88. H, 3.21. N, 13.96. S, 6.39 ; Found: C, 59.84. H, 3.19. N,

13.92. S, 6.35; LC-MS m/z: 501.48; M.P: 237-240 0C.

3-Amino-N-[(4Z)-4-(2-chlorobenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imida

zol-1-yl]6-fluoro-1-benzothiophene-2-carboxamide (6e):

SF

NH2

NH

O

NN

O

Cl


): 3390, 3330 (NH2), 1695 (C=O),

710 (C-Cl); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 9.42 (1H, bs, NH), 8.57 (1H, s),

7.79-7.43 (12H, m, Ar-H), 4.40 (2H, bs, NH2); Elemental analysis: Calculated (%) for

C25H16ClFN4O2S: C, 61.16. H, 3.28. N, 11.41. S, 6.53 Found: C, 61.10. H, 3.25. N,

11.39. S, 6.50 ; LC-MS m/z: 490.93 ; M.P: 264-267 0C.

Chapter - III

Page No. 76

3-Amino-N-[(4Z)-4-(4-chlorobenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imida

zol-1-yl]6-fluoro-1-benzothiophene-2-carboxamide (6f):

SF

NH2

NH

O

NN

O

Cl


): 3388, 3327 (NH2), 1691 (C=O),

690 (C-Cl); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 9.44 (1H, bs, NH), 8.55 (1H, s),

7.82-7.52 (12H, m, Ar-H), 4.42 (2H, bs, NH2);. Calculated (%) for C25H16ClFN4O2S: C,

61.16; H, 3.28; N, 11.41. S, 6.53; Found: C, 61.08; H, 3.17; N, 11.35. S, 6.52; LC-MS

m/z: 490.93 ; M.P: 272-275 0C.

Chapter - III

Page No. 77

REFERENCES

[1] H. Singh and V.K. Kapoor, Medicinal and Pharmaceutical Chemistry, Vallabh

Prakashan., 2008, 2, 1-2.

[2] D. Lednicer, L.A. Mitscher, In Organic Chemistry of Drug Synthesis, Wiley

Interscienc newYork., 1997, 1, 226.

[3] A.R. Katritzky, Rees. Comprehensive Heterocyclic Chemistry., 1984, 5, 469-

498.

[4] M.R. Grimmett. Imidazole and Benzimidazole Synthesis., Academic Press.,

1997.

[5] E.G. Brown, Ring Nitrogen and Key Biomolecules., Kluwer Academic Press.,

1998.

[6] A.F. Pozharskii, Heterocycles in Life and Society. John Wiley & Sons., 1997.

[7] T.L. Gilchrist, Heterocyclic Chemistry The Bath press., 1985.

[8] H. Debus, Annalen der Chemie und Pharmacie., 1858, 107(2), 199–208.

[9] F. Rondu, G. Le Bihan, X. Wang, A. Lamouri, E. Touboul, G. Dive, T.

Bellahsene, B. Pfeiffer, P. Renard, B. Guardiola-Lemaitre, D. Manechez, L.

Penicaud, A. Ktorza, J.J. Godfroid, J. Med.Chem., 1997, 40, 3793.

[10] P. Bousquet, Feldman, J. Drugs., 1999, 58, 799.

[11] H. Fujioka, K. Murai, Y. Ohba, A. Hiramastu, Y. Kita, Tetrahedron Lett., 2005,

46, 2197.

[12] E.E. Korshin, L.I. Sabirova, A.G. Akhadullin, Y.A. Levin , Russian Chem.

Bull., 1994, 43, 431. (b) G. Levesque, J.C. Gressier, M. Proust,. Synthesis.,

1981, 963.

[13] H. Vorbriiggen, K. Krolikiewicz, Tetrahedron, Lett., 1981, 22, 4471.

[14] G. Neef, U. Eder, G.J. Sauer, Org. Chem., 1981, 46, 2824.

[15] A.J. Hill, J.V. Johnston, J. Am. Chem. Soc., 1954, 76, 922.

[16] N.A. Boland, M. Casey, S.J. Hynes, J.W. Matthews, M.P. Smyth, J. Org.

Chem., 2002, 67, 3919.

[16] A.R. Katritzky, Rees. Comprehensive Heterocyclic Chemistry.

[17] Grimmett, M. Ross. Imidazole and Benzimidazole Synthesis. Academic Press.

Chapter - III

Page No. 78

[18] E.G. Brown, Ring Nitrogen and Key Biomolecules. Kluwer Academic Press,

1998.

[19] A.F. Pozharskii et al. Heterocycles in Life and Society. John Wiley & Sons,

1997.

[20] Heterocyclic Chemistry T.L. Gilchrist, the Bath press 1985, ISBN 0-582-01421-

2.

[21] C. Congiu, M.T. Cocco and V. Onnis, Bioorganic & Medicinal Chemistry

Letters., 2008, 18, 989–993.

[22] A.M. Venkatesan, A. Agarwal, T. Abe, H.O. Ushirogochi, D. Santos, Z. Li, G.

Francisco, Y.I. Lin, P.J. Peterson, Y. Yang, W.J. Weiss, D.M. Shales, T.S.

Mansour, Bioorg. Med. Chem., 2008, 16, 1890–1902.

[23] T. Nakamura, H. Kakinuma, H. Umemiya, H. Amada, N. Miyata, K. Taniguchi,

K. Bando and M. Sato, Bioorganic & Medicinal Chemistry Letters., 2004, 14,

333–336.

[24] M. Su Han and D.H. Kim, Bioorganic & Medicinal Chemistry Letters., 2001,

11, 1425- 1427.

[25] G. Roman, J.G. Riley, J.Z. Vlahakis, R.T. Kinobe, J.F. Brien, K. Nakatsu, W.A.

Szarek, Bioorg. Med. Chem., 2007, 15, 3225–3234.

[26] M.A. Bbizhayev, Life Sci., 2006, 78, 2343–2357.

[27] P.G. Nantermet, J.C. Barrow, S.R. Lindsley, M. Young, S. Mao, S. Carroll, C.

Bailey, M. Bosserman, D. Colussi, D.R. McMasters, J.P. Vacca, H.G. Selnick,

Bioorg. Med. Chem. Lett., 2004, 14, 2141–2145.

[28] J.L. Adams, J.C. Boehm, T.F. Gallagher, S. Kassis, E.F. Webb, Ralph Hall,

Margaret Sorenson, Ravi Garigipati, Don E. Griswold and John C. Lee,

Bioorg.Med. Chem.Lett., 2001, 11, 2867-2870.

[29] K. Bhandari, N. Srinivas, G.B.S. Keshava, P.K. Shukla, Eur.J.Med. Chem.,

2002, 1235.

[30] S. Emami, A. Foroumadi, M. Falahati, E. Lotfali, S. Rajabalian, d S Ahmed

Ebrahimi, S. Farahyarc and A. Shafiee, Bioorganic & Medicinal Chemistry

Letters., 2008, 18, 141–146.

[31] R.K. Ujjinamatada, A. Baier, P. Borowski, R.S. Hosmane, Bioorg. Med. Chem.

Lett., 2007, 17, 2285–2288.

[32] R.V. Shingalapur, K.M. Hosamani, R.S. Keri, European Journal of Medicinal

Chemistry, 2009, 44, 4244–4248.

Chapter - III

Page No. 79

[33] Jawaharmal et al. Indo Global Journal of Pharmaceutical Sciences, 2012, 2(2),

147-156.

[34] D.A. Williams and T.L. Lemke, Foye’s Principles of medicinal chemistry,

Lippincott Williams and Wilkins, 2002, 5, 36.

[35] S.N. Pandeya Nath, A Text Book of medicinal chemistry, SG publisher, 2004,

1(3), 2-3.

[36] H. Singh and V.K. Kapoor, Medicinal and Pharmaceutical Chemistry, Vallabh

Prakashan, 2008, 2, 1-2.

[37] D. Lednicer, L.A. Mitscher, In Organic Chemistry of Drug Synthesis, Wiley

Interscienc NewYork, 1997, 1, 226.

[38] A.R. Katritzky, Rees. Comprehensive Heterocyclic Chemistry, 1984, 5, 469-

498.

[39] Grimmett, M. Ross. Imidazole and Benzimidazole Synthesis. Academic Press,

1997.

[40] E.G. Brown, Ring Nitrogen and Key Biomolecules. Kluwer Academic Press,

1998.

[41] A.F. Pozharskii et al. Heterocycles in Life and Society. John Wiley & Sons,

1997.

[42] (a) G.J. Durant, J. Chem. Soc. Rev., 1985, 14, 375. (b) R.C. Gadwood, B.V.

Kamdar, L.A.C. Dubray, M.L. Wolfe, M.P. Smith, W. Watt, S.A. Mizsak and

V.E. Groppi, J. Med.Chem., 1993, 36, 1480. (c) F. Cafieri, E. Fattorusso, A.

Mangoni and O. Taglialatela-Scafati, Tetrahedron Lett., 2006, 37, 3587.

[43] M. Los, Pestic. Sci. Biotechnol., Proc. Int. Congr Pestic Chem., 6th

ed.1987, R.

Greenhalgh and T.R. Eds. Roberts, Blackwell, Oxford, U.K, 35.

[44] G.W. Chan, S. Mong, M.E. Hemling, A.J. Freyer, P.H. Offen, C.W. De Brosse,

H.M. Sarau and J.W. Westley, J. Nat. Prod., 1993, 56, 116.

[45] H.L. Yale and J.J. Piala, J. Med. Chem., 1966, 9, 42.

[46] Malla Reddy and G.V.S. Rama Sharma, Indian J. Heterocycl.Chem., 1997, 7,

21.

[47] Sangeeta Rajpurohit, S.P. Garg and Pramila Sah, Indian J. Heterocycl. Chem.,

2005, 15, 129.

[48] H.H. Parekh, K.A. Parekh, B.C. Merjs and S.B. Hirpara, Indian. J. Chem., 2003,

42, 1172.

Chapter - III

Page No. 80

[49] M.D. Shah, N.C. Desai, K.A. Awasthi and A.K. Saxena, Indian. J. Chem., 2001,

40, 201.

[50] M.S. Chande, N.V. Thakkar and D.V. Patil. Acta Poloniae Drug Research.,

1999, 56(3), 207-10.

[51] F.A. Attby, M.A.A. Elneairy and M.S. Elsayed, Arch Pharma Research., 1999,

222(2), 194-201.

[52] K.M. Thakkar, R.M. Ghateya, S.D. Tala, B.L. Dobiya, K.A. Joshi, K.L. Dubal

and H.S. Joshi. Indian J Chem., 2011, 50B(5), 738-44.

[53] N. Singh, N.K. Sangwan, K.S. Dhindsa. Pesticide Science., 2000, 56(3), 284-

88.

[54] P.L. Zhao, F. Wang, M.Z. Zhang, Z.M. Liu, W. Huang, G.F. Yang. J Agri Food

Chemistry., 2008, 56(22), 19767-73.

[55] S. Bondock, W. Khalifa, A.A. Fadda, Eur J Chem., 2011, 46(6), 2555-61.

[56] U. Deva Priya Kumar and G. Narharisastry,. Indian J Chem., 2000, 39(A), 92.

[57] E.C. Taylor, H. Patel, H. Kumar, Tetrahedron., 1992, 48, 8089.

[58] S.G. Roelfvan, C. Arnold, K.J. Wellnga, Agric. Food Chem., 1979, 84, 406.

[59] G.H. Keats, Brit. Pat. 1970, 1,209, 631.

[60] R.M. Kedar, N.N. Vidhale, M.M. Chincholkar, Orient. J. Chem., 1997, 13, 143.

[61] A. Singh, S. Rathod, B. N Berad, S.D. Patil, A.G. Dosh, Orient. J. Chem., 2000,

16, 315.

[62] H.Z. Katri, S.A.J. Vunii, Ind. Chem. Soc., 1981, 58, 168.

[63] N.B. Das, A.S. Mittra, Ind. J. Chem., 1978, 16B, 638.

[64] D. Azarifar, M. Shaebanzadeh, Molecules., 2002, 7, 885.

[65] B. Holla, Shivarama, P.M. Akberali, M.K. Shivanada, Farmaco., 2000, 55, 256.

[66] E. Palaska, M. Aytemir, I. Tayfun, K. Erol, E. Dilek, Eur. J. Med. Chem., 2001,

36, 539.

[67] H.G. Garge, Chandraprakash, J. Pharm. Sc., 1971, 14, 649.

[68] H.A. Regaila, A.K. El-Bayonk, M. Hammad, Egypt. J. Chem., 1979, 20, 197.

Chapter - III

Page No. 81

[69] R Krishna, B.R. Pande, S.P. Bharthwal, S.S. Parmar, Eur. J. Med. Chem., 1980,

15, 567.

[70] M.I. Husain, S. Shukla, Ind. J. Chem., 1986, 25B, 983.

[71] Yu.V. Tomilovi, G.P. Okonnishnikova, E.V. Shulishov, O.M. Nefedov, Russ.

Chem. Bt., 1995, 44, 2114.

[72] E.I. Klimova, M. Marcos, T.B. Klimova, A.T. Cecilio, A.T Ruben, R.R. Lena,

J.Organomet. Chem., 1999, 585, 106.

[73] D. Bhaskarreddy, A. Padmaja, P.V. Ramanareddy, B. Seenaiah., Sulfur Lett.

1993, 16, 227.

[74] V. Padmavathi, R.P. Sumathi, B.N. Chandrasekhar, D.J, Bhaskarreddy, Chem.

Research 1999, 610.

[75] M. Arnost, A. Pierce, E. Haar, D. Lauffer, J. Madden, K. Tanner, J. Green,

Bioorg. Med. Chem. Lett., 2010, 20, 1661.

[76] R. Venkat Ragavan, V. Vijaykumar, N. Suchetha Kumari, Eur. J. Med. Chem.,

2009, 44, 3852.

[77] A. Gursoy, S. Demirayak, G. Capan, K. Erol, K. Vural, Eur. J. Med. Chem.,

2000, 35, 359.

[78] D. Castagnolo, F. Manetti, M. Radi, B. Bechi, M. Pagano, A.D. Logu, R.

Meleddu, M. Saddi, M. Botta, Bioorg. Med. Chem., 2009, 17, 5716.

[79] Nikhil Parekh, Kalpana Maheria, Pratik Patel, Manoj Rathod, Int. J. PharmTech

Res., 2011, 3, 540.

[80] G. Mariappan, B.P. Saha, L. Sutharson, A. Haldar, Indian J. Chem., 2010, 49B,

1671.

[81] P. Manojkumar, T.K. Ravi, G. Subbuchettiar, Acta Pharm., 2009, 59, 159.


[83] A.M. Isloor, B. Kalluraya, M. Rao, J. Saudi Chem. Soc., 2000, 4, 265.

[84] B. Kalluraya, A.M. Isloor, P.V. Frank, R.L. Jagadesha, S. Shenoy, Indian J.

Heterocycl. Chem., 2001, 4, 159.

[85] D. Sunil, A.M. Isloor, P. Shetty, Der Pharma Chemica., 2009, 1, 19.

[86] A.M. Isloor, B. Kalluraya, K.S. Pai, Eur. J. Med. Chem., 2010, 45, 825.

Chapter - III

Page No. 82

[87] B. Chandrakantha, P. Shetty, V. Nambiyar, N. Isloor, A.M. Isloor, Eur. J. Med.

Chem.,2010, 45, 1206.

[88] U.S. Rai, A.M. Isloor, P. Shetty, A.M. Vijesh, N. Prabhu, S. Isloor, M.

Thiageeswaran, H.K. Fun, Eur. J. Med. Chem., 2010, 45, 2695.

[89] A.M. Vijesh, A.M. Isloor, V. Prabhu, S. Ahmad, S. Malladi, Eur. J. Med.

Chem., 2010, 45,5460.

[90] R. Khan, M.I. Uddin, M.S. Alam, M.M. Hossain, M.R. Islam, Bangladesh J.

Pharmacol., 2008, 3, 27.

[91] Mackie, Mc. Cartney, Practical Medicinal Microbiology 13th ed., Chuchill

Livingstone, Edinburgh., 1989, 87.

[92] P.G. Baraldi, C. Barbara, S. Giampiero, R. Romeo, B. Giovanni, N.Z. Abdel, J.

Maria, D.L. Pineda, Synthesis., 1997, 10, 1140.

[93] S. Ojha, A. Bapna, G.L. Talesara, ARKIVOC., 2008, 11, 112.

[94] G. Kuçukguze, S. Rollas, H. Erdeniz, M. Kiraz, A. Ekinci, V.A Cevdet, Euro. J.

Med. Chem., 2000, 35(7-8), 761-771.

[95] A.N. Evstropov, V.E. Yavorovskaya, E.S. Vorob’ev, Z.P. Khudonogova, S.G.

Medvedeva, V.D. Filimonov, T.P. Prishchep, A.S. Saratikov. Pharm.Chem.

Jour., 1992, 26(5), 426-430.

[96] K. Kumar Siva, A. Rajasekharan, Int. journal of research of pharmacy and

chemistry. 2012, 2(2), 327-337.

[97] Khan Rahat, Uddin Imam, M. Alam, D. Sultan, Journal of the Bangladesh

pharmacological society., 2008, 3, 27-35.

[98] S Sunitha, K.K. Aravindakshan, International journal pharm bio med sci.,

2011, 2(4), 108-113.

[99] Y.L. Chang, L.M. Klug, M.E Wolff, Eds Vol. 1, John Wiley and Sons, Inc.,

New York, USA, 1995, 10-20.

[100] L.A. Mitscher, Drug Design and Discovery: An Overview. In Text Book of

Drug Designand Discovery, 3rd ed.; K.P Larsen, T. LiljeforsMadsen, U. Eds,

Taylor and Francis, London., 2002, 1-33.

[101] L.G. Patrick, In. An introduction to medicinal chemistry, 2nd ed. In. Oxford

University Press Inc., New York., 2001, 153-167.

[102] K. Tanaka, F. Toda, Chem. Rev., 2000, 100, 1025-1074.

CHAPTER - IV

A convenient synthesis of methyl-3-amino-1-benzothiophene-2-

carboxylate substituted 1,3,4-oxadiazoles.

Chapter - IV

Page No. 84

INTRODUCTION

Synthetic organic chemistry has always played a vital role in drug discovery

process. The constant and growing interest in the development of new efficient and

general synthetic methods for the preparation of fused heterocyclic systems involving

benzothiophene and oxadiazole subunits is justified by their well-established valuable

physiological and pharmacological properties. Oxadiazole are cyclic compounds

containing one oxygen and two nitrogen atom in a five membered ring. The oxadiazole

drugs were the first effective chemotherapeutic agents to be employed systematically

for the prevention and cure of bacterial infection in human beings .The capacity of

1,3,4-oxadiazole nucleus to undergo variety of chemical reactions have made it

medicinal backbone on which number of potential molecules can be constructed,

Oxadiazole, a heterocyclic nucleus has attracted a wide attention for the chemist

in search for the new therapeutic molecules. The first synthesis of 1,2,4-oxadiazoles,

initially named furo[ab-1]diazoles, was achieved by Tiemann and Kruger in 1884.

Oxadiazole exists in different isomeric forms such as 1,2,4-, 1,2,5-, 1,3,4- and 1,2,3-

oxadiazole. Oxadiazole is a very weak base due to the inductive effect of the extra

heteroatom. The replacement of two -CH= groups in furan by two pyridine type

nitrogen (-N=) reduces aromaticity of resulting oxadiazole ring to such an extent that

the oxadiazole ring exhibit character of conjugated diene.

NO

N

NO

NO

NN

NO

N

1 2 3 4

1,2,4-oxadiazole 1,2,5-oxadiazole 1,3,4-oxadiazole 1,2,3-oxadiazole

Oxadiazole rings have been introduced into drug discovery programs for several

different purposes. In some cases, they have been used as an essential part of the

pharmacophore, favorably contributing to ligand binding1. In other cases, oxadiazole

Chapter - IV

Page No. 85

moieties have been shown to act as a flat, aromatic linker to place substituents in the

appropriate orientation as well as modulating molecular properties by positioning them

in the periphery of the molecule2. It has also recently been shown that significant

differences in thermodynamic properties can be achieved by influencing the water

architecture within the aldose reductase active site by using two structurally related

oxadiazole regioisomers3. In addition, oxadiazoles have been used as replacements for

carbonyl containing compounds such as esters, amides, carbamates, and hydroxamic

esters4.

There are large number of synthetic compounds with oxadiazole nucleus used for

antitumor5 antiparkinsonian

6, anti-TB

7, antiproliferative

8,9, anticancer

10-12, HIV-

1integrase inhibitory13,14

tyrosinase inhibitory activities15,16

and. Fluorescent

whiteners17

when substituted at 2 and 5 positions. Benzothiophene derivatives reported

in the literature are known to possess varied biological activities viz. antimicrobial18

,

anti-inflammatory19

, antituberculosis20

analgesic21

nervous system depressing22

,

herbicidal23

, muscle relaxant24

and tranquilizing activities25

.

It is perhaps not necessary to emphasize the importance of oxadiazole nucleus in

pharmacologically useful biheterocyclic compounds. Survey of literature revealed the

importance of oxadiazole, which exhibit large spectrum of biological activities25-32

.

Among various isomeric oxadiazoles, 1,3,4-oxadiazole play significant role especially

in pharmaceutical industry 1,3,4-oxadiazole are commonly utilized pharamacores due

to there metabolic profile and ability to engaged in hydrogen bonding. The

antihypertensive agents such as Tiodazosin and Nesapidil encompass oxadiazole ring in

their structure32-40

.

Amir et al, have synthesized various novel 1,3,4-oxadiazole derivatives 5 and

evaluated their anti-inflammatory, analgesic and ulcerogenic activity41

.

Chapter - IV

Page No. 86

OO

NN

R


Padmavathi et al, have carried out the synthesis and bioassay of a new class of

1, 3, 4-oxadiazoles 6 and found that some of the tested compounds exhibited promising

anti-bacterial activity42

.

NN

OSHR

6 R=pyridyl, phenyl, substituted phenyl

Tyrosinase, also known as polyphenol oxidase (PPO), is a multifunctional

copper-containing enzyme, widely distributed in plants and animals. It catalyses the o-

hydroxylation of monophenols and the oxidation of o-diphenols to o-quinones.

Tyrosinase is known to be a key enzyme for melanin biosynthesis in plants and

animals.

Therefore, tyrosinase inhibitors are clinically useful for the treatment of some

dermatological disorders associated with melanin hyper pigmentation and also

important in cosmetics for whitening and depigmentation after sunburn. Khan et al,

have screened novel 1,3,4-oxadiazole derivatives 7 for their tyrosinase inhibitory

activity43,44

. Some of the tested compounds exhibited more tyrosinase inhibitory

activity than standard drug kojic acid.

O

NN

R1

R

7 R=phenyl, substituted phenyl R1

=pyridyl, pheny, substituted phenyl

Tuberculosis (TB) is one of the most common infectious diseases known to the

mankind. Current control efforts are severely hampered due to fact that tuberculosis has

Chapter - IV

Page No. 87

become a leading opportunistic infection in patients with acquired immune deficiency

syndrome and the spreading of multidrug-resistant strains (MDR-MTB). Problems in

the chemotherapy of tuberculosis arise when patients develop bacterial resistance to the

first-line drugs. The ever-increasing drug resistance, toxicity and side effects of

currently used antituberculosis drugs highlight the need for new, safer and more

effective antimycobacterial compounds. One of the most effective first-line anti-TB

drugs is INH. Many analogues featuring the structure of INH have been synthesized

and tested as antimycobacterials. It has been reported that conversion of INH to its

oxadiazoles result in enhancing the activity of INH.

Vazquez et al, have synthesized novel oxadiazoles of INH 8 and evaluated their

anti-mycobacterial activity against M. tuberculosis strains H37Rv (ATCC 27294), and

two drug-sensitive and three drug-resistant clinical isolates. Some of the tested

compounds exhibited significant anti-mycobacterial activity45

.

O

NN

R

N


1,3,4-Oxadiazoles are of also of significant interest in medicinal chemistry in a

number of biological targets including benzodiazepine receptor agonists, 5-HT receptor

agonists, muscarinic agonists, 5-HT antagonists, human NK1 antagonists, antirhinoviral

compounds and anti-inflammatory agents46-50

. They have been used as peptide

mimetics due to their particular geometric and electrometric properties. This prompted

us to synthesize biheterocycles, which contain benzothiophene nucleus.

Shah et al, reported the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles 9 in

which oxadiazole ring is directly linked to the aromatic ring. Screening of these

compounds for antimicrobial, anticancer, tuberculostatic and anti HIV activities51

.

Chapter - IV

Page No. 88

Ar=C6H5, 2-Cl-C6H5, 3-OCH3-C6H4

Mogilaiah et al, connected 1,3,4-oxadiazoles moiety with napthyridine 10 and11

found that many of the compounds exhibited considerable activity against gram +ve

and gram -ve bacteria52

.

N N

O

N N

S-H

10

N N

O

N N

Ar-

11 Ar=4-CH3 C6H4, 4-OCH3 C6H4

Hiremath et al, observed that the biheterocyclices containg oxadiazole moiety

and indole 12 exhibited activity against some strains of bacteria53,54

. Similarly, Biradar

et al synthesized 13 similar compounds with an aim to obtain biologically potent

molecules55,56

.

NH

OH

R1

R2

ON

N

N

RR

12

NH

OH

R1

R2

O

NN

R

S

13

R=CH3 C6H5, R1=H, R2=Br R=CH3 C6H5

Oxadiazoles have been explored to maximum extent by various medicinal

chemists which have resulted in the accumulation of voluminous work in this field of

research and numerous research papers have appeared in the literature57-63

.

NH

NN

S

O

NH

Ar-

9

Chapter - IV

Page No. 89

KucuKguzel et al, have synthesized 14 some novel 2-substituted-1,3,4-

oxadiazoles derived from diflunisal hydrazide as potential antireflective and anti-

inflammatory agents64

.

F

FOH

O

N N

NH

R

14

In view of these findings and in continuation of research work on benzothiophene

containing heterocycles, an attempt have been made to develop synthetic route for a

novel series of 2,5-disubstituted-1,3,4-oxadiazole substituted benzothiophene

derivatives as better and potent antimicrobial65-73

.

Present work

The most popular synthetic routes for synthesis of 2,5-disubstituted-1,3,4-oxadiazoles

is based on the cyclization of carbohydrazide functionality with aromatic carboxylic

acids in the presence of hot phosphorus oxychloride, cyclization of hydrazones and

Schiff’s base with acetic anhydride, thermal or acid-catalyzed cyclization of 1,2-

diacylhydrazines etc., In the present work, cyclization of carbohydrazide functionality

of benzothiophene carbohydrazide with aromatic carboxylic acids in presence of

phosphorous oxychloride and cyclization of Schiff’s base with acetic anhydride is

utilized.

Chapter - IV

Page No. 90

O

N

Br

+ SHO

O

1

S cheme-III

S

NH2

NH

O

N

3a-e

4a-e

6a-e

7a-e5a-e

O

S

NH2

NH

O

N

S

NH2

N

O

N

O

S

NH2

N

O

N

O

OH

S

NH2

N

O

N

O

R

R

R

R

RRR

R

KOH

S

NH2

NH

O

NH2

S

NH2

O

O

2

NH2NH2

Comp R

Comp R Comp R

3a 2-OH 5a 3-NO2 7a 4-Cl

3b 2,4-NO2 5b 4-Cl 7b 4-OCH3

3c 4-NH2 5c 3-OH 7c 4-OH

3d 2-Cl 5d 4-NH2 7d 3-NH2

3e 4-F 5e 4-OCH3 7e 3-NO2

Chapter - IV

Page No. 91

The preparation of starting material methyl-3-amino-1-benzothiophene-2-

carboxylate 1 was discussed in earlier chapter. Hydrazine hydrate was added to

compound 1 to give methyl-3-amino-1-benzothiophene-2-corbohydrazide 2. The

compound 2-[5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-benzothiophen-3-amine 3a

was prepared by reacting compound 2 with 2-hydroxybenzoic acid in the presence of

phosphorous oxychloride underwent cyclization to give 2-[5-(2-chlorophenyl)-1,3,4-

oxadiazol-2-yl]-1-benzothiophen-3-amine 3a in good yield.

S NH

O

NH2

NH2

+ OH

O

S

N

O

N

NH2

OH

3a-e2

POCl3R

Formation of 3a was confirmed by spectral data. The 1H NMR spectrum of 3a

did not show the peaks corresponding to NH protons and for NH2 functional groups

two protons appears as singlet in the region 4.85. A multiplet exhibited in the region

8.27–7.42 due to eight aromatic protons. The mass spectrum of 3a exhibited molecular

ion peak at m/z 309 corresponding to its molecular weight. Similarly, the other series of

compounds 3b-e were prepared

In order to prepare 4a, compound 2 was refluxed with different substituted

benzaldehydes in alcohol containing catalytic amount of glacial acetic acid on water

bath to produce solid 3-amino-N'-[(E)-(3-nitroyphenyl)methylidene]-1-benzothiophene-

2-carbohydrazide 4a. Similarly, the compounds 4b-e were prepared.

S NH

O

NH2

NH2

O S NH

O

N

NH2

4a-e2

+ R

R

Chapter - IV

Page No. 92

The formation of compound 4a was confirmed by spectral data. The IR

spectrum of 4a showed NH2 and NH bands at 3452, 3383 and 3193 respectively. In

addition, C=O at 1647. The 1H NMR spectrum of 4a shows the singlet peak at δ 10.1

for NH group. A multiplet exhibited in the region δ 8.32–7.41 due to nine aromatic

protons, singlet at δ 4.95 indicate the presence of two protons of NH2 and the mass

spectrum of 4a exhibited molecular ion peak at m/z 340 corresponding to its molecular

weight. Similarly, the other series of compounds 4b-e were prepared and confirmed by

spectral data.

Schiff base 3-amino-N'-[(E)-(3-nitrophenyl)methylidene]-1-benzothiophene-2-

carbohydrazide 4a thus prepared was refluxed with little excess of acetic anhydride

which undergo cyclization to give 1-[5-(3-amino-1-benzothiophen-2-yl)-2-(3-

nitrophenyl)-1,3,4-oxadiazol-3(2H)-yl]ethanone 5a.

S

N

O

N

ONH2

AC2O

S NH

O

N

NH2

4a-eR R5a-e

IR spectrum of 5a exhibited absence of peak corresponding to NH functionality,

which indicates the cyclisation of 4a to 5a. The IR spectrum of 5a showed NH2 and

C=O bands at 3482, 3392 and 1693 respectively. This was further confirmed by 1H

NMR and mass spectral study of 5a. Exhibited multiplet corresponding to eight

aromatic protons at δ 8.27-7.36 and singlet at δ 2.05 three protons of CH3 group. The

characteristic peak for NH proton was absent in 1H NMR spectrum of 5a, which further

supports the formation of target compound. The mass spectral data of 5a complies with

structure of compound. By using similar procedure the compounds 5b-e were prepared.

Chapter - IV

Page No. 93

The compound 2 was refluxed with various acetophenone in alcohol containing

catalytic amount of glacial acetic acid on water bath to produce solid 3-amino-N'-[(1E)-

1-(4-hydroxyphenyl)ethylidene]-1-benzothiophene-2-carbohydrazide 6a.

S NH

O

NH2

NH2

O

S NH

O

N

NH2

2

+

6a-eR

R

Similarly, the compounds 6b-e were prepared using substituted acetophenones.

The formation of compound 6a was confirmed by spectral data. The 1H NMR

spectrum of 6a shows the singlet peak at δ 9.20 due to NH. A multiplet exhibited in the

region 8.20–6.80 due to 8 aromatic protons, three protons at δ 2.48 confirms the

presence of methyl group. The mass spectrum of 3a exhibited molecular ion peak at

m/z 309 corresponding to its molecular weight. Similarly, the other series of

compounds 6b-e were prepared and confirmed by spectral data.

Finally, the carbohydrazide thus prepared, for example 6a was refluxed with

acetic anhydride on oil bath which underwent cyclization to furnish 1-[5-(3-amino-1-

benzothiophen-2-yl)-2-methyl-2-(4-hydroxyphenyl)-1,3,4-oxadiazol-3(2H)-yl]ethanone

7a.

S

N

O

N

ONH2

S NH

O

N

NH2

Ac2O

6a-eR

7a -e R

The IR spectrum of 7a exhibited absence of bands corresponding to NH group.

This indicated the cyclization of hydrazone to corresponding to oxadiazoles. Further,

1H NMR spectrum of 7a indicated the absence of peak corresponding to NH protons,

presence of multiplet at δ 8.28-7.36 corresponding to eight aromatic protons and singlet

Chapter - IV

Page No. 94

at δ 2.2 and 1.7 corresponding to six protons of methyl group. The mass spectrum of 7a

showed molecular ion peak at m/z 386, which coincides with molecular weight of

compound. Similarly, the other compounds of the series 7b-e were also prepared.

S

NH2

N

O

N OH


S

NH2

N

O

N OH

Mass spectrum of 3a

S

NH2

N

O

N

O

N+

O-

O

IR spectrum of 5a

S

NH2

N

O

N

O

N+

O-

O


S

NH2

N

O

N

O

N+

O-

O

Mass spectrum of 5a

S

NH2

N

O

N

O

Cl

IR spectrum of 7a

S

NH2

N

O

N

O

Cl


S

NH2

N

O

N

O

Cl

Mass spectrum of 7a

Chapter - IV

Page No. 95

EXPERIMENTALS

2-[5-(4-Chlorophenyl)-1, 3, 4-oxadiazol-2-yl]-1-benzothiophen-3-amine (3a-e):

3-Amino-1-benzothiophene-2-corbohydrazide 2 (2.07g, 0.01mol) and 2-hydroxy

benzoic acid (1.56g, 0.01mol) were taken in a round bottom flask to this phosphorous

oxychloride (5ml) was added. The reaction mixture was refluxed on oil bath until

completion of the reaction. The completion of reaction was monitored by TLC. Then

reaction mass was allowed to room temperature and poured in to crushed ice.

Neutralized with 20% sodium bicarbonate solution, the solid separated was filtered,

washed with water, dried and recrystallized from ethyl acetate solvent to give

oxadiazole 3a. Similarly, the compounds 3b-e were prepared by using substituted

aromatic carboxylic acids.

2-[5-(3-Amino-1-benzothiophen-2-yl)-1,3,4-oxadiazol-2-yl]phenol (3a):

S

NH2

N

O

N OH


): 3436, 3355 (NH2), 1590 (C=N);

1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 8.27–7.42 (8H, m, Ar-H), 5.43 (1H, bs,

OH), 4.85 (2H, bs, NH2); Elemental analysis: Calculated (%) for C16H11N3O2S: C,

62.12. H, 3.58. N, 13.58. S, 10.36; Found: C, 62.08. H, 3.54. N, 13.55. S, 10.32; LC-

MS m/z: 309 ; M.P: 290-293 0C.

2-[5-(2,4-Dinitrophenyl)-1,3,4-oxadiazol-2-yl]-1-benzothiophen-3-amine (3b):

S

NH2

N

O

N N+ O

-O

N+

O-

O

Chapter - IV

Page No. 96


): 3429, 3365 (NH2), 1585 (C=N);


NH2); Elemental analysis: Calculated (%) for C16H9N5O5S: C, 50.13; H, 2.36; N, 18.26.

S, 8.36; Found: C, 50.10; H, 2.31; N, 18.23. S, 8.33; LC-MS m/z: 383.33 ; M.P: 311-

3140C.

2-[5-(4-Aminophenyl)-1,3,4-oxadiazol-2-yl]-1-benzothiophen-3-amine (3c):

S

NH2

N

O

N

NH2


): 3420, 3380 (NH2), 1605

(C=N); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 8.45–7.55 (8H, m, Ar-H), 5.57 (2H.

s, NH2), 4.80 (2H, bs, NH2); Elemental analysis: Calculated (%) for C16H12N4OS: C,

62.32. H, 3.92. N, 18.17. S, 10.39; Found: C, 62.29. H, 3.88. N, 18.14. S, 10.36; LC-

MS m/z: 308.35 ; M.P: 322-325 0C.

2-[5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-benzothiophen-3-amine (3d):

S

NH2

N

O

N

Cl


): 3418, 3379 (NH2), 1580 (C=N);


NH2); Elemental analysis: Calculated (%) for C16H10ClN3OS: C, 58.71. H, 3.07. N,

12.82. S, 9.78; Found: C, 58.67. H, 3.03. N, 12.79. S, 9.4; LC-MS m/z: 327.78 ; M.P:

344-347 0C.

Chapter - IV

Page No. 97

2-[5-(4-Fluorophenyl)-1,3,4-oxadiazol-2-yl]-1-benzothiophen-3-amine (3e):

S

NH2

N

O

N

F


): 3416, 3364 (NH2), 1570 (C=N);

1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 8.45–7.35 (8H, m, Ar-H), 4.78 (2H, s, NH2);

Elemental analysis: Calculated (%) for C16H10FN3OS: C, 61.72; H, 3.23; N, 13.50. S,

10.29; Found: C, 61.68; H, 3.19; N, 13.40. S, 10.26; LC-MS m/z: 311.33 ; M.P: 305-

308 0C.

3-Amino-N'-[(E)-(3-nitrohenyl)methylidene]-1-benzothiophene-2-carbohydrazide

(4a-e):

A mixture of compound 2 (0.176g, 0.001mol) and 3-nitro benzaldehyde (0.120g,

0.121ml 0.001mol) was dissolved in alcohol (20 ml) containing catalytic quantity of

acetic acid. The mixture was refluxed on water bath 8 hours. The reaction mixture was

cooled to room temperature and poured into crushed ice. The solid thus obtained was

filtered, washed with water, dried and recrystallized from alcohol. Similarly, 4b-e were

prepared by using appropriately substituted benzaldehydes.

S

NH2

NH

O

N

N+

O-

O


): 3452, 3383 (NH2), 1647 (C=O),

1606 (C=N); 1

H-NMR: (400 MHz: DMSO-d6) δ (ppm): 10.10 (1H, s, NH), 8.32–7.41

(9H, m, Ar-H), 4.95 (2H, s, NH2); Elemental analysis: Calculated (%) for

Chapter - IV

Page No. 98

C16H12N4O3S: C, 56.46; H, 3.55; N, 16.46; S, 9.42 Found: C, 56.43. H, 3.51. N,

16.43.S, 9.38; LC-MS m/z: 340 ; M.P: 266-269 0C.

3-Amino-N'-[(Z)-(4-chlorophenyl)methylidene]-1-benzothiophene-2-carbohy

drazide (4b):

S

NH2

NH

O

N

Cl


): 3469, 3375 (NH2), 1640 (C=O),

1620 (C=N); 1


(9H, m, Ar-H), 4.73 (2H, s, NH2); Elemental analysis: Calculated (%) for

C16H12ClN3OS: C, 58.26; H, 3.66; N, 12.74; S, 9.72; Found: C, 58.23. H, 3.62. N,

12.70. S, 9.68; LC-MS m/z: 329.80 ; M.P: 274-277 0C.

3-Amino-N'-[(Z)-(3-hydroxyphenyl)methylidene]-1-benzothiophene-2-carbohy

drazide (4c):

S

NH2

NH

O

N

OH


): 3473, 3378 (NH2), 1643 (C=O),

1622 (C=N); 1


(9H, m, Ar-H), 6.25 (1H, s, OH), 4.73 (2H, s, NH2); Elemental analysis: Calculated (%)

for C16H13N3O2S: C, 61.72. H, 4.20. N, 13.49. S, 10.30; Found: C, 61.68. H, 4.17. N,

13.45. S, 10.27; LC-MS m/z: 311.35 ; M.P: 258-261 0C.

Chapter - IV

Page No. 99

3-Amino-N'-[(Z)-(3-aminophenyl)methylidene]-1-benzothiophene-2-carbohy

drazide (4d):

S

NH2

NH

O

N

NH2


): 3480, 3382 (NH2), 1649 (C=O),

1626 (C=N); 1


(9H, m, Ar-H), 5.95 (2H, s, NH2), 4.53 (2H, s, NH2); Elemental analysis: Calculated

(%) for C16H14N4OS: C, 61.91. H, 4.54. N, 18.00. S, 10.33; Found: C, 61.87. H, 4.51.

N, 17.95. S, 10.28; LC-MS m/z: 310.37 ; M.P: 260-263 0C.

3-Amino-N'-[(Z)-(4-methoxyphenyl)methylidene]-1-benzothiophene-2-carbohydra

zide (4e):

S

NH2

NH

O

N

O


): 3485, 3384 (NH2), 1651 (C=O),

1629 (C=N); 1


(9H, m, Ar-H), 4.66 (2H, s, NH2), 3.76 (3H, s, OCH3); Elemental analysis: Calculated

(%) for C17H15N3O2S: C, 62.75. H, 4.64. N, 12.79. S, 9.85; Found: C, 63.65. H, 5.01.

N, 12.35. S, 9.39; LC-MS m/z: 325.38 ; M.P: 258-261 0C.

1-[5-(3-Amino-1-benzothiophen-2-yl)-2-(3-nitrophenyl)-1,3,4-oxadiazol-3(2H)-

yl]ethanone (5a-e):

A mixture of 4a (0.264g, 0.001mol) and acetic anhydride (10ml) was refluxed until the

completion of reaction. The resulting solution was cooled to room temperature and

Chapter - IV

Page No. 100

poured into ice-cold water. The solid thus separated was filter, dried and recrystallized

from alcohol to give compound 6a. Similarly, the compounds 5b-f were also prepared.

1-[5-(3-Amino-1-benzothiophen-2-yl)-2-(3-nitrophenyl)-1,3,4-oxadiazol-3(2H)-

yl]ethanone (5a):

S

NH2

N

O

N

O

N+

O-

O


): 3482, 3392 (NH2), 1693 (C=O),

1625 (C=N); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 8.27–7.36 (8H, m, Ar-H), 6.59

(1H, s), 4.85 (2H, s, NH2), 2.05 (3H, CH3); Elemental analysis: Calculated (%) for

C18H14N4O4S; C, 56.54. H, 3.69. N, 14.65. S, 8.38; Found: C, 56.51. H, 3.66. N, 14.62.

S, 8.35; LC-MS m/z: 382 ; M.P: 352-355 0C.

1-[5-(3-Amino-1-benzothiophen-2-yl)-2-(4-chlorophenyl)-1,3,4-oxadiazol-3(2H)-

yl]ethanone (5b):

S

NH2

N

O

N

O

Cl


): 3464, 3386 (NH2), 1687 (C=N),


(1H, s), 4.74 (2H, s, NH2), 2.09 (3H, CH3); Elemental analysis: Calculated (%) for

C18H14ClN3O2S; C, 58.14. H, 3.79. N, 11.30. S, 8.62; Found: C, 58.09; H, 3.75; N,

11.27. S, 8.59; LC-MS m/z: 371.84 ; M.P: 320-323 0C.

Chapter - IV

Page No. 101

1-[5-(3-Amino-1-benzothiophen-2-yl)-2-(3-hydroxyphenyl)-1,3,4-oxadiazol-3(2H)-

yl]ethanone (5c):

S

NH2

N

O

N

O

OH


): 3475, 3389 (NH2), 1695 (C=O),


(1H, s), 6.48 (1H, s, OH), 4.79 (2H, s, NH2), 2.09 (3H, CH3); Elemental analysis:

Calculated (%) for C18H15N3O3S; C, 61.17. H, 4.27. N, 11.89. S, 9.07; Found: C, 61.13.

H, 4.23. N, 11.86. S, 9.03; LC-MS m/z: 353.39 ; M.P: 331-334 0C.

1-[5-(3-Amino-1-benzothiophen-2-yl)-2-(4-aminophenyl)-1,3,4-oxadiazol-3(2H)-

yl]ethanone (5d):

S

NH2

N

O

N

O

NH2


): 3467, 3392 (NH2), 1697 (C=O),


(1H, s), 6.09 (2H, s, NH2), 4.95 (2H, s, NH2), 2.06 (3H, CH3); Elemental analysis:

Calculated (%) for C18H16N4O2S; C, 61.34. H, 4.57. N, 15.89. S, 9.09; Found: C, 61.30;

H, 4.53. N, 15.86. S, 9.05; LC-MS m/z: 352.41 ; M.P: 314-317 0C.

Chapter - IV

Page No. 102

1-[5-(3-Amino-1-benzothiophen-2-yl)-2-(4-methoxyphenyl)-1,3,4-oxadiazol-3(2H)-

yl]ethanone (5e):

S

NH2

N

O

N

O

O


): 3495, 3398 (NH2), 1705 (C=O),


(1H, s), 4.75 (2H, s, NH2), 3.85 (3H, OMe), 2.05 (3H, CH3); Elemental analysis:

Calculated (%) for C19H17N3O3S; C, 62.96. H, 4.27. N, 11.43. S, 8.72; Found: C, 62.93.

H, 4.24. N, 11.39. S, 8.65; LC-MS m/z: 367.42 ; M.P: 298-301 0C.

3-Amino-N'-[(1Z)-1-(4-chlorophenyl)ethylidene]-1-benzothiophene-2-carbohy

drazide (6a-e):

The compound 2 was refluxed with various acetophenone in alcohol containing

catalytic amount of glacial acetic acid on water bath to produce solid 3-amino-N'-[(1E)-

1-(4-flurophenyl)ethylidene]-1-benzothiophene-2-carbohydrazide 6a.

3-Amino-N'-[(1Z)-1-(4-chlorophenyl)ethylidene]-1-benzothiophene-2-carbohydraz

ide (6a):

S

NH2

NH

O

N

Cl


): 3471, 3369 (NH2), 3187 (NH)

1652 (C=O); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 9.21 (1H, NH), 8.22–6.85 (8H,

m, Ar-H), 4.59 (2H, s, NH2), 2.40 (3H, CH3); Elemental analysis: Calculated (%) for

Chapter - IV

Page No. 103

C17H14ClN3OS: C, 59.38. H, 4.10. N, 12.22. S, 9.32; Found: C, 59.35. H, 4.06. N,

12.15. S, 9.28; LC-MS m/z: 343.83 ; M.P: 265-268 0C.

3-Amino-N'-[(1Z)-1-(4-methoxyphenyl)ethylidene]-1-benzothiophene-2-carbohy

drazide (6b):

S

NH2

NH

O

N

O


): 3483, 3378 (NH2), 3197 (NH)


m, Ar-H), 4.73 (2H, s, NH2), 3.86 (3H, OMe) 2.40 (3H, CH3); Elemental analysis:

Calculated (%) for C18H17N3O2S: C, 63.69. H, 5.04. N, 12.38. S, 9.44; Found: C, 63.65.

H, 5.01. N, 12.35. S, 9.39; LC-MS m/z: 339.41 ; M.P: 281-284 0C.

3-Amino-N'-[(1E)-1-(4-hydroxyphenyl)ethylidene]-1-benzothiophene-2-carbohydr

azide (6c):

S

NH2

NH

O

N

OH


): 3480, 3376 (NH2), 3192 (NH)


m, Ar-H), 5.15 (1H, OH), 4.65 (2H, s, NH2), 2.48 (3H, CH3); Elemental analysis:


H, 4.61. N, 12.85. S, 9.79; LC-MS m/z: 325.38 ; M.P: 275-278 0C.

Chapter - IV

Page No. 104

3-Amino-N'-[(1Z)-1-(4-aminophenyl)ethylidene]-1-benzothiophene-2-carbohydraz

ide (6d):

S

NH2

NH

O

N

NH2


): 3478, 3373 (NH2), 3189 (NH)

1657 (C=O); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 9.12 (1H, NH2), 8.10–6.70

(8H, m, Ar-H), 5.61 (2H, s, NH2), 4.95 (2H, NH2) 2.39 (3H, CH3); Elemental analysis:

Calculated (%) for C17H16N4OS: C, 62.94. H, 4.97. N, 17.27. S, 9.88; Found: C, 62.91.

H, 4.93. N, 17.22. S, 9.85; LC-MS m/z: 324.40 ; M.P: 281-283 0C.

3-Amino-N'-[(1Z)-1-(3-nitrophenyl)ethylidene]-1-benzothiophene-2-carbohydra

zide (6e):

S

NH2

NH

O

N

N+

O-

O


): 3474, 3371 (NH2), 3188 (NH)

1655 (C=O); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 9.30 (1H, NH2), 8.32–6.90

(8H, m, Ar-H), 4.95 (2H, s, NH2), 2.52 (3H, CH3); Elemental analysis: Calculated (%)

for C17H14N4O3S: C, 57.61. H, 3.98. N, 15.80. S, 9.04; Found: C, 57.58. H, 3.94. N,

15.75. S, 9.01; LC-MS m/z: 354.38 ; M.P: 275-278 0C.

1-[5-(3-Amino-1-benzothiophen-2-yl)-2-(4-chlorophenyl)-2-methyl-1,3,4-oxadiazol-

3(2H)-yl]ethanone (7a-e):

A mixture of 6a (0.278g, 0.001mol) and acetic anhydride (10ml) was refluxed until the

completion of reaction as monitored by TLC. The resulting solution was cooled to

Chapter - IV

Page No. 105

room temperature and poured into ice-cold water. The solid thus separated was filtered,

dried and recrystallized from alcohol to give 7a. Similar procedure was adopted for the

synthesis of the compounds 7b-e.

S

NH2

N

O

N

O

Cl


): 3472, 3388 (NH2), 1685 (C=O);

1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 8.28–7.36 (8H, m, Ar-H), 4.68 (2H, s, NH2),

2.21 (3H, CH3), 1.70 (3H, s, CH3); Elemental analysis: Calculated (%) for

C19H16ClN3O2S; C, 59.13; H, 4.17; N, 10.89. S, 8.31; Found: C, 59.08; H, 4.13; N,

10.84. S, 8.28; LC-MS m/z: 386 ; M.P: 285-288 0C.

1-[5-(3-Amino-1-benzothiophen-2-yl)-2-(4-methoxyphenyl)-2-methyl-1,3,4-oxa

diazol-3(2H)-yl]ethanone.(7b):

S

NH2

N

O

N

O

O


): 3495, 3394 (NH2), 1697 (C=O);

1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 8.38–7.41 (8H, m, Ar-H), 4.78 (2H, s,

NH2),3.81 (3H, s), 2.28 (3H, CH3), 1.73 (3H, s, CH3); Elemental analysis: Calculated

(%) for C20H19N3O3S; C, 62.97. H, 5.02. N, 11.01. S, 8.40; Found: C, 62.91. H, 4.98.

N, 10.98. S, 8.36; LC-MS m/z: 381.44 ; M.P: 316-319 0C.

Chapter - IV

Page No. 106

1-[5-(3-Amino-1-benzothiophen-2-yl)-2-(4-hydroxyphenyl)-2-methyl-1,3,4-oxa

diazol-3(2H)-yl]ethanone (7c):

S

NH2

N

O

N

O

OH


): 3487, 3391 (NH2), 1692 (C=O);

1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 8.05–6.65 (8H, m, Ar-H), 5.55 (1H, OH),

4.86 (2H, s, NH2), 2.02 (3H, CH3), 1.89 (3H, s, CH3); Elemental analysis: Calculated

(%) for C19H17N3O3S; C, 62.96. H, 4.27. N, 11.43. S, 8.72; Found: C, 62.92. H, 4.25.

N, 11.40. S, 8.68; LC-MS m/z: 367.42 ; M.P: 328-331 0C.

1-[5-(3-Amino-1-benzothiophen-2-yl)-2-(4-aminophenyl)-2-methyl-1,3,4-oxadiazol-

3(2H)-yl]ethanone (7d):

S

NH2

N

O

N

O

NH2


): 3481, 3386 (NH2), 1689 (C=O);


4.80 (2H, NH2), 2.10 (3H, CH3), 1.80 (3H, s, CH3); Elemental analysis: Calculated (%)

for C19H18N4O2S; C, 62.27. H, 4.95. N, 15.28. S, 8.75; Found: C, 62.23; H, 4.91. N,

15.53. S, 8.71; LC-MS m/z: 366.43; M.P : 300-303 0C.

Chapter - IV

Page No. 107

1-[5-(3-Amino-1-benzothiophen-2-yl)-2-methyl-2-(3-nitrophenyl)-1,3,4-oxadiazol-

3(2H)-yl]ethanone (7e):

S

NH2

N

O

N

O

N+

O-

O


): 3476, 3389 (NH2), 1687 (C=O);


2.10 (3H, CH3), 1.90 (3H, s, CH3); Elemental analysis: Calculated (%) for

C19H16N4O4S; C, 57.56. H, 4.06. N, 14.13. S, 8.08; Found: C, 57.52. H, 4.02. N, 14.09.

S, 8.05 ; LC-MS m/z: 396.41 ; M.P: 319-322 0C.

Chapter - IV

Page No. 108

REFERENCE

[1] K. Ohmoto, T. Yamamoto, T. Horiuchi, H. Imanishi, Y. Odagaki, K. Kawabata,

T. Sekioka, Y. Hirota, S. Matsuoka, H. Nakai, M. Toda, J.C. Cheronis, L.W.

Spruce, A. Gyorkos, M. Wieczorek, J. Med. Chem., 2000, 43, 4927-4929.

[2] M. Ono, M. Haratake, H. Saji, M. Nakayama, Bioorg. Med. Chem., 2008, 16,

6867-6872.

[3] J.E. Ladbury, G. Klebe, E. Freire, Nat. Rev. Drug Discovery., 2010, 9, 23-27.

[4] G.A. Patani, E.J. LaVoie, Chem. Rev., 1996, 96, 3147-3176.

[5] Mohd Rashid, Asif Husain, Ravinesh Mishra, Eur J. Med. Chem., 2012, 54,

855-866.

[6] Zheng Li & Xicum Wang. Indian Journal of Chemistry., 2003, 42B, 941.

[7] N.G. Vazquez, G.M.M. Salinas, Z.V.D. Fajardo, Bio.Med. Chem., 2007, 15(16),

5502.

[8] H. Liszkieicz, M.W. Kowalska, J. Wietrzyk, A. Opolski, Indian J. Chem., 2003,

42B, 2846.

[9] B. Song, L. Jin, J. Chen, Z. Chen, S. Yang, Q. Li, D. Ho, R. Xu, Bioorg. Med.

Chem. Lett., 2006, 16(19), 5036.

[10] M.A. Abu-Zaied, E.M. El-Telbani, G.H. Elgemeie, G.A.M. Nawwar, Eur. J.

Med. Chem., 2011, 46, 229-235.

[11] Q.Z. Zheng, X.M. Zhang, Y. Xu, K. Cheng, Q.C. Jiao, H.L. Zhu, Bioorg. Med.

Chem., 2010, 18, 7836–7841.

[12] R.R. Somani, P.Y. Shirodkar, V.J. Kadam, Lett.Drug Des. Discov., 2008, 5,

364-368.

[13] V. Ravichandran, S. Shalini, K. Sundram, A.D. Sokkalingam, Eur. J. Med.

Chem., 2010, 45, 2791-2797.

[14] W.A. El-Sayed, F.A. El-Essawy, O.M. Ali, B.S. Nasr, M.M. Abdalla, A.A.H.

Abdel-Rahman, Naturforsch., 2009, 64, 773–778.

[15] M. Saitoh, J. Kunitomo, E. Kimura, Y. Hayase, H. Kobayashi, N. Uchiyama, T.

Kawamoto, T. Tanaka, C.D. Mol, D.R. Dougan, G.S. Textor, G.P. Snell, F.

Itoh, Bio org. Med. Chem., 2009, 17, 2017–2029.

[16] M.T.H. Khan, M.I. Choudhary, K.M. Khan, M. Rani, R. Attaur, Bio org. Med.

Chem., 2005, 13, 3385–3395.

Chapter - IV

Page No. 109

[17] Y.C Zhu, D.H. He, Z.R. Yang, Spectroc.Acta Pt. A-Molec. Biomolec. Spectr.,

2009, 72, 417-420.

[18] M.A. Gouda, M.A. Berghot, G.E. Abd El-Ghani, European journal of Elsevier.,

2010.

[19] I.C.F.R. Ferreira, R.C. Calhelha, L.M. Estevinho, Bioorganic & medicinal.,

2004.

[20] V.A Jagtap, Y.S. Agasimundin, journal of Pharmaceutical Research., 2011,

4(2), 378-379.

[21] R.V. Patel, J.K. Patel, P. Kumari, Wiley Online Library., 2012.

[22] J. LI, K. Gao, N. LV, EP Patent., 2011, 2,311, 828,

[23] D.A. Kennedy, L.A. Summers, J. Heterocycl. Chem., 1981, 409, 39-41.

[24] H.I. Yale, K.J. Losee, Med. Chem., 1966, 9, 478-480.

[25] J.J. Piala, H.L. Yale, Chem. Abstr., 1964, 61, 8317-8319.

[26] S. Vardan, S. Mookherjee, R Eich Clin Pharm Ther., 1983, 34, 290.

[27] R. Schlecker, P.C. Thieme, Tetrahedron., 1988, 44, 3289.

[28] M. Ogata, H. Atobe, H. Kushida, K. Yamamoto, J Antibiot., 1971, 24, 443.

[29] B.A. Johns, PCT Int Appl WO., 2004, 101512.

[30] M. Amir, K. Shikha, Eur J Med Chem., 2004, 39, 535.

[31] A. Almasirad, S.A Tabatabai, M. Faizi, A. Kebriaeezadeh, Bioorg Med Chem

Lett., 2004, 14, 6057.

[32] H.A. Rajapakse, H. Zhu, M.B. Young, B.T. Mott, Tetrahedron Lett., 2006, 47,

4827.

33] B.N. Goswami., J.C.S. Kataky, J.N. Baruash, J. Heterocycl. Chem., 1984, 21,

205-208.

34] M.M. Hamad., S.A. Said, Y.M. El-Ekyabi, Monatsh. Chem., 1996, 127, 549-

555.

35] U. Hiremath, C. Yelamaggad, B. Badmal, G. Puranik, J. Chem. Res.,1994, 12,

502-503.

36] B.S. Holla, K.N. Poojary, B. Kalluraya., P.V. Gowda, Indian J.Heterocycl.

Chem., 1996, 5, 273-276.

Chapter - IV

Page No. 110

37] B.S. Vashi, D.S. Mehta, V.H. Shah, Indian J. Chem. Sect. B., 1996, 35, 111-

115.

38] Asif Husain et al, Indian Journal of Heterocyclic Chemistry., 2008, 17, 265-

266.

39] S.R. Dhol et al, Indian Journal of Heterocyclic Chemistry., 2005, 15, 63-64.

40] Pinaki Sengupta & et al. Indian Journal of Chemistry., 2008, 47B, 460-462.

[41] Mohd Amir and Kumar Shikha, Eur. J. Med. Chem., 2004, 39, 535.

[42] V. Padmavathi, A.V. Nagendra Mohan, P. Thriveni and A. Shazia, Eur. J. Med.

Chem., 2008, 20, 1.

[43] Mahmud Tareq Hassan Khan, Muhammad Iqbal Choudhary, Khalid

Mohammed Khan, Mubeen Rani and Atta-ur-Rahman, Bioorg. Med. Chem.,

2005, 13, 3385.

[44] Gabriel Navarrete, Gloria Marıa, Molina-Salinas, Zetel Vahi, Duarte-Fajardo,

Javier Vargas-Villarreal, Samuel Estrada-Soto, Francisco Gonzalez, Emanuel

Hernandez-Nunza and Salvador Said-Fernandez, Bioorg. Med. Chem., 2007, 15,

5502.

[45] C. Chen, C.H. Senanayake, T.J. Bill, R.D. Larsen, T.R. Veshoeven and P.J.

Reider, J. Org. Chem., 1994, 59, 3738.

[46] J. Saunders, M. Cassidy, S.B. Freedman, E.A. Harley, L.L. Iversen, C. Kneen,

A.M. Macleod, K.J. Merchant, R.J. Snow and R. Baker, J. Med.Chem., 1990,

33, 1128.

[47] C.J. Swain, R. Baker, C. Kneen, J. Moseley, J. Saunders, E.M. Seward, G.

Stevenson, M. Beer, J. Stanton, and K. Walting., J. Med. Chem., 1991, 34, 140.

[48] T. Ladduwahetty, R. Baker, M.A. Cascieri, M.S. Chambers, K. Haworth, L.E.

Keown, D.E. Maclntyre, J.M. Metzer, S. Owen, W. Rycroft, S. Sadowski, E.M.

Seward, S.L. Shepheard, C.J. Swain, F.D. Tattersall, A.P. Watt, D.W.

Williamson and R.J. Hargreaves, J. Med. Chem., 1996, 39, 2907.

[49] G.D. Diana, D.L. Volkots, T.J. Nitz, T.R. Baily, M.A. Long, N. Vesico, A.

Aldous, D.C. Pevear and F.J. Dukto., J. Med. Chem., 1994, 37, 2421.

[50] F.A. Omar, N.M. Mahfouz and M.A. Rahman, Eur. J. Med. Chem., 1996, 31,

819.

[51] K. Mogilaiah, C.D. Srinivasa, R.R. Babu, Ind J Chem., 2001, 40B, 43-48.

[52] H.P. Shah, B.R. Shah, J.J. Bhatt, N.C. Desai, P.B. Trivedi and N.K. Undavia,

Ind J Chem., 1998, 37B, 180-82.

Chapter - IV

Page No. 111

53] S.P. Hiremath, V.N. Sonar, K.R. Sekhar & M.G. Purohit, Indian J Chem., 1989,

28B, 626.

54] S.P. Hiremath, N.N. Goudar, Ind. J. Chem., 1982, 21B, 321-324.

55] J.S. Biradar, S.Y. Manjunath, Ind J Chem., 2004, 43B.

56] R.D. Patil, J.S. Biradar, Indian Journal of Chemistry., 1999.

57] J.A. Jole, K. Mills, Heterocyclic Chemistry, 4th eds, Blackwell, 2004.

58] S.F. Macaev, G. Rusu, A. Gudima, Bio. Org. Med. Chem., 2005, 13, 4842-4850.

59] M. Farah, A. Pilotti, Drug Discovery Today, 2006, 11(3-4), 165-174.

60] N. Soni, J.P. Barthwal, T.K. Gupta, Indian Drugs., 1982, 23-26.

61] X.P. Hui, C. Chang-Hu, Z.Y. Zhang, Ind. J. Chem., 2000, 41B, 2176-2179.

62] T.P. Dabhi, V.H. Shah, A.R. Parikh, Indian Drugs., 1992, 54, 98-154.

63] J.A. Jole, K. Mills, Heterocyclic Chemistry, 4th ed, Blackwell, 2004.

64] S. Guniz Kucukguzel, Ilkay Kucukguzel, Esar Taror, Sevim Rollas, Fikrettin

Sachin, Medine Gulluce, Eur J Med Chem., 2007, 42, 893-901.

65] R. Alan, F.R. Katritzky, W. Charles, Comprehensive Heterocyclic Chemistry II,

1st ed. UK, Pergamon., 1996.

66] A. Almasirad, A. Sayyed, N. Mehrabi, M. Fazi, A. Shafie, A. Dalvanandi et al.,

Bioorg and Med chem letter., 2004,14 (24), 6057-59.

67] S.C. Bennur, M.B. Talwar, S.R. Desai Y.S. Sommanavar, S.C. Marihal et al.,

Indian J of Heterocycl Chem., 1996, 5, 215-18.

68] F.A. Omar, N.M. Manfouz, M.A. Rhaman, Eur j med chem., 1996, 31, 819-25.

69] Mymoona Akhter, Asif Husain, Bismillah Azad, Modh Ajmal, Bioorg.Med

Chem., 2008, 16, 3632-40.

70] V.R. Kusukuntla, G. Sabitha and R.A.V. Ssubba, Ind J Chem., 1998, 37B, 697-

99.

71] N.P. Shetgiri, B.K. Nayak, Ind J Chem., 2005, 44B, 1267-72.

72] H.B. Shivarama, P.K. Narayana, B.K. Subrahmanya, A. Mithun and P. Boja,

Ind J Chem., 2005 ,44B, 1669-73.

73] V.F. Priya, K. Balakrishna, Ind J Chem., 2005, 44B, 1456-59.

CHAPTER - V

An overview on synthesis of benzothiophene substituted

azetidinone and thiazolidinone derivatives.

Chapter-V

Page No. 112

INTRODUCTION

Since the advent of penicillin, the β-lactam antibiotics have been the subject of

much discussion and investigation, within the scientific sectors. The primary biological

targets of the β-lactam antibacterial drugs are the penicillin binding proteins, a group of

transpeptidases anchored within the bacterial cellular membrane, which mediate the

final step of cell wall biosynthesis1. The chemistry of β-lactams has taken an important

place in organic chemistry since the discovery of Penicillin by Sir Alexander Fleming

in 1928 and shortly thereafter cephalosporin, which were both used as successful

antibiotics. Even now, the research in this area is stimulated because of development of

bacterial resistance to widely used antibiotics of this type. There is a need for

functionalized β-lactams or for new active principles in β-lactam series. Apart from

antibiotic activity β-lactam also possess cholesterol inhibition, antithrombotic, antiviral

and antifungal activities.

The extensive use of common β-lactam antibiotics such as penicillins and

cephalosporin’s in medicine has resulted in an increasing number of resistant strains of

bacteria through mutation and β-lactamase gene transfer. Additional impetus for

research efforts on β-lactam chemistry has been provided by the introduction of the β-

lactam synthon method, a term coined by Ojima 20 years ago, according to which 2-

azetidinones can be employed as useful intermediates in organic synthesis. The cyclic

2-azetidinone skeleton has been extensively used as a template on which to build the

heterocyclic structure fused to the four membered rings, using the chirality and

fictionalization of the β-lactam nucleus as a stereo controlling element. The 2-

azetidinone (β -lactams) ring is a common structural feature of a number of broad

spectrum β-lactam antibiotics including penicillins 1, cephalosporins 2, carbapenems 3,

nocardicin and monobactams, which have been widely used as chemotherapeutic

Chapter-V

Page No. 113

agents to treat bacterial infection and microbial diseases2,3

. These molecules operate by

forming a covalent adducts with membrane bound bacterial transpeptidases which are

also known as penicillin binding proteins (PBPs) and they are involved in the

biosynthesis of cell wall4. These mechanism-based inhibitors prevent the construction

of cell wall and eventually lead to cell lysis and death. Moreover, due to their β-

lactamase inhibitory action 2-azetidinones based heterocycles represent an attractive

target of contemporary organic synthesis5.

R N

S CH3

CH3

O

NHO H

COOH

1

N

O

H

COOH

S

R

OH

H

2

N

S

O OH

R1

O

NHR

2

O

H

3

N

O

OH

O OH

NH

NOH

OOH

O

NH2

4

A β-lactam (beta-lactam) ring is a four-membered lactam6 (A lactam is a cyclic

amide). It is named as such, because the nitrogen atom is attached to the β-carbon

relative to the carbonyl. The simplest β-lactam possible is 2-azetidinone. β-lactam came

to be a generic descriptor for penicillin family. The ring ultimately proved to be the

main component of the pharmacophore. Therefore, the term possesses medicinal as

well as chemical significance7-10

. The recent and the advanced increase in both the

spectrum of β–lactam antibiotics and the number of the known producing organisms

are due to the development of new and more sensitive screening techniques. Further

progress had been added by continuous synthetic derivatization to that monocyclic β-

lactam compounds11-17

.

http://en.wikipedia.org/wiki/Lactam

http://en.wikipedia.org/wiki/Amide

Chapter-V

Page No. 114

The first synthetic β-lactam was prepared by Hermann Staudinger in 1907 by

reaction of the Schiff base of aniline and benzaldehyde with diphenylketene18,19

in a

[2+2] cycloaddition up until 1970, most β-lactam research was concerned with the

penicillin and cephalosporin groups, but since then a wide variety of structures have

been described20-26

.

Azetidinones has served an important and highly successful role in the

pharmaceutical industry in recent years. And renewed interest has been focused on the

synthesis and modification of β-lactam ring to obtain compounds with diverse

pharmacological activities such activities include antimicrobial27

, anti-tubercular28

,

carbonic anhydrase inhibitors29

, local anaesthatics30

, anti-inflammatory31

,

anthelmintic32

, anticonvulsant33

, hypoglycemic agents activity34

. The β-lactams also

serve as synthons for many biologically important classes of organic compounds35.

Due

to this, the investigation of chemistry and biology of these compounds continue to

appeal the synthetic and medicinal organic chemists.

In search for new biodynamic potent molecule, it was thought worthwhile to

incorporate some additional heterocyclic moieties in the β-lactam nucleus and study

their biological and pharmacological activity36-46

. The review of literature reveal

prompted us to synthesize substituted targeted azetidinones

Ajay Bagherwal et al, reported azetidinones 5 were synthesized and screened for

their anti-bacterial and anti-fungal activities47

.

NHNH

N

R

Cl

O

O

5

http://en.wikipedia.org/wiki/Hermann_Staudinger

http://en.wikipedia.org/wiki/Schiff_base

http://en.wikipedia.org/wiki/Aniline

http://en.wikipedia.org/wiki/Benzaldehyde

http://en.wikipedia.org/wiki/Diphenylketene

http://en.wikipedia.org/wiki/Cycloaddition

http://en.wikipedia.org/wiki/Penicillin

http://en.wikipedia.org/wiki/Cephalosporin

Chapter-V

Page No. 115

Yogesh Rokade et al, reported azetidinone derivatives 6 were synthesized from -

naphthol and screened for their anti-bacterial and analgesic activities48

.

O

O

NHN

Cl

O

Ar6

Panwar et al, have synthesized 2-[3-chloro-2-(substituted phenyl)-4-azetidinon-3-

yl]-1,3,4-thiadiazino[6,5-b]indole 7 as prospective antimicrobial agents49

.

N

NN

S N

OCl

7

Ishwar K. Bhat et al, reported Azetidinones 8 were synthesized from p-anisidine

and evaluated for their anti-bacterial and anti-fungal activiti50

.

NH CH2

C NH

N

RCl

O

O

O 8

M.C. Sharma et al, reported 1-(nicotinylamino)-2 substituted azetidin 4-ones 9

and fungi and also anti-tubercular and anti-inflammatory activities51

N

NH N

O

Cl

RO

9

Srivastava and his coworkers synthesized 1-[5'-{(2-benzothiazolylthio)methyl}-

1,3,4-thiadiazol-2-yl]-4-(substituted phenyl)-3-chloro-2-oxoazetidine 10 as antimicro

bial and anthelmintic agents52-54

.

Chapter-V

Page No. 116

N

S

SS

N N

N

O

Cl

R10

Thiazolidinone, a saturated form of thiazole with carbonyl group on fourth

carbon, has been considered as a magic moiety (wonder nucleus) which posses almost

all types of biological activities. This diversity in the biological response profile has

attracted the attention of many researchers to explore this skeleton to its multiple

potential against several activities. The synthesis of thiazolidinone from thioglycolic

acid was first reported in the year 194755

. Present article is sincere attempt to review

chemistry, synthesis, spectral studies and applications of 4- thiazolidinone56-65.

There are numerous biologically active molecules which contain various heteroatom’s

such as nitrogen, sulphur and oxygen, always drawn the attention of chemist over the

years mainly because of their biological importance. Thiazolidinones are thiazolidine

derivatives and have an atom of sulfur at position 1, an atom of nitrogen at position 3

and a carbonyl group at position 2, 4, or 5. However, its derivatives belong to the most

frequently studied moieties66-72

and its presence in penicillin was the first recognition of

its occurrence in nature.

The 4-thiazolidinone scaffold is very versatile and have been subjected to

extensive study in the recent years has featured in a number of clinically used drugs.

The 4-thiazolidinone ring system is a core structure in various synthetic pharmaceutical

agents, displaying a broad spectrum of biological activities such as, antitubercular73

,

antibacterial74

, anti-HIV75

, anti-inflammatory76

, anti-mycobacterial77

, anti convulsant78

,

anti histaminic79

, anticancer80

, anti protocol81

and analgesic82

. Numerous reports have

appeared in the literature, which highlight their chemistry and pharmacological uses83-

95.

Chapter-V

Page No. 117

In 2009, Nagarjuna et al, have reported the synthesis certain substituted

thiazolidinones 11 and characterized for antimicrobial and analgesic activities96

.

N

S

NS

O

R

11

R=Cl, Br, NO2

In 2009, Zhang et al, reported the synthesis of 2-substituted thiazolidinones 12

along with some pyrimidino substituted thiazolidinone and their derivatives as a

potential antiparasytic97

.

SN

NH O

O

R

O

O

OAc

OAc

12

R=p-NO2, C6H4. pCH3 C6H4, p-Cl, C6H4

In 2005, Liu et al, report the synthesis imino substituted thiazolidinones 13 and

evaluated their antifungal activity98,99

.

S

N

N

S

O

NH

Ar-

13

In 2009, Rawal et al, report the synthesis of pyrimidine substituted

thiazolidinones 14 as HIV-1 inhibitors100

.

Chapter-V

Page No. 118

N

S

NN

O

R

R1

14 R=H, F, Cl. R

1=Me, OMe, OH

In 2006, Kucukguzel et al, reported synthesis of some substituted thiazolidinon

es as 15 antimicrobial and antiviral activities101,102

.

F

F

NH

OH

O

NS

O

R

15

R=H, F, Cl. C6H5, OH

PRESENT WORK

Literature survey revealed that when one biodynamic heterocyclic system was

coupled with another, a molecule with enhanced biological activities was produced. In

view of these reports, under present investigation, it was planned prepare bridged

biheterocycles wherein biologically interesting benzothiophene moiety has been linked

to other heterocycles with a goal obtaining novel molecules endowed with increased

biological activities. The synthesis of all these compound is outlined in the following

scheme.

Chapter-V

Page No. 119

S

NH2

O

O

ClCOCH2Cl

S

O

O

NHCOCH2Cl

NH2CSNH2

ArCHO

SHCH2COOHClCOCH2Cl

1

2

3

4a-d

5a-d6a-d

S cheme - IV

S

O

O

NHN

S

NH2

S

O

O

NHN

S

N

R

S

O

O

NHN

S

N

R

O

Cl

S

O

O

NHN

S

N S

O

R


5a NH

O

6a

NH

O

5b

O

OO

O

6b

O

OO

O

5c O

O

6c

O

O

5d

O

N+

O-

O

6d

O

N+

O-

O

Chapter-V

Page No. 120

The starting material 3-amino-1-benzothiophene-2-corboxylate 1 was made to

react with chloroacetyl chloride to get a pure compound ethyl-3-(2-chloroacetamido)

benzo[b]thiophene-2-carboxylate 2.

S

NH2

O

O C2H5S

O

O C2H5

NHCOCH2Cl

ClCOCH2Cl

1 2

In order to synthesize benzothiophene substituted thiazole derivative, the

compound 2 was refluxed with thiourea, which undergo cyclisation to get targeted

product ethyl-3-(2-aminothiazol-4-ylamino)benzo[b]thiophene-2-carboxylate 3.

S

O

O C2H5

NHCOCH2Cl

2

NH2CSNH2

S

O

O C2H5

NH

N

S

NH2

3

Formation of compound 3 was confirmed by IR spectrum indicating the

presence of broad peak at 3426, 3320 cm-1

due to NH2 group, and at 3153 cm-1

due to

NH and 1671 cm-1

due to (C=O). The 1H NMR spectra of the same compound was

recorded in DMSO exhibited a singlet peak at δ 3.67 due to NH group, a multiplet in

the region between δ 8.15-7.48 corresponds to four aromatic proton, a singlet at δ 5.04

due to two protons of NH2. In addition, the structure of 3 was confirmed by mass

spectrum which showed formation of compound 3 indicated molecular ion peak at m/z

319.

In order to prepare Schiff bases, a mixture of compound 3 and different

substituted aromatic aldehydes were refluxed in methanol and catalytic amount of

glacial acetic acid was added. The progress of the reaction was monitored by TLC.

Chapter-V

Page No. 121

After the completion of the reaction, it was filtered, washed with water, dried and

purified by using suitable solvent to get ethyl-3-(2-((1H-indol-3-

yl)methyleneamino)thiazol-4-ylamino)benzo[b]thiophene-2-carboxylate 4a.

S

O

O C2H5

NH

N

S

NH2

ArCHO

Methanol/Acetic acid

4a-d3

S

NH

N

S

N

O

ONH

Schiff bases were made to cyclzed to get azitidinone derivatives, the compound

4a was allowed to react with chloroacetyl chloride in the presence of triethyl amine

which undergo cyclization to gave ethyl-3-(2-(3-chloro-2-(1H-indol-3-yl)-4-

oxoazetidin-1-yl)thiazol-4-ylamino)benzo[b]thiophene-2-carboxylate 5a. This was

confirmed spectral data.

4

S

O

OC2H5

NHN

S

N

O

Cl

NH5a-d

ClCOCH2Cl

S

NH

N

S

N

O

ONH

The compound 5a has shown peaks in its IR spectrum at 3380 and 3162 cm-1

corresponds to NH and NH groups respectively. C=O groups at 1703 and 1634 which

confirms IR spectrum. The 1H NMR spectra of the compound 5a exhibited singlet at δ

9.86 due to one proton of NH and a multiplet in the region between δ 8.0-7.1

corresponds to eight aromatic proton, a singlet at δ 3.4 due to one protons of NH. The

compound 5a exhibited molecular ion peak at m/z 523 in its mass spectrum, which

confirmed for its formation. The compounds 5b-d were prepared in a similar

methodology and confirmed by their spectral data.

Chapter-V

Page No. 122

To find out the pharmaceutical importance of thiazolidinone substituted

benzothiophene, a series of thiazolidinone derivatives 6a-d have been prepared by

refluxed compound 4 with thioglycolic acid in the presence of zinc chloride to get

ethyl-3-(2-(2-(1H-indol-3-yl)-4-oxothiazolidin-3-yl)thiazol-4-ylamino)benzo[b]thiophe

ne-2-carboxylate 6a.

S

NH

N

S

N

O

ONH

6a-d

4a-d

SHCH2COOH

S

NH N

S

N

S

O

NHO

O

The compound 6a has peaks in its IR spectrum at 3387 and 3175 cm-1

due to

NH groups and 1715 cm-1

is due to C=O of thiazolidinone ring. The 1H NMR spectra of

the compound 6a exhibited singlet at δ 10.50 due to one proton of NH and a multiplet

in the region between δ 8.11-5.12 corresponds to eleven aromatic proton, a singlet at δ

4.36 due to one protons of NH. The compound 6a exhibited molecular ion peak at m/z

520 in its mass spectrum, which confirmed for its formation. Similarly, the compounds

6b-d were prepared and confirmed by their spectral data.

S

NH

N

S

N

O

ONH

IR spectrum of 4a

S

NH

N

S

N

O

ONH

Mass spectrum of 4a

S

NH

N

S

N

O

ONH


S

O

O

NHN

S

N

O

Cl

NH

IR spectrum of 5a

S

O

O C2H5

NHN

S

N

O

Cl

NH


S

O

O C2H5

NHN

S

N

O

Cl

NH

Mass spectrum of 5a

S

NH N

S

N

S

O

NHO

O

IR spectrum of 6a

S

NH N

S

N

S

O

NHO

O


S

NH N

S

N

S

O

NHO

O

Mass spectrum of 6a

Chapter-V

Page No. 123

EXPERIMENTAL

Ethyl-3-(2-aminothiazol-4-ylamino)benzo[b]thiophene-2-carboxylate (3):

Thiourea (0.76g, 0.01mol) was added to compound 2 (2.97g, 0.01mol) in

ethanol 25ml. The reaction mixture was heated for 13 hours with occasional stirring.

Progress of reaction was monitored by TLC. After completion, excess of the solvent

removed by distillation. Residue obtained was poured into ice-cold water. Filtered,

dried and Purification with column chromatography by petroleum ether/ethyl acetate

8:2 gave compound 3.

S

O

O C2H5

NH

N

S

NH2


): 3426, 3320 (NH2), 3153 (NH)

1671 (C=O); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 8.15-7.48 (5H, m, Ar-H), 6.13

(1H, s), 5.04 (2H, bs, NH2), 4.39-4.34 (2H, q, J=7.2Hz), 3.67 (1H, s), 1.39-1.36 (3H, t,

J=7.2 Hz); Elemental analysis: Calculated (%) for C14H13N3O2S2: C, 52.64. H, 4.10. N,

13.55. S, 20.07; Found C, 52.60. H, 4.03. N, 12.49. S, 19.90; LC-MS m/z: 319 ; M.P:

226-229 0C.

Ethyl-3-(2-((1H-indol-3-yl)methyleneamino)thiazol-4-ylamino)benzo[b]thiophene-

2-carboxylate (4a):

To a solution of (0.319g, 0.01mol) of ethyl-3-(2-aminothiazol-4-

ylamino)benzo[b]thiophene-2-carboxylate in 25ml of methanol, (0.145g, 0.01mol) of

indole-3-carboxaldehyde was added. Catalytic amount of glacial acetic acid was added.

The reaction mixture was refluxed for 10-12 hours on water bath. After completion,

excess of solvent was distilled off. The reaction mixture was cooled and poured in to

crushed ice. Solid that obtained was filtered, washed with water, dried and purified

Chapter-V

Page No. 124

through column chromatography by using ethyl acetate and n-hexane.9:1 to get

compound 4.

S

NH

N

S

N

O

ONH


): 3383 (NH), 3146 (NH) 1681

(C=O); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 11.04 (1H, bs, NH), 8.60 (1H, s,),

8.12-7.14 (9H, m, Ar-H), 5.61 (1H, s), 4.31-4.26 (2H, q, J=7.2Hz), 3.54 (1H, s), 1.30-

1.28 (3H, t, J=7.2 Hz); Elemental analysis: Calculated (%) for C23H18N4O2S2: C, 61.86.

H, 4.06. N, 12.54. S, 14.36; Found C, 61.83. H, 4.02. N, 12.49. S, 14.32; LC-MS m/z:

446. ; M.P: 259-262 0C.

Ethyl-3-(2-(3,4,5-trimethoxybenzylideneamino)thiazol-4-ylamino)benzo[b]thio

phene-2-carboxylate (4b):

S

NH

N

S

N

O

O O

O

O


): 3359 (NH), 1605 (C=N), 1672

(C=O); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 8.45 (1H, s), 8.15-7.28 (6H, m, Ar-

H), 6.65 (1H, s) 5.19 (1H, bs), 4.37-4.32 (2H, q, J=7.2 Hz), 3.81 (9H, s), 1.31-1.29 (3H,

t, J=7.2 Hz); Elemental analysis: Calculated (%) for C24H23N3O5S2: C, 57.93. H, 4.65.

N, 8.44. S, 12.88; Found C, 57.89. H, 4.62. N, 8.40. S, 12.84; LC-MS m/z: 497.58;

M.P: 275-2780C.

Chapter-V

Page No. 125

Ethyl-3-(2-((tetrahydrofuran-3-yl)methyleneamino)thiazol-4-ylamino)benzothio

phene-2-carboxylate (4c):

S

NH

N

S

N

O

O

O


): 3366 (NH), 1618 (C=N), 1677

(C=O); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 8.15-7.23 (5H, m, Ar-H), 6.90 (1H,

s), 5.23 (1H, bs), 4.34-4.29 (2H, q, J=7.2 Hz), 3.90-3.70 (4H, m), 2.13-1.95 (3H, m),

1.28-1.25 (3H, t, J=7.2 Hz); Elemental analysis: Calculated (%) for C19H19N3O3S2: C,

56.83. H, 4.76. N, 10.46. S, 15.97; Found C, 56.79. H, 4.73. N, 10.42. S, 15.93; LC-MS

m/z: 401.50; M.P: 245-248 0C.

Ethyl-3-(2-((2-nitrobenzylideneamino)thiazol-4-ylamino)benzothiophene-2-carbo

xylate (4d):

S

NH

N

S

N

O

O

N+

O-

O


): 3360 (NH), 1601 (C=N), 1668


s), 5.43 (1H, bs), 4.39-4.33 (2H, q, J=7.2 Hz), 1.32-1.28 (3H, t, J=7.2 Hz); Elemental

analysis: Calculated (%) for C21H16N4O4S2: C, 55.74. H, 3.56. N, 12.38. S, 14.17;

Found C, 55.70. H, 3.53. N, 12.35. S, 14.14; LC-MS m/z: 452.50; M.P: 252-255 C.

Chapter-V

Page No. 126

Ethyl-3-(2-(3-chloro-2-(1H-indol-3-yl)-4-oxoazetidin-1-yl)thiazol-4-ylamino)benzo

[b]thiophene-2-carboxylate (5a):

A solution of compound 4 (0.446g 0.01mol) in dry dioxane 25ml, chloroacetyl

chloride (0.01mol) was added drop wise with constant stirring at 0-5C. and

triethylamine (0.01mol) was added to the reaction mixture. And it was refluxed for 6-8

hours. After completion, the excess of solvent distilled off. The resultant mixture was

poured in to crushed ice. The solid that obtained was filtered, washed with water, dried

and purified through suitable solvent,

S

O

O C2H5

NHN

S

N

O

Cl

NH


): 3380 (NH), 3162 (NH), 1703,

(C=O); 1H-NMR: (400 MHz: CDCL3) δ (ppm): 9.86 (1H, bs), 8.03-7.13 (8H, m, Ar-H),

6.30 (1H, s), 5.67-5.66 (2H, m) 5.08 (1H, s), 4.27-4.21 (2H, q, J=7.2 Hz), 3.40 (1H, s),

1.29-1.23 (3H, t, J=7.2 Hz); Elemental analysis: Calculated (%) for C25H19ClN4O3S2:

C, 57.41. H, 3.66. N, 10.71. S, 12.26; Found C, 57.38; H, 3.59. N, 10.68. S, 12.22.; LC-

MS m/z: 523. 525; M.P: 348-351 0C.

Ethyl-3-(2-(3-chloro-2-oxo-4-(3,4,5-dimethoxyphenyl)azetidin-1-yl)thiazol-4-ylami

no)benzo[b]thiophene-2-carboxylate (5b):

S

O

O C2H5

NHN

S

N

O

Cl

O

OO

Chapter-V

Page No. 127


): 3371 (NH), 1610 (C=N), 1692,

(C=O); 1H-NMR: (400 MHz: CDCL3) δ (ppm): 8.20-7.42 (4H, m, Ar-H), 7.21 (2H, s),

6.60 (1H, s), 5.40 (1H, s) 5.12-5.10 (2H, m), 4.18-4.14 (2H, q, J=7.2 Hz), 3.81 (9H, s),

1.17-1.14 (3H, t, J=7.2 Hz); Elemental analysis: Calculated (%) for C26H24ClN3O6S2:

C, 54.39. H, 4.21. N, 7.31. S, 11.17; Found: C, 54.36. H, 4.17. N, 7.28. S, 11.13 ; LC-

MS m/z:574. 576 ; M.P: 365-368 0C.

Ethyl-3-(2-(3-chloro-2-oxo-4-(tetrahydrofuran-3-yl)azetidine-1-yl)thiazol-4-yl

amino)benzo[b]thiophene-2-carboxylate (5c):

S

O

O C2H5

NHN

S

N

O

Cl

O


): 3376 (NH), 1621 (C=N), 1698

(C=O); 1H-NMR: (400 MHz: CDCL3) δ (ppm): 8.10-7.49 (5H, m), 6.85 (1H, s), 5.43

(1H, s) 5.21-5.19 (2H, m), 4.15-4.11 (2H, q, J=7.2 Hz), 3.91-3.72 (4H, m), 2.16-1.97

(3H, m), 1.16-1.13 (3H, t, J=7.2 Hz); Elemental analysis: Calculated (%) for

C21H20ClN3O4S2: C, 52.76; H, 4.21; N, 8.79. S, 13.41; Found: C, 52.73. H, 4.17. N,

8.76 S, 13.39; LC-MS m/z:477. 479; M.P: 385-389 0C.

Ethyl-3-(2-(3-chloro-2-(2-nitrophenyl)-4-oxoazetidin-1-yl)thiazol-4-ylamino)

benzo[b]thiophene-2-carboxylate (5d):

S

O

O C2H5

NHN

S

N

O

Cl

NO2


): 3368 (NH), 1608 (C=N), 1685

(C=O); 1H-NMR: (400 MHz: CDCL3) δ (ppm): 8.32-7.22 (8H, m, Ar-H), 6.66 (1H, s),

Chapter-V

Page No. 128

5.44 (1H, s) 5.22-5.20 (2H, m), 4.22-4.18 (2H, q, J=7.2 Hz), 1.22-1.18 (3H, t, J=7.2

Hz); Elemental analysis: Calculated (%) for C23H17ClN4O5S2: C, 52.22. H, 3.23. N,

10.59. S, 12.12 Found: C, 52.18; H, 3.20; N, 10.55. S, 12.08; LC-MS m/z: 528. 530;

M.P: 374-3770C.

Ethyl-3-(2-(2-(1H-indol-3-yl)-4-oxothiazolidin-3-yl)thiazol-4-ylamino)benzo[b]th

iophene-2-carboxylate (6a):

Thioglycolic acid (0.70ml, 0.01mol) was added to Schiff base 4 (0.446g,

0.01mol) in 25ml of dry dioxane. Catalytic amount of zinc chloride (1g) was added.

The reaction mixture was refluxed for 15 hours. The progress of the reaction monitored

by TLC. After the completion, reaction mixture was cooled and poured in to crushed

ice. Triturated with 10% sodium bicarbonate solution. Solid that obtained was filtered,

washed with water, dried and purified through column chromatography by using ethyl

acetate and n-hexane 8:2.

S

NH N

S

N

S

O

NHO

O


): 3387 (NH), 3175 (NH), 1715,

(C=O); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 10.50 (1H, bs), 8.11-7.48 (9H, m,

Ar-H), 6.47 (1H, s), 5.89 (1H, s) 5.12 (1H, bs), 4.36 (1H, s), 4.29-4.25 (2H, q,

J=7.2Hz), 3.42-3.34 (2H, m) 1.30-1.26 (3H, t, J=7.2 Hz); Elemental analysis:

Calculated (%) for C25H20N4O3S3: C, 57.74. H, 3.87. N, 10.77. S, 18.47; Found C,

57.71. H, 3.84. N, 10.72. S, 18.43; LC-MS m/z: 520; M.P: 363-367 0C.

Chapter-V

Page No. 129

Ethyl-3-(2-(4-oxo-2-(3,4,5-trimethoxyphenyl)thiazolidin-3-yl)thiazol-4-ylamino)

benzo[b]thiophene-2-carboxylate (6b):

S

NH N

S

O

O

N

SO

O

O

O


): 3376 (NH), 1613(C=N), 1697


s), 6.68 (1H, s),6.52 (1H, s) 5.23 (1H, bs), 4.25-4.19 (2H, q, J=7.2 Hz), 3.83 (9H, s),

3.85 (2H, m),1.24-1.20 (3H, t, J=7.2 Hz); Elemental analysis: Calculated (%) for

C26H25N3O6S3: C, 54.62. H, 4.40. N, 7.35. S, 16.82; Found C, 54.58. H, 4.36. N, 7.32.

S, 16.79; LC-MS m/z: 571.68; M.P: 353-358 0C.

Ethyl-3-(2-(4-oxo-2-(tetrahydrofuran-3-yl)thiazolidin-3-yl)thiazol-4-ylamino)

benzo[b]thiophene-2-carboxylate (6c):

S

NH N

S

O

O

N

SO

O


): 3380 (NH), 1628 (C=N), 1702

(C=O); 1H-NMR: (400 MHz: DMSO-d6) δ (ppm): 8.25-7.60 (5H, m), 6.65 (1H, s),

5.19 (1H, bs), 4.80 (1H, s), 4.29-4.24 (2H, q, J=7.2Hz), 3.90-3.60 (6H, m), 2.13-1.95

(3H, m), 1.29-1.26 (3H, t, J=7.2 Hz); Elemental analysis: Calculated (%) for

C21H21N3O4S3: C, 55.59. H, 4.45; N, 8.84. S, 8.83; Found C, 55.53. H, 4.38. N, 8.79. S,

8.80; LC-MS m/z: 475.60; M.P: 335-338 0C.

Chapter-V

Page No. 130

Ethyl-3-(2-(2-(2-nitrophenyl)-4-oxothiazolidin-3-yl)thiazol-4-ylamino)benzo[b]

thiophene-2-carboxylate (6d):

S

NH N

S

O

O

N

SO

NO2


): 3368 (NH), 1610 (C=N), 1693


s), 6.58 (1H, s) 5.29 (1H, bs), 4.22-4.18 (2H, q, J=7.2 Hz), 3.81 (2H, m),1.25-1.21 (3H,

t, J=7.2 Hz); Elemental analysis: Calculated (%) for C23H18N3O5S3: C, 52.45. H, 3.44.

N, 7.97. S, 18.26; Found C, 52.41; H, 3.40; N, 7.94. S, 18.22; LC-MS m/z: 526.60;

M.P: 310-3130C.

Chapter-V

Page No. 131

REFERENCES

[1] A. Benito and A. Pedro, Current medicinal chemistry., 2004, 11, 1921.

[2] C.D. Risi, G.P. Pollini, A.C. Veronese, and V. Bertolass, Tetrahedron Lett.,

1999 ,4, 6995.

[3] G.I. Georg and Ed, The organic Chemistry of β-lactams, VCH:New York, 1993.

[4] J.R. Knowles, Acc. Chem. Res., 1985, 18, 97.

[5] P.D. Buttero, G. Molteni and T. Pilati, Tetrahedron Lett., 2003, 44, 1425.

[6] T. Gilchrist, Heterocyclic Chemistry. Harlow: Longman Scientific, 1987, ISBN

0-582-01421-2.

[7] H. Staudinger and F. Enke, Die Ketene, Stuttgart, Germany, 1912.

[8] R. Joyeau, H. Molines, R. Labia and M. Wakselman, J. Med. Chem., 1988, 31,

370.

[9] M. Cardellini, F. Claudi and F.M. Moracci, Synthesis., 1984, 8, 1070.

[10] A.K. Bose, Y.H. Chiang and M.S. Manhas, Tetrahedron Lett., 1972, 12, 4091.

[11] V. Guner, S. Yildirir, B. Ozcelik and U. Abbasoglu, Il Farmaco, 2000, 55, 147.

[12] V.N. Pathak, R. Gupta and M. Garg, Heteroatom chemistry., 2004, 15, 494.

[13] K. Mistry and K.R. Desai, Cheminform., 2005, 36.

[14] G.S. Singh. and B.J. Mmolotsi, Il Farmaco, 2005, 60, 727.

[15] K.H. Patel. and A.G. Mehta, E-J.Chem., 2006, 3, 267.

[16] A.K. Halve, D. Bhadauria and R. Dubey, Bioorg. Med. Chem. Lett., 2007, 17,

341.

[17] T. Singh, V.K. Srivastava, K. Saxena, S.L. Goel and A. Kumar, Archiv der

Pharmazie., 2006, 339, 466.

[18] Tidwell, Thomas, Angewandte Chemie., 2008, 47 (6), 1016.

[19] H. Staudinger, Justus Liebigs Ann. Chem., 1907, 356, 51–123.

[20] E.H. Flynn, Chemistry and Biology. New York and London: Academic Press,

1972.

http://en.wikipedia.org/wiki/International_Standard_Book_Number

http://en.wikipedia.org/wiki/Special:BookSources/0-582-01421-2

Chapter-V

Page No. 132

[21] A. Dalhoff, N. Janjic, R. Echols, Biochemical Pharmacology., 2006, 71 (7),

1085–1095.

[22] R.B. Woodward, Phil Trans Royal Soc Chem., 1980, B 289(1036), 239–50.

[23] A. Nangia, K. Biradha, G.R. Desiraju, J Chem Soc, Perkin Trans., 1996, 2 (5),

943–53.

[24] O'Boyle, Niamh; Miriam Carr, Lisa Greene, Orla Bergin, Seema M. Nathwani,

Thomas McCabe, David G. Lloyd, Daniela M. Zisterer, Mary J.

Meegan, Journal of Medicinal Chemistry., 2010, 53(24), 8569–8584.

[25] O'Boyle, Niamh, Lisa Greene, Orla Bergin, Jean-Baptiste Fichet, Thomas

McCabe, David G. Lloyd, Daniela M. Zisterer, Mary J. Meegan, 2011, 19 (7),

2306–2625.

[26] Ehmann E. David. et al, PNAS., 2012, 109(29), 11663-11668.

[27] P. Chalreck, Chem. Abstr., 1988, 109, 3771.

[28] Sutoris, V. Halgas, J. Chem. Abstr., 1984, 100, 103234.

[29] Ares Jaffrey, Chem. Abstr., 1991, 114, 71453.

[30] O.W. Wollesdrof, H. Schwam, Chem. Abstr., 1989, 111, 194656.

[31] E. Costakes, G. Tsatsas, Chem. Abstr., 1979, 90, 203935.

[32] D. Sreenivasa Rao, E. Jayachandran, G.M. Sreenivasa, B. Shivakumar, Oriental

J. of Chemistry., 2005, 21(1), 113-116.

[33] G.M. Sreenivasa, E. Shivkumar Jayachandran, Indian Drugs., 2006, 43 (4), 126.

[34] R.A. Turner, XV edn., (Ed. Turner RA), Academic Press, New York., 1965,

165-172.

[35] V.P. Chernykh, O.F. Sidorenko, Chem. Abstr., 1983, 98, 89233.

[36] Desbois Michel., Eur Pat., APP.l EP. 248746 (IPC Co7Co85/00), Chem. Abstr.,

1987, 108, 159896.

[37] G.S. Singh, Tetrahedron., 2003, 59, 7631.

[38] G.S. Singh, Mini-Rev. Med. Chem., 2004, 4, 69.

[39] G.S. Singh, Mini-Rev. Med. Chem. 2004, 4, 93.

[40] P. Chalreck, Chem. Abstr., 1988, 109, 377.

[41] V. Sutoris, Halgas, J. Chem. Abstr., 1984, 100, 103234.

Chapter-V

Page No. 133

[42] Ares Jaffrey, Chem. Abstr., 1991, 114, 71453.

[43] O.W. Wollesdrof, H. Schwam, Chem. Abstr., 1989, 111, 194656.

[44] E. Costakes, G. Tsatsas, Chem. Abstr., 1979, 90, 203935.

[45] D. Sreenivasa Rao, E. Jayachandran, G.M Sreenivasa, B. Shivakumar, Oriental

J. of Chemistry, 2005, 21(1), 113-116.

[46] G.M. Sreenivasa, B. Shivkumar, E. Jayachandran, Indian Drugs., 2006, (4), 43.

[47] Ajay Bagherwal, Ashish Baldi, Rakesh Kumar Nagar, International Journal of

ChemTech Research., 2011, 3, 274-279.

[48] Yogesh Rokade and Nirmala Dongare, Rasayan J. Chem., 2010, 3, 641-645.

[49] H. Panwar, R.S. Verma, V.K. Srivastava and A. Kumar; Ind. J. Chem., 2006,

45B, 2099.

[50] Ishwar K. Bhat, Sunil K Chaithanya, P D Satyanarayana, J Serb. Chem, Soc,

2007, 72 (5), 437-442.

[51] M.C. Sharma, N.K. Sahu, D.V. Kohli, S.C. Chaturvedi, Smitha Sharma, Sunil

K. Chaithanya, P.D. Satyanarayana, synthesis., 2009, 4, 361-367.

[52] S.K. Srivastava, R. Yadav. and S.D. Srivastava, J. Ind. Chem. Soc., 2004, 81,

342.

[53] A. Rajasekaran and S. Murugesan, J. Pharmacy and bioresources, 2005, 2, 162.

[54] D.B. Arunkumar, G.K. Prakash, M.N. Kumaraswamy B.P. Nandeshwarappa.,

B.S. Sherigara and K.M. Mahadevan, Ind. J. Chem., 2007, 46B, 336.

[55] A.R. Surrey, J AM Chem soc., 1947, 69, 11:2911-12.

[56] F.C. Brown, Chem. Rev., 1961, 61, 463.

[57] A.S. Samarin, V.A. Loslcutov, Tr. Tomsk. Gos, Utiiv. Ser. Khim., 1965, 170,

157.

[58] S.S. Meher, S. Naik, R.K. Behera, A. Nayak, J. Indian Chem. Soc., 1981, 58,

274.

[59] J.V. Mandlik, V.A. Patwardham, K.S. Nargund, J. Univ. Poona. Sci. Technol.,

1966, 32, 39.

[60] J.J. Bronson, K.L. DenBleyker, P.J. Falk, R.A. Mate, H.T. Ho, M.J. Pucci, L.B.

Snyder, Bioorg. Med. Chem. Lett., 2003, 13, 873.

Chapter-V

Page No. 134

[61] W. Cunico, C.R.B. Gomes, W.T. Vellasco, Jr. Mini, Rev. Org. Chem., 2008, 5,

336.

[62] A. Verma, S.K. Saraf, Eur. J. Med. Chem., 2008, 43, 897.

[63] W.S. Hamama, M.A. Ismail, S. Shaaban, H.H. Zoorob, J. Heterocycl. Chem.,

2008, 45, 1.

[64] R. Markovic, M. Stodanovic, Heterocycles., 2005, 56, 2635.

[65] R.B. Pawar, V.V. Mulwad, Chem Heterocycl. Compd., 2004, 40, 219.

[66] N. Ocal, F. Aydogan, C. Yolacan, Z.J. Turgut, Heterocycl. Chem., 2003, 40,

721.

[67] O.S. Eltsov, V.S. Mokrushin, N.P. Belskaya, N.M. Kozlova, Rus. Chem. Bull.,

Int. Edn. 2003, 52, 461.

[68] W. Cunico, C.R.B. Gomes, M. Ferreira, L.R. Capri, M. Soares, S.M. Wardell,

S.V. Tetrahedron Lett., 2007, 48, 6217.

[69] P.D. Neuenfeldt, B.B. Drawanz, G.M. Siqueira, C.R.B. Gomes, S. N. Wardell,

A.F.C. Flores, W. Cunico, Tetrahedron Lett., 2010, 51, 3106.

[70]. U.R. Pratap, D.V. Jawale, M.R. Bhosle, R.A. Mane, Tetrahedron Lett., 2011,

52, 1689.

[71] J.R. Mali, U.R. Pratap, P.D. Netankar, R.A Mane, Tetrahedron Lett., 2009, 50,

5027.

[72] M.H. Bolli, S. Abele, C. Binkert, R. Bravo, S. Buchmann, D. Bur, J. Gatfield,

2001, 123.

[73] M. Naeem, M.N. Chaudhary, F.H. Baloch, R. Amjad, J.chem.soc.pak., 2009,

31, 4, 633-637.

[74] M.C. Sharma, N.K. Shahu, D.V. Kohli, S.C. Chaturvedi, S. Sharma, Digest

journal of Nanomaterials and Bio structure., 2009, 4, 1, 223-232.

[75] R.B. Patel, P.S. Desai, K.R. Desai, K.H. Chikhalia, Indian journal of chemistry.,

2006, 45B, 773.

[76] Z. Turgut, C. Yolacan, F. Aydogan, E. Bagdatli, N. Ocal, Molecules., 2007, 12,

2151-2159.

[77] S Bouzroura, Y. Bentarzi, R. Kaoua, B.N. Kolli, S.P. Martini, E. Dunach, Org.

Commun., 2010, 3, 1, 8-14.

[78] K.M. Mistry, K.R. Desai, E-journal of chemistry., 2004, 1, 4, 189-193.

Chapter-V

Page No. 135

[79] N. Shah, P.C. Pant, P.C. Joshi, Asian J. chem., 1993, 95, 83.

[80] N. Ramalakshmi, L, Aruloly, S. Arunkumar, K. Ilango, A. Puratchikody,

Malaysian journal of science., 2009, 28, 2, 197-203.

[81] N.B. Patel, V.N. Patel, Iranian journal of pharmaceutical research., 2007, 6, 4,

251-258.

[82] M.G. Vigorita, R. Ottana, F. Monforte, R. Maccari, Trovato, M.T. Monforte,

M.F. Taviang, Biorg.Med.Chem.Lett., 2001, 11, 2791-2794.

[83] V.K. Archana, Srivastava, Ashok Kumar, Euro. J. Med. Chem., 2002, 37 873-

882.

[84] B.M. Gurupadayya, M. Gopal, B. Padmashali, Y.N. Manohara, Int. J. Pharm.

Sci., 2008, 70, 572-577.

[85] D.P. Maia, D. Veras Wilke, J. Mafezoli, J.N. da Silva, M. Odorico, C. Pessoa,

L.V.C. Lotufo, Chemio-Biological Interactions., 2009, 220-225.

[86] F.A. Ragab, N.M. Eid, H.A. el-Tawab, Pharmazie., 1997, 52, 926-929.

[87]. G. Kucukguzel, A. Kocatepe, E. De Clercq, F. Sahin, M. Gulluce, Euro. J. Med.

Chem., 2006, 41, 353-359.

[88] J. Balzarini, B. Orzeszko, J.K. Maurin, A. Orzeszko, Euro. J. Med. Chem.,

2007, 42, 993-1003.

[89] K.C. Asati, S.K. Srivastava, S.D. Srivastava, Ind. J. Chem., 2006, 45B, 526-

231.

[90] L.L. Thomas, D.A. Williams. Foye’s 1, 1046, 1127, 1130 and 1134.

[91] M.D. Kakwani, N.H. Palsule Desai, A.C. Lele, M. Ray, M.S. Degani, Bioorg.

Med. Chem. Lett., 2011, 21, 6523-6526.

[92] M.G. Vigorita, R. Ottana, F. Monforte, R. Maccari, A. Trovato, M.T. Monforte

and M.F. Taviano. Synthesis., 2004, 1234.

[93] M. Naeem, M.N. Chaudhary, F.H. Baloch, R. Amjad, J.chem.soc.pak., 2009,

31, 4, 633-637.

[94] M.C. Sharma, N.K. Shahu, D.V. Kohli, S.C. Chaturvedi, S. Sharma, Digest

journal of Nanomaterials and Bio structures., 2009, 4, 1, 223-232.

[95] R.B. Patel, P.S. Desai, K.R. Desai, K.H. Chikhalia, Indian journal of chemistry.,

2006, 45B, 773.

Chapter-V

Page No. 136

[96] A.S. Nagarjuna, S. Sharma, C. Sharma, D. Bhambi, G.L. Talesara, Ind J Chem.,

2009, 48, 1577-82.

[97] X. Zhang, X. LI, D. LI, J. Wang, P.M. Loisean, X. Fan, BioorgMedChemLett.,

2009, 19, 6280-83.

[98] R. Ottana, R. Maccari, M.L. Barreca, G. Bruno, A. Rotonda, A. Rossi, G.

Chricosta, R. DIpaola, L. Sautebin, S. Cuzucrea, M.G. Vigortiya, Bioorg,Med

Chem., 2005, 13, 4243-52.

[99] L. Hui-ling, Li Z, T. Anthonsen, Molecule., 2000, 5, 1055-61.

[100] N. Zidar, J. Kladnik, D. Kikelj, Acta Chim Slov., 2009, 56, 635-42.

[101] J.P. Rawal, K.R. Desai, CHEMIJA., 2009, 20, 101-08.

[102] Kucukguzel et al, Eur J ,Med Chem., 2006, 41, 353-59.

CHAPTER - VI

A new approach to the synthesis of 3-amino-6-methoxy-

benzothiophene-2-carboxylate substituted pyrimidine derivatives.

Chapter -VI

Page No. 137

INTRODUCTION

The chemistry of chalcones generated intensive scientific studies throughout the

world. Especially, interesting for their biological and industrial applications1-3

.

Chalcones are coloured compounds because of the presence of the chromophore and

auxochromes. They are known as benzalacetophenones or benzylidene acetophenones.

Kostanecki and Tambor gave the name chalcone. The chalcones are α, β-unsaturated

ketones containing the reactive ketoethylenic group –CO–CH=CH–. Presence of α, β-

unsaturated carbonyl system in chalcone makes it biologically active. Some substituted

chalcones and their derivatives have been reported to possess some interesting

biological properties such as antibacterial, antifungal4, insecticidal

5, anaesthetic

6,

analgesic, ulcerogenic7 etc. Chalcones are considered as the precursor of flavonoids and

isoflavonoids, they are abundant in edible plants8. And have been shown to display a

diverse array of pharmacological activities, such as anti-protozoal9, anti-

inflammatory10

, anticancer11

and antihyperglycemic properties12

. Consequently, the

chalcone backbone could be a versatile scaffold for drug design. A survey of the

literature revealed that some natural13,14

and synthetic chalcones15

showed significant

ALR2 inhibitory activities.

Some substituted chalcones and their derivatives have been reported to possess

some interesting biological properties such as insecticidal16,17

, anaesthetic18

and

ulcerogenic19

activities. In addition, chalcones serve as intermediates for the synthesis

of various heterocycles such as pyrazolones, oxazoles and pyrimidines etc., which are

found to have extensive pharmaceutical applications. Oxopyrimidine and

thiopyrimidines are currently used in the chemotherapy of Acquired Immune

Deficiency Syndrome (AIDS). Several pyrimidine derivatives containing drugs have

exhibited antiulcer20

and anti-AIDS activities21,22

. The pyrimidine nucleus occurs in

Chapter -VI

Page No. 138

biologically important products such as nucleic acids, vitamins, coenzymes and

pharmacologically useful products of plant origin. With the intention to synthesize

more potent antimicrobial agents, the pyrimidine moiety has been condensed with

different types of heterocycles such as thiophene23-33

.

Oxopyrimidine have a long and distinguished history extending from the days

of their discovery as important constituents of nucleic acids to their current use in the

chemotherapy of AIDS. Uracil, thymine and cytosine (1,2,3) are the three important

constituents of nucleic acids contain oxopyrimidine ring structure34

.

N

H

NH

O

O NH

NH

O

O

CH3 NH

NH

O

NH2

1 2 3

Thymine Uracil Cytosine

There are a large number of pyrimidine-based antimetabolites 4 and 5, which

are used as anticancer agents35,36

. They are usually structurally related to the

endogenous substrates that they antagonize.

NH

NH

O

O

F

NH

NH

O

O

SH

4 5 5-Flourouracil 5-Thiourouracil

There are many more anticancer agents like Uramustine 6 which are under

clinical development for treatment for various types of cancers which contain

oxopyrimidine ring37

.

Chapter -VI

Page No. 139

NH

NH

O

N

O

Cl

Cl

6 Uramustine

Recently, pyrimidine derivatives have generated widespread interest due to their

antiviral properties. 5-Iododeoxyuridine and 5-iodo-2-deoxyuridine, has been

extensively used for treatment of viral infections, 5-trifluromethyl-2-deoxyuridine has

been found useful against infections resistant to IDU therapy38

.

Several members of a series of acyclic nucleosides, which contain a fused

pyrimidine ring (mainly purine), are found to be effective antiviral. Famciclovir and

Valacyclovir 7 are drugs used for several DNA viruses, including HSV types 1 and 239

.

Famciclovir

Valacyclovir

There are few examples of oxopyrimidine antibiotics. For example, amicetin 8

and Plicacetin 9 which contain oxopyrimidine ring structure, exhibit antibacterial

activity against acid fast and Gram-positive bacteria as well as some other organisms40

.

N

NHN

NNH2

O

R

R =

CH3

O

O

CH3

O

CH3

O

R = CH3 O

O

O

CH3

CH3

NH2

7

Chapter -VI

Page No. 140

N

N NH

O

OCH3

O

OH

OH

OH

ON

N NH

O

NH2

O

OO

CH3

OH

N

CH3

CH3

CH3

OH

8 9

. Amicetin Plicacetin

Pyrimidines also exhibit antifungal properties. Flucytosine 10 is a fluorinated

pyrimidine used as nucleosidal antifungal agent for the treatment of serious systemic

infections caused by susceptible strains of Candida and Cryptococcus41,42

.

Flucytosine

Afloqualone 11 has been evaluated as a successful anti-inflammatory agent with

lower back pain patients. Afloqualone, a condensed pyrimidin-2-one derivative, has

been reported to exhibit good NSAID potential. Both these agents contain

oxopyrimidine moiety43

.

N

NH

NH2

CH3

OCH3

NH

N O

CH3CH3

CH3

11 12 Afloqualone Proquazone

Apart from these, oxopyrimidine ring containing drug molecules are known

which possess wide range of biological and pharmacological activities like

N

NH

O

CH3

NH2

10

Chapter -VI

Page No. 141

anthelmintic, diuretic, uricosuric, anti-inflammatory, analgesic, CVS and CNS

activities44-52

.

Thus, literature survey reveals that, oxopyrimidne nucleus is an important

pharmacophore in process of discovery of novel drug molecules. Due to the clinical

availability of drug molecules which possess oxopyrimidne nucleus, enormous research

work is going on the synthesis of novel molecules which contain oxopyrimidine

nucleus, in hope of getting the compounds with wide range of activities.

Malla Reddy et al, have reported the synthesis and anti-inflammatory activity of

some 2-methyl-3-N-substituted quinazolinones 15. Some of compounds exhibited anti-

inflammatory activity equal to that of standard drug ibuprofen53-56

.

R=phenyl, substituted phenyl

Rama Murthy et al, have reported the synthesis and biological activities of

novel 16 quinazolinones57

.

N

N

O

CH3

NN

NSH

R

16

R=phenyl, substituted phenyl

Raghu Rama Rao and Malla Reddy have synthesized some novel

quinazolinones 17 and 18 evaluated their anti-histamine activity by guinea pig ileum

method. All the compounds exhibited moderate anti-histamine activity58

.

N

N

O

NHNH

O

S

RCH3

15

Chapter -VI

Page No. 142

N

N

O

R

O

O

NR

R1

N

N

O

R

O

O

OR

2

17 18 R=R

1=alkyl R

2=phenyl, substituted phenyl

Srivatsava et al, have reported the synthesis and anti-parkinson’s activity of

some 3-arylidene-4(3H)-quinazolinones 19 and found that some of the compounds

possess moderate anti-Parkinson’s activity59

.

N

N

O

N

R1

R

19 R=phenyl, substituted phenyl R

1=alkyl

Udupi et al, reported the synthesis of Mannich bases of quinazolinones 20 and

evaluated their anti-tubercular activity. Some of the compounds were more active than

standard drug INH60

.

N

N

O

R

R2

R1

20 R=Alkyl R

1=Cl, NO2 R

2=phenyl, substituted phenyl

El-Helby et al, reported a new series of 3-substituted quinazolinone derivatives

21 and evaluated their anticonvulsant activity61

.

N

N

O

S O

O

R

NH2


Chemistry of pyrimidine and its derivatives have been studied since the past

century since due to there close pharmaceutical association with diverse pharmaceutical

properties. Thiopyrimidine represent one of the most active classes of compounds

Chapter -VI

Page No. 143

possessing wide spectrum of biological activities, such as in vitro activity against

unrelated DNA and RNA viruses and it shows good pharmaceutical properties.

Including antiviral, analgesic, anti-inflammatory, antitumor, antimicrobial, herbicidal

and anticancer activities62-78

.

Ingle et al reported the synthesis of several substituted pyrimidines 22 by using

corresponding chalcones and evaluated their antimicrobial activity79

.

OH

NN

SH

R

22 R=C6H5, 2-OCH3, 2-NO2 -C6H4

Chintan C Raval et al, synthesized 23 novel 2-(4-(1,2-dihydro-6-phenyl-2-

thioxopyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile chalcone as starting material

and characterized their antimicrobial and analgesic activity80

.

N

N

NH NH

N

S

23

A.M. Srour and coworker synthesized 6-aryl-5-cyano-4-oxo-2-thioxo-3,4-

dihydropyrimidine 24 derivatives and evaluated their antiviral and antischistosomal

activities71.

NH

N

O

SH

N

24

M. Amir et al. synthesized and characterized some 4-(1H-indol-3-yl)-6-phenyl-

1,2,3,4-tetrahydropyrimidin-2-ones/thiones 25 as potent anti-inflammatory agents81

.

Chapter -VI

Page No. 144

NH

NH

NHS

R

25 R=C6H5, 4-Cl, C6H5,4-OCH3, C6H5

Yahia A Mohamed et al. synthesized and evaluated cytotoxicity and anti-HIV

activities of some new 26 thioxopyrimidine derivatives82

.

NH

NH

S

S

26 In this connection, we are inspired by wide range of activities exhibited by oxo-

pyrimidines and thioxopyrimidines, so in the present chapter various types of

benzothiophene substituted oxo and thio pyrimidines were prepared and evaluated for

their biological and pharmacological activities.

PRESENT WORK

This work is the continuation of a program with the aim to develop new simple

methods for the synthesis of functionality substituted heterocycles with anticipated

biological activity. Encouraged by research findings on pyrimidine moiety, we thought

of synthesizing pyrimidine derivatives as a part of research work and explore their

pharmacological aspects. In the present investigation, we focused our interest on the

synthesis of oxopyrimidine and thioxopyrimidine substituted with benzothiophene

derivatives. The synthesis of starting material methyl-3-amino-6-methoxy-1-

benzothiophene-2-carboxylate has been established in our laboratory. The reaction

carried out are depicted in scheme-v.

Chapter -VI

Page No. 145

N

BrO

+ SHO

O

KOH

SO

NH2

O

O

SO O

NH

ONH2

O H

RDMF/KOH

S

NH2

O

NH

O

O

R

Acetone

1

2

3a-e

S

NH2

O

NH

O

NH

N

S

R

S

NH2

O

NH

O

NH

N

O

R

4a-e5a-e

NH2 NH2

SNH2 NH2

O

Scheme-V


4a 4-Br2 5a 4-Br2

4b 4-OCH3 5b 4-OCH3

4c 4-OH 5c 4-OH

4d 4-Cl 5d 4-Cl

4e 4-NH2 5e 4-NH2

Chapter -VI

Page No. 146

The starting material methyl-3-amino-6-methoxy-1-benzothiophene-2-

carboxylate 1 was made to react with 4-aminoacetophenone in acetone to get N-(4-

acetylphenyl)-3-amino-6-methoxy-1-benzothiophene-2-carboxamide 2 in good yield.

SO

NH2

O

O

+ NH2

O Acetone

SO O

NH

ONH2

1 2

The IR spectrum of compound 2 showed broad absorption band at 3436, 3352

cm-1

due to NH2 and 3152 cm-1

due to NH stretching. The carbonyl group showed

absorption band at 1650 cm-1

. The 1H NMR spectra of compound 2 exhibited a singlet

peak at δ 8.42 due to one proton of NH, a multiplet in the region between δ 8.0-6.97

corresponding to seven aromatic protons. And singlet at δ 2.13 indicate the presence of

three protons of CH3 protons. The formation of the compound 2 was further confirmed

by recording its mass spectrum, which exhibited a molecular ion peak m/z 340.

In order to prepare chalcones 3a-e, compound 2 was condensed with various

aromatic aldehydes in the presence of KOH in DMF.

SO O

NH

ONH2

+

O H

R S

NH2

O

NH

O

O

R

DMF/KOH

2 3a-e

The IR spectra of chalcone 3a showed absorption band at 3452, 3372, 3165cm-1

due to NH2 and NH groups. C=O stretching absorption at 1655 respectively. The 1H

NMR spectrum of 3a exhibited a multiplet in the region between δ 8.27-7.14 due to

thirteen aromatic protons, and singlet at δ 8.93 corresponds to one proton of CONH,

two protons at δ 4.84 indicated the presence of NH2 functional group, and a singlet in

the δ 3.70 region corresponds to three protons of OCH3. As an additional proof of mass

Chapter -VI

Page No. 147

spectrum of compound exhibited a molecular ion peak at m/z 507, which confirms the

molecular weight of the compound. The selection of the aldehydes was based on the

presence of electron donating and electron withdrawing groups in various position of

aromatic ring, the following aldehydes were selected in the present study.

4-Bromobenzaldehyde

4-Methoxy benzaldehyde

4-Hydroxy benzaldehyde

4-Chloro benzaldehyde

4-Amino benzaldehyde

Similarly, 3b-e were prepared and confirmed by spectral data.

To find out the pharmaceutical importance of pyrimidine derivatives, a series of

thiopyrimidines 4a-e have been prepared by condensation of chalcones with thiourea in

the presence of alcoholic KOH as a catalyst.

S

NH2

O

NH

O

O

R

NH2 NH2

S

S

NH2

O

NH

O

NH

N

S

R

3 4a-e

IR spectra of compound 4a showed broad absorption band at 3467, 3392 and

3255, 3140 cm-1

indicated the presence of NH2 and two NH functional groups. 1662

cm-1

due to C=O stretching absorption frequencies. The 1H NMR spectrum of 4a

exhibited a singlet at δ 11.48 and δ 10.50 corresponds to NH group of pyrimidine and

thiophene ring, a multiplet in the region between δ 8.32-7.12 due to twelve aromatic

protons, a singlet at δ 4.87 indicating the presence of two protons of NH2 and three

protons at δ 3.77 indicating the presence of OCH3. Further, compound 4a confirmed by

Chapter -VI

Page No. 148

mass spectrum of which exhibited a molecular ion peak at m/z 563. Similarly, 4b-e

were prepared and confirmed by spectral data.

Similarly, chalcones underwent smooth cyclisation with urea in the presence of

alcoholic KOH as a catalyst to afford a series of oxopyrimidine 5a-e.

S

NH2

O

NH

O

O

R

NH2 NH2

O

S

NH2

O

NH

O

NH

N

O

R

35a-e

IR spectra of oxopyrimidine 5a showed broad absorption band at 3484, 3396

and 3260, 3145 cm-1

indicated the presence of NH2 and two NH functional group. 1716

cm-1

due to C=O stretching absorption frequencies. The 1H NMR spectrum of 5a

exhibited a singlet at 10.96 and 10.36 corresponds to NH groups of pyrimidine and

thiophene ring, a multiplet in the region between 8.19-7.05 due to twelve aromatic

protons, a singlet at 4.37 indicating the presence of two protons of NH2 and three

protons at 3.73 indicating the presence of OCH3 functional group. As an additional

proof of mass spectrum of compound exhibited a molecular ion peak at m/z 547, which

confirms the molecular weight of the compound, similarly, 5b-e were prepared and

confirmed by spectral data.

S

NH2

O

NH

O

O

BrIR spectrum of 3a

S

NH2

O

NH

O

O

Br


S

NH2

O

NH

O

O

Br

Mass spectrum of 3a

S

NH2

O

NH

N

ONH

S

Br

IR spectrum of 4a

S

NH2

O

NH

N

ONH

S

Br


S

NH2

O

NH

N

ONH

S

Br

Mass spectrum of 4a

S

NH2

O

NH

N

O

NH

O

BrIR spectrum of 5a

S

NH2

O

NH

N

O

NH

O

Br


S

NH2

O

NH

N

O

NH

O

Br

Mass spectrum of 5a

Chapter -VI

Page No. 149

EXPERIMENTAL

Preparation of methyl-3-amino-6-methoxy-1-benzothiophene-2-carboxylate (1):

2-bromo-4-methoxybenzonitrile (4.24g, 0.02mol) was added to stirred solution of

methylthioglycolate (1.8ml, 0.02mol) and potassium hydroxide (2.75g, 0.05mol) in

DMF and refluxed for 10 hours at 75C. Progress of the reaction was monitored

through TLC. After completion, the reaction mixture was cooled to room temperature

and poured in to crushed ice. Pale yellow solid that obtained was filtered, washed with

water, dried and purified through column chromatography by using ethyl acetate and n-

hexane.

N-(4-acetylphenyl)-3-amino-6-methoxy-1-benzothiophene-2-carboxamide (2):

A mixture of methyl-3-amino-6-methoxy-1-benzothiophene-2-carboxylate 1 (2.37g,

0.01mol) and 4-aminoacetophenone (1.35g, 0.01mol) were dissolved in dry acetone

(40ml).The reaction mixture was refluxed for 4 hours. Periodically, sodium carbonate

was added to quench the HCl evolved during the reaction. Finally, the reaction mixture

was poured in to crushed ice. The solid separated out was filtered washed with water,

dried and recrystallized from alcohol.

SO O

NH

ONH2

2


): 3436, 3352 (NH2), 3152 (NH),

1650 (C=O); 1H NMR(400 MHz, DMSO-d6) δ (ppm): 8.42 (1H, NH), 8.01-6.97 (7H,

m, Ar-H), 4.95 (2H, s, NH2), 3.81 (3H, s, OMe), 2.13 (3H, s, CH3); Elemental analysis:

Calculated (%) for C18H16N2O3S: C, 63.51; H, 4.73; N, 8.22; S, 9.42; Found: C, 63.47.

H, 7.69. N, 8.18. S, 9.39; LC-MS m/z: 340 ; M.P: 278-281 0C.

Chapter -VI

Page No. 150

(E)-3-amino-N-(4-(3-(4-bromophenyl)acryloyl)phenyl)-6-methoxybenzo[b]thio

phene-2-carboxamide (3a):

N-(4-acetylphenyl)-3-amino-6-methoxy-1-benzothiophene-2-carboxamide 2 (3.40g,

0.01mol) was dissolved in DMF (20ml). 4-bromo-benzaldehyde (1.85g, 0.01mol) was

added to the reaction mixture with constant stirring at room temperature. Then 40%

KOH in distilled water was added to the reaction mixture with constant stirring at room

temperature. After 24 hours, the reaction mixture was poured in to crushed ice and

quench with HCl. The product separated out was filtered, washed with water, dried and

purified by suitable solvent.

S

NH2

O

NH

O

O

Br


): 3452, 3372 (NH2), 3165 (NH)


m, Ar-H), 4.84 (2H, s, NH2), 3.70 (3H, s, OMe); Elemental analysis: Calculated (%) for

C25H19BrN2O3S: C, 59.17. H, 3.77. N, 5.52. S, 6.31; Found: C, 59.14; H, 3.73. N, 5.49.

S, 6.29; LC-MS m/z: 507 ; M.P: 284-287 0C.

(E)-3-amino-6-methoxy-N-(4-(3-(4-methoxyphenyl)acryloyl)phenyl)benzo[b]thio

phene-2-carboxamide (3b):

S

NH2

O

NH

O

O

O

Chapter -VI

Page No. 151


): 3478, 3389 (NH2), 3177 (NH)



C26H22N2O4S: C, 68.10. H, 4.83. N, 6.10. S, 6.99; Found: C, 68.05. H, 4.80. N, 6.07. S,

6.96 ; LC-MS m/z: 458.52 ; M.P: 261-263 0C.

(E)-3-amino-N-(4-(3-(4-hydroxyphenyl)acryloyl)phenyl)-6-methoxybenzo[b]thio

phene-2-carboxamide (3c):

S

NH2

O

NH

O

O

OH


): 3470, 3382 (NH2), 3172 (NH)


m, Ar-H), 5.33 (1H, s, OH), 5.14 (2H, s, NH2), 3.86 (3H, s, OMe); Elemental analysis:


H, 4.50. N, 6.26. S, 7.18 ; LC-MS m/z: 444.50; M.P: 259-262 0C.

(E)-3-amino-N-(4-(3-(4-chlorophenyl)acryloyl)phenyl)-6-methoxybenzo[b]thioph

ene-2-carboxamide (3d):

S

NH2

O

NH

O

O

Cl


): 3458, 3378 (NH2), 3168 (NH)


Chapter -VI

Page No. 152


C25H19ClN2O3S: C, 64.86. H, 4.13. N, 6.05. S, 6.92; Found: C, 64.82. H, 4.10. N, 6.01.

S, 6.89; LC-MS m/z: 462.94 ; M.P: 283-286 0C.

(E)-3-amino-N-(4-(3-(4-aminophenyl)acryloyl)phenyl)-6-methoxybenzo[b]thio

phene-2-carboxamide (3e):

S

NH2

O

NH

O

O

NH2


): 3460, 3380 (NH2), 3170 (NH)


m, Ar-H), 5.75 (2H, s, NH2), 4.95 (2H, s, NH2), 3.89 (3H, s, OMe); Elemental analysis:


H, 4.73. N, 9.43. S, 7.18; LC-MS m/z: 443.51; M.P: 298-301 0C.

3-amino-N-(4-(6-(4-bromophenyl)-2-thioxo-1,2-dihydropyrimidin-4-yl)phenyl)-6-

methoxybenzo[b]thiophene-2-carboxamide (4a):

A mixture of compound 3 (0.916g, 0.002mol) and thiourea (0.152g, 0.002mol) in 1,4-

diaxone (20ml) was refluxed for 15 hours. The completion of the reaction monitored by

TLC. After completion, the reaction mixture was cooled to room temperature and

poured in to crushed ice. Solid that obtained was filtered, washed with water, dried and

purified through column chromatography by using ethyl acetate and n-hexane.

S

NH2

O

NH

N

ONH

S

Br

Chapter -VI

Page No. 153


): 3467, 3392 (NH2), 3255 (NH)

3140 (NH) 1662 (C=O), 627 (C-Br); 1H NMR(400 MHz, CDCL3) δ (ppm): 11.48 (1H,

NH), 10.50 (1H, NH), 8.32-7.12 (11 H, m, Ar-H), 5.52 (1H, s), 4.87 (2H, s, NH2), 3.77

(3H, s, OMe); Elemental analysis: Calculated (%) for C26H19BrN4O2S2: C, 55.47. H,

3.40. N, 9.94. S, 11.38; Found: C, 55.43. H, 3.35. N, 9.91. S, 11.34; LC-MS m/z: 563 ;

M.P: 379-3820C.

3-amino-6-methoxy-N-(4-(6-(4-methoxyphenyl)-2-thioxo-1,2-dihydropyrimidin-4-

yl)phenyl)benzo[b]thiophene-2-carboxamide (4b):

S

NH2

O

NH

N

ONH

S

O


): 3485, 3415 (NH2), 3269 (NH)

3158 (NH) 1675 (C=O); 1H NMR(400 MHz, CDCL3) δ (ppm): 11.61 (1H, NH), 10.62

(1H, NH), 8.13-6.76 (11 H, m, Ar-H), 5.48 (1H, s), 4.95 (2H, s, NH2), 3.80 (6H, s,

OMe); Elemental analysis: Calculated (%) for C27H22N4O3S2: C, 63.01. H, 4.30. N,


M.P: 358-361 0C.

3-amino-N-(4-(6-(4-hydroxyphenyl)-2-thioxo-1,2-dihydropyrimidin-4-yl)phenyl)-

6-methoxybenzo[b]thiophene-2-carboxamide (4c):

S

NH2

O

NH

N

ONH

S

OH

Chapter -VI

Page No. 154


); 3479, 3409 (NH2), 3262 (NH)


(1H, NH), 8.05-6.70 (11H, m, Ar-H), 5.50 (1H, s), 5.03 (2H, s, NH2), 3.80 (3H, s,

OMe); Elemental analysis: Calculated (%) for C26H20N4O3S2: C, 62.45. H, 4.03. N,


M.P: 343-347 0C.

3-amino-N-(4-(6-(4-Chlorophenyl)-2-thioxo-1,2-dihydropyrimidin-4-yl)phenyl)-6-

methoxybenzo[b]thiophene-2-carboxamide (4d):

S

NH2

O

NH

N

ONH

S

Cl


); 3470, 3396 (NH2), 3259 (NH)

3145 (NH) 1666 (C=O), 650 (C-Cl); 1H NMR(400 MHz, CDCL3) δ (ppm): 11.69 (1H,

NH), 10.61 (1H, NH), 8.00-6.71 (11 H, m, Ar-H), 5.49 (1H, s), 4.99 (2H, s, NH2), 3.84

(3H, s, OMe); Elemental analysis: Calculated (%) for C26H19ClN4O2S2: C, 60.15. H,


519.03; M.P: 352-357 0C.

3-amino-N-(4-(6-(4-aminophenyl)-2-thioxo-1,2-dihydropyrimidin-4-yl)phenyl)-6-

methoxybenzo[b]thiophene-2-carboxamide (4e):

S

NH2

O

NH

N

ONH

S

NH2

Chapter -VI

Page No. 155


): 3473, 3399 (NH2), 3261 (NH)


(1H, NH), 8.25-6.85 (11 H, m, Ar-H), 5.68 (2H, s, NH2), 5.41 (1H, s) 4.94 (2H, NH2),

3.89 (3H, s, OMe); Elemental analysis: Calculated (%) for C26H21N5O2S2: C, 62.50. H,


499.60; M.P: 360-363 0C.

3-amino-N-(4-(6-(4-bromophenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)phenyl)-6-

methoxybenzo[b]thiophene-2-carboxamide (5a):

To the compound 3 (0.916g, 0.002mol) was added urea (0.120g, 0.002mol) in 1,4-

diaxone (20ml) was refluxed for 15 hours. The progress of the reaction was monitored

by TLC. After completion, the reaction mixture was poured in to crushed ice. The solid

that obtained was filtered, washed with water, dried and purified through column

chromatography by using ethyl acetate and n-hexane.

S

NH2

O

NH

N

O

NH

O

Br


): 3484, 3396 (NH2), 3260 (NH)


(1H, NH), 8.19-7.05 (11 H, m, Ar-H), 5.31 (1H, s), 4.37 (2H, s, NH2), 3.73 (3H, s,

OMe); Elemental analysis: Calculated (%) for C26H19BrN4O3S: C, 57.05. H, 3.41. N,

12.91. S, 5.85; Found: C, 57.02. H, 3.39. N, 12.86. S, 5.82; LC-MS m/z: 547 ; M.P:

389-391 0C.

Chapter -VI

Page No. 156

3-amino-6-methoxy-N-(4-(6-(4-methoxyphenyl)-2-oxo-1,2-dihydropyrimidin-4-

yl)phenyl)benzo[b]thiophene-2-carboxamide (5b):

S

NH2

O

NH

N

O

NH

O

O


): 3495, 3420 (NH2), 3275 (NH)


(1H, NH), 8.08-6.70 (11 H, m), 5.39 (1H, s) 4.88 (2H, s, NH2), 3.78 (6H, s, OMe);

Elemental analysis: Calculated (%) for C27H22N4O4S: C, 65.04. H, 4.44. N, 11.23. S,

6.43; Found: C, 64.99. H, 4.41. N, 11.19. S, 6.40; LC-MS m/z: 498.55; M.P: 363-365

0C.

3-amino-N-(4-(6-(4-hydroxyphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)phenyl)-6-

methoxybenzo[b]thiophene-2-carboxamide (5c):

S

NH2

O

NH

N

O

NH

O

OH


): 3490, 3416 (NH2), 3270 (NH)


(1H, NH), 8.02-6.66 (11 H, m, Ar-H), 5.62 (1H, s), 5.42 (1H, s), 4.93 (2H, s, NH2),

3.77 (3H, s, OMe); Elemental analysis: Calculated (%) for C26H20N4O4S: C, 64.45. H,


484.52; M.P: 370-373 0C.

Chapter -VI

Page No. 157

3-amino-N-(4-(6-(4-Chlorophenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)phenyl)-6-

methoxybenzo[b]thiophene-2-carboxamide (5d):

S

NH2

O

NH

N

O

NH

O

Cl


) 3486, 3400 (NH2), 3270 (NH)


(1H, NH), 8.03-6.71 (11 H, m, Ar-H), 5.40 (1H, s) 4.95 (2H, s, NH2), 3.88 (3H, s,

OMe); Elemental analysis: Calculated (%) for C26H19ClN4O3S: C, 62.08. H, 3.80. N,

11.14. S, 6.37; Found: C, 62.04. H, 3.77. N, 11.11. S, 6.33; LC-MS m/z: 502.97; M.P:

380-383 0C.

3-amino-N-(4-(6-(4-aminophenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)phenyl)-6-

methoxybenzo[b]thiophene-2-carboxamide (5e):

S

NH2

O

NH

N

O

NH

O

NH2


) 3488, 3405 (NH2), 3268 (NH)

3154 (NH) 1718 (C=O); 1H NMR(400 MHz, CDCL3): δ (ppm): 11.65 (1H, NH), 10.55

(1H, NH), 8.15-6.82 (11 H, m, Ar-H), 5.67 (2H, s, NH2), 5.28 (1H, s), 4.84 (2H, NH2),

3.88 (3H, s, OMe); Elemental analysis: Calculated (%) for C26H21N5O3S: C, 64.58. H,


483.54; M.P: 368-371 0C.

Chapter -VI

Page No. 158

REFERENCE

[1] Y.B. Vibhute and M.A. Basser, Ind J of Chem., 2003, 42B, 202-205.

(b) R. Kalirajan et al. Int.J.ChemTech Res., 2009, 1(1), 34.

[2] B.A. Bhat. K.L. Dhar. A.K. Saxena. M. Shanmugavel, Bio org. & Med. Chem.,

2005, 15, 177-3180.

[3] M.L. Edwards, D.M. Stemerick, and P.S. Sunkara, J. of Med. Chem., 1990, 33,

1948-54.

[4] K.J. Mehta, V.S. Patel and A.R. Parikh, J. Indian Chem. Soc., 1978, 50, 241.

[5] V. Mudaliar and V. Joshi, Indian J. Chem., 1995, 34B, 456.

[6] G. Hosni and S.F. Saad, Acta Chim Acad Sci. Hung., 1995, 86, 263.

[7] O.H. Hishmat, H.I. El-Diwani and F.R. Melek, Indian J. Chem., 1996, 35B, 30.

[8] J.F. Stevens, A.V. Taylor, G.B. Nickerson, M. Ivancic, Phytochemistry., 2000,

53, 759-775.

[9] M. Liu, P. Wilairat and M.L. Go, J. Med. Chem., 2001, 44, 4443-4452.

[10] M.A. Babu, N. Shakya, P. Prathipati, S.G. Kaskhedikar and A.K. Saxena,

Bioorg. Med. Chem., 2003, 10, 4035-4041.

[11] S.K. Kumar, E. Hager, C. Pettit, H. Gurulingappa and N.E. Davidson, J. Med.

Chem., 2003, 46, 2813-2815.

[12] M. Satyanarayana, P. Tiwari, B.K. Tripathi, A.K. Srivastava and R. Pratap,

Bioorg. Med. Chem., 2004, 12, 883-889.

[13] H. Matsuda, T. Morikawa, I. Toguchida and M. Yoshikawa, Chem. Pharm.

Bull., 2002, 50, 788-795.

[14] K. Aida, M. Tawata, H. Shindo, T. Onaya, H. Sasaki, T. Yamaguchi, M. Chin

and H. Mitsuhashi, Planta Med., 1990, 56, 254-258.

[15] F. Severi, S. Benvenuti, L. Costantino, G. Vampa, M. Michele and L. Antolini,

Eur. J. Med. Chem., 1998, 33, 859-866.

[16] K.J. Mehta, V.S. Patel, A.R. Parikh, J. Indian. Chem. Soc., 1978, 50, 241-246.

[17] V. Mudaliar, V. Joshi, Indian. J. Chem., 1995, 34B, 456-459.

[18] G. Hosni, S.F. Saad, Acta. Chim. Aca. S dci. Hung., 1995, 86, 263-269.

[19] O.H. Hishmat, H.I. El-Diwani, F.R. Melek, Indian. J. Chem., 1996, 35B, 30-35.

Chapter -VI

Page No. 159

[20] Kuki Masakatsu, SakamotoYosuhiko, OtaYoichiro, Chem. Abstr., 1992, 117,

131220.

[21] M. Okabe, R.C. Sun. G.B. Zenchoff, J. Org. Chem., 1991, 56, 439-449.

[22] R. Spada, R.S. Kleinm, B.A. Otter, J. Heterocycl. Chem., 1989, 26, 1851-1857.

[23] R.J. Gilespie, P.R. Giles, J. Lerpiniere, C.E. Dawson, D. Bebbington, Adv.

Heterocycl. Chem., 2005, 64, 1921-1927.

[24] V. Alagaraswamy, U.S. Pathak and R.K. Goyal, Indian. J. Pharm. Sci., 2000,

65.

[25] Radhey Shyam and Vikas Tiwari, Curr. Sci., 1975, 44,572.

[26] N.B. Das and A.S. Mitra, J. Ind. Chem. Soc., 1979, 56,398.

[27] A. Kumar, S. Sharma, K. Balaji, S. Shilpa and H. Panwar, Bioorg. Med. Chem.,

2003, 11, 5293.

[28] M.S. Manhas, S.D. Sharma and S.G. Amin, J. Med.Chem., 1971, 15, 106.

[29] H.K. Gakhar and K. Gill, Indian J. Chem., 1985, 24B, 432.

[30] S.S. Vaghasiya, D.K. Dodiya, A.R. Trevedi and V.H. Shah, Arkivoc., 2008, 12,

1.

[31] F. Christine, L. Daniel and R. Max, J. Heterocycl.Chem., 1995, 32,627.

[32] El-Bahie, S. Kardy, A.M. Assy and M.G. Ibrahim, Pharmazie., 1971, 27, 487.

33] S. Modica and R. Santagati, J. Med. Chem., 2000, 40, 573.

[34] J.A. Eussell, Annu. Rev. Biochem., 1945, 14, 309.

[35] R.A. Cox, Quart. Rev., 1968, 22, 934.

[36] P. Callery, and P. Gannett, Foye’s Principles of Medicinal Chemistry (eds D.A.

Williams and T.L Lemke), Lippincott Williams and Wilkins, Philadelphia.,

2002, 934.

[37] B.J. Kennedy, J.L. Torkelson and E. Torlakovic, Cancer., 1999, 85, 2265.

[38] M.S.K. Kwee and L.M.L. Stolk, Pharm. Weekbl. (Sci.)., 1984, 6, 101.

[39] M.A. Johnson, G.A. Verpooten, M.J. Daniel, R. Plumb, Moss, D. Van

Caesbroeck, and M.E. De Broe, Br. J. Clin. Pharmacol., 1998, 46, 21-27.

Chapter -VI

Page No. 160

[40] P. Singh, R. Kumar and B.K. Sharma, J. Enzyme Inhib. Med .Chem., 2003, 18,

395.

[41] A. Polak and H.J. Scholer, Chemotherapy., 1975, 21, 113.

[42] B. Chadwick, M. Addy and D.M. Walker, Br. Dent. J., 1991, 71, 83.

43] C.R. Ganellin, Engl. Reg. Allergy Proc., 1986, 7, 126.

[44] J. Tani, J. Med. Chem., 1979, 22, 95.

[45] J. Huges, L. Roberts and A.J. Coppridge, J. Urol., 1975, 114,912-914.

[46] L.P.G. Wakelin and M.J. Waring, DNA-Intercalating agents, In Comprehensive

Medicinal Chemistry, Drug Compendium (ed.) Sammers, P. G, Pergamon Press,

1990, 2, 731.

[47] B. Chadwick, M. Addy and D.M. Malker, Br. J. Dent., 1991, 71, 83.

[48] S. Nomoto, J. Antibiot., 1977, 30, 955.

[49] R.A. Cox, Quart. Rev., 1968, 22, 934.

[50] J. Vida and J. Yevich, Sedative hypnotics. In Burger’s Medicinal Chemistry and

Drug Discover John Wiley, New Jersy., 2003, 6, 203.

[51] J. Klosa, Arch. Pharm. Ber. Dtsch. Pharm. Ges., 1955, 288, 301.

[52] Pfizer, US Patent, 1970, 3, 511, 836.

[53] M.E. Jones, Annu. Rev. Biochem., 1980, 49, 233.

[54] K.S.L. Srivatsava, Indian J. Pharmcol., 1990, 97, 23.

[55] C.H. Ravi Shankar, A.D. Rao, E.J. Reddy and V. Malla Reddy, J. Ind .Chem.

Soc., 1983, 60, 61.

[56] A. Malla Reddy, Y. Jayamma and V. Malla Reddy, Indian Drugs., 1988,

25,182.

[57] A. Malla Reddy, G. Rama Murthy and V.M. Reddy, Sulphur Letters., 1988, 8,

1.

[58] A. Raghu Ram Rao and V. Malla Reddy, Arzneim-Forsch(Drug research).,

1993, 43, 663.

[59] V.K. Srivatsava, S. Singh, A. Gulati and K. Shanker, Indian J. Chem., 1987,

26B, 652.

Chapter -VI

Page No. 161

[60] R.H. Udupi, B. Ramesh and A.R. Bhat, Indian J Heterocycl. Chem., 1999, 8,

301.

[61] Adbel Ghany, El-Helby and M.D. Hemeda, Act. Pharm., 2003, 53, 127.

[62] S.S. Bahekar and D.B. Shinde, Acta Pharm., 2003, 53, 223.

[63] A.M. El-Agrody, F.M. Ali, F.A. Eid, A.A. Mohammed, G. El-Nassag, El-

Sherbeny and A.H. Bedair, Phosphorus,Sulfur and Silicon., 2006, 181, 839.

[64] L. Guarneri, A. Patrizia, I. Marina, P. Elena, T. Carlo, L. Amedeo and T.

Rodolfo, Arzneimittel Forschung., 1996, 46,15.

[65] Priyanka Pathak, Ramandeep Kaur and Balbir Kaur, Arkivok., 2006 (xvi), 160.

[66] Veerachamy Alagarsamy, Durairaj Shankar and Viswas Raja Solomon,

Arkivok., 2006 (xvi), 149.

[67] Y.L. Huang, C.F. Lin, Y.J. Lee, W.W. Li and T.C. Chao, Bio. Org. Med. Chem.,

2003, 11, 67.

[68] S. Shigeta, S. Mori, F. Watanabe and M. Saneyoshi, Antivir Chem. Chemother,

2002, 13, 145.

[69] Somnath Nag, Richa Pathak, Manish Kumar, P.K. Shukla and Sanjay Batra,

Bioorganic & Medicinal Chemistry., 2006, 16, 3824.

[70] G.F. Sun, Y.Y. Kuang, F.E. Chen, De Clercq and C. Pannecouque, Arch.

Pharm. (Weinheim), 2005, 338, 457.

[71] K.S. Nimavat, K.H. Popat, S.L. Vasoya and H.S. Joshi, Indian Journal of

Heterocyclic Chemistry., 2003, 12, 217.

[72] Shankaraiah G Konda, Vishnu T Khedkar and Bhaskar S Dawane, Journal of

Chemical and Pharmaceutical Research., 2010, 2(1), 187-191.

[73] O.A. Fatalla et al, Arch Pharm Res., 2005, 28(11), 1205-1212.

[74] V.N. Ingle et al, Indian Journal of chemistry., 2008, 47B, 1260-1270.

[75] Raga Basawaraj, Ravi Hassappa, Neelavathi Chillargi and shivanand Noola,

Indian Journal of Heterocyclic Chemistry., 2010, 19, 252-256.

[76] M.L. Ladani, S.D. Tala, J.D. Akbari, M.F. Dhaduk and H.S. Joshi, Journal of

Indian Chemical Soc., 2009, 86, 104-108.

[77] V. Harinadha Babu, P. Senthil Kumar, K.K. Srinivasan and G.V. Aradaraja

Bhat, Indian J. Pharm. Sci., 2004, 66.

Chapter -VI

Page No. 162

[78] V.N. Ingle, S.T. Karche and U.G. Upadyaya, Indian.j. Chem., 2004, 42B, 2027.

[79] Chintan C Raval, B.M. Sharma Hardik Mehta, A.J. Rojiwadiya, RJPBCS.,

2012, 3, 56.

[80] A.M. Sroura, A. Abd El-Hamid, Ismailb, M. Salah, El-Kosyb and F. Ibrahim, Z.

Zeidb, Naturforsch., 2009, 64, 483-489.

[81] M. Amir et al, Acta Pharm., 2008, 58, 467–477.

[82] Y.A. Mohamed et al, J. Chem. Sci., 2012, 124, 693–702.

CHAPTER - VII

Synthesis of benzothiophene linked triazolothiadiazole

derivatives.

Chapter VII

Page No. 163

INTRODUCTION

Over the years, synthetic heterocyclic chemistry is providing momentum to the

development of new drug scaffolds, through interactive manipulation of functional

groups around the basic skeleton. Among these, heterocyclic compounds have been

given special importance because of a wide variety of biological properties associated

with them. The importance of heterocycles in biological systems encouraged chemists

to design and modify new heterocyclic compounds1,2

. During the last two decades, the

chemistry of 1,2,4-triazole and 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole and their

derivatives have received considerable attention owing to their synthetic and effective

biological importance3-5

. The 1,2,4-triazole ring is an integral part found in various

drugs such as rizatriptan, ribavirin, and fluconazole, which find a wide range of

applications in pharmaceutical industry10-12

.

Triazolothiadiazole is a fused heterocyclic contained triazole and thiadiazole

nucleus and exhibited immense pharmacological activities13-19

. The triazolothiadiazole

nucleus is present in compounds are evaluating for new products that possess some

remarkable pharmacological activities. Triazolothiadiazole constitute an important class

of biologically active drug molecules which has attracted attention of medicinal

chemists due to their wide range of pharmacological properties. These compounds are

being synthesized as drugs by many researchers in order to combat diseases with

minimal toxicity and maximal effects. These predictions has provided therapeutic

pathway to develop new effective biologically active triazolothiadiazole20-30

.

Recently, it was reported that the [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles and

[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines possess antimicrobial activities31

. Also, 6-

substituted 3-(1-adamantyl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles have been

evaluated for their antiviral activity32

. The [1,2,4]triazoles and [1,3,4]thiadiazoles are

Chapter VII

Page No. 164

known for their broad-spectrum of biological activities and many other uses33-37

.

Moreover, the triazolothiadiazoles substituted in the 3 and 6 positions by aryl, alkyl or

heterocyclic moiety possess pharmacological activity such as antibacterial38

, anti-

inflammatory39

, herbicidal40

and anti-HIV-1 effects41

. On the other hand, it has been

reported that certain compounds bearing a thiadiazole and 1,2,4-triazole nucleus

possess significant anti-inflammatory activity42-45

. In addition, it was mentioned that

[1,3,4] thiadiazoles exhibit various biological activities possibly due to the presence of

the =N-C-S moiety46

. The synthesis of triazoles fused to another heterocyclic ring has

attracted particular attention due to their diverse applications as antibacterial,

antidepressant, antiviral, antitumor, anti-inflammatory agents, pesticides, herbicides,

lubricant and analytical reagents47,48

. A number of triazoles fused to thiadiazines or

thiadiazoles are incorporated into a wide variety of therapeutically important

compounds possessing a broad spectrum of biological activities49-55

.

Compounds classified as heterocycles probably constitute the largest and most

varied family of organic compounds. They are rich sources of diverse physical,

chemical and biological properties. In medicinal chemistry they are commonly used as

template to design biologically active agents. A number of compounds having

heterocyclic nucleus such as thiadiazole, triazole, benzothiazole, benzoxazole,

oxadiazole etc and their derivatives have been associated with broad spectrum of

biological activities56-70

. In addition, it was reported the synthesis of triazole fused with

another heterocyclic ring has attracted widespread attention due to their diverse

applications. Among them symmetrical triazole fused with thiadiazole represent an

interesting class of compound since 1,2,4, triazole and1,3,4 thiadiazole both possess

wide spectrum of activities71-80

.

Chapter VII

Page No. 165

1,2,4-triazole is a basic aromatic heterocycles, that has a five-membered ring containing

two carbon atoms and three nitrogen atoms. It is interesting to use 1,2,4-triazole

derivatives is an important biologically active heterocycle agent, which constitute an

important class of organic compounds with diverse biological activities80-85

. They are of

two types 1,2,3 triazole and 1,2,4 triazole. If two triazole units are linked by carbon

atoms, then they are bis-triazole various 1,2,4 triazole are found to linked with diverse

pharmacological activities86-91

.

1,2,4-triazoles have drawn the attention of medicinal chemists due to its low

toxicity and good pharmacokinetic and pharmaco dynamic profiles92-96

. Their stability

to metabolic degradation, affinity for various bio targets, increased solubility in

metabolic systems impart them the wide pharmacological spectrum. 1,2,4-triazole

constitute the promising therapeutic agents and is the core structural component of

many drugs. Added to its significant pharmacological features, the incorporation of

various aromatic and aliphatic substituents97-102

.

It is well known that 1,3,4 thiadiazole is a versatile moiety and many drugs

containing thiadiazole nucleus are available in market such as diuretic-Acetazolamide,

Methazolamide, antibacterial-Sulphamethazole, antibiotic-Cefazoline etc., The review

of literature showed that the thiadiazole derivatives possess antimicrobial103-105

, anti-

inflammatory, anticancer106-108

, anticonvulsant, antidepressant carbonic anhydrase

inhibitor and antioxidant activities109-115

. The derivatives from 1,2,4-triazole, possess

potent biological activities such as antifungal116

, antibacterial, antiviral, antimigraine

activities117-119

. Some available therapeutically important medicines containing triazole

nucleus are, hypnotic-Triazolam, Estazolam, antifungal drugs-Fluconazole,

Voriconazole and antiviral drug- Ribavirin120-132

.

Chapter VII

Page No. 166

G.L. Almajan et al, reported the synthesis and antimicrobial evaluation of some

fused heterocyclic [1,2,4]triazolo[3,4-b][1,3,4]thiadiazolo derivatives 1 such as 6-(4-

methoxy phenyl)-3-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole133

.

NN

NS

N

O1

Synthesis of some novel 2-substituted-5-[isopropylthiazole] clubbed 1,2,4-

triazole and 1,3,4-oxadiazole 2 such as 3-(4-isopropylthiazol-2-yl)-5-(methylthio)-4-

phenyl-4H-1,2,4triazole were reported as potential antimicrobial and anti-tubercular

agents by G.V.S. Kumar et al134

.

S

NN

NN

SCH3

2

Synthesis of compounds possessing anti-inflammatory and molluscicidal agents

with 3-((2,4-dichlorophenoxy)methyl)-1,2,4-triazolo(thiadiazoles and thiadiazines) 3 as

basic nuclei and derivative of the type 3-methoxy-[1,2,4]triazolo[3,4-

b][1,3,4]thiadiazole were reported by M.F.E. Shehry et al.135

.

N

N

N

S

N

O

3

D.J. Prasad et al, reported synthesis of some new triazolothiadiazoles bearing 4-

methylthiobenzyl moiety, 3-(3-methylthiobenzyl)-6-(3-methoxyphenyl)-[1,2,4] triazolo

[3,4b] [1,3,4] thiadiazole 4 as one of the derivative having antimicrobial activity136

.

Chapter VII

Page No. 167

NN

N

S

N

O

SCH3 4

M. Amir et al, reported the synthesis of 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole

derivatives of ibuprofen 5 and biphenyl-4-yloxy acetic acid having condensed

bridgehead nitrogen heterocyclic system and N-methoxy-3-phenyl-[1,2,4]triazolo[3,4-

b][1,3,4]thiadiazol-6-amine as one of the derivative having various pharmacological

activities137

.

N

N

N

S

N NH

O

5

Studies on synthesis and pharmacological activities of 3,6-disubstituted-1,2,4-

triazolo[3,4-b]-1,3,4-thiadiazoles and their dihydro analogues of the type 2,6-

dimethoxyl-3-((3-phenyl-[1,2,4]triazolo3,4-b][1,3,4]thiadiazol-6-yl)methyl)-1H-indole

6 were carried out by Mathew V et al138

.

NN

N

S

N

NH

O

O

6

Synthesis, characterization and biological evaluation of 7 some novel condensed

3, 6-disubstituted-1,2,4-triazolo-1,3,4-thiadiazole derivatives. P. Chaturvedia, P. Valen

tinab and P. Kamariac Der Pharmacia Lettre, reported as potential antimicrobial and

antioxidant agents139

.

Chapter VII

Page No. 168

NN

N

S

NAr

Ar1

7

Toxicity Studies of Triazolo-Thiadiazoles 8 in Ehrlich Ascitic Carcinoma Cells

Dhanya Sunil, Arun M Isloor, Prakash Shetty and K.S. Pai reported the anticancer

activity140

.

PRESENT WORK

NN

N

S

N

NH

N

R1

R

8

continuation of our research work on fused heterocycles, in view of the

activities exhibited by 1,2,4 –triazole, 1,3,4 thiadiazole, and triazolothiadiazole rings,

we thought of interest to couple these biolabile rings together with the hope of

achieving compounds with better biological activities. Benzothiophene derivatives

exhibit various biological activities as referred in the literature and discussed in the

chapter 1. The incorporation of pharmacologically lead moieties such as triazole,

thiadiazole, and triazolothiadiazole rings in to the benzothiophene derivatives would

enhance the biological profile many folds. Envisaged by this thinking, it was thought of

to synthesize benzothiophene linked to triazole, thiadiazole, and triazolothiadiazole.

Chapter VII

Page No. 169

S

NH2

O

ONH

NH2

K+S

-

S

NH2

OO

NH NH

S

S

NH2

O

N

N N

NH2

SH

O

OH

NH2NH2.H2O

CS2/KOH/EtOH

R

S

NH2

O

O

O

NH2NH2.H2O

1

2

3

4

5a-fR

S

NH2

O

N

N N

N

S

S cheme - VI

Compounds R

5a 2-OH

5b 4-CN

5c 2-NO2

5d 4-CH3

5e 4-Cl

5f 4-OCH3

Chapter VII

Page No. 170

The compound 3-amino-6-methoxy-1-benzothiophene-2-carbohydrazide 2 was

used for synthesis of triazole derivatives. The CS2 was added drop wise to a stirred

solution of compound 2 in absolute ethyl alcohol containing potassium hydroxide at

0C. The reaction mixture was stirred at room temperature for about 16 hours, and then

it was diluted with diethyl ether, to get potassium salt of 2-[(3-amino-6-methoxy-1-

benzothiophene-2-carbonyl]hydrazine carbodithioic acid 3.

The potassium salt obtained in quantitative yield and used immediately without

further purification as it was moisture sensitive.

S

NH2

O

ONH

NH2

K+S

-

S

NH2

OO

NH NH

S

CS2/KOH/EtOH

0oC

23

The hydrazine hydrate was added to a stirred solution of compound 3 in

minimum quantity of water. And the mixture was refluxed with stirring for about 4

hours. Then reaction mixture was cooled to room temperature, diluted with ice cold

water and acidified with dilute HCl to get 4-amino-5-(3-amino-6-methoxy-1-

benzothiophen-2-yl)-4H-1,2,4-triazole-3-thiol. The triazole derivative found in low

yield found to be associated with many impurities and was purified through

recrystallization several times by using ethyl alcohol to get pure compound 4

K+S

-

S

NH2

OO

NH NH

S

S

NH2

O

N

N N

NH2

SH

NH2NH2.H2O

3 4

The IR spectrum of the compound 4 exhibited broad peak corresponding to NH2

group at 3432cm-1

and 3365 and SH at 2562. 1H NMR spectra of the same compound

was recorded in DMSO exhibited a singlet peak at δ 13.74 is due to presence of SH

Chapter VII

Page No. 171

group. A multiplet in the region δ 8.10-6.96 corresponds to three aromatic proton, a

singlet at δ 5.49 due to two protons of NH2. In addition, the structure of 4 was

confirmed by mass spectrum which showed formation of compound 4 indicated

molecular ion peak at m/z 293.Which confirms the molecular weight of the compound.

The triazole 4 was utilized for the synthesis of triazalothiadiazole derivatives. A

mixture of benzoic acid and excess of POCl3 was taken in a round bottom flask and was

refluxed on steam bath for about 30 minutes. To the above reaction mixture, the triazole

4 was added in small portions and the reaction mixture was refluxed for about 12 hours

on occasional shaking. The reaction was carried out in an efficient fuming cupboard by

monitoring through TLC. After completion of the reaction, the excess of POCl3 was

distilled off under reduced pressure and poured into crushed ice with vigorous stirring

and then neutralized with saturated solution of sodium bicarbonate solution. The solid

obtained was dried and purified through column chromatography by using ethyl acetate

and n-hexane in the ratio 2:8 as an eluent to pure get 5a.

S

NH2

O

N

N N

NH2

SHO

OH R

R

S

NH2

O

N

N N

N

SPOCl3

4 5a-f

The formation of the 5a was confirmed by IR spectrum compound 5a exhibited broad

peak corresponding to NH2 group at 3465, 3372cm-1

and peak at 733 cm-1

due to C-Cl.

The 1H NMR spectra showed a multiplet in the region between δ 8.05-7.04

corresponding to 7 aromatic protons. A singlet at δ 4.39 due to two protons of NH2

group and three protons of OCH3 appears in the region δ 3.74. The formation of the 5a

compound further confirmed by recording its mass spectrum, which exhibited a

molecular ion peak m/z 414. Similarly, 5b-f were prepared and confirmed by spectral

data.

S

NH2

O

N

N N

NH2

SH

IR spectrum of 4

S

NH2

O

N

N N

NH2

SH


S

NH2

O

N

N N

NH2

SH

Mass spectrum of 4

S

NH2

O

N

N N

N

S

Cl

IR spectrum of 5a

S

NH2

O

N

N N

N

S

Cl


S

NH2

O

N

N N

N

S

Cl

Mass spectrum of 5a

Chapter VII

Page No. 172

EXPERIMENTAL

2-[(3-amino-6-methoxy-1-benzothiophene-2-carbonyl]hydrazine carbodithioic acid

(3):

Carbon disulfide (0.075mol, 5.71g, 4.53ml ) was added drop wise to a solution of

compound 2 (0.05mol, 11.85g) in absolute ethanol (50 ml) containing potassium

hydroxide (0.075mol, 3g) at 0C. The reaction was stirred for 16 hours and completion

of the reaction was monitored through TLC. After completion, the reaction mixture was

cooled and diluted with diethyl ether. The precipitate was filtered, washed with diethyl

ether and dried. The potassium salt obtained was in quantitative yield and used without

further purification as it was moisture sensitive.

4-Amino-5-(3-amino-6-methoxy-1-benzothiophen-2-yl)-4H-1,2,4-triazole-3-thiol.

(4):

Hydrazine hydrate (0.10mol, 3.20g, 3.14ml) was added to a suspension of the

potassium salt (0.05 mol, 17.55g) in water (40 ml) and the reaction mixture was

refluxed with stirring for about 4 hours. Then after cooling, it was diluted with water

and acidified with aqueous hydrochloric acid. The precipitate obtained was filtered,

washed with water and recrystallized from ethyl alcohol to get compound 4.

S

NH2

O

N

N N

NH2

SH


): 3432, 3365 (NH2), 3303, 3213

(NH2) 1621 (C=N) 2562 (C-SH); 1H NMR(400 MHz, DMSO-d6) δ (ppm): 13.74 (1H,

s, SH), 8.10-6.96 (3H, m, Ar-H), 5.49 (2H, s, NH2), 4.42 (2H, s, NH2), 3.76 (3H, s,

Chapter VII

Page No. 173

OMe); Elemental analysis: Calculated (%) for C11H11N5OS2: C, 45.03. H, 3.77. N,

23.87. S, 21.86 ; Found: C, 45.00. H, 3.74. N, 23.84. S, 21.83; LC-MS m/z: 293 ; M.P:

256-259 0C.

2-[6-(4-Chlorophenyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl]-6-methoxy-1-

benzothiophen-3-amine (5a) :

A mixture of 4-amino-5-(3-amino-6-methoxy-1-benzothiophen-2-yl)-4H-1,2,4-triazole-

3-thiol (0.01 mol, 2.93g) And 2-hydroxy benzoic acid (0.01mol, 1.38g)in POCl3

(0.099mol, 15.2g, 9.1ml) was taken 100 ml round bottom flask was refluxed at reflux

temperature for about 12 hours and the completion of the reaction was monitored

through TLC. After completion of the reaction, the reaction mixture was cooled to

room temperature and crushed ice with vigorous stirring and then neutralized with

saturated sodium bicarbonate solution. The solid that obtained was filtered, dried and

purified through column chromatography by using ethyl acetate and n-hexane (2:7) as

an eluent to get pure compound 5a. Similarly, 5b-f compounds were prepared.

S

NH2

O

N

N N

N

S

Cl


): 3465, 3372 (NH2), 1628 (C=N),

733 (C-Cl); 1H NMR(400 MHz, DMSO-d6) δ (ppm): 8.05-7.04 (7H, m, Ar-H), 4.39

(2H, s, NH2), 3.74 (3H, s, OMe); Elemental analysis: Calculated (%) for

C18H12ClN5OS2: C, 52.23. H, 2.92. N, 16.92 S, 15.49; Found: C, 52.20. H, 2.89. N,

16.87. S, 15.46 ; LC-MS m/z: 414, 416; M.P: 287-290 0C.

Chapter VII

Page No. 174

2-[3-(3-Amino-6-methoxy-1-benzothiophen-2-yl)[1,2,4]triazolo[3,4-b] [1,3,4]thiadi

azol-6-yl]phenol (5b) :

S

NH2

O

N

N N

N

S

OH


): 3474, 3381 (NH2), 1632 (C=N);

1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.00-7.12 (7H, m, Ar-H), 5.35 (1H, s, OH),

4.70 (2H, s, NH2), 3.75 (3H, s, OMe). Elemental analysis: Calculated (%) for

C18H13N5O2S2: C, 57.95; H, 4.38; N, 6.75. S, 16.21; Found: C, 57.89; H, 4.35; N, 6.72.

S, 16.19; LC-MS m/z: 293.36; M.P: 288-291 0C.

4-[3-(3-amino-6-methoxy-1-benzothiophene-2-yl)[1,2,4]triazolo[3,4-b][1,3,4]thiad

iazol-6-yl]benzonitrile (5c) :

S

NH2

O

N

N N

N

S

N


): 3457, 3362 (NH2), 1628 (C=N);

1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.25-7.15 (7H, m, Ar-H), 4.44 (2H, s, NH2),

3.72 (3H, s, OMe); Elemental analysis: Calculated (%) for C19H12N6OS2: C, 56.42. H,

2.99. N, 20.77. S, 15.85; Found: C, 56.38. H, 2.95. N, 20.73. S, 15.82 ; LC-MS m/z:

404.46.; M.P: 298-301 0C.

Chapter VII

Page No. 175

6-Methoxy-2-[6-(2-nitrophenyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl]-1-

benzothiophen-3-amine (5d):

S

NH2

O

N

N N

N

S

NO2


): 3468, 3376 (NH2), 1630 (C=N);



2.84. N, 19.80. S, 15.11; Found: C, 50.88. H, 2.81. N, 19.77. S, 15.08 ; LC-MS m/z:

424.42; M.P: 267-270 0C.

6-Methoxy-2-[6-(4-methylphenyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl]-1-

benzothiophen-3-amine (5e):

S

NH2

O

N

N N

N

S


): 3460, 3368 (NH2), 1622 (C=N),

733 (C-Cl); 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.10-7.14 (7H, m, Ar-H), 4.30

(2H, s, NH2), 3.75 (3H, s, OMe), 2.42 (3H, s. CH3); Elemental analysis: Calculated (%)

for C19H15N5OS2: C, 57.99. H, 3.84. N, 17.79. S, 16.29; Found: C, 57.96. H, 3.80. N,

17.77. S, 16.24 ; LC-MS m/z: 393.48; M.P: 259-261 0C.

Chapter VII

Page No. 176

6-Methoxy-2-[6-(4-methoxyphenyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl]-1-

benzothiophen-3-amine (5f) :

S

NH2

O

N

N N

N

S

O


): 3478, 3386, (NH2), 1632 (C=N);



3.69. N, 17.12. S, 15.66 Found: C, 55.70. H, 3.63. N, 16.98. 15.64 ; LC-MS m/z:

409.48; M.P: 290-293 0C.

Chapter VII

Page No. 177

REFERENCES

[1] R. K. Tiwari et al, Bioog Med Chem Lett., 2006, 16, 413.

[2] P. Kumar, A. Kumar, J.K. Makrandi, J. Heterocyclic Chem., 2013.

[3] J.G. Sadaf, A.K. Suroor, S. Nadeem, Bioorg. Med. Chem. Lett., 2010, 20, 4762-

4765.

[4] L.A. Gabriela, F.B. Stefania, B. Gabriela, S. Ioana, S. Gabriel, D. Constantin,

Eur. J. Med. Chem., 2010, 45, 6139-6146.

[5] V. Padmavathi, G. Sudhakar Reddy, A. Padmaja, P. Kondaiah, P. Ali-Shazia,

Eur. J. Med. Chem., 2009, 44, 2106-2112.

[6] I.R. Ezabadi, C. Camoutsis, P. Zoumpoulakis, A. Geronikaki, M. Sokovic, J.

Glamocilija, A. Ciric, Bioorg Med Chem., 2008, 16, 1150.

[7] L. Meerpoel et al, J Med Chem., 2005, 48, 2184.

[8] K. Walczak, A. Gondela, J. Suwinski, Eur. J. Med. Chem., 2004, 39, 849.

[9] L. Labanauskas, V. Kalcas, E. Udrenaite, P. Gaidelis, A. BrukÐtus, Farmaco.,

2004, 59, 255.

[10] D. Bianchi, P. Cesti, S. Spezia, C. Garavaglia, L. Mirenna, Chemoenzymic., J.

Agric. Food Chem., 1991, 39, 197.

[11] T. Chen, C. Dwyre-Gygax, S.T. Hadfield, C. Willetts, C. Breuil, J. Agric. Food

Chem., 1996, 44, 1352.

[12] K.M. Thaker, H.S. Joshi, I. J. Chem., 2005, 36(23).

[13] S.R. Desai, U. Laddi, R.S. Bennur, P.A. Patil, S. Bennur, Indian J Pharm Sci.,

2011, 73(1), 115–120.

[14] G.V.S. Kumar, Y.R. Prasad, B.P. Mallikarjuna, S.M. Chandrashekar, Eur J Med

Chem., 2010, 45, 5120-5129.

[15] C.S. Reddy, L.S. Rao, A. Nagaraj, Acta Chim Slov., 2010, 57, 726-732.

[16] G.L. Almajan, I. Saramet, S.F. Barbuceanu, C. Draghici, G. Bancescu, C.

Cristea, CHIM., (Bucharest) 2010, 61(9), 886-889.

[17] M. Ashok, B.S. Holla., J pharmacol & Toxicol., 2007, 2(3), 256-263.

[18] Q. Hu, W.L. Huang, H. Wang, Phase Chinese Chem Lett., 2005, 16, 1309-1312.

Chapter VII

Page No. 178

[19] A.M. Sridharaa, K.R.V. Reddy, J. Keshavayyac, B. Chidananda, Y. Prasada,

G.S. Kumara, S.G. Vadiraja, P. Bosea S.K. Gouda, S.K. Peethambard, Der

Pharma Chemica., 2010, 2(5), 201-211.

[20] A. Subramani, I. Kaliapan, R. Bairam, N. Ramalakshmi, Der Pharma Chemica.,

2009, 1(1), 70-77.

[21] M.S. Karthikeyan, B.S. Holla, B. Kalluraya, N.S. Kumar, Monatshefte fur

Chemie., 2007, 138, 1309-1316.

[22] B.S. Holla C.S. Prasanna, B. Poojary, K.S. Rao, K. Shridhara. Indian J Chem.,

2006, 45B, 2071-2076.

[23] K.C. Ravindra, H.M. Vagdevi, V.P. Vaidya, Indian J Chem, 2008, 47B, 1271-

1276.

[24] S.J. Gilani, S.A. Khan, N. Siddiqui, Bioorg & Med Chem Lett., 2010, 20, 4762–

4765.

[25] P.F. Xu, Z.H. Zhang, X.P. Hui, Z.Y. Zhanga, R.L. Zheng, J Chinese Chem.Soc.,

2004, 51, 315-319.

[26] N. Demirbas, A. Demirbas, S.A. Karaoglu, E. Çelikb, Arkivoc., 2005, (i), 75-91.

[27] B.S. Holla, K.N. Poojary, B. Poojary, K.S. Bhat, N.S. Kumari, Indian J Chem.,

2005, 44B, 2114-2119.

[28] D.J. Prasad, M. Ashok, P. Karegoudar, B. Poojary, B.S. Holla, N.S. Kumarie.,

Eur J Med Chem., 2009, 44, 551-557.

[29] P. Karegoudar, D.J. Prasad, M. Ashok, M. Mahalinga, B. Poojary, B.S. Holla,

Eur J Med Chem., 2008, 43, 808-815.

[30] Z. Fan, Z. Yang, H. Zhang, N. Mi, H. Wang, F. Cai, X. Zuo, Q. Xiang, Zheng,

H. Song, Agric Food Chem., 2010, 58, 2630-2636.

[31] S.L. Vasoya, D.J. Paghdar, P.T. Chovatia, H.S. Joshi, Journal of sciences,

Islamic Republic of Iron., 2005, 16(1), 33-36.

[32] N. Demirbas, A. Demirbas, S.A. Karaoglu, E. Çelik, ARKIVOC., 2005, (i), 75.

[33] M. Kritsanida, A. Mouroutsou, P. Marakos, N. Pouli, S. Papakonstantinou

Garoufalias, C. Pannecouque, M, Witvrouw, E. De Clercq, Il Farmaco., 2002,

57, 253.

[34] M.M. Ghorab, A.M. El-Sharief, Y.A. Ammar, S.H. Mohamed, Phosphorus,

Sulfur, Silicon & Relat. Elem., 2001, 173, 223.

[35] Wang, Zhongyi Shi, Haoxin Shi, Haijian. J. Heterocycl. Chem., 2001, 38, 355.

Chapter VII

Page No. 179

[36] E. Palaska, G. Sahin, P. Kelicen, N.T. Durlu, G. Altinok, Farmaco., 2002, 57,

101.

[37] L. Labanauskas, V. Kalcas, E. Udrenaite, P. Gaidelis, A. Brukstus, V. Dauksas,

Pharmazie., 2001, 56, 617.

[38] A. Foroumadi, M. Mirzaei, A. Shafiee, Pharmazie., 2001, 56, 610.

[39] Sun, Xiao-Wen, Zhang, Yan, Zhang, Zi-Yi, Wang Qin; Wang, Shu-Fang,

Indian J. Chem., 1999, 38B(3), 380.

[40] R.H. Udupi, G.V. Suresh, S.R. Setty, A.R. Bhat, J. Indian Chem. Soc., 2000, 77,

302.

[41] Nizamuddin, M.M. Gupta, H. Khan, M.K. Srivastava, J. Sci. Ind. Res., 1999,

58, 538.

[42] F.P. Invidiata, D. Simoni, F. Scintu, N. Pinna, Farmaco., 1996, 51, 659.

[43] M.D. Mullican, M.W. Wilson, D.T. Connor, C.R. Kostlan, D.J. Schrier, R.D.

Dyer, J.Med. Chem., 1993, 36, 1090.

[44] F.A. Omar, N.M. Mahfouz, M.A. Rahman, Eur. J. Med. Chem., 1996, 31, 819.

[45] M. Amir, A. Oberoi, S. Alam, Indian. J. Chem., 1999, 38B, 237.

[46] B. Tozkoparan, N. Gokhan, G. Aktay, E. Yesilada, M. Ertan, Eur. J. Med.

Chem., 2000,35, 743.

[47] B.S. Holla, N.K. Poorjary, S.B. Rao, M.K, Shivananda, Eur. J. Med. Chem.

2002, 37,511.

[48] B.S. Holla, P.M. Akberali, M.K. Shivananda, Il Farmaco., 2001, 56, 919.

[49] G. Turan-Zitouni, Z.A. Kaplancikli, K. Erol, F.S. Kilic, Il Farmaco., 1999, 54

218.

[50] B.S. Holla, R. Gonsalves, S. Shenoy, Il Farmaco., 1998, 53, 574.

[51] B.S. Holla, B. Sarojini, S.B. Rao, P.M. Akberali, N.S. Kumari, V. Shetty, Il

Farmaco., 2001, 56, 565.

[52] A.A. Farghaly. P. Vanelle, H.S. El-Kashef, Heterocycl. Commun., 2005, 11 (3-

4), 255.

[53] A. Farghaly, H. El-Kashef, ARKIVOC., 2006, (x) xxx.

[54] E. De Clercq, J. Descamps, G. Verhelst, R.T. Walker, A.S. Jones, P.F.

Torrence, D. Shugar, J. Infect. Dis., 1980, 141, 563.

Chapter VII

Page No. 180

[55] E. De Clercq, Antimicrob. Agents Chemother., 1985, 28, 84.

[56] M.L. Cohen, Science., 1992, 57, 1050.

[57] J.E. Bandow, H. Brotz, L.I.O. Leichert, H. Labischinski, M. Hecker,

Antimicrobial Agents and Chemotherapy., 2003, 47, 948.

[58] A. Almasirad, S.A. Tabatabai, M. Faizi, A. Kebriaeezadeh, N. Mehrabi, A.

Dalvandi, A. Shafiee, BMCL., 2004, 14, 24, 6057.

[59] G.L. Almajan, S.F. Barbuceanu, E.R. Almajan, C. Draghici, G. Saramet, Eur. J.

Med. Chem., 2009, 44,3083.

[60] J.M. Kane, M.W. Dudley, S.M. Sorensen, F.P. Miller, J. Med. Chem., 1988, 31,

1253.

[61] R. Romagnoli, P.G. Baraldi, O.P. Lopez, C.C. Lopez, M.D. Carrion, A.

Brancale, E. Hamel, L. Chen, R. Bortolozzi, G. Basso, G. Viola, J. Med. Chem.,

2010, 53, 4248.

[62] J. Xu, Y. Cao, J. Zhang, S. Yu, Y. Zou, X. Chai, Q. Wu, D. Zhang, Y. Jiang, Q.

Sun, Eur. J. Med. Chem., 2011, 46, 7, 3142.

[63] D. Kumar, N.K. Maruthi, K.H. Chang, K. Shah, Eur. J. Med. Chem., 2010,

45,4664.

[64] F. Clerici, D. Pocar, M. Guido, A. Loche, V. Perlini, M. Brufani, J. Med.

Chem., 2001, 44, 931.

[65] T.E.S. Ali, A. M. El-Kazak, European journal of chemistry., 2010, 1, 6.

[66] V. Mathew, J. Keshavayya., V.P. Vaidya, D. Giles., Eur. J. Med. Chem., 2007,

42, 823.

[67] S.N. Swamy, Basappa, B.S. Priya, B. Prabhuswamy, B.H. Doreswamy, J.S.

Prasad, K.S. Rangappa, Eur. J.Med. Chem., 2006, 41,531.

[68] F.P. Invidiata, D. Simoni, F. Scintu, N. Pinna, Farmaco., 1996, 51, 659.

[69] M.F. Shehry, A.A. Abu-Hashem, E.M. El-Telbani, Eur. J. Med. Chem.,

2010,45,1906.

[70] Mahendra Shiradkar, Unnat Pandit, Kalyan Charavarthy Akula, Abhay Maheta

and Gorentla Venkata Suresh Kumar, ARKIVOC., 2006, (xiv), 141-154.

[71] Xiang-Lin Zhao, Yan-Fang Zhao, Shu-Chun Guo, Hai-Sheng Song, Ding Wang

and Ping Gong, 2007, 12, 1136-1146.

Chapter VII

Page No. 181

[72] S.K. Srivastava, Sowmya Srivastava and S.D. Srivastava, Indian J Chem., 2002,

41B, 1937-1945.

[73] S.K. Srivastava, Sowmya Srivastava and S.D. Srivastava. Indian J Chem., 2002,

41B, 2357-2363.

[74] Peiyuan Wang, Laurent Holleckes, Krzysztof, W. Pankiewiez, Steven E.

Patterson, Tony Whitaker, J. Med. Chem., 2004, 47, 6100-6103.

[75] S.N. Pandeya, D. Sriram, G. Nath, E. de Clercq, Arzneimittel Forsch., 2000, 50,

55-59.

[76] Krishtina Brokaite, Vytutasb Mickevicius and gema Mikulskiene, ARKIVOC.,

2006, (ii): 1-7.

[77] Xin-Pin Hui, Lin-Mei Zhang and Zi-Yi Zhang, Indian J Chem., 1999, 38B,

1066-1069.

[78] C.A. Winter, E.A. Risky and G.W. Nuss.Carageenan, Proc.Soc.Exp.Biol Med.,

1962, 111, 544-547.

[79] Dayanand Kadadevar, K.C. Chaluvaraju, M.S. Niranjan, Chandrasekhar

Sultanpur, Santhosh Kumar Madinur, Nagaraj et al, Int.J.ChemTech.Research .,

2011, 3(3), 1064-1069.

[80] Harish Rajak, Bhupendra S Thakur, Poonam Parmar, Pramod Kumar, Arun

Kumar Gupta, Navneet Agarwal et al. Agric Food Chem., 2010, 58, 2630-2636.

[81] R. Gupta, S. Paul, A.K. Gupta, P.L. Kachroo, Indian J Chem., 1994, 33B, 888–

91.

[82] K.C. Ravindra, H.M. Vagdevi, V.P. Vaidya, Indian J Chem., 2008, 47B, 1271–

6.

[83] J. Nayak, K.S. Grisha, N.S. Shetty, B. Kalluraya, 2008, 17, 209-12.

[84] D.E. Snider, M. Raviglione, A. Kochi, in B. Bloom (Ed.).ASM Press,

Washington DC, 1994.

[85] L. Ballell, R.A. Field, K. Duncan, R.J. Young, Chemother., 2005, 49(6), 2153-

2163.

[86] R.H. Udupi, S.R. Setty, N. Srinivasulu. Indian Drugs., 2002, 39, 318–21.

[87] A.R. Farghalya, E. De Clercq, H. El-Kashef, Arkivoc., 2006, (x), 137-151.

[88] N.A. Al-Masoudi, Y.A. Al-Soud, 2008, 27, 1034-1044.

Chapter VII

Page No. 182

[89] M. Kritsanida, A. Mouroutsou, P. Marakos, N, Pouli. S. Papakonstantinou-

Garoufalias, C. Pannecouque, M. Witvrouw, E. De Clercq, Il Farmaco., 2002,

57, 253–257.

[90] M.P. Kumar, J. Mazumder, R. Chawla, S. Bhuvana, S. George, S.

Gopalakrishan et al, Indian J Heterocycl Chem., 2008, 17, 263–64.

[91] G.V.S. Kumar, Y.R. Prasad, B.P. Mallikarjuna, S.M. Chandrashekar, Eur J Med

Chem., 2010, 45, 5120-5129.

[92] F.A. Omar, N.M. Mahfouz, M.A. Rahman, Eur. J. Med. Chem., 1996, 31, 819.

[93] B.N. Goswami, J.C.S. Kataky, J.N. Baruah, S.C. Nath, J. Heterocycl. Chem.,

1984, 21, 205.

[94] M.T. Omar, Arch. Pharm. Res., (Seoul) 1997, 20, 602.

[95] M.M. Hamad, S.A. Said, Y.M. El-Ekyabi, Monatsh. Chem., 1996, 127, 549.

[96] G.D. Diana, D.L. Volkots, T.J. Nitz, T.R. Biailly, M.A. Long, N. Vesico, A.

Aldous, D.C. Pevear, F.J. Dukto, J. Med. Chem., 1994, 37, 2421.

[97] S. Liras, M.P. Allen, B.E. Segelstein, Synth. Commun., 2000, 30, 437.

[98] H.J. Carlsen, K.B. Jorgensen, J. Heterocycl. Chem., 1994, 31, 805.

[99] W.R. Tully, C.R. Cardner, R.J. Gillespie, R. Westwood, J. Med. Chem., 1991,

34, 2060.

[100] M. Al-Talib, H. Tashtoush, N. Odeh, Synth. Commun., 1990, 20, 1811.

[101] A.B. Theocharis, N.E. Alexandrou, J. Heterocycl. Chem., 1990, 27, 1685.

[102] F.W. Short, L.M. Long, J. Heterocycl. Chem., 1969, 6, 707.

[103] F. Bentiss, M. Lagrenee, J. Heterocycl. Chem., 1999, 36, 1029.

[104] D.L. Hill, Cancer Chemother. Pharmacol., 1980, 4, 215.

[106] H.N. Dogan, A. Duran, S. Rollas, G. Sener, M.K. Uysal, D. Gulen, Bioorg.

Med.Chem., 2002, 10, 2893.

[107] M.L. Thomasco. C.R. Godwood, A.E. Weaver, M.J. Ochoada and W.C. Ford,

Bioorg. Medi.Chem. Lett., 2003, 13, 4193.

[108] N.K. Wadokar and M.A. Dhiman, Indian J. of Chem., 2001, 40B, 636.

[109] S.H. Joshi and K.A. Thakar, Indian J. of Chem., 2005, 44B, 410.

Chapter VII

Page No. 183

[110] A. Foroumadi, A. Mirzaei and A. Shafiee, II Farmaco., 2001, 56, 621.

[111] E. Plaska, G. Shahin, P. Kelicen, T.N. Duslu and G. Altino, II Farmaco., 2002,

57, 101.

[112] N.H. Dogan, A. Duran, S. Rollas, G. Sener, K.M. Uysal and D. Gulen, Bioorg.

Med. Chem., 2002, 10, 2893.

[113] A. Mohammad and A. Chhavi, Int.J.of ChemTech Research., 2009, 1(4), 1200-

1205.

[114] M. Ashok and B. S Holla, Phosphorous, Sulfur, and Silicon., 2007, 182, 981.

[115] D.J. Prasad, M.S. Karthikeyan, P.B. Karegoudar and B.S. Holla, Phosphorous,

Sulfur, and Silicon., 2007, 182, 1083.

[116] B.T. Mahadev, R.D. Shoba, S.S. Yallappa, C.M. Subash and C.B. Shankar, Ind.

J. of hetro. chemi., 1996, 5, 215-218.

[117] Silver stenin, R.M. Bassler and T.C. Morrd, Spectrometric identification of

organic compounds., 1979, 5, 328.

[118] H.W. Seely and P.J. Van Denmark, In. Microbes in action: A Lab. Manual of

Microbiology., 1975, 2, 55.

[119] T. Nogrady, F.D. Weaver, Medicinal Chemistry, A Molecular & Biochemical

Approach, Oxford University Press, NewYork., 2005.

[120] T.G. Zitouni, A.Z. Kaplancikli, T.M. Yildiz, P. Chevallet, D. Kaya, Eur. J. Med.

Chem. 2005, 40,607.

[121] N.S. Swamy, Basappa, S.B. Priya. B. Prabhuswamy, B.H. Doreswamy, S.J.

Prasad S. Rangappa, Eur. J. Med. Chem., 2006, 41, 531.

[122] P. Karegoudar, J.D. Prasad, M. Ashok, M. Mahalinga, B. Poojary, S.B. Holla,

Eur. J. Med. Chem., 2008, 43, 808.

[123] V. Mathew, J. Keshavayya, P.V. Vaidya, Eur. J.Med. Chem., 2006, 41, 1048.

[124] D.A. Ibrahim, Eur. J. Med. Chem., 2009, 44, 2776.

[125] M. Amir, H. Kumar, A.S. Javed, Bioorg. Med.Chem. Lett., 2007, 17, 4504.

[126] V. Padmavathi, N.V.A. Mohan, P. Thriveni, A. Shazia, Eur. J. Med. Chem.,

2007, 44, 2313.

[127] A.A. Kadi, R.N. El-Brollosy, A.O. Al-Deeb, E.E. Habib, M.T. Ibrahim, A.A.

El-Emam Eur.J. Med. Chem., 2007, 42, 235.

Chapter VII

Page No. 184

[128] H. Kumar, S.A. Javed, S.A. Khan, M. Amir, Eur. J. Med. Chem., 2008, 43,

2688.

[129] T. Onkol, S.D. Dogruer, Leylauzun, S. Adak, S. Ozkan, F.M. Sahin, J. Enz. Inh.

Med. Chem., 2008, 23, 277.

[130] A.L. Barry, V.L. Corian, Ed, Williams and Wilkins, Baltimore., 1991.

[131] G.L. Almajan, S.F. Barbuceanu, G. Bancescu, I. Saramet, G. Saramet, Eur J

Med Chem., 2010, 45, 6139-46.

[132] G.V.S. Kumar, Y. Rajendraprasad, B.P. Mallikarjun, S.M. Chandrashekar, C.

Kistayya. Eur J Med Chem., 2010, 45, 2063-74.

133] M.F.E. Shehry, A.A. Abu, Hashem, E.M. El-Telbanin, Eur J Med Chem., 2010,

45, 1906-11.

[134] D.J. Prasad, M. Ashok, P. Karegaudar, B. Poojary, B.S. Holla, N.S. Kumari,

Eur J Med Chem., 2009, 44, 551-57.

135] M. Amir, H. Kumar, S.A. Javed, Eur J Med Chem., 2007, 1-11.

[136] V. Mathew, J. Keshavayya, D. Giles, V.P. Vaidya, Eur J Med Chem., 2007, 42,

823-40.

[137] P. Chaturvedia, P. Valentinab and P. Kamariac, Der Pharmacia Lettre., 2013, 5

(4), 344-350.

[138] Dhanya Sunil, Arun M Isloor, Prakash Shetty and K.S.R. Pai, Research Journal

of Pharmaceutical Sciences., 2013.

[139] Mohammad Amir, Harish Kumar and. S.A. Javed, Bioorganic & Medicinal

Chemistry Letters., 2007, 17, 4504–4508.

CHAPTER - VIII

Biological evaluation.

Chapter - VIII

185

BIOLOGICAL AND PHARMACOLOGICAL EVALUATION

INTRODUCTION

One of the major causes for the progress of chemistry of benzothiophene

derivatives is the association of these moieties with various biological activities. This

fact stimulated several researchers to take up the synthesis, identification and biological

evaluation of benzothiophene compounds. With the increase in number of cases of

multiple drug resistant pathogenic infections, emergence of newer disease like AIDS

and emergence of drug-drug interactions and side effects, always there is need for

discovery of newer drugs which possess potential biological action with lesser side

effects. This has been one of the major reasons for the progress of synthetic chemistry.

Among the many method employed for discovery of newer drugs, one of the widely

used method is preparation of analogs of biologically potent heterocycles. Biological

and pharmacological significance of benzothiophenes is already discussed in detail in

Chapter-I.

The major objective of the present investigation is to explore biological potency

of benzothiophene derivatives. Hence, a number of benzothiophene compounds with

possible biological activities are designed synthesized and selected compounds have

been evaluated for

Antibacterial activity

Antifungal activity

Anthelmintic activity

Analgesic activity

Which are described in the following pages.

Chapter - VIII

186

ANTIBACTERIAL ACTIVITY

The development of resistance by various pathogens towards antibiotics has

stimulated the invention of newer antimicrobial agents. It is evident from the literature

survey that simple substituted benzothiophene, fused benzothiophene systems,

biheterocyclic benzothiophenes and benzothiophene coupled with other heterocyclic

systems and benzothiphenes. Thienobenzothiophenes and thienopyrimidines are

capable of exhibiting antibacterial activities. Hence, selected benzothiophene

derivatives prepared in the course of present work are screened for antibacterial

activity.

Evaluation of antibacterial activity

The antibacterial activity of benzothiophene derivatives was studied by cup-

plate method and the results are compared with of standard antibiotics,

Chloramphenicol using two Gram +ve organisms - Staphylococcus aureus and Bacillus

subtilis and two Gram -ve organisms namely, Escherichia coli and Salmonella

paratyphi-A.

Materials and Method

1. Medium A as described in Indian Pharmacopoeia.

2. Sterilised petri dishes, pipettes and beakers.

3. 8 to 24 hrs Old growth cultures in nutrient broth.

4. Sterilised test tubes.

5. Sterile 6 mm cork borer.

6. Sterile inoculation loops.

7. Sterilised fine pointed forceps.

8. Nutrient agar.

Chapter - VIII

187

Preparation of media

Medium was prepared as per Indian Pharmacopoeia. Bacteriological peptone

(6g), pancreatic digest of casein (4g), yeast extract (3g), beef extract (1.5g), dextrose

(1.0g) and agar (l5.0g) were dissolved in distilled water to produce 1 litre of medium.

The pH of the solution was adjusted to 6.5-6.6 by using 1M sodium hydroxide and 1 M

HCl. Thus, prepared media was sterilized for 30 minutes at 15 lbs pressure in an

autoclave.

Preparation of sub-cultures

Nutrient broth was prepared by dissolving bacteriological peptone (6g),

pancreatic digest of casein (4g), yeast extract (3g), beef extract (1.5g), dextrose (1.0g)

in distilled water to produce 1 litre of nutrient broth. Then the pH was adjusted to 6.2

and sterilized by autoclaving for two hr. at 15 lbs pressure.

The organisms used for antibacterial study were obtained from the

Microbiology Department of Bapuji Medical College, Davanagere. On the day of

testing, the organisms were sub cultured into sterile nutrient broth. After incubating

sterile nutrient broth, the growth thus obtained was used as inoculum for the test.

Sterilization of media and Glassware’s

The media used in the present study are nutrient agar and nutrient broth. And

were sterilized in conical flasks of suitable capacity by autoclaving at 15 lbs pressure

for about 20 minutes. The cork borer, petri dishes, test tubes and pipettes were

sterilized in hot air oven at 160 0C for an hour.

Preparation of solutions of test compounds

All the tested compounds were dissolved in minimum amount of dimethyl

formamide (DMF) and the final volume made with distilled water to get 40 g/ml.

Chapter - VIII

188

Method of testing

Cup-plate Method: In this method, the diffusion of an antibiotic from a cavity

through the solidified agar layer in a petri dish to an extent such that growth of the

added microorganism is prevented entirely in a circular area or zone around the cavity

containing a solution of antibiotic.

Previously liquified medium was inoculated with the requisite quantity of the

suspension of the microorganisms between 40-50 0C and the inoculated medium was

poured into petri dishes to give a depth of 3 to 4 mm. This was to ensure that the layers

of medium were uniform in thickness by placing the dishes on a leveled surface.

The dishes thus prepared were stored in a manner so as to ensure that no significant

growth or death of the test organism occurs before the dishes were used and the surface

or the agar layer was dry at the time of use. With the help of a sterile cork borer, five

cups of each 6 mm diameter were punched and agar was scooped out of the in each

petri dish (five cups were numbered for the particular compound and standard). Using

sterile pipettes, the standard and the sample solutions of known concentrations were

poured into the bored cups. The order of the solutions was as follows:

Cup- 1: Standard-1 (40 g/ml)

Cup- 4: Test compound-2 (40 g/ml)

Cup- 5: Solvent control (DMF)

The dishes were allowed to stand at room temperature for one hour to minimize

the effects of variation in time among the applications of different solutions. These

were then incubated for 24 hrs at 37°C. The zone of inhibition developed, if any, was

then accurately measured and recorded. Each zone of inhibition recorded was average

of three measurements. Zone of inhibition for water was done separately. The results

are tabulated in tables.

Chapter - VIII

189

Microorganisms used for test

S. aureus : Staphylococcus aureus

B. subtilis : Bacillus subtilis

E. coli : Escherichia coli

S. paratyphi-A : Salmonella paratyphi-A

Index

Conc. of penicillin : 40 g/ml in distilled water

Conc. of streptomycin : 40 g/ml in distilled water

Conc. of test compound : 40 g/ml in minimum amount of DMF

in distilled water

Diameter of cup : 6 mm.

Treatment

Zone of inhibition(in mm)

Gram positive bacteria Gram negative bacteria

Staphylococcus

aureus

Bacillus

subtilis

Salmonella

paratyphi-A

Escherichia

coli

DMF(Control) 00 00 00 00

Chloramphenicol 20 21 18 22

Chapter - VIII

190

Table-1: Antibacterial activity of pyrazole, pyrazolone, oxadiazole and imidazole

substituted benzothiophene derivatives

S

NH2

O

N

N

O

CH3

N

NH

S

NH2

O

N

NH3a-f 4a-f

RR

S

ClN

O

S

F

NH2 N

4a-c

S

FNH2

NH

O

N

N

O

6a-f

R

Compound R

Diameter of zone of inhibition (in mm )

Staphylococc

us aureus

Bacillus

subtilis

Salmonella

paratyphi-

A

Escherichi

a coli

3a 2-OCH3 14 12 14 15

3e 4-F 20 22 20 18

4b 4-NO2 14 14 13 14

4d 4-Cl 19 17 15 20

4e 4-OCH3 13 15 14 13

6a 2-OH 12 12 15 12

6d 4-NO2 11 13 14 14

6f 4-Cl 22 16 19 23

4a S

Cl

O

Cl 24 22 17 21

4c O

Cl

16 15 15 15

DMF 00 00 00 00


Chapter - VIII

191

Table-2: Antibacterial activity of thiopyrimidines, triazole-thiadiazole,

azetidinone, oxadiazole substituted benzothiophene derivatives

S

NH2

O

NH

N

ONH

S4a-d

R

S

NH2

ON

N N

N

S

R

5a-e

S

O

O

NHN

S R

O

Cl

5a-d

S

NH2

N

O

N

O

R

7a-d

Compound R


Staphylococc

us aureus

Bacillus

subtilis

Salmonella

paratyphi-

A

Escherichi

a coli

4a 4-Br 24 17 20 19

4c 4-OH 12 14 14 14

5a 2-OH 13 12 13 13

5b 4-CN 16 15 15 15

5c 2-NO2 12 12 13 14

5a NH

O

21 19 16 21

5d

O

N+

O-

O

15 10 14 19

7a 4-Cl 14 15 15 13

7b 4-OCH3 16 12 16 17

7c 4-OH 23 18 19 18

DMF 00 00 00 00


Chapter - VIII

192

Table-3: Antibacterial activity of oxadiazole, pyrazole, indol-3-

ylmethylideneamino]-1,3-thiazolyl-4-yl, thiazole, and carboxamide substituted


S

NH2

N

O

N

R

3a-d

SF

NH2

O

N

N

O

5

S

NH2

N

O

N

O

R

5a-d

S

O

O

NHN

S

N

NH4a

S

O

O

NHN

S

NH2

3

S

NH2

NH

O

NR

6a-d

Compound R


Staphylococc

us aureus

Bacillus

subtilis

Salmonella

paratyphi-A

Escheric

hia coli

3a 2-OH 17 18 16 17

3c 4-NH2 16 17 15 18

4a 13 12 16 14

5 14 13 14 15

5a 3-NO2 15 14 16 14

5c 3-OH 14 15 14 15

5d 4-NH2 22 24 15 24

3 14 14 15 16

6a 4-OH 15 13 14 18

6c 4-Cl 17 19 16 20

DMF 00 00 00 00


Chapter - VIII

193

Table-4: Antibacterial activity of triazole, carboxamide, carbohydrazide, and

pyrimidine substituted benzothiophene derivatives

SO O

NH

ONH2

2

S

NH2

O

NH

O

O

R

3a-d

S

Cl

NH

O

SF

NH2

NH

O

3a

S

NH2

O

N

N N

NH2

SH

4

S

NH2

O

NH

N

O

NH

O

R

5a-d

Compound R


Staphylococcu

s aureus

Bacillus

subtilis

Salmonella

paratyphi-A

Escheric

hia coli

2 14 12 16 15

3a 13 11 15 14

4 15 13 14 12

3a 4-Br 19 18 15 20

3b 4-OCH3 16 15 15 18

3c 4-OH 15 16 14 16

3d 4-Cl 17 18 16 19

5a 4-Br 19 17 17 18

5b 4-OCH3 18 16 17 19

5c 4-OH 15 14 13 17

DMF 00 00 00 00


Chapter - VIII

194

Results and Discussion

The antibacterial activity (in terms of zone of inhibition) of some selected synthesized

compounds was evaluated against gram positive and gram negative organisms at

concentration (40 g/ml) and the results are compared with that of standard drugs,

Chloramphenicols respectively.

Table-1: The anti-bacterial activity exhibited by compounds 3e, 4a and 6f exhibited

more antibacterial activity than standard drug against. Remaining tested compounds

exhibited weak to moderate antibacterial activity against standard Chloramphenicol.

Table-2: Among the tested compounds, 4a, 5a and 7c exhibited more antibacterial

activity against both the than standard. All the tested compounds exhibited weak to

moderate antibacterial activity against standard.

Table-3: Compound 5d exhibited more anti-bacterial activity as that of standard

against both the gram positive as well as gram –ve pathogens where as remaining

exhibited weak to moderate activity as that of standard against drug.

Table-4: The tested compounds 3a and 5a showed equipotent antibacterial activity as

that of standard drug Chloramphenicol. And remaining all the tested compounds

exhibited weak to moderate antibacterial activity.

Chapter - VIII

195

ANTIFUNGAL ACTIVITY

The antifungal activity of benzohiophene derivatives was studied in comparison with

that of standard antifungal drug, Fluconazole, by cup-plate method against A. niger, P.

notatum, A. fumigatus, and C. albicans.

Materials and method

1. Potato dextrose agar

2. Sterilized petridishes

3. Micropipette

4. Potato dextrose broth (48 hours old)

5. Sterile test tubes for preparation of solutions of the test compounds.

Sterilization of media and glassware

The media used in the present study i.e., nutrient agar and nutrient broth, were sterilized

in conical flasks of suitable capacity by autoclaving at 15 lbs pressure for about 20

minutes. The cork borer, petridishes, test tubes and pipettes were sterilized in hot air

oven at 160 0C for an hour.

Preparation of solution of test compounds

All the tested compounds were dissolved in minimum amount of dimethyl formamide

(DMF) and the final volume made with distilled water to get 40 g/ml.

Preparation of media

Potato dextrose agar medium was prepared by dissolving potato dextrose agar (20g) in

distilled water (500 ml). The pH of the solution was adjusted to 5.6 and then sterilized

for 15 minutes at 1210C at 15 lbs pressure in an autoclave.

Chapter - VIII

196

Preparation of sub-culture

Two days prior to the experiment, the microorganism were inoculated into sterilized

potato dextrose broth tubes and incubated at 25 0C for 48 hours.

Method of testing: Cup-plate method

This method depends on the diffusion of an antifungal agent from a cavity through the

solidified agar layer in a petridish to such extent that growth of the added

microorganism is prevented entirely in a circular area or zone around the cavity

containing a solution of antifungal agent.

A previously liquified medium was inoculated with the suspension of the

microorganisms between 40-50 0C and the inoculated medium was poured into

petridishes to give a depth of 3 to 4 mm. ensuring that the layers of medium were

uniform in thickness by placing the dishes on a leveled surface.

The dishes thus prepared were stored in a manner so as to ensure that no

significant growth of death of the test organism occurs before the dishes were used and

the surface or the agar layer was dry at the time of use. With the help of a sterile cork

borer, six cups of each 6 mm diameter were punched and agar m medium was scooped

out the set agar in each petridish using sterile pipettes. Test and standard sample

solutions solutions (0.1 ml) of known concentrations were fed into the bored cups.

The dishes were left allowed to stand at room temperature for 2 hours at room

temperature as a period of pre-incubation diffusion, to minimize the effects of variation

in time among the application of different solutions. After two hours, these petri dishes

were incubated for three days at 25 0C. The zone of inhibition developed, if any, was

then accurately measured and recorded in the. Each zone of inhibition recorded was

average of three measurements.

Chapter - VIII

197

Table - 2

Antifungal activity of standard and control

Treatment

Zone of inhibition ( in mm )

Aspergillus

niger

Pencillium

notatum

Aspergillus

fumigatus

Candiada

albicans

40 g/ml 40 g/ml 40 g/ml 40 g/ml

Standard:

Flucanazole

25

24

25

19

Control:

DMF

-00-

--00

--00

--00

Chapter - VIII

198

Table-1: Antifungal activity of pyrazole, pyrazolone, oxadiazole and imidazole

substituted benzothiophene derivatives

S

NH2

O

N

N

O

CH3

N

NH

S

NH2

O

N

NH3a-f 4a-f

RR

S

ClN

O

S

F

NH2 N

4a-c

S

FNH2

NH

O

N

N

O

6a-f

R

Compound

Diameter of zone of inhibition ( in mm)

Aspergillus

niger

Pencillium

notatum

Aspergillus

fumigatus

Candiada

albicans

3a 2-OH 20 21 19 14

3b 4-OCH3 17 19 15 18

3f 4-CH3 19 17 20 16

4a 4-Br 12 18 18 14

4c 2-NO2 22 20 17 15

4d 4-Cl 23 21 24 18

6a 2-OH 17 18 18 14

6c 4-OCH3 22 20 23 15

4b S

O

Cl 15 18 19 13

4c O

Cl

17 15 16 14

DMF 00 00 00 00

Fluconazole 25 24 25 19

Chapter - VIII

199

Table-2: Antifungal activity of thiopyrimidines, triazole-thiadiazole, azetidinone,

oxadiazole substituted benzothiophene derivatives

S

NH2

O

NH

N

ONH

S4a-d

R

S

NH2

ON

N N

N

S

R

5a-e

S

O

O

NHN

S R

O

Cl

5a-d

S

NH2

N

O

N

O

R

7a-d

Compound


Aspergillus

niger

Pencillium

notatum

Aspergillus

fumigatus

Candiada

albicans

4a 4-Br 23 17 24 16

4b 4-OCH3 17 19 15 17

4c 4-OH 20 21 19 14

5a 4-OH 20 19 18 16

5b 4-CN 21 20 23 15

5c 2-NO2 19 17 17 16

7a 4-OH 18 18 18 14

7c 4-Cl 22 20 21 17

5b

O

OO

O

27 23 28 20

5c O

O

26 25 27 18

DMF 00 00 00 00


Chapter - VIII

200

Table-3: Antifungal activity of oxadiazole, pyrazole, indol-3-ylmethylideneamino]-

1,3-thiazolyl-4-yl, thiazole, and carboxamide substituted benzothiophene

derivatives.

S

NH2

N

O

N

R

3a-d

SF

NH2

O

N

N

O

5

S

NH2

N

O

N

O

R

5a-d

S

O

O

NHN

S

N

NH4a

S

O

O

NHN

S

NH2

3

S

NH2

NH

O

NR

6a-d

Compound


Aspergillus

niger

Pencillium

notatum

Aspergillus

fumigatus

Candiada

albicans

3a 2-OH 17 15 13 15

3c 4-NH2 22 20 21 17

4a 19 16 20 16

5 13 17 18 13

3 18 19 17 16

5a 3-NO2 20 21 16 17

5b 4-Cl 23 19 16 15

6a 4-OH 19 21 17 14

6b 4-OCH3 14 17 19 13

6c 4-Cl 20 18 16 15

DMF 00 00 00 00


Chapter - VIII

201

Table-4: Antifungal activity of carboxamide, carbohydrazide, triazole and

pyrimidine substituted benzothiophene derivatives

SO O

NH

ONH2

2

S

NH2

O

NH

O

O

R

3a-d

S

Cl

NH

O

SF

NH2

NH

O

3a

S

NH2

O

N

N N

NH2

SH

4

S

NH2

O

NH

N

O

NH

O

R

5a-d

Compound


Aspergillus

niger

Pencillium

notatum

Aspergillus

fumigatus

Candiada

albicans

2 16 18 14 18

3a 15 16 16 16

4 20 19 18 17

3b 4-OCH3 19 20 21 13

3c 4-OH 17 16 20 16

3d 4-Cl 22 20 19 18

5a 4-Br 28 22 29 18

5b 4-OCH3 18 21 20 12

5c 4-OH 15 15 19 15

5d 4-Cl 27 25 26 20

DMF 00 00 00 00


Chapter - VIII

202


Antifungal activity of some selected synthesized compounds was evaluated

against four fungal strains Aspergillus niger, Pencillium notatum, C. albicans and A.

fumigatus at the concentrations that is 40 g/ml concentrations. The results are

compared with that of standard antifungal drug Greseofulvin.

Table-1: Among the tested compounds, 3a, 4c and 4d exhibited equipotent activity as

that of standard drug flucanazole, whereas remaining compounds exhibited weak

activity against the standard

Table-2: Most of the tested compounds exhibited nearly equipotent antifungal activity

as that of standard drug flucanazole. Whereas 5d exhibited more activity against than

standard.

Table-3: compounds 3a 3c 5b and 6c showed equipotent activity. Where as remaining

tested compounds exhibited weak to moderate antifungal activity against tested

organisms.

Table-4: Among the tested compounds 5a and 5d exhibited more activity than standard

drug fluconazole. All the remaining compounds exhibited moderate antifungal activity

against fungal strains.

Chapter - VIII

203

ANTHELMINTIC ACTIVITY

It is estimated that over 800 million people in the world suffer from the helminthiasis.

Helminthiasis is believed to be endemic in many parts of the world, where there is poor

sanitation, poor living conditions, poor family hygiene and crowded living conditions.

The problem of treatment of helminthiasis is therefore, of great practical importance.

The most common worms that live in the host alimentary canal are tapeworms

(Cestodes), round worms (Nematodes) and fluke worms (Tremetodes). A good

anthelmintic agent should be able to penetrate the cutical of the worms or gain access to

its alimentary tract , it should have minimum toxic effect on the host and maximum

toxic effect on the parasite, should be easy to administer and be of low cost.

Anthelmintic activity of selected syntheisized compounds was evaluated on

earthworms (pheretima posthuma). The technique adopted to carry out anthelmintic

activity in vitro was that of Gaind5 et al,

with slight modification.

Materials and Method

Normal saline:

Sodium chloride (9g) was dissolved in sufficient distilled water to make one litre (0.

9%w/v).

Albendazole suspension:

Albendazole powder suspension was prepared by using Tween 80, as it is insoluble in

water. Albendazole powder (500mg) was weighed accurately and transferred to a glass

mortar to which Tween 80 (0.2ml) was added. The mixture was triturated well to obtain

a well distributed system. The volume was adjusted to 100ml with normal saline to

obtain 0.5% w/v concentrations.

Chapter - VIII

204

Tween 80 solution

Tween 80 (0.2 ml) was dissolved in small quantity of normal saline and volume was

adjusted to 100 ml with normal saline to get Tween 80 solution, which was used as

blank.

Suspension of test compounds:

Suspensions of test compounds at concentrations 0.5% w/v were prepared in 0.1%

Tween 80 in normal saline.

Method of testing

Earthworms (pheretima posthuma) were collected from the Horticulture Department.

These worms were thoroughly washed with normal saline to remove the adhering

materials and then kept in a dish containing normal saline.

To two petri dishes of equal size, normal saline(20 ml) and Tween 80 solution (0.1%

v/v, 20 ml)was poured in which were used as blank.

Albendazole suspension (20ml) of solution of concentrations 0.5% were added

respectively to different petri dishes and used as standard. The suspension of the

compounds (20ml) test in 0.1% Tween 80 in normal saline at concentrations 0.5% were

poured in to different petri dishes.

Three earthworms of nearly equal size were placed in each petri dish and time taken for

complete paralysis and the death by earthworms in each petri dish was recorded and

tabulated. All the worms were observed for 8 hours. The time taken by worms to

become motionless was noted as paralysis and to ascertain the death of motionless

worms, the earthworms were frequently applied with external stimuli (pricking of

needle) which stimulates and induce movement in the worms, if alive. Results are given

in tables.

Chapter - VIII

205

Table – 3 Anthelmintic activities of standard and control

Treatment % Conc. ( w/v ) Time in minutes

For paralysis For death

Standard:

Albendazole

0.5

27

56

Control:

Normal Saline

Tween-80

--

--

NP

NP

ND

ND

NP = No Paralysis; ND = No Death

Chapter - VIII

206

Table-1: Anthelmintic activity of pyrazolone, triazole-thiadiazole, pyrimidines and

thiazolidinones substituted benzothiophene derivatives.

S

NH2

O

N

N

O

CH3

N

NH

4a-f

R

S

NH2

ON

N N

N

S

R

5a-e

S

NH2

O

NH

N

O

NH

O

R

5a-d

S

O

O

NHN

S

N S

O

R

6a-c

Compound R % conc.

Time in minutes


4a 4-Br 0.5 42 75

4b 4-NO2 0.5 55 83

5a 2-Cl 0.5 38 72

5b 4-CN 0.5 55 79

5c 2-NO2 0.5 45 89

6a NH

O

0.5 65 120

6b O

OO

O

0.5 51 76

6c

O

O

0.5 63 95

5b 4-OCH3 0.5 28 65

5d 4-Cl 0.5 24 54

Albendazole 0.5 27 56

Chapter - VIII

207

Table-2: Anthelmintic activity of thiopyrimidines, pyrazolone, azetidinone,

oxadiazole substituted benzothiophene derivatives.

S

NH2

O

NH

N

ONH

S4a-d

R

S

NH2

O

N

N

O

N

NH

R

4a-f

S

O

O

NHN

S R

O

Cl

5a-d

S

NH2

N

O

N

O

R

7a-d

Compound R % conc.

Time in minutes


4a 4-Br 0.5 37 69

4b 4-OCH3 0.5 45 92-

5a

NH

O

0.5 25 57

5b O

OO

O

0.5 35 68

5c

O

O

0.5 55 83

4b 4-NO2 0.5 48 75

4d 4-Cl 0.5 33 62

7a 4-Cl 0.5 42 76

7b 4-OCH3 0.5 39 84

7d 3-NH2 0.5 26 65


Chapter - VIII

208

Table-3: Anthelmintic activity of oxadiazole, pyrazole, indol-3-

ylmethylideneamino]-1,3-thiazolyl-4-yl, thiazole, and carboxamide substituted


S

NH2

N

O

N

R

3a-d

SF

NH2

O

N

N

O

5

S

NH2

N

O

N

O

R

5a-d

S

O

O

NHN

S

N

NH4a

S

O

O

NHN

S

NH2

3

S

NH2

NH

O

NR

6a-d

Compound R % conc.

Time in minutes


3a 2-OH 0.5 41 63

3c 4-NH2 0.5 38 74

4a 0.5 89 145

3 0.5 60 91

5a 3-NO2 0.5 75 96

5b 4-Cl 0.5 32 72

5c 3-OH 0.5 97 121

6a 4-Cl 0.5 38 79

6b 4-OCH3 0.5 105 165

6d 3-NH2 0.5 97 158


Chapter - VIII

209

Table-4: Anthelmintic activity of carboxamide, carbohydrazide, triazole and

pyrimidine substituted benzothiophene derivatives.

SO O

NH

ONH2

2

S

NH2

O

NH

O

O

R

3a-d

S

Cl

NH

O

SF

NH2

NH

O

3a

S

NH2

O

N

N N

NH2

SH

4

S

NH2

O

NH

N

O

NH

S

R

5a-d

Compound R % conc.

Time in minutes


2 0.5 80 145

3b 4-OCH3 0.5 71 99

3c 4-OH 0.5 55 95

3d 4-Cl 0.5 32 65

4 0.5 105 159

3a 0.5 29 71

5a 4-Br 0.5 35 61

5b 4-OCH3 0.5 48 79

5c 4-OH 0.5 45 95

5d 4-Cl 0.5 26 60


Chapter - VIII

210


Some selected synthesized compounds have been screened for anthelmintic

activity against earthworms (Pherethima posthuma) using albendazole as standard at

three different concentrations 0.5 %. The time required for paralysis and death of

earthworms in each case is recorded and compared with that of standard.

Table-1: Compound 4a and 5d exhibited potent anthelmintic activity in respect to time

taken for paralysis on earthworms than any other tested compounds, and all other

compounds were exhibit moderate activity against standard.

Table-2: Among the tested compounds, 4a and 5a exhibited highest anthelmintic

acivity. However, the anthelmintic potency exhibited by all the compounds is moderate

compared with standard drug Albendazole.

Table-3: All the tested compounds exhibited weak anthelmintic activity. Except 3a and

5a they are very near to standard.

Table-4: Among the compounds tested, 5a and 5d exhibited highest anthelmintic

acivity. However, the anthelmintic potency exhibited by 4 and 2 is not significant

compared with standard drug Albendazole.

Chapter - VIII

211

ANALGESIC ACTIVITY

Analgesics are pain relievers. Analgesics can be divided into two types.

1) Narcotic analgesics

2) Non-narcotic analgesics.

As it is evident from the literature that several benzothiophene derivatives are known to

exhibit analgesic activity, some of the selected synthesized compounds were evaluated

for analgesic activity.

The analgesic activity of synthesized compounds was evaluated by acetic acid induced

writhing method6,7

using 0.6% v/v acetic acid which produces pain reaction which is

characterized as a writhing response.

Materials and method

1. Mice each weighing between 20-25g of Swiss strain.

2. Aspirin (Standard drug).

3. Acetic acid (0.6% v/v).

4. Stop clock.

5. Tween-80 solution.

Suspensions of standard drug and test compounds

1) Suspension of aspirin (10mg/ml) was prepared (Dose 100mg/kg per oral, 1

ml/100g body weight of a mouse) in 2% gum acacia.

2) Suspensions of test compounds (10mg/ml) were prepared (Dose 100mg/kg per

oral, 1 ml/100g body weight of a mouse) in 0.1% Tween 80.

Housing of animals

Swiss albino mice of Wistar strain of either sex were obtained from Sri

Venkateshwara enterprises, Bangalore and were maintained at the animal house of

S.C.S. College of Pharmacy, Harapanahalli. Animals were housed under standard

Chapter - VIII

212

environmental conditions of temperature (23 2C), 12 hours light/dark cycle, fed with

pellet rodent diet and water adlibitum. Before performing the experiments, ethical

clearance was obtained.

Evaluation of analgesic activity

After an over night fast, mice were divided into different groups of six each and 0.6%

v/v acetic acid (dose 10ml/Kg) was administered ip. Each group was administered

orally with the suspension of test compounds in 0.1% Tween-80 at the dose of

100mg/Kg body weight of the animals 1 hour before the injection of acetic acid. The

numbers of writhes [constriction of abdomen, turning of trunk (twist) and extension of

hind legs] were recorded 10 min after administering acetic acid for next 10 min. The

percentage protection for each group was calculated and compared with the control.

Aspirin was used as standard drug at 100mg/kg body weight for the comparison of

analgesic activity. Control group received 0.2 ml of 0.1% Tween 80. Statistical

significance was analyzed using one way ANOVA followed by Turkey-Krammer

Multiple Comparison Test and P<0.001 was considered significant. The results are

tabulated in Tables 4, 4a-d. The percentage protection was calculated using the

formula

Rc – R t

% protection = x 100

Rc

Where R c = Mean No. of writhings in control group

R t = Mean No. of writhings in test group

Chapter - VIII

213

Table - 4

Analgesic activity of control and standard

Compound

Mean No. of Writhings

SEM

% Protection

Control :

Tween 80(0.2ml of 0.1%)

45.83 3.66 --

Standard :

Ibuprofen

11.99 1.27 73.83

Chapter - VIII

214

Table-1: Analgesic activity of pyrazole, pyrazolone, oxadiazole and imidazole

substituted benzothiophene derivatives.

S

NH2

O

N

N

O

CH3

N

NH

S

NH2

O

N

NH3a-f 4a-f

RR

S

ClN

O

S

F

NH2 N

4a-c

S

FNH2

NH

O

N

N

O

6a-f

R

compound R Dose

mg/kg

Mean No of

Writhing % Protection

3a 2-OH 100 21.78 ± 2.43 52.47

3c 2-NO2 100 19.42 ± 1.84 57.62.

4c 2-NO2 100 18.09 ± 1.67 60.05

4d 4-Cl 100 16.84 ± 1.54 63.32

4e 4-OCH3 100 24.51 ± 2.94 46.51

4a

S

Cl

O

Cl

100 20.75 ± 1.34 54.72

6a 2-OH 100 18.52 ± 1.69 59.58

6c 4-OCH3 100 23.66 ± 2.52 48.37

6f 4-Cl 100 15.93 ± 1.20 62.54

Ibuprofen 100 11.65 ± 1.27 74.57

Chapter - VIII

215

Table-2: Analgesic activity of thiopyrimidines, triazole-thiadiazole, azetidinone,

oxadiazole substituted benzothiophene derivatives.

S

NH2

O

NH

N

ONH

S4a-d

R

S

NH2

ON

N N

N

S

R

5a-e

S

O

O

NHN

S R

O

Cl

5a-d

S

NH2

N

O

N

O

R

7a-d compound R Dose

mg/kg

Mean No of


4a 4-Br 100 10.45 ± 1.36 77.19

4b 4-OCH3 100 17.29 ± 2.15 57.62.

4c 4-OH 100 16.42. ± 1.68 64.17

5a 2-Cl 100 13.42 ± 1.84 70.71

5b 4-CN 100 16.25 ± 1.20 64.54

5c 2-NO2 100 22.75 ± 2.14 50.36

5d O

N+

O-

O

100 30.41 ± 2.26 33.64

7a 4-Cl 100 19.89 ± 1.28 56.66

7d 4-NH2 100 23.51 ± 2.52 42.35

Ibuprofen 100 11.65 ± 1.27 74.57

Chapter - VIII

216

Table-3: Analgesic activity of oxadiazole, pyrazole, indol-3-ylmethylideneamino]-

1,3-thiazolyl-4-yl, thiazole, and carboxamide substituted benzothiophene

derivatives.

S

NH2

N

O

N

R

3a-d

SF

NH2

O

N

N

O

5

S

NH2

N

O

N

O

R

5a-d

S

O

O

NHN

S

N

NH4a

S

NH2

NH

O

NR

6a-d

compound R Dose

mg/kg

Mean No of


3a 2-OH 100 22.66 ± 2.52 50.55.

3d 2-Cl 100 15.21 ± 1.88 66.81.

4a 100 26.13 ± 1.60 42.98

5 100 20.19 ± 1.84 55.91

5a 3-NO2 100 21.56 ± 1.55 52.95

5b 4-Cl 100 16.93 ± 1.20 63.05

6a 4-OH 100 28.04 ± 1.86 38.81

6b 4-OCH3 100 20.83 ± 2.43 54.55

6d 3-NH2 100 16.08 ± 1.24 64.91

Ibuprofen 100 11.65 ± 1.27 74.57

Chapter - VIII

217

Table-4: Analgesic activity of triazole, carboxamide, carbohydrazide, and

pyrimidine substituted benzothiophene derivatives.

SO O

NH

ONH2

2

5a-fR

S

NH2

O

N

N N

N

S

S

Cl

NH

O

SF

NH2

NH

O

3a

S

NH2

O

N

N N

NH2

SH

4

S

NH2

O

NH

N

O

NH

O

R

5a-d

compound R Dose

mg/kg

Mean No of


2 100 18.62 ± 1.70 50.01

3a 100 20.02 ± 1.84 56.31.

4 100 21.56 ± 1.56 52.95

5a 2-Cl 100 29.85± 2.34 34.86

5b 4-CN 100 26.42 ± 1.69 42.35

5c 2-NO2 100 23.51 ± 2.96 44.36

5a 4-Br 100 10.64 ± 1.70 76.78

5b 4-OCH3 100 16.08 ± 1.24 64.91

5d 4-Cl 100 10.45 ± 1.52 77.19

Ibuprofen 100 11.65 ± 1.27 74.57

Chapter - VIII

218

RESULT AND DISCUSSION

Analgesic activity of some selected newly synthesized compounds prepared in the

course of present investigation was evaluated and the results were compared with the

analgesic activity of standard drug Ibuprofen. The following broad conclusions are

made on the basis of the results.

Table-1: Among the tested compounds, 4d and 6f have shown significant analgesic

activity. Compounds 3c, 4c, 6a exhibited moderate analgesic activity and have shown

lesser % MPE than the standard drug.

Table-2: The compound 4a exhibited better analgesic activity than standard drug, the

compounds 4b, 5a, 7a have shown moderate activity remaining compounds 5c, 7d, 5d

have shown lesser % MPE than the standard drug.

Table-3: All the tested compounds exhibited moderate analgesic activity and have

shown lesser % MPE than the standard drug.

Table-4: Compounds 5a and 5d have shown more potent analgesic activity than

standard drug. The others exhibited moderate analgesic activity and have shown lesser

% MPE than the standard drug.

Chapter - VIII

219

REFERENCES.

[1] L.J. Powers and M.P. Mertes, J. Med. Chem., 1970, 13, 1102.

[2] R. Royer, L, Rne, P. Demerseman and R. Cavier, J. Cenac, Chim. Ther., 1972,

7, 361.

[3] Controller of Publications, Indian Pharmacopoeia, Delhi, India, 1996, 1, 353.

[4] G. Morris, J. App .Bacteriol., 1976, 40, 229.

[5] J.D. Balantine Pathology of oxygen Toxicity., Academic Press, New York,

1982.

[6] C.S. Moody and H.M. Hassan Proc. Nats. Acad. Sci.,1982, 79, 2855.

[7] E.R. Stadtman, Biochemistry., 1990, 29, 6323.

[8] R.E. Pacifici Y. Kono and K.J.A. Davies, J. Biol. Chem., 1993, 268, 405.

[9] K.D. Tripati Essentials of Medical pharmacology, Jaypee Brothers Medical

publishers (P) Ltd. New Delhi; 5th

edition, 2004, 298, 708.

[10] F.D. Robert, Wilson and Gisvold’s text book of organic medicinal and

pharmaceutical chemistry 8th

edition. J.B. Lippincott company, Philadelphia,

1996.

[11] Williams F, David A and Thomas L, Foye’s principles of Medicinal Chemistry.

5th

edition. Lippincott Willaims and Wilkings, 2002.

[12] Harsh Mohan. Text book of pathology 4th

edition. Jaypee Brothers Medicinal

Publishers Ltd., 2000, 114.

PUBLICATIONS

1 “An insight into the pharmacological potency of novel benzothiophene

derivatives” H. K. Nagesh. Basavaraj Padmashali* and C. Sandeep. journal of

Applicable Chemistry, 2013, 2(5): 1281-1288.

2 “Design, synthesis and pharmacological studies of imidazole, oxadiazole and

pyrazolone containing benzothiophene derivatives” Nagesh HK, Basavaraj

Padmashali,*Sandeep C, Siddesh MB and Thriveni KS, Universal journal of

pharmacy, 2013, 2(4) 78-83.

3 Synthesis and antimicrobial activity of benzothiophene substituted coumarins,

pyrimidines and pyrazole as new scaffold. H. K. Nagesh, Basavaraj Padmashali*

C. Sandeep, T.C.M. Yuvaraj, M.B. Siddesh, S. M. Mallikarjuna. Int. J. Pharm.

Sci. Rev. Res. (Accepted)

4 “Synthesis and antimicrobial screening of napthofuran-1,3,4-oxadiazole linked

piperzines” K.S Thriveni, Basavaraj Padmashali,*

M. B. Siddesh, C. Sandeep,

H. K. Nagesh and S.M. Mallikarjuna. Universal Journal of Pharmacy, 2013,

2(4) 129-134.

5 “Synthesis and antioxidant activity of thiophene linked methoxybenzimidazole

substituted pyrimidines and 4- substituted pyrimidine 2- phenylamino

acetamides” M. B. Siddesh, Basavaraj Padmashali,* C. Sandeep, H. K. Nagesh

and S.M. Mallikarjuna Universal Journal of Pharmacy, 2013, 2(4) 150-156.

6 Synthesis, Characterization and Antibacterial Studies For N-Alkyl and N-Aryl of

[1-(4-Chlorophenyl) Cyclopropyl] (Piperazin-1-Yl) Methanone Derivatives

S.M. Mallikarjuna, Basavaraj Padmashali*, C. Sandeep, M.B. Siddesh,

H.K. Nagesh, K.S.Thriveni. Journal of Applicable Chemistry.

7 Synthesis of substituted 5-acetyl-3- benzoylindolizine-1-carboxylate from

substituted 2 acetyl pyridinium bromides.

C. Sandeepa a,

a bBasavaraj Padmashali*

cRashmi S. Kulkarni,

aMallikarjuna S. M.

aSiddesh M. B,

aNagesh H. K,

aThriveni K. S. Heterocyclic letters.

CONFERENCES ATTENDED

1 UGC sponsored on “APPLICATIONS OF ANALYTICAL TOOLS

THROUGH THE INSTRUMENTS” March-2013 2011 Organized by

Department of Chemistry, Sahyadri Science College (Autonomous), Kuvempu

university.

2 Two day National Symposium on “FREONTIER AREAS IN CHEMICAL

SCIENCES AND NANO TECHNOLOGY” May 1-2, 2010 Held at

Department of Industrial Chemistry, Kuvempu University, Shankaraghatta.

3 UGC sponsored one day State Level Seminar on “ANALYTICAL

TECHNIQUES IN THE PRESENT SCENARIO” held at Sahyadri Science

College (Autonomous), Kuvempu University.

4 One day National Seminar on “NANO-CHEMISTRY - A SCIENCE OF

DIMINISHED DIMENSIONS” held at Sahyadri Science College

(Autonomous), Kuvempu University on March 2009.

1147

Available online at www.joac.info

ISSN: 2278-1862

Journal of Applicable Chemistry 2013, 2 (5):1147-1154

(International Peer Reviewed Journal)

An Insight into the Pharmacological Potency of Novel

Benzothiophene Derivatives

H. K. Nagesh, Basavaraj Padmashali* and C. Sandeep

*Department of Chemistry, Sahyadri Science College (Autonomous), Shimoga-577 203,

Karnataka, INDIA.

Email: [email protected]

Received on 15th August and finalized on 20th August 2013.

____________________________________________________________________________

ABSTRACT A series of significant compounds containing pyrazole and pyrazolone substituted benzothiophene

derivatives 2a-f and 3a-f have been synthesized from 2-bromobenzonitrile and methyl thioglycolate. The

structure of newly synthesized compounds have been characterized by elemental analysis and spectral

data. Some of the synthesized compounds have been found to exhibit better antibacterial and anti fungal activity.

Keywords: Benzo[b]thiophene derivatives, Pyrazolone, Pyrazole, Antifungal, Anti-microbial.

______________________________________________________________________________

INTRODUCTION

Novel benzo[b]thiophene derivatives are privileged structures present in many biologically active

compounds. Benzo[b]thiophenes serve as very useful heterocyclic cores in the development of new drugs[1] and found to possess varied biological activities, via, estrogen receptor modulators[2], antimitotic

agents [3], modulators of multidrug resistance[4], angiogenesis inhibitors[5], cognition enhancers[6],

antifungal[7] and anti-inflammatory[8] etc. Pyrazolone derivatives are an important class of heterocyclic compounds that occur in many drugs and synthetic products. These compounds exhibit remarkable

analgesic[9-11], antimicrobial[12-13], anti-inflammatory[14], antioxidant and antitumor activities[15-17].

Similarly, pyrazoles are five membered ring heterocyclic compounds, have some structural features with

two nitrogen atoms in adjacent position. Pyrazole derivatives have showed significant biological activities such as antiproliferative[18], antiparasitic[19-20], anti-inflammatory[21], antiprotozoal[22-23] and anti-

microbial[24, 25] activities. In order to synthesize active molecules of widely different composition such

as combination of two heterocyclic frameworks to achieve good biological profile, it was planned to synthesize some benzothiophene derivatives containing pyrazolone and pyrazole moieties.

MATERIALS AND METHODS

All the melting points were determined in an open capillary and were uncorrected. IR spectra were

recorded on Bruker alpha FT IR spectrophotometer, 1H NMR spectra were measured on Bruker AV

400MHZ using CDCl3 and DMSO as solvent. Chemical shifts are expressed in δ ppm. Mass spectra were

kuvempu universitykuls-ir.kuvempu.ac.in/1603/1/t-2922.pdf · 2017-04-05 · kuvempu university...

Documents