CHAPTER-I

1

CHAPTER-I

Introduction

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2

1.0. Introduction

eterocyclic chemistry persists an interesting psychology these

days. Commonly majority of the published work in organic

chemistry involves at least one heterocyclic ring. Moreover, in

providing us with a wealth of fascinating molecular arrays, over

half of which posses heterocyclic constitution, nature presents a most cogent

argument for developing an appreciation for this area. Heterocyclic chemistry is a vast

and expanding area of chemistry because of the obvious applications of compounds

derived from heterocyclic rings in pharmacy, medicine, agriculture and other fields.

The chemistry of heterocyclic compounds is as relevant as that of aliphatic or

aromatic compounds. Their study is of great interest both from the theoretical as well

as practical stand point. An important application of small molecule libraries is the

preparation of a directed or focused combinatorial library for assay against a specific

biological target. Heterocyclic compounds play a vital role in organic chemistry,

especially in the field of medicinal chemistry. More than half of the naturally

occurring compounds and a high proportion of drugs contain heterocycles.

Heterocyclic compounds may be classified in to aliphatic and aromatic heterocyclic

compounds. The aliphatic heterocycles are the cycles analogues of amines, ethers,

thioethers, amides etc. Heterocyclic compounds are organic compounds with

incorporation of nitrogen, sulfur, oxygen, or an atom of a related element into an

organic ring structure in place of a carbon atom gives rise to a heterocyclic

compound. A cyclic organic compound containing all carbon atoms in ring formation

is referred to as a carbolic compound. If at least one atom other than carbon forms a

part of the ring system then it is designed as a heterocyclic compound [1-4].

HHHH

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3

These are containing at least one atom of carbon, and at least one element other than

carbon, such as nitrogen, oxygen or sulfur within a ring structure. These structures

may comprise either simple aromatic rings or non aromatic rings. Nitrogen, oxygen,

and sulfur are the most common hetero atoms, but heterocyclic rings containing other

hetero atoms are also widely known. A heterocyclic ring may comprise of three or

more atoms which may be saturated or unsaturated. Also the ring may contain more

than one heteroatom which may be similar or dissimilar. Some heterocyclic

compounds are shown below.

S

N

Thiazole

Figure:- Some examples of heterocyclic compounds.

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4

1.1. Significance of heterocyclic compounds

There are a vast number of pharmacologically active heterocyclic compounds, many

of which are in regular clinical use. Some of these are natural products, for example

antibiotics such as penicillin and cephalosporin, alkaloids such as vinblastine,

ellipticine, morphine, and reserpine and cardiac glycosides such as those of digitals.

However, the large majority are synthetic heterocycles which found wide spread use,

for example as anticancer agents, analeptics, analgesis, hypnotics and vasopressin

modifiers and as pesticides, insecticides, weed killers and rodenticides. There are also

a large number of synthetic heterocyclic compounds with other important practical

applications, as dye stuffs, copolymers, solvents, photographic sensitizers and

developers, as antioxidants and vulcanization acceleration in the rubber industry, and

many are valuable intermediates in synthesis.

The successful application of heterocyclic compounds in these and many other ways

and their appeal as materials in applied chemistry and in more fundamental and

theoretical studies, stems form their very complexity; this ensures a virtually limitless

series of structurally novel compounds with a wide range of physical, chemical and

biological properties, spanning a broad spectrum of reactivity and stability. Another

consequence of their varied chemical reactivity, including the possible destruction of

the heterocyclic ring is their increasing use in the synthesis of specifically

functionalized non-heterocyclic structures.

More important is the recognition that, heterocycles can play a pivotal role not only as

goals in synthesis, but as mediators of synthetic transformations since the appearance

of the benchmark monograph by Meyers [5], which formally legitimized the use of

heterocycles as a viable and occasionally superior means of arriving at the

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5

functionalized materials. Just as the synthetic organic chemistry has blossomed since

that time, so has the use of heterocycles in synthesis.

The number of possible heterocyclic systems is almost limitless. An enormous

number of heterocyclic compounds are known and this number is increasing very

rapidly. The literature of the subject is correspondingly vast and of the three major

divisons of organic chemistry aliphatic, aromatic and heterocyclic, the last is much the

biggest. Over six million compounds are recorded in chemical abstracts and

approximately half of these are heterocyclic.

1.2. Introduction to pyrimidinones

One of the main objectives of organic and medicinal chemistry is the design, synthesis

and production of molecules having value as human therapeutic agents. During the

past decade, combinatorial chemistry has provided access to chemical libraries based

on privileged structures [6], with heterocyclic structures receiving special attention as

they belong to a class of compounds with proven utility in medicinal chemistry [7-

10]. Pyrimidine is the most important member of all the diazines as this ring system

occurs widely in living organisms. Purines, uric acid, alkoxan, barbutiric acid and a

mixture of anti-malarial and anti-bacterials also contain the pyrimidine ring. The

chemistry of pyrimidine has been widely studied [11, 12]. Pyrimidine was first

isolated by Gabriel and Colman in 1899. The derivatives of fused pyrimidinones have

been the focus of great interest over many years due to the fact that many compounds

containing a fused pyrimidinone ring play an important role in the biochemistry of

living cell [13-16]. Heterofused pyrimidines exhibit promising antiviral [17],

antibacterial [18], anti-AIDS [19], and antinociceptive [20] activities. The group of

pyrido [1,2-a] pyrimidin-4-ones is a well-known class of aza-bridgehead fused

heterocyclic compounds which have miscellaneous pharmaceutical applications [21].

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6

This kind of structural pattern is present in the known psychotropic agents risperidone

and paliperidone [22, 23], the human leukocyte elastase inhibitor SSR69071 [24], the

antiallergic agent ramastine [25], and antioxidants [26]. Fused pyrimidines are

extensively used in neurology, particularly in the treatment of neurodegenerative

disorders such as Parkinson’s disease [27], antianxiety disorders [28] and depression

[29]. Fused pyrimidines are selective inhibitors for multidrug resistance (MDR) [30].

Folate metabolism has long been recognized as an attractive target for cancer

chemotherapy because of indispensable role of fused pyrimidines antifolates as

antitumor agents [31]. Risperidone a derivative of pyrido[1,2-a]pyrimidines [32, 33]

and derivatives showed antipsychotic activity [34] which were used as α-2 antagonists

[35-37]. They exhibits high affinity for α-2- adrenoceptor with high selectivity versus

the α- receptor and posses potent in vivo central activity [38, 39]. Many other

examples of pyrimidine based derivative have been investigated as potential antitumor

agents, including 2-phenyl amino derivatives [40-43], 4-phenyl amino derivatives[44,

45], 2.4-bis(phenylamino)derivatives [46], 4.6-bis(phenylamino)derivatives [47, 48],

and 4-aryl substituted derivatives [49]. All these observations point out that pyrimidin

ones occupies distant and remarkable place in medicinal chemistry. Keeping in view

of these above facts, it was thought of synthesizing some pyrimidinone derivatives to

explore their biological significance.

1.3. Biological significance of pyrimidinones

Signal transduction, angiogenesis and cancer activity

In 1996 Pfizer researchers reported the first selective Src-family inhibitors, named

PP1, (1) and PP2 (2) [50], endowed with good potency, but poor selectivity toward

the different members of SFKs. A very large amount of biological data is reported for

PP1 and PP2; they inhibited Lck, Fyn, c-Src and Hck activity kinase with IC50 values

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7

ranging from 4 to170 nM, while were essentially inactive against other non-Src

family TK, such as ZAP-70 or JAK 2. Some inhibition of EGFR was also observed

with IC50 values of 250 and 480 nM for PP1 and PP2, respectively. The compounds

appeared to be ATP competitive inhibitors. The library of compounds (3) and (4) 4-

amino-substtuted pyrazolo [3,4-d] pyrimidines bearing a 2-chloro-2-phenyl N1 side

chain showed a submicromolar to nanomolar activity toward isolated Src as well as

antiproliferative activity toward the epidermoid (A431) and breast cancer (BC-8701)

cell lines (that overexpress Src) blocking Src phosporylation and inducing apoptosis

with potency about two-fold higher than that of the reference compound 4-amino-5-

(4-chlorophenyl)-7-(tert-butyl)pyrazolo[3,4-d] pyrimidine (PP2) (2).

In 1997, Parke-Davis reported a family of pyrido[2,3-d]pyrimidines, belonging to the

important class of urea TK inhibitors [51], as potent, but non-selective inhibitors of

several kinases, acting with an ATP - competitive mechanism [52]. The most

interesting compounds are represented by the soluble 2-substituted aminopyrido

N

N

N

N

X

R

NHR1

SR2

4

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8

[2,3-d]pyrimidin-7-yl ureas, such as (5) that showed IC50 values of 18, 210 and 49

nM, toward Src, PDGFR, FGFR, respectively, in enzymatic assays. Compound (6)

(PD 166285) is a tyrosine kinase inhibitor with moderate selectivity for Src, PDGFR,

FGFR and EGFR, respectively [53, 54]. This derivative has been also reported to

inhibit tumor cell growth particularly of human leukemic cell lines and leukemic

blasts [55]. Compound (7) (PD 173955) has been found to be a more selective Src

inhibitor with IC50 values of 22, 1600 and 1600 nM, for Src, PDGFR, FGFR,

respectively. Treatment of MDA-MB-468 cells, a breast cancer line with this

compound causes a loss in Src activity, with a reduction in the tyrosine

phosphorylation of the enzymes; the cell growth of this tumor line resulted also

blocked, for the ability of (7) to cause mitotic arrest [56]. PD 173955 also inhibits

Bcr-Ab1 and c-Kit, with IC50 values of 2 and 50 nM, respectively [57].

Compound (8) (PD 166326) [58] is a potent dual inhibitor of Src and Abl with IC50

values of 6 and 8 nM, respectively moreover, it is a picomolar inhibitor of K562 cells

growth, showing an IC50 of 300 pM, and leading to apoptotic G1 arrest, PD 0166326

is also effective against imatinib-resistant Brc-Ab1 mutants and could represent a

prototype of a new generation of potential agents useful in the treatment of CMl [59].

Compound (9) (PD 180970) is one of the most recent member of this class, and shows

a similar biological behaviour to that of (8), inducing apoptosis in K562 cells and of

CD34-positive leukemic cells from patients with imatinib-resistant CMl [60, 61].

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9

Gangjee et al., [62] synthesized 2-amino-4-m-bromoanilino-6-arylmethyl-7H-pyrrolo

[2,3-d] pyrimidines (10). Embarked on the design of RTK inhibitors using the

pyrrolo[2,3-d] pyrimidine scaffold with an additional 2-NH2 moiety which is not

present in most other 6-6 or 6-5 ring system RTK inhibitors. The 2-NH2 group in our

compounds provides a third H-bonding moiety in the Hinge region of RTKs, and was

anticipated to increase binding and consequently potency against RTKs. This has

recently been shown to be true in most instances, but is dependent on the nature of the

scaffold and its substitutions [63].

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10

An initial series of 2-amino-4-(3-bromoanilino)-6-(arylmethyl)-pyrrolo[2,3-d]pyrimid

ine derivatives 10 (a-c) indicated that substitution on the 6-aryl moiety dictates both

the selectivity and potency against a variety of RTKs.

The pyrimidine moiety with some substitution shows promising antitumor activity as

there is large number of pyrimidine based antimetabolites. Early metabolite prepared

was 5-flurouracil (11) [64] a pyrimidine derivative followed by 5-thiouracil (12)

which also exhibits some useful antineoplastic activities [65].

Palwinder singh et al., [66] reported the synthesis of 5-substituted-1,3-dimethylpyri

midine-2,4,6-trione derivatives (13) reacted with amines provided enamines. The

investigation for anticancer activity of molecule with 59 human tumor cell lines was

done representing leukemia, melanoma and cancer of lung, colon, brain, ovary, breast

as well as kidney.

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11

Anti-inflammatory activity

Marylene Favre et al., [67] synthesized some substituted tetrahydrothieno[3, 2-

d]pyrimidin-4-one derivatives (14) and screened them for analgesic and anti-

inflammatory activity.

Cannito et al., [68] investigated analgesic and anti-inflammatory activity of some of

3,5,6-trisubstituted-2-thioxo-2,3-dihydrothieno[2,3-d]pyrimidine-4-one derivatives

(15). The i.p. administration of these products at a dose of 1000 mg/kg shows that

they are not toxic (one excepted). Some compounds showed analgesic and anti-

inflammatory activities equivalent to those of acetylsalicylic acid.

F. Russo et al., [69] described new thienopyrimido benzothiazole and thieno

pyrimidobenzo oxazoles (16) and screened them for analgesic and anti-inflammatory

activities.

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12

Nargund et al., [70] synthesised substituted 2-mercapto-3-(N-alkyl)pyrimido[5,4-C]

cinnolin-4-(3H)-ones (17) refluxing 4-aminocinnoline, 3-carboxylic acids, with aryl

isothiocyanates in anhydrous pyridine. These derivatives were evaluated for their

anti-microbial and anti-inflammatory activities. Some of the compounds possessed

potent anti-microbial activity.

Ishwaarsingh S. Rathod et al., [71] studied the analgesic activity of thieno[2,3-d]pyri

midine-4-(3H)-ones (18), 2-aryl amino-3-aryl-5-methyl-6-(substituted)thieno[2, 3- d]

pyrimidin-4(3H)-ones (19) by tail flick method in albino rats and by wriftling method

in albino mice.

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13

A series of 3-substituted amino-2-methyl thieno[2,3-d]pyrimidin-4-(3H)-ones (20)

were synthesized and screened for acute (30mg/kg p.o) and chronic (10mg/kg p.o)

anti-inflammatory activity using carrageenan induced rat paw edema model and

carrageenan-induced granuloma air pouch model respectively. The tested compounds

have exhibited significant (P<0.05) anti-inflammatory activity in acute model while in

chronic model only compounds 20(a-g) have exhibited significant activity

(P < 0.05) [72].

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14

Proquazone (21) a non-steroidal anti-inflammatory agent (NSAID) which, unlike

most other NSAIDs, does not have a free acid group in its structure. It is advocated

for use in rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, musculoskeletal

disorders, acute inflammatory conditions and acute pain states such as

dysmenorrhoea, post-operative pain and headache. Preliminary studies have

confirmed the efficacy of proquazone in acute inflammatory disorders, and shown that

it provides useful analgesic relief in acute pain states such as dysmenorrhoea,

Compound R

20(a) 4-methyl

20(b) 2-hydroxy

20(c) 4-hydroxy

20(d) 4-methoxy

20(e) 2-chloro

20(f) 4-chloro

20(g) N, N-dimethlamino

20(h) 2-nitro

20(i) 3-nitro

20(j) 3-methoxy,4-hydroxyl

20(k) 3,4-dimethoxy

20(l) 3,4,5-trimethoxy

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15

headache and after minor surgery produces a high incidence of gastrointestinal

symptoms such as diarrhoea [73].

Platelet aggregation inhibition activity

1,2,3,5-tetrahydroimidazo[l,2-a]thieno pyrimidin-2-one (22) derivatives have been

prepared and tested for platelet aggregation inhibitory activity in rats in vitro and ex

vivo. Few of the compounds are identified potent inhibitors of blood platelet

aggregation. Compounds 1,2,3,5,6,7,8,9-octahydro-[ l]benzothieno[2,3-d] imidazo[l,2

-a]pyrimidin-2-one exhibited the most favourable activity [74].

Antihypertensive activity

Mery Press et al., [75] synthesized of 3-substituted-thieno[2,3-d]pyrimidine-2,4-dione

(23) and for their antihypertensive activity.

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16

Russell et al., [76] evaluated the antihypertensive activity of thienopyrimidine

derivatives (24).

Atwal et al., [77] synthesized dihydropyrmidinone derivatives (25). Where as the

modifications of the substituent at N3 led to the development of orally long-lasting

antihypertensive activity. Furthermore, it has been established that the absolute

stereochemistry at the C4 carbon atom is very important. For example, the desired

antihypertensive effect was observed only with the (R)-enantiomer of the compound.

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17

Ketanserin (26) a serotonin receptor antagonist, reduces blood pressure appears as a

new and important alternative in the treatment of mild and moderate essential

hypertension [78].

CNS activity

Howard et al., [79] screened Risoperidone (27) for CNS activity, its structural hybrid

is of butyrophenone and can be used as anxiolytic, antidepresant and antiparkinsonian

drug.

Abott et al., [80] synthesized and checks the anesthetic activity of pyrimidine

analogue, thimylal (28).

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18

Sugiyama et al., [81] condensed thieno[3,2-d]-, [3,4-d], and [2,3-d]pyrimidin-5-one

derivatives (29) in which the oxygen atom of the oxazolidine moiety in 29 was

replaced by a sulfur atom or methylene groups, and evaluated for their gastric

antisecretory activity in pylorus-ligated rats.

Sedative/hypnotic/antiepileptic agents

Agents of the anxiolytic, sedative and hypnotic group include a wide variety of

barbiturates 30(a-i) used as sedative and hypnotics and are classified as drugs having

short, intermediate and long duration of action [82]. Allobarbital 30(a), aprobarbital

30(b), pentobarbital 30(e), phenobarbital 30(g) and secobarbital 30(i) are frequently

used clinically as hypnotic barbiturates [83]. Hexobarbital 30(c), cyclobarbital 30(d)

and propallylonal 30(f) are some of the current drugs in the market used as sedative

hypnotics [84]. Barbiturates as sedative hypnotics hava a long and fascinating history.

Eli Lilly patented secbutabarbital 30(h) in 1932 [85] .

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19

Compound R R1 R2

30(a) -H -H

30(b) -H -H

30(c) -H -CH3

30(d) -H -H

30(e) -H -H

30(f) -H -H

30(g) -H -H

30(h) -H -H

30(i) -H -H

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20

Flucytosine (31) is a fluorinated pyrimidene used as nucleosidal anti-fungal agent for

the treatment of serious systemic infections caused by susceptible strains of candida

and Cryptococcus [86].

Non-peptide Luteinizing Hormone-Releasing Hormone (LHRH) Antagonists

Sasaki et al., [87] designed, synthesized, and evaluated a new class of non-peptide

luteinizing hormone-releasing hormone (LHRH) receptor antagonists, the 2-phenylimi

dazo[1,2-a]pyrimidin-5-ones, a heterocyclic 5-6 ring (32). This study resulted in the identi

fication of a new class of potent LHRH antagonists, represented by the methoxyurea

‘32 g’ possessing high binding affinity and potent in vitro antagonism, with IC50

values of 0.4 and 7 nM, respectively. These results conclude that the imidazopyrimidin

-5-one provide a new scaffold for small molecule LHRH antagonists devoid of a

thiophene ring. Taking this finding into consideration, it is suggested that the heterocycl

ic 5-6 ring system bearing a pendant phenyl group attached to the five-membered ring

is the key structural motif for a LHRH antagonist scaffold system (32) in which an

imidazole ring is embedded, as a novel scaffold for non-peptide LHRH antagonists.

CHAPTER-I

21

Stadler et al., [88] described nitrofuryl-substituted DHPM derivative Nitracin (33) and

the compound displayed activity against viruses of the trachoma group and modest

antibacterial activity.

Calcium channel blocking activity

Rovnyak et al., [89] investigated 2-(methylthio)-4-(2-(methylthio)-3-nitrophenyl)-4,7-

dihydrofuro[3,4-d]pyrimidin-5(1H)-one (34), Alajarin et al., [90] investigated a

monocyclic dihydropyrimidine (35). Besides the monocyclic DHMP derivatives,

some fused analogs, which incorporate hetero- or carbocyclic rings attached to either

C2/N3 or the C5/C6 positions of dihydropyrimidine such as (34) and (35) possess

calcium channel blocking activity.

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22

1.4. Introduction to Thiazoles

Thiazoles (36) are structurally related to thiopene and pyridine, but in most of its

properties it resembles to the latter. Thiazole was first described by Hantzch and

Waber in 1889. The numbering in thiazole starts from the sulphur atom. Structure

(37) is benzothiazole. The basic structure of benzothiazole consists of benzene ring

fused with 4, 5 position of thiazole. The two rings together constitute the basic

nucleus 1,3-benzothiazole.

Thiazole is a five-membered ring containing one nitrogen and one sulfur.

Benzothiazole is a heterocyclic compound, weak base, having varied biological

activities and still of great scientific interest now a days. They are widely found in

bioorganic and medicinal chemistry with application in drug discovery. Benzothiazole

moieties are part of compounds showing numerous biological activities such as

antimicrobial [91-95], anticancer [96-98], anthelmentic [99], antidiabetic [100],

activities. They have also found application in industry as anti-oxidants, vulcanization

accelerators. Various benzothiazoles such as 2-arylbenzothiazole received much

attention due to unique structure and its uses as radioactive amyloid imaging agents

[101], and anticancer agents [102]. Benzothiazoles are bicyclic ring system with

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23

multiple applications. In the 1950’s, a number of 2-aminobenzothiazoles were

intensively studied, as the 2-aminobenzothiazole scaffold is one of privileged

structure in medicinal chemistry [101-103] and reported cytotoxic on cancer cells

[103]. It must be emphasized that combination of 2-aminobenzothiazoles with other

heterocyclic is a well known approach to design new drug like molecules, which

allows achieving new pharmacological profile, action, toxicity lowering. The 2-(4-

aminophenyl) benzothiazoles are novel class of potent and selective antitumor agents

and display characteristic profile of cytotoxic response across the cell lines. In

addition, benzothiazole ring is present in various marine or terrestrial natural

compounds, which have useful biological properties. Sulphur and nitrogen atoms

constitute the core structure of thiazole and many pharmacologically and biologically

active compounds.

1.5. Biological significance of Thiazoles

Antimicrobial activity

Yadav et al., [104] synthesized a series of fluoro, chloro 2-(α-substituted aryl amino

acetamido)benzothiazole (38) and screened for antibacterial activity against

B. subtilis, S. typhi, E. coli, and S. aureus bacterial strains. The fluoro, and chloro

substituents showed a significant antibacterial activity.

Basavaraja K. M. et al., [105] described 2-[1-aryl azo]methyleneimino-6-chloro

benzothiazole derivatives (39) and tested for antimicrobial activity against B. subtilis,

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24

S. typhi, E. coli, and S. aureus bacterial strains. The compounds showed a significant

antibacterial activity.

Murthy Y. et al., [106] evaluated some new 2-mercaptobenzothiazoles (40) and

correlated the effect on anti microbial potency by varying the substituents in benzene

part of the benzothiazole ring system. Anti-microbial screening was performed

against E. coli, S. aureus, C. albicans and antifungal activity against Aspergillus

flavus and Candida albicans at conc. 100 µg/mL using agar plate Kirby-Bauer disc

diffusion method.

Pandurangan A. et al., [107] reported N-2-benzothiazolylthiourea derivatives (41) as

good antimicrobial agents against Gram-positive and Gram-negative bacteria such as

S. aureus, P. aeruginosa, E. coli, and a yeast (C. albicans) and a mould (Microsporum

gypseum).

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25

Maharan M. et al., [108] discussed a series of benzothiazole-2-yl-dithiocarbamates

(42) along with copper complexes via reaction of suitable alkyl or hetroaryl halide

with sodium salt of benzothiazole-2-yl-dithiocarbamic acid followed by complexation

with copper sulphate and selected derivatives checked for their schistosomicidal

activity against Schistosoma mansoni.

Amir M. et al., [109] examined thiadiazole derivatives containing benzothiazole (43)

and screened for both antibacterial and antifungal activites using cup-plate agar

diffusion method. Anti-microbial screening was performed against E. coli, S. aureus,

C. albicans and antifungal activity against Aspergillus flavus and Candida albicans.

Soni B. et al., [110] reported newer Schiff bases of benzothiazole derivatives (44) and

they tested for antibacterial activity. The synthesized derivatives exhibited moderate

antibacterial activity against Gram-positive (S. aureus and S. pyrogenus),

Gram-negative bacteria (E. coli and P. aeruginasa) and Fungi (C. albicans, A. niger

and A. clavatus). The results demonstrated that compounds with a 4-hydroxy, 4-

dimethylamino and 3,4-dimethoxy group on the aromatic ring showed good

antibacterial activity.

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26

S

NNH

N N

N

SH

N

R

44

R= 4-OH, 2-Cl, 4-N(CH3)2 and 3, 4-OCH3

Alang et al., [111] studied seven new derivatives of 2-substituted benzothiazole (45)

and found them as good antibacterial agent against Gram-positive bacteria (S. aureus,

S. epidermis) and Gram-negative bacteria (P. aeruginasa and E. coli).

Malik et al.,[112] synthesized some new 2-amino substituted benzothiazoles (46) and

evaluated for in vitro antifungal activity against fungal strains such as C. albicans,

A. niger and A. flavus.

Barot H. K. et al., [113] evaluated nitrogen mustards of flurobenzothiazoles (47, 48)

and was determined for antibacterial and antifungal activites against S. aureus, B.

subtilis, C. tropicans, A. niger, and F. heterosporium. The synthesized compounds

showed an excellent inhibition at a conc. of 50µg/0.1mL.

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27

Anthelmentic activity

Sreenivasa M. et al., [114] synthesized fluorobenzothiazole comprising sulphanamide

pyrazole derivatives (49). The synthesized compounds were screened for anthelmentic

activity by using earthworms (Peritumaposthum). The compounds were evaluated by

time taken for complete paralysis and death of worms.

4-Fluoro-3-chloroaniline treated with potassium thiocyanate in presence of glacial

acetic acid and bromine was converted into 2-amino-6-fluoro-7-chlorobenzothiazole.

The synthesized compound in presence of p-dimethylaminobenzaldehyde refluxed in

ethanol to obtain a corresponding 6-fluoro benzothiazole Schiff’s base (50) the above

said compound was treated with ortho, meta and para nitroanilines, ortho, meta, para

chloroanilines, morpholino, piperazine, diphenylamine in the presence of DMF to

obtain different new moieties. Some new moieties showed promising anthelmintic

activity [115].

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28

Anti-inflammatory activity

Shashank et. al., [116] described synthesis of 2-substituted benzothiazole derivatives

(51) and evaluated for anti-inflammatory activity. The maximum activity may be due

to presence of -F and -OCH3 groups. The same series of compounds also showed good

anticancer activity.

A series of 2-(benzo[d]thiazol-2-ylthio)-N-(2-oxoindolin-3-ylidene)acetohydrazide

52(a-g), 2(benzo[d]thiazol-2-ylthio)-N-(2,4-dioxospiro[indolin-3,2-thiazolidin]-3’-yl)

acetamide 53(a-g) and 2'-((benzo[d]thiazol-2-ylthio)methyl)spiro[indoline-3,5'-thiazolo

[4,3-b][1,3,4]oxadiazol]-2-ones 54(a-g) have been synthesized and screened for their

anti-inflammatory, analgesic and anti-bacterial activities. The most potent anti-inflamm

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29

atory and anti-bacterial compound of this series was compound 54d and most potent

analgesic compound was compound 54e [117].

Oketani et al., [118] studied the in vitro pharmacological profiles of 6-hydroxy- 5, 7-

dimethyl-2-(methylamino)-4-(3-pyridylmethyl)benzothiazole (55) against the 5 lipooxy

genase activity of rat basophilic leukemia cells. This result indicated that the compound

effectively inhibited 5-lipoxygenase and thromboxane B2 production in rat peritoneal

and human blood vessels.

Cyclooxygenase inhibitor activity

Gurupadaya B. et al., [119] synthesized azatidin-2-ones and thiazoline-4-ones (56)

encompassing benzothiazole derivatives and evaluated for anti-inflammatory activity

using carrageenan induced rat hind paw edema method.

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30

Anti-cancer activity

The 2-arylsubstituted benzothiazole derivatives (57) were synthesized by refluxing o-

aminothiophenol with substituted benzoic acids in the presence of polyphosphoric

acid at 220 0C 2-Mercaptothiazole was used along with thionyl chloride to get the

carbothioates. The screening for antitumour activity was done as per the National

Cancer Institute drug screening strategy 3 compounds were found to be significantly

cytotoxic as compared to [2-(3-bromo-4-aminophenyl)benzothiazole] against the

human cervical cancer cell lines [120].

Fluorinated 2-arylbenzothiazoles (58) are new potential antitumor drugs, which show

potent and selective inhibitory activity against breast, lung, and colon cancer cell

lines. Carbon-11 labeled fluorinated 2-arylbenzothiazoles may serve as novel probes

for positron emission tomography (PET) to image tyrosine kinase in cancers [121].

Gupta S. et al., [122] synthesized benzothiazole derivatives (59) and screened for in

vitro cytotoxic activity against HL-60 and U-937 cell lines. In silico pharmacokinetic

study revealed that benzothiazole dimere were free from teratoginicity, irritation and

sensitivity properties than monomers. The QSAR study showed that increase in

CHAPTER-I

31

hydrogen donor count is conductive for cytotoxic activity of benzothiazole derivatives

against HL-60 cell lines.

MTP inhibition activity

A series of triamide derivatives bearing a benzothiazole (60) core is shown to be

potent microsomal triglyceride transfer protein (MTP) inhibitors. In order to minimize

liver toxicity, these compounds have been optimized to have activity only in the

enterocytes and have limited systemic bioavailability. Upon oral administration,

selected analogs within this series have been further demonstrated to reduce food

intake along with body weight and thereby improve glucose homeostasis and insulin

sensitivity in a 28 day mice induced obesity (Dio) model [123].

Amyloid imaging agent in Alzheimer’s disease

Serdons K. et al., [124] examined F-labelled 2-(4-fluorophenyl)benzo[d]thiazoles (61)

evaluated it as amyloid imaging agent in Alzheimer’s disease and they showed good

affinity for amyloid plaques present in human Alzheimer’s disease.

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32

Antimalarial activity

Hout S. et al., [125] synthesized 2-substituted-6-nitro (62) and 6-aminobenzothiazoles

(63) and their anthranilic acids were carried out on W2 and 3D7 strains of

P. falciparum. The results revealed the potency of compounds 62 and 63 as the

antimalarial agents of clinical and biological research.

PPAR δ activity

To find novel PPAR δ-selective agonists, Fujida et al., [126] designed and

synthesized phenylpropanoic acid derivatives bearing 6-substituted benzothiazole

derivatives. Optimization of this series led to the identification of a potent and

selective PPAR δ-agonist. Among the synthesized compounds, compound (65) has

shown PPAR δ activity and selectivity. The introduction of Cl group at the C-6

position of the benzothiazole ring and methyl group at the ortho position of phenyl

propanoic acid further improved PPAR δ transcriptional activity. Compound (65) was

found to be the most potent and selective PPAR δ agonist.

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33

Anti convulsive activity

Several benzothiazoles containing sulphanamide derivatives (66) [127], benzothiazolyl

guanidones (67) [128], benzothiazolamines (68) [129], were synthesized and evaluated

for their activity against electro shock and phenyl tetrazolone induced seizures. The review

of these literatures revealed the benzothiazole moiety as a dynamic agent against convulsive

seizures.

Siddiqui et al., [130] reported N-(6-substituted-1, 3-benzothiazole-2-yl)-4-sulphanami

des (69) and screened for anticonvulsive activity. The tested compound showed an

anticonvulsive effect in MES and PTZ induced seizures.

Amnerkar N. et al., [131] investigated prop-2-eneamido and 1-acetyl-pyrazolin

derivative of aminobenzothiazole (70) and the compound was evaluated for anticonvu

lsive activity. The screened compound showed anticonvulsive activity in MES and

PTZ induced seizures.

CHAPTER-I

34

Anti-diabetic activity

Pattan S. R. et al., [132] described a series of 2-amino[5’(4-sulphonylbenzylidene)-2,

4-thiazolidinone]-6-flurobenzothiazoles (71) and examined for anti-diabetic activity.

All the compounds of this series showed promising anti-diabetic activity.

Paoli and co-workers [133] prepared a small library of 2-arylsulphonyl aminobenzothi

azoles (72, 73) and screened them for protein tyrosine phosphatase 1B inhibition. The

most active compounds (72) and (73) were observed as rapid reversible inhibitors of

PTP-1B and significantly lowered plasma glucose concentration.

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35

1.6. Scope of the present work

Heterocyclic chemistry is a vast and expanding area of chemistry, because of the

obvious applications of compounds derived from heterocyclic rings in pharmacy,

medicine, agriculture and other fields. This study is of great interest both from

theoretical as well as practical standpoint. In five-membered and six-membered ring

systems, the presence of nitrogen, oxygen, and sulphur heteroatom defines an

interesting class of compounds. An important application of small molecule libraries

is the preparation of a directed or focused combinatorial library for assay against a spe

cific biological target. Pyrimidinone and thiazole is among the most important heteroc

yclic compounds, which exhibit their therapeutic activity is due to their

conformationally flexible nature. The accentuated interest in the pyrimidinone and

thiazoles class of opiate analgesics continues to be expressed in the pharmaceutical

community and biological properties of these agents have been the subject of ongoing

investigations. In this connection the present investigation is undertaken and is

divided in to three chapters. Chapter-I gives the introduction to pyrimidinone and

benzothiazole derivatives. Pyrimidinones and benzothiazoles were proven to be

biologically very potent and selective. A wide spectrum of pharmacological activities

has been reported for these compounds. These include anti-cancer, anti-inflammatory,

platelet aggregation inhibition, C.N.S activity, antimicrobial, anthelmentic, anti-

inflammatory, cyclooxygenase inhibitor activity, anti-diabetic, antimalarial, MTP

inhibition activity, PPAR-δ activity. Such varieties of interesting biological activity

for this class of compounds prompted us to synthesize pyrimidinone and thiazole

derivatives and investigate their biological importance. It is expected that these would

result in highly potent and selective pharmaceutical agents.

CHAPTER-I

36

Chapter-II deals with the synthesis of 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-

4H-pyrido[1,2-a]pyrimidin-4-one derivatives 6(a-s) and investigate for antimicrobial

activity. From the results obtained compounds 6c and 6i showed inhibitory activity

against tested bacterial strains. Synthesis of 2-methyl-3-(2-(piperazin-1-yl)ethyl)-6,7,8

,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one derivatives 8(a-g) and 9(a-f) and inve

stigate for antimicrobial activity. From the results obtained compounds 8a and 9d

showed inhibitory activity against tested bacterial strains. Synthesis of 2-methyl-3-(2-

(piperazin-1-yl)ethyl)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one derivatives

8(a-d) and 9(a-e) and screened for anti-angiogenesis by EAT cells in vivo. From the

results obtained compounds 8d and 9a showed potent activity against EAT cells in

vivo.

Chapter III contains the evalution of 1-(substituted phenyl)-3-(6-ethoxybenzo[d]thiaz

ol-2-yl)thiourea derivatives 5(a-i) and evaluated for anti-angiogenesis by EAT cells in

vivo. From the results obtained compounds 5e and 5g can be considered as anti-angi

ogenic compounds against EAT cells in vivo.

Synthesis of N-(benzyl)-6-ethoxybenzo[d]thiazol-2-amine derivatives 7(a-i) and scree

ned for anti-angiogenesis by EAT cells in vivo. From the results obtained compounds

7b and 7g have shown good anti-angiogenic effects against mouse Ehrlich Ascites

Tumour. Synthesis of N-(benzylidene)-6-ethoxybenzo[d]thiazol-2-amine derivatives

9(a-i) and tested for anti-diabetic agents. From the results obtained compounds 9a and

9d can be considered as anti-diabetic agents against sucrase, maltase, glucosidase, and

amylase of in vitro activity.

CHAPTER-I

37

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