DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL PYRROLIDINE-2,5-DIONES TETHERED WITH AZETIDINONE MOIETY

SYNOPSIS FOR M.PHARM DISSERTATION

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA

BY

VANISHREE B RI M.PHARM (2009-10)

DEPARTMENT OF PHARMACEUTICAL CHEMISTRYM.S. RAMAIAH COLLEGE OF PHARMACY

BANGALORE-560054

1

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1. NAME OF THE CANDIDATE AND ADDRESS

VANISHREE B RC\O DAYANAND J ARTD HIGH SCHOOL TEACHERNO:92/90C, SRINIDHI NILAYAKOLAR ROAD, MALUR TOWNKOLAR DIST, KARNATAKAPIN:563130.

2. NAME OF INSTITUTION M.S.RAMAIAH COLLEGE OF PHARMACY, M.S.R.I.T. POST, M.S.R. NAGAR, BANGALORE-560054

3. COURSE OF THE STUDY AND SUBJECT

M.PHARM PHARMACEUTICAL CHEMISTRY

4. DATE OF ADMISSION 20TH JUNE 2009

5.

TITLE OF THE TOPIC

DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL PYRROLIDINE-2,5-DIONES TETHERED WITH

AZETIDINONE MOIETY

2

6. BRIEF RESUME OF THE INTENDED WORK6.1 NEED FOR THE STUDY

Although Human beings are endowed with the resistance to the micro organisms, most of the

micro organisms have been very infectious leading to various microbial infections. In this case

antibiotics have been successfully used since the ages to treat such infections.1,2

The first effective antimicrobial agent which came into existence was in 1930s, the first

antibiotic in 1940 and the semi-synthetic antibiotic in early 1970s. The world wide commerce in

antibiotics is measured in multiple tons in the year 2000 and is valued over $10 million, above half

of which is associated with β-lactam antibiotics alone.

β -lactam is the basic nucleus that is present in the penicillins, cephalosporins, carbapenems

and monobactams. It is fortunate that this is main pharmacophore for all these compounds.

β –lactam is cyclic amide with four atoms in the ring and the synonym for this ring is 2-

Azetidinone this ring with appropriate substitution possess several interesting applications viz.,

antibacterial activity 3-16 , antifungal activity 17-25, anti tubercular activity 26-31, anti-inflammatory

activity 32-36, anticonvulsant activity, antiviral activity 37.

Pyrrolidinedione is a five membered heterocyclic aliphatic amine, saturated and with ketone

groups at 2nd and 5th positions have interesting properties including antitumor and antidiabetic

activities55.

The side chain substituted group of Azetidinone, which is electron withdrawing decreases the

density on the side chain carbonyl group and protects the β –lactam amide bond from acid degradation.

The more lipophilic the side chain the more serum bound antibiotic and this has an added advantage in

terms of protecting the β –lactam ring from degradation. Keeping these two points in mind, we had

selected the side chain containing pyrrolidine dione moiety.

3

Literature survey reveals that there is no work done on the molecular entity containing

azetidinone moiety and pyrrolidine dione moiety as a single molecular frame work. Hence a drug

strategy has been planned to synthesize several pyrrolidine dione derivatives possessing azetidinone

moiety with the hope that this new molecular entity possessess better biological activity.

6.2 REVIEW OF LITERATURE

4

Synthesis of some new N9 – [hydrazinoacetyl-(2-oxo-3-chloro-4-substituted aryl

azetidine)]-carbazoles using conventional as well as micro wave methods and screening

for antifungal and antibacterial activity was reported.3

Synthesis of 2-(2’-arylidene-hydrazino-acetyl-amino)-4-phenyl-1,3-thiazoles and 2-[2’-

{4”-substituted-aryl-3”-chloro-2”-oxo-azetidine}-acetyl-amino]-4-phenyl-1,3-thiazoles as

antimicrobial agents was reported. 4

Stereoselective synthesis of monocyclic β –lactams from the reaction of acid

Chlorides/mixed Anhydrides with Substituted Imines was reported. 5

A novel approach for the rapid and efficient synthesis of heterocyclic schiff bases and

azetidinones under microwave irradiation was reported. 6

Synthesis of pyrazole imines and azetidinone compounds using conventional and

microwave technique and studies of their antibacterial activity was reported. 7

Convenient synthesis and biological activity of 2-azetidinones and

4-thiazolidinones was reported. 8

Antibacterial screening of N-arylamino-3-chloro-4(4’-Dimethyl Amino) Phenyl-Azetidin-

2-Ones was reported. 9

Synthesis of some new Thiazolidinones and Azetidinones of 6-Amino Coumarin and their

biological activity was reported. 10

Formation of 2-azetidinones from selective ester cleavage in 1,3,3-tri substituted 4-[2’-(O-

diarylacyl) hydroxyphenyl]-2-azetidinones as antimicrobial agents was reported. 11

Synthesis and antimicrobial evaluation of some 2-Azetidinone derivatives was reported. 12

5

Synthesis and antibacterial screening of N-[Naphtho[1,2-b]pyrano[3,4-d] thiazol-8-yl]

spiroindoloazetidin-2-ones/thiazolidin-4-ones was reported. 13

A synthesis and QSAR study of 4-oxo-thiazolidines and 2-oxo-azetidines as potential

antibacterial agents was reported. 14

Synthesis and biological activity of some new schiff’s bases, thiazolidinones and

azetidinones of 4-hydroxy coumarin was reported. 15

Synthesis and antibacterial activity of some 4-oxo-thiazolidines and 2--oxo-azetidines was

reported 16

Rapid and efficient synthesis of some biologically active 2-azetidinones under microwave

irradiation was reported. 17

Synthesis of some azetidin-2-ones and thiazolidin-4-ones as potential antimicrobial agents

was reported. 18

Synthesis and antimicrobial screening of N-[6’-coumarinylamino-3-chloro-4-aryl

azetidine-2-ones] was reported 19

Synthesis of new (3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl)-N-(4-aryl-3-chloro-2-oxo-

azetidin-1-yl) acetamides was reported. 20

Synthesis and biological activity of 2-azetidinones,4-thiazolidinones, 5-imidazolinones

having benzthiazole moiety was reported. 21

Synthesis of some new 2- azetidinones as potential antimicrobial agents was reported. 22

Synthesis and antimicrobial screening of N-substituted -3-chloro-4-dithiocarbamato

azetidin-2-ones was reported. 23

6

2D-QSAR studies of some 1,3,4-thidiazole-2yl azetidine 2-one as antimicrobial activity

was reported. 24

Synthesis of some new 5-[2-{(1,2,3-benzotriazole)-1-yl-methyl}-1’-(4’-substituted aryl-3’-

chloro-2’oxo azetidine)]-amino-1,3,4-thiadiazoles as antifungal and antibacterial agents

was reported. 25

Synthesis, characterization and biological activities of some 1-(nicotinylamino)-2

substituted azetidine-4-ones as potential antibacterial agents was reported. 26

Synthesis and biological activity of 4-thiazolidinones, 2-azetidinones, 4-imidazolinone

derivatives having thymol moiety was reported. 27

Synthesis and biological evaluation of some new azetidinones and thiazolidinones was

reported. 28

QSAR studies on 4-thiazolidinones and 2- azetidinones bearing benzothiophene nucleus as

potential anti-tubercular agents was reported. 29

Synthesis of azetidinone and thiazolidinone derivatives of pyrazinoic acid for possible anti-

tubercular, antifungal and antibacterial activity was reported. 30

Synthesis of pyrimidine based thiazolidinones and azetidinones as antibacterial and anti-

tubercular agents was reported. 31

Synthesis of new carbazolyl-thiadiazol-2-oxo-azetidines as antimicrobial, anticonvulsant

and anti-inflammatory agents was reported. 32

7

Design and synthesis of novel quinazolin incorporated azetidinones and thiazolidinones as

sedative, antibacterial and antifungal agents was reported. 33

Synthesis and pharmacological evaluation of (N-phenotiazinomethyl)-4-[N-(3-chloro-2-

oxo-4-substituted-azetidin)]-5-mercapto-1,2,4-triazoles was reported. 34

Synthesis of some new 1-methyl [(N-alkyl phthalyl)-benzimidazolo]-3’-chloro-4’-

substituted azetidine-2 ones as antimicrobial agents was reported35

Synthesis and pharmacological studies of some azetidinones bearing ibuprofen moiety was

reported. 36

Synthesis, characterization and biological activity of 1,3,4-substituted 2-azetidinones was

reported. 37

Proline-catalyzed Diastereoselective direct Aldol reaction between 4-Oxoazetidine-2-

carbaldehydes and ketones was reported. 38

Synthesis of 2-azetidinones and other heterocycles from N-(3-hydroxypropyl) imines was

reported. 39

Triphenylphosphine / Germanium chloride combination as a new agent for the reduction of

α- bromo carboxylic acid derivative was reported. 40

Synthesis of 1-arylazetidin-2-ones using calixarenes as phase-transfer catalysts was

reported. 41

Stereochemical aspects of the Bose reaction for α-Amino-β-lactam Synthesis was

reported.42

8

Formation of four-member heterocycles through electrophilic heteroatom cyclization was

reported. 43

A new synthesis of azetidin-2-ones was reported. 44

Transformation of 3-Isopropenylazetidin-2-ones to 3-[1-(Hydroxymethyl)ethylidene]

azetidin-2-ones was reported. 45

One-pot Reformatsky-Imine addition reaction-leading to the synthesis of structurally

diverse β-lactams was reported. 46

A new Radical Route to C4-Unsubstituted β-lactams was reported. 47

Memory of chirality in the stereo selective synthesis of β-lactams was reported. 48

Synthesis of O-benzyl azetidinone derivatives of (R) and (S)-2-aminobutanols was

reported. 49

Synthesis of some new N-(4-(N,N’-Dimethylaminosulfonylphenyl)-3-chloro-4-phenyl

azetidin-2-ones was reported.50

Synthesis of 1-[4’-(5”,6”-dimethoxypyrimidino sulphonamoyl) phenylamino] -3-chloro-

4,4-diphenylazetidin-2-one and its electrochemical investigations was reported. 51

Synthesis and biological evaluation of novel 2,5-disubstituted 1,3,4-oxadiazoles tethered

with azetidinone moiety. 52

Chemo-enzymatic synthesis of chiral 3-hydroxy-azetidin-2-ones was reported. 53

Synthesis and biological activity of Pyrrole, Pyrroline and Pyrrolidine derivatives with two

aryl groups on adjacent positions was reported. 54

9

In silico design and synthesis of piperazine-1-pyrrolidine-2,5-dione scaffold-based novel

malic enzyme inhibitors was reported. 55

Synthesis of pyrrolidine-2,4-diones from Urethane N-carboxyanhydrides was reported. 56

Synthesis of Polysubstitued Pyrroles from sulfinimines (N-sulfinyl imines) was reported. 57

Stereoselective synthesis of trans-2,3-disubstituted pyrrolidines via addition to N-

acyliminium ions was reported. 58

Synthesis of cis-2,5-disubstituted pyrrolidines via diastereoselective reduction of N-

acyliminium ions was reported. 59

Synthesis of highly substituted pyrrolidines via palladium catalysed formal (2+3) cyclo

addition of 5-vynyloxazolidin-2-ones to activated alkenes was reported. 60

Design, synthesis and evaluation of novel galloyl pyrrolidine derivatives as potential anti-

tumor agents was reported. 61

Synthesis of 2,4-, 3,4- and 2,3,4- substituted pyrrolidines by cyclization of neutral C-

centered α-aminoalkyl radicals was reported.62

Ring-opening of N-alkoxycarbonyl γ-lactams with lithium methylphenylsulphone:

application to the synthesis of cis 2,5-disubstituted pyrrolidines was reported. 63

A greener approach for the synthesis of 1-N-methyl-(spiro[2,3’]oxindolespiro

[3,2”]/spiro[2.3’]indan-1,3-dionespiro[2.2”])cyclopentanone- 4-aryl pyrrolidines was

reported. 64

Cis-Selective synthesis of 2,5-disubstituted pyrrolidines was reported. 65

10

2-Aryl (pyrrolidin-4-yl) acetic acids are potent agonists of sphingosine-1-phosphate (SIP)

receptors was reported. 66

4-(pyrrolidinyl)methoxybenzoic acid derivatives as a potent, orally active VLA-4

antagonist was reported. 67

Synthesis of N-[2-and 3-(substituted aryloxy)] acetyl and propanoyl

pyrrolidine/morpholine/piperidine/piperazines and their bio-evaluation was reported. 68

An easy access to novel steroidal dispiropyrrolidines through 1,3-dipolar cycloaddition of

azomethine ylides was reported. 69

Pyrrolidine-Carboxamides and oxadiazoles as potent hNK1 antagonists was reported. 70

Enantioselective synthesis of both Enantiomers of 3-Hydroxy-4,4-dimethyl-1-phenyl-2-

pyrrolidinone was reported. 71

A novel one-step efficient method for the synthesis of tetrahydroindoles from 1-(1-

pyrrolidino)cyclohexene and chloropyruvates was reported. 72

Pyrrolidine bis-cyclic guanidines with antimicrobial activity against drug-resistant Gram-

positive pathogens identified from a mixture-based combinatorial library was reported. 73

Novel, potent P2 _P 3 Pyrrolidine derivatives of ketoamide-based cathepsin K inhibitors was

reported. 74

Stereoselective synthesis of 3,4-trans-disubstituted pyrrolidines and cyclopentanes via

intramolecular radical cyclizations mediated by CAN was reported. 75

Triphenylphosphine oxide supported on non-cross-linked maleimide-styrene copolymer

used as a novel Hendrickson reagent was reported. 76

11

Pyrrolidine-based chiral pyridinium ionic liquids (ILs) as recyclable and highly efficient

organocatalysts for the asymmetric Michael addition reactions were reported. 77

A new synthesis of pyrrolidines via imino-aldol reaction of (2-

trimethylsilylmethyl)cyclopropyl ketones with imines was reported. 78

A practical route to enantiopure 3-hydroxy-pyrrolidines was reported. 79

A short and efficient synthesis of the NMDA glycine site antagonist (3R, 4R)-3-amino-1-

hydroxy-4-methyl pyrrolidin-2-one was reported80

Pyrrolidinones as orally bioavailable antagonists of the human melanocortin-4 receptor

with anti-cachectic activity was reported. 81

2(S)-(Cycloalk-1-enecarbonyl)-1-(4-phenyl-butanoyl) pyrrolidines and 2(S)-(aroyl)-1-(4-

phenylbutanoyl) pyrrolidines as prolyl oligopeptidase inhibitors was reported.82

Synthesis and biological evaluation of 5-Oxopyrrolidine-3-carboxamide derivatives as

anti-HIV-1 agents was reported. 83

12

6.3 AIMS AND OBJECTIVES OF THE STUDY

To synthesize the title compounds by both conventional and microwave methods and compare their

applicability with respect to the percentage yield and reaction time.

To purify the title compounds by regular recrystallisation and chromatographic techniques.

Identification and characterization of the compounds by Qualitative tests, Elemental and spectral

analysis.

The synthesized compounds will be screened for anti-microbial and in-vitro anti-inflammatory

activity.

13

7. MATERIAL AND METHODS

7.1 SOURCE OF DATA

1. Literature survey, chemical abstracts.

2. Journals and publications, e.g. Indian Journal of Heterocyclic Chemistry,

Indian Journal of Chemistry, Journal of Indian chemical society,

Indian journal of chemical Research (s), Tetrahedron Letters etc.

7.2 METHODS OF COLLECTION OF DATA

1) PRE-LABORATORY WORK:

The chemicals and reagents required for the synthesis and evaluation of the proposed

compounds will be procured from reputed chemical suppliers like Merck, Ranbaxy, Rankem,

Himedia etc.

2) LABORATORY WORK:

A) SYNTHESIS OF THE COMPOUNDS:

Conventional methods of synthesis1,7 as well as microwave assisted synthesis3,17 will be

attempted. The completion of the reaction will be determined by TLC. Advantages and

feasibility of the methods will be analyzed.

B) PURIFICATION OF THE COMPOUNDS:

The synthesized compounds will be purified by different methods like fractional

crystallization, recrystallization, distillation and chromatographic methods.The purity will be

ascertained by TLC.

C) CHARACTERIZATION OF THE COMPOUNDS:

The synthesized compounds will be characterized by:

1. Chemical tests for important functional groups.

2. Study of spectral data.

14

D) SCREENING OF BIOLOGICAL ACTIVITY

a) SCREENING OF ANTIBACTERIAL ACTIVITY BY DISC DIFFUSION METHOD:

This will be carried out on both Gram positive and Gram negative organisms like Staphylococcus

aureus, pseudomonas aeruginosa, Escherichia coli, Bacillus subtilis etc using sterile Media like

Mueller-Hinton Agar etc by Disc Diffusion Method. Zone of inhibition of the compounds

synthesized will be noted and compared with that of standard drugs like Amoxicillin, Ciprofloxacin

etc.84

b) SCREENING OF ANTIFUNGAL ACTIVITY BY DISC DIFFUSION METHOD:

This will be carried out on organisms like Candida albicans and Aspergillus niger using Media like

Sabouraud Dextrose Agar. Zone of inhibition of the compounds synthesized will be compared with

that of standard drugs like griseofulvin. The entire work will be done using Horizontal Laminar

Flow hood.85

c) SCREENING FOR INVITRO ANTI INFLAMMATORY ACTIVITY:

This will be carried out according to the procedure suggested by Mizushima.86,87

7.3 DOES THE STUDY REQUIRE ANY INVESTIGATION TO BE CONDUCTED ON

PATIENTS OR OTHER HUMAN OR ANIMALS? IF SO PLEASE DESCRIBE

BRIEFLY.

-Not applicable-

7.4 HAS ETHICAL CLEARANCE HAS BEEN OBTAINED FROM YOUR INSTITUTION

IN CASE OF 7.3?

-Not applicable-

15

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16

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18

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19

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20

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26

9. SIGNATURE OF THE STUDENT:

10. REMARK OF THE GUIDE: Recommended for registration

11. NAME AND DESIGNATION OF:

11.1 GUIDE:

11.2 SIGNATURE:

Prof. M. NARAYANA BABUDepartment of Pharmaceutical ChemistryM.S. Ramaiah College Of PharmacyM.S.R.I.T Post,M.S.R. Nagar,Bangalore-560054

11.3 CO-GUIDE:

11.4 SIGNATURE:

Not Applicable

Not Applicable

11.5 HEAD OF THE DEPARTMENT:

11.6 SIGNATURE:

Prof. C.H.S. VENKATARAMANAProfessor and HOD ( In-charge )Department of Pharmaceutical ChemistryM.S.Ramaiah College Of PharmacyM.S.R.I.T. Post,Bangalore-560054

12. 12.1:-REMARK OF THE PRINCIPAL

12.2:-SIGNATURE OF THE

PRINCIPAL:

27