SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF

SOME NOVEL

PYRROLIDINE DERIVATIVES

SYNOPSIS FOR

M.PHARM DISSERTATION

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

KARNATAKA

BY

LALITA SHARMA

I M. PHARM

Department of Pharmaceutical Chemistry

M. S. Ramaiah College of Pharmacy

BANGALORE – 560 054

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA

ANNEXURE – II

PROFORMA FOR REGISTRATION OF SUBJECTS

FOR DISSERTATION

1.0 NAME OF THE

CANDIDATE AND

ADDRESS

LALITA SHARMA

L-8, TEACHER’S CAMPUS

JIWAJI UNIVERSITY

GWALIOR-474011

MADHYA PRADESH

2.0 NAME OF THE

INSTITUTION

M. S. RAMAIAH COLLEGE OF

PHARMACY

M.S.R. NAGAR, M.S.R.I.T. POST,

BANGALORE – 560 054

3.0 COURSE OF STUDY

AND SUBJECT

M. PHARM

PHARMACEUTICAL CHEMISTRY

4.0 DATE OF

ADMISSION

26th April 2007

5.0 TITLE OF TOPIC SYNTHESIS AND ANTIMICROBIAL

ACTIVITY OF SOME NOVEL

PYRROLIDINE DERIVATIVES

6.0 BRIEF RESUME OF THE INTENDED WORK

6.1:- NEED FOR PRESENT STUDY

Pyrrolidines are well known for their versatile pharmacological activities such

as antimicrobial,5,10,23 antiarrhythmic,1,3 antitumor,2,21 anti-HIV-1,5 antineoplastic

agents,5 anticonvulsant,7,9,17 antifungal,10 aromatase inhibitors,4 sphingosine-1-

phosphate (S1P) receptor agonists,24,25 malic enzyme inhibitors,26 herbicidal,16

Neurokinin1 antagonists,31 ketoamide-based cathepsin K inhibitors,22 human

melanocortin-4 receptor agonists, 32 etc.

Bacterial resistance to the antibiotics and antimicrobial agents is a big blow to

humanity and continual search for newer chemotherapeutic agents is the only way

to fortify against this awful threat.

A vast potential exists for pyrrolidines as potential antimicrobial agents since

limited work has been carried out in this regard.

Thus, in this study, a strategy has been planned to synthesize novel pyrrolidine

derivatives and screening for their antimicrobial activity as per standard

methodology 35,36 by the use of bacterial strains like S. aureus, E. coli, B. subtilis

etc.

6.2:- REVIEW OF LITERATURE

Synthesis and antiarrhythmic activity of -1,2,3,4-(Aminoalkyl)-׀1

tetrahydronaphthalene-1-spiro-3ا-pyrrolidine-2 5,ا ı–dione derivatives was

reported1.

Synthesis and biological evaluation of novel pyrrolidine-2,5-dione inhibitors

as potential anti-tumor agents was reported2.

Synthesis and antiarrhythmic properties of basic amide derivatives of

imidazoline-2,4-dione and pyrrolidine-2,5-dione was reported3.

Synthesis and biological evaluation of 3-(prop-2-enyl)- and 3-(prop-2-ynyl)

pyrrolidine-2,5-dione derivatives as potential aromatase inhibitors was

reported4.

Synthesis of some 3-substituted 1,5-diphenylpyrrolidine-2,4-diones as

potential antimicrobial, anti-HIV-1 and antineoplastic agents were reported5.

Regioselective synthesis of dispiro (oxindole-cyclohexanone)-pyrrolidines

and dispiro (oxindole-hexahydroindazole) pyrrolidines was reported6.

Synthesis and anticonvulsant properties of new 1–phenyl and 1-phenyl

amino-3-phenyl pyrrolidine –2,5-dione derivatives were reported7.

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

neutral C-centered α- amino alkyl radicals were reported8.

Synthesis and anticonvulsant properties of new N-[(4-arylpiperzin-1-yl)-

methyl] derivatives of 3-arylpyrrolidine–2,5–dione and 2-aza–Spiro(4.4)

nonane-1, 3-dione were reported9.

Synthesis of 4-(pyrrolidine anilino)-N-aryl/substituted aryl and heteroaryl

succinimides as antimicrobial and antifungal agents were reported10.

Synthesis and 5-HT1A/5-HT2A receptor activity of new N-[3,(4-

phenylpiperazin-1-yl)-propyl] derivatives of 3-spiro–cyclohexane

pyrrolidine-2,5-dione and 3-spiro-β-tetralonepyrrolidine-2,5-dione were

reported11.

Synthesis of 3,3-diaryl pyrrolidines from diaryl ketones was reported12.

Ring opening of N-alkoxy carbonyl γ-lactams with lithium methylphenyl

sulphone: application to the synthesis of cis 2,5–disubstituted pyrrolidines

was reported13.

Synthesis of cis–2,5-disubstituted pyrrolidines via diastereoselective

reduction of N-acyl iminium ions was reported14.

Cis-selective synthesis of 2,5-disubstituted pyrrolidines was reported15.

Synthesis and herbicidal evaluation of novel 3-[(α-hydroxy- substituted)

benzylidene] pyrrolidine-2,4-diones was reported16.

Synthesis and anticonvulsant activity of N-(4-methylpiperazine-1–yl)-and N-

[3-(4-methyl–piperazine-1-yl) propyl] derivatives of 3-aryl- and 3-spiro

cycloalkyl–pyrrolidine-2,5-dione was reported17.

Straightforward synthesis of enantiopure 2-amino methyl and 2-hydroxy

methyl pyrrolidines with complete stereocontrol was reported18.

Synthesis of 1-[(2-naphthylsulfonyl)oxy] pyrrolidine-2,5-dione was

reported19.

Synthesis of highly substituted pyrrolidines via palladium catalyzed formal

[2+3] cycloaddition of 5-vinyl oxazolidin-2-ones to activated alkenes was

reported20

Design, synthesis and evaluation of novel galloyl pyrrolidine derivatives as

potential anti-tumor agents were reported21.

Synthesis of some novel, potent P2-P3 pyrrolidine derivatives of ketoamide –

based cathepsin K inhibitors was reported22.

Pyrrolidine bis-cyclic guanidines with antimicrobial activity against drug–

resistant gram–positive pathogens identified from a mixture–based

combinatorial library was reported23.

Synthesis of some 2,5-disubstituted pyrrolidine carboxylates as potent, orally

active sphingosine-1-phosphate (S1P) receptor agonists was reported24.

Synthesis of 2-aryl (pyrrolidin–4-yl) acetic acids as potent agonists of

sphingosine-1-phosphate (S1P) receptors was reported25.

In silico design and synthesis of piperazine–1-pyrrolidine–2,5-dione

scaffold-based novel malic enzyme inhibitors was reported26.

Stereoselective synthesis of 3,4-trans–disubstituted pyrrolidines and

cyclopentanes via intra molecular radicals cyclization was reported27.

Synthesis and biological activity of pyrrole, pyrroline and pyrrolidine

derivatives with two-aryl group on adjacent positions was reported28.

Synthesis and characterization of 3,4 dichloro-1-phenyl-1H-pyrrole-2,5-

dione was reported29.

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

to N-acyliminium ions was reported30.

Pyrrolidine- carboxamide and oxadiazoles as potent Neurokinin1 antagonists

was reported31.

Synthesis of pyrrolidine as potent functional agonists of the human

melanocortin-4 receptor was reported32.

Synthesis, affinity profile and functional activity of muscarinic antagonists

with 1-methyl -2-(2,2- alkyl aryl -1,3-oxathiolan-5-yl) pyrrolidine structure

were reported33.

Asymmetric nitrone cycloadditions and their application to the synthesis of

enantiopure pyrrolidine and pyrrolizidine derivatives was reported34.

6.3:- OBJECTIVES OF STUDY

Synthesis of novel pyrrolidine derivatives.

Characterization of the same by UV, IR, NMR and Mass spectral data.

Screening for antimicrobial activity.

7.0 MATERIALS AND METHODS:

7.1:- SOURCE OF DATA

The data was obtained from Chemical Abstracts and various Journals like Indian

Journal of Chemistry, Journal of Heterocyclic Chemistry, Tetrahedron Letters,

Tetrahedron, Bioorganic and Medicinal Chemistry Letters. Data was also collected

from Indian Institute of Science, Bangalore, and from Helinet of RGUHS.

7.2:- METHOD OF COLLECTION OF DATA

A) SYNTHESIS OF THE COMPOUNDS:

Chemicals and other reagents required for synthesis will be procured from

standard company sources.

Compounds will be synthesized by using standard techniques and also if

required by the use of microwave irradiation. TLC will be used to monitor the

reaction at various stages and purification of the compound will be done by

standard procedures like recrystallization.

B) CHARACTERIZATION OF THE COMPOUNDS:

The synthesized compounds will be characterized by preliminary laboratory

techniques such as melting point, boiling point etc. Compounds synthesized will

be confirmed by FTIR, Mass Spectroscopy and NMR spectral data. The Mass

and NMR spectral data of the synthesized compound will be collected by

sending compound to other research centers like IISc, Bangalore, IICT,

Hyderabad, IIT, Chennai, etc.

C) SCREENING OF ANTIMICROBIAL ACTIVITY:

SCREENING OF ANTIBACTERIAL ACTIVITY BY DISC DIFFUSION

METHOD:

Antimicrobial studies 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.The entire work will be done using horizontal

Laminar Flow hood.

7.3:- DOES THE STUDY REQUIRE ANY INVESTIGATION OR

INTERVENTIONS TO BE CONDUCTED ON THE PATIENTS OR OTHER

HUMAN/ANIMALS? IF SO, PLEASE DESCRIBE BRIEFLY.

- Not Applicable

7.4:- HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR

INSTITUTION IN CASE OF 7.3?

- Not Applicable

8.0 LIST OF REFERENCES

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antiarrythmic agents .4.1’-(Aminoalkyl)-1,2,3,4- tetrahydronaphthalene-1-spiro-3’-

pyrrolidine-2’5-dione derivatives. J Med Chem., 1981; 24(1): 47-53.

2) Ahmed S, Smith J H, Nicholls P J, Whomsley R et al. Synthesis and biological

evaluation of novel pyrolidine -2,5- dione inhibitors as potential anti-tumor agents.

Drug Des Discov., 1995; 12 (4): 275-287.

3) Kiec- Kononowicz K, Byrtus H, Zejc A, Filipek B, Chevallet P. Synthesis and

antiarrhythmic properties of basic amide derivatives of imidazolidine-2,4- dione

and pyrrolidine –2,5-dione. Farmaco, 1995; 50 (5): 355-360.

4) Barrell K J, Woo W L, Ahmadi M, Smith H J et al. Synthesis and biological

evaluation of 3-(prop-2-enyl)-and 3-(prop-2-ynyl) pyrrolidine-2,5-dione derivatives

as potential aromatase inhibitors. J Pharm Pharmacol., 1996; 48 (2): 154-159.

5) Shams el-dine S A, Soliman F S, Ashour F A, Saudi M N. Reactions

with pyrrolidine-2,4-diones, Part4: Synthesis of some 3-substituted 1,5-

diphenylpyrrolidine-2,4- diones as potential antimicrobial, anti-HIV-1 and anti

neoplastic agents. Pharmazie, 2001; 56 (12) 933-937.

6) Raj A A, Raghunathan R. A novel entry into a new class of

spiroheterocyclic framework: regioselective synthesis of dispiro [oxindole-

cyclohexanone]- pyrrolidines and dispiro [oxindole-hexahydroindazole]

pyrrolidines. Tetrahedron, 2001; 57:10293-10298.

7) Obniska J, Zeic A, Zagorska A. Synthesis and anticonvulsant properties of new

1-phenyl and 1-phenylamino-3-phenylpyrrolidine-2, 5-dione derivatives. Acta Pol

Pharm., 2002; 59(3): 209-213.

8) Bustos F, Gorgojo J M, Suero R, Aurrecoechea J M. Synthesis of 2,4-, 3,4- and

2,3,4-substituted pyrrolidines by cyclization of neutral C- centered - amino alkyl

radicals. Tetrahedron, 2002; 58:6837-6842.

9) Obniska J, Zagorska A. Synthesis and anticonvulsant properties of new N- [(4-

arylpiperazin-1-yl)- methyl] derivatives of 3-arylpyrrolidine -2,5 - dione and 2-aza

–Spiro (4.4) nonane-1, 3-dione. Farmaco, 2003; 58(12): 1227-1234.

10) Lokhande T N, Bobade A S, Khadse B G. Synthesis of 4-(pyrrolidine anilino)-

N-aryl/substituted aryl and heteroaryl succinimides as antimicrobial and antifungal.

Indian Drug, 2003; 40(3): 147-150.

11) Obniska J, Pawlowski M, Kolaczkowski M, Czopek A et al. Synthesis and 5-

HT1A/5-HT2A receptor activity of new N- [3- (4-phenylpiperazin-1-yl)-propyl]

derivatives of 3-spiro–cyclohexane pyrrolidine-2,5-dione and 3-spiro-β-

tetralonepyrrolidine-2,5-dione. Pol J Pharmacol., 2003; 55: 553-557.

12) Katritzky A R, Nair S K, Witek R M., Hutchins S M, Synthesis of 3,3-diaryl

pyrrolidines from diaryl ketones. Arkivoc, 2003; V: 9-18.

13) Mota A J, Langlois N. Ring - opening of N-alkoxy carbonyl γ-lactams with

lithium methylphenylsulphone: application to the synthesis of cis 2,5 –

disubstituted pyrrolidines. Tetrahedron Lett., 2003; 44:1141-1143.

14) Rudolph A C, Machauer R, Martin S F. Synthesis of cis-2,5-disubstituted

pyrrolidines via diastereoselective reduction of N-acyl iminium ions. Tetrahedron

Lett., 2004; 45: 4895-4848.

15) Hussaini S R, Moloney M G. cis-Selective synthesis of 2,5-disubstituted

pyrrolidines. Tetrahedron Lett., 2004; 45:1125-1127.

16) Zhu Y, Zou X, Hu F, Yao C et al. Synthesis and Herbicidal Evaluation of

Novel 3-[(α-Hydroxy- substituted) benzylidene] pyrrolidine-2,4-diones. J Agric

Food chem., 2005; 53(24): 9566-9570.

17) Obniska J, Jurezyk S, Zejc A, Kaminski K et al. Anticonvulsant properties of

N- (4-methylpiperazine-1 –yl)-and N- [3-(4-methyl –piperazine-1-yl) propyl]

derivatives of 3-aryl- and 3-spiro cycloalkyl –pyrrolidine-2, 5-dione. Pharmacol

Rep., 2005; 57(2): 170-175.

18) Marradi M, Cicchi S, Delso J I, Rosi L et al. Straightforward synthesis of

enantiopure 2-aminomethyl and 2-hydroxymethyl pyrrolidines with complete

stereocontrol. Tetrahedron Lett., 2005; 46:1287-1290.

19) Stefanowicz P, Jaremko L, Jaremko M, Lis T. 1-[(2-Naphthylsulfonyl) oxy]

pyrrolidine-2, 5-dione. Acta Cryst., 2005; E61: 01326-01328.

20) Knight J G, Tchabanenko K, Stoker P A, Harwood S J. Synthesis of highly

substituted pyrrolidines via palladium catalyzed formal [2+3] cycloaddition of 5-

vinyloxazolidin-2-ones to activated alkenes. Tetrahedron Lett., 2005; 46:6261-

6264.

21) Li X, Li Y, Xu W. Design, synthesis and evaluation of novel galloyl

pyrrolidine derivatives as potential anti-tumor agents. Bioorg & Med Chem., 2006;

14:1287-1293.

22) Barrett D G, Gatalano J G, Deaton D N. Hassell A M. Novel, potent P2-P3

pyrrolidine derivatives of ketoamide – based cathepsin K inhibitors. Bioorg & Med

Chem Lett., 2006; 16: 1735-1739.

23) Hensler M E, Bernstein G, Nizet V, Nefzi A. Pyrrolidine bis-cyclic guanidines

with antimicrobial activity against drug – resistant gram – positive pathogens

identified from a mixture – based combinatorial library. Bioorg & Med Chem Lett.,

2006; 16: 5073-5079.

24) Colandrea V J, Legiec I E, Huo P, Yan L et al. 2,5-Disubstituted pyrrolidine

carboxylates as potent, orally active sphingosine –1-phosphate (S1P) receptor

agonists. Bioorg & Med Chem Lett., 2006; 16: 2905-2908.

25) Yan L, Budhu R, Huo P, Lynch C L et al, 2-Aryl (pyrrolidin –4-yl) acetic acids

as potent agonists of sphingosine –1-phosphate (S1P) receptors. Bioorg & Med

Chem Lett., 2006; 16: 3564-3568.

26) Zhang Y J, Wang Z, Sprous D, Nabioullin R. In silico design and synthesis of

piperazine –1-pyrrolidine – 2,5- dione scaffold-based novel malic enzyme

inhibitors. Bioorg & Med Chem Lett., 2006; 16: 525-528.

27) Nair V, Mohanan K, Suja T D, Suresh E. Stereoselective synthesis of 3,4-trans

– disubstituted pyrrolidines and cyclopentanes via intra molecular radicals

cyclizations mediated by cerium (IV) ammonium nitrate (CAN). Tetrahedron Lett.,

2006; 47:2803-2806.

28) Bellina F, Rossi R. Synthesis and biological activity of pyrrole, pyrroline and

pyrrolidine derivatives with two-aryl group on adjacent positions. Tetrahedron,

2006; 62: 7213-7256.

29) Silva L L, Oliveira K N D, Nunes R J. Synthesis and characterization of

chloromaleimidobenzenesulphonylhydrazones. Arkivoc, 2006;(xiii): 124-129.

30) Buezo N D, Jimenez A, Pedregal C, Vidal P. Stereoselective synthesis of tans-

2, 3-disubstituted pyrrolidines via addition to N-acyliminium ions. Tetrahedron

Lett., 2006; 47: 2489-2492.

31) Young J R, Eid R, Turner C, Kurtz M M. et al. Pyrrolidine- carboxamides and

oxadiazoles as potent hNK1 antagonists. Bioorg & Med Chem Lett., 2007; 17:

5310-5315.

32) Tran J A, Chen C W, Jiang W, Tucci F C et al. Pyrrolidine as potent functional

agonists of the human melanocortin-4 receptor. Bioorg & Med Chem Lett., 2007;

17: 5165-5170.

33) Dei S, Bellucci C, Buccioni M, Ferraroni M et al. Synthesis, Affinity Profile

and Functional Activity of Muscarinic Antagonists with 1-Methyl –2-(2,2- alkyl

aryl –1,3- oxathiolan-5-yl) pyrrolidine Structure. J Med Chem., 2007; 50:1409-

1413.

34) Argyropoulos N G, Panagiotidis T, Argyropoulou E C, Raptopoulou C.

Asymmetric nitrone cycloadditions and their application to the synthesis of

enantiopure pyrrolidine and pyrrolizidine derivatives. Tetrahedron, 2007; 63:321-

330.

35) Edwin H L, Alberbalows, William J H, Jean S H. “Manual of Clinical

Microbiology “ 1985,4th Edition, American Society for Microbiology,

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36) Hugo W B, Russel A D. “Pharmaceutical Microbiology” 1998, 6th Edition,

Blackwell Science Ltd., London, 237-251.

9.0 SIGNATURE OF THE CANDIDATE

10.0 REMARKS OF THE GUIDE Recommended for Research

11.0 NAME AND DESIGNATION OF:

11.1 GUIDE A. CENDIL KUMARAssistant Professor,Dept. of Pharmaceutical Chemistry,M.S. Ramaiah College of Pharmacy,Bangalore – 560 054

11.2 SIGNATURE

11.3 CO-GUIDE NIL

11.4 SIGNATURE NIL

11.5 HEAD OF THE DEPARTMENT

( INCHARGE )

Prof. C.H.S. VENKATARAMANADept. of Pharmaceutical Chemistry,M.S. Ramaiah College of Pharmacy,Bangalore – 560 054

11.6 SIGNATURE

12.0 12.1 REMARKS OF THE PRINCIPAL

12.2 SIGNATURE