SYNTHESIS AND EVALUATION OF NEW
PYRAZOLES OF BENZIMIDAZOLE AS POTENT
ANALGESIC AND ANTI INFLAMMATORY
AGENTS.
M. Pharm. Dissertation Protocol
Submitted to the
RajivGandhiUniversity of Health Sciences, Bangalore ,Karnataka.
By
Miss. SHARMILA A. GOTE
B. Pharm.
Under the guidance of,
Dr. B.SHIVAKUMAR
M. Pharm., Ph. D.
BLDEA’S COLLEGE OF PHARMACY
BLDE UNIVERSITY CAMPUS
BIJAPUR-586103
RajivGandhiUniversity of Health Sciences, Bangalore, Karnataka.
Annexure – II
01 /Name and Address of the Candidate
/ Miss.Sharmila A.Gote.37, A Maji sainik nagar, bijapur road, solapur 413003.
02 / Name of the Institution / B.L.D.E.A’S COLLEGE OF PHARMACY,
BIJAPUR.
03 / Course of the StudyBranch / M. Pharm (Previous)
PHARMACEUTICAL CHEMISTRY
04 / Date of Admission to course / 30 JUNE 201005 / Title of the Topic / SYNTHESIS AND EVALUATION OF NEW PYRAZOLES OF BENZIMIDAZOLE AS POTENT ANALGESIC AND ANTI INFLAMMATORY AGENTs.
06 / Brief resume of the intended work :
6.1 Need for the study:
Benzimidazole structures are classified under several classes of drugs1
Based on the possible substitution at a different position of benzimidazole nucleus. Introduction of small substituent on 2& 5th position is characteristic for benzimidazole anthelmintic, alternatively bulky 2-substituents characterized drugs used in the treatment of peptic ulcer or sometime referred as proton pump inhibitors, bulky 1-&2- substituent are found in H1 antihistaminic. All these compound contain benzimidazole skeleton & hence it has been assumed that this skeleton is necessary for therapeutic effect.
Pyrazoles are the one of the most active classes of compounds possessing wide spectrum of biological activities.2to4 Many of therapeutically useful compound such as phenylbutazone5,oxiphenabutazone6,celecoxib7, belonging to pyrazoles exhibited anti inflammatory ,antipyretic & analgesic properties. Moreover several pyrazole derivatives have emerged as group of compound possessing broad spectrum of useful medicinal properties8,9 Benzothiazole are bicyclic ring system with multiple applications ,2-substituted benzothiazole was intensively studied as central muscle relaxant, So benzothiazole derivative have been studied extensively and found to have diverse chemical reactivity& broad spectrum of biological activities, like antimicrobial10to12 , antitumor13,14, anthelmintic15to17, antileishmanial18 ,19 , anticonvulsant20,21 , & anti inflammatory activity.
Hence in continuation22,23,24 work on benzothiazoles , it is thought worthwhile to synthesis some new pyrazolobenzimidazole by incorporating 2-Hydrazinobenzothiazole moieties in a single molecular frame work.
6.2) Review of Literature / A literature survey done by referring chemical abstracts, journals, internet, journals of Helnet of RGUHS also availing facilities at NCL Pune. Further references work will be carried out at Gulbarga university Gulbarga, Karnataka university dharwad & Sholapur university Sholapur.
6.3 Objective of the Study / A literature survey reveals that very few literatures are available on the synthesis of pyrazolobenzimidazole, associated with benzothiazoles in a molecular frame work. In present work we report synthesis of new benzimidazolopyrazoles associated with benzothiazoles, starting from 2-Acetylbenzimidazole.
Synthesis of these benzimidazolechalcone involves the base catalyzed aldol condensation reaction of 2-Acetylbenzimidazole to give unsaturated ketones, which undergo subsequent cyclization with 2-Hydrazinobenzothiazole 2-pyrazolines which undergo fissile oxidation to corresponding pyrazoles. The structure of the synthesized compound will be establish on the basis of elemental & spectral properties (HNMR& mass)
The synthesized compounds will also be screened for theiranthelmintic,antimicrobial, analgesic & anti inflammatory activities.
Materials and methods 7.1) Source of data / Preparation and screening methods will be followed according to literature procedure.
Journal of Medicinal Chemistry.
Tetrahedron Letter.
Tetrahedron.
Chemical Abstracts.
Indian Journal of Heterocyclic Chemistry.
Indian Journal of Chemistry.
Journal of Chemical Society.
Journal of American Chemical Society.
Standard test books for screening of biological and pharmacological activities.
Indian Pharmacopoeia.
7.2) Methods of Collection of Data (including sampling procedure, if any) / a) Spectroscopic data:
IR of all new compounds will be obtained by using of spectrometers available in our college, NMR and Spectroscopic data will be obtained from I.I.T.Madras and I.I.S.C. Bangalore etc.
b) Pharmacological and Biological Activity:
1) Anti-inflammatory activity27in-vitro - Selected synthesized compounds will be subjected to screen for inhibit the denaturation of protein as an In-vitro screening model for anti-inflammatory compounds.
2) Analgesic activity28 – Selected synthesized compound will be subjected to screen for analgesic activity by acetic acid induced writhing method in albino mice.
3) Antimicrobial activity29- All synthesized compounds will be evaluated for antimicrobial activity by cup plate method.
7.3)Does the study require any
investigations or interventions to be conducted on patients or other humans or animals? If so, please describe briefly. / -YES-
7.4) Has ethical clearance been obtained from your institution in case of 7.3 / -YES-
Registration No-1076/c/07/CPCSEA Dt-27/07/2007
References :
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2)Sharm. S, Srivastav V Kand Kumar. A, Synthesis and anti inflammatory,analgesic,ulcerogenic and lipid peroxidation activities of 3,5-dimethyl pyrazoles, 3-methyl pyrazol-5-ones and 3,5-disubstituted pyrazolines. Indian J.chem. 41B (2002), 2647.
3)Sawhney S.N, Bhutaniand Vir .D. Synthesis and anti inflammatory,analgesic,ulcerogenic and lipid peroxidation activities of 3,5-dimethyl pyrazoles, 3-methyl pyrazol-5-ones and 3,5 disubstituted pyrazolines.Indian J. Chem.28B(1989),667
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5)Gennro A.R,Remington:Synthesis of fluorinated ethyl 4-aryl-6-methyl-1,2,3,4-tetrahydropyrimidin-2-one 1 thione-5- carboxylates under the microwave irradiation.The science and practice of pharmacy vol.II,20th edition (Lippncott Williams and Wilkins) (2001) ,1459.
6)Clemette D& GOA. , Celecoxib: A review of its use in osteoarthritis,Rheumatoid Athritis and acute pain. Drugs59(2000), 957.
7) a) Secor H.V and Bardelabeh J.F. Structure and confermation of cis-benzoyl-2- chloracetyl-4,5-hexamethylenepyrazolidineian X-ray study.J.med.d.chem.14(1971).
b)Baner. V.J, Fanshawe. W.J.dalalian H.P,Safir. S.R.,Tocus.E.C. and Boshart. C.R,J.med. chem.. 11(1968)981.
C)Durham N.N,Chestnut R.W,Hashed M.M, and Berlin K.D. Heterocyclic Monoazo dyes derived from 3-cyano-2(H)-pyridinethione part 2:2 –[(4(Arylazo)-3,5-disubstituted-pyrazol-1-yl)carbonyl]-thieno[2,3-b] pyridine derivatives -J.med.Chem.19(1976) 229
8) Ranjana Aggarwal, Vinod Kumar ,Shiv P Sing. Synthesis of some new 1-(6- fluorobenzothiazole-2yl)-3-(4-fluoro-phenyl)-5-aryl pyrazolines and their iodine(III) mediated oxidation to corresponding pyrazoles.Indian.J.Chem.,46B,2007,1332-36
9) Sreenivasa, M.V.,Nargund, L.V.G.,Various benzothiazolotriazole derivatives possess good microbial activity. Indian J.Heterocyclic .Chem.8,1998,23.
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11) Bhusari,S.R.,Pawar,R.P., and Bibupe Y.B., Some new to –(substituted phenyl sulphonamido)-6-sustituted benzothiazoles and ereened them for antimicrobial activity. Indian J. Heterocycl.Chem,11,2001,79.
12)Shi,D.F.,Bradshaw,T.D., Wrigley,S.,Carol J.,Mccall, P.L.,Nacolm,F. and Stevens, F.G.,2-(4-Aminophenyl) benzothiozoles,comprise a novel mechanistic class of antitumor agents, J.Med.chem.,39,1996.3375.
13) Kashiyarna, E. Hutchinsson, I., Chua, M.S., Stinson, S.F., Phillips, L.R.,Kaur, G., Sausville, E.A.,Bradshow,T.D.,Westwell,A.D. and Stevans, M.F.G,2-(4-aminophenyl) benzothiazol-antitumor agents, Med.Chem,43,1999,4172.
14) Nargund, L.V.G., Few novel 8-fluoro-9-substituted(1,3)benzothiozolo(5,1-b)-1,3,4-triazoles studid for there anthelmintic activity., Indian Drugs. 36,1999,137.
15)Bhusari,K.P., Khedekar, P.B.,Umathe,S.N., Bahekar, R.H., and Rao R.R.8-bromo-9-substituteb(1,3) benzothiazolo[5,1-b]-1,3,4-triazoles screened for there anthamentic activity. Inaian J.Heterocycl. Chem.,9,2000,275.
16)Amit,B.N.,Kamath,R.V.,And Khadse,G.B.,Some substituted imidazobenzothiazoles were tested for in vivo anthelmintic activity, Indian J.Heterocycl. Chem.,9,2000,309.
17) Delmas, F.,Avellaneda, A.,Giorgio,C.D., Robin,M., Clercq,E.D.,Timon-David,P.and Galy,J.P.,(1,3benzothiazol- 2-yl)amino-9-(10H)-acridinone derivatives were assessed for there invitro antileishmanial and anti AHIV activities., Eur.j.Med.Chem.,39,2004,685
18)Delmas ,F.,Giorgio, C.D., Robin, M.,Gasquest, N.A.M.Detang, C.,Costa, M., Timon-David,P. and Galy, J.P.,Position 2-substitution –bearing 6-nitro and 6-amino benzothiazoles and their corresponding anthranillic acids and assessed the in vitro antiparasitic activity. Antimicrob.Agents Chmother.,46, 2002,2588.
19) Siddiqui, N., Pandeya,S.N., Sen, A.P. and Singh,G.S.,A series of benzothiazolyl guanidiness were synthesized for there significant anticonvulsant actinity, Pharmak Eftiki,4,1992,121
20)Singh S.P.,Misra, R.S.,Parmar S.S. and Brumleve,S.J.,Some 2-(4-arylthiosemicarazidocarbonylthio) benzothiazoles, sreened for there anticonvulsant activity. J. Pharm. Sci.,64,1978,1245
22)Oketani,K.,Nagakura, N.,Harada, K. and Inoue T.,Invitro pharmacological profiles 6 hydroxy -5,7-dimethyl-2(methyl amino)-4-(3-pyridylmethyl)benzothiazoles, were assessed for there anti inflammatory activity. Indian J. Chem.,26B,1987,348
23) Sawhney,S.N.,Bhutani,S. and Dharanvir, Somenobel 2- (2-benzothiazolelyl)-6- aryl-4,5-dihydro-3(2H)- pyridazinone, sreen for their anti inflammatory activity.Indian J. Chem.,25B,1986,288.
24)Shivakumar B,Sojan K Paul, Nagendra Rao R, Jaychandran. E.Synthesis and microbial evaluation of 6-fluro-7-substituted -1,2.,3,4-tetrazolo[5,1-b]benzothiazoles. Indian J.HereroChem,15,2005,71-72.
25)Jaychandran.E, Naragund L VG,Shivakumar B,Kamal Bhatia. Synthesis and Pharmacologial screening of 2-(3-amino-5-S-methyl-4-carboxamido pyrazol-1-yl)-6-fluoro-7-substituted (1,3) benzothiazoles.Oriental J Chem, 19 (1),2002, 139.
26)Sreenivasa Rao D,Jaychandran.E,Sreenivasa GM,Shivakumar. Innhibition of albumin denaturation and anti inflammatory activity of 2-[N-P-tolyl sulphon hydrazine ]-6-fluoro-7-substituted (1,3) benzothiazoles. Oriental JChem, 21(1), 2005,113.
27) Singh, S.P. and Vaid, R.K., Some new 2-(4-butyl-3,5-dimethylpyrazol-1-yl)-6-substituted benzothiazoles, were assessed for their anti-inflammatory activity. Indian J. Chem. 25B, 1986, 288.
28)Russo, F.; Romeo, G.; Santagati, N. A.; Caruso, A.; Cutuli, V.; Amore, D. Synthesis of new thienopyrimidobenzothiazoles and thienopyrimidobenzoxazoles with analgesic and anti-inflammatory properties. Eur. J. Med. Chem. 1994, 29, 569-578.
29) Katsura, Y.; Inoue, Y.; Nishino, S.; Tomoi, M.; Takasugi, H. Studies on antiulcer drugs. IV.Synthesis and antiulcer activities of imidazo[1,2-a]pyridinylethylbenzothiazoles andbenzimidazoles. Chem. Pharm. Bull (Tokyo). 1992, 40, 1818-1822.
SCHEME
9 /Signature of the Candidate
/ (SHARMILA A. GOTE)10 /
Remarks of the Guide
/ The Mentioned Title Compound will be Synthesized and Screened for the activity. They are confirmed by the Spectroscopical Studies under my guidance in the P.G.Department of Pharmaceutical Chemistry of our College.11 /
11.I. Name and Designation of
GUIDE:
(in Block Letters)
Guide ship Reference No. of RGUHSACA/PGT-M.Ph/SCS/02/99-2000/5821 Date: 05.06.1999
11.2.Signature
11.3.Co-Guide (if any)
11.4.Signature
11.5. Head of the Department
Guide ship Reference No. of RGUHS
ACA-2/RP-TEA/01/97-98/3-6-98
11.6. Signature / Dr. B. SHIVAKUMAR
Professor and Head,
Dept. of Pharmaceutical Chemistry,
BLDEA’s College of Pharmacy,
Bijapur-586103.
Dr. B. SHIVAKUMAR
Professor and Head,
Dept. of Pharmaceutical Chemistry,
BLDEA’s College of Pharmacy,
Bijapur-586103.
12 /