STUDIES ON SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF CERTAIN NOVEL PHENOTHIAZINE INCORPORATED HETEROCYCLIC COMPOUNDS

M. PHARM. DISSERTATION PROTOCOL SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BENGALURU

BY

MR. SHRISHAIL Y. SHAHAPUR B. Pharm.

Under the guidance of

Dr. SHREENIVAS R . DESHAPANDE M. Pharm., Ph. D

P. G. DEPARTMENT OF PHARMACHEMISTRY H.S.K COLLEGE OF PHARMACY, BAGALKOT-587 101

1

Annexure – II

Mr. SHRISHAIL Y SHAHAPUR 1 Name and Address of the Candidate H.S.K COLLEGE OF PHARMACY, B.V.V.S CAMPUS, BAGALKOT-587 101

B.V.V. SANGH’S 2 Name of the Institution H.S.K COLLEGE OF PHARMACY, BAGALKOT-587 101

Course of the Study MASTER OF PHARMACY 3 Branch PHARMACEUTICAL CHEMISTRY

4 Date of Admission to course OCTOBER 2010

STUDIES ON SYNTHESIS AND 5 Title of the Topic ANTIMICROBIAL ACTIVITY OF CERTAIN NOVEL PHENOTHIAZINE INCORPORATED HETEROCYCLIC COMPOUNDS

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6) 6.1) Brief resume of the intended work Bacterial infections are rampant in developing countries such as India due to poor public hygiene and sanitation. Microbial infections and Tuberculosis (TB) are considered to be dreadful diseases which have created havoc for the global population. Microbial infections are the leading cause for the suffering and death since time immemorable. Despite lot of advances made in the field of chemotherapy, TB still remains one of the major health problems today. It is estimated that more than 2 billion people are infected with Mycobacterium tuberculosis leading to approximately 6% of all the deaths worldwide.1 Poverty, HIV and drug resistance are the major contributors to the resurging global TB epidemics.2 Hence there seems to be an urgent need for new anti-TB agents. Even though great progress is made in understanding molecular biology of Anti-microbial resistance; still it remains a major public health problem throughout the world.

Phenothiazines (heterocyclic ring system consisting of two benzene rings ortho –fused to 1,4- thiazine ring) and their analogues constitute an important class of bioactive heterocycles. They possess a wide spectrum of pharmacological/biological activities and their several derivaties are in clinical use as drugs and medicinal agents. Phenothiazines have been found to possess promising pharmacological activities and used as major tranquilizers, anti-histamines, diuretics, analgesics, neuroleptics, sedatives, anti-psychotics, anti- inflammatories, anti-emetics, anti-virals, anesthetic, anti-tubercular, CNS depressants, anti-cancer, anti- depressants, anti-pyretics, anti-parkinson drugs, anti-bacterial and anti- fungal3 etc. H N

S phenothiazine

Prompted by this information, we wish to undertake the present study involving the synthesis of some novel phenothiazine incorporated heterocyclic compounds as possible anti-microbial4 and anti-tubercular agents5.

3 6.3) Objective of the work

The objectives of the present study include 1)To synthesize novel Phenothiazine incorporated heterocyclic compounds by appropriate method as per the following scheme

Phenothiazine

Ethyl chloroacetate

Phenothiazine intermediate 1

Hydrazine hydrate

Phenothiazine intermediate 2

Carbon disulfide/Pot. Hydroxide Acetylacetone Aldehydes Oxadiazoles 3,5-dimethyl pyrazoles 3-Methyl pyrazoles Schifs bases

2) To confirm the structures of newly synthesized compounds by spectral data. 3) To biologically evaluate these newly synthesized compound for Antibacterial, Antifungal and Antitubercular activity by following standard protocol.

4 7 Materials and methods 7.1) Methods of Collection of Data (including sampling procedure, if any) UV and IR spectra of the newly synthesized a) Spectroscopic data compounds will be obtained in our college, HNMR, mass spectroscopic data of selected compounds will be obtained from research institutes.

b) Pharmacological and 1)Anti-microbial10,11 Selected synthesized compounds Biological Activity will be screened for their anti bacterial and anti-fungal activity by cup- plate agar diffusion method. 2) Anti-TB12- Selected compounds will be screened for anti-Tubercular activity against Mycobacterium

tuberculosis H37Rv Strain by Lowenstein-Jenson egg medium method as described by Watt. Synthesis and screening will be carried out according 7.2) Source of data to literature method by referring

 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 text books for screening of biological and pharmacological activities. Indian Pharmacopoeia. Etc

7.3.Does the study require any investigations or interventions to be No conducted on patients or other humans or animals? If so, please describe briefly.

7.4 .Has ethical clearance been Not applicable obtained from your institution in case of 7.3?

5 8. List of References:

1. Lonnorth K, Rviglione M., Global epidemiology of tuberculosis: prospects for control. Semin Respir Crit Care Med 2008;29:481. 2. Cobert EL, Marston B, Churchuard GJ, De Cock KM., Tuberculosis in Sub- Saharan Africa: opportunity, challenges and change in the era of antiretroviral treatment .Lancet 2006;367:926. 3. Yogesh Dixit ,Rahul Dixit Naveen Gautam and D.C.Gautam.synthesis of bioactive Fluorinated 10H- phenothiazines and there sulfone derivatives E-Journal of Chemistry 2008, 5(S1), 1063-1068 4. Leonard Amaral, Miguel Viveros and Joseph Molnar, Antimicrobial activity of phenothiazines. invivo 18:725-732(2004) 5. Pawan kumar swarnkar et.al., “Synthesis and Antibacterial Activity of Some New Phenothiazine Derivatives”.E-Journal of chemistry Vol.4,No.1,pp14-20,January 2007 6. a) Noga E.J., Barthalmus G.T.,Mitechely M K.cell Biol int .Rep.10 1986. 239-247 b)Craig P.N.M Comprehensive Medicinal chemistry , Dryton, C.J.Ed. Peramon press; NEW YORK 1991 Vol-8. c)Codama T.Tamora, M.odat.,Yamazaki Y. ohkuchi M. U S patent 983928,2003

7.Sharad Kumar, D.N Srivastava, Sarita Singhal, Vipin Saini1, A.K. Seth., Antimicrobial activity of 10H- Phenothiazine -1-Carboxyllic acid hydrazide derivative s IJPS,(2010) 487-495 8.R..K.Upadhyay, Megh .S. Upadhyay and S.Jain synthesis and Antimicrobial activityof 1-[2(10-p-Chlorobenzyl)phenothizinyl]-3-(substituted aryl )-2-propen -1-ones E-Journal of Chemistry 2009,6(S1),S254-S258 9. Subramanyan Arulmurugan Helen p. Kavitha Bathey R. Venkataraman., synthesis Characterization and study Antibacterial activity of some novel tetrazole Derivatives EJC Vol-2 No.3July-Sept 2010 Page No.271-276 10. Bauer R W, Kirby MDK, Sherris JC, Turck M. Antibiotic susceptibility testing by standard single disc diffusion method .Amer J Clin pathology 1966;45:

6 493-96. 11. Seely HW, Demark VPT. Laboratory Manual of Microbiology 2nd ed. Bombay: Taraporevala; 1975;55 and 80. 12. Watt B, Rayner A, Harrish G, Mycobacterium. In: Gerald JC, Barrie PM, Andrew GF, Anthony S. (Ed). Mackie Mc Cartney. Practical Medical Microbiology 14th ed. New York: Churchill Livingstone;1996;329-41

7 9 Signature of the Candidate

The present work which is assigned to Mr. Shrishail Y. Shahapur is verified and found correct. The study will be 10 Remarks of the Guide carried out under my direct supervision and guidance in the P.G.Department of Pharmaceutical Chemistry of our College.

11.1. NAME AND DESIGNATION OF Dr. SHREENIVAS R. DESHPANDE GUIDE SHIP REFERENCE NO. OF M.Pharm. Ph. D. RGUHS PROFFESSOR 11 ACA/CDC/PGT-MPH/KLE/55/2005 DEPT. OF PHARMACEUTIAL CHEMISTRY -2006/36 H.S.K.COLLEGE OF PHARMACY, DATE: 04.04.2005 BAGALKOT-587 101

11.2.SIGNATURE

11.3.CO-GUIDE (IF ANY) NO

11.5. HEAD OF THE DEPARTMENT Dr.SHREENIVAS R. DESHPANDE M.Pharm, Ph.D. DEPT. OF PHARMACEUTIAL CHEMISTRY H.S.K.COLLEGE OF PHARMACY, BAGALKOT- 587 101

11.6. SIGNATURE

12 12.1 REMAKS OF THE PRINCIPAL The above-mentioned information is correct and I recommend the same for approval.

12.2. SIGNATURE

8 9