Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore s33

SYNTHESIS OF NOVEL PYRAZOLE DERIVATIVES BEARING PIPERONAL MOIETY AS PROMISING CHEMOTHERAPEUTIC AGENTS

M. PHARM. DISSERTATION PROTOCOL

Submitted to

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BENGALURU

Mr. SUDARSHAN N. NAGRALE B. Pharm.

Under the guidance of

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

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY H.S.K COLLEGE PHARMACY BAGALKOT-587101

Annexure – II

SUDARSHAN N.NAGRALE. H.S.K. COLLEGE OF PHARMACY 01 Name and Address of the Candidate BAGALKOT-587101 KARNATAKA

H.S.K. COLLEGE OF PHARMACY 02 Name of the Institution BAGALKOT – 587 101

Course of the Study MASTER OF PHARMACY IN 03 Branch PHARMACEUTICAL CHEMISTRY

04 Date of Admission to course OCT 2010 SYNTHESIS OF NOVEL PYRAZOLE DERIVATIVES BEARING PIPERONAL 05 Title of the Topic MOIETY AS PROMISING CHEMOTHERAPEUTIC AGENTS.

06 Brief resume of the intended work : 6.1 Need for the study: Cancer still remains one of the most feared disease in the modern world .according to world health organization (WHO)it affected one person in three and caused a quarter of all death in the developed world during the year 2000.After heart disease it is the largest cause of death. There are three traditional approaches to the treatment of cancer –surgery, radiotherapy, chemotherapy.24 Even though great progress is made in understanding molecular biology of cancer, still it remains a major public health problem throughout the world. One in three people will be diagnosed with cancer during their life time and in 2001, 270,000 new cases were reported in UK with lung and bowel cancer. The American cancer society (ACS) estimated that approximately 180,000 deaths per year. And it have been estimated that approximately 1,444,920 new cases of cancer will be diagnosed in 2007 27. This situation prompted us to synthesize some novel pyrazole derivatives bearing piperonal moiety as promising anti-microbial and anti-cancer agents. These information prompted us to synthesize some novel heterocyclic substituted Pyrazole as a possible anti-microbial and anti-cancer activity.

2 2 Review of Literature : Pyrazole are an entity which is being synthesized in many of its derivative form from fast few years. The entity in major source of interest for many of medicinal chemist to explore of its various pharmacological potential. The ring system plays important role in many biological process and many therapeutic agents contain pyrazole moiety .pyrazole derivative recently drawn much attention due to its various broad pharmacological activity Pyrazole ring has shown to be the basic moiety for number of drugs.amoung the wide variety of heterocycle that have been explored for developing potentially pharmacologically active compound. Substituted pyrazole derivative are known to contribute to various chemotherapeutic effects have antimicrobial 1,2,4,8 ,antifungal 15,20 , Antiviral 16,23 agent . Some fused pyrazole derivative were reported to induce various anticancer 2,14,17,18 , antitumor 3,6 , antitubercular 4,antiangiogenic 5,Anti-inflamatory 7,20, Pyrazole derivative also known to pusses as COX-II inhibitor11, potent adenosine receptor antagonist12, and potent highly selective monoamine oxidase A inhibitor 13,also shows antitubulin activity 10 ,anticonvulsant 9 ,antileukemic 19,insecticidal 21,herbicidal activity 22 has been reported.

3 6.3 Objective of the Study : The objectives of the present study includes : 1. To Develop the Synthetic method for the synthesis of the titled Pyrazole compounds. 2. To characterize the synthesized compounds by IR, NMR, and mass spectral data. 3. To Screen the Newly Synthesized Compounds for Antimicrobial and Anticancer activity.  To synthesize novel heterocyclic substituted coumarin derivatives by appropriate methods as per following scheme.

Piperonaldehyde + substituted acetophenones

chalcones

Hydrazine hydrate

pyrazoles

To Evaluate the Synthesized Compounds for their Antifungal, Antibacterial, Anticancer activity

4 7 Materials and methods

7.1 Source of data Extensive literature survey will be carried out in our college library, visiting various websites through internet and helinet of RGUHS KARNATAKA BENGALURU.

7.2 Methods of Collection of Data (including sampling procedure, if any)

a) Spectroscopic data- UV and IR spectra will be obtained from the instrumental laboratory of our college. Necessary NMR and MASS spectra of some selected compounds will be procured on the commercial basis.

b) Pharmacological and Biological Activity 1)Anti-microbial25- Selected synthesized compounds will be screened for their anti bacterial and anti-fungal activity by turbid metric method. 2)Anti-cancer26-All synthesized compound will be screened for In vitro cytotoxic activity by MTT Assay Method. Or Tryphan blue exclusion technique

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

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

5 8 List of references: 1. Bhaskar s .Dawane., Santosh S. Chobe., Gajanan G. Mandawad., Baseer M. Shaikh et al.,Design ,Synthesis of New Pyrazole [3,4-C] pyrazole thiazole and Evaluation of their Antimicrobial activity ,.pelagia research library;Der pharmacia sinica ,2010,1(3):140-146. 2. Hasan M.Faidallah., Sherif A.F.Rostom., and Mohammed S. Al-Saadi et al., Synthesis and Biological Evaluation of some new substituted Fused pyrazole ring system as possible Anticancer and antimicrobial agent . JKAU:Sci.,vol 22 No.1 pp:177-191 (2010 A.D/1431 A.H;4197/Sci 22-1.12. 3. Abdel-Rahman Farghaly., synthesis of some new indole derivative containing pyrazole with potential antitumor activity .ARKIVOC 2010(xi) 177-187. 4. P.T.Chovatia., J.D.Akabari., P.K. Kachhadia ., P.D.Zalavadia and H.S.Joshi et al, Synthesis and Selective Anti tubercular and Anti microbial inhibitory activity of 1-acetyl-3,5-diphenyl -4,5-dihydro –(1H)-pyrazole derivative; J.Serb.Chem.Soc 71(7) 713-720(2007) 5. H.Raju S. Chandrappa., M. K. Ramakrishna., T. S. Nagamani., H.Anada et al., Synthesis ,Characerisation and Anti angiogenic Effect of Novel 5-amino pyrazole derivative on Ehrlich Ascites tumor (EAT)Cells in vivo . Journal of cancer therapy 2010, 1:1-9. 6. Pier Giovanni Baraldi., Italo Beria., Paolo Cozzi., Cristina Geroni., et al., Cinnamoyl nitrogen mustard derivative of Pyrazole analogue of Tallimustine modified at the amino moiety:Design,Synthesis,Molecular modeling ,antitumor activity studies ; Bioorganic and Medicinal Chemistry 12 (2004)3911-3921. 7. Asuncian Burguete ., Eleni Pontiki., Dimitra Hadjipavlou- Litina ., Raquel Villar et al ; Synthesis and anti inflammatory /antioxidant activity of some new ring substituted 3-phenyl-1-(1,4-di-N-Oxide quinoxalin -2-yl)-2-Propen -1-one derivatives and of their 4,5-dihydro –(1H)-pyrazole analogue ,Bioorganic and Medicinal Chemistry Letters 17(2007)6439-6443. 8. Mostafa .M.Ghorab. Helmy.I.Heiba. Amina. A. Haseen., Amany. B. Abd EI Aziz.,et.al., Antimcrobial Evaluation of Novel Pyrrole, Pyrazole,Pyrimidine,and Pyrrole[2,3-d]-Pyrimidine derivatives Bearing Sulphonamide moiety., Journal of American Science,2011;7(1).

6 9. Nadeem Siddiqui., Anticonvulsant activity of a compound pharmacophore of Pyrazolo-Pyridines with Lesser toxicity in mice. Bulk Korean Chem.Soc 2011 .vol -32,No-2 10. Bojan Burga et al., Pyrazolone Fused combretastatins and their precurcer: Synthesis Cytotoxicity, antitubulin activity and molecular modeling studies; Bioorganic and Medicinal Chemistry 18(2010) 2375-2387. 11. Ramasamy Thilagavathi and Asit K. Chakraborti et al ; Importance of alignment in Developing 3-D QSAR model of 1,5-Diaryl Pyrazoles for the prsdection of COX-2 inhibitory activity ., Internet Journal of molecular design 2005 ,4,603- 612. 12. Siew Lee Cheong ., Gopalkrishnan Venkatesan ., Priyankar Paira ., Ramasamy Jothibasu et al ; Pyrazolo derivatives as potent Adenosine receptor antagonist:AN overview on the structure activity relationship ;Hindawi publishing Corporation ., International J.Med.Chem.vol. 2011, article I.D 480652. 13. Franco Chimenti ., Adriana Bolasco ., Fedele Manna ., Daniele Secci et al ; Synthesis and molecular modeling of Novel Substituted 4,5-dihydro-(1H)- Pyrazolo derivatives as potent and highly selective monoamine oxidase inhibitor., Chem Biol Drug Des 2006;67:206-214. 14. LIU-Xinhua, BAI Linshan., pan chunxia. Song Baon., et al ; Novel Dihydropyrazole derivatives Linked with 1, 2, 3, 4- tetrahydroisoquinoline ring: Synthesis and Anticancer activity . Chin. J. Chem 2009 Vol-(10) 1957-1961. 15. Chuan-Yu.Zhang., Xing-Hai Liu., Bao-Lei wang., Su-hua wang., Zheng-ming Li et al ; synthesis and Antifungal Evaluation Activities of New Pyrazole derivatives via 1, 3-dipolar cycloaddition reaction. Chem.Biol.and Drug design, vol-75, issue 5, May2010 page 489-493. 16. Mara R.P.de Oliveira.et al., Synthesis and Antiviral activities of new Pyrazolo [4, 3-c] quinolin-3-ones and their ribonucleoside derivative .vol-23, issue 5, 2004 page 735-748. 17. Peng –Cheng LV , Huan Qiu Li., Zhu-Ha-l et al. Synthesis and biological evaluation of Pyrazole derivatives containing thiourea skeleton as anticancer agents. Bioorganic and Medicinal Chem, vol -18, issue 13,1 july 2010, pp -4606 -4614.

7 18. George Mihai Nitulescu., Constatin Draghichi., Alexandru vasile missir et al ; synthesis of new Pyrazole derivatives and their anticancer Evaluation. European Journal of Med.Chem. Vol-45, issue 11, November 2010, pp – 4914-4919. 19. Gluseppe Daidone., Benedetta maggio., Demetrio Raffa., Salvatore plescia et al. Synthesis and in vitro antileukemic activity of new 4-Triazenopyrazole derivatives. ii Farmaco ,vol -59 ,issue 5,May 2004 ,page 413-417. 20. B.Ramesh and Chetan M. Bhalgat et al., Novel dihydropyridines and its Pyrazole derivatives: Synthesis and Pharmacological Screening. European Journal of Medicinal Chemistry vol -46, issue 5 May 2011 .page – 1882-1891. 21. Hong Dai, Young-Qiang li., DingDu., Xue Qin., Xin Zhang et al ; Synthesis and Biological activity of Novel Pyrazole Oxime derivative containing 2- Chloro 5- thiazolyl moiety . Journal of Agricultural and Food chemistry vol -56, issue 22 page 10805-10810. 22. Hong –ju ma, Yong-Hong LI et al ; synthesis and Herbicidal activities of novel N-(2,2,2)-TrifluroethylPyrazole derivatives . J.Agric.Food.Chem .2010, 58(7) page -4356-4360. 23. Ahmed H. Shamroukh., Magdi., A.Zaki., Eman M.H.Morsy., Faiza M. Abdel Motti et al. Synthesis of Pyrazolo [4, 3, 5, 6] Pyrano [2-3-d] Pyrimidine derivative for Antiviral evaluation.Archiv der Pharmazie .vol-340 page -236-243 .May 2007. 24. Graham.L.Patric. An introduction to medicinal Chemistry. Third edition 2005 page no. 489.edition. American Cancer Society, Cancer facts. 25. Gannaro R., Alfonso.Remington. The science and Practice of Pharmacy. Indian. Delhi. BI Publication, 20th ed: 2005, 1:548. 26. Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assay. Journal of Immunological methods 1983;16,55-63. 27. Mary A. K.,Brian A. K., Robin L., Joseph B. G., Wayne A. K., Williams B. R. Applied Therapeutics 9th ed. American Cancer Society, Cancer facts and figures 2007. Atlanta, GA: American Cancer Society 2007; 881-882.

8 9 09 Signature of the Candidate (Sudarshan N. Nagrale) Remarks of the Guide This work assigned to Mr. Sudarshan N. Nagrale is verified and corrected. The work 10 will be carried Out under are direct Supervision and Guidance.

Name and Designation of Dr. SHREENIVAS R. DESHPANDE (in Block Letters) M.PHARM,Ph.D 11.1. GUIDE: PROFESSOR, Guide ship Reference No. of P.G. DEPT. OF PHARMACEUTICAL RGUHS: ACA/CDC/PGT- CHEMISTRY, MPH/KLE/55/2005 -2006/36 H.S.K. COLLEGE OF PHARMACY, Date: 04.04.2005 BAGALKOT-587 101.

11.2.Signature

Dr. SHREENIVAS R. DESHPANDE 11 M.PHARM,Ph.D 11.3. Head of the Department PROFESSOR, P.G. DEPT. OF PHARMACEUTICAL Guide ship Reference No. of CHEMISTRY, RGUHS: ACA/CDC/PGT- H.S.K. COLLEGE OF PHARMACY, MPH/KLE/55/2005 -2006/36 BAGALKOT-587 101. Date: 04.04.2005

11.4. Signature

12.1Remarks of the Principal The Above Mentioned Information is correct and I Recommend the same for approval.

12 12.2. Signature

10 (Dr. I. S. MUCHCHANDI) 11