DESIGN, SYNTHESIS AND TARGETING OF SUBSTITUTED BENZIMIDAZOLES AS TOPOISOMERASE I INHIBITOR
SYNOPSIS FOR
M.PHARM DISSERTATION
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA
BY
VIVEK G. PETE
I M.PHARM
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY
NARGUND COLLEGE OF PHARMACY
BANGLORE-560085
2009-11
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA.
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR
DISSERTATION
1.0 / NAME OF CANDIDATE AND ADDRESS / Mr. VIVEK G. PETENargund College Of Pharmacy,
Dattatreyanagar, 2nd Main,
100FT Ring Road, Bsk3rd Stage,
Bangalore-85
2.0 / NAME OF THE INSTITUTION / NARGUND COLLEGE OF PHARMACY
Dattatreyanagar, 2nd Main,
100FT Ring Road, Bsk3rd Stage,
Bangalore-85
3.0 / COURSE OF STUDY AND SUBJECT / M. PHARM.
Pharmaceutical Chemistry
4.0 / DATE OF ADMISSION / 1 June 2009
5.0 / TITLE OF TOPIC :-
DESIGN, SYNTHESIS AND TARGETING OF SUBSTITUTED BENZIMIDAZOLES AS TOPOISOMERASE I INHIBITOR
5.1:- SYSTEM OF STUDY:-6.0 / BRIEF RESUME OF THE INTENDED WORK
6.1:-NEED FOR THE STUDY
Benzimidazoles are important compounds because of their antibacterial, antifungal, antimicrobial, antiprotozoal and antihelmintic activities. Some benzimidazole derivatives also interfere with the reactions of DNA topoisomerases, enzymes functioning at almost all stages of the cell cycle.
DNA topoisomerases are essential enzymes that regulate conformational changes in DNA topology by transient breakage of nucleic acid backbone during many genetic processes, including DNA replication, transcription and recombination. DNA topoisomerases were shown to be important targets for several chemotherapeutic agents. They are potent against leukaemia cell lines, and anti-proliferative properties were tested against human MCF-7 breast cancer cell lines i.e cytotoxic activities, they act as potent anti-mycobacterial activity, biocides like fungicides and insecticides.
In this project it is proposed to synthesize various substituted Benzimidazoles for better biological activities.
6.2:-REVIEW OF LITERATURE
1. Guns C et al synthesized and reported biological activity evaluation of 1 H benzimdazoles via mammalian DNA topoisomerase-І and cytostaticity assay1.
2. Sabiha A et al some new bi- and ter-benzimidazole derivatives as topoisomerase I inhibitors2.
3. Meera R et al topoisomerase I inhibition and cytotoxicity of 5-bromo- and 5-phenylterbenzimidazoles3.
4. June CS et al solid phase combinatorial synthesis of benzothiazoles and evaluation of topoisomerase II inhibitory activity4.
5. Hua YJ et al tris-benzimidazole derivatives: designed, synthesized and DNA sequence recognition 5.
6. Ozlem T et al 3D-QSAR analysis on benzazole derivatives as eukaryotic topoisomerase II inhibitors by using comparative molecular field analysis method6.
7. Jakub S et al synthesized 2-aryl-4-(benzimidazol-2-yl)-1,2-dihydro [1,2,4] triazino[4,5-a]benzimidazol-1-one derivatives with preferential cytotoxic against carcinoma cell lines7.
8. Devinder K et al synthesized and evaluation of anticancer benzoxazoles and benzimidazoles related to UK-18.
9. Stephen P et al DNA gyrase (GyrB)/topoisomerase IV (ParE) inhibitors: Synthesis and antibacterial activity9.
10. Dhvanit S et al designed, synthesized and evaluation of substituted carboxamida benzimidazole derivatives: Angiotensin II-AT1 receptor antagonist10.
11. Armand G et al synthesized and cytotoxicity evaluation of some benzimidazole-4,7-diones as bioreductive anticancer agents11.
12. Evansl D et al synthesized a group of lH-benzimidazoles and their screening for antiinflammatory activity12.
13. Fei YL et al identification of 1-isopropylsulfonyl-2-amine Benzimidazoles as a new class of inhibitors of hepatitis B virus13.
14. Andrzejewska M et al polyhalogenobenzimidazoles: synthesized and their inhibitory activity against casein kinases14.
15. Jose L et al synthesis, pharmacology and molecular modeling of N-substituted 2-phenyl-indole and benzimidazoles as potent GABAA agonist15.
16. Sharma P et al synthesized and QSAR studies on 5-[2-(2-methylpropl-enyl)-1H benzimidazole-1yl]-4,6-diphenyl-pyrimidin-2-(5H)-thione derivatives as antibacterial agents16.
17. Sukalovic V et al synthesized, dopamine D2 receptor binding studies and docking analysis of 5-[3-(4-arylpiperazin-1-yl)propyl]-1H-benzimidazole, 5-[2[(4[arylpiperazin-1-yl)ethoxy]-1H-benzimidazole and their analogs17.
18. Gokce M et al synthesized, in vitro cytotoxic and antiviral activity of cis-[Pt(R(-) and S(+)-2-α-hydroxybenzylbenzimidazole)2Cl2] complexes18.
19. Kopanska K et al synthesized and activity of 1H-benzimidazole and 1H-benzotriazole derivatives as inhibitors of Acanthamoeba castellanii19.
20. Hakan G et al synthesized and potent antibacterial activity against MRSA of some novel 1,2-disubstituted-1H-benzimidazole-N- alkylated-5-carboxamidines20.
6.3:- OBJECTIVE OF STUDY
1. To synthesize substituted benzimidazole derivatives based on structure activity relationship of similar literature molecules for better anti-bacterial and topoisomerase inhibitory activity.
2. To find suitability and feasibility of different synthetic methods available in the literature for the preparation of benzimidazole derivatives (or by microwave approach).
3. To purify and characterize the structure of newly synthesized compounds by TLC, IR and UV spectral facilities available in house and by NMR spectral data.
4. To evaluate the in vitro topoisomerase inhibitor activity of the newly synthesized compounds
7.0 / MATERIALS AND METHODS
Chemicals and other reagents will be purchased from standard companies. The reactions will be monitored by thin layer chromatography. The standard protocols will be followed for purification of the products. The product will be purified according to the standard protocols. The separated compounds shall be characterized by IR spectroscopy, UV spectroscopy, NMR spectroscopy.
Structures of the synthesized molecules will be confirmed by the spectral data. The biological results will be used to study structure- activity relationship and there by optimize the structure.
7.1:- SOURCE OF DATA
Ø Institutes:
§ IISc Library, Bangalore.
§ Nargund college of Pharmacy, Bangalore, Library.
§ RGUHS Digital library (Helinet).
§ Central College Library, Bangalore.
7.2:- METHODS OF DATA COLLECTION
Chemical abstract and other journals like Journal of medicinal chemistry, European Journals of Medicinal Chemistry, Tetrahedron Letters, Medical Microbiology and Immunology Springer, Chemistry of Heterocyclic compounds, Indian Journal of Pharmaceutical Science, Chemical and Pharmaceutical Bulletin, IL Formaco, Bio-organic and Medicinal Chemistry, Indian Institute of Science, www.sciencedirect.com.
DURATION OF STUDY:-9 Months (JUNE 2010 – FEB.2011)
Literature Survey - Continuous Process.
Synthesis of Proposed Molecules - 5 months (June 2010-Oct2010).
Pharmacological
Activity Determination - 2 months (Nov 2010-Dec 2010).
Thesis Writing - 2 months (Jan 2011-Feb 2011).
7.3:- DOES THE STUDIES REQUIRE ANY INVESTIGATION TO BE CONDUCTED ON PATIENTS OR ANIMALS.
NO
7.4:- HAS ETHICAL CLEARENCE BEEN OPTAINED FROM YOUR INSTITUTION IN CASE OF 7.3?
N/A
8.0 / REFERENCES:
1. Gunes C, Sevil Z, Istva´n Z, Borba´la R, Semih G et al Synthesis and biological activity evaluation of 1 H-benzimdazoles via mammalian DNA topoisomerase I and cytostaticity assay. Eur J.Med Chem 2009; 44:2280-85.
2. Sabiha A, O¨zlem T, Esin S, Ismail Y et al some new bi- and ter-benzimidazole derivatives as topoisomerase I inhibitors. IL Formaco 2003; 58:497-07.
3. Meera R, Jung S, Sai-Peng S, Angela L, Leroy F, Edmond J et al topoisomerase I inhibition and cytotoxicity of 5-bromo- and 5-phenylterbenzimidazoles. Bioorg Med Chem.2000; 8:2591-00.
4. June SC, Hyen J, Sang K, Sang WK, Gyoonhee H et al Solid phase combinatorial synthesis of benzothiazoles and evaluation of topoisomerase II inhibitory activity. Bioorg Med Chem 2006; 14:1229-35.
5. Hua YJ, Daniel B, Walter H, Runtz S, Arnulf D, Christian B, Michael J et al Tris-benzimidazole Derivatives: design, synthesis and DNA sequence recognition. Bioorg Med chem 2001; 9:2905-19.
6. Ozlem T, Betul TG, Ilkay Y, Esin A, Ismail Y et al 3D-QSAR analysis on benzazole derivatives as eukaryotic topoisomerase II inhibitors by using comparative molecular field analysis method. Bioorg Med chem 2005; 13:6354-59.
7. Jakub S, Libuse S, Jan S, Marian H et al Synthesis of 2-aryl-4-(benzimidazol-2-yl)-1,2-dihydro[1,2,4]triazino[4,5-a]benzimidazol-1-one derivatives with preferential cytotoxic against carcinoma cell lines. Eur J Med Chem 2008; 43:449-55.
8. Devinder K, Melissa RJ, Michael BR and Sean MK et al Synthesis and evaluation of anticancer benzoxazoles and benzimidazoles related to UK-1. Bioorg Med chem 2002; 10:3997-04.
9. Dhvanit S, Manu S, Yogita B, Gulshan B, Manjeet S et al Design, synthesis and evaluation of substituted carboxamida benzimidazole derivatives: Angiotensin II-AT1 receptor antagonist. Eur J Med Chem 2008; 43:1808-12.
10. Stephen P, Clara B, Oliver B, Stephanie B, James B, David B et al DNA gyrase (GyrB)/topoisomerase IV (ParE) inhibitors: synthesis and antibacterial activity. . Bioorg Med chem lett 2009; 19:894-99.
11. Armand G, Herve K, Narimene B, Patrice V et al Synthesis and cytotoxicity evaluation of some benzimidazole-4,7-diones as bioreductive anticancer agents. Eur J of Med Chem 2008; 43:1858-64.
12. Evansl D, Hicksl TA, Williamson I, Dawson W, Meacockz SC, Kitchen EA et al Synthesis of a group of lH-benzimidazoles and their screening for antiinflammatory activity. Eur J Med Chem 1996; 31:635-42.
13. Fei YL, Feng GW, Yu L, Gang WH, Wei T, Chun L et al. Identification of 1-isopropylsulfonyl-2-amine benzimidazoles as a new class of inhibitors of hepatitis B virus. Eur J Med Chem 2007; 42: 1358-64.
14. Mariola A, Mario AP, Flavio M, Anna MB, Zygmunt K et al Polyhalogenobenzimidazoles: synthesis and their inhibitory activity against casein kinases, Bioorg Med Chem 2003; 11:3997-02.
15. Jose LF , Maria P, Miguel G, Irma B, Eva M et al Synthesis, pharmacology and molecular modeling of n-substituted 2-phenyl-indole and benzimidazoles as potent GABAA agonist. Eur J Med Chem 2006; 41: 985-90.
16. Sharma P, Kumar A, Sharma M et al Synthesis and QSAR studies on 5-[2-(2-methylpropl-enyl)-1H benzimidazole-1yl]-4,6-diphenyl-pyrimidin-2-(5H)-thione derivatives as antibacterial agents. Eur J Med Chem 2006; 41: 833-40.
17. Sukalovic V, Deana A, Roglic G, Sladjana KR, Schrattenholz A, Soskic V et al Synthesis, dopamine D2 receptor binding studies and docking analysis of 5-[3-(4-arylpiperazin-1-yl)propyl]-1H-benzimidazole, 5-[2[(4[arylpiperazin-1-yl)ethoxy]-1H-benzimidazole and their analogs. Eur J Med Chem 2005; 40: 481-93.
18. Gokce M, Utka S, Gur S, Ozkul A et al Synthesis, in vitro cytotoxic and antiviral activity of cis-[Pt(R(-) and S(+)-2-α-hydroxybenzylbenzimidazole)2Cl2] complexes. Eur J Med Chem 2005; 40:135-41.
19. Kopanska K , Andz’elika N, Justyna Z, Lidia C, Janusz P, Przemysław M et al Synthesis and activity of 1H-benzimidazole and 1H-benzotriazole derivatives as inhibitors of Acanthamoeba castellanii. Bioorg Med Chem.2004; 12:2617-24
20. Hakan G, Seckin O, Sulhiye Y, David W et al Synthesis and potent antibacterial activity against MRSA of some novel 1,2-disubstituted-1H-benzimidazole-N-alkylated-5-carboxamidines. Eur J Med Chem. 2005; 40: 1062-69.
9.0 / SIGNATURE OF THE CANDIDATE / (Vivek G. Pete)
10.0 / REMARKS OF THE GUIDE / Recommended for Dissertation work.
11.0 / NAME AND DESIGNATION OF
11.1 / GUIDE / Dr. J.N. NARENDRA SHARATH
CHANDRA
Professor,
Department Of Pharmaceutical Chemistry,
Nargund College Of Pharmacy,
Bangalore- 85
11.2 / SIGNATURE
11.3 / CO-GUIDE / NA
11.4 / SIGNATURE / --
11.5 / HEAD OF THE DEPT / Dr. L. V. G. NARGUND
Professor And Head,
Dept. Of Pharmaceutical Chemistry,
Nargund College Of Pharmacy,
Bangalore-85.
11.6 / SIGNATURE
12.0 / REMARKS OF THE PRINCIPAL / Forwarded And Recommended For Favorable Consideration
PROF M.S.HARISH
Principal,
Nargund College Of Pharmacy
Bangalore-560085.
12.1 / SIGNATURE
9