‘‘ DESIGN AND SYNTHESIS OF SUBSTITUTED BENZIMIDAZOLE AS ANTI-BACTERIAL AGENT ’’
SYNOPSIS FOR
M.PHARM DISSERTATION
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA
BY
BHARGAVI M
I M.PHARM
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY
NARGUND COLLEGE OF PHARMACY
BANGLORE-560 085
2010-12
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA.
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR
DISSERTATION
1.0 / NAME OF CANDIDATE AND ADDRESS / Mrs. BHARGAVI MNARGUND COLLEGE OF PHARMACY,
DATTATREYANAGAR, 2nd MAIN,
100 FEET RING ROAD, BSK3rd STAGE,
BANGALORE-85
2.0 / NAME OF THE INSTITUTION / NARGUND COLLEGE OF PHARMACY
DATTATREYA NAGAR, 2nd MAIN,
100 FEET RING ROAD, BSK3rd STAGE,
BANGALORE-85
3.0 / COURSE OF STUDY AND SUBJECT / M. PHARM.
PHARMACEUTICAL CHEMISTRY
4.0 / DATE OF ADMISSION / 7th JULY 2010
5.0 / TITLE OF TOPIC :-
“DESIGN AND SYNTHESIS OF SUBSTITUTED BENZIMIDAZOLES AS ANTI-BACTERIAL AGENT’’
5.1:- SCHEME OF STUDYR1 = H, Aryloxy / alkyloxy
R2 = H, Aryloxy / alkyloxy
R3 = Aryloxy / alkyloxy
6.0 / BRIEF RESUME OF THE INTENDED WORK
6.1:- NEED FOR THE STUDY
The increase in bacterial resistance has attracted considerable interest in the discovery and development of new classes of antibacterial agents. The new agents should preferably consist of chemical characteristics that clearly differ from those of existing agents.
Antibiotic resistance is the ability of bacteria or other microbes to resist the effects of an antibiotic. Antibiotic resistance occurs when bacteria changes in a way that reduces or eliminates the effectiveness of drug chemicals or other agents designed to cure or prevent infections. The microbes continue to multiply causing more harm. Obviously, if a bacterial pathogen able to develop resistance to an antibiotic then that substance becomes useless in the treatment of the infection caused by that pathogen. So as pathogen resistance increases, we must find novel drugs to replace the existing ones.
The recent drug candidates are mostly derivatives of existing pharmacophores with no novelty in their mechanism of action. This leaves us ample scope for investigating newer varieties of molecules and screening them for antibacterial activity.
The benzimidazole has been an important pharmacophore and privileged structure in medicinal chemistry, encompassing a diverse range of biological activities. Apart from anti infective activities, they are also found to possess antitumor1-6 and anthelmintic activity7.
The role fluorine is well established and known to increase bioavailability of a molecule by increasing lipid solubility. Our present proposal is to synthesize benzimidazoles having fluorine as a substituent and screen them for antibacterial activity.8-16
6.2:- Review of literature
Ø Synthesis and evaluation of biological activity of Substituted 2-mercapto benzimidazole by Siva Murru and co-workers and they reported that 2-(benzyl 2-mercapto-1-(beta-4-pyridethyl) benzimidazole as an antitumour agent.1
Ø Antitumour evaluation of novel symmetrical bis-benzimidazoles was carried out by Yan-Hui Yang and co-workers. These novel compounds showed IC50s in the single digit micromolar range for cytotoxicity in several tumor cell lines.2
Ø Shadia A Galal and team designed a new transition metal ion complexes with benzimidazole-5-carboxylic acid hydrazides with antitumor activity.3
Ø The synthesis of new benzimidazole linked pyrrolobenzodiazepine conjugates was described by Ahmed Kamal and co-workers. Some of these conjugates showed significant DNA-binding affinity and potential in-vitro cytotoxicity against a number of human cancer cell lines.4
Ø Michael Devereux and team reported the antitumor activities of copper(II)carboxylate complexes incorporating benzimidazole and they described that all of the complexes are poor catalase mimics in the presence of imidazole and totally inactive in its absence.5
Ø Novel benzofuran and related benzimidazole derivatives are evaluated for in-vitro anti-HIV-1, anticancer and antimicrobial activities by Samia M Rida and co-workers and they described the presence of spacer between the heterocyclic substituent and the benzofuran nucleus may be essential for the biological activity.6
Ø Molecular evaluation of benzimidazole resistance in nematodes was investigated by V. Leignel and team. They have evaluated benzimidizole resistance in controlled conditions.7
Ø Synthesis and antimicrobial activity of 1,3,4-oxadiazoles with benzimidazole moiety was reported by Janardhana Gowada and team. They synthesized a series of 2-substituted - 1 - [(5-substituted phenyl-1,3,4-oxadiazol-2-yl)methyl]-1 H – benzimidazole and the synthesized compounds have shown antifungal and antibacterial activity.8
Ø Semra UTKU and co-workers have synthesized new platinum (II) complexes of 2-phenylbenzimidazole ligands and have reported antibacterial and antifungal activities.9
Ø Bacterial topoisomerase I inhibitor activity was reported by Sandhya Bansal and team. They focused on the synthesis of new dimethoxy analogues of benzimidazole with improved DNA minor groove-binding affinity and having lower cytotoxicity to mammalian cells.10
Ø Zun-Ting Zhang and team reported the synthesis of 2, 3-Diarylpyrimido [1, 2-a] benzimidazole which showed antibacterial activity and they described the polysubstituted pyrimido[1,2-a]benzimidazoles have biological properties such as antiparasitic, antibacterial activity.11
Ø Novel antivirulence agents like N-Hydroxybenzimidazole inhibitors of the transcription factor in LcrF was reported by Oak K Kim and co-workers. They described the inhibitors exhibited no measurable antibacterial activity in-vitro. These inhibitors have the potential to prevent the infections caused by Yersinia spp.12
Ø A series of novel actinonin derivatives containing a benzimidazole heterocycle linked as amide isostere have been designed and synthesized by Datong Zhang and co-workers. These derivatives were evaluated in-vitro against Staphylococcus aureus, Klebsiella pneumoniae, and Sarcina lutea.13
Ø Synthesis and antimicrobial activity of some novel phenyl and benzimidazole substituted benzyl ethers were done by Ozden Onel Guven and co-workers. They have evaluated antibacterial and antifungal activities.14
Ø Some benzimidazole derivatives were synthesized and their in-vitro antifungal activities were tested by Gulgun Ayhan Kilcigil and team against candida albicans, candida glabrata and candida krusei.15
Ø Antiprotozoal activity of some 2-(trifluoromethyl)-1H-benzimidazole bioisosteres was evaluated by Gabriel Navarrete-Vazquez and co-workers. Each analogue was tested in-vitro against the protozoa Giardia intestinalis and Trichomonas vaginalis in comparison with albendazole and metronidazole.16
6.3:- OBJECTIVE OF STUDY
1. To synthesize substituted benzimidazole derivatives based on structure activity relationship of similar literature molecules for better anti-bacterial activity.
2. To find suitability and feasibility of different synthetic methods available in the literature for the preparation of substituted benzimidazole derivatives (or by microwave approach).
3. To purify and characterize the structure of newly synthesized compounds by TLC and IR, UV spectral facilities available in house and by NMR & Mass spectral data.
4. To evaluate the in-vitro anti-bacterial activity of the newly synthesized compounds by agar plate method.
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, Mass spectroscopy Structures of the synthesized molecules will be confirmed by the spectral data. The biological results will be used to study structure- activity relationship.
7.1:- SOURCE OF DATA
Institutes:
§ IISc. Library, Bangalore.
§ 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, Molecules, Chemistry of Heterocyclic Compounds, Indian Journal of Pharmaceutical Science, Chemical and pharmaceutical bulletin, Bio-organic and Medicinal Chemistry Letters, Indian Institute of Science, Acta Pharma, Turk Journal of Chemistry, Journal of Organic Chemistry, International Journal of Antimicrobial Agent, Journal of Combinatorial Chemistry.
DURATION OF STUDY:-9 Months (JUNE 2011 – FEB.2012)
Literature Survey: - Continuous Process.
Synthesis of Proposed Molecules: - 5 months (June 2011-Oct2011).
Anti-microbial and Pharmacological
activity Determination: - 2 months (Nov 2011-Dec 2011).
Thesis Writing: - 2 months (Jan 2012-Feb 2012).
7.3:- DOES THE STUDIES REQUIRE ANY INVESTIGATION TO BE CONDUCTED ON PATIENTS OR ANIMALS.
- NA -
7.4:- HAS ETHICAL CLEARENCE BEEN OPTAINED FROM YOUR INSTITUTION IN CASE OF 7.3
- N A -
8.0 / References:
1. Devereux M, Shea DO, Connor MO, Grehan H, Connor G, Mccann M, Rosair G. et al. Antitumor activities of copper(II)carboxylate complexes incorporating benzimidazole. Polyhedron 2007 Sep 20;26(15):4073-84.
2. Rida SM, El-Hawash SAM, Fahmy HTY, Hazzaa AA and El-Meligy MMM. Novel benzofuran and related benzimidazole derivatives are evaluated for in-vitro anti-HIV-1, anticancer, and antimicrobial activities. Arch Pharm Res 2006;29(10):826-33.
3. Murru S, Bhishma KP, Bras LJ and Muzart J. Synthesis and evaluation of biological activity of substituted 2-mercapto Benzimidazole. J Org Chem 2009;74:2217-20.
4. Yang YH, Cheng MS, Wang QH, Nie H, Liao N, Wang J, et al. Antitumour evaluation of novel symmetrical bis-benzimidazoles. Eur J Med Chem 2009;44:1808-12.
5. Galal SA, Hegab KH, Kassab AS, Rodriguez ML, Kerwin SM, El-Kharmry AMA, et al. Designed a new transition metal ion complexes with benzimidazole-5-carboxylicacid hydrazides with antitumor activity. Eur J Med Chem 2009;44:1500-08.
6. Kamal A, Kumar PP, Sreekantha K, Seshadria BN and Ramulua P. Synthesis of new benzimidazole linked pyrrolobenzodiazepine conjugates. Bioorg Med Chem Lett 2008;18(8):2594-98.
7. Leignela V, Silvestreb A, Humbertc JF and Cabaretb J. Molecular evaluation of benzimidazole resistance in nematodes. Veterinary Parasitology 2010 Aug 27;172(1-2):80-88.
8. Gowda J, Khadar AMA, Kalluraya B and Nalilu SK. Synthesis and anti-microbial activity of 1,3,4-oxadiazoles with benzimidazole moiety. Indian J Chem 2010; 49B:1130–34.
9. Utku S, Topal M, Dogen A and Serin MS. Synthesis and characterized antibacterial and antifungal evaluation. Turk J Chem 2010;34:427–36.
10. Bansal S, Tawar U, Singh M, Nikravesh A, Good L and Tandon V. Bacterial topoisomerase I inhibitor activity was evaluateed. Intr J Antimicrob Agents 2010;35:186-90.
11. Zhang ZT, Qiu L, Xue D, Wu J and Xu FF. Synthesis of 2, 3-Diarylpyrimido [1, 2-a] benzimidazole which showed antibacterial activity. Comb Chem 2010;12:225–30.
12. Kim OK, Lynne K, Ryan G, Bartlett VK, Grier MC, Verma AK, et al. N-Hydroxybenzimidazole inhibitors of the transcription factor in LcrF has antivirulence activity. J Med Chem 2009.
13. Zhang D, Wang Z, Xu W, Sun F, Tang L, Wang J. Synthesis and antibacterial activity of novel actinonin derivatives containing a benzimidazole heterocycles. Eur J Med Chem 2009;44:2202-10.
14. Guven OO, Erdogan T, Goker H and Yildiz S. Synthesis and antimicrobial activity of some novel phenyl and benzimidazole substituted benzyl ethers. Biorg Med Chem Lett 2007 April 15;17(8):2233-36.
15. Kilcigil GA and Altanlar N. Synthesis and antifungal properties of some benzimidazole derivatives. Turk J Chem 2006;30:223-28.
16. Vazquez NG, Vilchis MMR, Mulia LY, Melendez V, Gerena L, Campos AH, Castillo R, et al. Antiprotozoal activity of some 2-(trifluoromethyl)-1H-benzimidazole bioisosteres. Eur J Med Chem 2006;41:135-41.
9.0 / SIGNATURE OF THE CANDIDATE / (Mrs. BHARGAVI M)
10.0 / REMARKS OF THE GUIDE / Recommended for Dissertation work.
11.0 / NAME AND DESIGNATION OF
11.1 GUIDE / Mr. SHANTHARAM. U
Asst. PROFFESSOR.
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY
NARGUND COLLEGE OF PHARMACY,
BANGALORE- 85
11.2 SIGNATURE
113 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 / 12.1 REMARKS OF THE PRINCIPAL / Forwarded and Recommended for favorable consideration
Dr. D. S. PURANIK
PRINCIPAL
NARGUND COLLEGE OF PHARMACY
BANGALORE-560085.
12.2 SIGNATURE
9