Design, Synthesis and Docking Studies of a Novel

Topics: Bacteria, Gram-positive bacteria, Gram-negative bacteria Pages: 11 (2437 words) Published: June 20, 2013
http://www.ejchem.net

ISSN: 0973-4945; CODEN ECJHAO E-Journal of Chemistry 2012, 9(2), 980-987

Design, Synthesis and Docking Studies of a Novel Ciprofloxacin Analogue as an Antimicrobial AGENT S.JUBIE*, R. KALIRAJAN and PAVANKUMAR YADAV, Department of Pharmaceutical Chemistry J.S.S. College of Pharmacy, off campus - JSS University, Mysore jubiejawahar@gmail.com Received 31 July 2011; Accepted 4 October 2011 Abstract: The carboxylic acid group of ciprofloxacin was modified and amino mercapto triazole was substituted. The compound was confirmed by physical parameters (solubility, melting point), chromatographic methods (TLC) and consistent with its IR & 1HNMR spectra. The synthesized analogue was screened for antibacterial activity against one gram positive & two gram negative species. The compound exhibited good antibacterial effect towards gram negative species when compared to the standard ciprofloxacin. At the same time the analogue was retaining antibacterial activity towards gram positive species when compared to standard ciprofloxacin. The molecular docking studies showed a good correlation between their antibacterial activity and autodock binding free energy. Keywords: Ciprofloxacin, 1,2,4-Triazole, Molecular docking, Antimicrobial

Introduction
Quinolones have become a major class of antibacterial agents, which are under extensive clinical development. They have an attraction because of their extremely potent activity, rapid bactericidal effects and low incidence of resistance development1. The main disadvantage of the quinolones is their limited activity against gram positive pathogens and methicillin-resistant Staphylococcus aureus (MRSA)2. In addition, quinolones can cause certain adverse effects, such as CNS effects, phototoxicity, tendonitis, hypoglycemia, and serious cardiac dysrhythmias3-4. Thus, despite many advances in the fluoroquinolone field, there exists continuous need for novel quinolones with better activity profile, pharmacokinetics and tolerability, to overcome the limitations of existing drugs. Ciprofloxacin is a second generation fluoroquinolone used to treat various bacterial infections. It is more effective against gram- negative organisms than gram- positive ones. This moderate activity against some of the gram positive species limited its use in bacterial infections5. Molecular docking plays an important role in the rational design of drugs. In the field of molecular modeling, docking is a method which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex. Molecular docking

Design, Synthesis and Docking Studies of a Novel Ciprofloxacin 981

can be defined as an optimization problem, which would describe the “best-fit” orientation of a ligand that binds to a particular protein of interest6. 1, 2, 4-Triazole was reported to have a broad spectrum of antibacterial activity7-8. Therefore on continuation of our work9-11, in this study we introduced 1, 2, 4-triazole into the quinolone antibacterial ciprofloxacin at its C-3 position and screen their antibacterial activity. Molecular docking studies was then employed for the analysis with training set composed synthesized compound whose inhibitory activity is unknown, in order to find out the molecular facilities responsible for biological activities.

Experimental
Melting points were taken in glass capillary tubes on a Veego VMP-1 Apparatus and are uncorrected. The synthetic work was done by using CATALYST Scientific microwave synthesis system. The 1H-NMR were recorded on Bruker DRX-300 (300 MHz FT-NMR) using DMSO as solvent and TMS as internal standard. The IR spectra of compounds were recorded on Shimadzu FT-IR spectrometer using KBr pellet technique and are expressed in cm-1. 1HNMR spectra were recorded on a DPX-300 MHz Bruker FTNMR spectrometer (Bruker, USA). Chemical shifts were reported as parts per million (∂ ppm) with tetramethyl silane (TMS) as an internal standard....

References: 1. Hooper D C and Wifson J C, Antimicrob Agents Chemother, 1985, 28, 716. 2. Ball P, Infection, 1994, 22,Triazole substituted ciprofloxacin 140. 3. Ball P L, Mandell Y N and Tilloston G, Drug Safety, 1999, 21, 407. 2 4. Ball P J, Antimicrob Agents Chemother., 2000, 45, 557.
Scheme
Design, Synthesis and Docking Studies of a Novel Ciprofloxacin 987
5. Kawahara S and Nippon R, Chemother., 1998, 56 (12), 3096-3099. 6. Lengauer T and Rarey M, Curr Opin Struct Biol., 1996, 6(3), 402-406. 7. Nagalakshmi G D, Univ J Pharm Sci., 2006, 6(2), 69-75. 8. Wu J, Liu X, Cheng X, Cao Y, Wang D and Li Z, Molecules, 2007, 12, 2003-2016. 9. Jubie S, Prabitha P, Rajesh Kumar R, Kalirajan R, Gayathri R, Sankar S and Elango K, Med Chem Res., DOI 10.1007/s00044-011-96588. 10. Jubie S, Pranabesh S, Kalirajan R, Gowramma B, Gomathy S, Sankar S and Elango K, J Pharm Res., 2010, 3(3), 511-513. 11. Jubie S, Rajeshkumar R, Yellareddy B, Siddhartha G, Sandeep M, Surendrareddy K, Dushyanth H.S and Elango K, J Pharm Sci Res., 2010, 2(2), 69-76. 12. Lengauer T and Rarey M, Curr Opin Struct Biol., 1996, 6(3), 402-406. 13. Jorgensen W L, Science, 1991,254, 954-955. 14. Foroumadi A, Godsi S, Emami S, Samadi N and Ali G, Bioorg Med Chem Lett., 2006, 16, 3499-3503.
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