Comparative molecular similarity indices analysis of some 1-substituted imidazole analogs as Candida albicans P450-demet
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Med Chem Res (2013) 22:2570–2577 DOI 10.1007/s00044-012-0251-3
ORIGINAL RESEARCH
Comparative molecular similarity indices analysis of some 1-substituted imidazole analogs as Candida albicans P450-demethylase inhibitors Nagaraj Selvaraj • Swastika Ganguly
Received: 28 January 2012 / Accepted: 18 September 2012 / Published online: 2 October 2012 Ó Springer Science+Business Media New York 2012
Abstract A three-dimensional quantitative structure– activity relationship of 66 structurally and functionally diverse series of 1-substituted imidazoles with antifungal activity was studied using the CoMSIA method. The compounds were divided into a training set of 56 molecules and a test set of 10 molecules. The optimum CoMSIA model obtained for the training set were all statistically significant with cross-validated coefficients (q2) of 0.725 and conventional coefficients (r2ncv) of 0.998. The predictive ability of CoMSIA was determined using a test set of ten imidazole derivatives. CoMSIA model (Model 1) obtained from steric, electrostatic, and H-bond acceptor fields were found to have best predictivity with a predictive correlation coefficient (r2pred) of 0.60. Based upon the information derived from CoMSIA, it is evident that steric, electrostatic, and hydrogen bond acceptor groups may be important for the design of more potent imidazole analogs as potent Candida P450DM inhibitors. Keywords 3D-QSAR CoMSIA Imidazole Antifungal activity
Introduction The treatment of systemic mycoses has acquired increasing importance in recent years as a result of the sustainability of opportunistic yeast infections in immunocompromised N. Selvaraj (&) S. Ganguly Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India e-mail: [email protected] S. Ganguly e-mail: [email protected]
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patients, the major contributors to this situation being the widespread use of immunosuppressants following organ transplant operations, the AIDS epidemic and cancer (Zampieri et al., 2007). The azoles represent a class of versatile antifungal agents with highly substituted imidazoles such as clotrimazole (Fig. 1a) and miconazole (Fig. 1b) being the early members of this class. However, despite the progress made in antifungal drug discovery, relatively few agents have been found that combine the properties for the treatment of systemic yeast infections and a reasonable margin of safety. Moreover, the emergence of azole-resistant strains calls for the search for newer antimycotic compounds. At high concentrations, the azoles are fungicidal, while at low concentrations they are fungistatic. The latter effect has been correlated with the inhibition of cytochrome P-450-dependent lanosterol 14ademethylase (P-450DM) involved in fungal sterol biosynthesis. Although P-450DM enzymes have been purified from different sources (Yoshida and Aoyama, 1984; Hitchcock et al., 1989), no experimental structural information on the active site of the target enzyme Candida P450DM is available. Ligand
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