Pharmacophore an International Research Journal
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Open Access | Published: 2013 - Issue 3

2D & 3D QSAR STUDIES OF BIARYL ANALOGUES OF PA-824 HAVING VARIOUS ETHER LINKERS: AN APPROACH TO DESIGN ANTITUBERCULAR AGENTS Download PDF


Sawarkar Vaibhav M, Dudhe Prashik B, Nagras Madhuri A, Bhosle Pallavi V, Jadhav Supriya B and Meshram Rutuja S
Abstract

New analogues of PA-824 having alternative side chain ether linkers of varying size & flexibility shows 8-fold better activity than parent drug i.e. PA-824 as Mycobacterium tuberculosis (M.tb.) inhibitors. Recent work suggests that bicyclic nitroimidazole-based prodrugs PA-824 as intracellular nitric oxide (NO) releaser is key to their activity against non replicating persistent M.tb. 2D & 3D QSAR studies were performed on a set of 72 Biaryl analogues of PA-824 having various ether linkers using V-Life Molecular Design Suite (MDS 3.5) QSAR plus module. The best model were generated using Multiple linear regression (MLR) analysis (r2 = 0.8416, q2 = 0.7853, F test = 47.8273, pred_r2 = 0.8481, pred_r2se = 0.2880) and Principle Component Regression (PCR) (r2 = 0.7781, q2 = 0.7274, F test = 42.517, pred_r2 = 0.8405, pred_r2se = 0.2951) for 2D and 3D QSAR respectively. For each set of descriptors, the best multi-linear QSAR equations were obtained by the stepwise variable selection method using leave-one-out cross-validation as selection criterion. Alignment independent descriptors were the most important descriptors in predicting antitubercular inhibitory activity. New Chemical Entities (NCEs) were designed using results of QSAR studies.

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Pharmacophore
ISSN: 2229-5402


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