2D & 3D QSAR STUDIES OF BIARYL ANALOGUES OF PA-824 HAVING VARIOUS ETHER LINKERS: AN APPROACH TO DESIGN ANTITUBERCULAR AGENTS
Sawarkar Vaibhav M, Dudhe Prashik B, Nagras Madhuri A, Bhosle Pallavi, Jadhav Supriya B, Meshram Rutuja S · 2013
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 (r 2 = 0.8416, q 2 = 0.7853, F test = 47.8273, pred_r 2 = 0.8481, pred_r 2 se = 0.2880) and Principle Component Regression (PCR) (r 2 = 0.7781, q 2 = 0.7274, F test = 42.517, pred_r 2 = 0.8405, pred_r 2 se = 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-oneout 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.