Synthesis, biological evaluation and in silico molecular modeling of pyrrolyl benzohydrazide derivatives as enoyl ACP reductase inhibitors

摘要

In efforts to develop lead anti-TB compounds, a novel series of 19 pyrrolyl benzohydrazides were synthesized and screened to target enoyl-ACP reductase enzyme, which is one of the important enzymes involved in type II fatty acid biosynthetic pathway of M. tuberculosis. Pharmacophores were constructed using GALAHAD to generate alignment of data sets and calculated by Pareto ranking. The pharmacophore features were then filtered by Surfiex-dock study using enoyl ACP reductase from M. tuberculosis. Compounds 5b and 5d showed H-bonding interactions with Tyr158, Thr196 and co-factor NAD(+) that fitted well within the binding pocket of InhA. All the synthesized compounds were screened for preliminary antibacterial activities against Gram-positive S. aureus and Gram-negative E. colt and M. tuberculosis H(37)Rv to evaluate their antitubercular activities. Some representative compounds were further tested for mammalian cell toxicity using human lung cancer cell-line (A549) that was found to be nontoxic. These compounds exhibited moderate inhibition activities against InhA. (C) 2016 Elsevier Masson SAS. All rights reserved.