Pharmacophore mapping, molecular docking, chemical synthesis of some novel pyrrolyl benzamide derivatives and evaluation of their inhibitory activity against enoyl-ACP reductase (InhA) and Mycobacterium tuberculosis

Abstract

In an effort to produce new lead antimycobacterial compounds, herein we have reported the synthesis of a sequence of new pyrrolyl benzamide derivatives. The new chemical entities were screened to target enoyl-ACP reductase enzyme, which is one of the key enzymes of M. tuberculosis that are involved in type II fatty acid biosynthetic pathway. Compound 3q exhibited H-bonding interactions with Tyr158, Thr196 and co-factor NAD⁺ that binds the active site of InhA. All the pyrrolyl benzamide compounds were evaluated as inhibitors of M. tuberculosis H₃₇Rv as well as inhibitors of InhA. Among them, few representative compounds were tested for mammalian cell toxicity on the human lung cancer cell-line (A549) and MV cell line that presented no cytotoxicity. Five of these compounds exhibited a good activity against InhA.

Keywords: Enoyl-ACP reductase; GALAHAD; InhA; Pyrroles; Tuberculosis.