Discovery of target based novel pyrrolyl phenoxy derivatives as antimycobacterial agents: An in silico approach

A new series of pyrrolyl phenoxy derivatives bearing alkoxy linker were synthesized and evaluated for anti-tubercular activity (anti-TB) against Mycobacterium tuberculosis. Molecular modeling, pharmacophore constructed using GALAHAD to produce an effective alignment of data set and evaluated by Pareto ranking. The pharmacophore features were filtered by Surflex-dock study using enoyl ACP reductase from M. tuberculosis, which is one of the key enzymes involved in type II fatty acid biosynthesis pathway of M. tuberculosis. Compound 6a27 showed the H-bond with NAD+, whereas compound 6a26 showed H-bonds with Tyr158, Thr196, Met199 and NAD+ that fitted well into the binding pocket of target InhA. The alkoxy linker bridge and acceptor groups with benzene ring were advantageous for anti-TB activity, which merit further investigation. Antitubercular activity of novel series of pyrrolyl phenoxy derivatives bearing alkoxy linker was analyzed. Molecular modeling, pharmacophore constructed using GALAHAD to produce an effective alignment of data set and evaluated by Pareto ranking, pharmacophore features were filtered by Surflex-dock study using enoyl ACP reductase from Mycobacterium tuberculosis. Crystal structure of highly active compound in a complex with InhA and H-bond is indicated by a dashed yellow line. [Display omitted] •Inhibitors of mycobacterial Enoyl ACP reductase were designed using in silico approach.•Synthesis of a range of these pyrrolyl phenoxy derivatives is described.•Pharmacophore and Surflex docking studies were carried out to understand the SAR.•Inhibitors were active against Mycobacterium tuberculosis.