Chemical synthesis, molecular modeling and pharmacophore mapping of new pyrrole derivatives as inhibitors of InhA enzyme and Mycobacterium tuberculosis growth

Substituted phenylthiazolyl benzamide and pyrrolyl benzamide derivatives were developed using molecular hybridization technique to create novel lead antimycobacterial molecules used to fight against Mycobacteriumtuberculosis. The newly synthesized molecules have inhibited InhA, the enoyl-ACP reductase enzyme from the mycobacterial type II fatty acid biosynthetic pathway. Of these, compound 3b showed H-bonding interactions with Tyr158 and co-factor NAD+ that binds the active site of InhA. All the molecules were screened for in vitro antitubercular activity against M. tuberculosis H37Rv, as well as some representative molecules as the inhibitors of InhA. Thirteen compounds exhibited good anti-TB activities (MIC = 1.6 μg/mL), but only few representative molecules showed the moderate InhA enzyme inhibition activity.