Anti-tubercular activity and molecular docking studies of indolizine derivatives targeting mycobacterial InhA enzyme

Abstract

A series of 1,2,3-trisubstituted indolizines (<b>2a-2f, 3a-3d</b>, and <b>4a-4c</b>) were screened for <i>in vitro</i> whole-cell anti-tubercular activity against the susceptible H37Rv and multidrug-resistant (MDR) <i>Mycobacterium tuberculosis</i> (MTB) strains. Compounds <b>2b-2d</b>, <b>3a-3d</b>, and <b>4a-4c</b> were active against the H37Rv-MTB strain with minimum inhibitory concentration (MIC) ranging from 4 to 32 µg/mL, whereas the indolizines <b>4a-4c,</b> with ethyl ester group at the 4-position of the benzoyl ring also exhibited anti-MDR-MTB activity (MIC = 16-64 µg/mL). <i>In silico</i> docking study revealed the enoyl-acyl carrier protein reductase (InhA) and anthranilate phosphoribosyltransferase as potential molecular targets for the indolizines. The X-ray diffraction analysis of the compound <b>4b</b> was also carried out. Further, a safety study (<i>in silico</i> and <i>in vitro</i>) demonstrated no toxicity for these compounds. Thus, the indolizines warrant further development and may represent a novel promising class of InhA inhibitors and multi-targeting agents to combat drug-sensitive and drug-resistant MTB strains.