| Summary: | In the present investigation, the parent compound 4-amino-5-(4-fluoro-3-phenoxyphenyl)-4<i>H</i>-1,2,4-triazole-3-thiol (<b>1</b>) and its Schiff bases <b>2</b>, <b>3</b>, and <b>4</b> were subjected to whole-cell anti-TB against H37Rv and multi-drug-resistant (MDR) strains of <i>Mycobacterium tuberculosis</i> (MTB) by resazurin microtiter assay (REMA) plate method. Test compound <b>1</b> exhibited promising anti-TB activity against H37Rv and MDR strains of MTB at 5.5 µg/mL and 11 µg/mL, respectively. An attempt to identify the suitable molecular target for compound <b>1</b> was performed using a set of triazole thiol cellular targets, including β-ketoacyl carrier protein synthase III (FABH), β-ketoacyl ACP synthase I (KasA), CYP121, dihydrofolate reductase, enoyl-acyl carrier protein reductase, and <i>N</i>-acetylglucosamine-1-phosphate uridyltransferase. MTB β-ketoacyl ACP synthase I (KasA) was identified as the cellular target for the promising anti-TB parent compound <b>1</b> via docking and molecular dynamics simulation. MM(GB/PB)SA binding free energy calculation revealed stronger binding of compound <b>1</b> compared with KasA standard inhibitor thiolactomycin (TLM). The inhibitory mechanism of test compound <b>1</b> involves the formation of hydrogen bonding with the catalytic histidine residues, and it also impedes access of fatty-acid substrates to the active site through interference with α5–α6 helix movement. Test compound <b>1</b>-specific structural changes at the ALA274–ALA281 loop might be the contributing factor underlying the stronger anti-TB effect of compound <b>1</b> when compared with TLM, as it tends to adopt a closed conformation for the access of malonyl substrate to its binding site.
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