Anti-Tubercular Properties of 4-Amino-5-(4-Fluoro-3- Phenoxyphenyl)-4-1,2,4-Triazole-3-Thiol and Its Schiff Bases: Computational Input and Molecular Dynamics.

In the present investigation, the parent compound 4-amino-5-(4-fluoro-3-phenoxyphenyl)-4-1,2,4-triazole-3-thiol () and its Schiff bases , , and were subjected to whole-cell anti-TB against H37Rv and multi-drug-resistant (MDR) strains of (MTB) by resazurin microtiter assay (REMA) plate method. Test compound 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 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 -acetylglucosamine-1-phosphate uridyltransferase. MTB β-ketoacyl ACP synthase I (KasA) was identified as the cellular target for the promising anti-TB parent compound via docking and molecular dynamics simulation. MM(GB/PB)SA binding free energy calculation revealed stronger binding of compound compared with KasA standard inhibitor thiolactomycin (TLM). The inhibitory mechanism of test compound 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 -specific structural changes at the ALA274-ALA281 loop might be the contributing factor underlying the stronger anti-TB effect of compound when compared with TLM, as it tends to adopt a closed conformation for the access of malonyl substrate to its binding site.