Anti-Tubercular Properties Of 4-Amino-5-(4-Fluoro-3-Phenoxyphenyl)-4h-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)-4H-1,2,4-triazole-3-thiol (1) and its Schiff bases2,3, and4were subjected to whole-cell anti-TB against H37Rv and multi-drug-resistant (MDR) strains ofMycobacterium tuberculosis(MTB) by resazurin microtiter assay (REMA) plate method. Test compound1exhibited promising anti-TB activity against H37Rv and MDR strains of MTB at 5.5 mu g/mL and 11 mu g/mL, respectively. An attempt to identify the suitable molecular target for compound 1 was performed using a set of triazole thiol cellular targets, including beta-ketoacyl carrier protein synthase III (FABH), beta-ketoacyl ACP synthase I (KasA), CYP121, dihydrofolate reductase, enoyl-acyl carrier protein reductase, andN-acetylglucosamine-1-phosphate uridyltransferase. MTB beta-ketoacyl ACP synthase I (KasA) was identified as the cellular target for the promising anti-TB parent compound 1 via docking and molecular dynamics simulation. MM(GB/PB)SA binding free energy calculation revealed stronger binding of compound 1 compared with KasA standard inhibitor thiolactomycin (TLM). The inhibitory mechanism of test compound 1 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 alpha 5-alpha 6 helix movement. Test compound 1-specific structural changes at the ALA274-ALA281 loop might be the contributing factor underlying the stronger anti-TB effect of compound 1 when compared with TLM, as it tends to adopt a closed conformation for the access of malonyl substrate to its binding site.