Research Paper on 4-Amino-5-(4-Fluoro-3-Phenoxyphenyl)-4H-1,2,4-Triazole-3-Thiol and Its Schiff Bases Have Anti-Tubercular Properties: Computational Input and Molecular Dynamics

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

Abstract: In the current study, the parent compound 4-amino-5-(4-fluoro-3-phenoxyphenyl) -4H-1,2,4-triazole-3-thiol (1) and its Schiff bases 2, 3, and 4 were tested using the resazurin microtiter assay (REMA) plate method for whole-cell anti-TB against H37Rv and MDR strains of Mycobacterium tuberculosis (MTB). Test substance 1 demonstrated positive anti-TB activity at concentrations of 5.5 g/mL and 11 g/mL against the MDR and H37Rv strains of MTB, respectively. With the help of a number of triazole thiol cellular targets, including CYP121, dihydrofolate reductase, enoyl-acyl carrier protein reductase, and N-acetylglucosamine-1-phosphate uridyltransferase, an attempt was made to pinpoint the best molecular target for compound 1. Through molecular dynamics simulation and docking, the potential anti-TB parent compound 1’s cellular target, MTB -ketoacyl ACP synthase I (KasA), was found. Stronger binding of compound 1 was found by MM(GB/PB)SA binding free energy calculations compared to KasA standard inhibitor thiolactomycin (TLM). Test compound 1’s inhibitory mechanism involves the formation of hydrogen bonds with the catalytic histidine residues. It also prevents fatty acid substrates from reaching the active site by interfering with the movement of the 5-6 helix. Given that Test Compound 1 tends to adopt a closed conformation for the access of malonyl substrate to its binding site, structural changes at the ALA274-ALA281 loop may be a contributing factor underlying the stronger anti-TB effect of Compound 1 when compared to TLM.

Keywords: Mycobacterium tuberculosis; triazole analogues; molecular dynamics studies; β-ketoacyl carrier protein synthase III (FABH); β-ketoacyl ACP synthase I (KasA); CYP121; dihydrofolate reductase; enoyl-acyl carrier protein reductase; N-acetylglucosamine-1-phosphate uridyltransferase; multi-drug-resistant tuberculosis

Paper Quality: SCOPUS / Web of Science Level Research Paper

Subject: Antibiotics

Writer Experience: 20+ Years

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