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

• Main Authors: Katharigatta N. Venugopala (Author), Mahmoud Kandeel (Author), Melendhran Pillay (Author), Pran Kishore Deb (Author), Hassan H. Abdallah (Author), Mohamad Fawzi Mahomoodally (Author), Deepak Chopra (Author)
• Format: Book
• Published: MDPI AG, 2020-08-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antibiotics9090559; 2079-6382
• Keywords: <i>Mycobacterium tuberculosis</i>; triazole analogues; molecular dynamics studies; β-ketoacyl carrier protein synthase III (FABH); β-ketoacyl ACP synthase I (KasA); CYP121; Therapeutics. Pharmacology; RM1-950
• Source: Antibiotics, Vol 9, Iss 9, p 559 (2020)

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.