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

Abstract

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 bases 2, 3, and 4 were subjected to whole-cell anti-TB against H37Rv and multi-drug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) by resazurin microtiter assay (REMA) plate method. Test compound 1 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 1 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 N-acetylglucosamine-1-phosphate uridyltransferase. MTB β-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 α5–α6 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.

In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies of substituted 1,2,4-oxadiazole analogues against Mycobacterium tuberculosis

“…Secondly, the individual scores of the designed compounds were showing higher or comparable docking scores as compared to the redocked native co-crystallized ligand. Particularly, the relative docking (RD) scores 17 of the most active compounds (compounds 3a , and 3d ) were generally greater than or close to one; indicating that these compounds are expected to show good inhibitory potential against the putative target ( Table 4 ). Once a putative target was identified, further analysis of the binding modes and binding interactions of the compounds was conducted by calculating their total free binding energies to Pks13-TE enzyme ( Table 4 ).…”

“…In continuation to our anti-TB drug discovery efforts and in search of novel scaffolds as anti-TB agents, we have designed, synthesised and reported several natural products, cyclic depsipeptides and compounds belonging to various heterocyclic scaffolds such as aminoquinazolines, benzothiazoles, pyrrolo [1,2a]quinolines, dihydropyrimidines, 1-(5-isoquinolinesulfonyl)piperazines, triazoles, triazolyl 1,2,3,4-tetrahydropyrimidines, and various substituted indolizines as potential anti-TB agents [15][16][17][18][19][20][21][22][23][24][25] .…”

Transition metal complexes of triazole-based bioactive ligands: synthesis, spectral characterization, antimicrobial, anticancer and molecular docking studies

“…1,2,4-triazole possesses a wide variety of pharmacological activity including antimicrobial, anti-cancer, anti-diabetic, anti-tubercular, anxiolytics, anticonvulsants, etc. [25][26][27][28][29][30]. Schiff base ligands having triazole ring can be considered as "privileged structures" and are widely used due to their novel structural features.…”

Highly Luminescent 4H-1,2,4-Triazole Derivatives: Synthesis, Molecular Structure and Photophysical Properties

“…This scaffold occurs in two tautomeric forms with the 1 H -1,2,4-triazole system predominating over the 4 H -1,2,4-triazole form [ 6 , 7 ]. The derivatives of 4 H -1,2,4-triazole exhibit interesting properties and, thus, have applications in diverse fields such as optoelectronics (emission properties) [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ], materials science (corrosion inhibition) [ 15 , 16 , 17 , 18 , 19 , 20 ], medicine [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ] and agriculture [ 33 , 34 , 35 , 36 , 37 , 38 ] (biological properties). Due to the numerous applications, the 1,2,4-triazole core has been the subject of several recent literature reviews commenting on the synthesis of these moieties [ 7 , 39 , 40 , 41 , 42 , 43 ].…”