ADME, Synthesis and Antimycobacterial Activity of 1,2,4-Triazol-3-thiol Linked Phenylacetamide Derivatives

Abstract

aims: We report herein the design of 2-(5-(substituted)-4H-1,2,4-triazole-2-ylthio)-N-(substituted) phenyl acetamide (5A-5E) derivatives using SAR studies as an inhibitor of Groel2 enzyme. These designed compounds were subjected to molecular docking, synthesis, ADME analysis, and biological evaluation against the H37Ra strain. background: Tuberculosis (TB) is one of the most contagious and deadly infectious diseases and contributes to an increase in fatalities. According to the WHO’s 2022 report, there is an increase in TB-related illnesses due to Covid-19. objective: We report herein the design of 2-(5-(substituted)-4H-1,2,4-triazole-2-ylthio)-N-(substituted) phenyl acetamide (5A-5E) derivatives using SAR studies as an inhibitor of Groel2 enzyme. These designed compounds were subjected to molecular docking, synthesis, ADME analysis, and biological evaluation against the H37Ra strain. method: On the basis of SAR and molecular docking using Autodock/vina the highest dock score compounds were synthesized using a conventional method. The synthesized compounds (5A-5E) were analyzed for the pharmacokinetic parameters to check their drug-likeness property using the molsoft program. The biological screening against Mycobacterium tuberculosis H37Rv strain was done using MABA assay to check its antimycobacterial activity. result: All the synthesized compounds have shown docking scores (-8.0 to -9.1Kcal/mol) that reflected their drug-binding affinities towards the Groel2 enzyme. ADME analysis predicts that compound 5B shows the highest drug-likeness score of 1.13 followed by compound 5C possesses a 0.8 score compared to other compounds. The minimum inhibitory concentrations of these compound 5D reached 0.8μM, which is superior to all the current first-line anti-tuberculosis drugs. Furthermore, almost all compounds possess excellent antimycobacterial activity compared to the standard drugs used. conclusion: All the compounds show excellent inhibitory activity against the Mycobacterium tuberculosis H37Rv strain. Compound 5D shows a promising activity as compared to standard and also shows the highest docking score towards the GroEl2 enzyme. The emphasis of this work is the development and synthesis of new antimycobacterial agents and their In-silico studies. other: No