Exploring 1, 2, 4-triazole-3-thiol Scaffolds: Design, Synthesis, and Molecular Docking Studies for Tuberculosis Therapy

Abstract

Background: Tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis, remains a pressing global health challenge. To design, synthesize, and evaluate novel 1,2,4-triazole-3-thiol derivatives as potential antitubercular agents to combat drug-resistant M. tuberculosis. Materials and Methods: A series of six 1,2,4-triazole3-thiol derivatives (R1–R6) was rationally designed and synthesised, with structural confirmation by infrared and nuclear magnetic resonance spectroscopy. Molecular docking was performed using AutoDock Vina via the PyRx platform against epidermal growth factor receptor kinase (EGFRK; Protein Data Bank ID: 5OEQ). The stability of ligand–protein complexes was assessed using normal mode analysis (NMA) through the iMODS server. Pharmacokinetic and toxicity profiles were predicted using pkCSM, PreADMET, and OSIRIS tools. In vitro anti-tubercular activity was evaluated against M. tuberculosis H37Rv using the microplate alamar blue assay. Results and Discussion: Docking studies identified compound R1 as the most promising candidate, exhibiting  the highest binding affinity (−8.1 kcal/moL) with key interactions in the ATP-binding pocket of EGFRK. NMA supported the stability and flexibility of the docked complexes. Absorption, distribution, metabolism, excretion,and toxicity predictions showed that all compounds complied with Lipinski’s rule, possessed favorable absorption characteristics, low blood-brain barrier permeability, and minimal predicted toxicity. Biological evaluation revealed that compounds R1, R2, and R4 demonstrated significant anti-tubercular activity, with minimum inhibitory concentrations ranging from 6.25 to 12.5 µg/mL. Conclusion: The combined computational and experimental results highlight 1,2,4-triazole-3-thiol derivatives, particularly R1, as promising lead candidates for further development of novel anti-tubercular therapeutics.