Design, Synthesis, In Vitro Evaluation, Multitargeted Molecular Docking, and In Silico Analysis of Some Azo-Linked 1,3,4-Thiadiazole and 1,2,4-Triazole Heterocyclic Hybrids as Potent Antitubercular Agents

The swift emergence of multidrug- and highly drug-resistant strains of Mycobacterium tuberculosis (Mtb) makes it essential to develop new agents with varied chemical structures and multitarget mechanisms of action. In the current investigation, we have designed and synthesized 24 novel heterocyclic ring-substituted 1,3,4-thiadiazole (5a-l) and 1,2,4-triazole (6a-l) hybrids to be tested against the H37RV strain of M. tuberculosis. Compounds 5b, 5d, 5e, 5f, 6b, 6c, 6d, and 6f showed good to moderate effectiveness against tuberculosis, with minimum inhibitory concentration (MIC) values ranging from 4 to 64 μg/mL. Compounds 5b and 6b display an MIC value of 4 μg/mL, suggesting significant antitubercular potential and warranting further exploration as effective antitubercular agents. The chemical structures of the synthesized compounds were determined through spectral techniques (Fourier transform infrared (FT-IR), NMR {¹H, ¹³C}, and mass spectroscopy). The molecular docking analysis shows that these compounds can successfully bind to the active site of the five most promising proteins for treating tuberculosis. ADME-T, molecular dynamics (MD) simulation, and Density Functional Theory (DFT) analysis confirm that these compounds have good drug-like properties and remain stable in the binding sites of the selected target proteins. We assessed the cytotoxicity of the chosen compounds. According to the findings, this research thoroughly indicated that these newly created derivatives could serve as promising and effective multitargeted antitubercular agents.