Novel Phenyl-Triazolo-Thiadiazole Derivatives: Synthesis, Computational Insights and Anti-inflammatory Potential

Abstract

A novel series of phenyl-triazolo-thiadiazole derivatives (6a-m) was designed and synthesised via a stepwise synthetic route starting with benzoic acid. The key transformation involved the cyclo-condensation of 4-amino-3-mercapto-5-phenyl-2,4-dihydro-1,2,4-triazole with appropriately substituted benzoic acids to afford the target compounds. All the synthesised derivatives were subjected to comprehensive in silico evaluation, like molecular docking, toxicity and density functional theory (DFT) studies. Docking analysis demonstrated that compound 6i exhibited greater binding affinity (-9.9 kcal/mol) toward the selected inflammatory target when compared with the reference drug mefenamic acid (-8.0 kcal/mol). Toxicological assessment suggested that the synthesised molecules possess acceptable and comparable safety profiles. DFT calculations indicated that compound 6i displays favourable chemical reactivity, attributed to its moderate electrophilicity index. Furthermore, Molecular dynamics (MD) simulations bear stable protein–ligand interactions for compound 6i, although minor conformational fluctuations were observed, indicating limited dynamic stability. The anti-inflammatory effectivity of compounds 6a-m was further validated through in vivo rat paw edema experiments, where compound 6i emerged as the most active candidate, exhibiting the statistically significant activity (p < 0.01).