Integrative Experimental Paradigm of Oxadiazole-Schiff Base Hybrids: Pharmacophore-Driven Docking Simulations and DFT...

Diabetes mellitus and gastrointestinal infections remain major global health concerns, contributing to high morbidity, mortality, and economic burden. To address these challenges, a series of oxadiazole-bearing imine scaffolds were designed and synthesized as dual α-glucosidase and urease inhibitors. Among them, compound 5 (IC₅₀ = 5.30 ± 0.20 μM for α-glucosidase; 8.60 ± 0.30 μM for urease) and compound 6 (IC₅₀ = 3.80 ± 0.60 μM; 5.20 ± 0.40 μM) exhibited the most potent inhibitory activity. The in vitro potential of these compounds was compared with the standard compounds urease (IC₅₀ = 12.20 ± 0.21 μM) and acarbose (IC₅₀ = 10.30 ± 1.10 μM). All compounds were synthesized and characterized using ¹H NMR, ¹³C NMR, and HREI-MS. In silico studies, including molecular docking, revealed strong binding interactions between the active molecules and target enzymes. Density Functional Theory (DFT) analysis provided insights into electronic characteristics such as HOMO-LUMO energy gaps and reactive molecular regions, while ADMET profiling confirmed favorable drug-likeness. Pharmacophore modeling of compound 6 highlighted critical hydrogen-bonding interactions, and molecular dynamics simulations further validated the stability and affinity of the protein-ligand complexes. Collectively, these findings suggest that the synthesized oxadiazole derivatives are promising dual inhibitors with potential therapeutic relevance in diabetes and gastrointestinal infections.