Exploring 1,3,4-oxadiazolyl sulfide derivatives as antidiabetic candidates: synthesis, antioxidant activity, SAR-study, molecular docking, and DFT-insights

Abstract 1,3,4-Oxadiazoles are a vital class of heterocyclic compounds known for their diverse biological activities. In this study, a series of eight novel 1,3,4-oxadiazolyl sulfide derivatives 4a – h were synthesized and characterized using IR, NMR, and elemental analysis. The antioxidant activity of these derivatives was evaluated via DPPH and ABTS assays, revealing promising radical scavenging capabilities Compound 4 h emerged as the most potent antioxidant with SC 50 values of 9.88 µM (ABTS) and 12.34 µM (DPPH), outperforming standard antioxidants surpassing standard antioxidants such as ascorbic acid (SC₅₀ = 23.92 µM) and gallic acid (SC₅₀ = 21.24 µM). The impact of electron-donating and electron-withdrawing substituents on activity was demonstrated through a comprehensive structure-activity relationship (SAR) study. Molecular docking against α -glucosidase (PDB: 3W37) validated the potential of these compounds as enzyme inhibitors, with docking scores ranging from − 8.59 to -9.81 kcal/mol and similar modes of binding. Insights into electronic properties were obtained through density functional theory (DFT) calculations, emphasizing that compound with the lowest HOMO–LUMO energy gaps ( 4b ) exhibited higher polarizability and enhanced reactivity, which correlates with their biological antioxidant performance. This integrated study underscores the therapeutic potential of these derivatives as antioxidants and enzyme inhibitors, offering paths for further drug development.