Design, Synthesis, and Computational Analysis of 4-Amino-1,2,4-Triazol-3-one Schiff Base Derivatives as Potent α-Glucosidase Inhibitors

Type 2 diabetes mellitus (T2DM) remains a major global health challenge, driving the search for novel α-glucosidase inhibitors with improved efficacy and safety profiles over existing therapies. Here, we report the design, synthesis, and biological evaluation of a new series of Schiff bases derived from 4-amino-1,2,4-triazol-3(4H)-one (compounds 1–10) as potential antidiabetic agents. The compounds were synthesized and characterized by ¹ H-NMR and EI-MS, and their α-glucosidase inhibitory activities were assessed in vitro using acarbose as the reference standard. The series exhibited a broad range of potencies, with IC₅₀ values ranging from 10.2 ± 0.19 to 39.4 ± 0.15 µg/mL. Notably, compounds 8 (10.2 ± 0.19 µg/mL) and 10 (11.0 ± 0.68 µg/mL) exhibited significantly stronger inhibition than acarbose (23.0 ± 0.13 µg/mL), while compounds 4 (17.5 ± 0.56 µg/mL) and 5 (18.0 ± 0.41 µg/mL) demonstrated comparable or slightly higher activity. To elucidate structure-activity relationships and potential multitarget antidiabetic profiles, density functional theory (DFT)-optimized geometries were subjected to molecular docking against three validated targets: α-glucosidase (AglA, PDB ID: 10BB), dipeptidyl peptidase-4 (DPP-4, PDB ID: 1NU6), and sodium-glucose cotransporter-2 (SGLT2, PDB ID: 8HDH). Several derivatives, particularly compounds 1 and 7, exhibited binding affinities comparable to or exceeding those of reference ligands acarbose, sitagliptin, and empagliflozin. These ligands formed crucial hydrogen bonds with catalytic residues, including GLU205, ARG125, and TYR631, and engaged in stabilizing π–π stacking interactions, thereby supporting the experimentally observed inhibitory trends. In silico ADMET and drug-likeness analyses using the ADMETSAR 3.0 indicated that the majority of the derivatives comply with Lipinski’s and Veber’s criteria, show favorable lipophilicity (log P 0–3), moderate aqueous solubility (log S > − 4), and low predicted toxicity. Within the series, one candidate displayed the most balanced pharmacokinetic and safety profile, combining high intestinal absorption, acceptable metabolic stability, and low predicted hepatotoxicity. These integrated experimental and computational findings identify 4-amino-1,2,4-triazol-3-one Schiff bases, particularly compounds 8 and 10, as promising lead scaffolds for the development of next-generation oral antidiabetic agents that target α-glucosidase and potentially other clinically relevant enzymes.