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