Design, synthesis, and in vitro/in vivo evaluation of novel diphenyl-1,2,4-triazine-3-yl-thioacetamide-chalcone hybrids as potent α-glucosidase inhibitors targeting type 2 diabetes.

A novel series of 5,6-diphenyl-1,2,4-triazine-3-yl-thioacetamide-chalcone hybrids (9a-n) was designed, synthesized, and evaluated for their antidiabetic potential. All derivatives exhibited potent in vitro α-glucosidase inhibitory activity (IC50 = 0.2-112 μM) compared with acarbose (IC50 = 750.0 μM). The most potent compound, 9b (IC50 = 0.2 μM), acted as a competitive inhibitor with a Ki value of 200 nM and demonstrated significant glucose-lowering activity in a zebrafish model. In addition, compound 9b effectively inhibited bovine serum albumin (BSA) glycation relative to aminoguanidine. Molecular docking and molecular dynamics revealed stable binding of compound 9b within the α-glucosidase active site, with a binding energy of -9.2 kcal/mol, compared with -4.04 kcal/mol for acarbose. According to the in silico ADMET analysis, compound 9b showed oral bioavailability comparable to acarbose, together with improved drug-like properties. Overall, these findings identify compound 9b as a promising lead α-glucosidase inhibitor with potent in vitro and in vivo antihyperglycemic activity, warranting further investigation for the treatment of type 2 diabetes.