Novel diazene-tri(phenoxy-1,2,3-triazole-acetamide) derivatives as potent α-glucosidase inhibitors: synthesis, biological evaluation, and in silico studies
α-Glucosidase is a key therapeutic target for treating type 2 diabetes mellitus. A new series of novel diazene-tri(phenoxy-1,2,3-triazole-acetamide) derivatives 9a–p was designed by hybridizing previously reported potent α-glucosidase inhibitors. The target compounds were successfully synthesized and structurally characterized by 1H NMR, 13C NMR, and elemental analysis. All synthesized compounds were evaluated for their anti-α-glucosidase efficacy and exhibited excellent inhibitory effects, with IC50 values ranging from 0.10 to 10.9 µM, which are approximately 69- to 7500-fold more potent than the reference drug acarbose (IC50 = 750.0 µM). Among this series, compound 9f showed the most potent activity. Kinetic enzyme assays revealed that compound 9f acts as a competitive inhibitor of α-glucosidase, competing with the natural substrate for binding to the active site, with a Ki value of 100 nM. To gain mechanistic insight into the binding mode and the stability of the inhibitor–enzyme complex, molecular docking and molecular dynamics (MD) simulations were performed for compound 9f in the α-glucosidase active site. Furthermore, pharmacokinetic predictions using SwissADME and admetSAR showed that compound 9f exhibits a bioavailability radar and drug-likeness profile similar to that of acarbose. Based on the promising in vitro and in silico results, compound 9f represents a valuable lead compound for further structural optimization and development of efficient and potent new α-glucosidase inhibitors.