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 K i 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.