Synthesis and In Vitro/In Silico α-Glucosidase Inhibitory Study of Novel Ethanones Containing Naphthalene-Linked 1,2,4-Triazole

Type 2 diabetes mellitus is a chronic-metabolic disorder characterized by insulin resistance, resulting in persistent hyperglycemia and severe complications. α-Glucosidase inhibitors (AGIs) effectively control postprandial blood glucose level by delaying carbohydrate digestion. This study reports the synthesis of novel naphthalene-linked 1,2,4-triazole-bearing ethanones (5a–e and 7a–f) as potential AGIs. Enzymatic assay demonstrated significantly superior α-glucosidase inhibitory potency of aryl-substituted derivatives (7a−f) compared to ethyl-substituted analogs (5a−e), highlighting the advance of aromatic substituents. Compounds 7b and 7c exhibited exceptional inhibitory activity (IC₅₀ = 9.23–9.61 μM), conferring 37-fold more potency than voglibose. Molecular docking and dynamics simulations indicated predominant π-π stacking and hydrophobic interactions contributing to their stable enzyme binding. MM/GBSA binding-affinity calculation further supported their enhanced binding affinity, providing mechanistic insights into their potent activity. Collectively, these findings highlight the promise of naphthalene- and 1,2,4-triazole-bearing ethanones for the development of effective antidiabetic therapies.