Computational Insights into Imidazole‐Phenazine Derivatives as Potential α‐Glucosidase Inhibitors: Docking, Dynamics, Free Energy, and Quantum Studies

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by sustained hyperglycemia caused by impaired insulin secretion, insulin resistance, or both. Although drugs such as metformin, acarbose, and linagliptin are widely prescribed, their therapeutic performance is often constrained by gastrointestinal side effects and inadequate glycemic control. To address this limitation, thirteen novel imidazole‐phenazine derivatives (IPDs) were examined as potential α‐glucosidase inhibitors using integrated in‐silico approaches. Molecular docking results indicated that compound‐6 (−10.2 kcal/mol) and compound‐9 (−9.8 kcal/mol) displayed stronger binding affinities than the reference drug voglibose (−7.6 kcal/mol), forming stable hydrogen bonds with key catalytic residues Asp214, Glu276, and Asp349. Binding free energy calculations (MM/GBSA) further supported these findings, with ΔGbind values of −63.4 and −61.7 kcal/mol for compound‐6 and compound‐9, respectively, compared to −49.2 kcal/mol for voglibose. Molecular dynamics simulations (100 ns) confirmed the structural stability of these complexes, maintaining RMSD within 2.1–2.4 Å and stable hydrogen‐bond interactions. Additionally, density functional theory (DFT) analysis revealed lower band gaps (1.24 and 1.69 eV) and higher softness and electrophilicity than voglibose, indicating favorable electronic reactivity. Collectively, these results suggest that compound‐6 and compound‐9 are promising α‐glucosidase inhibitor candidates, meriting further in‐vitro and in‐vivo validation for T2DM therapy.