Synthesis of imidazole derivatives and in silico/in vitro evaluation of potential antidiabetic activity

Abstract

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia due to insulin resistance or deficiency. The imidazole scaffold, a privileged heterocycle in medicinal chemistry, has shown significant promise in targeting key enzymes involved in type 2 DM (T2DM). In this study, eight novel imidazole derivatives were designed, synthesized, and structurally characterized using 1H NMR, 13C NMR, and mass spectrometry. Molecular docking studies against α-amylase and α-glucosidase revealed favourable binding affinities (−7.2 to −8.8 kcal/mol) and strong interactions with key catalytic residues. ADMET predictions using ADMET Lab 3.0 and SwissADME indicated good drug-likeness for most derivatives, and the top docking hit was subjected to a 100 ns molecular dynamics simulation (Desmond), which confirmed complex stability with minimal RMSD fluctuations (~1.8 Å) and persistent hydrogen bonding. In vitro α-amylase inhibition assays demonstrated potent activity, with compound SM-04 exhibiting an IC₅₀ of 21.5 ± 1.2 μM, comparable to the reference drug acarbose (18.9 ± 1.4 μM). MTT assays on 3T3-L1 cells indicated low cytotoxicity for all compounds. Overall, the synthesized imidazole derivatives displayed promising in silico and in vitro antidiabetic potential, supporting their development as leads for T2DM therapy.