Computer-aided molecular engineering of novel imidazolone-chalcone conjugates as antidiabetic agent: synthesis, molecular docking, DFT study, enzyme kinetics and ADME profiling.

This study aimed to identify potent drug candidates against diabetes mellitus (DM), particularly through inhibition of the key carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase. For this purpose, a series of novel imidazolone-based chalcone derivatives was synthesized through an efficient and rapid synthetic route. The synthesized analogues were initially monitored and confirmed by thin-layer chromatography (TLC). Their structural characteristics were established using 1H NMR and 13C NMR spectroscopy, while high-resolution electron ionization mass spectrometry (HREI-MS) was employed to determine their accurate molecular masses. The synthesized analogues were evaluated for their inhibitory potential against α-amylase and α-glucosidase, and their activities were compared with the standard inhibitor acarbose. Among the synthesized compounds, analogue 5 exhibited the highest inhibitory activity, with IC₅₀ values of 6.80 ± 0.10 µM against α-amylase and 7.10 ± 0.30 µM against α-glucosidase. Enzyme kinetic studies were subsequently performed at different substrate and inhibitor concentrations to investigate the mode and mechanism of enzyme inhibition. To further elucidate the protein-ligand interactions, the most potent analogues were subjected to molecular docking and pharmacophore modeling, which provided insights into their binding orientations and key interactions with active-site amino acid residues. Molecular dynamics (MD) simulations were additionally performed to investigate the stability and dynamic behavior of the selected protein-ligand complexes. Furthermore, density functional theory (DFT) calculations and ADMET analyses were conducted to examine the electronic properties, molecular electrostatic potential, and drug-like and pharmacokinetic characteristics of the potent analogues. Collectively, these experimental and computational investigations provided comprehensive insights into the antidiabetic potential and molecular characteristics of the synthesized imidazolone-based chalcone derivatives.