Antihyperglycemic hydantoin derivative: Design, molecular docking, synthesis, crystal structure, computational studies, pharmacological and toxicological activities

Abstract

The phenytoin-derived compound 2-(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)-N-(4-methoxyphenyl)acetamide referred to as Cpd3, investigated in this paper, was studied using Density Functional Theory (DFT) with the B3LYP method and 6–311++G(d,p) basis set, and its theoretical structure was validated against the experimental one. Frontier Molecular Orbitals (FMOs) analysis determined the energy gap between LUMO and HOMO, while a Molecular Electrostatic Potential (MEP) map identified nucleophilic and electrophilic regions. Hirshfeld Surface (HS) analysis examined intermolecular interactions. Then Molecular docking revealed strong binding affinities for α-glucosidase and α-amylase, with binding energies of -7.2 and -7.8 kcal/mol, respectively. These interactions were stabilized by various bonds, including hydrogen bonds and aromatic interactions. In vitro, the newly synthesized compound was evaluated for its antidiabetic activity against α-glucosidase and α-amylase enzymes and for antioxidant activity by utilizing several tests as DPPH (1, 1-diphenyl-2-picryl hydrazyl), ABTS (2, 2′-azino-bis(3-ethyl benzthiazoline-6-sulfonicacid) and reducing power test (FRAP). Hydrolase enzyme inhibition assays showed potent inhibitory effects, with an IC50 of 43.58 ± 1.02 µM for α-glucosidase and 108.28 ± 1.20 µM for α-amylase, comparable to the standard drug approved Acarbose. These findings suggest Cpd3 as a promising candidate for antihyperglycemic therapy.