Synthesis, spectroscopic characterization and computational evaluation of 2-alkylthio imidazol-4-one derivatives as potential CDK5 inhibitors

The compounds 2(b-d) of 2-thiohydantoin derivative were synthesized via an S-alkylation reaction, following an aniline-based transamination step. The synthesized compounds were characterized and structurally validated using NMR analysis. Computational methods, including Density Functional Theory (DFT), Molecular Docking, and Molecular Dynamics simulations, were applied to explore their chemical properties. According to DFT calculations, the compounds’ HOMO-LUMO gap energies ranged from 3.632 to 3.861 eV, with compound 2b being the most reactive and 2c the most stable. Electrostatic surface potential maps revealed electrophilic behavior in the carbonyl groups and electropositive behavior in the amino groups. Molecular docking studies demonstrated strong binding interactions between the CDK5 protein and compound 2d , having the affinity of (− 8.040 kcal/mol). Additionally, compound 2d displayed favorable druglikeness, with high gastrointestinal absorption and a low likelihood of crossing the blood-brain barrier (BBB). According to molecular dynamics simulations of compounds 2b, 2c, and 2d, compound 2d showed the most stable association with the protein.