Synthesis, anti-proliferative evaluation, DFT, in silico ADME and molecular modeling studies of novel imidazolones as potential EGFR inhibitors

Abstract

A series of novel bromophenyl-substituted imidazolone derivatives were synthesized from (Z)-4-(2-bromobenzylidene)-2-phenyloxazol-5(4H)-one through reactions with various nitrogen nucleophiles. The antiproliferative activities of the synthesized candidates were evaluated against HepG-2 (liver), MCF-7 (breast), and HCT-116 (colon) human cancer cell lines, together with normal WI-38 fibroblasts. Among the tested candidates, the carboethoxy-substituted imidazolone derivative 5 exhibited the most promising anticancer activity, displaying IC50 values of 9.52, 12.39, and 7.32 µM against HepG-2, MCF-7, and HCT-116 cells, respectively, with a good selectivity index (SI = 7.2), markedly exceeding that of doxorubicin. Compound 2 also demonstrated potent cytotoxicity against HepG2 and MCF-7 cells with favorable selectivity. In silico ADME evaluation demonstrated that the majority of the synthesized derivatives complied with Lipinski's Rule of Five and Veber's guidelines, indicating promising oral bioavailability and favorable pharmacokinetic characteristics. Molecular docking studies against epidermal growth factor receptor tyrosine kinase (EGFR-TK, PDB ID: 6V5N) revealed strong binding affinities for the active derivatives, with imidazolone 5 exhibiting the highest docking score (−8.035 kcal mol−1) and forming key interactions with important residues, including LYS745, ASP855, and ARG841. Frontier molecular orbital and molecular electrostatic potential analyses further supported the observed biological activities by revealing favorable electronic properties and reactive sites. Collectively, these findings identify bromophenyl-substituted imidazolone derivatives, particularly compound 5, as promising anticancer lead candidates, while suggesting EGFR as a plausible molecular target.