Synthesis, Antitumor Activities, and Apoptosis-Inducing Activities of Schiff’s Bases Incorporating Imidazolidine-2,4-dione Scaffold: Molecular Docking Studies and Enzymatic Inhibition Activities

Abstract

Background/Objective: Cancer is the leading cause of death worldwide despite the diversity of antitumor therapies, which highlights the necessity to explore new anticancer agents. Methods: We synthesized 5,5-diphenylhydantoin derivatives including Schiff’s bases 7–27 and evaluated their cytotoxicity via the MTT assay. Enzymatic inhibition assays, cell cycle and apoptosis analyses, and molecular docking studies were also conducted. Results: Derivative 24 demonstrated the highest cytotoxic activity, with IC50 values of 12.83 ± 0.9 μM, 9.07 ± 0.8 μM, and 4.92 ± 0.3 μM against the cell lines HCT-116, HePG-2, and MCF-7, respectively. Compounds 10, 13, and 21 showed potent antitumor activities versus the examined cell lines (average IC50 = 13.2, 14.5, and 13.1 μM), respectively; moreover, these compounds also demonstrated promising EGFR and HER2 inhibitory activities, with IC50 values in the range 0.28–1.61 µM. Derivative 24 displayed the highest EGFR and HER2 inhibitory activity values (IC50 = 0.07 and 0.04 µM), respectively, which were close to those of the reference drugs erlotinib and lapatinib. Therefore, compound 24 was selected for further examinations and exhibited an inducing effect on apoptosis via diminishing the anti-apoptotic protein levels of BCL-2 (8.598 ± 0.29 ng/mL) and MCL-1 (261.20 ± 8.97 pg/mL) and promoting cell cycle arrest at the G2/M phase (33.46%). The binding relationships between compound 24 and the active sites of EGFR and HER2, which are similar to the co-crystallized inhibitors, were investigated using a molecular docking approach. Conclusions: These findings provide insights into the potential anticancer activities of the synthesized derivatives for further optimization to achieve therapeutic use.