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

<b>Background/Objective:</b> Cancer is the leading cause of death worldwide despite the diversity of antitumor therapies, which highlights the necessity to explore new anticancer agents. <b>Methods:</b> We synthesized 5,5-diphenylhydantoin derivatives including Schiff's bases <b>7</b>-<b>27</b> and evaluated their cytotoxicity via the MTT assay. Enzymatic inhibition assays, cell cycle and apoptosis analyses, and molecular docking studies were also conducted. <b>Results</b>: Derivative <b>24</b> 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 <b>10</b>, <b>13</b>, and <b>21</b> 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 <b>24</b> 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 <b>24</b> 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 <b>24</b> and the active sites of EGFR and HER2, which are similar to the co-crystallized inhibitors, were investigated using a molecular docking approach. <b>Conclusions</b>: These findings provide insights into the potential anticancer activities of the synthesized derivatives for further optimization to achieve therapeutic use.