Design, Synthesis, In Vitro Cytotoxicity, and Molecular Docking of Novel 2-Thioxoimidazolidin-4-one Derivatives

Objective: A novel series of 2-thioxoimidazolidin-4-one derivatives (T1A–K4A) was efficiently synthesized via a convergent multi-step approach involving the preparation of substituted maleimides from maleic anhydride, intermediate hydrazide formation, and subsequent cyclo-condensation with functionalized isothiocyanates. Methods: The chemical structures of all target compounds were rigorously confirmed using FT-IR, 1H, 13C NMR, and mass spectrometry. The in vitro cytotoxicity was evaluated against human prostate cancer cells (PC-3) using the colorimetric MTT assay. Apoptosis induction was quantified via Annexin V-FITC/PI flow cytometry, and molecular docking simulations were performed targeting the androgen receptor (PDB ID: 2PNU). Results and Discussion: Compounds T1B and T4B exhibited the most potent cytotoxic profiles, displaying IC50 values of 3.80 and 5.65 µM, respectively. Flow cytometric analysis demonstrated that both lead compounds significantly induce apoptosis, increasing late apoptotic populations to 0.29% (T1B) and 1.36% (T4B) relative to the untreated control (0.096%). Furthermore, molecular docking studies revealed a strong binding affinity for T4B (−11.95 kcal/mol), driven by key hydrogen bonding with Arg752 and critical hydrophobic interactions with Trp741 and Phe764. Conclusions: These findings highlight these newly synthesized 2-thiohydantoin derivatives as promising scaffolds for the development of advanced therapeutic agents against prostate cancer.