Design, synthesis, and cytotoxic evaluation of new thiosemicarbazone/thiazolidin-4-one derivatives on PC3 cells.

[AIM] To design, synthesize, and evaluate a series of thiosemicarbazone and thiazolidin-4-one hybrids bearing arylsulfonate groups as potential androgen receptor-targeted anticancer agents.

[MATERIALS AND METHODS] The compounds were synthesized via sequential sulfonylation, thiosemicarbazone formation, and cyclization to thiazolidin-4-ones. The structures of the compounds were characterized using NMR (H and C), FTIR, and HRMS spectroscopic techniques. cytotoxicity was assessed against prostate cancer (PC3) and human umbilical vein endothelial cell lines (HUVEC) using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Molecular docking and MM-GBSA calculations were performed to predict binding affinities toward the androgen receptor. Molecular dynamics simulations (250 ns) were conducted to evaluate the stability and dynamics of the ligand - protein complexes.

[RESULTS] Thiazolidin-4-one derivatives, particularly compound 9, exhibited potent cytotoxicity (IC = 6.35 µM) and high selectivity (SI = 6.05) over HUVEC cells. Docking and MM-GBSA analyses revealed strong interactions with key residues His-874, Met-742, Trp-741, and Arg-752. MD simulations confirmed minimal deviation from the docking pose (0.75 Å), low RMSD/RMSF values, and persistent hydrogen-bonding networks, supporting the structural stability and binding affinity observed . Structure-activity relationship (SAR) analysis indicated that scaffold cyclization and appropriate arylsulfonate substitution enhance receptor engagement and selectivity.

[CONCLUSIONS] The combined synthetic, computational, and biological results demonstrate that thiazolidin-4-one-based hybrids, particularly compound 9, are promising selective androgen receptor-targeted anticancer agents, warranting further optimization and development.