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

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

The compounds were synthesized via sequential sulfonylation, thiosemicarbazone formation, and cyclization to thiazolidin-4-ones. The structures of the compounds were characterized using NMR (¹H and ¹³C), FTIR, and HRMS spectroscopic techniques. In vitro 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.

Thiazolidin-4-one derivatives, particularly compound 9, exhibited potent cytotoxicity (IC₅₀ = 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 in vitro. Structure-activity relationship (SAR) analysis indicated that scaffold cyclization and appropriate arylsulfonate substitution enhance receptor engagement and selectivity.

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.