Design, synthesis and biological evaluation of novel thiohydantoin derivatives as antiproliferative agents: A combined experimental and theoretical assessments

Abstract In our endeavors to develop potent anticancer agents, novel two series of 3,5-disubstituted-2-thiohydantoins 5a–c and the S-methyl counterparts 6a–c were designed and synthesized. The structural modifications were based on some reported thiohydantoins derivatives which showed promising antiproliferative activity. The activity of the compounds was verified via the in vitro cytotoxicity assay against prostate (PC-3) and breast (MCF-7) cancer cell lines along with normal lung fibroblast cell line (WI-38) to determine their safety on the normal cells. The tested compounds 5a–c and 6a–c showed promising cytotoxicity with IC50 ranges from 1.980 to 19.089 µM and from 1.619 to 16.976 µM against PC-3 and MCF-7, respectively. Interestingly, compound 6c is the most potent derivative against both PC-3 and MCF-7 (IC50 = 1.980 and 1.619 µM, respectively). Compound 5c is the second most potent derivative against PC-3 and MCF-7(IC50 = 2.385 and 2.084 µM, respectively). The antiproliferative activities on the normal lung fibroblast cell line (WI-38) implied that the most potent cytotoxic derivatives 5c and 6c are safe on the healthy cells. The docking solutions of 5c and 6c into the active site of TOP1 inferred comparable binding interactions to the co-crystallized ligand with docking scores = - 6.859 and 6.939 Kcal/mol, respectively. The computational studies using DFT calculations with B3LYP/6-31+G (d,p) level were performed to study the electronic and geometric properties obtained from the stable structure of the investigated compounds. A good correlation was found between the quantum chemical parameters and experimental observations. Therefore, these promising thiohydantoins can be subjected for further optimization to develop more potent counterparts.