Novel 5-arylidene-3-(substituted phenyl)-2-(p-tolylamino)-3,5-dihydro-4H-imidazol-4-ones 9a-f were designed and synthesized based on a thioxoimidazolidinone derivative (I) that has been reported to have cytotoxicity with topoisomerase I inhibition. The synthesized compounds were evaluated in vitro for their cytotoxicity against prostate cancer (PC-3) and breast cancer (MCF-7) cell lines along with normal lung fibroblast cell line (WI-38). Regarding PC-3, compounds 9b-f showed potent selective cytotoxicity with IC50 range (28-68 nmol/ml). While for MCF-7, 9b, 9d-f possessed potent selective cytotoxicity with IC50 range (34-82 nmol/ml). Compound (9b) emerged as the most potent analogue against both PC-3 and MCF-7 cells, with IC50 = 28 and 34 nmol/ml, respectively. While, compound (9e) is the second most potent against both PC-3 and MCF-7 cells, with IC50 = 33 and 36 nmol/ml and also is the most selective one against both cancer cell lines with Selectivity index = 4.15 and 3.80, respectively. Moreover, the docking results of 9b, e against topo I (PDB: 1SC7) versus compound (I) and (VI) were consistent with the cytotoxicity results and revealed that they bound to topo I in a similar manner with docking scores = -28.018 and -28.1490 kcal/mol, respectively suggesting their use as lead compounds for developing topo I inhibitors.
Key words: 4-imidazolones, cytotoxicity, prostate cancer, breast cancer, topoisomerase I.
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