Based on modulation of the monastrol scaffold, two series of pyrimidinone derivatives, 3a-e and 5a-k, were designed, synthesized, and investigated for their in vitro anticancer activity. Compound 5j exhibited the most potent cytotoxic activity against four cancer cell lines, including HCT-116, HeLa, HEPG-2, and MCF-7, with IC50 values of 3.75-5.13 µM, while proving to be safe in the normal human cell line WI-38, with a selectivity index value of 13.7 on HCT-116 cells. Compounds 3d, 3e, and 5h-j were further assessed for their Eg5 inhibitory activity, where 3d and 5h-j showed high Eg5 inhibition with IC50 values of 28.48, 24.22, 18.90, and 12.89 µM, respectively, when compared to monastrol (IC50 = 14.89 µM). Cell cycle distribution of HCT-116 cells monitored with compound 5j illustrated that the cell cycle was arrested at the G2/M phase, with considerable apoptotic effect. A molecular docking study was performed to investigate the mode of action of the synthesized anticancer agents as Eg5 inhibitors.
Keywords: ADMET; Eg5 inhibitors; anticancer; antimitotic; cell cycle analysis; molecular docking; monastrol; pyrimidinone.
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