Enantioselective synthesis and evaluation of 4-styryldihydropyrimidin-2-thiones as anti-proliferative agents

A series of novel chiral 4-styryldihydropyrimidin-2-thiones were prepared with high yields and enantioselective by a Biginelli reaction. In the condensation reaction, substituted cinnamaldehyde, thiourea, and β-ketoester were organocatalyzed to afford 4-styryldihydropyrimidin-2-thiones 4a–v using self-assembled methanoproline-thiourea as catalysts. Anti-proliferative activity of these 4-styryldihydropyrimidin-2-thiones was tested against the HepG2 and PC-3 cells. Among all the tested compounds, 4e, 4k, and 4s bearing CF3- groups at styryl group displayed moderate anti-proliferative activity with IC50 ranged between 29.3–38.5 μM. The structure–activity relationship showed that substituents (R1) on the C-4 styryl ring of 4-styryldihydropyrimidin-2-thiones and R3 at ester group affected the anti-proliferative activity, yet R2 at C-6 position had little influence for anti-proliferative activity.