Design, Synthesis, Molecular Docking, and Anticancer Activity of Chalcone Derivatives as VEGFR-2 Inhibitors

A series of 4-phenylurea chalcones (<b>2a</b>-<b>2s</b>) as VEGFR-2 inhibitors has been designed, synthesized, and evaluated for in vitro cytotoxic activity against K562, SiHa, and B16 cancer cells. Compared to sorafenib, the compounds exhibited strong cytotoxicity against K562, SiHa and B16 cells. Compounds <b>2r</b>, <b>2o</b>, and <b>2l</b> exhibited remarkable cytotoxicity against K562, SiHa, and B16 cells, with IC₅₀ values of 0.97 μM, 1.22 μM, and 1.39 μM, respectively. Moreover, compound <b>2l</b> exhibited potent cytotoxicity against K562, SiHa, and B16, with IC₅₀ values ranging from 1.25 μM to 1.39 μM. Compounds <b>2l</b> and <b>2o</b> also exhibited excellent inhibitory activity on VEGFR-2 kinase, with IC₅₀ values of 0.42 ± 0.03 and 0.31 ± 0.02 μM, respectively. Molecular docking proved that the target compounds had strong binding interactions with VEGFR-2 proteins. Flow cytometry analysis showed that compound <b>2l</b> induced apoptosis and arrested the cell cycle at the G1 and S phases.