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New Coumarin Derivatives as Anti‐Breast and Anti‐Cervical Cancer Agents Targeting VEGFR‐2 and p38α MAPK

Breast and cervical cancers are the most common gender‐specific cancers affecting women worldwide. In this investigation, we highlighted the synthesis, VEGFR‐2 and p38α MAPK inhibitory activity of new series of fluorinated coumarin‐based derivatives featuring a variety of bioactive chemical moieties attached or fused to the coumarin nucleus at the 3 and/or 4 position. The bioactive inhibitors were further assessed for their anti‐proliferative effect against human MCF‐7 breast cancer and HeLa cervical cancer cell lines, respectively. Most of the tested compounds showed potent preferential inhibition effects against human VEGFR‐2 and remarkable anticancer activities in the human breast cancer cell line MCF‐7. Compounds 29, 24, and 2 displayed the highest inhibitory activity against VEGFR‐2 (94% inhibition) and they were the most potent anticancer agents toward MCF‐7 cancer cells with IC50 values of 7.90, 8.28, and 8.30 μg/mL, respectively. Compound 13 inhibited p38α MAPK phosphorylation with a significant reduction in % cell viability against HeLa cancer cells at 10 and 30 µM. Docking experiments carried out on VEGFR‐2 and p38 MAPK crystallographic structures revealed that the active compounds bind to the active sites through H‐bonds, arene–cation, and hydrophobic π–π interactions. QSAR analysis demonstrated considerable correlation coefficient (R2 = 0.76969) and root mean square error (RMSE = 0.10446) values. Also, the residual values between the experimental pIC50 and predicted pIC50 are very close, indicating the reliability of the established QSAR model.