Novel 2‐oxo‐2‐phenylethoxy and benzyloxy diaryl urea hybrids as VEGFR‐2 inhibitors: Design, synthesis, and anticancer evaluation

Two series of diaryl urea derivatives, 6a–k and 7a–n, were synthesized. All the newly synthesized compounds were tested against the NCI (US) cancer cell lines via SRB assay. The p-chloro-m-trifluoromethyl phenyl derivatives 6e–g and 7e–g showed the most potent cytotoxic activity with a GI50 value range of 1.2–15.9 µM. Furthermore, the p-fluorobenzyloxy diaryl urea derivative 7g revealed the most potent cytotoxicity against eight cancer cell lines in the MTT assay with IC50 values below 5 µM. Compounds 6a–k and 7a–n were tested for their vascular endothelial growth factor receptor-2 (VEGFR-2) kinase inhibitory activities. The p-chloro-m-trifluoromethyl diaryl urea benzyloxy derivatives 7e–i and the p-methoxydiaryl urea benzyloxy derivatives 7k, 7l, and 7n were found to be the most active compounds as VEGFR-2 inhibitors in the benzyloxy series 7, with an IC50 range of 0.09–4.15 µM. In the 2-oxo-2-phenylethoxy series 6, compounds 6e–g and 6i were reported with IC50 values of 0.94, 0.54, 2.71, and 4.81 µM, respectively. Moreover, compounds 7e and 7g induced apoptosis, causing cell cycle arrest in the G2/M phase. In addition, 7g showed an antimigratory effect in A-375 cells and inhibited the VEGFR-2 expression in an immunohistofluorescence study. Molecular docking simulations on VEGFR-2 as well as ADME properties prediction were also performed.