Design, synthesis, molecular docking, and anticancer activity of benzoxazole derivatives as VEGFR-2 inhibitors.

Novel series of benzoxazoles 4 -16 were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT-116, and MCF-7 cells. HCT-116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 5 was found to be the most potent against HepG2, HCT-116, and MCF-7 with IC  = 4.13 ± 0.2, 6.93 ± 0.3, and 8.67 ± 0.5 µM, respectively. Compounds 5 , 5 , 6 , 5 , and 6 showed the highest anticancer activities against HepG2 cells with IC of 5.93 ± 0.2, 6.58 ± 0.4, 8.10 ± 0.7, 8.75 ± 0.7, and 9.95 ± 0.9 µM, respectively; HCT-116 cells with IC of 7.14 ± 0.4, 9.10 ± 0.8, 7.91 ± 0.6, 9.52 ± 0.5, and 12.48 ± 1.1 µM, respectively; and MCF-7 cells with IC of 8.93 ± 0.6, 10.11 ± 0.9, 12.31 ± 1.0, 9.95 ± 0.8, and 15.70 ± 1.4 µM, respectively, compared with sorafenib as a reference drug with IC of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 5 and 6 were further evaluated for their vascular endothelial growth factor receptor-2 (VEGFR-2) inhibition. Compounds 5 and 5 potently inhibited VEGFR-2 at lower IC values of 0.07 ± 0.01 and 0.08 ± 0.01 µM, respectively, compared with sorafenib (IC  = 0.1 ± 0.02 µM). Compound 5 potently inhibited VEGFR-2 at low IC value (0.10 ± 0.02 µM) equipotent to sorafenib. Our design was based on the essential pharmacophoric features of the VEGFR-2 inhibitor sorafenib. Molecular docking was performed for all compounds to assess their binding pattern and affinity toward the VEGFR-2 active site.