Benzoxazole/benzothiazole-derived VEGFR-2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluations.

A novel series of benzoxazole/benzothiazole derivatives 4a-c-11a-e 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 4c was found to be the most potent derivative against HepG2, HCT-116, and MCF-7 cells, with IC ₅₀ values = 9.45 ± 0.8, 5.76 ± 0.4, and 7.36 ± 0.5 µM, respectively. Compounds 4b, 9f, and 9c showed the highest anticancer activities against HepG2 cells with IC ₅₀ values of 9.97 ± 0.8, 9.99 ± 0.8, and 11.02 ± 1.0 µM, respectively, HCT-116 cells with IC ₅₀ values of 6.99 ± 0.5, 7.44 ± 0.4, and 8.15 ± 0.8 µM, respectively, and MCF-7 cells with IC ₅₀ values of 7.89 ± 0.7, 8.24 ± 0.7, and 9.32 ± 0.7 µM, respectively, in comparison with sorafenib as reference drug with IC ₅₀  values of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 4a-c, 9b,c,e,f,h, and 11c,e were further evaluated for their VEGFR-2 inhibition. Compounds 4c and 4b potently inhibited VEGFR-2 at IC ₅₀ values of 0.12 ± 0.01 and 0.13 ± 0.02 µM, respectively, which are nearly equipotent to the sorafenib IC ₅₀ value (0.10 ± 0.02 µM). Furthermore, molecular docking studies were performed for all synthesized compounds to assess their binding pattern and affinity toward the VEGFR-2 active site.
(© 2019 Deutsche Pharmazeutische Gesellschaft.)