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 IC50 values = 9.45 +/- 0.8, 5.76 +/- 0.4, and 7.36 +/- 0.5 microM, respectively. Compounds 4b, 9f, and 9c showed the highest anticancer activities against HepG2 cells with IC50 values of 9.97 +/- 0.8, 9.99 +/- 0.8, and 11.02 +/- 1.0 microM, respectively, HCT-116 cells with IC50 values of 6.99 +/- 0.5, 7.44 +/- 0.4, and 8.15 +/- 0.8 microM, respectively, and MCF-7 cells with IC50 values of 7.89 +/- 0.7, 8.24 +/- 0.7, and 9.32 +/- 0.7 microM, respectively, in comparison with sorafenib as reference drug with IC50 values of 9.18 +/- 0.6, 5.47 +/- 0.3, and 7.26 +/- 0.3 microM, 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 IC50 values of 0.12 +/- 0.01 and 0.13 +/- 0.02 microM, respectively, which are nearly equipotent to the sorafenib IC50 value (0.10 +/- 0.02 microM). Furthermore, molecular docking studies were performed for all synthesized compounds to assess their binding pattern and affinity toward the VEGFR-2 active site.