Abstract
Novel 2-indolinone thiazole hybrids were designed and synthesized as VEGFR-2 inhibitors based on sunitinib, an FDA-approved anticancer drug. The proposed structures of the prepared 2-indolinone thiazole hybrids were confirmed based on their spectral data and CHN analyses. The target compounds were screened in vitro for their anti-VEGFR-2 activity. All tested compounds exhibited a potent submicromolar inhibition of VEGFR-2 kinase with IC50 values ranging from 0.067 to 0.422 μM, relative to sunitinib reference drug (IC50 = 0.075 ± 0.002 μM). Compounds 5, 15a, 15b, 17, 19c displayed excellent VEGFR-2 inhibitory activity, comparable or nearly equipotent to sunitinib. Compound 13b stood out as the most potent against VEGFR-2 showing IC50 value of 0.067 ± 0.002 μM, lower than that of sunitinib. In addition, the most potent derivatives were assessed for their anticancer activity against two renal cancer cell lines. Compound 13b (IC50 = 3.9 ± 0.13 μM) was more potent than sunitinib (IC50 = 4.93 ± 0.16 μM) against CAKI-1 cell line. Moreover, thiazole 15b displayed excellent anticancer activity against CAKI-1 cell line (IC50 = 3.31 ± 0.11 μM), superior to that of sunitinib (IC50 = 4.93 ± 0.16 μM). Thiazole 15b was also equipotent to sunitinib (IC50 = 1.23 ± 0.04 μM) against A498 cell line. Besides, compound 15b revealed a safety profile much better than that of sunitinib against normal human renal cells. Furthermore, a docking study revealed a proper fitting of the most active compounds into the ATP binding site of VEGFR-2, rationalizing their potent anti-VEGFR-2 activity.
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•Novel 2-indolinone thiazole hybrids were synthesized as VEGFR-2 inhibitors.•Compounds 5, 15a, 15b, 17, 19c displayed excellent VEGFR-2 inhibitory activity.•Compound 13b (IC50 = 3.9 ± 0.13 μM) was more potent than sunitinib (IC50 = 4.93 ± 0.16 μM) against CAKI-1 cell line.•Thiazole 15b was also equipotent to sunitinib (IC50 = 1.23 ± 0.04 μM) against A498 cell line.•The most active compounds were docked into the ATP binding site of VEGFR-2.