Dual Targeting of VEGFR2 and C-Met Kinases via the Design and Synthesis of Substituted 3-(Triazolo-thiadiazin-3-yl)indolin-2-one Derivatives as Angiogenesis Inhibitors.

The vascular endothelial growth factor receptor 2 (VEGFR2) and c-mesenchymal epithelial transition factor (c-Met) are members of receptor tyrosine kinases which have a crucial role in the process of angiogenesis. Isatin moiety is a versatile group that is shared in many compounds targeting both c-Met and VEGFR2 kinases. In this study, we designed and synthesized different derivatives of substituted 3-(triazolo-thiadiazin-3-yl)indolin-2-one derivatives () as dual inhibitors for c-Met and VEGFR2 enzymes. Eight compounds , , , , , , , and were assessed for their anticancer activities against a panel of 58 cancer cell lines according to the US-NCI protocol. Compound revealed the most effective antiproliferative potency (GI %), with broad-spectrum activity against different subpanels of the most NCI 58 tumor cell lines. An in vivo hen's egg-chorioallantoic membrane (HET-CAM) angiogenic study was carried out for 21 compounds , , , , , , , , and to check their mortality and toxicity. At 100 μM concentration, all compounds produced 100% mortality of the chick embryos. At 40 μM concentration, 13 compounds did not exhibit any detectable mortality (nontoxic) and revealed a potent antiangiogenic effect. Seven compounds , , , , , , and significantly decreased the number of blood vessels, and compound was the most effective antiangiogenic agent comparable to dexamethasone. Molecular docking studies were conducted for compound to investigate its mode of interaction within the binding site of both c-Met and VEGFR2 kinases.