Design, synthesis, and antitumor activity of novel benzoheterocycle derivatives as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase

Abstract

The vascular endothelial growth factor receptor-2 signaling pathway promotes the formation of new blood vessels, and vascular endothelial growth factor receptor-2 tyrosine kinase exists in both active and inactive conformations. Novel indole–benzimidazole and indole–benzothiazole derivatives joined by different linkers are designed and synthesized as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. All the synthesized compounds were evaluated for their cytotoxicity against four human cancer cell lines (HeLa, HT29, A549, and MDA-MB-435) and human umbilical vein endothelial cell. Meanwhile, the inhibitory activities against vascular endothelial growth factor receptor-2 are estimated in vitro and the binding interactions with dual conformations of vascular endothelial growth factor receptor-2 tyrosine kinase are evaluated by molecular docking. Compounds 5a–c and 14 show inhibitory activity against vascular endothelial growth factor receptor-2 tyrosine kinase and promising cytotoxicity, specifically with IC50 values ranging between 0.1 and 1 μM, which imply broad-spectrum antitumor activity. These results provide a deep insight into potential structural modifications for developing potent vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors.

Benzimidazole hybrids as anticancer drugs: An updated review on anticancer properties, structure–activity relationship, and mechanisms of action (2019–2021)

“…Further study indicated that introduction of the linker between benzimidazole and indole moieties was permitted and the ester tethered hybrids 36 (IC 50 : 0.2-0.6 µM, MTT assay) and 37 (IC 50 : 0.2-0.6 µM, MTT assay) were comparable to SU11248 (IC 50 : 0.1-0.4 µM) against HeLa, HT-29, A549, HUVEC, and MDA-MB-435 cancer cell lines. [81,82] The mechanistic studies demonstrated that one of the pathways of antiproliferative action was to inhibit VEGFR-2 TK activity.…”

New benzimidazole‐oxadiazole derivatives as potent VEGFR‐2 inhibitors: Synthesis, anticancer evaluation, and docking study

“…There are many studies in the literature regarding the VEGFR‐2 inhibition of benzimidazoles (Abd El‐Lateef et al, 2023a; Abdel‐Mohsen et al, 2020a; Ali et al, 2022; Ding et al, 2020; Mostafa et al, 2019; Tong et al, 2021; Yuan et al, 2019). In 2023, a new series of Schiff base‐benzimidazole hybrids has been developed and synthesized by Abd El‐Lateef et al (2023a, 2023b).…”