A critical analysis of design, binding pattern and SAR of benzo-fused heteronuclear compounds as VEGFR-2 inhibitors

Abstract

Vascular endothelial growth factors (VEGFs) are a class of homodimeric ligands that bind to their receptors (VEGFRs) to carryout physiological and pathological angiogenesis essential for regulating homeostasis of body. Overexpression of VEGF results in metastasis of benign tumor into malignant tumor. An active role of VEGFR-2 in cancer angiogenesis makes it a major target for cancer therapy. FDA approved VEGFR-2 inhibitors like sorafenib, vemurafenib and dabrafenib, and monoclonal antibodies such as bevacizumab and ramucirumab are available in market but possess side effects like hypertension, CVS disorders, liver damage and adverse effects like Iatrogenicity. Several research groups across the globe have designed and reported varied small molecules from different heteronuclei like quinazoline, pyrimidine, coumarin, pyrazole, indoline, benzimidazole, benzoxazole, etc. as VEGFR-2 inhibitors based on the information available on active site of the receptor, and pharmacophoric features of FDA approved drugs. The present review compiles the information available on benzo-fused heteronuclear compounds including benzimidazole, benzoxazole and benzothiazole in recent years, with emphasis on their design, activity, structure-activity relationship (SAR) and docking analysis for understanding binding interactions in the active site of VEGFR-2. In addition to this, a topological similarity analysis of these compounds is performed taking sorafenib as template, and a comprehensive SAR is proposed for researchers to further explore the anticancer potential of these pharmacophore.

Keywords: Angiogenesis; Anticancer; Benzimidazole; Benzothiazole; Benzoxazole; VEGFR-2.