Molecular Design and Synthesis of Certain Indazole Derivatives with Potential Anticancer Activity

Abstract

Cancer is one of the major health problems as it is one of the most common causes of death worldwide. Development of targeted anticancer therapy has recently received more attention in order to inhibit some overexpressed molecular targets (enzymes and receptors) that are related to the abnormal nature of cancerous cell. Antiangiogenic therapy was introduced as promising anticancer treatment making use of the continuous need of tumor cell to nutrients and oxygen received through activating certain signalling pathways to provide high micro vessel density. Vascular endothelial growth factor (VEGFa) and its receptor VEGFR-2 are identified as key regulators of angiogenesis. Therefore, inhibition of VEGFR-2 tyrosine kinase (also known as kinase insert domain KDR) through design of small molecule inhibitors was the aim of this study. A novel series of indazole-based compounds was designed, synthesized and biologically evaluated for their antiangiogenic and anticancer activity. The design process was based on comprehensive SAR study of various potent VEGFR-2 kinase inhibitors and supported by a field alignment study using Cresset BMD FieldAlign application.