Synthesis, biological evaluation, and in silico study of novel coumarin-quinazoline analogs as potential Anti-Angiogenesis agents

Abstract

In the current study, a new series of coumarin-quinazoline derivatives was designed and synthesized based on the quinazoline pharmacophore of VEGFR-2 inhibitors. Human umbilical vein endothelial cells (HUVECs) were utilized as the primary endothelial cells in the development of preliminary screening models to identify potential inhibitors of angiogenesis, given their importance in this process. In cytotoxic tests conducted using the MTT assay, compound 13f exhibited significant anti-proliferative potency against HUVECs, with an IC50 value of 20.2 μM, compared to that of sorafenib (12.8 μM). Furthermore, the cell growth inhibition in the MCF-7 (breast cancer cell line) and HT-29 (human colon adenocarcinoma cell line) was explored to investigate the potential anticancer properties. The compounds examined exhibited minimal toxicity on the cancer cell lines in contrast to sorafenib, underscoring the specificity of this framework for HUVECs over cancer cells. The selectivity index of the most potent compound 13f was further evaluated using HU02 cells (human foreskin fibroblast cells of healthy individuals), resulting into greater selectivity for this compound compared to sorafenib. Finally, computational Molecular modelling experiments were performed to enhance understanding of the potential manner in which the target compounds bind to the active sites of VEGFR-2 (PDB code: 4asd), demonstrating encouraging unique interactions within the active site of VEGFR-2.

Keywords

• Angiogenesis
• Coumarin
• Quinazoline
• HUVEC
• VEGFR-2 inhibitor