Synthesis, Molecular Docking, and Biological Evaluation of 2,3-Diphenylquinoxaline Derivatives as a Tubulin's Colchicine Binding Site Inhibitor Based on Primary Virtual Screening.

Abstract

Tubulin inhibitors have proved to be a promising treatment against cancer. Tubulin inhibitors target different areas in microtubule structure to exert their effects. The colchicine binding site (CBS) is one of them for which there is no FDA-approved drug yet. This makes CBS a desirable target for drug design. Primary virtual screening is done by developing a possible pharmacophore model of colchicine binding site inhibitors of tubulins, and 2,3-diphenylquinoxaline is chosen as a lead compound to synthesis. In this study, 28 derivatives of 2,3-diphenylquinoxalines are synthesized, and their cytotoxicity is evaluated by the MTT assay in different human cancer cell lines, including AGS (Adenocarcinoma gastric cell line), HT-29 (Human colorectal adenocarcinoma cell line), NIH3T3 (Fibroblast cell line), and MCF-7 (Human breast cancer cell). Furthermore, the activity of the studied compounds was investigated using computational methods involving molecular docking of the 2,3-diphenylquinoxaline derivatives to β-tubulin. The results showed that the compounds with electron donor functionalities in positions 2 and 3 and electron-withdrawing groups in position 6 are the most active tubulin inhibitors. Apart from the high activity of the synthesized compounds, the advantage of this report is the ease of the synthesis, work-up, and isolation of the products in safe, effective, and high-quality isolated yields.