New quinoxaline-based VEGFR-2 inhibitors: design, synthesis, and antiproliferative evaluation with in silico docking, ADMET, toxicity, and DFT studies

• Published in: RSC advances Vol. 11; no. 48; pp. 30315 - 30328
• Main Authors: Alanazi, Mohammed M, Elkady, Hazem, Alsaif, Nawaf A, Obaidullah, Ahmad J, Alkahtani, Hamad M, Alanazi, Manal M, Alharbi, Madhawi A, Eissa, Ibrahim H, Dahab, Mohammed A
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 06.09.2021; The Royal Society of Chemistry
• Subjects: Antiproliferatives; Apoptosis; Cell cycle; Chemical properties; Chemistry; Cytochromes P450; Docking; Inhibitors; Molecular orbitals; Quinoxalines; Toxicity
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/d1ra05925d

A new series of 3-methylquinoxaline-based derivatives having the same essential pharmacophoric features as VEGFR-2 inhibitors have been synthesized and evaluated for their antiproliferative activities against two human cancer cell lines, MCF-7 and HepG-2. Compounds 15b and 17b demonstrated a significant antiproliferative effect with IC ranging from 2.3 to 5.8 μM. An enzymatic assay was carried out for all the tested candidates against VEGFR-2. Compound 17b was the most potent VEGFR-2 inhibitor (IC = 2.7 nM). Mechanistic investigation including cell cycle arrest and apoptosis was performed for compound 17b against HepG-2 cells, and the results revealed that 17b induced cell apoptosis and arrested cell cycle in the G2/M phase. Moreover, apoptosis analyses were conducted for compound 17b to evaluate its apoptotic potential. The results showed upregulation in caspase-3 and caspase-9 levels, and improving the Bax/Bcl-2 ratio by more than 10-fold. Docking studies were performed to determine the possible interaction with the VEGFR-2 active site. Further docking studies were carried out for compound 17b against cytochrome P450 to present such compounds as non-inhibitors. ADMET, toxicity, and physico-chemical properties revealed that most of the synthesized members have acceptable values of drug-likeness. Finally, DFT studies were carried out to calculate the thermodynamic, molecular orbital and electrostatic potential properties.