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

Mohammed M. Alanazi, Hazem Elkady, Nawaf A. Alsaif, Ahmad J. Obaidullah, Hamad M. Alkahtani, Manal M. Alanazi, Madhawi A. Alharbi, Ibrahim H. Eissa, Mohammed A. Dahab

Research output: Contribution to journalJournal articlepeer-review

1 Scopus citations

Abstract

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 IC50 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 (IC50 = 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. In silico 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.

Original languageEnglish
Pages (from-to)30315-30328
Number of pages14
JournalRSC Advances
Volume11
Issue number48
DOIs
StatePublished - 12 Sep 2021
Externally publishedYes

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