New quinoxaline-based VEGFR-2 inhibitors: design,synthesis, and antiproliferative evaluation with in silico docking,ADMET, toxicity,and DFT studies |
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Authors: | 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 |
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Institution: | Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11541 Saudi Arabia ; Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884 Egypt, |
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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.A new series of 3-methylquinoxaline-based derivatives having the same pharmacophoric features of VEGFR-2 inhibitors have been synthesized and evaluated for their antiproliferative activities against MCF-7 and HepG-2 cells. |
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