New quinoxaline-2(1H)-ones as potential VEGFR-2 inhibitors: design, synthesis, molecular docking, ADMET profile and anti-proliferative evaluations

Abstract

Eleven new quinoxaline derivatives were designed and synthesized as modified VEGFR-2 inhibitors of our previous work. The synthesized compounds were tested against three human cancer cell lines (HepG-2, MCF-7 and HCT-116). Compounds 11g, 11e and 11c were the most potent members against the tested cells. Compound 11g (IC₅₀ = 4.50, 2.40, and 5.90 μM) was the most potent member compared to doxorubicin (IC₅₀ = 8.29, 9.65, and 7.68 μM) and sorafenib (IC₅₀ = 7.33, 9.41, and 7.23 μM) against HepG-2 and HCT-116, and MCF-7 cell lines, respectively. Compound 11e showed better anti-proliferative activities than doxorubicin and sorafenib with IC₅₀ values of 5.34, 4.19, and 6.06 μM, against HepG-2 and HCT-116 and MCF-7 cell lines, respectively. In addition, the most active anti-proliferative derivatives 11c, 11e, 11f, and 11g were selected to evaluate their inhibitory activities against VEGFR-2. The tested compounds displayed good inhibitory activity with IC₅₀ values ranging from 0.75 to 1.36 μM. Among them, compound 11g was the most active member with an IC₅₀ value of 0.75 μM, compared to the reference drug; sorafenib (IC₅₀ = 1.29 μM). Moreover, docking studies revealed that the synthesized compounds have good binding patterns against the prospective molecular target; VEGFR-2. In addition, in silico, ADMET and toxicity studies showed a high level of drug likeness for the synthesized compounds.