Abstract
A new series of bis([1,2,4]triazolo)[4,3-a:3',4' -c]quinoxaline derivatives were designed and synthesized to have the main essential pharmacophoric features of VEGFR-2 inhibitors. VEGFR-2 inhibitory activities were assessed for the designed compounds. In addition, cytotoxic activity was evaluated for all derivatives against two human cancer cell lines namely, HepG-2 and MCF-7. The most cytotoxic compound 20 h was subjected to further biological investigations including cell cycle, apoptosis, caspase-3, caspase-9, BAX, and Bcl-2 analyses. Different in silico studies as docking, ADMET and toxicity were carried out. The results exhibited that compounds 20b, 20e, 20h and 20m showed promising VEGFR-2 inhibitory activities with IC50 values of 5.7, 6.7, 3.2, and 3.1 mu M, respectively. Moreover, these promising members exhibited the highest antiproliferative activities against the two cell lines with IC50 values ranging from 3.3 to 14.2 mu M, comparing to sorafenib (IC50 = 2.17 and 3.43 mu M against HepG2 and MCF-7, respectively). Additionally, compound 20h induced cell cycle arrest of HepG2 cells at G2/M phase. Also, such compound increased the progress of apoptosis by 3.5-fold compared to the control. As well, compound 20h showed a significant increase in the level of caspase-3 (2.07-fold), caspase-9 (1.72-fold), and BAX (1.83-fold), and a significant decrease in Bcl-2 level (1.92-fold). The in silico studies revealed that the synthesized compounds have binding pattern like that of sorafenib.