New bis([1,2,4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers: Design, synthesis, in silico studies, and anticancer evaluation

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 and20mshowed promising VEGFR-2 inhibitory activities with IC₅₀values of 5.7, 6.7, 3.2, and 3.1 µM, respectively. Moreover, these promising members exhibited the highest antiproliferative activities against the two cell lines with IC₅₀values ranging from 3.3 to 14.2 µM, comparing to sorafenib (IC₅₀ = 2.17 and 3.43 µM 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.

Keywords: Anti-proliferative; Apoptosis; Bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline; Docking studies; VEGFR-2 inhibitors.