Tumor angiogenesis is mainly regulated by VEGFR-2. In this study, a new series of [1,2,4]triazolo[4,3-a]quinoxaline based-derivatives has been designed and synthesized to develop new anti-proliferative and anti-VEGFR-2 members. Anti-proliferative activities of the synthesized compounds were tested against MCF-7 and HepG2 cell lines. Compound 19a exhibited the highest activity towards both MCF-7 and HepG2 cell lines (IC₅₀ = 8.2 and 5.4 µM, respectively), compared to sorafenib (IC₅₀ = 3.51 and 2.17 µM, respectively). Additionally, all compounds were screened to evaluate their effect as VEGFR-2 inhibitors. Compound 19a (IC₅₀ = 3.4 nM) exhibited good activity compared to sorafenib (IC₅₀ = 3.12 nM). Furthermore, compound 19a disrupted the HepG2 cell cycle by arresting the G2/M phase. Also, marked increase in the percentage apoptotic cells was achieved by compound 19a. The induced apoptotic effect of compound 19a in HepG2 cells was assured by increased pro‐apoptotic marker (Bax) expression by 2.33-fold and decreased anti‐apoptotic (Bcl‐2) expression by 1.88-fold, resulting in an elevation of the Bax/Bcl-2 ratio in HepG2 cells. Comparing to the control cells, compound 19a induced an increase in expression of cleaved caspase-3 and caspase-9 by 2.44- and 2.69-fold, respectively. Finally, the binding modes of the target derivatives were investigated through docking studies against the proposed molecular target (VEGFR-2, PDB ID: 2OH4).

肿瘤血管生成主要受 VEGFR-2 调控。在这项研究中，设计并合成了一系列新的基于 [1,2,4] 三唑并 [4,3 - a ] 喹喔啉的衍生物，以开发新的抗增殖和抗 VEGFR-2 成员。针对 MCF-7 和 HepG2 细胞系测试了合成化合物的抗增殖活性。与索拉非尼（IC _{50 分别}为 3.51 和 2.17 µM ）相比，化合物19a对 MCF-7 和 HepG2 细胞系的活性最高（IC _{50 分别}为 8.2 和 5.4 µM ）。此外，筛选所有化合物以评估它们作为 VEGFR-2 抑制剂的效果。与索拉非尼 (IC ₅₀ = 3.4 nM) 相比，化合物19a (IC ₅₀ = 3.4 nM) 表现出良好的活性₅₀ = 3.12 nM）。此外，化合物19a通过阻止 G2/M 期破坏了 HepG2 细胞周期。此外，化合物19a实现了凋亡细胞百分比的显着增加。化合物19a在 HepG2 细胞中的诱导凋亡作用是通过将促凋亡标志物 (Bax) 表达增加 2.33 倍和将抗凋亡 (Bcl-2) 表达减少 1.88 倍，导致 Bax/ HepG2 细胞中的 Bcl-2 比率。与对照细胞相比，化合物19a诱导裂解的 caspase-3 和 caspase-9 的表达分别增加 2.44 和 2.69 倍。最后，通过针对提议的分子靶标（VEGFR-2，PDB ID：2OH4）的对接研究，研究了靶标衍生物的结合模式。