LAUSR

In continuation of our previous efforts in the field of design and synthesis of vascular endothelial growth factor receptor (VEGFR)‐2 inhibitors, a new series of [1,2,4]triazolo[4,3‐c]quinazoline derivatives were designed and synthesized as modified analogs of some reported VEGFR‐2 inhibitors. The synthesized compounds were designed to have the essential pharmacophoric features of VEGFR‐2 inhibitors. Antiproliferative activities of the synthesized compounds were investigated against two tumor cell lines (HepG2 and HCT‐116) using sorafenib as a positive control. Compound 10k emerged as the most promising antiproliferative agent with IC50 values of 4.88 and 5.21 µM against HepG2 and HCT‐116 cells, respectively. Also, it showed the highest inhibitory activity against VEGFR‐2 with an IC50 value of 53.81 nM compared to sorafenib (IC50 = 44.34 nM). Cell cycle analysis revealed that compound 10k can arrest HepG2 cells at both the S and G2/M phases. In addition, this compound produced a tenfold increase in apoptotic cells compared to the control. Furthermore, the effect of compound 10k on the expression level of BAX, Bcl‐2, and caspase‐3 was assessed. This compound caused a 3.35‐fold increase in BAX expression levels and a 1.25‐fold reduction in Bcl‐2 expression levels. The BAX/Bcl‐2 ratio was calculated to be 4.57, indicating a promising apoptotic effect. It also showed a significant increase in the level of caspase‐3 (4.12‐fold) compared to the control cells. In silico docking, absorption, distribution, metabolism, excretion, and toxicity, and toxicity studies were performed for the synthesized compounds to investigate their binding patterns against the proposed biological target (VEGFR‐2) and to assess the drug‐likeness characters.