Design, synthesis, molecular modeling, in vivo studies and anticancer evaluation of quinazolin-4(3H)-one derivatives as potential VEGFR-2 inhibitors and apoptosis inducers.

• Twenty-four compounds of novel quinazolin-4(3 H)-one derivatives were designed and synthesized. • Cytotoxic activities were evaluated against HepG-2, MCF-7 and HCT-116 cell lines. • In vitro anti VEGFR-2 and in vivo antitumor activities were evaluated. • Molecular docking studies were carried out. Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. Accordingly, new quinazoline-based derivatives having the structural features of VEGFR-2 inhibitors were designed and synthesized. Anti-proliferative activities were evaluated against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) using MTT assay method. Doxorubicin and sorafenib were used as positive controls. Compounds 26 b , 29 a , 29 b and 30 showed excellent anti-cancer activities against all cell lines. Moreover, compound 31 was the most active with IC 50 values of 3.97 ± 0.2, 4.83 ± 0.2 and 4.58 ± 0.3 µM, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities, compound 31 showed a high activity against VEGFR-2 with an IC 50 value of 2.5 ± 0.04 µM, almost equal to that of sorafenib (IC 50 = 2.4 ± 0.05 µM). Further studies revealed the ability of this promising quinazoline derivative 31 to induce apoptosis and arrest cell cycle growth at G2/M phase. In vivo antitumor activities of the synthesized compounds revealed that compounds 30 and 31 possessed significant tumor growth inhibition effect. Molecular docking studies were also performed and finally we can say that VEGFR-2 inhibition confers the reported cytotoxic activities. [ABSTRACT FROM AUTHOR]