Synthesis, biological evaluation, and molecular docking of new series of antitumor and apoptosis inducers designed as VEGFR-2 inhibitors

Based on quinazoline, quinoxaline, and nitrobenzene scaffolds and on pharmacophoric features of VEGFR-2 inhibitors, 17 novel compounds were designed and synthesised. VEGFR-2 IC50 values ranged from 60.00 to 123.85 nM for the new derivatives compared to 54.00 nM for sorafenib. Compounds 15(a) , 15(b) , and 15(d) showed IC50 from 17.39 to 47.10 mu M against human cancer cell lines; hepatocellular carcinoma (HepG2), prostate cancer (PC3), and breast cancer (MCF-7). Meanwhile, the first in terms of VEGFR-2 inhibition was compound 15(d) which came second with regard to antitumor assay with IC50 = 24.10, 40.90, and 33.40 mu M against aforementioned cell lines, respectively. Furthermore, Compound 15(d) increased apoptosis rate of HepG2 from 1.20 to 12.46% as it significantly increased levels of Caspase-3, BAX, and P53 from 49.6274, 40.62, and 42.84 to 561.427, 395.04, and 415.027 pg/mL, respectively. Moreover, 15(d) showed IC50 of 253 and 381 nM against HER2 and FGFR, respectively.

Automated summary

Based on the pharmacophoric features of VEGFR-2 inhibitors, 17 novel compounds were designed and synthesized, with compound 15(d) showing the strongest inhibitory activity and significant apoptosis and antitumor effects against hepatocellular carcinoma.