Pyrazole/pyrimidine derivatives endowed with azobenzenes as dual EGFRT790M and VEGFR-2 inhibitors: anticancer, docking, synthesis, design and ADMET assessments

Abstract

New pyrazole/pyrimidine derivatives endowed with azobenzenes were synthesized using microwave and traditional methods. Our compounds were assessed for cytotoxicity against HepG2, MCF-7, HCT-116 and A549 cell lines as dual inhibitors of EGFR^T790M and VEGFR-2. A docking study was carried out to show the binding affinities and orientations of our derivatives in the active sites of VEGFR-2 and EGFR^T790M. The data of the docking study were highly correlated with the biological data. The HCT116 and A549 cell lines were extremely affected by our derivatives. Derivative 12 showed the greatest activity against A549, HepG2, MCF-7 and HCT116 cells, with IC₅₀ = 5.12, 6.77, 5.85 and 5.25 µM, respectively. It showed higher cytotoxicity than erlotinib (IC₅₀ = 5.49, 7.73, 8.20 and 13.91 µM, respectively) and lower cytotoxicity than sorafenib (IC₅₀ = 4.04, 4.00, 5.58 and 5.05 µM, respectively) against the tested cell lines. The cytotoxicity of the highly active derivatives 5, 6, 8, 9, 10 and 12 against the MCF-10 healthy cell lines was evaluated. The assessed derivatives showed low cytotoxicity against MCF-10 cells, with IC₅₀ = 50.90–55.50 µM. Additionally, all derivatives were assessed as dual VEGFR-2 and EGFR^T790M inhibitors. Compounds 12, 8 and 10 displayed very good inhibitions toward VEGFR-2, with IC₅₀ = 0.90, 0.95 and 1.00 µM, respectively. Similarly, structures 12, 8, 10, 5 and 9 showed strong EGFR^T790M inhibitions, with IC₅₀ = 0.25, 0.30, 0.33, 0.35 and 0.40 µM, respectively. In addition, in silico ADMET predictions were calculated for the highly active derivatives 8, 10 and 12 and correlated to Lipinski's rule of five using erlotinib and sorafenib as standard ligands. The results presented our derivatives as promising candidates for advanced manipulations to get more potent anticancer agents with advanced VEGFR-2 and EGFR^T790M inhibitions.