New Series of 4,6-diaryl Pyrimidines: Facile Synthesis and Antiproliferative Activity As Dual EGFR/VEGFR-2 Inhibitors

Introduction: We developed and produced a new series of 4,6-diaryl-pyrimidines as antiproliferative agents targeting EGFR/VEGFR-2.

Methods: The antiproliferative efficacy of the novel targets was assessed against a panel of 60 NCI cancer cell lines and four cancer cell lines .

Results And Discussion: Compounds , , , , , and demonstrated the greatest potency among the derivatives, with GI values between 22 and 33 nM; compounds and exhibited the highest potency, with GI values of 22 and 24 nM, respectively. We subsequently examined the most efficient derivatives as dual EGFR/VEGFR-2 inhibitors, finding that compounds and functioned as dual inhibitors. Moreover, and can act as apoptotic inducers by increasing Bax levels and decreasing levels of the anti-apoptotic protein Bcl2. At both 24- and 48-h intervals, the cell migration rates of compounds and were lower than those of untreated cells, according to the migration rate and wound closure percentage assessment. The wound closure rate reached 100% after 72 h of therapy with compound but only 80% with compound . The docking study showed that compounds and had docking scores similar to those of Erlotinib and Sorafenib, co-crystallized ligands, for the EGFR and VEGFR-2 proteins. The experiments on lipophilicity showed that the new pyrimidines had a consistent result. This group of compounds has better biological activity in all the biological systems studied with low lipophilicity.