New series of 4,6-diaryl pyrimidines: facile synthesis and antiproliferative activity as dual EGFR/VEGFR-2 inhibitors

Compounds <b>14</b>, <b>17</b>, <b>19</b>, <b>22</b>, <b>25</b>, and <b>29</b> demonstrated the greatest potency among the derivatives, with GI₅₀ values between 22 and 33 nM; compounds <b>22</b> and <b>29</b> exhibited the highest potency, with GI₅₀ values of 22 and 24 nM, respectively. We subsequently examined the most efficient derivatives as dual EGFR/VEGFR-2 inhibitors, finding that compounds <b>22</b> and <b>29</b> functioned as dual inhibitors. Moreover, <b>22</b> and <b>29</b> 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 <b>22</b> and <b>29</b> 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 <b>22</b> but only 80% with compound <b>29</b>. The docking study showed that compounds <b>22</b> and <b>29</b> 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.