6,7-Dimethoxy-2-methyl-4-substituted quinazolines: Design, synthesis, EGFR inhibitory activity, in vitro...

Six series of 2,4,6,7-tetrasubstituted quinazolines 4a-c, 6a-c, 8a-c, 10a-d, 13a-d along with quinazoline-tetrahydropyrimidine hybrids 15a-c were designed and synthesized based on keeping the essential key binding pattern of some EGFR inhibitors to appraise their EGFR inhibition and anticancer activity. Twelve compounds out of twenty displayed a significant EGFR inhibition in a subnanomolar level (IC₅₀ = 0.143-0.946 nM) compared to afatinib (IC₅₀ = 0.102 nM). The most potent derivatives 4a, 6c, 8b, 13a and 15b (IC₅₀ = 0.143-0.313 nM) were further screened for their anticancer activity against lung (A549) and colon (HCT116) cancer cell lines, in addition to, normal fibroblast cells (WI-38). It was found that, compounds 6c and 13a show a nearly equipotent to superior cytotoxicity towards (A549) (IC₅₀ = 0.020 and 0.006 μM; respectively) and (IC₅₀ = 0.020 and 0.038 μM; respectively) against HCT116 in comparison to afatinib (IC₅₀ = 0.025 and 0.030 μM; respectively). Also, compounds 6c and 13a caused a cell cycle arrest at S phase and induced apoptosis in A549 and HCT116; respectively. Moreover, in silico studies clarified the binding pattern of the potent compounds in EGFR enzyme active site and confirmed their ability to gratify the structural features meted for binding and rationalized their selectivity. Furthermore, the most active candidates possess promising predicted pharmacokinetic properties.