Design, synthesis, and in vitro antitumor activity of 6-aryloxyl substituted quinazoline derivatives

Quinazoline derivatives are a class of important antitumor drugs known as small molecule inhibitors that include epidermal growth factor receptor (EGFR) inhibitors. Based on the structure of poziotinib, a series of 6-aryloxyl substituted quinazoline derivatives were designed and synthesized. The in vitro antitumor activities of the compounds were evaluated by the 3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) method using the human gastric cancer N87 (HER2), nonsmall-cell lung cancer H1975 (EGFR T790M/L858R ), and A549 (EGFR WT ) cell lines. The most promising compound 4m exhibited potent antitumoral activities with IC 50 values of 6.3 nM and 7.5 nM for N87 and H1975 cell lines, respectively. Meanwhile, it was less potent against A549 cancer cells with an IC 50 value of 29.9 μM. The molecular docking results suggested that compound 4m has different binding modes to the wild-type and mutated EGFR.