6,7-Dimorpholinoalkoxy quinazoline derivatives as potent EGFR inhibitors with enhanced antiproliferative activities against tumor cells

A series of novel 6,7-dimorpholinoalkoxy quinazoline derivatives was designed, synthesized and evaluated as potent EGFR inhibitors. Most of synthesized derivatives exhibited moderate to excellent antiproliferative activities against five human tumor cell lines. Compound 8d displayed the most remarkable inhibitory activities against tumor cells expressing wild type (A431, A549 and SW480 cells) or mutant (HCC827 and NCI-H1975 cells) epidermal growth factor receptor (EGFR) (with IC50 values in the range of 0.37–4.87 μM), as well as more potent inhibitory effects against recombinant EGFR tyrosine kinase (EGFR-TK, wt or T790M) (with the IC50 values of 7.0 and 9.3 nM, respectively). Molecular docking showed that 8d can form four hydrogen bonds with EGFR, and two of them were located in the Asp855-Phe856-Gly857 (DFG) motif of EGFR. Meanwhile, 8d can significantly block EGF-induced EGFR activation and the phosphorylation of its downstream proteins such as Akt and Erk1/2 in human NSCLC cells. Also, 8d mediated cell apoptosis and the prolongation of cell cycle progression in G0/G1-phase in A549 cells. The work would have remarkable implications for further design and development of more potent EGFR tyrosine kinase inhibitors (TKIs). [Display omitted] •Novel EGFR inhibitors, the 6,7-dimorpholinoalkoxy quinazoline derivatives, were designed and synthesized.•Most of the compounds exhibited good antiproliferative activity against human tumor cell lines harboring wild type or mutant EGFR.•Molecular docking showed that 8d can form four hydrogen bonds with EGFR, and two of them were located in DFG motif of EGFR.•8d can significantly inhibit the activity of wild type or T790M mutant EGFR, and suppress the phosphorylation of EGFR and its downstream signaling proteins in tumor cells.•8d induced cell apoptosis and G1-phase cell cycle arrest in A549 cells in a concentration-dependent manner.