Design, synthesis and biological evaluation of 2,3-dihydro-[1,4]dioxino[2,3-f]quinazoline derivatives as EGFR inhibitors.

Epidermal growth factor receptor (EGFR) is the most attractive target for drug research in non-small cell lung cancer (NSCLC). The first-generation EGFR tyrosine kinase inhibitors (TKIs) Gefetinib and Elotinib showed good clinical efficacy on lung adenocarcinoma tumors, but almost all patients developed resistance to these inhibitors over time. Quinazoline and quinoline derivatives are common targeted inhibitors of EGFR kinase, and their structural optimization is an important direction for the development of effective targeted anticancer drugs. Based on these facts, a series of heterocyclic 2,3-dihydro-[1,4]dioxino[2,3-f]quinazoline derivatives have been designed and synthesized and their structures were confirmed by spectral analyses. The cytotoxic activity of the newly synthesized compounds was evaluated against the human kidney epithelial T293 cell line, normal lung cell lines WI-38, non-small cell lung cancer A549 and NCI-H157 cell lines using MTT. The tested compounds showed an evident anticancer activity against the tested cell lines, especially compound 13c, which was the most potent anticancer agent with half maximal inhibitory concentrations (IC50) between 8.82 and 10.24 μM. Docking study showed that compound 13b could be nicely bound to the ATP binding pocket of EGFR. In addition, the inhibitory activity of the target compounds against epidermal growth factor receptor tyrosine kinase (EGFR-TK) was evaluated. Results indicated the ability of the target compounds to inhibit EGFR-TK with half maximal inhibitory concentrations (IC50) in the range of 10.29 nM to 652.3 nM. In view of the reported compound activity, the structure deserves further optimization as cancer treatment agents.