Novel 4-arylaminoquinazoline derivatives: design, synthesis, crystal structure and biological evaluation as potent antitumor agents

A series of novel 4-arylaminoquinazoline derivatives were designed and synthesized. All target compounds synthesized were characterized and confirmed by H-1 NMR and IR. The crystal structures of compounds 4a and 4h were prepared by the natural solvent evaporation method, and the crystal data were collected by X-ray single crystal diffractometer. The crystal data of 4a are: C19H19N3O3, M = 337.37, monoclinic, a = 10.1213(4) angstrom, b = 16.0054(6) angstrom, and c = 10.5629(4) angstrom. The crystal data of 4h are: C21H22N4O4, M = 394.42, monoclinic, a = 13.2448(6) angstrom, b = 16.3553(7) angstrom, and c = 9.0453(5) angstrom. In addition, IC50 values of all synthesized derivatives were evaluated against MKN45 cell lines. Most of the synthetic derivatives had moderate to good antiproliferative activity against the MKN45 tumor cell line. The IC50 value of compound 4a against MKN45 cell line was 2.5 mu M and the inhibitory activity was higher than that of the positive control Gefitinib (IC50 = 3.2 mu M), showing the better antitumor activity. Molecular docking further revealed that the better inhibitory activity of compound 4a was obtained due to the hydrogen bonding between 4a and EGFR. Moreover, AO/EB staining results showed that compound 4a could induce apoptosis of human lung cancer A549 cells. More importantly, ADME data exhibited the new compounds were all readily absorbed and had good drug-likeness. Therefore, these compounds offer the possibility to develop novel antitumor drugs.