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 ¹H NMR and IR. The crystal structures of compounds <b>4a</b> and <b>4h</b> were prepared by the natural solvent evaporation method, and the crystal data were collected by X-ray single crystal diffractometer. The crystal data of <b>4a</b> are: C₁₉H₁₉N₃O₃, <i>M</i> = 337.37, monoclinic, <i>a</i> = 10.1213(4) Å, <i>b</i> = 16.0054(6) Å, and <i>c</i> = 10.5629(4) Å. The crystal data of <b>4h</b> are: C₂₁H₂₂N₄O₄, <i>M</i> = 394.42, monoclinic, <i>a</i> = 13.2448(6) Å, <i>b</i> = 16.3553(7) Å, and <i>c</i> = 9.0453(5) Å. 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 <b>4a</b> against MKN45 cell line was 2.5 μM and the inhibitory activity was higher than that of the positive control Gefitinib (IC₅₀ = 3.2 μM), showing the better antitumor activity. Molecular docking further revealed that the better inhibitory activity of compound <b>4a</b> was obtained due to the hydrogen bonding between <b>4a</b> and EGFR. Moreover, AO/EB staining results showed that compound <b>4a</b> 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.