Design, synthesis, and biological evaluation of novel quinazolinyl-diaryl urea derivatives as potential anticancer agents

• In the design of the compounds, molecular hybridization approach was used.
• Thirty novel quinazolinyl–diaryl urea derivatives were synthesized.
• Compound 8g exhibited the most potent inhibitory activity.
• The cellular- and molecular-level mechanisms of compound 8g were investigated.

Through a structure-based molecular hybridization approach, a series of novel quinazolinyl-diaryl urea derivatives were designed, synthesized, and screened for their in vitro antiproliferative activities against three cancer cell lines (HepG2, MGC-803, and A549). Six compounds (7g, 7m, 7o, 8e, 8g, and 8m) showed stronger activity against a certain cell line compared with the positive reference drugs sorafenib and gefitinib. Among the six compounds, 8g exhibited the strongest activity. In particular, compound 8g induced A549 apoptosis, arrested cell cycle at the G0/G1 phase, elevated intracellular reactive oxygen species level, and decreased mitochondrial membrane potential. This compound can also effectively regulate the expression of apoptosis- and cell cycle-related proteins, and influence the Raf/MEK/ERK pathway. Molecular docking and structure–activity relationship analyses revealed that it can bind well to the active site of the receptor c-Raf, which was consistent with the biological data. Therefore, compound 8g may be a potent antitumor agent, representing a promising lead for further optimization.

Molecular hybridization approach was used and 30 novel quinazolinyl–diaryl urea derivatives were synthesized. Compound 8g exhibited the strongest antiproliferative activities and the mechanisms were investigated.Figure optionsDownload as PowerPoint slide