Design, synthesis and bioevaluation of N-trisubstituted pyrimidine derivatives as potent aurora A kinase inhibitors

• A new series of N-trisubstituted pyrimidine derivatives were synthesized.
• Docking studies were performed to gain insight about protein–ligand interactions.
• Most compounds exhibited good inhibitory activities against aurora A kinase and various human tumor cell lines.
• Four compounds selectively blocked cell-cycle progression at the G2/M phase in the solid CNE-2 tumor cell.
• The work has excellent scope to probe further structure activity relationships.

The design and synthesis of a new series of N-trisubstituted (at C2, C4 and C6 respectively) pyrimidine derivatives were reported, their in vitro structure–activity relationships vs. aurora A kinase were also discussed. Our results demonstrated that the introduction of characteristic N-substituted side chain at C2 of pyrimidines possessed a potent aurora A inhibitory activity, the position and the nature of the substituents on the phenyl ring of aniline side chain played key roles in cellular kinase inhibitory potency. Most tested compounds exhibited good inhibitory activities against aurora A kinase and various human tumor cell lines. Compounds 7j, 7m–n and 7p showed strong growth–inhibitory activities in the solid CNE-2 tumor cell and selectively blocked cell-cycle progression at the G2/M phase.

Modifications/substitutions prevail: A new series of N-trisubstituents pyrimidine derivatives were designed and synthesized. Most compounds showed good inhibitory activities against aurora A kinase and various human tumor cell lines.Figure optionsDownload as PowerPoint slide