Design and synthesis of novel 6-aryl substituted 4-anilinequinazoline derivatives as potential PI3Kδ inhibitors

Bioorg Med Chem Lett. 2017 May 1;27(9):1972-1977. doi: 10.1016/j.bmcl.2017.03.020. Epub 2017 Mar 11.

Abstract

In this study, a series of new 6-aryl substituted 4-anilinequinazolines was designed and synthesized as PI3Kδ inhibitors based on our reported chemical structures. The preliminary structure-activity relationship (SAR) was established, and compounds 13h and 13k displayed most potent PI3Kδ inhibitory activities with the IC50 values of 9.3nM and 9.7nM, respectively. Compound 13h demonstrated similar anti-proliferative profiles to idelalisib against three human B cell lines. Three key hydrogen bonding interactions were found in the docking of 13h with PI3Kδ enzyme. These results suggest that compound 13h possessed nanomolar PI3Kδ inhibitory activity and distinctive chemical structure, deserving further structural optimization.

Keywords: 6-Aryl substituted 4-anilinequinazolines; Drug design; PI3Kδ inhibitors; Structure-activity relationship.

MeSH terms

  • Aniline Compounds / chemical synthesis
  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacology*
  • Cell Line
  • Cell Proliferation / drug effects
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism
  • Drug Design
  • Humans
  • Hydrogen Bonding
  • Molecular Docking Simulation
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Aniline Compounds
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Quinazolines
  • Class Ia Phosphatidylinositol 3-Kinase