The Guareschi Pyridine Scaffold as a Valuable Platform for the Identification of Selective PI3K Inhibitors

Molecules. 2015 Sep 18;20(9):17275-87. doi: 10.3390/molecules200917275.

Abstract

A novel series of 4-aryl-3-cyano-2-(3-hydroxyphenyl)-6-morpholino-pyridines have been designed as potential phosphatidylinositol-3-kinase (PI3K) inhibitors. The compounds have been synthesized using the Guareschi reaction to prepare the key 4-aryl-3-cyano-2,6-dihydroxypyridine intermediate. A different selectivity according to the nature of the aryl group has been observed. Compound 9b is a selective inhibitor against the PI3Kα isoform, maintaining a good inhibitory activity. Docking studies were also performed in order to rationalize its profile of selectivity.

Keywords: Guareschi reaction; PI3 kinase; isoforms; pyridine; selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Mice
  • Models, Molecular
  • Molecular Docking Simulation
  • NIH 3T3 Cells
  • Phosphoinositide-3 Kinase Inhibitors*
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyridines