Synthesis and Evaluation of Imidazo[1,2-a]pyridine Analogues of the ZSTK474 Class of Phosphatidylinositol 3-Kinase Inhibitors

Chem Asian J. 2019 Apr 15;14(8):1249-1261. doi: 10.1002/asia.201801762. Epub 2019 Mar 12.


Using a scaffold-hopping approach, imidazo[1,2-a]pyridine analogues of the ZSTK474 (benzimidazole) class of phosphatidylinositol 3-kinase (PI3K) inhibitors have been synthesized for biological evaluation. Compounds were prepared using a heteroaryl Heck reaction procedure, involving the palladium-catalysed coupling of 2-(difluoromethyl)imidazo[1,2-a]pyridines with chloro, iodo or trifluoromethanesulfonyloxy (trifloxy) substituted 1,3,5-triazines or pyrimidines, with the iodo intermediates being preferred in terms of higher yields and milder reaction conditions. The new compounds maintain the PI3K isoform selectivity of their benzimidazole analogues, but in general show less potency.

Keywords: biological activity; cross-coupling; hydrogen bonds; inhibitors; kinases; scaffold hopping.

MeSH terms

  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyridines
  • imidazo(1,2-a)pyridine