Synthesis of Bioactive 2-(Arylamino)thiazolo[5,4-f]-quinazolin-9-ones via the Hügershoff Reaction or Cu- Catalyzed Intramolecular C-S Bond Formation

Molecules. 2016 Jun 18;21(6):794. doi: 10.3390/molecules21060794.

Abstract

A library of thirty eight novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives (series 8, 10, 14 and 17) was prepared via the Hügershoff reaction and a Cu catalyzed intramolecular C-S bond formation, helped by microwave-assisted technology when required. The efficient multistep synthesis of the key 6-amino-3-cyclopropylquinazolin-4(3H)-one (3) has been reinvestigated and performed on a multigram scale from the starting 5-nitroanthranilic acid. The inhibitory potency of the final products was evaluated against five kinases involved in Alzheimer's disease and showed that some molecules of the 17 series described in this paper are particularly promising for the development of novel multi-target inhibitors of kinases.

Keywords: CDK5; CK1; CLK1; DYRK1A; GSK-3; Hügershoff reaction; microwave-assisted synthesis; protein kinases; thiazolo[5,4-f]quinazolin-9(8H)-ones.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology
  • Barbiturates / chemistry
  • Catalysis
  • Copper / chemistry
  • Humans
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / isolation & purification
  • Protein Kinase Inhibitors / therapeutic use
  • Quinazolinones / chemical synthesis
  • Quinazolinones / chemistry*
  • Quinazolinones / therapeutic use
  • Structure-Activity Relationship

Substances

  • Barbiturates
  • Protein Kinase Inhibitors
  • Quinazolinones
  • Copper
  • 4-hydroxyquinazoline
  • 5-nitrobarbituric acid