Synthesis and biological evaluation of N-aryl-7-methoxybenzo[b]furo[3,2-d]pyrimidin-4-amines and their N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amine analogues as dual inhibitors of CLK1 and DYRK1A kinases

Eur J Med Chem. 2013 Jan;59:283-95. doi: 10.1016/j.ejmech.2012.11.030. Epub 2012 Nov 24.

Abstract

Novel N-aryl-7-methoxybenzo[b]furo[3,2-d]pyrimidin-4-amines (1) and their N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amine analogues (2) were designed and prepared for the first time via microwave-accelerated multi-step synthesis. Various anilines were condensed with N'-(2-cyanaryl)-N,N-dimethylformimidamide intermediates obtained by reaction of 3-amino-6-methoxybenzofuran-2-carbonitrile (3) and 3-amino-6-methoxybenzothiophene-2-carbonitrile (4) precursors with dimethylformamide dimethylacetal. The inhibitory potency of the final products against five protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, DYRK1A and CLK1) was estimated. Compounds (2a-z) turned out to be particularly promising for the development of new pharmacological dual inhibitors of CLK1 and DYRK1A kinases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemical synthesis*
  • Amines / chemistry
  • Amines / pharmacology*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Furans / chemical synthesis
  • Furans / chemistry
  • Furans / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry
  • Thiophenes / pharmacology

Substances

  • Amines
  • Enzyme Inhibitors
  • Furans
  • Pyrimidines
  • Thiophenes
  • Clk dual-specificity kinases
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases