Kinase inhibitions in pyrido[4,3-h] and [3,4-g]quinazolines: Synthesis, SAR and molecular modeling studies

Bioorg Med Chem. 2019 May 15;27(10):2083-2089. doi: 10.1016/j.bmc.2019.04.005. Epub 2019 Apr 4.

Abstract

New pyrido[3,4-g]quinazoline derivatives were prepared and evaluated for their inhibitory potency toward 5 protein kinases (CLK1, DYRK1A, GSK3, CDK5, CK1). A related pyrido[4,3-h]quinazoline scaffold with an angular structure was also synthesized and its potency against the same protein kinase panel was compared to the analogous pyrido[3,4-g]quinazoline. Best results were obtained for 10-nitropyrido[3,4-g]quinazoline 4 toward CLK1 with nanomolar activities.

Keywords: CLK1; Protein kinase inhibition; Pyrido[3,4-g]quinazolines; Pyrido[4,3-h]quinazoline.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclin-Dependent Kinase 5 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 5 / metabolism
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinases / chemistry
  • Protein Kinases / metabolism*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Pyridines / chemistry*
  • Quinazolines / chemistry*
  • Quinazolines / metabolism
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Pyridines
  • Quinazolines
  • Protein Kinases
  • Clk dual-specificity kinases
  • Protein-Tyrosine Kinases
  • Cyclin-Dependent Kinase 5
  • Protein Serine-Threonine Kinases
  • Glycogen Synthase Kinase 3