Syntheses, neural protective activities, and inhibition of glycogen synthase kinase-3β of substituted quinolines

Bioorg Med Chem Lett. 2014 Aug 1;24(15):3392-7. doi: 10.1016/j.bmcl.2014.05.085. Epub 2014 Jun 4.

Abstract

A new series of fifteen 5-, 6-, and 8-appended 4-methylquinolines were synthesized and evaluated for their neural protective activities. Selected compounds were further examined for their inhibition of glycogen synthase kinase-3β (GSK-3β) and protein kinase C (PKC). Two most potent analogs, compounds 3 and 10, show nanomolar protective activities in amyloid β-induced MC65 cells and enzymatic inhibitory activities against GSK-3β, but poor PKC inhibitory activities. Using normal mouse model, the distribution of the most potent analog 3 in various tissues and possible toxic effects in the locomotors and inhibition of liver transaminases activities were carried out. No apparent decline of locomotor activity and no inhibition of liver transaminases were found. The compound appears to be safe for long-term use in Alzheimer's disease mouse model.

Keywords: Alzheimer’s disease; Amyloid β; Glycogen synthase kinase-3β; Neural protective activity; Protein kinase C; Quinolines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / metabolism
  • Animals
  • Cell Line
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism
  • Mice
  • Models, Animal
  • Molecular Structure
  • Protein Kinase C / metabolism
  • Quinolines / chemical synthesis
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Quinolines
  • Protein Kinase C
  • Glycogen Synthase Kinase 3