Tetrahydropyranodiquinolin-8-amines as new, non hepatotoxic, antioxidant, and acetylcholinesterase inhibitors for Alzheimer's disease therapy

Eur J Med Chem. 2017 Jan 27:126:576-589. doi: 10.1016/j.ejmech.2016.11.050. Epub 2016 Nov 23.

Abstract

Herein we report an efficient two step synthesis and biological assessment of 12 racemic tetrahydropyranodiquinolin-8-amines derivatives as antioxidant, cholinesterase inhibitors and non-hepatotoxic agents. Based on the results of the primary screening, we identified 7-(3-methoxyphenyl)-9,10,11,12-tetrahydro-7H-pyrano[2,3-b:5,6-h']diquinolin-8-amine (2h) as a particularly interesting non-hepatotoxic compound that shows moderate antioxidant activity (1.83 equiv Trolox in the ORAC assay), a non competitive inhibition of hAChE (IC50 = 0.75 ± 0.01 μM), and brain permeable as determined by the PAMPA-Blood Brain Barrier assay.

Keywords: Acetylcholinesterase inhibitors; Alzheimer's disease; Antioxidants; Brain blood barrier; Hepatotoxicity; Molecular modeling; Multifunctional agents.

MeSH terms

  • Acetylcholinesterase
  • Alzheimer Disease / drug therapy
  • Aminoquinolines / chemical synthesis
  • Aminoquinolines / pharmacology*
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Blood-Brain Barrier / metabolism
  • Chemical and Drug Induced Liver Injury
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • GPI-Linked Proteins / antagonists & inhibitors
  • Humans

Substances

  • Aminoquinolines
  • Antioxidants
  • Cholinesterase Inhibitors
  • GPI-Linked Proteins
  • ACHE protein, human
  • Acetylcholinesterase