Novel tacrine-8-hydroxyquinoline hybrids as multifunctional agents for the treatment of Alzheimer's disease, with neuroprotective, cholinergic, antioxidant, and copper-complexing properties

J Med Chem. 2010 Jul 8;53(13):4927-37. doi: 10.1021/jm100329q.

Abstract

Tacrine and PBT2 (an 8-hydroxyquinoline derivative) are well-known drugs that inhibit cholinesterases and decrease beta-amyloid (Abeta) levels by complexation of redox-active metals, respectively. In this work, novel tacrine-8-hydroxyquinoline hybrids have been designed, synthesized, and evaluated as potential multifunctional drugs for the treatment of Alzheimer's disease. At nano- and subnanomolar concentrations they inhibit human acetyl- and butyrylcholinesterase (AChE and BuChE), being more potent than tacrine. They also displace propidium iodide from the peripheral anionic site of AChE and thus could be able to inhibit Abeta aggregation promoted by AChE. They show better antioxidant properties than Trolox, the aromatic portion of vitamin E responsible for radical capture, and display neuroprotective properties against mitochondrial free radicals. In addition, they selectively complex Cu(II), show low cell toxicity, and could be able to penetrate the CNS, according to an in vitro blood-brain barrier model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / metabolism
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology
  • Blood-Brain Barrier / metabolism
  • Butyrylcholinesterase / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chelating Agents / chemical synthesis
  • Chelating Agents / chemistry
  • Chelating Agents / pharmacology
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Copper / metabolism
  • Humans
  • Hydroxyquinolines / chemical synthesis*
  • Hydroxyquinolines / chemistry
  • Hydroxyquinolines / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology
  • Propidium / metabolism
  • Spectrometry, Mass, Electrospray Ionization
  • Tacrine / analogs & derivatives*
  • Tacrine / chemical synthesis
  • Tacrine / chemistry
  • Tacrine / pharmacology*

Substances

  • Amyloid beta-Peptides
  • Antioxidants
  • Chelating Agents
  • Cholinesterase Inhibitors
  • Hydroxyquinolines
  • Neuroprotective Agents
  • Propidium
  • Tacrine
  • Copper
  • Acetylcholinesterase
  • Butyrylcholinesterase