The Antioxidant Additive Approach for Alzheimer's Disease Therapy: New Ferulic (Lipoic) Acid Plus Melatonin Modified Tacrines as Cholinesterases Inhibitors, Direct Antioxidants, and Nuclear Factor (Erythroid-Derived 2)-Like 2 Activators

J Med Chem. 2016 Nov 10;59(21):9967-9973. doi: 10.1021/acs.jmedchem.6b01178. Epub 2016 Oct 31.

Abstract

Novel multifunctional tacrines for Alzheimer's disease were obtained by Ugi-reaction between ferulic (or lipoic acid), a melatonin-like isocyanide, formaldehyde, and tacrine derivatives, according to the antioxidant additive approach in order to modulate the oxidative stress as therapeutic strategy. Compound 5c has been identified as a promising permeable agent showing excellent antioxidant properties, strong cholinesterase inhibitory activity, less hepatotoxicity than tacrine, and the best neuroprotective capacity, being able to significantly activate the Nrf2 transcriptional pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism*
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Cell Death / drug effects
  • Cell Survival / drug effects
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Cholinesterases / metabolism
  • Coumaric Acids / chemical synthesis
  • Coumaric Acids / chemistry
  • Coumaric Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • Hep G2 Cells
  • Humans
  • Melatonin / chemical synthesis
  • Melatonin / chemistry
  • Melatonin / pharmacology*
  • Molecular Structure
  • NF-E2-Related Factor 2 / agonists*
  • NF-E2-Related Factor 2 / metabolism
  • Structure-Activity Relationship

Substances

  • Antioxidants
  • Cholinesterase Inhibitors
  • Coumaric Acids
  • NF-E2-Related Factor 2
  • ferulic acid
  • Cholinesterases
  • Melatonin