Novel cinnamamide-dibenzylamine hybrids: Potent neurogenic agents with antioxidant, cholinergic, and neuroprotective properties as innovative drugs for Alzheimer's disease

Eur J Med Chem. 2017 Oct 20:139:68-83. doi: 10.1016/j.ejmech.2017.07.077. Epub 2017 Aug 1.

Abstract

By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a novel series of cinnamamide-dibenzylamine hybrids have been designed, synthesized, and evaluated biologically. In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit ChEs, strong potency inhibitory of self-induced β-amyloid (Aβ) aggregation and to act as potential antioxidants and biometal chelators. A Lineweaver-Burk plot and molecular modeling study showed that compound 7f targeted both the CAS and PAS of AChE. In addition, compound 7f could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Overall, all of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7f as the lead structure worthy of further investigation.

Keywords: AP2238; Alzheimer's disease; Antioxidant activity; Cholinesterase; Cinnamamide.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Animals
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Benzylamines / chemistry
  • Benzylamines / pharmacology*
  • Blood-Retinal Barrier / drug effects
  • Butyrylcholinesterase / metabolism
  • Cell Death / drug effects
  • Cholinergic Agents / chemical synthesis
  • Cholinergic Agents / chemistry
  • Cholinergic Agents / pharmacology*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Cinnamates / chemistry
  • Cinnamates / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Oxidative Stress / drug effects
  • PC12 Cells
  • Rats
  • Structure-Activity Relationship

Substances

  • Antioxidants
  • Benzylamines
  • Cholinergic Agents
  • Cholinesterase Inhibitors
  • Cinnamates
  • Neuroprotective Agents
  • dibenzylamine
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • cinnamamide