Novel benzylidenephenylpyrrolizinones with pleiotropic activities potentially useful in Alzheimer's disease treatment

Eur J Med Chem. 2016 May 23:114:365-79. doi: 10.1016/j.ejmech.2016.03.023. Epub 2016 Mar 12.

Abstract

This work describes the synthesis and the biological evaluation of novel benzylidenephenylpyrrolizinones as potential antioxidant, metal chelating or amyloid β (βA) aggregation inhibitors. Some derivatives exhibited interesting results in regard to several of the performed evaluations and appear as valuable Multi-Target Directed Ligands with potential therapeutic interest in Alzheimer's disease. Among them, compound 29 particularly appears as a valuable radical and NO scavenger, a Cu(II) and Fe(II) chelating agent and exhibits moderate βA aggregation inhibition properties. These activities, associated to a good predictive bioavailability and a lack of cytotoxicity, design it as a promising hit for further in vivo investigation.

Keywords: Alzheimer; Anti βA aggregation; Antichelating; Antioxidant; MTDL; Pleiotrope; Pyrrolizinone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Benzyl Compounds / chemical synthesis
  • Benzyl Compounds / chemistry
  • Benzyl Compounds / pharmacology*
  • Cell Proliferation
  • Dose-Response Relationship, Drug
  • Humans
  • KB Cells
  • Models, Molecular
  • Molecular Structure
  • Protein Aggregates / drug effects*
  • Protein Binding / drug effects
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Amyloid beta-Peptides
  • Antioxidants
  • Benzyl Compounds
  • Protein Aggregates
  • Pyrroles