Fluorinated benzophenone derivatives: balanced multipotent agents for Alzheimer's disease

Eur J Med Chem. 2014 May 6:78:157-66. doi: 10.1016/j.ejmech.2014.03.042. Epub 2014 Mar 16.

Abstract

In an effort to develop multipotent agents against β-secretase (BACE-1) and acetylcholinesterase (AChE), able to counteract intracellular ROS formation as well, the structure of the fluorinated benzophenone 3 served as starting point for the synthesis of a small library of 3-fluoro-4-hydroxy- analogues. Among the series, derivatives 5 and 12, carrying chemically different amino functions, showed a balanced micromolar potency against the selected targets. In particular, compound 12, completely devoid of toxic effects, seems to be a promising lead for obtaining effective anti-AD drug candidates.

Keywords: Acetylcholinesterase; Alzheimer's disease; Antioxidant activity; BACE-1; Benzophenone; Drug design; Lead identification.

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Benzophenones / chemical synthesis
  • Benzophenones / chemistry
  • Benzophenones / pharmacology*
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Antioxidants
  • Benzophenones
  • Enzyme Inhibitors
  • Acetylcholinesterase
  • Amyloid Precursor Protein Secretases