Multitarget-directed benzylideneindanone derivatives: anti-β-amyloid (Aβ) aggregation, antioxidant, metal chelation, and monoamine oxidase B (MAO-B) inhibition properties against Alzheimer's disease

J Med Chem. 2012 Oct 11;55(19):8483-92. doi: 10.1021/jm300978h. Epub 2012 Oct 1.

Abstract

A novel series of benzylideneindanone derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer's disease. The in vitro studies showed that most of the molecules exhibited a significant ability to inhibit self-induced β-amyloid (Aβ(1-42)) aggregation (10.5-80.1%, 20 μM) and MAO-B activity (IC(50) of 7.5-40.5 μM), to act as potential antioxidants (ORAC-FL value of 2.75-9.37), and to function as metal chelators. In particular, compound 41 had the greatest ability to inhibit Aβ(1-42) aggregation (80.1%), and MAO-B (IC(50) = 7.5 μM) was also an excellent antioxidant and metal chelator. Moreover, it is capable of inhibiting Cu(II)-induced Aβ(1-42) aggregation and disassembling the well-structured Aβ fibrils. These results indicated that compound 41 is an excellent multifunctional agent for the treatment of AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid / chemistry
  • Amyloid beta-Peptides / chemistry*
  • Antioxidants / chemical synthesis*
  • Antioxidants / chemistry
  • Benzylidene Compounds / chemical synthesis*
  • Benzylidene Compounds / chemistry
  • Cations, Divalent
  • Chelating Agents / chemical synthesis*
  • Chelating Agents / chemistry
  • Copper / chemistry
  • Humans
  • Indans / chemical synthesis*
  • Indans / chemistry
  • Iron / chemistry
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • Molecular Docking Simulation
  • Monoamine Oxidase / chemistry
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / chemical synthesis*
  • Monoamine Oxidase Inhibitors / chemistry
  • Peptide Fragments / chemistry*
  • Recombinant Proteins / chemistry
  • Structure-Activity Relationship
  • Zinc / chemistry

Substances

  • 5,6-dihydroxy-2-(4-(methyl(propyl)amino)benzylidene)-2,3-dihydro-1H-inden-1-one
  • Amyloid
  • Amyloid beta-Peptides
  • Antioxidants
  • Benzylidene Compounds
  • Cations, Divalent
  • Chelating Agents
  • Indans
  • Isoenzymes
  • Monoamine Oxidase Inhibitors
  • Peptide Fragments
  • Recombinant Proteins
  • amyloid beta-protein (1-42)
  • Copper
  • Iron
  • Monoamine Oxidase
  • Zinc

Associated data

  • PDB/2Z5X