Rational design, synthesis and biological evaluation of novel multitargeting anti-AD iron chelators with potent MAO-B inhibitory and antioxidant activity

Bioorg Med Chem. 2020 Jun 15;28(12):115550. doi: 10.1016/j.bmc.2020.115550. Epub 2020 May 11.

Abstract

A series of (3-hydroxypyridin-4-one)-coumarin hybrids were developed and investigated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through the incorporation of iron-chelating and monoamine oxidase B (MAO-B) inhibition. This combination endowed the hybrids with good capacity to inhibit MAO-B as well as excellent iron-chelating effects. The pFe3+ values of the compounds were ranging from 16.91 to 20.16, comparable to more potent than the reference drug deferiprone (DFP). Among them, compound 18d exhibited the most promising activity against MAO-B, with an IC50 value of 87.9 nM. Moreover, compound 18d exerted favorable antioxidant activity, significantly reversed the amyloid-β1-42 (Aβ1-42) induced PC12 cell damage. More importantly, 18d remarkably ameliorated the cognitive dysfunction in a scopolamine-induced mice AD model. In brief, a series of hybrids with potential anti-AD effect were successfully obtained, indicating that the design of iron chelators with MAO-B inhibitory and antioxidant activities is an attractive strategy against AD progression.

Keywords: 3-Hydroxypyridin-4-one; Alzheimer’s disease; Iron chelators; MAO-B inhibitors; Multitarget agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / chemically induced
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / pharmacology
  • Animals
  • Antioxidants / chemistry*
  • Behavior, Animal / drug effects
  • Binding Sites
  • Cell Survival / drug effects
  • Coumarins / chemistry
  • Disease Models, Animal
  • Drug Design*
  • Humans
  • Iron Chelating Agents / chemical synthesis*
  • Iron Chelating Agents / pharmacology
  • Iron Chelating Agents / therapeutic use
  • Mice
  • Mice, Inbred ICR
  • Molecular Docking Simulation
  • Monoamine Oxidase / chemistry
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / chemical synthesis*
  • Monoamine Oxidase Inhibitors / pharmacology
  • Monoamine Oxidase Inhibitors / therapeutic use
  • PC12 Cells
  • Peptide Fragments / pharmacology
  • Rats
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Antioxidants
  • Coumarins
  • Iron Chelating Agents
  • Monoamine Oxidase Inhibitors
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • coumarin
  • Monoamine Oxidase