Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents

Bioorg Med Chem. 2015 Aug 1;23(15):4442-4452. doi: 10.1016/j.bmc.2015.06.010. Epub 2015 Jun 14.


Tremendous efforts have been dedicated to the development of effective therapeutics against Alzheimer's disease, which represents the most common debilitating neurodegenerative disease. Multifunctional agents are molecules designed to have simultaneous effects on different pathological processes. Such compounds represent an emerging strategy for the development of effective treatments against Alzheimer's disease. Here, we report on the synthesis and biological evaluation of a series of nitroxoline-based analogs that were designed by merging the scaffold of 8-hydroxyquinoline with that of a known selective butyrylcholinesterase inhibitor that has promising anti-Alzheimer properties. Most strikingly, compound 8g inhibits self-induced aggregation of the amyloid beta peptide (Aβ1-42), inhibits with sub-micromolar potency butyrylcholinesterase (IC50=215 nM), and also selectively complexes Cu(2+). Our study thus designates this compound as a promising multifunctional agent for therapeutic treatment of Alzheimer's disease. The crystal structure of human butyrylcholinesterase in complex with compound 8g is also solved, which suggests ways to further optimize compounds featuring the 8-hydroxyquinoline scaffold.

Keywords: Alzheimer’s disease; Butyrylcholinesterase; Chelation; Multifunctional ligands; Nitroxoline.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / metabolism
  • Binding Sites
  • Butyrylcholinesterase / chemistry
  • Butyrylcholinesterase / metabolism
  • Chelating Agents / chemistry
  • Chelating Agents / metabolism
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / therapeutic use
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Metals / chemistry
  • Metals / metabolism
  • Molecular Docking Simulation
  • Nitroquinolines / chemical synthesis
  • Nitroquinolines / chemistry*
  • Nitroquinolines / therapeutic use
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Spectrophotometry, Ultraviolet


  • Amyloid beta-Peptides
  • Chelating Agents
  • Cholinesterase Inhibitors
  • Metals
  • Nitroquinolines
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • nitroxoline
  • Butyrylcholinesterase