Increasing Polarity in Tacrine and Huprine Derivatives: Potent Anticholinesterase Agents for the Treatment of Myasthenia Gravis

Molecules. 2018 Mar 11;23(3):634. doi: 10.3390/molecules23030634.


Symptomatic treatment of myasthenia gravis is based on the use of peripherally-acting acetylcholinesterase (AChE) inhibitors that, in some cases, must be discontinued due to the occurrence of a number of side-effects. Thus, new AChE inhibitors are being developed and investigated for their potential use against this disease. Here, we have explored two alternative approaches to get access to peripherally-acting AChE inhibitors as new agents against myasthenia gravis, by structural modification of the brain permeable anti-Alzheimer AChE inhibitors tacrine, 6-chlorotacrine, and huprine Y. Both quaternization upon methylation of the quinoline nitrogen atom, and tethering of a triazole ring, with, in some cases, the additional incorporation of a polyphenol-like moiety, result in more polar compounds with higher inhibitory activity against human AChE (up to 190-fold) and butyrylcholinesterase (up to 40-fold) than pyridostigmine, the standard drug for symptomatic treatment of myasthenia gravis. The novel compounds are furthermore devoid of brain permeability, thereby emerging as interesting leads against myasthenia gravis.

Keywords: acetylcholinesterase inhibitors; butyrylcholinesterase inhibitors; click chemistry; copper-catalyzed azide-alkyne cycloaddition; quinolinium compounds; structural biology; triazoles.

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism*
  • Aminoacridines / chemical synthesis*
  • Aminoacridines / chemistry
  • Aminoacridines / pharmacology
  • Aminoquinolines / chemical synthesis*
  • Aminoquinolines / chemistry
  • Aminoquinolines / pharmacology
  • Butyrylcholinesterase / chemistry
  • Butyrylcholinesterase / metabolism
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Down-Regulation
  • GPI-Linked Proteins / chemistry
  • GPI-Linked Proteins / metabolism
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Myasthenia Gravis / drug therapy
  • Myasthenia Gravis / enzymology
  • Structure-Activity Relationship
  • Tacrine / chemistry


  • Aminoacridines
  • Aminoquinolines
  • Cholinesterase Inhibitors
  • GPI-Linked Proteins
  • Heterocyclic Compounds, 4 or More Rings
  • huprine Y
  • Tacrine
  • ACHE protein, human
  • Acetylcholinesterase
  • Butyrylcholinesterase