Increasing polarity in tacrine and huprine derivatives: Potent anticholinesterase agents for the treatment of myasthenia gravis

Carles Galdeano, Nicolas Coquelle, Monika Cieslikiewicz-Bouet, Manuela Bartolini, Belén Pérez, M. Victòria Clos, Israel Silman, Ludovic Jean, Jacques Philippe Colletier, Pierre Yves Renard, Diego Mu oz-Torrero

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10 Citations (Scopus)

Abstract

© 2018 by the authors. 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.
Original languageEnglish
Article number634
JournalMolecules
Volume23
Issue number3
DOIs
Publication statusPublished - 1 Jan 2018

Keywords

  • Acetylcholinesterase inhibitors
  • Butyrylcholinesterase inhibitors
  • Click chemistry
  • Copper-catalyzed azide-alkyne cycloaddition
  • Quinolinium compounds
  • Structural biology
  • Triazoles

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    Galdeano, C., Coquelle, N., Cieslikiewicz-Bouet, M., Bartolini, M., Pérez, B., Victòria Clos, M., Silman, I., Jean, L., Colletier, J. P., Renard, P. Y., & oz-Torrero, D. M. (2018). Increasing polarity in tacrine and huprine derivatives: Potent anticholinesterase agents for the treatment of myasthenia gravis. Molecules, 23(3), [634]. https://doi.org/10.3390/molecules23030634