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Open AccessFeature PaperArticle

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

1
Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain
2
Institut de Biologie Structurale, Université Grenoble Alpes, Centre National de la Recherche Scientifique (CNRS)-Commissariat à l’Énergie Atomique (CEA) (UMR 5075), F-38054 Grenoble, France
3
Large-Scale Structures Group, Institut Laue-Langevin, 71 Avenue des Martyrs, 38000 Grenoble, France
4
Laboratory COBRA (UMR 6014), Normandie Université, UNIROUEN, Institut National des Sciences Appliquées (INSA) Rouen, CNRS, 76000 Rouen, France
5
Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy
6
Department of Pharmacology, Therapeutics and Toxicology, Neuroscience Institute, Autonomous University of Barcelona, E-08193 Barcelona, Spain
7
Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this study.
Molecules 2018, 23(3), 634; https://doi.org/10.3390/molecules23030634
Received: 9 February 2018 / Revised: 6 March 2018 / Accepted: 9 March 2018 / Published: 11 March 2018
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. View Full-Text
Keywords: acetylcholinesterase inhibitors; butyrylcholinesterase inhibitors; quinolinium compounds; triazoles; structural biology; copper-catalyzed azide-alkyne cycloaddition; click chemistry acetylcholinesterase inhibitors; butyrylcholinesterase inhibitors; quinolinium compounds; triazoles; structural biology; copper-catalyzed azide-alkyne cycloaddition; click chemistry
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Galdeano, C.; Coquelle, N.; Cieslikiewicz-Bouet, M.; Bartolini, M.; Pérez, B.; Clos, M.V.; Silman, I.; Jean, L.; Colletier, J.-P.; Renard, P.-Y.; Muñoz-Torrero, D. Increasing Polarity in Tacrine and Huprine Derivatives: Potent Anticholinesterase Agents for the Treatment of Myasthenia Gravis. Molecules 2018, 23, 634.

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