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

• Published in: Molecules (Basel, Switzerland)
• Main Authors: Galdeano Cantador, Carlos, Coquelle, Nicolas, Cieslikiewicz-Bouet, Monika, Bartolini, Manuela, Pérez, Belén, Clos, M. Victòria, Silman, Israel, Jean, Ludovic, Colletier, Jacques-Philippe, Renard, Pierre-Yves, Muñoz-Torrero López-Ibarra, Diego
• Format: Journal Article
• Language: English
• Published: MDPI 11-03-2018
• Subjects: Acetilcolinesterasa; Acetylcholinesterase; Malalties neuromusculars; Neuromuscular diseases; Triazoles
• ISSN: 1420-3049; 1420-3049

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.