ae7b4b0838875cf634e15db59c2d66a2 pmc_29534488.pdf 84812c87d327b8fa12821893653c83d9eafc838f pmc_29534488.pdf 2f60ab1c778f9676beb18880fe1aa67615a7595ae2bcfa1ba1a0ed243ead847f pmc_29534488.pdf Title: Increasing Polarity in Tacrine and Huprine Derivatives: Potent Anticholinesterase Agents for the Treatment of Myasthenia Gravis Subject: 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; quinolinium compounds; triazoles; structural biology; copper-catalyzed azide-alkyne cycloaddition; click chemistry Author: Carles Galdeano, Nicolas Coquelle, Monika Cieslikiewicz-Bouet, Manuela Bartolini, Belén Pérez, M. 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