{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:53:29Z","timestamp":1791824009962,"version":"4.3.4"},"reference-count":48,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2018,3,11]],"date-time":"2018-03-11T00:00:00Z","timestamp":1520726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010198","name":"MINECO","doi-asserted-by":"publisher","award":["SAF2014-57094-R"],"award-info":[{"award-number":["SAF2014-57094-R"]}],"id":[{"id":"10.13039\/501100010198","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002809","name":"Generalitat de Catalunya","doi-asserted-by":"publisher","award":["2014SGR52"],"award-info":[{"award-number":["2014SGR52"]}],"id":[{"id":"10.13039\/501100002809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100016394","name":"ANR","doi-asserted-by":"publisher","award":["ANR-12-BS07-0008-01"],"award-info":[{"award-number":["ANR-12-BS07-0008-01"]}],"id":[{"id":"10.13039\/501100016394","id-type":"DOI","asserted-by":"publisher"}]},{"name":"France Alzheimer Foundation","award":["FA-AAP-2013-65-101349"],"award-info":[{"award-number":["FA-AAP-2013-65-101349"]}]},{"DOI":"10.13039\/501100003407","name":"MIUR","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"INSA Rouen"},{"name":"CRUNCh network"},{"name":"Labex SynOrg","award":["ANR-11-LABX-0029"],"award-info":[{"award-number":["ANR-11-LABX-0029"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/molecules23030634","type":"journal-article","created":{"date-parts":[[2018,3,12]],"date-time":"2018-03-12T13:13:48Z","timestamp":1520860428000},"page":"634","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Increasing Polarity in Tacrine and Huprine Derivatives: Potent Anticholinesterase Agents for the Treatment of Myasthenia Gravis"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1702-0369","authenticated-orcid":false,"given":"Carles","family":"Galdeano","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8501-4908","authenticated-orcid":false,"given":"Nicolas","family":"Coquelle","sequence":"additional","affiliation":[{"name":"Institut de Biologie Structurale, Universit\u00e9 Grenoble Alpes, Centre National de la Recherche Scientifique (CNRS)-Commissariat \u00e0 l\u2019\u00c9nergie Atomique (CEA) (UMR 5075), F-38054 Grenoble, France"},{"name":"Large-Scale Structures Group, Institut Laue-Langevin, 71 Avenue des Martyrs, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0783-1590","authenticated-orcid":false,"given":"Monika","family":"Cieslikiewicz-Bouet","sequence":"additional","affiliation":[{"name":"Laboratory COBRA (UMR 6014), Normandie Universit\u00e9, UNIROUEN, Institut National des Sciences Appliqu\u00e9es (INSA) Rouen, CNRS, 76000 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2890-3856","authenticated-orcid":false,"given":"Manuela","family":"Bartolini","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5801-1704","authenticated-orcid":false,"given":"Bel\u00e9n","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Therapeutics and Toxicology, Neuroscience Institute, Autonomous University of Barcelona, E-08193 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7389-3351","authenticated-orcid":false,"given":"M.","family":"Clos","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Therapeutics and Toxicology, Neuroscience Institute, Autonomous University of Barcelona, E-08193 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Israel","family":"Silman","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1745-4952","authenticated-orcid":false,"given":"Ludovic","family":"Jean","sequence":"additional","affiliation":[{"name":"Laboratory COBRA (UMR 6014), Normandie Universit\u00e9, UNIROUEN, Institut National des Sciences Appliqu\u00e9es (INSA) Rouen, CNRS, 76000 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1819-4686","authenticated-orcid":false,"given":"Jacques-Philippe","family":"Colletier","sequence":"additional","affiliation":[{"name":"Institut de Biologie Structurale, Universit\u00e9 Grenoble Alpes, Centre National de la Recherche Scientifique (CNRS)-Commissariat \u00e0 l\u2019\u00c9nergie Atomique (CEA) (UMR 5075), F-38054 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9094-9778","authenticated-orcid":false,"given":"Pierre-Yves","family":"Renard","sequence":"additional","affiliation":[{"name":"Laboratory COBRA (UMR 6014), Normandie Universit\u00e9, UNIROUEN, Institut National des Sciences Appliqu\u00e9es (INSA) Rouen, CNRS, 76000 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8140-8555","authenticated-orcid":false,"given":"Diego","family":"Mu\u00f1oz-Torrero","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,3,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/S1474-4422(15)00145-3","article-title":"Myasthenia gravis: Subgroup classification and therapeutic strategies","volume":"14","author":"Gilhus","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1007\/s00415-016-8045-z","article-title":"Clinical features, pathogenesis, and treatment of myasthenia gravis: A supplement to the guidelines of the German Neurological Society","volume":"263","author":"Melzer","year":"2016","journal-title":"J. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2843","DOI":"10.1172\/JCI29894","article-title":"Myasthenia gravis: Past, present, and future","volume":"116","author":"Milani","year":"2006","journal-title":"J. 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