{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:55:11Z","timestamp":1790362511686,"version":"4.1.0"},"reference-count":77,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2019,4,1]],"date-time":"2019-04-01T00:00:00Z","timestamp":1554076800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2019,4,1]],"date-time":"2019-04-01T00:00:00Z","timestamp":1554076800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2020,2,23]],"date-time":"2020-02-23T00:00:00Z","timestamp":1582416000000},"content-version":"am","delay-in-days":328,"URL":"http:\/\/www.elsevier.com\/open-access\/userlicense\/1.0\/"}],"funder":[{"name":"Labex SynOrg","award":["ANR-11-LABX-0029"],"award-info":[{"award-number":["ANR-11-LABX-0029"]}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-12-BS07-008-01"],"award-info":[{"award-number":["ANR-12-BS07-008-01"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007850","name":"INSA Rouen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007850","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Rouen Normandy University"},{"DOI":"10.13039\/501100004794","name":"Centre National de la Recherche Scientifique","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004794","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Region Normandie"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Medicinal Chemistry"],"published-print":{"date-parts":[[2019,4]]},"DOI":"10.1016\/j.ejmech.2018.12.063","type":"journal-article","created":{"date-parts":[[2019,2,13]],"date-time":"2019-02-13T11:32:38Z","timestamp":1550057558000},"page":"58-77","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":68,"special_numbering":"C","title":["Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3"],"prefix":"10.1016","volume":"168","author":[{"given":"Killian","family":"Oukoloff","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Coquelle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Bartolini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Naldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00e9my","family":"Le Guevel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Bach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9atrice","family":"Josselin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Ruchaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Catto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Pisani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nunzio","family":"Denora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa Maria","family":"Iacobazzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Israel","family":"Silman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel L.","family":"Sussman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Buron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques-Philippe","family":"Colletier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1745-4952","authenticated-orcid":false,"given":"Ludovic","family":"Jean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvain","family":"Routier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Yves","family":"Renard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ejmech.2018.12.063_bib1","series-title":"World Alzheimer Report 2015: the Global Impact of Dementia: an Analysis of Prevalence, Incidence, Cost and Trends","author":"Prince","year":"2015"},{"key":"10.1016\/j.ejmech.2018.12.063_bib2","doi-asserted-by":"crossref","first-page":"5147","DOI":"10.1021\/cr3000994","article-title":"The amyloid beta peptide: a chemist's perspective. Role in Alzheimer's and fibrillization","volume":"112","author":"Hamley","year":"2012","journal-title":"Chem. Rev."},{"key":"10.1016\/j.ejmech.2018.12.063_bib3","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1111\/j.1471-4159.2009.06511.x","article-title":"Tau oligomers and aggregation in Alzheimer's disease","volume":"112","author":"Meraz-Rios","year":"2010","journal-title":"J.\u00a0Neurochem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib4","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1056\/NEJMra0909142","article-title":"Alzheimer's Disease","volume":"362","author":"Querfurth","year":"2010","journal-title":"N.\u00a0Engl. J. Med."},{"key":"10.1016\/j.ejmech.2018.12.063_bib5","doi-asserted-by":"crossref","first-page":"899","DOI":"10.2146\/ajhp070622","article-title":"Treatment of Alzheimer's disease in the long-term-care setting","volume":"66","author":"Smith","year":"2009","journal-title":"Am. J. Health Syst. Pharm."},{"key":"10.1016\/j.ejmech.2018.12.063_bib6","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1159\/000200013","article-title":"Memantine therapy of behavioral symptoms in community-dwelling patients with moderate to severe Alzheimer's disease","volume":"27","author":"Grossberg","year":"2009","journal-title":"Dement. Geriatr. Cognit. Disord."},{"key":"10.1016\/j.ejmech.2018.12.063_bib7","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1159\/000353801","article-title":"Memantine in patients with moderate to severe Alzheimer's disease: meta-analyses using realistic definitions of response","volume":"37","author":"Wilkinson","year":"2014","journal-title":"Dement. Geriatr. Cognit. Disord."},{"key":"10.1016\/j.ejmech.2018.12.063_bib8","doi-asserted-by":"crossref","first-page":"654","DOI":"10.12968\/hosp.2003.64.11.2346","article-title":"Memantine (Ebixa) in the later stages of dementia","volume":"64","author":"Findlay","year":"2003","journal-title":"Hosp. Med."},{"key":"10.1016\/j.ejmech.2018.12.063_bib9","doi-asserted-by":"crossref","first-page":"245","DOI":"10.2147\/nedt.2007.3.2.245","article-title":"Memantine: efficacy and safety in mild-to-severe Alzheimer's disease","volume":"3","author":"Tampi","year":"2007","journal-title":"Neuropsychiatric Dis. Treat."},{"key":"10.1016\/j.ejmech.2018.12.063_bib10","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/alzrt269","article-title":"Alzheimer's disease drug-development pipeline: few candidates, frequent failures","volume":"6","author":"Cummings","year":"2014","journal-title":"Alzheimer's Res. Ther."},{"key":"10.1016\/j.ejmech.2018.12.063_bib11","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1002\/med.21434","article-title":"Drugs in clinical trials for Alzheimer's disease: the major trends","volume":"37","author":"Bachurin","year":"2017","journal-title":"Med. Res. Rev."},{"key":"10.1016\/j.ejmech.2018.12.063_bib12","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.pharep.2015.07.006","article-title":"Therapeutic strategies for Alzheimer's disease in clinical trials","volume":"68","author":"Gody\u0144","year":"2016","journal-title":"Pharmacol. Rep."},{"key":"10.1016\/j.ejmech.2018.12.063_bib13","doi-asserted-by":"crossref","first-page":"4833","DOI":"10.1007\/s12035-015-9390-0","article-title":"Dissecting complex and multifactorial nature of Alzheimer's disease pathogenesis: a clinical, genomic, and systems biology perspective","volume":"53","author":"Talwar","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"10.1016\/j.ejmech.2018.12.063_bib14","doi-asserted-by":"crossref","first-page":"4949","DOI":"10.2174\/092986711797535245","article-title":"Multi-target-directed ligands in Alzheimer's disease treatment","volume":"18","author":"Bajda","year":"2011","journal-title":"Curr. Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib15","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1021\/jm7009364","article-title":"Multi-target-directed ligands to combat neurodegenerative diseases","volume":"51","author":"Cavalli","year":"2008","journal-title":"J.\u00a0Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib16","doi-asserted-by":"crossref","first-page":"373","DOI":"10.2174\/0929867321666141106122628","article-title":"Recent development of multifunctional agents as potential drug candidates for the treatment of Alzheimer's disease","volume":"22","author":"Guzior","year":"2015","journal-title":"Curr. Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib17","doi-asserted-by":"crossref","first-page":"6523","DOI":"10.1021\/jm058225d","article-title":"Designed multiple ligands. An emerging drug discovery paradigm","volume":"48","author":"Morphy","year":"2005","journal-title":"J.\u00a0Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib18","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1021\/jm049112h","article-title":"Rational approach to discover multipotent anti-Alzheimer drugs","volume":"48","author":"Rosini","year":"2005","journal-title":"J.\u00a0Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib19","doi-asserted-by":"crossref","first-page":"3017","DOI":"10.2174\/1568026617666170707130652","article-title":"Multi-targeting strategies for Alzheimer's disease therapeutics: pros and cons","volume":"17","author":"Das","year":"2017","journal-title":"Curr. Top. Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib20","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1021\/acschemneuro.8b00069","article-title":"Alzheimer's disease, the \u201cOne-Molecule, one-target\u201d paradigm, and the multitarget directed ligand approach","volume":"9","author":"Oset-Gasque","year":"2018","journal-title":"ACS Chem. Neurosci."},{"key":"10.1016\/j.ejmech.2018.12.063_bib21","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.2174\/15680266113139990135","article-title":"The multifactorial nature of Alzheimer disease for developing potential therapeutics","volume":"13","author":"Carreiras","year":"2013","journal-title":"Curr. Top. Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib22","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1080\/14756366.2017.1368019","article-title":"Synthesis and biological evaluation of aminomethyl and alkoxymethyl derivatives as carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase inhibitors","volume":"32","author":"Gulcin","year":"2017","journal-title":"J.\u00a0Enzym. Inhib. Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib23","doi-asserted-by":"crossref","first-page":"205","DOI":"10.3389\/fphar.2015.00205","article-title":"Multi-target pharmacology: possibilities and limitations of the \u201cskeleton key approach\u201d from a medicinal chemist perspective","volume":"6","author":"Talevi","year":"2015","journal-title":"Front. Pharmacol."},{"key":"10.1016\/j.ejmech.2018.12.063_bib24","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1002\/ddr.20287","article-title":"Advances in the development of kinase inhibitor therapeutics for Alzheimer's disease","volume":"70","author":"Savage","year":"2009","journal-title":"Drug Dev. Res."},{"key":"10.1016\/j.ejmech.2018.12.063_bib25","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.arr.2012.06.003","article-title":"Tau protein kinases: involvement in Alzheimer's disease","volume":"12","author":"Martin","year":"2013","journal-title":"Ageing Res. Rev."},{"key":"10.1016\/j.ejmech.2018.12.063_bib26","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.molmed.2009.01.003","article-title":"Tau phosphorylation: the therapeutic challenge for neurodegenerative disease","volume":"15","author":"Hanger","year":"2009","journal-title":"Trends Mol. Med."},{"key":"10.1016\/j.ejmech.2018.12.063_bib27","doi-asserted-by":"crossref","first-page":"4328","DOI":"10.1007\/s12035-015-9369-x","article-title":"The role of Cdk5 in Alzheimer's disease","volume":"53","author":"Liu","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"10.1016\/j.ejmech.2018.12.063_bib28","doi-asserted-by":"crossref","first-page":"7392","DOI":"10.1523\/JNEUROSCI.0889-12.2012","article-title":"Selectively silencing GSK-3 isoforms reduces plaques and tangles in mouse models of Alzheimer's disease","volume":"32","author":"Hurtado","year":"2012","journal-title":"J.\u00a0Neurosci."},{"key":"10.1016\/j.ejmech.2018.12.063_bib29","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/nature01640","article-title":"GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides","volume":"423","author":"Phiel","year":"2003","journal-title":"Nature"},{"key":"10.1016\/j.ejmech.2018.12.063_bib30","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.2174\/15680266113139990138","article-title":"Lessons learnt from glycogen synthase kinase 3 inhibitors development for Alzheimer's disease","volume":"13","author":"Martinez","year":"2013","journal-title":"Curr. Top. Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib31","doi-asserted-by":"crossref","first-page":"280502","DOI":"10.4061\/2011\/280502","article-title":"Glycogen synthase kinase 3 inhibitors in the next horizon for Alzheimer's disease treatment","volume":"2011","author":"Martinez","year":"2011","journal-title":"Int. J. Alzheimer's Dis."},{"key":"10.1016\/j.ejmech.2018.12.063_bib32","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1074\/jbc.M112.409250","article-title":"Inhibition of glycogen synthase kinase-3 ameliorates beta-amyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the Alzheimer disease mouse model: in\u00a0vivo and in\u00a0vitro studies","volume":"288","author":"Avrahami","year":"2013","journal-title":"J.\u00a0Biol. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib33","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.bbrc.2013.04.065","article-title":"Newly developed glycogen synthase kinase-3 (GSK-3) inhibitors protect neuronal cells death in amyloid-beta induced cell model and in a transgenic mouse model of Alzheimer's disease","volume":"435","author":"Noh","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"10.1016\/j.ejmech.2018.12.063_bib34","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1021\/cn300110c","article-title":"Glycogen synthase kinase 3 inhibition promotes Adult hippocampal neurogenesis in\u00a0vitro and in\u00a0vivo","volume":"3","author":"Morales-Garcia","year":"2012","journal-title":"ACS Chem. Neurosci."},{"key":"10.1016\/j.ejmech.2018.12.063_bib35","first-page":"381029","article-title":"Small-molecule inhibitors of GSK-3: structural insights and their application to Alzheimer's disease models","author":"Kramer","year":"2012","journal-title":"Int. J. Alzheimer's Dis."},{"key":"10.1016\/j.ejmech.2018.12.063_bib36","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1111\/j.1742-4658.2007.06238.x","article-title":"Amyloid-cholinesterase interactions. Implications for Alzheimer's disease","volume":"275","author":"Inestrosa","year":"2008","journal-title":"FEBS J."},{"key":"10.1016\/j.ejmech.2018.12.063_bib37","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1006\/jmbi.1997.1245","article-title":"Acetylcholinesterase promotes the aggregation of amyloid-beta-peptide fragments by forming a complex with the growing fibrils","volume":"272","author":"Alvarez","year":"1997","journal-title":"J.\u00a0Mol. Biol."},{"key":"10.1016\/j.ejmech.2018.12.063_bib38","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3389\/fnmol.2011.00019","article-title":"Interactions of AChE with A\u03b2 aggregates in Alzheimer's brain: therapeutic relevance of IDN 5706","volume":"4","author":"Carvajal","year":"2011","journal-title":"Front. Mol. Neurosci."},{"key":"10.1016\/j.ejmech.2018.12.063_bib39","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/S0896-6273(00)80108-7","article-title":"Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer's fibrils: possible role of the peripheral site of the enzyme","volume":"16","author":"Inestrosa","year":"1996","journal-title":"Neuron"},{"key":"10.1016\/j.ejmech.2018.12.063_bib40","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.2174\/15680266113139990136","article-title":"Multifunctional tacrine derivatives in Alzheimer's disease","volume":"13","author":"Minarini","year":"2013","journal-title":"Curr. Top. Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib41","doi-asserted-by":"crossref","first-page":"3522","DOI":"10.2174\/0929867324666170309123920","article-title":"Tacrine-based multifunctional agents in Alzheimer's disease: an old story in continuous development","volume":"24","author":"Milelli","year":"2017","journal-title":"Curr. Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib42","doi-asserted-by":"crossref","first-page":"e3108","DOI":"10.1371\/journal.pone.0003108","article-title":"N-acetylcholinesterase-induced apoptosis in Alzheimer's disease","volume":"3","author":"Toiber","year":"2008","journal-title":"PLoS One"},{"key":"10.1016\/j.ejmech.2018.12.063_bib43","doi-asserted-by":"crossref","first-page":"3000","DOI":"10.2174\/1568026617666170717114944","article-title":"Therapeutic agents in Alzheimer's disease through a multi-targetdirected ligands strategy: recent progress based on tacrine core","volume":"17","author":"Lin","year":"2017","journal-title":"Curr. Top. Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib44","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.ejmech.2016.10.060","article-title":"A\u00a0review on tacrine-based scaffolds as multi-target drugs (MTDLs) for Alzheimer's disease","volume":"128","author":"Sameem","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib45","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.2174\/1568026605666160927152728","article-title":"Multitarget tacrine hybrids with neuroprotective properties to confront Alzheimer's disease","volume":"17","author":"Spilovska","year":"2017","journal-title":"Curr. Top. Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib46","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1021\/acsmedchemlett.7b00463","article-title":"Dual GSK-3\u03b2\/AChE inhibitors as a new strategy for multitargeting anti-Alzheimer\u2019s disease drug discovery","volume":"9","author":"Jiang","year":"2018","journal-title":"ACS Med. Chem. Lett."},{"key":"10.1016\/j.ejmech.2018.12.063_bib47","doi-asserted-by":"crossref","first-page":"32","DOI":"10.3389\/fnmol.2011.00032","article-title":"GSK-3 inhibitors: preclinical and clinical focus on CNS","volume":"4","author":"Eldar-Finkelman","year":"2011","journal-title":"Front. Mol. Neurosci."},{"key":"10.1016\/j.ejmech.2018.12.063_bib48","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.ejmech.2015.06.046","article-title":"Advances in tetrahydropyrido[1,2-a]isoindolone (valmerins) series: potent glycogen synthase kinase 3 and cyclin dependent kinase 5 inhibitors","volume":"101","author":"Boulahjar","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib49","doi-asserted-by":"crossref","first-page":"9589","DOI":"10.1021\/jm3008536","article-title":"Novel tetrahydropyrido[1,2-a]isoindolone derivatives (valmerins): potent cyclin-dependent kinase\/glycogen synthase kinase 3 inhibitors with antiproliferative activities and antitumor effects in human tumor xenografts","volume":"55","author":"Boulahjar","year":"2012","journal-title":"J.\u00a0Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib50","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1073\/pnas.0308206100","article-title":"Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation","volume":"101","author":"Bourne","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U. S. A"},{"key":"10.1016\/j.ejmech.2018.12.063_bib51","doi-asserted-by":"crossref","first-page":"6686","DOI":"10.1021\/ja043031t","article-title":"In situ selection of lead compounds by click chemistry: target-guided optimization of acetylcholinesterase inhibitors","volume":"127","author":"Krasinski","year":"2005","journal-title":"J.\u00a0Am. Chem. Soc."},{"key":"10.1016\/j.ejmech.2018.12.063_bib52","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1002\/1521-3773(20020315)41:6<1053::AID-ANIE1053>3.0.CO;2-4","article-title":"Click chemistry in situ: acetylcholinesterase as a reaction vessel for the selective assembly of a femtomolar inhibitor from an array of building blocks","volume":"41","author":"Lewis","year":"2002","journal-title":"Angew. Chem. Int. Ed."},{"key":"10.1016\/j.ejmech.2018.12.063_bib53","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.cbi.2005.10.018","article-title":"Structural insights into conformational flexibility at the peripheral site and within the active center gorge of AChE","volume":"157\u2013158","author":"Bourne","year":"2005","journal-title":"Chem. Biol. Interact."},{"key":"10.1016\/j.ejmech.2018.12.063_bib54","doi-asserted-by":"crossref","first-page":"4526","DOI":"10.1021\/ja058683b","article-title":"Conformational flexibility in the peripheral site of Torpedo californica acetylcholinesterase revealed by the complex structure with a bifunctional inhibitor","volume":"128","author":"Colletier","year":"2006","journal-title":"J.\u00a0Am. Chem. Soc."},{"key":"10.1016\/j.ejmech.2018.12.063_bib55","doi-asserted-by":"crossref","first-page":"5491","DOI":"10.1021\/jm060164b","article-title":"Complexes of alkylene-linked tacrine dimers with Torpedo californica acetylcholinesterase: binding of Bis5-tacrine produces a dramatic rearrangement in the active-site gorge","volume":"49","author":"Rydberg","year":"2006","journal-title":"J.\u00a0Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib56","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.ejmech.2016.02.072","article-title":"Novel optimization of valmerins (tetrahydropyrido[1,2-a]isoindolones) as potent dual CDK5\/GSK3 inhibitors","volume":"115","author":"Ouach","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib57","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J.\u00a0Comput. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib58","doi-asserted-by":"crossref","first-page":"9601","DOI":"10.1002\/anie.201603797","article-title":"Discovery of a highly selective glycogen synthase kinase-3 inhibitor (PF-04802367) that modulates tau phosphorylation in the brain: translation for PET neuroimaging","volume":"55","author":"Liang","year":"2016","journal-title":"Angew. Chem. Int. Ed."},{"key":"10.1016\/j.ejmech.2018.12.063_bib59","doi-asserted-by":"crossref","first-page":"9589","DOI":"10.1021\/jm3008536","article-title":"Novel tetrahydropyrido[1,2-a]isoindolone derivatives (valmerins): potent cyclin-dependent kinase\/glycogen synthase kinase 3 inhibitors with antiproliferative activities and antitumor effects in human tumor xenografts","volume":"55","author":"Boulahjar","year":"2012","journal-title":"J.\u00a0Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib60","doi-asserted-by":"crossref","first-page":"2450","DOI":"10.1002\/ejoc.201403649","article-title":"Synthetic route to rare isoindolones derivatives","author":"Oukoloff","year":"2015","journal-title":"Eur. J. Org. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib61","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.ejmech.2017.12.017","article-title":"1,3,5-triazaspiro[5.5]undeca-2,4-dienes as selective Mycobacterium tuberculosis dihydrofolate reductase inhibitors with potent whole cell activity","volume":"144","author":"Yang","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib62","article-title":"A\u00a0review of butyrylcholinesterase as a therapeutic target in the treatment of Alzheimer's disease","volume":"15","author":"Nordberg","year":"2013","journal-title":"Prim. Care Companion CNS Disord."},{"key":"10.1016\/j.ejmech.2018.12.063_bib63","first-page":"1985","article-title":"Oxcarbazepine-loaded polymeric nanoparticles: development and permeability studies across in\u00a0vitro models of the blood-brain barrier and human placental trophoblast","volume":"10","author":"Lopalco","year":"2015","journal-title":"Int. J. Nanomed."},{"key":"10.1016\/j.ejmech.2018.12.063_bib64","doi-asserted-by":"crossref","first-page":"3178","DOI":"10.1021\/acs.molpharmaceut.7b00405","article-title":"Oxazepam\u2013Dopamine conjugates increase dopamine delivery into striatum of intact rats","volume":"14","author":"Cassano","year":"2017","journal-title":"Mol. Pharm."},{"key":"10.1016\/j.ejmech.2018.12.063_bib65","doi-asserted-by":"crossref","first-page":"W443","DOI":"10.1093\/nar\/gkv315","article-title":"PLIP: fully automated protein-ligand interaction profiler","volume":"43","author":"Salentin","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.ejmech.2018.12.063_bib66","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/0006-2952(61)90145-9","article-title":"A\u00a0new and rapid colorimetric determination of acetylcholinesterase activity","volume":"7","author":"Ellman","year":"1961","journal-title":"Biochem. Pharmacol."},{"key":"10.1016\/j.ejmech.2018.12.063_bib67","doi-asserted-by":"crossref","first-page":"362","DOI":"10.3390\/molecules21030362","article-title":"Searching for multi-targeting neurotherapeutics against Alzheimer's: discovery of potent AChE-MAO B inhibitors through the decoration of the 2H-Chromen-2-one structural motif","volume":"21","author":"Pisani","year":"2016","journal-title":"Molecules"},{"key":"10.1016\/j.ejmech.2018.12.063_bib68","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.ejmech.2016.09.050","article-title":"Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists","volume":"125","author":"Franchini","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2018.12.063_bib69","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1007\/s11095-007-9255-y","article-title":"Novel L-Dopa and dopamine prodrugs containing a 2-phenyl-imidazopyridine moiety","volume":"24","author":"Denora","year":"2007","journal-title":"Pharm. Res. (N. Y.)"},{"key":"10.1016\/j.ejmech.2018.12.063_bib70","first-page":"57","article-title":"Python: a programming language for software integration and development","volume":"17","author":"Sanner","year":"1999","journal-title":"J.\u00a0Mol. Graph. Model."},{"key":"10.1016\/j.ejmech.2018.12.063_bib71","series-title":"The PyMOL Molecular Graphics System","author":"DeLano","year":"2002"},{"key":"10.1016\/j.ejmech.2018.12.063_bib72","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/0022-2836(88)90213-6","article-title":"Purification and crystallization of a dimeric form of acetylcholinesterase from Torpedo californica subsequent to solubilization with phosphatidylinositol-specific phospholipase C","volume":"203","author":"Sussman","year":"1988","journal-title":"J.\u00a0Mol. Biol."},{"key":"10.1016\/j.ejmech.2018.12.063_bib73","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1107\/S0907444909047374","article-title":"Integration, scaling, space-group assignment and post-refinement","volume":"66","author":"Kabsch","year":"2010","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"10.1016\/j.ejmech.2018.12.063_bib74","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1107\/S0021889807021206","article-title":"Phaser crystallographic software","volume":"40","author":"McCoy","year":"2007","journal-title":"J.\u00a0Appl. Crystallogr."},{"key":"10.1016\/j.ejmech.2018.12.063_bib75","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1107\/S0907444910026582","article-title":"Joint X-ray and neutron refinement with phenix","volume":"66","author":"Afonine","year":"2010","journal-title":"refine, Acta Crystallogr. D Biol. Crystallogr."},{"key":"10.1016\/j.ejmech.2018.12.063_bib76","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1107\/S0907444910007493","article-title":"Features and development of Coot","volume":"66","author":"Emsley","year":"2010","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"10.1016\/j.ejmech.2018.12.063_bib77","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1107\/S0907444904011679","article-title":"PRODRG: a tool for high-throughput crystallography of protein-ligand complexes","volume":"60","author":"Schuttelkopf","year":"2004","journal-title":"Acta Crystallogr. D Biol. Crystallogr."}],"container-title":["European Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523418311097?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523418311097?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T13:47:03Z","timestamp":1759326423000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0223523418311097"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4]]},"references-count":77,"alternative-id":["S0223523418311097"],"URL":"https:\/\/doi.org\/10.1016\/j.ejmech.2018.12.063","relation":{},"ISSN":["0223-5234"],"issn-type":[{"value":"0223-5234","type":"print"}],"subject":[],"published":{"date-parts":[[2019,4]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3","name":"articletitle","label":"Article Title"},{"value":"European Journal of Medicinal Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejmech.2018.12.063","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2019 Elsevier Masson SAS. All rights reserved.","name":"copyright","label":"Copyright"}]}}