{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T16:41:57Z","timestamp":1787676117839,"version":"build-2784847793"},"reference-count":33,"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"}],"funder":[{"DOI":"10.13039\/501100005089","name":"Beijing Municipal Natural Science Foundation, China","doi-asserted-by":"publisher","award":["7172141"],"award-info":[{"award-number":["7172141"]}],"id":[{"id":"10.13039\/501100005089","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005089","name":"Beijing Municipal Natural Science Foundation, China","doi-asserted-by":"publisher","award":["7182115"],"award-info":[{"award-number":["7182115"]}],"id":[{"id":"10.13039\/501100005089","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China, China","doi-asserted-by":"publisher","award":["81573445"],"award-info":[{"award-number":["81573445"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China, China","doi-asserted-by":"publisher","award":["81503339"],"award-info":[{"award-number":["81503339"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Drug Innovation Major Project of China, China","award":["2018ZX09711001-003-001"],"award-info":[{"award-number":["2018ZX09711001-003-001"]}]},{"name":"Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, China","award":["BZ0150"],"award-info":[{"award-number":["BZ0150"]}]},{"name":"CAMS Innovation Fund for Medical Science, China","award":["2017-I2M-3-011"],"award-info":[{"award-number":["2017-I2M-3-011"]}]}],"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.2019.02.053","type":"journal-article","created":{"date-parts":[[2019,2,21]],"date-time":"2019-02-21T06:45:34Z","timestamp":1550731534000},"page":"207-220","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":39,"special_numbering":"C","title":["Design, synthesis, and evaluation of isoflavone analogs as multifunctional agents for the treatment of Alzheimer's disease"],"prefix":"10.1016","volume":"168","author":[{"given":"Dongmei","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinpeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengjuan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junmin","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaona","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5804-5293","authenticated-orcid":false,"given":"Tiantai","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ejmech.2019.02.053_bib1","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.jalz.2016.03.001","article-title":"Alzheimer's disease facts and figures","volume":"12","year":"2016","journal-title":"Alzheimers Dement"},{"key":"10.1016\/j.ejmech.2019.02.053_bib2","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/nrneurol.2011.2","article-title":"Epidemiology of Alzheimer disease","volume":"7","author":"Reitz","year":"2011","journal-title":"Nat. Rev. Neurol."},{"key":"10.1016\/j.ejmech.2019.02.053_bib3","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1146\/annurev-pharmtox-011613-135932","article-title":"Emerging therapeutics for Alzheimer's disease","volume":"54","author":"Chiang","year":"2014","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"10.1016\/j.ejmech.2019.02.053_bib4","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1126\/science.aau0437","article-title":"Alzheimer's disease: the right drug, the right time","volume":"362","author":"Golde","year":"2018","journal-title":"Science"},{"key":"10.1016\/j.ejmech.2019.02.053_bib5","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.ejmech.2018.07.033","article-title":"Multi-target-directed ligands for treating Alzheimer's disease: butyrylcholinesterase inhibitors displaying antioxidant and neuroprotective activities","volume":"156","author":"Knez","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2019.02.053_bib6","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1021\/acs.jmedchem.7b01417","article-title":"Design, synthesis, and evaluation of orally bioavailable quinoline-indole derivatives as innovative multitarget-directed ligands: promotion of cell proliferation in the Adult murine Hippocampus for the treatment of Alzheimer's disease","volume":"61","author":"Wang","year":"2018","journal-title":"J.\u00a0Med. Chem."},{"key":"10.1016\/j.ejmech.2019.02.053_bib7","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.ejmech.2018.06.044","article-title":"Tacripyrimidines, the first tacrine-dihydropyrimidine hybrids, as multi-target-directed ligands for Alzheimer's disease","volume":"155","author":"Chioua","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2019.02.053_bib8","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.ejmech.2017.08.025","article-title":"Discovery of novel propargylamine-modified 4-aminoalkyl imidazole substituted pyrimidinylthiourea derivatives as multifunctional agents for the treatment of Alzheimer's disease","volume":"143","author":"Xu","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2019.02.053_bib9","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1021\/acs.jmedchem.5b01119","article-title":"Novel tacrine-benzofuran hybrids as potent multitarget-directed ligands for the treatment of Alzheimer's disease: design, synthesis, biological evaluation, and X-ray crystallography","volume":"59","author":"Zha","year":"2016","journal-title":"J.\u00a0Med. Chem."},{"key":"10.1016\/j.ejmech.2019.02.053_bib10","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.ejmech.2017.01.042","article-title":"New tacrine-derived AChE\/BuChE inhibitors: synthesis and biological evaluation of 5-amino-2-phenyl-4H-pyrano[2,3-b]quinoline-3-carboxylates","volume":"128","author":"Eghtedari","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2019.02.053_bib11","doi-asserted-by":"crossref","first-page":"9046","DOI":"10.1039\/C8OB02741B","article-title":"New 3,5-dimethylorsellinic acid-based meroterpenoids with BACE1 and AchE inhibitory activities from Aspergillus terreus","volume":"16","author":"Qi","year":"2018","journal-title":"Org. Biomol. Chem."},{"key":"10.1016\/j.ejmech.2019.02.053_bib12","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.bbr.2009.12.044","article-title":"The history of the cholinergic hypothesis","volume":"221","author":"Contestabile","year":"2011","journal-title":"Behav. Brain Res."},{"key":"10.1016\/j.ejmech.2019.02.053_bib13","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.bbr.2016.06.051","article-title":"Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases","volume":"312","author":"Sadek","year":"2016","journal-title":"Behav. Brain Res."},{"key":"10.1016\/j.ejmech.2019.02.053_bib14","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/0006-8993(90)91240-H","article-title":"Three histamine receptors (H1, H2 and H3) visualized in the brain of human and non-human primates","volume":"526","author":"Martinez-Mir","year":"1990","journal-title":"Brain Res."},{"key":"10.1016\/j.ejmech.2019.02.053_bib15","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1152\/physrev.00043.2007","article-title":"Histamine in the nervous system","volume":"88","author":"Haas","year":"2008","journal-title":"Physiol. Rev."},{"key":"10.1016\/j.ejmech.2019.02.053_bib16","doi-asserted-by":"crossref","first-page":"705","DOI":"10.2174\/138161206775474251","article-title":"Neuroprotective therapies for Alzheimers disease","volume":"12","author":"Huber","year":"2006","journal-title":"Curr. Pharmaceut. Des."},{"key":"10.1016\/j.ejmech.2019.02.053_bib17","doi-asserted-by":"crossref","first-page":"85","DOI":"10.3389\/fnagi.2018.00085","article-title":"Methyl salicylate lactoside protects neurons ameliorating cognitive disorder through inhibiting amyloid beta-induced neuroinflammatory response in Alzheimer's disease","volume":"10","author":"Li","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"10.1016\/j.ejmech.2019.02.053_bib18","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1080\/14756366.2017.1347163","article-title":"Discovery of novel isoflavone derivatives as AChE\/BuChE dual-targeted inhibitors: synthesis, biological evaluation and molecular modelling","volume":"32","author":"Feng","year":"2017","journal-title":"J.\u00a0Enzym. Inhib. Med. Chem."},{"key":"10.1016\/j.ejmech.2019.02.053_bib19","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1111\/cbdd.12981","article-title":"Design, synthesis, biological evaluation, and molecular docking of novel flavones as H3 R inhibitors","volume":"90","author":"Wen","year":"2017","journal-title":"Chem. Biol. Drug Des."},{"key":"10.1016\/j.ejmech.2019.02.053_bib20","doi-asserted-by":"crossref","first-page":"3938","DOI":"10.1021\/jm030185v","article-title":"A\u00a0new class of diamine-based human histamine H3 receptor antagonists: 4-(Aminoalkoxy)benzylamines","volume":"46","author":"Apodaca","year":"2003","journal-title":"J.\u00a0Med. Chem."},{"key":"10.1016\/j.ejmech.2019.02.053_bib21","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/sj.bjp.0705964","article-title":"Acute wake-promoting actions of JNJ-5207852, a novel, diamine-based H3 antagonist","volume":"143","author":"Barbier","year":"2004","journal-title":"Br. J. Pharmacol."},{"key":"10.1016\/j.ejmech.2019.02.053_bib22","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1016\/j.bmcl.2014.03.098","article-title":"Benzylpiperidine variations on histamine H3 receptor ligands for improved drug-likeness","volume":"24","author":"Wingen","year":"2014","journal-title":"Bioorg. Med. Chem. Lett"},{"key":"10.1016\/j.ejmech.2019.02.053_bib23","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.2019.02.053_bib24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pneurobio.2016.07.005","article-title":"Oxidative stress: a major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson's disease and Alzheimer's disease","volume":"147","author":"Jiang","year":"2016","journal-title":"Prog. Neurobiol."},{"key":"10.1016\/j.ejmech.2019.02.053_bib25","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.foodchem.2014.12.087","article-title":"Comparing antioxidant capacity of purine alkaloids: a new, efficient trio for screening and discovering potential antioxidants in\u00a0vitro and in\u00a0vivo","volume":"176","author":"Tsoi","year":"2015","journal-title":"Food Chem."},{"key":"10.1016\/j.ejmech.2019.02.053_bib26","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1021\/jf0305231","article-title":"Extending applicability of the oxygen radical absorbance capacity (ORAC-fluorescein) assay","volume":"52","author":"Davalos","year":"2004","journal-title":"J.\u00a0Agric. Food Chem."},{"key":"10.1016\/j.ejmech.2019.02.053_bib27","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1006\/jmbi.1996.0897","article-title":"Development and validation of a genetic algorithm for flexible docking","volume":"267","author":"Jonse","year":"1997","journal-title":"J.\u00a0Mol. Biol."},{"key":"10.1016\/j.ejmech.2019.02.053_bib28","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/nrn3880","article-title":"Immune attack: the role of inflammation in Alzheimer disease","volume":"16","author":"Heppner","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"10.1016\/j.ejmech.2019.02.053_bib29","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","article-title":"Neuroinflammation in Alzheimer's disease","volume":"14","author":"Heneka","year":"2015","journal-title":"Lancet Neurol."},{"key":"10.1016\/j.ejmech.2019.02.053_bib30","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1111\/j.1365-2990.2012.01307.x","article-title":"Review: systemic inflammation and Alzheimer's disease","volume":"39","author":"Holmes","year":"2013","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"10.1016\/j.ejmech.2019.02.053_bib31","doi-asserted-by":"crossref","first-page":"5843","DOI":"10.1021\/jm400567s","article-title":"Design, synthesis, and evaluation of multitarget-directed resveratrol derivatives for the treatment of Alzheimer's disease","volume":"56","author":"Lu","year":"2013","journal-title":"J.\u00a0Med. Chem."},{"key":"10.1016\/j.ejmech.2019.02.053_bib32","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.ejmech.2017.04.054","article-title":"Design, synthesis and evaluation of scutellarein-O-acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease","volume":"135","author":"Sang","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2019.02.053_bib33","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/1742-2094-8-98","article-title":"Methyl salicylate 2-O-beta-D-lactoside, a novel salicylic acid analogue, acts as an anti-inflammatory agent on microglia and astrocytes","volume":"8","author":"Lan","year":"2011","journal-title":"J.\u00a0Neuroinflammation"}],"container-title":["European Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523419301679?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523419301679?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T13:47:29Z","timestamp":1759326449000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0223523419301679"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4]]},"references-count":33,"alternative-id":["S0223523419301679"],"URL":"https:\/\/doi.org\/10.1016\/j.ejmech.2019.02.053","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, synthesis, and evaluation of isoflavone analogs as multifunctional agents for the treatment of Alzheimer's disease","name":"articletitle","label":"Article Title"},{"value":"European Journal of Medicinal Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejmech.2019.02.053","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"}]}}