{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T12:11:47Z","timestamp":1790424707319,"version":"4.1.0"},"reference-count":55,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Excellent Young and Middle-aged Scientific and Technological Innovation Team Program of Hubei Province","award":["T2023042"],"award-info":[{"award-number":["T2023042"]}]},{"name":"Research and Development Fund of Wuchang University of Technology","award":["X2024ZZ001"],"award-info":[{"award-number":["X2024ZZ001"]}]},{"name":"Innovation Foundation of the Synergy Innovation Center of Biological Peptide Antidiabetics of Hubei Province","award":["HBSWDT202503Z"],"award-info":[{"award-number":["HBSWDT202503Z"]}]},{"name":"Innovation Foundation of the Synergy Innovation Center of Biological Peptide Antidiabetics of Hubei Province","award":["HBSWDT202505Z"],"award-info":[{"award-number":["HBSWDT202505Z"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A new series of tacrine\u2013coumarin hybrids (compounds 15a\u201318b) linked by 1,2,3-triazole had been designed and synthesized as multifunctional ligands for the treatment of Alzheimer\u2019s disease (AD). The inhibitory effects of the synthesized compounds on AChE and BuChE, their ability to inhibit A\u03b2 aggregation, and their MAO inhibitory activities were evaluated. In vitro studies showed that some of the hybrids (compounds 17a\u201318b) exhibited significant abilities to inhibit both AChE and BuChE, self-induced A\u03b2 aggregation, and MAO-B. In particular, compound 17d showed a well-balanced inhibitory profile against AChE and BuChE (IC50 = 0.080 \u00b1 0.007 \u03bcM for AChE, IC50 = 0.044 \u00b1 0.004 \u03bcM for BuChE), self-induced A\u03b2 aggregation (58.4% \u00b1 2.1% at 20 \u03bcM), and MAO-B (IC50 = 0.18 \u00b1 0.01 \u03bcM), suggesting that 17d might be an excellent multifunctional agent for AD treatment. In addition, compounds 15a and 15b were identified as selective inhibitors of BuChE at micromolar concentrations.<\/jats:p>","DOI":"10.3390\/molecules31040595","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T12:42:42Z","timestamp":1770640962000},"page":"595","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Design and Synthesis of Tacrine\u2013Coumarin Hybrids via Click Chemistry as Multifunctional Cholinesterase Inhibitors for the Treatment of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6867-1893","authenticated-orcid":false,"given":"Xiaohua","family":"Wang","sequence":"first","affiliation":[{"name":"Synergy Innovation Center of Biological Peptide Antidiabetics of Hubei Province, College of Life Science, Wuchang University of Technology, Wuhan 430223, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueliang","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Chemistry and Environmental Engineering, Key Laboratory of Green Chemical Engineering Process of Ministry of Education, Wuhan Institute of Technology, Wuhan 430205, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanwan","family":"Jin","sequence":"additional","affiliation":[{"name":"Synergy Innovation Center of Biological Peptide Antidiabetics of Hubei Province, College of Life Science, Wuchang University of Technology, Wuhan 430223, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Tan","sequence":"additional","affiliation":[{"name":"Synergy Innovation Center of Biological Peptide Antidiabetics of Hubei Province, College of Life Science, Wuchang University of Technology, Wuhan 430223, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0358-2347","authenticated-orcid":false,"given":"Gang","family":"Wang","sequence":"additional","affiliation":[{"name":"Synergy Innovation Center of Biological Peptide Antidiabetics of Hubei Province, College of Life Science, Wuchang University of Technology, Wuhan 430223, China"},{"name":"School of Chemistry and Environmental Engineering, Key Laboratory of Green Chemical Engineering Process of Ministry of Education, Wuhan Institute of Technology, Wuhan 430205, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.jalz.2011.05.2410","article-title":"Neuropsychiatric symptoms in Alzheimer\u2019s disease","volume":"7","author":"Lyketsos","year":"2011","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_2","unstructured":"(2019). GBD 2016 Dementia Collaborators. Global, regional, and national burden of Alzheimer\u2019s disease and other dementias, 1990\u20132016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol., 18, 88\u2013106."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1002\/alz.12694","article-title":"Global estimates on the number of persons across the Alzheimer\u2019s disease continuum","volume":"19","author":"Gustavsson","year":"2023","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_4","unstructured":"GBD 2019 Dementia Forecasting Collaborators (2022). Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the Global Burden of Disease Study 2019. Lancet Public Health, 7, e105\u2013e125."},{"key":"ref_5","first-page":"a006262","article-title":"Biochemistry of amyloid \u03b2-protein and amyloid deposits in Alzheimer disease","volume":"2","author":"Masters","year":"2012","journal-title":"CSH Perspect. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1177\/1533317517709549","article-title":"Oxidative stress markers and metal ions are correlated with cognitive function in Alzheimer\u2019s disease","volume":"32","author":"Pu","year":"2017","journal-title":"Am. J. Alzheimers. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1002\/ana.410300410","article-title":"Physical basis of cognitive alterations in alzheimer\u2019s disease: Synapse loss is the major correlate of cognitive impairment","volume":"30","author":"Terry","year":"1991","journal-title":"Ann. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S567","DOI":"10.3233\/JAD-179941","article-title":"The amyloid-\u03b2 oligomer hypothesis: Beginning of the third decade","volume":"64","author":"Cline","year":"2018","journal-title":"J. Alzheimers. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.nurt.2008.05.001","article-title":"Therapeutics for Alzheimer\u2019s disease based on the metal hypothesis","volume":"5","author":"Bush","year":"2008","journal-title":"Neurotherapeutics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1126\/science.7046051","article-title":"The cholinergic hypothesis of geriatric memory dysfunction","volume":"217","author":"Bartus","year":"1982","journal-title":"Science"},{"key":"ref_11","first-page":"1479","article-title":"Cholinesterase inhibitors as Alzheimer\u2019s therapeutics (review)","volume":"20","author":"Sharma","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1002\/cne.903060202","article-title":"Acetylcholinesterase-rich neurons of the human cerebral cortex: Cytoarchitectonic and ontogenetic patterns of distribution","volume":"306","author":"Mesulam","year":"1991","journal-title":"J. Comp. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.2174\/092986708785909067","article-title":"Acetylcholinesterase inhibitors as disease-modifying therapies for Alzheimer\u2019s disease","volume":"15","year":"2008","journal-title":"Curr. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1021\/jm070154q","article-title":"Bis-(\u2212)-nor-meptazinols as novel nanomolar cholinesterase inhibitors with high inhibitory potency on amyloid-\u03b2 aggregation","volume":"51","author":"Xie","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_15","first-page":"759","article-title":"Outcomes of Alzheimer\u2019s disease therapy with acetylcholinesterase inhibitors and memantine","volume":"13","author":"Zemek","year":"2014","journal-title":"Expert Opin. Drug. Saf."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1126\/science.1678899","article-title":"Atomic structure of acetylcholinesterase from Torpedo californica: A prototypic acetylcholine-binding protein","volume":"253","author":"Sussman","year":"1991","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4309","DOI":"10.1021\/jm300106z","article-title":"Tacrine\u2013ferulic acid\u2013nitric oxide (NO) donor trihybrids as potent, multifunctional acetyl-and butyrylcholinesterase inhibitors","volume":"55","author":"Chen","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1097\/NEN.0b013e31823cc7a6","article-title":"Butyrylcholinesterase is associated with \u03b2-amyloid plaques in the transgenic APPSWE\/PSEN1dE9 mouse model of Alzheimer disease","volume":"71","author":"Darvesh","year":"2012","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2232","DOI":"10.1016\/j.bmc.2010.01.066","article-title":"Differential binding of phenothiazine urea derivatives to wild-type human cholinesterases and butyrylcholinesterase mutants","volume":"18","author":"Darvesh","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Behl, T., Kaur, D., Sehgal, A., Singh, S., Sharma, N., Zengin, G., Andronie-Cioara, F.L., Toma, M.M., Bungau, S., and Bumbu, A.G. (2021). Role of monoamine oxidase activity in Alzheimer\u2019s disease: An insight into the therapeutic potential of inhibitors. Molecules, 26.","DOI":"10.3390\/molecules26123724"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4017","DOI":"10.2174\/1381612827666210612051713","article-title":"Exploring the role of monoamine oxidase activity in aging and alzheimer\u2019s disease","volume":"27","author":"Rahman","year":"2021","journal-title":"Curr. Pharm. Des."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4220","DOI":"10.1021\/bi900413g","article-title":"Molecular and mechanistic properties of the membrane-bound mitochondrial monoamine oxidases","volume":"48","author":"Edmondson","year":"2009","journal-title":"Biochemistry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.2174\/0929867043364810","article-title":"Monoamine oxidases: Certainties and uncertainties","volume":"11","author":"Tipton","year":"2004","journal-title":"Curr. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2460","DOI":"10.1093\/brain\/awx172","article-title":"Brain monoamine oxidase B and A in human parkinsonian dopamine deficiency disorders","volume":"140","author":"Tong","year":"2017","journal-title":"Brain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/s00702-024-02866-z","article-title":"Type A monoamine oxidase; its unique role in mood, behavior and neurodegeneration","volume":"132","author":"Naoi","year":"2025","journal-title":"J. Neural. Transm."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Nam, M.H., Sa, M., Ju, Y.H., Park, M.G., and Lee, C.J. (2022). Revisiting the role of astrocytic MAOB in Parkinson\u2019s disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23084453"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.pnpbp.2013.02.001","article-title":"An update on amine oxidase inhibitors: Multifaceted drugs","volume":"44","author":"Song","year":"2013","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S0161-813X(03)00106-2","article-title":"Monoamine oxidase-B inhibition in Alzheimer\u2019s disease","volume":"25","author":"Riederer","year":"2004","journal-title":"Neurotoxicology"},{"key":"ref_29","first-page":"463","article-title":"Multi-target design strategies for the improved treatment of Alzheimer\u2019s disease","volume":"158","author":"Zhang","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1021\/acs.chemrev.8b00138","article-title":"Development of multifunctional molecules as potential therapeutic candidates for alzheimer\u2019s disease, parkinson\u2019s disease, and amyotrophic lateral sclerosis in the last decade","volume":"119","author":"Savelieff","year":"2019","journal-title":"Chem. Rev."},{"key":"ref_31","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\u2019s disease","volume":"22","author":"Guzior","year":"2015","journal-title":"Curr. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wang, X.H., Ma, M.L., Feng, Y.L., Liu, J., and Wang, G. (2025). Multifunctional Tacrine\u2013Quinoline Hybrids as Cholinesterase Inhibitors, A\u03b2 Aggregation Blockers, and Metal Chelators for Alzheimer\u2019s Therapy. Molecules, 30.","DOI":"10.3390\/molecules30173489"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1016\/j.bmc.2011.12.042","article-title":"A review on coumarins as acetylcholinesterase inhibitors for Alzheimer\u2019s disease","volume":"20","author":"Anand","year":"2012","journal-title":"Bioorganic Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2434","DOI":"10.1016\/j.bmc.2013.02.017","article-title":"A comprehensive review on synthesis and designing aspects of coumarin derivatives as monoamine oxidase inhibitors for depression and Alzheimer\u2019s disease","volume":"21","author":"Patil","year":"2013","journal-title":"Bioorganic Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2210","DOI":"10.2174\/156802612805220002","article-title":"Focusing on new monoamine oxidase inhibitors: Differently substituted coumarins as an interesting scaffold","volume":"12","author":"Uriarte","year":"2012","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1021\/jm801496u","article-title":"Synthesis, molecular modeling, and selective inhibitory activity against human monoamine oxidases of 3-carboxamido-7-substituted coumarins","volume":"52","author":"Chimenti","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.ejmech.2015.03.040","article-title":"Multi-target tacrine-coumarin hybrids: Cholinesterase and monoamine oxidase B inhibition properties against Alzheimer\u2019s disease","volume":"95","author":"Xie","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7073","DOI":"10.1021\/jm5008648","article-title":"Synthesis and biological evaluation of novel tacrine derivatives and tacrine\u2013coumarin hybrids as cholinesterase inhibitors","volume":"57","author":"Hamulakova","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4784","DOI":"10.1016\/j.bmc.2014.06.057","article-title":"Syntheses of coumarin\u2013tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, A\u03b2 aggregation, and \u03b2-secretase","volume":"22","author":"Sun","year":"2014","journal-title":"Bioorganic Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.ejmech.2013.03.051","article-title":"Design, synthesis and evaluation of novel tacrine\u2013coumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer\u2019s disease","volume":"64","author":"Xie","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3614","DOI":"10.1016\/j.bmc.2013.02.047","article-title":"Investigation of the role of linker moieties in bifunctional tacrine hybrids","volume":"21","author":"Eckroat","year":"2013","journal-title":"Bioorganic Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.ejmech.2015.01.044","article-title":"Potent acetylcholinesterase inhibitors: Design, synthesis, biological evaluation, and docking study of acridone linked to 1,2,3-triazole derivatives","volume":"92","author":"Saeedi","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1002\/ardp.201400365","article-title":"9H-Carbazole derivatives containing the n-benzyl-1,2,3-triazole moiety as new acetylcholinesterase inhibitors","volume":"348","author":"Akrami","year":"2015","journal-title":"Archiv. Der. Pharmazie."},{"key":"ref_44","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. USA"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Cicco, L., Perna, F.M., Capriati, V., and Vitale, P. (2024). A sustainable synthetic approach to tacrine and cholinesterase inhibitors in deep eutectic solvents under aerobic conditions. Molecules, 29.","DOI":"10.3390\/molecules29061399"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.ejmech.2017.12.005","article-title":"Development of tacrine-bifendate conjugates with improved cholinesterase inhibitory and pro-cognitive efficacy and reduced hepatotoxicity","volume":"144","author":"Cen","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/0006-2952(61)90145-9","article-title":"A new and rapid colorimetric determination of acetylcholinesterase activity","volume":"7","author":"Ellman","year":"1961","journal-title":"Biochem. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/0028-3908(87)90189-4","article-title":"Time course of ethylcholine aziridinium ion (AF64A)-induced cholinotoxicity in vivo","volume":"26","author":"Leventer","year":"1987","journal-title":"Neuropharmacology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1016\/j.bbapap.2010.04.001","article-title":"Molecular mechanism of Thioflavin-T binding to amyloid fibrils","volume":"18","author":"Biancalana","year":"2010","journal-title":"BBA-Proteins. Proteom."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"341","DOI":"10.2174\/157018010791163532","article-title":"Design, synthesis and evaluation of tacrine based acetylcholinesterase inhibitors","volume":"7","author":"Shen","year":"2010","journal-title":"Lett. Drug. Des. Discov."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4559","DOI":"10.1016\/j.bmc.2013.05.028","article-title":"Design, synthesis and neuroprotective evaluation of novel tacrine\u2013benzothiazole hybrids as multi-targeted compounds against Alzheimer\u2019s disease","volume":"21","author":"Keri","year":"2013","journal-title":"Bioorganic Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Shi, Z.L., Liu, N., Zhao, F.B., Kang, D.W., De Jonghe, S., Neyts, J., Ni, G., and Liu, X.Y. (2025). Discovery of Small Molecules Targeting Norovirus 3CL Protease by Multi-Stage Virtual Screening. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26125625"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"427","DOI":"10.2174\/1871527320666210928160159","article-title":"Acetylcholinesterase enzyme inhibitor molecules with therapeutic potential for alzheimer\u2019s disease","volume":"21","author":"Sivaraman","year":"2022","journal-title":"CNS Neurol. Disord.-Drug Targets-CNS Neurol. Disord."},{"key":"ref_54","unstructured":"Dong, C.Z., Wang, G., Huang, J., Wang, R., and Quan, L.Y. (2019). A containing triazol Tacrine\u2014Coumarin Derivatives and Application Thereof. (CN105503840)."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.ejphar.2015.07.015","article-title":"Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against A\u03b2 (1\u201342)-induced toxicity","volume":"764","author":"Caraci","year":"2015","journal-title":"Eur. J. Pharmacol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/4\/595\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T12:44:43Z","timestamp":1770641083000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/4\/595"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,9]]},"references-count":55,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["molecules31040595"],"URL":"https:\/\/doi.org\/10.3390\/molecules31040595","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,9]]}}}