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Subsequently, a subset of these derivatives was investigation to inhibit A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    aggregation and promote A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    disaggregation effects. Among them, compounds\n                    <jats:bold>8b<\/jats:bold>\n                    ,\n                    <jats:bold>8c<\/jats:bold>\n                    ,\n                    <jats:bold>8j<\/jats:bold>\n                    , and\n                    <jats:bold>8ab<\/jats:bold>\n                    possessing good activity were further assayed for their inhibitory effects on BACE\u20101 and GSK3\u03b2, as well as their PI displacement activity.\n                    <jats:bold>8b<\/jats:bold>\n                    (AChE, IC\n                    <jats:sub>50<\/jats:sub>\n                    : 0.11\u2009\u03bcM; BChE, IC\n                    <jats:sub>50<\/jats:sub>\n                    : 0.18\u2009\u03bcM; A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    aggregation, IC\n                    <jats:sub>50<\/jats:sub>\n                    : 3.40\u2009\u03bcM; their ability to promote A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    disaggregation, IC\n                    <jats:sub>50<\/jats:sub>\n                    : 4.53\u2009\u03bcM; BACE\u20101, IC\n                    <jats:sub>50<\/jats:sub>\n                    : 1.82\u2009\u03bcM; GSK3\u03b2, IC\n                    <jats:sub>50<\/jats:sub>\n                    : 0.98\u2009\u03bcM) exhibited prominent bioactivities across the above assays. Meanwhile, the molecular docking and the molecular dynamics simulations were performed to analyze the interactions between\n                    <jats:bold>8b<\/jats:bold>\n                    and the key amino acid residues of the target proteins, which verified the stability of the corresponding protein ligand complexes. Furthermore,\n                    <jats:bold>8b<\/jats:bold>\n                    significantly attenuated the cytotoxicity induced by Fe\n                    <jats:sup>3+<\/jats:sup>\n                    and Cu\n                    <jats:sup>2+<\/jats:sup>\n                    in BV\u20102 microglial cells, L\u2010Glu in HT\u201022 hippocampal neuronal cells, and A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    in both BV\u20102 and SH\u2010SY5Y neuroblastoma cells. Additionally,\n                    <jats:bold>8b<\/jats:bold>\n                    reduced the levels of intracellular ROS and NO in LPS\u2010stimulated BV\u20102 cells, demonstrating potent anti\u2010inflammatory and neuroprotective properties. Acute toxicity tests in mice confirmed the safety profile of\n                    <jats:bold>8b<\/jats:bold>\n                    . In in\u00a0vivo studies, compound\n                    <jats:bold>8b<\/jats:bold>\n                    effectively protected against neuroinflammation\n                    <jats:bold>8b<\/jats:bold>\n                    ameliorated cognitive deficits in mice induced by AlCl\n                    <jats:sub>3<\/jats:sub>\n                    combined with L\u2010galactose, which was associated with the upregulation of\n                    <jats:italic>p<\/jats:italic>\n                    \u2010GSK3\u03b2 and the downregulation of\n                    <jats:italic>p<\/jats:italic>\n                    \u2010Tau expression. In conclusion,\n                    <jats:bold>8b<\/jats:bold>\n                    holds great potential as a promising multitarget\u2010directed new lead compound for the treatment of AD.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70316","type":"journal-article","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T10:20:58Z","timestamp":1779531658000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Donepezil\u2013Chalcone Hybrids as Potential Multifunctional Anti\u2010Alzheimer\u2019s Disease Agents: Design, Synthesis, Computational Simulation, and In\u00a0Vitro\/In Vivo Biological Evaluation"],"prefix":"10.1111","volume":"107","author":[{"given":"Zhiqi","family":"Lin","sequence":"first","affiliation":[{"name":"Food and Pharmacy College Zhejiang Ocean University  Zhejiang Zhoushan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenze","family":"Jiang","sequence":"additional","affiliation":[{"name":"Trine Engineering Institute, Shaanxi University of Technology  Shaanxi Hanzhong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Die","family":"Chen","sequence":"additional","affiliation":[{"name":"Food and Pharmacy College Zhejiang Ocean University  Zhejiang Zhoushan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanxiu","family":"Liu","sequence":"additional","affiliation":[{"name":"Food and Pharmacy College Zhejiang Ocean University  Zhejiang Zhoushan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixin","family":"He","sequence":"additional","affiliation":[{"name":"Food and Pharmacy College Zhejiang Ocean University  Zhejiang Zhoushan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Ning","sequence":"additional","affiliation":[{"name":"Food and Pharmacy College Zhejiang Ocean University  Zhejiang Zhoushan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1398-3360","authenticated-orcid":false,"given":"Sihong","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Natural Resource of the Changbai Mountain and Functional Molecules, Ministry of Education Yanbian University  Jilin Yanji China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Guan","sequence":"additional","affiliation":[{"name":"Food and Pharmacy College Zhejiang Ocean University  Zhejiang Zhoushan 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