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Thus, studying compounds with moderate copper affinity is a promising strategy to prevent its interaction with A\u03b2 and reduce toxicity. Here, we evaluated a new tri\u2010coordinating thiosemicarbazone (\n                    <jats:bold>HXE<\/jats:bold>\n                    ) with chelating properties to regulate cuprotoxicity in AD. The ligand was nontoxic against HT\u201022 hippocampal neuronal cells and bound Cu\n                    <jats:sup>+<\/jats:sup>\n                    and Cu\n                    <jats:sup>2+<\/jats:sup>\n                    at pH 7.4, with affinity constants (log\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>cond<\/jats:sub>\n                    ) of 8.7 and 12.3, respectively, showing high selectivity over Zn\n                    <jats:sup>2+<\/jats:sup>\n                    (log\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>app<\/jats:sub>\n                    = 5.0). In the presence of A\u03b2 and Cu\n                    <jats:sup>2+<\/jats:sup>\n                    ,\n                    <jats:bold>HXE<\/jats:bold>\n                    formed stable ternary complexes at physiological pH. Ascorbate consumption and coumarin\u20103\u2010carboxylic acid fluorescence assays showed that the ligand significantly reduces Cu(A\u03b2\n                    <jats:sub>16<\/jats:sub>\n                    )\u2010mediated ROS production. It also prevented Cu\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010induced modulation of A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    self\u2010assembly and restored the typical fibrillar structure of apo\u2010A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    aggregates. Overall,\n                    <jats:bold>HXE<\/jats:bold>\n                    effectively modulates metal\u2010associated A\u03b2 toxicity and emerges as a promising candidate for AD bioinorganic management.\n                  <\/jats:p>","DOI":"10.1002\/chem.202502754","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T10:09:32Z","timestamp":1764324572000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Evaluation of a New Methylimidazole\u2010Containing Thiosemicarbazone as a Cu\n                    <sup>+<\/sup>\n                    \/Cu\n                    <sup>2+<\/sup>\n                    \u2010Targeting Ligand in the Context of Alzheimer's Disease"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1203-7237","authenticated-orcid":false,"given":"Barbara","family":"Marinho Barbosa","sequence":"first","affiliation":[{"name":"Department 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Viana","family":"Costa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Basic Health Sciences Institute Federal University of Rio Grande Do Sul  Rio Grande do Sul Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ad\u00e8le","family":"Brison","sequence":"additional","affiliation":[{"name":"Laboratoire De Chimie de Coordination (LCC) CNRS, University of Toulouse  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2446-6697","authenticated-orcid":false,"given":"Sonia M.","family":"Ladeira","sequence":"additional","affiliation":[{"name":"Laboratoire De Chimie de Coordination (LCC) CNRS, University of Toulouse  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1454-2866","authenticated-orcid":false,"given":"Jade","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Basic Health Sciences Institute Federal University of Rio Grande Do Sul  Rio Grande do Sul Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3910-2499","authenticated-orcid":false,"given":"Csilla","family":"K\u00e1llay","sequence":"additional","affiliation":[{"name":"Department of Inorganic and Analytical Chemistry University of Debrecen  Debrecen Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3339-0239","authenticated-orcid":false,"given":"Christelle","family":"Hureau","sequence":"additional","affiliation":[{"name":"Laboratoire De Chimie de Coordination (LCC) CNRS, University of Toulouse  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0624-7560","authenticated-orcid":false,"given":"Nicol\u00e1s A.","family":"Rey","sequence":"additional","affiliation":[{"name":"Department of Chemistry Pontifical Catholic University of Rio de Janeiro (PUC\u2010Rio)  Rio de Janeiro Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.16370"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr400327t"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21239259"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00011.2024"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2025.216684"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-024-07206-3"},{"key":"e_1_2_9_8_1","first-page":"23","article-title":"Copper Imbalance in Alzheimer's Disease and Its Link With the Amyloid Hypothesis: Towards a Combined Clinical, Chemical, and Genetic Etiology","volume":"83","author":"Squitti R.","year":"2021","journal-title":"Journal of Advanced 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