Evaluation of a New Methylimidazole‐Containing Thiosemicarbazone as a Cu+/Cu2+‐Targeting Ligand in the Context of Alzheimer's Disease
Résumé
The binding of copper ions to amyloid‐β (Aβ) peptide leads to reactive oxygen species (ROS) formation and toxic soluble oligomers, contributing to oxidative stress in Alzheimer's disease (AD). Thus, studying compounds with moderate copper affinity is a promising strategy to prevent its interaction with Aβ and reduce toxicity. Here, we evaluated a new tri‐coordinating thiosemicarbazone (HXE) with chelating properties to regulate cuprotoxicity in AD. The ligand was nontoxic against HT‐22 hippocampal neuronal cells and bound Cu+ and Cu2+ at pH 7.4, with affinity constants (log Kcond) of 8.7 and 12.3, respectively, showing high selectivity over Zn2+ (log Kapp = 5.0). In the presence of Aβ and Cu2+, HXE formed stable ternary complexes at physiological pH. Ascorbate consumption and coumarin‐3‐carboxylic acid fluorescence assays showed that the ligand significantly reduces Cu(Aβ16)‐mediated ROS production. It also prevented Cu2+ ‐induced modulation of Aβ40 self‐assembly and restored the typical fibrillar structure of apo‐Aβ40 aggregates. Overall, HXE effectively modulates metal‐associated Aβ toxicity and emerges as a promising candidate for AD bioinorganic management.
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