Evaluation of a New Methylimidazole‐Containing Thiosemicarbazone as a Cu + /Cu 2+ ‐Targeting Ligand in the Context of Alzheimer's Disease

ABSTRACT 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 Cu 2+ at pH 7.4, with affinity constants (log K cond ) of 8.7 and 12.3, respectively, showing high selectivity over Zn 2+ (log K app = 5.0). In the presence of Aβ and Cu 2+ , HXE formed stable ternary complexes at physiological pH. Ascorbate consumption and coumarin‐3‐carboxylic acid fluorescence assays showed that the ligand significantly reduces Cu(Aβ 16 )‐mediated ROS production. It also prevented Cu 2+ ‐induced modulation of Aβ 40 self‐assembly and restored the typical fibrillar structure of apo‐Aβ 40 aggregates. Overall, HXE effectively modulates metal‐associated Aβ toxicity and emerges as a promising candidate for AD bioinorganic management.