Novel Copper Chelators Enhance Spatial Memory and Biochemical Outcomes in Alzheimer’s Disease Model

This study explores the potential of novel molecules that can act as copper chelators to treat Alzheimer's disease. Eight imines <b>L03-10</b> and one quinoline-based compound <b>L11</b> were synthesized, characterized, and evaluated as compounds that can act to reverse neurodegeneration in vivo. Their ability to extract copper from the Cu-β-amyloid complex, a key factor in Alzheimer's pathology, was assessed, achieving a remarkable in vitro activity for <b>L09</b>, <b>L10</b>, and <b>L11</b>. They effectively extracted it from the Cu-β-amyloid complex, which was confirmed using electron paramagnetic resonance (EPR) spectroscopy. In silico studies predicted that compounds <b>L09</b>, <b>L10</b>, and <b>L11</b> demonstrated favorable absorption, distribution, metabolism, and excretion (ADME) properties, suggesting suitability for oral administration and blood-brain barrier permeability. Cellular studies showed that compounds <b>L09</b> and <b>L10</b> (at concentrations up to 500 μM) exhibited low cytotoxicity. They reduced lipid peroxidation and DNA damage induced by beta-amyloid oligomers at lower concentrations. Compound <b>L11</b> showed more significant cytotoxicity but reduced beta-amyloid-induced DNA damage. In vivo studies (STZ-induced Alzheimer's rat model) proved that compound <b>L10</b> significantly reduced neuroinflammation, oxidative stress, and restored copper homeostasis in the hippocampus. This was accompanied by improved spatial memory performance in the Barnes maze test. Compounds <b>L09</b> and <b>L11</b> showed less impact on these parameters. The study presents compelling evidence that specifically designed copper chelators could offer a new therapeutic strategy for Alzheimer's disease. Compound <b>L10</b> is an up-and-coming candidate and warrants further investigation. The detailed in silico, in vitro, and in vivo analyses provide a solid motivation for future research and drug development efforts.