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 L03-10 and one quinoline-based compound L11 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 L09, L10, and L11. 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 L09, L10, and L11 demonstrated favorable absorption, distribution, metabolism, and excretion (ADME) properties, suggesting suitability for oral administration and blood-brain barrier permeability. Cellular studies showed that compounds L09 and L10 (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 L11 showed more significant cytotoxicity but reduced beta-amyloid-induced DNA damage. In vivo studies (STZ-induced Alzheimer's rat model) proved that compound L10 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 L09 and L11 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 L10 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.