Tridentate Orotate-Inspired N-Acylhydrazone as a Potential Metal-Protein Attenuating Compound for Cu2+ in Alzheimer's Disease

As life expectancy increases, the prevalence of Alzheimer's disease (AD) also continues to rise. Metal dyshomeostasis, particularly involving Cu²⁺, has been implicated in AD pathogenesis by promoting β-amyloid (Aβ) aggregation and oxidative stress. N-Acylhydrazones have emerged as promising Metal-Protein Attenuating Compounds (MPACs) due to their ability to modulate metal-Aβ interactions. Based on recent findings identifying lithium orotate as a promising lithium salt for AD, we designed and synthesized X1Oro, a novel orotate-inspired N-acylhydrazone ligand. We hypothesized that the incorporation of the orotate moiety could redirect metal ions away from Aβ, thereby modulating metal-amyloid interactions. UV-Vis spectrophotometric titration studies demonstrated that X1Oro coordinates Cu²⁺ in buffered solution (pH 7.4), forming a 1:1 metal-ligand complex. These findings support its potential application as an MPAC for the development of new therapeutic strategies against AD.