Enhanced chelating agent with multi-target activity potentially useful for the treatment of Alzheimer’s Disease

Alzheimer's disease is a neurodegenerative disorder with deep implications for healthcare and economic systems. The onset of the disease is still unknown, even if a multifactorial origin has been proposed, entailing the co-occurrence of different pathological events such as Aβ aggregation, tau protein hyperphosphorylation, cholinergic disorders and metal dyshomeostasis. In previously published studies we identified multi-target compounds characterized by the presence of scaffolds mimicking the anti-AD drugs donepezil and rivastigmine (Fig.1) linked to different aryloxyacetic acids capable to donate extra-pharmacological properties such as chelating properties towards Fe3+, Cu2+ and Zn2+. An alteration of the concentration of these metal ions seems to be strictly linked to the formation of amyloid plaques, neurofibrillary tangles and oxidative stress typical of the disease. In detail, compounds bearing the nitro group in ortho position on the aryloxyacetic moiety showed high anticholinesterase activity but poor chelating properties towards Fe3+ and Cu2+ [3,4]. We subsequently replaced the nitro moiety of these compounds with the goal of improving their chelating capacity while keeping good anti-cholinesterase activities of this class of compounds. This communication will discuss the activity results of these new potential anti-AD small molecules.