Repurposing Rivastigmine Anti-AD Drug By Aryloxyacetic Hybridization: Biometal Chelation And Potential Increased Anti-Amyloidogenic Ability

Alzheimer’s disease (AD) is the most prevalent form of neurodegenerative disorders, affecting around 47 million people worldwide and by 2050 this number is expected to rise threefold. Despite thorough research, aimed at understanding AD pathophysiology and discovering new efficient anti-AD drugs, the precise mechanism and biological chemistry of AD are still unknown and so far, there is still no cure for this disease. Several hypotheses have been proposed for the disease mechanism and the neuropathology of AD, mainly associated with the accumulation of toxic amyloid peptides in the Central Nervous System (CNS), metal dyshomeostasis, oxidative stress, Tau-related pathologies, and cholinergic system dysfunction. The difficulties associated to the study of the brain, as well as the multifactorial nature of this disease, have greatly restricted the development of effective therapies. In fact, FDA-approved drugs (e.g. donepezil, rivastigmine) are mono-target compounds acting on cholinergic dysfunction with only symptomatic effects. So lately new AD therapeutic targets have emerged, namely polyfunctional drugs envisaging the tackling of multiple targets, with potential additive or synergistic effects and so with improved therapeutic efficacy. By adopting a multitarget strategy for drug design, combined with drug-reposition, rivastigmine templates (for cholinesterase inhibition) were hybridized with aryloxyacetic moieties to donate extra-pharmacological ability to the resulting hybrids (RIV-AOA). A series of RIV-AOA hybrids (Figure 1) were previously evaluated for cholinesterase (AChE, BChE) inhibition and some of them presented excellent inhibitory capacities, like donepezil drug. Unfortunately, their assayed anti-amyloidogenic abilities were poor and not interfering in copper-induced amyloid aggregation. Then, two further derivatives were projected and synthesized, as model compounds able of biometal (Cu, Zn) chelation, with the aim of obtaining additive properties like the inhibition of amyloid aggregation (absence or presence of Cu) and antioxidant activity.