2- Aryloxymethylene-substituted scaffolds as privileged moieties for the design of new potential metal chelators in the multi-target therapy of Alzheimer's disease

Alzheimer's disease (AD) is the most spread neurodegenerative disorder and, at the moment, no drugs have been approved for its treatment. Different causes contribute to the onset and the progression of AD, in particular cholinergic disfunction, oxidative stress, metal dyshomeostasis and aggregation of proteins such as amyloid β (Aβ) and hyperphosphorylated tau. This multifactorial origin has directed the most recent studies towards the design of new multi-target hybrids for innovative therapies. In our last published studies, scaffolds mimicking donepezil2 or rivastigmine, two anti-AD drugs, were condensed with different aryloxyacetic acids through an amide bond. The resulting hybrids were chemically characterized and tested against different enzymes. Some of them, bearing nitro group in ortho position of aryloxy portion, showed an excellent activity as cholinesterases (ChEs) inhibitors. In order to increase the capability of these hybrids to chelate metals (such as Cu2+, Zn2+ and Fe3+) and inhibit Aβ aggregation, while maintaining some activity against both ChEs, specific modifications have been then introduced in a new series of compounds. In this communication the preliminary results of this new challenge will be presented.