Improved 2-aryloxymethylene moieties as novel potential chelators for the multi-target treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and it is characterized by a progressive loss of cognitive functions. Several factors are involved in the onset of this pathology, including a dysfunction in cholinergic system, metal dyshomeostasis, oxidative stress and aggregation of amyloid β (Aβ) and hyperphosphorylated tau proteins . At the moment, the most clinically relevant drugs, such as donepezil and rivastigmine, are only capable to mildly improve its symptoms and mostly act on cholinergic function. The multifactorial profile of AD has led researchers to study new multi-target compounds. Recently, scaffolds mimicking anti-AD drugs donepezil or rivastigmine were combined, through an amide bond, with selected aryloxyacetic acids. These hybrids were chemically and biologically characterized. Some compounds, presenting a nitro group in ortho position of the aryloxy portion, exhibited an excellent inhibitory activity against cholinesterases. Starting from these promising compounds, specific structural modifications have been then introduced, aiming to increase their ability to chelate biometals, in particular Cu2+, Zn2+ and Fe3+ and to inhibit the aggregation of Aβ, while trying to maintain their promising anticholinesterase activity. These new hybrids were synthesized in the framework of green chemistry, for example by the use of deep eutectic solvents (DESs) and neat conditions4. Moreover, they were in vitro tested on aforementioned targets and some pharmacokinetic properties were evaluated with analytical methods. This communication will present these preliminary results.