Naturally inspired molecules as multifunctional agents for Alzheimer's disease treatment

Alzheimer's disease (AD) has been defined as a multi-factorial disorder resulting from a complex array of networked cellular and molecular mechanisms. In particular, elevated levels of Aβ protein and its aggregation products in the presence of metal ions proved to be highly neurotoxic and therapeutic strategies aimed at preventing Aβ generation and oxidative stress may represent an effective approach for AD treatment. A recent paradigm for the treatment of complex diseases such as AD suggests the employment of multifunctional compounds, single chemical entities capable of simultaneously modulating different targets involved in the pathology. In this paper, the "pharmacophores combination" strategy was applied, connecting the main scaffold of the BACE-1 ligand 1 to that of the chalcone 2, as metal chelating pharmacophore, to obtain a small library of compounds. Conjugate 5 emerged as the most interesting derivative, proving to inhibit BACE-1 with low-micromolar potency, and showing neuroprotective effects. In particular, 5 proved to be able to protect from metal-associated oxidative stress by hampering intracellular Cu2+-induced ROS formation without any direct neurotoxic effect.