Discovery of N-methylpiperazinyl flavones as a novel class of compounds with therapeutic potential against Alzheimer's disease: synthesis, binding affinity towards amyloid β oligomers (Aβo) and ability to disrupt Aβo-PrPC interactions

With no currently available disease-modifying drugs, Alzheimer's disease is the most common type of dementia affecting over 47 million people worldwide. In light of the most recent discoveries placing the cellular prion protein (PrPC) as a key player in amyloid beta oligomer (A beta o)-induced neurodegeneration, we investigated whether the neuroprotective potential of nature-inspired flavonoids against A beta-promoted toxicity would translate into the ability to disrupt PrPC-A beta o interactions. Hence, we synthesized a small library of flavones and studied their binding affinity towards A beta o by STD-NMR. C-glucosyl flavones exhibited improved binding affinity with morpholine, thiomorpholine or N-methylpiperazine rings attached to the flavone skeleton in ring B para position. Moreover, a N-methylpiperazinyl flavone displayed suitable physico-chemical properties and optimal water solubility even without the sugar moiety, and a high interaction with A beta o involving the whole flavone core. Its C-glucosyl derivative, was, however, the best compound to inhibit PrPC-A beta o interactions in a dose-dependent manner, with 41 % of inhibition capacity at 10 mu M. The potential of C-glucosyl flavones and their aglycones as protein-protein interaction inhibitors able to tackle PrPC-A beta o interactions is here presented for the first time, and supports this class of compounds as new prototypes for further development in the treatment of Alzheimer's disease.