Drug development of new diphenylmethane scaffold-based compounds for the treatment of neurodegenerative disorders.

As life expectancy rises worldwide, we’re assisting to a worrying increase in the number of people affected by neurodegenerative disorders (NDDs), like Alzheimer’s Disease and Parkinson disease, for which there is no cure. NDDs comprehend a broad number of pathological conditions characterized by a diversified symptomatology and peculiar hallmarks, but united by a progressive and irreversible loss of neuronal functionality, i.e. neurodegeneration. Behind this neurodegenerative process there is a tangled network of pathogenic mechanisms affecting the fragile neuronal homeostasis, including proteostasis collapse, malfunctioning of lipid metabolism, and neuroinflammation. This complexity represents one of the main reasons of high rate of failures occurring in the drug discovery process for NDDs. Herein, we’ll describe the rational design and synthetic approach employed to develop new diphenylmethane scaffold-based polypharmacological agents, namely SG compounds, with a potential role in NDDs therapy. Results from a complete screening of new SG compounds on more than 20 assays to delineate their ADME-Tox profile will be presented. Moreover, we'll discuss the biological in vitro evaluation studies conducted on most promising SG compounds, along with their effects on lifespan, lipid metabolism, and autophagy observed in a C. elegans model of Alzheimer’s Disease.