Nature-inspired design of new anti-Alzheimer’s multi-target drugs: the NInFA project

Alzheimer's disease (AD) is one of the most common causes of dementia in the elderly with a major impact on the economy and healthcare, affecting about 50 million patients worldwide. It is characterized by an unknown origin and absence of effective treatments. In fact, the few available drugs can only improve symptoms with a low impact on the progression of the disease. Several hypotheses have been proposed to describe the complex AD physiopathology suggesting the multi- target paradigm as a promising approach to discover new potential anti-AD drugs. Since the nature has always been considered as an important source inspiration for the discovery and development of drugs, natural scaffolds can be used as starting point for the design of new anti-Alzheimer agents with innovative profiles. Then, starting from recently published results, new nature-inspired molecules have been designed in silico within the activity planned in the framework of the recently funded project NInFA. These molecules will be obtained by a semisynthetic approach combining fungal secondary metabolites (ochratoxin α, OTα and/or ochratoxin β, OTβ) with different synthetic moieties able to mimic some of the few drugs currently available for the therapy of AD. The different synthetic pathways will be optimized in the framework of green chemistry, in particular by using Deep eutectic solvents, alcoholic media or neat conditions. Lastly, their potential anti-AD activity will be evaluated through biological assays performed on classical and innovative targets of AD. In this communication, preliminary results of both synthesis and production/extraction activities will be discussed.