Leveraging nature as source of potential anti-Alzheimer’s drugs: The NInFA project

Alzheimer's disease (AD) is a multifactorial condition that is currently considered a global emergency due to its significant economic and social impact. Currently, the few available drugs could only improve the symptoms with a minor influence on the progression of the disease. In recent years monoclonal antibodies, such as Lecanemab, have been developed as the first disease-modifying agents, even if their use is not yet common due to the high costs and serious side effects. Following a different approach, the ambitious goal of discovering new potential small molecules with anti-AD activity is the point of the PRIN PNRR 2022 NinFA project (Nature-Inspired structures: Fungal metabolites for a sustainable semi-synthetic approach to the discovery of new multi-target anti-Alzheimer's drugs). Specifically, we planned to leverage nature as a source of chemical scaffolds for the semi-synthesis of new molecules with anti-AD potential multi-target activity. The project activities allowed the development of an innovative process for the extraction and purification of ochratoxin A from extracts produced by selected high producing microfungi strains using environmentally friendly methodologies such as the use of Deep Eutectic Solvents (DESs) and hydroalcoholic mixtures. The obtained OTA were employed as the starting point to obtain Ot-alpha, the key natural scaffold to be included the final hybrids, through the combination with different fragments from classical anti-AD drugs (e.g. donepezil and rivastigmine). All the synthetic pathways involved have been optimized applying green chemistry principles by using neat reactions, hydroalcoholic mixtures and DESs, reducing the use of volatile solvents when possible [3]. The potential biological activity of the different hybrids will be evaluated through in vitro assays against classic and innovative targets.