From fungal metabolites to multi-target ligands: a nature-inspired and green semi-synthetic strategy for Alzheimer’s disease drug discovery

The funded NInFA (Nature-Inspired structures: Fungal metabolites for a sustainable semi-synthetic approach to the discovery of new multi-target anti-Alzheimer’s drugs) project addressed the urgent need for innovative therapeutic strategies against Alzheimer’s disease (AD). The acronym, derived from the Greek “νύμφη” (minor deities of nature), reflects the central role of nature as both inspiration for drug design and a source of bioactive compounds [2]. Building on previous studies conducted by the participating research groups, and supported by international collaborations (University of Lisbon and University of Vienna), the project delivered a series of new chemical entities with multi-target activity (multi-target-directed ligands, MTDLs) acting on key pathological pathways involved in AD. Molecular design combined fungal secondary metabolites (ochratoxin α, OTα, and ochratoxin β, OTβ) with synthetic moieties inspired by approved anti-AD drugs (rivastigmine and donepezil), through linking and fusing strategies guided by in silico approaches. These hybrid compounds were successfully synthesized, structurally characterized, and biologically evaluated across both established (ChEs) and emerging targets (GSK-3β, FAAH), as well as for their antioxidant activity and metal-chelating properties. The preparation of MTDLs was further optimized under green chemistry conditions (including deep eutectic solvents (DESs), alcoholic media, and solvent-free systems), both for the extraction of natural metabolites and for synthesis, thereby enhancing the sustainability of the process. Selected compounds exhibited promising biological profiles, supported by preliminary pharmacokinetic characterization, identifying valuable hit candidates for further development.