A sustainable and semi-synthetic strategy for the discovery of novel multi-target anti-Alzheimer's agents

Alzheimer’s disease (AD) is the most widespread neurodegenerative disorder and represents a global socioeconomic emergency. Its origin is still unknown and currently there are only few available drugs that cannot alter its progression. The multifactorial profile of AD has led researchers to design multi-target direct ligands (MTDLs) as potential disease-altering agents. In this context, NInFA project uses nature as a source of inspiration for obtaining new potential multi-target drugs for the treatment of AD, following a semisynthetic approach. The starting point for the design of novel hybrids is the fungal secondary metabolite ochratoxin α (OTα), which has been combined with different portions mimicking clinically relevant anti-AD drugs, selected on the basis of previous works [2-4]. OTα was chosen as a natural scaffold due to its chemical versatility and potential biological activities, with the aim of giving extra-pharmacological properties to drug-like fragments. OTα was obtained by the hydrolysis of its precursor, ochratoxin A (OTA), which was produced by selected fungal strains. On the other hand, fragments inspired by anti-AD drugs (donepezil, rivastigmine and tacrine) were chemically synthetized according to the optimization of previous procedures. Both production/extraction of OTs and obtainment of synthetic moieties have been improved through the application of green chemistry, in particular by using deep eutectic solvents (DESs), neat conditions and alcoholic/hydroalcoholic media. Final hybrids will be purified, chemically characterized and tested in vitro on various classical and innovative AD targets. This communication explores results and possible follow-up of the NInFA project.