Rational approach to an antiprion compound with a multiple mechanism of action

Background: The main pathogenic event of prion disorders has been identified in the deposition of the disease-associated prion protein (PrP(Sc)), which is accompanied by metal dyshomeostasis. Results: The multitarget-directed ligand 1, designed by combining a heteroaromatic prion recognition motif to an 8-hydroxyquinoline metal chelator, has been developed as a potential antiprion disease-modifying agent. Importantly, 1 was found to effectively clear PrP(Sc) from scrapie-infected cells, and, at the same time, inhibit metal-induced prion aggregation and reactive oxygen species generation. 1 was also characterized in terms of pharmacokinetic properties in a preliminary in vitro investigation. Conclusion: Compound 1 has emerged as a suitable lead candidate against prion diseases and as a good starting point for a further optimization process.