Protein misfolding diseases (PMDs) are chronic and progressively degenerative disorders, characterized by the accumulation of insoluble aggregates of misfolded proteins. Particularly, amyloid-\u3b2 and tau protein in Alzheimer\u2019s disease, prion protein in prion diseases, and \u3b1-synuclein in Parkinson disease are prototypical misfolded proteins that aggregate and accumulate in the brain, being responsible for the respective neurodegenerative disease. In the last decades, neurodegenerative PMDs have drawn public and scientific attention due to an increasing number of cases, becoming a critical issue in terms of healthcare and social costs. Moreover, while the list of neurodegenerative PMDs is long and growing, the pipeline of disease-modifying drugs is dry. In light of this clear unmet medical need, the present PhD thesis has been devoted to the development of three small-molecule libraries for neurodegenerative PMDs, through different and innovative strategies. First, we applied the multi-target directed ligand approach and we developed the first class of multi-target compounds able to hit the tau cascade at two different hubs. The synthesized 2,4-thiazolidinedione derivatives were able to concomitantly inhibit the phosphorylating tau kinase GSK-3\u3b2, as well as the tau aggregation process. Thus, these multi-target compounds could be promising tools for the validation of a completely new tau-centric approach as a disease-modifying strategy to treat Alzheimer\u2019s disease. Secondly, we applied the theranostic approach and we designed and synthesized a library of fluorescent bivalent derivatives. These bivalent compounds could be able, in principle, to stain A\u3b2 and tau protein aggregates and to inhibit the protein aggregation process. If we will be able to further demonstrate their theranostic profile in vitro and in vivo, these compounds could serve as innovative tools to potentially diagnose, deliver therapy, and monitor response to therapy in PMDs. Finally, we designed a focused library of compounds with the aim of optimizing the drug-like properties of a previously identified antiprion compound. Namely, we inserted on a position amenable to derivatization solubilizing groups, specifically tailored for CNS drug optimization. If our design strategy will be successful, we will have improved the pharmacokinetic properties of a promising antiprion compound, making possible its progression to further in vivo studies
