Parkinson’s disease is one of the most common neurodegenerative disorders in elderly age.
One of the mechanisms involved in the neurodegeneration appears related to the aggregation
of the presynaptic protein alpha synuclein (α-syn) into toxic oligomers and fibrils. To
date, no highly effective treatment is currently available; therefore, there is an
increasing interest in the search of new therapeutic tools. The modulation of α-syn
aggregation represents an emergent and promising disease-modifying strategy for reducing
or blocking the neurodegenerative process. Herein, by combining
in
silico
and
in vitro
screenings we initially
identified 3-(cinnamylsulfanyl)-5-(4-pyridinyl)-1,2,4-triazol-4-amine (
3
) as
α-syn aggregation inhibitor that was then considered a promising hit for the further
design of a new series of small molecules. Therefore, we rationally designed new
hit-derivatives that were synthesised and evaluated by biological assays. Lastly, the
binding mode of the newer inhibitors was predicted by docking studies.