Exploitation of the nitro- and/or 4-Trifluoromethyl-decorated phenyl fragment to develop small inhibitors of Alpha-Syn fibril aggregation

Here, we report new 2-nitro and/or 4-trifluoromethylphenyl-based small molecules developed as inhibitors of alpha-Syn fibril formation. The set of eighteen compounds was inspired by well-known alpha-Syn aggregation modulators retrieved from literature. The preliminary biochemical data suggested that the two molecules out of eighteen compounds exerted activity comparable to that of reference compound SynuClean-D (SC-D, 5-nitro-6(3-nitrophenyl)-2-oxo-4-(trifluoromethyl)-1H-pyridine-3-carbonitrile), according to Thioflavin T kinetics. Pharmacophore modelling deciphered the main structural requirements for alpha-Syn aggregation modulators. Moreover, docking and molecular dynamics simulations depicted the binding mode with the targeted alpha-Syn fibrils. The structural data of these new potential alpha-Syn binders might furnish additional information for understanding the mechanism of action of the ligands that specifically target the NAC domain as theranostic agents for alpha-synucleopathies.