Unravelling the potency of triazole analogues for inhibiting α-synuclein fibrillogenesis andin vitrodisaggregation

A series of triazole-based compounds was synthesized using a click chemistry approach and evaluated for the inhibition of α-synuclein (α-syn) fibrillogenesis and its disaggregation. CompoundsTr3,Tr7,Tr12,Tr15, andTr16exhibited good effect in inhibiting α-syn fibrillogenesis confirmed by Thioflavin-T assay and fluorescence microscopy and α-syn disaggregation confirmed by fluorescence microscopy. Molecular docking was used to understand the plausible mechanism of the test compounds for inhibiting the α-syn fibrillogenesis and to verify thein vitroresults. CompoundsTr3,Tr7,Tr12,Tr15andTr16showed good binding interactions with the essential amino acid residues of α-syn. The compounds which were found to be good inhibitors or disaggregators had no toxic effects on the SH-SY5Y cell line. These compounds have the potential to be developed as therapeutic interventions against synucleinopathies including Parkinson's disease and Lewy body dementia.