The potential of Rhein's aromatic amines for Parkinson's disease prevention and treatment: α-Synuclein aggregation inhibition and disaggregation of preformed fibers

The aggregation of alpha-Syn is a pivotal mechanism in Parkinson's disease (PD). Effectively maintaining alpha-Syn proteostasis involves both inhibiting its aggregation and promoting disaggregation. In this study, we developed a series of aromatic amide derivatives based on Rhein. Two of these compounds, 4,5-dihydroxy-N-(3-hydrox-yphenyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide (a5) and 4,5-dihydroxy-N-(2-hydroxy-4-chlor-ophenyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide (a8), exhibited good binding affinities to alpha-Syn residues, demonstrating promising inhibitory activity against alpha-Syn aggregation in vitro, with low IC50 values (1.35 and 1.08 mu M, respectivly). These inhibitors acted throughout the entire aggregation process by stabilizing alpha-Syn's conformation and preventing the formation of 8-sheet aggregates. They also effectively disassembled preformed alpha-Syn oligomers and fibrils. Preliminary mechanistic insights indicated that they bound to the specific domain within fibrils, inducing fibril instability, collapse, and the formation of smaller aggregates and monomeric alpha-Syn units. This research underscores the therapeutic potential of Rhein's aromatic amides in targeting alpha-Syn aggregation for PD treatment and suggests broader applications in managing and preventing neurodegenerative diseases.

Automated summary

This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.