Therapeutic potential of Coumarin-polyphenolic acid hybrids in PD: Inhibition of α-Syn aggregation and disaggregation of preformed fibrils, leading to reduced neuronal inclusion formation

This study focuses on the discovery of new potential drugs for treating PD by targeting the aggregation of alpha-Syn. A series of hybrids combining Coumarin and phenolic acid were designed and synthesized. Four particularly promising compounds were identified, showing strong inhibitory effects with IC50 values ranging from low micromolar to submicromolar concentrations, as low as 0.63 mu M. These compounds exhibited a higher binding affinity to alpha-Syn residues and effectively hindered the entire aggregation process, maintaining the proteostasis conformation of alpha-Syn and preventing the formation of beta-sheet aggregates. This approach holds significant promise for PD prevention. Additionally, these candidate compounds demonstrated the ability to break down preformed alpha-Syn oligomers and fibrils, resulting in the formation of smaller aggregates and monomers. Moreover, the candidate compounds showed impressive effectiveness in inhibiting alpha-Syn aggregation within nerve cells, thereby reducing the likelihood of alpha-Syn inclusion formation resembling Lewy bodies, which highlights their potential for treating PD.