Targeting oxidative stress and protein misfolding: cannabinoid-inspired N-acylhydrazones as multi-target agents in synucleinopathy

Synucleinopathies are neurodegenerative disorders characterized by α-synuclein aggregation, oxidative stress, and metal dyshomeostasis. In this study, we investigated two cannabinoid-inspired N-acylhydrazones, X1CANA and X1GALATO, as multifunctional agents targeting these interconnected pathological mechanisms. Both compounds exhibited high stability under physiological conditions and formed Cu(II) complexes, with X1CANA displaying an affinity comparable to that reported for α-synuclein. Antioxidant activity was demonstrated through superoxide scavenging assays, while biological studies in Saccharomyces cerevisiae revealed increased resistance to oxidative stress and reduced lipid peroxidation. Furthermore, Thioflavin-T and RT-QuIC assays showed that both compounds effectively inhibited α-synuclein aggregation and seed-induced fibril formation. Collectively, these findings highlight the potential of cannabinoid-inspired N-acylhydrazones as multifunctional lead compounds for the development of disease-modifying therapies for synucleinopathies.