α-Synuclein Aggregation Inhibitory and Antiplasmodial Activity of Constituents from the Australian Tree Eucalyptus cloeziana

Amyloid protein aggregates are linked to the progression of neurodegenerative conditions and may play a role in life stages of Plasmodium falciparum, the parasite responsible for malaria. We hypothesize that amyloid protein aggregation inhibitors may show antiplasmodial activity and vice versa. To test this hypothesis, we screened antiplasmodial active extracts from 25 Australian eucalypt flowers using a binding affinity mass spectrometry assay to identify molecules that bind to the Parkinson's disease-implicated protein alpha-syn. Myrtucommulone P (1) from a flower extract of Eucalyptus cloeziana was shown to have alpha-syn affinity and antiplasmodial activity and to inhibit a-syn aggregation. 1 exists as a mixture of four interconverting rotamers. Assignment of the NMR resonances of all four rotamers allowed us to define the relative configuration, conformations, and ratios of rotamers in solution. Four additional new compounds, cloeziones A-C (2-4) and cloeperoxide (5), along with three known compounds were also isolated from E. cloeziana. The structures of all compounds were elucidated using HRMS and NMR analysis, and the absolute configurations for 2-4 were determined by comparison of TDDFT-calculated and experimental ECD data. Compounds 1-3 displayed antiplasmodial activities between IC50 6.6 and 16 mu M. The alpha a-syn inhibitory and antiplasmodial activity of myrtucommulone P (1) supports the hypothesized link between antiamyloidogenic and antiplasmodial activity.

Automated summary

The study suggests a potential link between amyloid protein aggregation and the progression of neurodegenerative conditions and malaria. By screening antiplasmodial active extracts from Australian eucalypt flowers, researchers discovered a compound (Myrtucommulone P) that not only showed affinity to a Parkinson's disease-implicated protein but also exhibited antiplasmodial activity and inhibited protein aggregation. In addition, several other compounds were isolated from E. cloeziana.