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

Abstract

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 α-syn. Myrtucommulone P (1) from a flower extract of Eucalyptus cloeziana was shown to have α-syn affinity and antiplasmodial activity and to inhibit α-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 IC 50 6.6 and 16 μM. The α-syn inhibitory and antiplasmodial activity of myrtucommulone P (1) supports the hypothesized link between antiamyloidogenic and antiplasmodial activity.

Structure Revision of Formyl Phloroglucinol Meroterpenoids: A Unified Approach Using NMR Fingerprinting and DFT NMR and ECD Analyses

“…The genus Eucalyptus resides within the Myrtaceae family of flowering plants and comprises more than 800 species, of which >99% are endemic to Australia. The diversity of Eucalyptus is primarily distributed throughout three subgroups: Eucalyptus (717 species), Corymbia (90 species), and Angophora (12 species) [11]. At the chemotaxonomic level, formyl phloroglucinol meroterpenoids (FPCs) isolated from Eucalyptus contrast with the chemical profiles of sister genera Corymbia and Angophora, both of which contain tetramethyl β-triketone acyl phloroglucinol derivatives [12][13][14][15][16][17].…”