Profiling plants with antimalarial blood stage activity using metabolomics: an added dimension to drug discovery

Natural products and their derivatives have historically contributed significantly to the treatment of malaria. However, despite their promising potency diversity, it is challenging to determine their mode of action (MoA), which is essential for antimalarial drug discovery. Metabolomics is a robust tool that had been successfully used to profile the MoA of antimalarial compounds, but it has seldom been applied to complex matrices such as plant extracts and natural compounds. In this study, three plants were used: Poupartia borbonica Gmel, a dioecious endemic plant from the Mascarene Islands belonging to the Anacardiaceae family, and its alkyl cyclohexenone derivatives with antiplasmodial properties1; Artemisia afra and Artemisia annua, both known for their antimalarial activities2, collected from the Adamawa Region of the Republic of Cameroon in the same season. Trophozoite-synchronized Plasmodium falciparum cultures were treated with extracts and purified compounds derived from these plants and were analysed by LC-MS and 1H NMR metabolomics to estimate their metabolic profile. Results were compared against metabolic responses to established antimalarial drugs with defined MoAs – atovaquone, chloroquine, quinine and artemisinin. Our findings suggest that P. borbonica and isolated compounds are active on hemoglobin metabolism related pathways, whereas A. afra and A. annua have differing profiles, with A. afra affecting nucleotide metabolism and A. annua impacting glutathione metabolism and associated redox pathways. Therefore, metabolomics is a viable tool to profile plant extracts and natural compounds with promising antiplasmodial activity and should be incorporated as a standard screening method in drug discovery.