Agronomy and Horticulture, Department of
Document Type
Article
Date of this Version
1-24-2024
Citation
ACS Infect. Dis. 2024, 10, 1000−1022. https://doi.org/10.1021/acsinfecdis.3c00670
Abstract
In this study, we identified three novel compound classes with potent activity against Plasmodium falciparum, the most dangerous human malarial parasite. Resistance of this pathogen to known drugs is increasing, and compounds with different modes of action are urgently needed. One promising drug target is the enzyme 1-deoxy-D-xylulose-5- phosphate synthase (DXPS) of the methylerythritol 4-phosphate (MEP) pathway for which we have previously identified three active compound classes against Mycobacterium tuberculosis. The close structural similarities of the active sites of the DXPS enzymes of P. falciparum and M. tuberculosis prompted investigation of their antiparasitic action, all classes display good cell-based activity. Through structure−activity relationship studies, we increased their antimalarial potency and two classes also show good metabolic stability and low toxicity against human liver cells. The most active compound 1 inhibits the growth of blood-stage P. falciparum with an IC50 of 600 nM. The results from three different methods for target validation of compound 1 suggest no engagement of DXPS. All inhibitor classes are active against chloroquine-resistant strains, confirming a new mode of action that has to be further investigated.
Included in
Agricultural Science Commons, Agriculture Commons, Agronomy and Crop Sciences Commons, Botany Commons, Horticulture Commons, Other Plant Sciences Commons, Plant Biology Commons
Comments
Used by permission.