Dobinin K Displays Antiplasmodial Activity through Disruption of Plasmodium falciparum Mitochondria and Generation of Reactive Oxygen Species

Dobinin K is a novel eudesmane sesquiterpenoids compound isolated from the root of <i>Dobinea delavayi</i> and displays potential antiplasmodial activity in vivo. Here, we evaluate the antiplasmodial activity of dobinin K in vitro and study its acting mechanism. The antiplasmodial activity of dobinin K in vitro was evaluated by concentration-, time-dependent, and stage-specific parasite inhibition assay. The potential target of dobinin K on <i>Plasmodium falciparum</i> was predicted by transcriptome analysis. Apoptosis of <i>P. falciparum</i> was detected by Giemsa, Hoechst 33258, and TUNEL staining assay. The reactive oxygen species (ROS) level, oxygen consumption, and mitochondrial membrane potential of <i>P. falciparum</i> were assessed by DCFH-DA, R01, and JC-1 fluorescent dye, respectively. The effect of dobinin K on the mitochondrial electron transport chain (ETC) was investigated by enzyme activity analysis and the binding abilities of dobinin K with different enzymes were learned by molecular docking. Dobinin K inhibited the growth of <i>P. falciparum</i> in a concentration-, time-dependent, and stage-specific manner. The predicted mechanism of dobinin K was related to the redox system of <i>P. falciparum</i>. Dobinin K increased intracellular ROS levels of <i>P. falciparum</i> and induced their apoptosis. After dobinin K treatment, <i>P. falciparum</i> mitochondria lost their function, which was presented as decreased oxygen consumption and depolarization of the membrane potential. Among five dehydrogenases in <i>P. falciparum</i> ETC, dobinin K displayed the best inhibitory power on NDH2 activity. Our findings indicate that the antiplasmodial effect of dobinin K in vitro is mediated by the enhancement of the ROS level in <i>P. falciparum</i> and the disruption of its mitochondrial function.