Drug-parasite-host interaction action of artemisinin and its novel derivatives on Plasmodium falciparum

Abstract

Artemisinin or qinghaosu is an endoperoxide-containing sesquiterpene lactone, isolated from Artemisia annua L. It is effective against both chloroquine-sensitive and -resistant Plasmodium falciparum malaria. However, the parasite infecting Hemoglobin (Hb) H and/or Hb Constant Spring red cells had higher resistance to artemisinin in vitro than that infecting normal red cells. This was due to low drug accumulation of infected red cells resulting from competition with uninfected variant red cells. Which had a higher accumulation capacity than genetically normal cells. Drug accumulation of the parasite was shown to be saturable and dependent on metabolic energy. The accumulation was least for the ring stage parasite and gradually increased with parasite maturation; however, its antimalarial activity was highest at ring stage. The 50% inhibitory concentrations IC(,50) for the parasite in HbH/Hb Constant Spring red cells were decreased when normal red cells were added to the infected cells, and correspondingly the IC(,50) in normal red cells were increased when HbH/Hb Constant Spring red cells were added to the infected cells. The changes of IC(,50) corresponded to the variation in drug accumulation of mixtures of normal and variant red cells of different compositions The IC(,50) for the parasite in variant red cells were also greatly decreased when the hematocrit of the culture was lowered, whereas the IC(,50) in normal red cells were independent of the hematocrit. The increase in IC(,50) values for the parasites infecting variant red cells was also related to the decrease in parasite accumulation, indicating that drug accumulation capacity of parasite also had a role in determining drug sensitivity. Artemisinin sensitivity therefore is determined by its accessibility to the parasite, which is decreased in infected variant red cells. Artemisinin is believed to exert its antimalarial activity through an oxidant mode. Its derivatives, therefore. Were developed on the basis of its requirement of iron in the antimalarial action. Caffeic, kojic, benzohydroxamic and salicylhydroxamic acid. and pyrogallol were selected for covalent linking with artemisinin. Since superoxide dismutase. an antioxidant enzyme, had countering effect on artemisinin action, its inhibitor. diethyldithiocarbamate was also been chosen for linking with artemisinin. The derivatives obtained have IC(,50) in the range of 5-50 nM. Although these derivatives so far show no improvement over the parent compound in their antimalarial activity, they may still be useful in near future in giving a basis for further designs and modifications.