40 febrifugine

40 febrifugine in support of the above has been reviewed (Wright and Warhurst, 2002) and a brief summary of the main points is presented below.

The importance of the endoperoxide moiety in the artemisinin molecule is clearly demonstrated by the lack of antiplasmodial activity of deoxyartemisinin 11, a constituent of A. annua that has a single oxygen in place of the peroxide group of artemisinin. Since it is well known that peroxides react with iron to give free radicals (Halliwell and Gutteridge, 1989), the interaction of artemisinin with iron and iron-containing molecules was investigated (Meshnick, 1994). Of particular significance is the observation that artemisinin does not react with the haemoglobin of uninfected red blood cells, but does react with heme (Hong et al., 1994). This explains the selectivity of artemisinin for parasite-infected red blood cells and why the drug kills the blood stages of malaria parasites while having no effect on parasites in the liver cells where haemoglobin digestion does not take place. The above is supported by cyclic voltammetry studies in which the reduction of the peroxide group of artemisinin in the presence of heme was examined (Chen et al., 1998). These studies also suggest that artemisinin preferentially reacts with heme containing Fe(II) iron rather than Fe(III). Molecular modeling studies have provided further support for the interaction between heme and the endoperoxide group of artemisinin (Shukla et al., 1995).

Chloroquine-resistant P. berghei does not have visible hemozoin and is also resistant to artem-isinin, suggesting that haemoglobin breakdown is essential for its action (Peters et al., 1986). The observation that the action of artemisinin is antagonised by iron chelators that chelate heme iron (Meshnick et al., 1993) and by chloroquine that binds to heme (Chou et al., 1980) also indicates a pivotal role for heme. Electron microscopy has revealed that when parasites are treated with artemisinin derivatives, damage to the parasite food vacuoles is seen first (Li et al., 1981). As artemisinin was also found to damage mitochondrial membranes, Zhao et al. (1986) investigated the possibility that inhibition of the mitochondrial heme-containing enzyme cytochrome oxidase

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