extracellular space

cytosolic compartment

**Figure 1.** Schematic illustration of the glutathione (GSH) system. GSH homeostasis involves intra- and extracellular mechanisms. GSH is synthesized from amino acids (AA) by the action of γ-glutamylcysteine synthetase (γ-GCS) and glutathione synthase (GSH-S), both requiring ATP. As antioxidant, GSH participates in the reduction of peroxides, cata‐ lysed by glutathione peroxidase (GPx), in the reduction of protein-disulfides, catalysed by glutaredoxins (Grx) and in conjugation reactions with electrophils (eg. xenobiotics, X), catalysed by glutathione transferases (GSTs). The gluta‐ thione conjugates (GS-X) and GSSG are transported out of the cell via GS-X/GSSG pumps. The NADPH-dependent GSH reductase (GR) is responsible for the intracellular recycling of GSH, while extracellular GSH gets sequentially hydro‐ lysed by γ-glutamyl transpeptidase (γ-GT) and dipeptidase (DPD), with glutamate, cysteine and glycine being recycled for GSH synthesis (γ-glutamyl cycle).

A number of drugs have been identified that act as inhibitors of the hemozoin formation by binding to heme. This leads to an accumulation of free heme, causes high levels of oxidative stress and ends in the death of the parasite (Meunier et al., 2010). Quinolinecontaining derivatives such as amopyroquine, amodiaquine, tebuquine, halofantrine, py‐ ronaridine, quinine, mepacrine, epiquinine, quinidine, bisquinoline chloroquine (see figure 2) are highly potent antimalarials that inhibit hemozoin formation at EC50-values in the low nano-molar range (Egan et al., 2000; Kotecka et al., 1997; O'Neill et al., 2003; Vennerstrom et al., 1992). Azole derivatives are also inhibitors of the hemozoin forma‐ tion and reveal efficacy against chloroquine sensitive as well as resistant plasmodial strains (Banerjee et al., 2009; Rodrigues et al., 2011). Another novel class, which has been identified to interact with heme and thereby prevent the hemozoin formation, are xan‐ thones (Docampo et al., 1990; Ignatushchenko et al., 1997; Xu Kelly et al., 2001). More‐ over, a variety of isonitrile derivatives gain their antimalarial activity from inhibition of the hemozoin synthesis (Kumar et al., 2007; Wright et al., 2001) resulting in EC50-values in the low nano-molar range (Badyopadhyay et al., 2001; Singh et al., 2002; Kumar et al., 2007). Benzylmenadione derivatives do not show any cytotoxicity against two human cell lines while they are effective against the chloroquine resistant *P. falciparum* strain Dd2 (Muller et al., 2011). The precise mode of action of benzylmenadione remains for elucidation, but it has been suggested that the molecule is initially oxidized to a naph‐ thoquinone derivative within the food vacuole of the parasite which leads subsequently to the inhibition of the hemozoin formation (Davioud-Charvet et al., 2003).
