**9. Drugs inhibiting hemozoin formation and thereby inducing oxidative stress**

Besides the attacks of the immune systems of the respective host, where ROS are deployed to kill invading pathogens, the parasite faces another even bigger challenge: *Plasmodium* relies al‐ so on the digestion of human haemoglobin to obtain amino acids for its metabolism (Sherman, 1977). Haemoglobin is the major protein inside the erythrocyte and the parasite has evolved a unique pathway to utilise this molecule (Muller et al., 2011). Heme is the degradation product of haemoglobin, which has to be detoxified and stored as hemozoin within the food vacuole of the parasite – the place where the haemoglobin degradation occurs. Non-detoxified heme is extremely toxic (Papalexis et al., 2001) and leads not only to the generation of H2O2, ‧ OH and O2-. (Francis et al., 1997), but also to the highly reactive, non-radical molecule, singlet oxygen (1 O2) (Freinbicherler et al., 2011). Moreover, one 1 O2 molecule can be either synthesised by the reac‐ tion of ‧ OH and O2-. or two O2-. with two hydrogen ions (Khan and Kasha, 1994). In order to de‐ toxify these ROS, *Plasmodium* has developed – as outlined above - multiple antioxidant defence systems. However - excluding the membrane located lipophilic tocopherol (vitamin E) (Wang and Quinn, 1999) - none of the above mentioned defense systems are capable to detoxify 1 O2. The fact that vitamin B6 is linked to the defense against 1 O2 in plants and fungi (Tambasco-Stu‐ dart et al., 2005; Ehrenshaft et al., 1999), suggests that the vitamin B6 biosynthesis might also play a yet unrecognized role in combating 1 O2 in the malaria parasite *P. falciparum*. Very recent‐ ly this role of 1 O2 detoxification has been verified in the malaria parasite (Wrenger et al., 2005; Knöckel et al., 2012; Butzloff et al., 2012). Figure 1:

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

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to the inhibition of the hemozoin formation (Davioud-Charvet et al., 2003).

Helminths are parasitic worms that encompass nematodes (roundworms), cestodes and trematodes (flatworms) and affect humans in all areas of the world, with more than onethird of humans harbouring these parasites that cause chronic, debilitating morbidity. Fur‐ thermore, co-endemicity and polyparasitism increase the burden of millions (Hotez et al., 2008). In the absence of vaccines, control relies on pharmacotherapy and pharmacoprophy‐ laxis to easy symptoms and reduce transmission. Helminthosis are treated with a limited number of anthelmintics by chemotherapy of symptomatic individuals or, more general, by control programmes that rely on mass drug administration (MDA) and require annual or bi‐ annual treatment of at-risk populations over prolonged period of time (Prichard et al., 2012). A major problem, however, is the development of resistance or tolerance by the parasites to these common antiparasitic drugs (Vercruysse et al., 2011). It is therefore essential to under‐ stand the underlying mechanisms of drug resistance and find new drugs to circumvent it.

Praziquantel has been used for over 20 years to treat a variety of human trematode infec‐ tions. Its precise mechanism of action has not been fully elucidated, however, there is exper‐ imental evidence that praziquantel acts by increasing the permeability of cell membranes towards calcium ions and/or by interfering with adenosine uptake (Jeziorski and Greenberg, 2006; Angelucci et al., 2007). Furthermore, it has been suggested that praziquantel reduces GSH concentrations, making the parasite more susceptible to the host immune response (Ribeiro et al., 1998). Interestingly, exposure to sub-lethal concentrations of praziquantel shows that schistosomes undergo a transcriptomic response similar to that observed during

**10. Druggability of oxidative stress systems in helminths**

oxidative stress (Aragon et al., 2009).
