**3.3 Malaria**

Malaria is caused by an intracellular protozoan parasite belongs to the genus Plasmodium. Malaria is endemic in most of tropical countries and subtropical regions of Asia, Africa, South, and Central America. Plasmodium can differentiate and replicate inside hepatocytes, and then released as merozoites into the bloodstream, which subsequently invades red blood cells (RBCs) [81]. Plasmodium parasite uses SOD to reduce the toxicity of ROS throughout the intra-erythrocytic stage of parasite survival. The SOD activity in *Plasmodium falciparum* and rodent malaria species is characterized as iron-dependent and the first level of the antioxidant defense system of the parasite [40, 81, 82]. *P. falciparum* consists two distinct genes coding for different SOD such as *Pf*FeSOD-1 and *Pf*FeSOD-2 [40]. *Pf*FeSOD-1 is a cytosolic protein and expressed during the intra-erythrocytic cycle of the parasite [41, 83]. FeSOD-1 is also reported in *P. ovale*, *P. malariae*, and *P. vivax* and very close apicomplexan parasites such as *Toxoplasma gondii* [42]. Since FeSOD-1 is a cytosolic protein, it is unlikely to act on a superoxide anion in the parasite food vacuole during hemoglobin digestion. Thus, it is plausible that parasites might be taking a large amount of Cu/ Zn-SOD from the host erythrocyte to detoxify the superoxide anions in their organelles [84]. Plasmodium parasite utilizes SODs enzymes to limit the toxicity of ROS produced during hemoglobin degradation in the erythrocytic cycle. These enzymes play a crucial role in parasite persistence and their intracellular survival during the

intra-erythrocytic stage of the life cycle. FeSOD1 of *Plasmodium vinckei* (PvSOD1) also plays a central role in the oxidative defense of these parasites. However, PvSOD1 is inhibited by H2O2 and peroxynitrite, but not by cyanide and azide [85]. The FeSOD-2 of *P. falciparum* is a mitochondrial SOD with an elongated N-terminal protein extension, reminiscent of a bipartite apicoplast-localized protein [43, 86]. An inhibition study of recombinant *P. falciparum* FeSOD suggested that SOD is a highly selective drug target to designed antimalarial drugs. The study further identified many antimalarial drugs which have shown antimalarial activities against *P. falciparum and even* a strain moderately resistant to chloroquine [87].
