**3. Antimalarial drugs resistance**

There are five groups of antimalarial drugs that are currently used for treatment of human malaria, that are classified on basis of their structure and action [77, 78].

The five classes include: - (1). antifolates (pyrimethamine, proguanil, sulfadoxine), (2). 4-aminoquinolines (like chloroquine, amodiaquine, hydroxychloroquine, and aryl amino alcohols (such as quinine, mefloquine) (3). Endoperoxides (like artemisinin and its derivatives), (4) naphthoquinones (like atovaquone), and (5). 8-aminoquinolines (primaquine, tafenoquine). 4- aminoquinolines, anitifolates, naphthoquinones and aryl amino alcohols cause inhibition by detoxification of haem, pyrimidine biosynthesis and mitochondrial cytochrome b involved in oxidoreduction, respectively. Whereas endoperoxides, such as artemisinin, act on multiple cellular processes involving reactive oxygen species in Plasmodium cells [78].

One of the major challenges to control malaria is the emergence and spread of antimalarial drug-resistant plasmodium parasites [3–5]. The most important plasmodium parasites (*P. vivax* and *P. falciparum*) have already developed resistance against convectional antimalarial drugs such as chloroquine, sulfadoxine-pyrimethamine, atovaquone [79–85]. In response to the evolution of drug resistance strains of *P. falciparum* malaria, since the mid-2000s, artemisinin-based combination therapies (ACTs) constitute the standard of care for uncomplicated falciparum malaria and are increasingly also taken into consideration for the treatment of nonfalciparum malaria (*P. ovale, P. vivax, P. knowlesi* and *P.* malariae) [35].

The artemisinin and its derivatives in ACTs confer rapid and potent effectiveness, whereas their partner drugs are longer-lived antimalarial (such as lumefantrine, mefloquine, piperaquine (PPQ ), amodiaquine or sulfadoxinepyrimethamine). The reason for use of ACTs is the fact that the artemisinin and its derivatives rapidly eliminate the majority of the parasites within days by mechanisms that are distinct from those of the partner drug, which eliminates residual parasites over weeks, so that parasites that may develop resistance to the artemisinin drug would still be eliminated by the partner drug [86].

There is also widespread resistance of *P. vivax* to chloroquine and sulfadoxinepyrimethamine [84, 85, 87, 88]. Since the early 1990s chloroquine-resistant *P. vivax* (CRPV) has been reported from different parts of the world, mostly from Papua New Guinea, the Solomon Islands and Indonesia, Burma (Myanmar), India, Vietnam, Turkey, and Central and South America [83]. In Africa, chloroquine resistance started in late 1970s, and treatment failure became alarmingly high until the introduction of ACT in 2005 [89, 90]. Now, the recommended drugs for the treatment of CRPV malaria by the U.S. Centers for Disease Control and Prevention (CDC) succeeded by primaquine include; quinine sulfate plus either doxycycline or tetracycline; atovaquone-proguanil; and mefloquine [91]. ACTs has been demonstrated to be effective for both chloroquine-resistant and chloroquine-sensitive strains of *P. vivax* malaria. Therefore, ACTs can be now used to treat malaria caused by P vivax [92–94]. So far, there are no reports of *P. vivax* resistance to artemisinins. The main drawback of using ACTs for the treatment of *P vivax* malaria with ACTs is that the dormant liver-stage (hypnozoites) are not targeted by the ACTs, and, therefore, primaquine is necessarily required in combination with ACTs to prevent relapse.

Chloroquine targets the polymerization of free haem (the toxic substance for the parasite) within the food vacuole of the parasite. The drug disrupts haemozoin formation so that the parasite dies by the effect of the poisonous haem. The mechanism of chloroquine resistance is drug efflux via the *P. falciparum* chloroquine-resistance transporter (encoded by pfcrt) located at the food vacuole. Chloroquine-resistance was connected with mutations in pfcrt [95–97].

Sulfadoxine and pyrimethamine inhibit two enzymes of *P. falciparum* that involve in the folate pathway, that are dihydropteroate synthase (PfDhps) and dihydrofolate reductase (PfDhfr), respectively. Resistance to these antimalarials

#### *Plasmodium Species and Drug Resistance DOI: http://dx.doi.org/10.5772/intechopen.98344*

arises from multiple mutations in pfdhps and pfdhfr genes [98–101]. In Ethiopia, *P. falciparum* resistance to Sulfadoxine-pyrimethamine (SP) had led to replacement of SP with ACT, which is composed of consisted of artemether and lumefantrine (Coartem) in 2004 [102]. However, artemisinin resistance in *P. falciparum* has emerged in different parts of the world, especially in Southeast Asia and Africa [103–106], which indicates the possibility of the spread of artemisinin resistance to all over the world.
