**10.2 Atovaquone and proguanil**

Two separate and unrelated mechanisms of action against the parasite serve as the foundation for this combination. Atovaquone is a dihydrofolate reductase inhibitor, and cycloguanil is a selective inhibitor of the Plasmodium mitochondrial electron transport system. In a ratio of 2.5 atovaquone to 1 proguanil HCl calculated

**Figure 14.** *Chemical structure of pyrimethamine and sulfadoxine in combination.*

in mg (not mmoles), atovaquone and proguanil are given together [93]. The sporozoite stage is the primary focus of this mixture. Proguanil decreases the effective concentration of atovaquone needed to damage the mitochondrial membrane, while atovaquone increases the effectiveness of proguanil but not its active metabolite (Malarone) (**Figure 15**) [94–96].

Atovaquone was first formulated as an antimalarial, however due to its high failure rate (30%), it is no longer prescribed as a single chemical entity. However, atovaquone has been combined with proquanil to produce an effective prophylactic and therapeutic antimalarial [98]. Proguanil is an early example of a prodrug, having been produced in 1945. CYP2C19 is the enzyme that converts it to cycloguanil (**Figure 16**).

The chemistry of atovaquone is based on the fact that it is a naphthoquinone that participates in oxidation–reduction reactions as part of its quinonehydroquinone mechanism. The drug targets mitochondrial electron transport, specifically at the cytochrome bc1 site of the parasite. This deprives the cell of required ATP, potentially contributing to anaerobic conditions. A mutation in the parasite's cytochrome causes resistance to this drug, and a single-point mutation appears to be adequate [99]. The pharmacokinetics of atovaquone, when used as a monotherapy, are thought to be related to resistance. Since atovaquone is lipophilic and has a slow absorption rate, the pathogen is exposed to low concentrations of the medication for a prolonged period of time, which promotes resistance growth.

Cycloguanil (Proguanil) inhibits dihydrofolate reductase, which prevents deoxythymidylate synthesis. Amino acid shifts near the dihydrofolate reductase binding site are linked to resistance to proguanil/cycloguanil. Malaria immune to chloroquine, halofantrine, mefloquine, and amodiaquine is treated with this drug combination. To date, there has been no evidence of resistance to the combination [100].

**Figure 15.**

*Chemical structure of atovaquone and proguanil in combination. Sulfadoxine–pyrimethamine are among the other reportedly used combinations [97].*

**Figure 16.** *Metabolic activation of proguanil to cycloguanil.*

*Molecular Approaches for Malaria Therapy DOI: http://dx.doi.org/10.5772/intechopen.98396*

**Figure 17.** *Chemical structure of artemether and lumefantrine in combination.*

#### **10.3 Artemether and lumefantrine**

Artemether–lumefantrine (Coartem) is one of the artemisinin-based combination therapy's fixed-dose formulations (ACT). The cure rates for these ACTs have been stated to be greater than 90%. Artesunate–fosmidomycin, amodiaquine– artesunate, chloroquine–artemisinin, and artesunate.

Artemether–lumefantrine interferes with heme metabolism, preventing development of parasite in erythrocyte states. Artemether acts oxidatively due to its endoperoxide, and lumefantrine can form a complex with hemin (**Figure 17**).

#### **11. Future prospects of antimalarial drugs**

With the recent emergence of resistance to existing frontline artemisinin-based combination therapy, the antimalarial drug pipeline is in dire need of newer lead molecules. The need for new anti-malarials that function through novel mechanisms of action has been moved to the forefront of the development agenda (**Figure 18**).

A variety of criteria are used to determine the ability of newer compounds to function as new anti-malarials: single-dose cures (artesunate and chloroquine are unable to do this); activity against both the asexual blood stages that trigger disease and the gametocytes that transmit the disease; compounds that avoid infection (chemoprotective agents); and compounds that clear *P. vivax* hypnozoites from the liver (anti-relapse agents) [101, 102].

Researchers can experiment with new combinations and formulations of currently available anti-malarial drugs. This may aid in the delivery of the drug, allowing it to be more successful, or it may help resolve issues with resistance to a specific component. The following are some recent methods used in the detection of new antimalarial agents:

1.Use of available antimalarial drugs to improve antimalarial therapy

2.Development of analogs of currently available medications.

3.Covalent bitherapy

**Figure 18.** *Structures of some drugs repurposed for malaria therapy and are under various phases of clinical trials.*

