Atovaquone Proguanil Malarone

Structural Formula

Ball-and-Stick Model

Space-filling Model

Structural Formula

Ball-and-Stick Model

Space-filling Model

Year of discovery: 1945 (proguanil), 1980s (atovaquone); Year of introduction: 2000 (GlaxoSmith-Kline); Drug category: Antiparasitic/hydroxynaphthoquinone; Main uses: For the prevention of malaria in travelers and for the treatment of mild-to-moderate cases involving drug-resistant strains of P. falciparum; Also as a monotherapy for the treatment of infections caused by the fungus P. carinii and the protozoan T. gondii especially in immunocompromized patients. Related drugs: Pyrimethamine (Daraprim), Chlorproguanil (Lapudrine), Chloroquine (Aralen), Mefloquine (Lariam).

Atovaquone is used in combination with proguanil (Malarone™, GSK) for the prevention and treatment of malaria. The critical part ("pharmacophore") for activity is the naphthoquinone subunit (shown in red above). The combination is often recommended as prophylactic for those traveling to countries where malaria due to P. falciparum is common.1

A fixed-dose oral combination with proguanil is used because resistance develops quickly with atovaquone alone. Proguanil, a biguanide prodrug, is metabolized to cycloguanil (see below) which is a potent and selective inhibitor of the plasmodial enzyme dihydrofolate reductase. Standard treatment with Malarone should begin 2 days before possible exposure and should be continued for a week after final exposure. Malarone is well-tolerated and adverse effects are rare compared to older drugs.

Proguanil

Two other commonly used preventive drugs, mefloquine (Lariam™, Roche) and chloroquine (Aralen™, Sanofi Aventis; see page 167), often cause side effects in the gastrointestinal and central nervous system. In addition, these older drugs do not always prevent the disease in non-immune individuals and they are ineffective against multidrug-resistant strains.

Mefloquine (Lariam)

Mefloquine (Lariam)

Atovaquone was first developed during the 1980s at Glaxo as a broad-spectrum antiparasitic agent (marketed as Mepron™) for the treatment of pneumonia caused by Pneumocystis carinii. In the 1990s atovaquone was demonstrated to have potent antimalarial activity and to be more effective against the erythrocytic stages of P. falciparum than any other known drug.2 Atovaquone is also effective against the liver stages of the parasitic life cycle, allowing it to be used as a preventive medicine (casual prophylaxis).

Atovaquone functions as a highly lipophilic analog of ubiquinone (coenzyme Q), which is involved in the transport of electrons in parasitic mitochondria. Atovaquone interrupts electron-transfer from dehydrogenase enzymes to cytochromes via ubiquinone and kills the parasite.

Ubiquinone (Coenzyme Q)

1. Drugs 2003, 63, 597-623. 2. Antimicrob. Agents Chemother. 2002, 46. 1163-1173; Refs. p. 179

Ubiquinone (Coenzyme Q)

1. Drugs 2003, 63, 597-623. 2. Antimicrob. Agents Chemother. 2002, 46. 1163-1173; Refs. p. 179

^ = Carbon = Hydrogen = Oxygen ; ; = Phosphorous ^ = Nitrogen

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