ATOVAQUONE

 

Name: Atovaquone

Synonym: Mepron, Wellvone, Acuvel

Chemical formula: C₂₂H₁₉ClO₃

Molecular weight: 366.8 g/mol

IUPAC name: 2-hydroxy-3-[(1r,4r)-4-(4-chlorophenyl)cyclohexyl]-1,4-dihydronaphthalene-1,4-dione

SMILES: OC1=C([C@H]2CC[C@@H](CC2)C2=CC=C(Cl)C=C2)C(=O)C2=CC=CC=C2C1=O

Indication: It has antiprotozoal, antimicrobial and antipneumocystis activity and thus used for the treatment or prevention of Pneumocystis carinii pneumonia in patients who are intolerant to trimethoprim-sulfamethoxazole.

Developmental stage: In combination with proguanil, it is available commercially as Malarone and used for the prevention and treatment of malaria caused by Plasmodium falciparum.

Company: GlaxoSmithKline

Description: Atovaquone or 2-(trans-4-(p-chlorophenyl)cyclohexyl)-3-hydroxy-1,4-naphthoquinone, is a hydroxynaphthoquinone analog of ubiquinone and an inhibitor of cytochrome bc₁ complex (Mather et al., 2005). It is found to be well tolerated, metabolically stable, and a very effective agent with a broad-spectrum antiparasite activity (Baggish and Hill, 2002). It is currently used against Pneumocystis jevorici (carinii) pneumonia and toxoplasmosis in patients with AIDS (Clinicalinfo, 2020).

Atovaquone has low bioavailability, which depends on formulation and diet and thus it is recommended to be taken with high-fat meal. It is highly bound to plasma protein (99.9%), and has a long half-life (2.2 to 3.2 days). Elimination is primarily via liver, with over 90% of drug excreted in bile in the parent form. It is generally well tolerated and may cause few side effects like mild fever, vomiting, diarrhoea, abdominal pain and headache (Rossiter, 2020).

Mechanism of action: Atovaquone acts by selectively affecting parasite mitochondrial electron transport chain by binding to the Q_o site of cytochrome bc₁ complex, where the oxidation of ubiquinol takes place. Thus inhibiting pyrimidine and ATP and preventing DNA synthesis, leading to protozoal death. Cytochrome bc₁ complex (complex III) serves as a molecular target for atovaquone in Plasmodia (Kessl et al., 2007).

When used as a single agent, resistance to atovaquone developed rapidly in falciparum malaria due to mutations within a catalytic domain of the cytochrome bc₁, which prevents its use as monotherapy. To overcome this resistance, it is used in combination with proguanil for treatment of multidrug-resistant malaria and also for prophylaxis in areas with chloroquine resistance (Bueno et al., 2012). Proguanil is a prodrug of cycloguanil which is a dihydrofolate reductase inhibitor in malaria parasite. Proguanil is the synergistic partner of atovaquone that lowers the concentration of atovaquone at which it collapses mitochondrial membrane potential (Srivastava and Vaidya, 1999). The price of this drug combination is very high making its use restrictive in resource deficit, endemic areas (Nixon et al., 2013).

References: 

Baggish, A.L. and Hill, D.R. (2002) Antiparasitic agent atovaquone. Antimicrobial Agents and Chemotherapy. 46(5), 1163-1173.

Bueno, J.M., Herreros, E., Angulo-Barturen, I., Ferrer, S., Fiandor, J.M., Gamo, F.J., Gargallo-Viola, D., Derimanov, G. (2012) Exploration of 4(1H)-pyridones as a novel family of potent antimalarial inhibitors of the plasmodial cytochrome bc₁. Future Med Chem. 4(18), 2311-2323.

Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. Clinicalinfo. Available from: https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic-infection/whats-new-guidelines.

Kessl, J.J., Meshnick, S.R. and Trumpower, B.L. (2007) Modeling the molecular basis of atovaquone resistance in parasites and pathogenic fungi. Trends in Parasitology. 23(10), 494-501.

Mather, M.W., Darrouzet, E., Valkova-Valchanova, M., Cooley, J.W., McIntosh, M.T., Daldal, F., Vaidya, A.B. (2005) Uncovering the molecular mode of action of the antimalarial drug atovaquone using a bacterial system. Journal of Biological Chemistry. 280(29), 27458-27465.

National Guidelines for The Prevention of Malaria, South Africa (2018). Department of health. Republic of South Africa. Available from: https://www.nicd.ac.za/wp-content/uploads/2019/03/National-Guidelines-for-prevention-of-Malaria_updated-08012019-1.pdf

Nixon, G.L., Moss, D.M., Shone, A.E. et al. (2013) Antimalarial pharmacology and therapeutics of atovaquone. Journal of Antimicrobial Chemotherapy. 68(5), 977-985.

Rossiter, D. (2020) Chapter P: Antiparasitic products. In South African Medicines Formulary, 13th Edition. South African Medical Association, Pretoria.

Srivastava, I. K. and Vaidya, A. B. (1999) A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrobial Agents and Chemotherapy. 43(6), 1334-1339.