Proguanil and atovaquone

Proguanil was first reported in 1945 as one of the first antifolate antimalarial drugs [45], while atovaquone was first reported in 1991 for the treatment of protozoan infections [46]. The combination of these, commonly sold as Malarone™, has been marketed by GlaxoSmithKline (GSK) since the early 2000s, and has proven to be a very effective anti-malarial due to the synergistic effect of the two components. This is, in large part, due to the different MoAs for each compound. Atovaquone acts as a cytochrome bc₁ complex inhibitor which blocks mitochondrial electron transport [47]. Proguanil (when used alone) acts as a dihydrofolate reductase (DHFR) inhibitor through its metabolite, cycloguanil (CG) which disrupts deoxythymidylate synthesis. When used in combination with atovaquone, however, proguanil does not act as a DHFR inhibitor but has instead been shown to reduce the concentration of atovaquone required for treatment [48]. Generic atovaquone/proguanil is still available today for the treatment of chloroquine-resistant malaria.