Antifolates: Pyrimethamine, proguanil, sulphadoxine and dapsone

The inhibition or disruption of folate metabolism remains an attractive target for the discovery of new antimalarial drugs. The importance of this pathway was proved in the 1940s with the discovery of the triazine proguanil. Proguanil is converted in vivo to the active metabolite, cycloguanil, an inhibitor of the dihydrofolate reductase enzyme. Proguanil has mainly been used for prophylaxis and currently is used in combination with atovaquone (Malarone^®) for this purpose. Pyrimethamine was discovered based on its similarity to cycloguanil, and has been combined with the sulpha drug sulphadoxine. This combination of pyrimethamine/sulphadoxine has been the drug of choice to replace chloroquine in the treatment of uncomplicated malaria. However, resistance to pyrimethamine/sulphadoxine is now common, and its use is now restricted to the treatment of malaria in pregnancy, and "intermittent preventive treatment." Efforts are under way to discover and develop new antifolates. In this chapter, I summarize our knowledge of folate metabolism in the malarial parasite, and discuss the role and place of antifolates in the treatment of malaria and new strategies of folate disruption as a drug target.