**3.4 Resistance to antifolate and sulpha drugs**

Proguanil, also known as chlorguanide and chloroguanide, is the first antifolate used to treat malaria. Proguanil is converted by the liver to its active metabolite, cycloguanil. The success of proguanil in treating human malaria led to further study of its chemical class and to the development of pyrimethamine in 1952. Resistance to the monotherapies of proguanil or pyrimethamine developed rapidly (within one year in the case of proguanil). A clear cut resistance to antifolate was proven in *P. falciparum, P. vivax* and *P. malariae* [66–68]. Sulfones and sulfonamides were then combined with proguanil or pyrimethamine in hopes of increasing efficacy and preventing or delaying resistance. By 1953, *P. falciparum* resistance had already been noted in Tanzania. When Sulfadoxine-pyrimethamine (SP) was introduced in Thailand in 1967, resistance appeared in the same year and spread quickly throughout South-East Asia. Resistance to SP in Africa remained low until the late 1990s but since then it has spread rapidly [69]. The SP has never been recommended for *P. vivax* treatment but evidence suggest that this compound is also effective to treat uncomplicated *P. vivax* [70, 71]. In response to resistance to SP and chloroquine, a combination of proguanil with a new class antimalarial compound, atovaquone, was introduced in 1999 by Glaxo-Smith Kline [72]. Nevertheless, prior

#### **Figure 2.**

*Chloroquine -resistant* P. vivax *infections. Source: World Wide Antimalarial Resistance Network (WWARN), available at: http://www.wwarn.org/vivax/surveyor/#0 and [64].*

to its introduction, resistance to atovaquone has been rapidly selected up in rodent plasmodia and *P. falciparum* [73, 74]. Since 2011, atovaquone-proguanil is available as a generic drug.
