ABSTRACT
Malaria is the most important parasitic infection of man. Plasmodium falciparum is estimated to kill over a million people each year. Most of these deaths occur in African children. Mortality is rising-directly as a result of drug resistance. The naturally occurring ancient antimalarials, qinghaosu (artemisinin) and quinine (from Cinchona bark), have been used to treat fever since at least AD 340 and 1631, respectively (1,2). These two plant-derived medicines remain the mainstay of treatment for severe malaria to this day having survived over decades that have seen synthetic antimalarials come and then fall to resistance (Fig. 1). The first synthetic antimalarial, the 8-aminoquinoline pamaquine, was discovered in 1926, followed in the next decade by mepacrine (1932) and chloroquine (CQ) (1934). The discovery of the antifols, proguanil (1945), pyrimethamine (1952), and the 4-aminoquinoline amodiaquine (AQ) (1952) coincided with a global initiative by the newly formed World Health Organisation to eradicate malaria. Research stimulated by the conflict in Vietnam led to the discovery of mefloquine and halofantrine by the Walter Reed Army Institute of Research in the United States. Mefloquine was ready for use in 1977 but was not deployed in an endemic area until 1984 (3). This was followed by a hiatus in antimalarial drug development in the West despite the emergence and spread of CQ and antifol resistance in Asia and South America. In 1979, Chinese scientists reported the discovery, chemical structure, and antimalarial activity in vitro and in vivo of a plant-derived compound qinghaosu (artemisinin) with an entirely novel chemical structure. They then described the subsequent synthesis of more active derivatives artesunate, artemether, arteether (artemotil), and dihydroartemisinin (DHA) (4,5). Use of one of these compounds in combination with another antimalarial with a different mechanism of action [(artemisinin combination treatment (ACT)] is now the preferred treatment strategy in areas where multiple drug resistance is established (6). Indeed the World Health Organisation now recommends that any country changing antimalarial drug policy should switch to an ACT. In the last 10 years, there has been renewed interest in antimalarial drug development as part of global initiatives to alleviate the major diseases of poverty, and realization of the enormous health and economic consequences of antimalarial
drug resistance. New antimalarials developed include several compounds, e.g., lumefantrine, naphthoquine, and pyronaridine discovered and manufactured in China. Lumefantrine is available only in a fixed combination with artemether. New combinations of older drugs have also been introduced, e.g., atovaquone-proguanil, chlorproguanil-dapsone, and DHA-piperaquine.
