Conflicts of interest: the genesis of synthetic antimalarial agents in peace and war

Malaria has had an enormous impact on human history, not least in times of war. The disease has been treatable by a natural remedy, quinine, since the 17th century, but the production of synthetic antimalarial agents was first achieved in Germany in the wake of the Great War of 1914-1918, in which malaria had caused immense problems. In the 1920s research workers in the Bayer laboratories of the IG Farbenindustrie consortium developed the 8-aminoquinoline plasmoquine (the forerunner of primaquine). They went on to develop the acridine dye, atebrin (mepacrine) and the 4-aminoquinolines, Resochin (developed at the end of the Second World War in America as chloroquine) and Sontochin. British attempts to match the advances achieved by the Germans were at first unproductive, partly because collaboration between academic and industrial organizations in the UK was beset by concerns over patent rights. However, with the outbreak of World War II, when supplies of antimalarials were scarce, ICI succeeded in the large-scale production of mepacrine (essential to prosecution of the war, particularly in the Far East) and also initiated a programme of collaborative research that eventually led to the discovery of proguanil (Paludrine); this, in its turn led to the diaminopyrimidine, pyrimethamine. A massive cooperative screening programme in the USA during World War II eventually bore fruit in the realization of the therapeutic potential of chloroquine, and in the later development of amodiaquine and primaquine. Some of this work also influenced the subsequent discovery of mefloquine and halofantrine at the Walter Reed Army Institute of Research.