1960s (Peters, 1970). Loss of quinine sensitivity and treatment failures became more common in Southeast Asia in the 1980s (Bjorkman and Phillips-Howard, 1990), although, to this day, high-level quinine resistance has not yet been convincingly documented (Personal communication, N. White, Mahidol University, March 2004).

Because the Allies controlled Java and its valuable quinine stores during World War I, German troops in East Africa suffered heavy casualties from malaria. Determined never to lack for malaria drugs again, the German government commissioned a search for a quinine substitute following Armistice. The center of operations was I.G. Farben, part of the Bayer Dye Works. Farben chemists tested thousands of compounds until they found some that worked. The first promising agent was Plasmochin (pamaquine) in 1926, followed, in 1932, by Atabrine (quinacrine, mepacrine). Plasmochin, an eight-amino quinoline, was quickly abandoned due to toxicity, although its close structural analog primaquine is now used to treat latent liver parasites of P. vivax and P. ovale. Atabrine was in many ways superior, persisting in the blood for at least a week. However, it too had unacceptable side effects, including yellowing of the skin and, occasionally, psychotic reactions.

The breakthrough came in 1934 with the synthesis of Resochin (chloroquine), followed by Sontochin (3 methyl chloroquine). These compounds belonged to a new class of antimalarials known as four-amino quinolines. Although Farben scientists overestimated the compounds’ toxicity and failed to explore them further, ironically, they passed the formula for Resochin to Winthrop Stearns, Farben’s U.S. sister company, in the late 1930s. Resochin was then forgotten until the outbreak of World War II, when Allied forces were cut off from quinine—first by the German invasion of Holland, then by the Japanese occupation of Java. After French soldiers raided a supply of German-manufactured Sontochin in Tunis and handed it over to the Americans, Winthrop researchers made slight adjustments to the captured drug to enhance its efficacy. They called their new formulation chloroquine. Only after comparing chloroquine to the older and supposedly toxic Resochin did they realize that the two chemical compounds were identical (Honigsbaum, 2002).

Although the synthesis of chloroquine came too late to help malaria sufferers in the Pacific theater or Sicily (another malaria-ridden front), following World War II, chloroquine and DDT emerged as the two principal weapons in the WHO’s ambitious “global eradication” malaria campaign. Subsequently, chloroquine-resistant P. falciparum (CRPF) probably arose de novo from four independent geographic locations: the Thai-