Primaquine

Abstract

During the First World War, the shortage in supplies of the antimalarial drug quinine prompted the Germans to search for a synthetic substitute. Their chemical starting point was methylene blue, the only compound (with the exception of the cinchona alkaloids and arsenicals) then known to possess activity, albeit weak, against malaria (Guttmann and Ehrlich, 1891). Attempts were made to enhance the antimalarial properties of this dye : by changing the alkyl substituents attached to the extranuclear nitrogen atoms, it was found that the activity varied and by replacing one of the N-methyl constituents with a dialkylamino group, the potency was greatly increased (Schulemann, 1932). Having discovered that the attachment of a basic side chain to the phenothiazine nucleus of methylene blue led to an enhancement of antimalarial activity, the effect of attaching various dialkylaminoalkyl groupings to other heterocyclic nuclei was investigated. Since the quinoline nucleus in quinine was thought to be important for activity, a large series of quinoline derivatives were synthesized. After testing for antimalarial efficacy using a model laboratory screen devised by Röehl (1926) in which canaries were infected with Plasmodium relictum, an 8(4-diethylamino-l-methylbutyl-amino)-6-methoxyquinoline, named pamaquine, was selected for practical clinical investigation (Schulemann, 1932).