The mode of action of chloroquine. Non-weak base properties of 4-aminoquinolines and antimalarial effects on strains of Plasmodium.

The mode of action of chloroquine was investigated by studying the properties of its 7-H derivatives, which retain the weak base properties of the quinolines but exhibit low antimalarial activity. Using a specific probe [4-(1-amino-butylamino)quinoline] it has been shown that weak base properties are sufficient to induce concentration of the drug in the parasite's food vacuole. However, the chloroquine uptake we measured for the 7-H derivatives revealed a significantly low concentration of drug within the parasitized red blood cell--about 1/20 of that of chloroquine. Thus, the substitution of the chlorine atom of chloroquine by a proton produces a compound which can always be targeted to the parasite's food vacuole, but which is less easily taken up by the parasite than is chloroquine. Antimalarial activities of 4-aminoquinoline drugs seem to be due not only to their weak base properties but also to other characters of these molecules. The mechanism of uptake of chloroquine by the parasites is apparently linked to structural characters of the quinoline ring, such as the presence of the chlorine atom. The importance of the lysosomotropic properties of chloroquine has to be reconsidered in the light of this new information.