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Antimalarial Activity of 2,4-Diamino-6-[(3,4-Dichlorobenzyl) Nitros-Amino] Quinazoline (CI-679 Base) and CI-679 Acetate

Laboratory Studies in Mice and Rhesus Monkeys

To assess their potential value as antimalarial drugs, we studied CI-679 (base) and CI-679 acetate extensively in oral form and parenteral repository form in mice infected with Plasmodium berghei and in rhesus monkeys infected with Plasmodium cynomolgi. All infections were induced with blood forms of the parasites. Suppressive activity was assayed against four drug-resistant lines of P. berghei. The two drug forms had sufficiently similar effects to permit their being summarized together. The drug was highly effective in mice and monkeys when given either orally or parenterally in repository form. Orally, one large dose or several doses rapidly suppressed the parasitemia and either terminated the infections or suppressed growth of the parasites for many days. The drug caused both nuclear and cytoplasmic damage in asexual forms of P. berghei and P. cynomolgi. A repository dose was active for several weeks in mice and for several months in monkeys. Given orally against P. berghei, the drug 1) was several hundredfold more active than quinine, 2) was effective against a group of lines that collectively are resistant to all suppressive drugs in use and thus appeared to represent a new mode of action, 3) acted synergistically with 4,4'-diaminodiphenylsulfone without apparent commensurate increase in toxicity for mice, and 4) was partially antagonized by para-aminobenzoic acid but not by folinic acid or sodium folate.

^* Present address: School of Veterinary Medicine, University of Georgia, Athens, Georgia 30601.