Dipeptide derivatives of primaquine as transmission-blocking antimalarials: effect of aliphatic side-chain acylation on the gametocytocidal activity and on the formation of carboxyprimaquine in rat liver homogenates.

PURPOSE: Dipeptide derivatives of primaquine (PQ) with reduced oxidative deamination to the inactive metabolite carboxyprimaquine were synthesized and evaluated as a novel class of transmission-blocking antimalarials. METHODS; Antimalarial activity was studied using a model consisting of mefloquine-resistant Plasmodium berghei ANKA 25R/10, Balb C mice, and Anopheles stephensi mosquitoes. Metabolic studies were performed with rat liver homogenates, and the incubates were analyzed by HPLC.
RESULTS: All dipeptide derivatives and glycyl-PQ completely inhibited the appearance of oocysts in the midguts of the mosquitoes at 15 mg/ kg, while N-acetylprimaquine was not active at this dose. However, none of the title compounds were able to block oocyst production at 3.75 mg/kg, in contrast with primaquine. Exception for sarc-gly-PQ, all remaining compounds prevented sporozoite formation in the salivary glands of mosquitoes at a dose of 3.75 mg/kg. Simultaneous hydrolysis to primaquine and gly-PQ ocurred with the following order of Vmax/Km: for primaquine formation. L-ala-gly-PQ > L-phe-gly-PQ > gly-gly-PQ; and for gly-PQ formation, L-phe-gly-PQ > L-ala-gly-PQ > gly-gly-PQ. In contrast, primaquine was not released from D-phe-gly-PQ, sarc-gly-PQ, and N-acetylprimaquine. Neither carboxyprimaquine nor 8-amino-6-methoxyquinoline were detected in any of the incubation mixtures.
CONCLUSIONS: The title compounds prevent the development of the sporogonic cycle of Plasmodium berghei. Gametocytocidal activity is independent of the rate and pathway of primaquine formation. Acylation of the aliphatic side-chain effectively prevents the formation of carboxyprimaquine, but the presence of a terminal amino group appears to be essential for the gametocytocidal activity.