Antiparasitic activities and toxicities of individual enantiomers of the 8-aminoquinoline 8-[(4-amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3,4-dichlorophenoxy]quinoline succinate

Abstract

8-Aminoquinolines are an important class of antiparasitic agents, with broad utility and excellent efficacy, but also limitations due to hematological toxicities, primarily methemoglobinemia and hemolysis. One representative from this class, (+/-)-8-[(4-amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3,4-dichlorophenoxy]quinoline succinate (NPC1161C), proved extremely efficacious in animal models of malaria and pneumocystis pneumonia. This racemic mixture was separated into its component enantiomers by chemical and chromatographic means. The enantiomers were evaluated for antiparasitic activity in murine models of Plasmodium berghei, Pneumocystis carinii, and Leishmania donovani infection, as well as the propensity to elicit hematotoxicity in dogs. The (-)-enantiomer NPC1161B was found to be more active (by severalfold, depending on the dosing regimen) than the (+)-enantiomer NPC1161A in all of these murine models. In addition, the (-) enantiomer showed markedly reduced general toxicity in mice and reduced hematotoxicity in the dog model of methemoglobinemia. It is concluded that the configuration at the asymmetric center in the 8-amino side chain differentially affects efficacy and toxicity profiles and thus may be an important determinant of the "therapeutic window" for compounds in this class.

FIG. 1.

Structures of primaquine and primaquine analogs.

FIG. 2.

Suppressive antimalarial activities of NPC1161C, tafenoquine, and primaquine against P. berghei in mice represented as survival curves.

FIG. 3.

Suppressive antimalarial activities of NPC1161A, NPC1161B, and NPC1161C against P. berghei in mice represented as survival curves.

FIG. 4.

Methemoglobin formation in dogs treated with NPC1161C succinate, tafenoquine succinate, or primaquine diphosphate, at 0.0116 mmol/kg orally on days 1 to 4. The doses in mg/kg for the salts are as follows: NPC1161C, 6.4; tafenoquine, 6.7; and primaquine, 5.3. Each curve represents data from a single dog.

FIG. 5.

Methemoglobin formation in dogs treated with NPC1161B or NPC1161A at 0.64 mg/kg of base (upper panel) or 1.91 mg/kg (lower panel) orally on days 1 to 4. Each curve represents data from a single dog, presented as mean + standard deviation of duplicate determinations.