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Antimicrobial Agents and Chemotherapy, June 2008, p. 2130-2137, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.00645-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

N. P. Dhammika Nanayakkara,^1* Arba L. Ager Jr.,⁴ Marilyn S. Bartlett,⁵ Vanessa Yardley,⁶ Simon L. Croft,⁶ Ikhlas A. Khan,^1,2 James D. McChesney,^1,2, and Larry A. Walker^1,3

National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences,¹ Departments of Pharmacognosy,² Pharmacology, School of Pharmacy, the University of Mississippi, University, Mississippi,³ Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida,⁴ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana,⁵ Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom⁶

Received 16 May 2007/ Returned for modification 6 October 2007/ Accepted 22 March 2008

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.

Published ahead of print on 31 March 2008.

Present address: Tapestry Pharmaceuticals, 4840 Pearl East Circle, 300W, Boulder, CO 80301-2408.