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Antimicrobial Agents and Chemotherapy, March 1999, p. 598-602, Vol. 43, No. 3
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

8-Aminoquinolines Active against Blood Stage Plasmodium falciparum In Vitro Inhibit Hematin Polymerization

Jonathan L. Vennerstrom,1,* Edwin O. Nuzum,2 Robert E. Miller,2 Arnulf Dorn,3 Lucia Gerena,2 Prasad A. Dande,1 William Y. Ellis,2 Robert G. Ridley,3 and Wilbur K. Milhous2

College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska1; Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, D.C.2; and Pharma Research, Preclinical Infectious Diseases, F. Hoffmann-LaRoche Ltd., CH-4070 Basel, Switzerland3

Received 7 August 1998/Returned for modification 20 October 1998/Accepted 22 December 1998

From the Walter Reed Army Institute of Research (WRAIR) inventory, thirteen 8-aminoquinoline analogs of primaquine were selected for screening against a panel of seven Plasmodium falciparum clones and isolates. Six of the 13 8-aminoquinolines had average 50% inhibitory concentrations between 50 and 100 nM against these P. falciparum clones and were thus an order of magnitude more potent than primaquine. However, excluding chloroquine-resistant clones and isolates, these 8-aminoquinolines were all an order of magnitude less potent than chloroquine. None of the 8-aminoquinolines was cross resistant with either chloroquine or mefloquine. In contrast to the inactive primaquine prototype, 8 of the 13 8-aminoquinolines inhibited hematin polymerization more efficiently than did chloroquine. Although alkoxy or aryloxy substituents at position 5 uniquely endowed these 13 8-aminoquinolines with impressive schizontocidal activity, the structural specificity of inhibition of both parasite growth and hematin polymerization was low.

* Corresponding author. Mailing address: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198-6025. Phone: (402) 559-5362. Fax: (402) 559-9543. E-mail: jvenners{at}mail.unmc.edu.

Antimicrobial Agents and Chemotherapy, March 1999, p. 598-602, Vol. 43, No. 3
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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