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Antimicrobial Agents and Chemotherapy, August 2003, p. 2598-2605, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2598-2605.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

In Vivo Antimalarial Activities of Mono- and Bis Quaternary Ammonium Salts Interfering with Plasmodium Phospholipid Metabolism

Marie L. Ancelin,1 Michèle Calas,2 Anne Bonhoure,1 Serge Herbute,1 and Henri J. Vial1*

UMR 5539,1 LAPP, UMR 5810, CNRS, Université Montpellier II, 34095 Montpellier Cedex 5, France2

Received 14 November 2002/ Returned for modification 22 February 2003/ Accepted 10 May 2003

We previously showed that quaternary ammonium salts have potent antimalarial activities against the blood stage of drug-resistant Plasmodium falciparum. In the present study, 13 compounds of this series were comparatively assessed in murine in vivo malarial models. Mice infected with Plasmodium berghei were successfully treated with 11 quaternary ammonium salts in a 4-day suppressive test with a once-daily intraperitoneal administration. The dose required to decrease parasitemia by 50% (ED50) ranged from 0.04 to 4.5 mg/kg of body weight. For six mono- and three bis-quaternary ammonium salts, the therapeutic indices (i.e., 50% lethal dose and ED50) were higher than 5, and at best, around 20 to 30 for five of them (E6, E8, F4, G5, and G25), which is comparable to that of chloroquine under the same conditions. Plasmodium chabaudi was significantly more susceptible to G5, G15, and G25 compounds than P. berghei. Similar therapeutic indices were obtained, regardless of the administration mode or initial parasitemia (up to 11.2%). Parasitemia clearance was complete without recrudescence. Subcutaneously administered radioactive compounds had a short elimination half-life in mice (3.5 h) with low bioavailability (17.3%), which was likely due to the permanent cationic charge of the molecule. The high in vivo therapeutic index in the P. chabaudi-infected mouse model and the absence of recrudescence highlight the enormous potential of these quaternary ammonium salts for clinical malarial treatment.

* Corresponding author. Mailing address: UMR 5539, CNRS, Université Montpellier II, CP 107, Place Bataillon, 34095 Montpellier Cedex 5, France. Phone: 33 0 4 6714 3745. Fax: 33 0 4 6714 4286. E-mail: vial{at}univ-montp2.fr.

Antimicrobial Agents and Chemotherapy, August 2003, p. 2598-2605, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2598-2605.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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