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Antimicrobial Agents and Chemotherapy, September 2005, p. 3631-3639, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3631-3639.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Pharmacological Properties of a New Antimalarial Bisthiazolium Salt, T3, and a Corresponding Prodrug, TE3

Olivier Nicolas,1 Delphine Margout,1 Nicolas Taudon,1 Sharon Wein,2 Michèle Calas,3 Henri J. Vial,2 and Françoise M. M. Bressolle1*

Clinical Pharmacokinetic Laboratory, Faculty of Pharmacy, University Montpellier I,1 CNRS UMR 5539,2 CNRS UMR 5810, University Montpellier II, Montpellier, France3

Received 21 April 2005/ Returned for modification 25 May 2005/ Accepted 6 June 2005

A new approach to malarial chemotherapy based on quaternary ammonium that targets membrane biogenesis during intraerythrocytic Plasmodium falciparum development has recently been developed. To increase the bioavailability, nonionic chemically modified prodrugs were synthesized. In this paper, the pharmacological properties of a bisthiazolium salt (T3) and its bioprecursor (TE3) were studied. Their antimalarial activities were determined in vitro against the growth of P. falciparum and in vivo against the growth of P. vinckei in mice. Pharmacokinetic evaluations were performed after T3 (1.3 and 3 mg/kg of body weight administered intravenously; 6.4 mg/kg administered intraperitoneally) and TE3 (1.5 and 3 mg/kg administered intravenously; 12 mg/kg administered orally) administrations to rats. After intraperitoneal administration, very low doses offer protection in a murine model of malaria (50% efficient dose [ED50] of 0.2 to 0.25 mg/kg). After oral administration, the ED50 values were 13 and 5 mg/kg for T3 and TE3, respectively. Both compounds exerted antimalarial activity in the low nanomolar range. After TE3 administration, rapid prodrug-drug conversion occurred; the mean values of the pharmacokinetic parameters for T3 were as follows: total clearance, 1 liter/h/kg; steady-state volume of distribution, 14.8 liters/kg; and elimination half-life, 12 h. After intravenous administration, T3 plasma concentrations increased in proportion to the dose. The absolute bioavailability was 72% after intraperitoneal administration (T3); it was 15% after oral administration (TE3). T3 plasma concentrations (8 nM) 24 h following oral administration of TE3 were higher than the 50% inhibitory concentrations for the most chloroquine-resistant strains of P. falciparum (6.3 nM).

* Corresponding author. Mailing address: Laboratoire de Pharmacocinétique Clinique, Faculté de Pharmacie, B.P. 14491, 34093 Montpellier Cedex 5, France. Phone: (33) 4 67 54 80 75. Fax: (33) 4 67 54 80 75. E-mail: Fbressolle{at}aol.com.

Antimicrobial Agents and Chemotherapy, September 2005, p. 3631-3639, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3631-3639.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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