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Antimicrobial Agents and Chemotherapy, December 2005, p. 4950-4956, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.4950-4956.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Efficacy of Orally Administered 2-Substituted Quinolines in Experimental Murine Cutaneous and Visceral Leishmaniases

Department of Tropical Medicine, Casilla de Correo 2511, Instituto de Investigaciones en Ciencias de la Salud Asunción, Universidad Nacional de Asuncion, Paraguay,¹ Laboratoire de Pharmacognosie et Groupe Chimiothérapie Antiparasitaire UMR 8076 CNRS, Faculté de Pharmacie, Université Paris-Sud, rue J.B. Clément, 92296 Chtenay-Malabry cédex, France,² IRD US 084 BIODIVAL, Laboratoire de Pharmacognosie, Faculté de Pharmacie, rue J. B. Clément, 92296 Chtenay-Malabry cedex, France³

Received 28 March 2005/ Returned for modification 2 May 2005/ Accepted 13 September 2005

We report in this study the in vivo efficacy of nine 2-substituted quinolines on the Leishmania amazonensis cutaneous infection murine model and on the Leishmania infantum and Leishmania donovani visceral infection murine models. In the case of the L. amazonensis model, quinolines were administered orally at 25 mg/kg twice daily for 15 days. Quinolines 1, 2, 3, and 7 reduced by 80 to 90% the parasite burdens in the lesion, whereas N-methylglucamine antimoniate (Glucantime), administered by subcutaneous injections at 100 mg [28 mg Sb(V)] per kg of body weight daily, reduced the parasite burdens by 98%. In visceral leishmaniasis due to L. infantum, mice treated orally at 25 mg/kg daily for 10 days with quinolines 1, 4, 5, and 6 showed a significant reduction of parasite burdens in the liver and spleen. These quinolines were significantly more effective than meglumine antimoniate to reduce the parasite burden in both the liver and spleen. Also, the oral in vivo activity of three quinolines (quinolines 4, 5, and 2-n-propylquinoline) were determined against L. donovani (LV 9) at 12.5 and 25 mg/kg for 10 days. Their activity was compared with that of miltefosine at 7.5 mg/kg. Miltefosine, 2-n-propylquinoline, and quinoline 5 at 12.5 mg/kg significantly reduced the parasite burdens in the liver by 72, 66, and 61%, respectively. From the present study, quinoline 5 is the most promising compound against both cutaneous and visceral leishmaniasis. The double antileishmanial and antiviral activities of these compounds suggest that this series could be a potential treatment for coinfection of Leishmania-human immunodeficiency virus.