Antileishmanial 2-substituted quinolines: in vitro behaviour towards biological components.
Quinolines substituted on their carbon 2 have in vivo antileishmanial activity but some of them could not be detected in plasma when assayed for pharmacokinetic studies, suggesting a sequestration of the drugs by components of the blood compartment. The present study, performed on three quinolines (1, 2 and 3), showed strong affinity for two of them (2 and 3) with red blood cells (RBCs), whereas quinoline 1 did not react with them. This process was saturable, temperature dependant and positively correlated with the in vitro antileishmanial activity of the quinolines. In addition, a rapid and spontaneous reaction with thiol groups was demonstrated for unsaturated quinolines 2 and 3. The reactivity with RBCs could be part of the compounds targeting to the parasite. These results illustrate that derivatives of the quinoline series with similar antileishmanial in vivo activity have different behaviour in the blood compartment.
Desrivot
Julie
J
Laboratoire de Pharmacognosie et Chimiothérapie Antiparasitaire, Centre d'Etudes Pharmaceutiques, BioCIS UMR 8076, Université Paris-Sud 11, 5 rue J-B Clément, 92290 Châtenay-Malabry, France.
Herrenknecht
Christine
C
Ponchel
Gilles
G
Garbi
Najla
N
Prina
Eric
E
Fournet
Alain
A
Bories
Christian
C
Figadère
Bruno
B
Hocquemiller
Reynald
R
Loiseau
Philippe M
PM
D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects*; D007894:Leishmania mexicana / Q000187:drug effects*; D008297:Male; D051379:Mice; D021261:Parasitic Sensitivity Tests; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D052616:Solid Phase Extraction; D013329:Structure-Activity Relationship; D013696:Temperature
D000981:Antiprotozoal Agents; D011804:Quinolines