title: In vitro activity of bisquinoline WR268,668 against African clones and isolates of Plasmodium falciparum.
abstract: The in vitro activity of a new bisquinoline, WR268,668, was determined against chloroquine-susceptible and chloroquine-resistant African clones and isolates of Plasmodium falciparum using an isotopic semimicro drug susceptibility assay. The chloroquine-resistant clone (mean 50% inhibitory concentration [IC50] = 61.2 nM) was 11 times less susceptible to WR268,668 than the chloroquine-susceptible clone (IC50 = 5.75 nM). A similar result was obtained with fresh clinical isolates, with the chloroquine-susceptible isolates (IC50 = 5.36 nM, n = 11) being significantly (P < 0.05) more susceptible to WR268,668 than the chloroquine-resistant isolates (IC50 = 16.1 nM, n = 18). The compound WR268,668 exhibited a high activity against some moderately chloroquine-resistant isolates. There was a significant positive correlation between the in vitro responses to chloroquine and WR268,668 (r = 0.904, P < 0.05). Combinations of WR268,668 and desipramine, a chloroquine efflux inhibitor, showed that resistance to WR268,668 can be reversed against the chloroquine-resistant clone and that desipramine has no effect on the activity of WR268,668 against the chloroquine-susceptible clone. The results of the study indicate the presence of cross-resistance between chloroquine and WR268,668, and suggest that the basis of resistance to WR268,668 may be similar to that of other 4-aminoquinolines.
authors.affiliation: Centre National de Reference pour la Chimiosensibilite du Paludisme, Hopital Bichat-Claude Bernard, Paris, France.
authors.forename: L K
authors.initials: LK
authors.lastname: Basco
authors.forename: S L
authors.initials: SL
authors.lastname: Andersen
authors.forename: W K
authors.initials: WK
authors.lastname: Milhous
authors.forename: J
authors.initials: J
authors.lastname: Le Bras
authors.forename: J L
authors.initials: JL
authors.lastname: Vennerstrom
mesh_terms: D000349:Africa; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D002738:Chloroquine / Q000737:chemistry / Q000494:pharmacology; D003514:Cyclohexylamines / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology; D004347:Drug Interactions; D004351:Drug Resistance; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D003514:Cyclohexylamines; D011804:Quinolines; C074925:WR 268668; D002738:Chloroquine; D003891:Desipramine