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 OC,, = 5.36 nM, n = If) 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.
