1. Synergistic interaction of a chloroquine metabolite with chloroquine against drug-resistant malaria parasites.
- Author
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Kalkanidis M, Klonis N, Tschan S, Deady LW, and Tilley L
- Subjects
- Animals, Chloroquine metabolism, Drug Interactions, Drug Synergism, Hemeproteins metabolism, Hemin pharmacology, Malaria parasitology, Parasitic Sensitivity Tests, Aminoquinolines pharmacology, Antimalarials pharmacology, Chloroquine pharmacology, Drug Resistance, Plasmodium falciparum drug effects
- Abstract
We have previously shown that structural modification of chlorpromazine to introduce a basic side chain converts this chloroquine (CQ) resistance-reversing agent into a compound that has activity against Plasmodium falciparum in vitro. In an effort to further dissect the structural features that determine quinoline antimalarial activity and drug resistance-reversing activity, we have studied a series of aminoquinolines that are structurally related to CQ. We have analysed their haematin-binding activities, their antimalarial activities and their abilities to synergise the effect of CQ against drug-resistant P. falciparum. We found that a number of the aminoquinolines were able to interact with haematin but showed no or very weak antiparasitic activity. Interestingly, 4-amino-7-chloroquinoline, which is the CQ nucleus without the basic side chain, was able to act as a resistance-reversing agent. These studies point to structural features that may determine the resistance-modulating potential of weakly basic amphipaths. Interestingly, 4-amino-7-chloroquinoline is a metabolic breakdown product of CQ and may contribute to CQ activity against resistant parasites in vivo.
- Published
- 2004
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