Synergistic interaction of a chloroquine metabolite with chloroquine against drug-resistant malaria parasites

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 [Biochem. Pharmacol. 63 (2002) 833]. In an effort to further diss...

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Bibliographic Details
Published in:Biochemical pharmacology 2004-04, Vol.67 (7), p.1347-1353
Main Authors: Kalkanidis, Martha, Klonis, Nectarios, Tschan, Serena, Deady, Leslie W, Tilley, Leann
Format: Article
Language:English
Subjects:
4-Aminoquinoline
Aminoquinolines - pharmacology
Animals
Antimalarials - pharmacology
Biological and medical sciences
Chloroquine
Chloroquine - metabolism
Chloroquine - pharmacology
Drug Interactions
Drug Resistance
Drug Synergism
Haem
Hemeproteins - metabolism
Hemin - pharmacology
Malaria
Malaria - parasitology
Medical sciences
Parasitic Sensitivity Tests
Pharmacology. Drug treatments
Plasmodium
Plasmodium falciparum - drug effects
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Summary: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 [Biochem. Pharmacol. 63 (2002) 833]. 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.
ISSN:0006-2952
1873-2968
DOI:10.1016/j.bcp.2003.12.005