title: Synergistic interaction of a chloroquine metabolite with chloroquine against drug-resistant malaria parasites.
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.
authors.affiliation: Department of Chemistry, La Trobe University, Melbourne, Victoria 3086, Australia.
authors.forename: Martha
authors.initials: M
authors.lastname: Kalkanidis
authors.forename: Nectarios
authors.initials: N
authors.lastname: Klonis
authors.forename: Serena
authors.initials: S
authors.lastname: Tschan
authors.forename: Leslie W
authors.initials: LW
authors.lastname: Deady
authors.forename: Leann
authors.initials: L
authors.lastname: Tilley
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000378:metabolism / Q000494:pharmacology*; D004347:Drug Interactions; D004351:Drug Resistance; D004357:Drug Synergism; D006420:Hemeproteins / Q000378:metabolism; D006427:Hemin / Q000494:pharmacology; D008288:Malaria / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D006420:Hemeproteins; C020753:hemozoin; D006427:Hemin; D002738:Chloroquine; C001920:4-aminoquinoline