Quinoline antimalarials: mechanisms of action and resistance and prospects for new agents.
Quinoline-containing antimalarial drugs, such as chloroquine, quinine and mefloquine, are mainstays of chemotherapy against malaria. The molecular basis of the action of these drugs is not completely understood, but they are thought to interfere with hemoglobin digestion in the blood stages of the malaria parasite's life cycle. The parasite degrades hemoglobin, in an acidic food vacuole, producing free heme and reactive oxygen species as toxic by-products. The heme moieties are neutralized by polymerisation, while the free radical species are detoxified by a vulnerable series of antioxidant mechanisms. Chloroquine, a dibasic drug, is accumulated several thousand-fold in the food vacuole. The high intravacuolar chloroquine concentration is proposed to interfere with the polymerisation of heme and/or the detoxification of the reactive oxygen species, effectively killing the parasite with its own metabolic waste. Chloroquine resistance appears to arise as a result of a decreased level of chloroquine uptake, due to an increased vacuolar pH or to changes in a chloroquine importer or receptor. The more lipophilic quinolinemethanol drugs mefloquine and quinine do not appear to be concentrated so extensively in the food vacuole and may act on alternative targets in the parasite. Resistance to the quinolinemethanols is thought to involve a plasmodial homolog of P-glycoprotein. As the malaria parasites become increasingly resistant to the quinoline antimalarials, there is an urgent need to understand the molecular mechanisms for drug action and resistance so that novel antimalarial drugs can be designed. A number of modified quinolines and bisquinoline compounds show some promise in this regard.
School of Biochemistry, La Trobe University, Bundoora, Victoria, Australia.
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Foley
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Tilley
D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D010961:Plasmodium / Q000187:drug effects; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology*
D000962:Antimalarials; D011804:Quinolines