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 mol ecular basis of the action of these drugs is not completely understood , but they are thought to interfere with hemoglobin digestion in the b lood stages of the malaria parasite's life cycle. The parasite degrade s hemoglobin, in an acidic food vacuole, producing free heme and react ive oxygen species as toxic by-products. The heme moieties are neutral ized by polymerisation, while the free radical species are detoxified by a vulnerable series of antioxidant mechanisms. Chloroquine, a dibas ic 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 reac tive oxygen species, effectively killing the parasite with its own met abolic waste. Chloroquine resistance appears to arise as a result of a decreased level of chloroquine uptake, due to an increased vacuolar p H or to changes in a chloroquine importer or receptor. The more lipoph ilic quinolinemethanol drugs mefloquine and quinine do not appear to b e concentrated so extensively in the food vacuole and may act on alter native targets in the parasite. Resistance to the quinolinemethanols i s thought to involve a plasmodial homolog of P glycoprotein. As the ma laria parasites become increasingly resistant to the quinoline antimal arials, there is an urgent need to understand the molecular mechanisms for drug action and resistance so that novel antimalarial drugs can b e designed. A number of modified quinolines and bisquinoline compounds show some promise in this regard. (C) 1998 Elsevier Science Inc.