Quinoline Antimalarials: Mechanisms of Action and Resistance and Prospects for New Agents
Introduction
Almost one-half of the world’s population lives under the constant threat of malaria, and the disease is responsible for about 2 million deaths each year (World Health Organisation, 1997). A large percentage of the fatalities occur in Africa; however, malaria is endemic throughout most of Southeast Asia, the Indian subcontinent, the South Pacific region, and Latin America.
Malaria is caused by protozoan parasites of the genus Plasmodium. There are four species of Plasmodium that infect humans, the most deadly of these being P. falciparum. The parasite requires two hosts, a female Anopheles mosquito and a human. The malaria life-cycle begins when an infected female mosquito bites her prey, withdrawing blood and at the same time injecting sporozoite-containing saliva into the capillaries of the skin. The sporozoites enter liver cells and multiply to form about 30,000 merozoites each. After about 5 days, the merozoites are released into the blood stream. They enter red blood cells and develop through the so-called ring, trophozoite, and schizont stages. The erythrocyte provides the parasite with a safe haven from the host’s immune system, but presents certain logistical problems with regard to access to nutrients and disposal of waste products (for a review, see Foley and Tilley, 1995). Parasite growth is supported by the ingestion of host hemoglobin. During a 48-hr (or 72-hr for P. malariae) cycle the parasite divides to produce 16–20 daughter merozoites. The merozoites burst from the mature schizont, releasing cell debris, which causes a febrile episode in the host. Within minutes, the merozoites invade new red blood cells and the cycle continues. After several cycles, some of the intraerythrocytic parasites develop into sexual stage gametocytes. The gametes are ingested when a mosquito bites an infected individual. They mate in the gut of the insect and then pass through the gut wall, where they develop into oocysts that release sporozoites that migrate to the salivary glands to be passed on to another individual.
It is the intraerythrocytic stages of the malaria parasite that produce the disease pathology. Most deaths occur due to a complication of infections with P. falciparum, whereby erythrocytes infected with mature-stage parasites adhere to the vascular endothelium of post-capillary venules, particularly in the brain. Vascular occlusion and/or an inappropriate host immune reaction (for a review, see Grau and De Kossodo, 1994) can lead to coma. Once a coma is established, the patient has only a 10–50% chance of survival, even with optimal medical care. Whilst the blood forms of the parasite cause most of the pathology of the disease, they are also the stages that are most susceptible to attack by antimalarial drugs. In this review, we will concentrate on the action of the quinoline antimalarials, most of which act exclusively on the blood stages of Plasmodium.
Quinoline-containing antimalarials have long been used to combat malaria. In the 1940s, the synthetic quinoline compound chloroquine was introduced (Loeb et al., 1946) (Fig. 1A) and proved invaluable in the fight against the disease. The success of chloroquine led to the hope that malaria might be completely eradicated from the world. Population-based prophylaxis with antimalarial drugs was initiated in many areas in the 1960s. In addition, there was widespread use of insecticides and programs to drain swamps and other breeding grounds for mosquitos. The depressing outcome of these efforts was the development of insecticide-resistant mosquitos, and even more worryingly, the appearance of drug-resistant strains of the malaria parasite. Indeed, resistance to chloroquine is now so widespread that this drug has been rendered virtually useless in some parts of the world. Furthermore, changes in global ecosystems and weather patterns recently have been implicated in a resurgence of malaria in South America and Africa Haines et al. 1993, Bouma et al. 1994, Loevinsohn 1994. The alarming spread of malaria, particularly drug-resistant malaria, has led the World Health Organisation to predict that in the absence of new antimalarial strategies, the number of people suffering from malaria will increase dramatically over the next 10 years (World Health Organisation, 1997).
Malaria is not confined to the poorer people of the world. As international travel becomes more common, imported malaria is becoming an increasingly serious problem Molyneux and Fox 1993, Freedman 1992. Thus, it is imperative that novel drugs are developed to treat the disease, or that mechanisms are found to circumvent the phenomenon of drug resistance. The development of novel treatments would be greatly enhanced by a detailed molecular knowledge of the modes of action of current antimalarial drugs. Somewhat surprisingly, the precise modes of action of the quinoline antimalarials, which represent a major part of our armory against malaria, are still not completely understood. This article reviews some of the efforts that have been made to understand the mechanisms of quinoline drug action and resistance, and examines attempts to synthesize effective new quinoline antimalarials.
Section snippets
Quinine
The first quinoline antimalarial drugs were alkaloids extracted from the cinchona tree. The cinchona tree is named after the Countess of Chinchon, who according to legend was cured of malaria in 1630 by a powder made from its bark. The pulverized bark of the “fever tree” was widely distributed in Europe by the Jesuits during the 17th century (see Wallace, 1996). Variations in the quality of the bark preparations led to efforts to isolate the active ingredients. A crude mixture of crystalline
Interaction of Chloroquine with DNA
Chloroquine has toxic effects against a wide range of cells, as evidenced by the fatal effects of the drug when taken as an overdose and by the various side effects experienced when the drug is taken even at moderate doses (see Section 3.5). The multiple effects of chloroquine have hampered efforts to establish the molecular basis for its inhibitory activity against the malaria parasite. Early studies suggested that interactions of chloroquine with DNA might underlie the antimalarial activity
Mechanisms of action of other quinoline antimalarials
The quinolinemethanols, quinine and cinchonine, and their respective stereoisomers, quinidine and cinchonidine (see Fig. 1A), are the major alkaloids of the cinchona bark, and all possess antimalarial properties (for a review, see Thompson and Werbel, 1972). Quinine and quinidine continue to be important in the therapy of malaria Hofheinz and Merkli 1984, Barennes et al. 1996, either alone or in combination with antibiotic antimalarials (Kremsner et al., 1997). Quinidine is a more potent
Development of Chloroquine Resistance
The need to understand the mechanisms of action of the quinoline antimalarials is becoming more urgent as levels of resistance to these drugs increase. Resistance to chloroquine was slow to develop, taking almost 20 years, despite extensive use of the drug, suggesting that mutations in several genes were required to produce the resistance phenotype. This is in marked contrast to the situation with resistance to the antifolate drug pyrimethamine, where point mutations in the gene encoding
Development of Quinolinemethanol Resistance
The first reports of decreased sensitivity to quinine occurred in Brazil as early as 1910 (see Bjorkman and Phillips-Howard 1990, Meshnick 1997). However, as quinine has been used much less extensively than chloroquine, it has retained its efficacy in the field much longer (Kain, 1995). Nonetheless, reports of quinine resistance are increasing (Watt et al., 1992), and efficacy with quinine treatment has fallen below 50% in some parts of Southeast Asia where quinine has been used to treat
Pharmacokinetics of Chloroquine
The pharmacokinetics of chloroquine have been reviewed extensively McChesney and Fitch 1984, White 1985, Peters 1987, Na-Bangchang et al. 1994. Chloroquine is well absorbed (70–80% bioavailability) when given orally (for a review, see Furst, 1996). With weekly administration of 300 mg of chloroquine, the peak plasma level of the drug is estimated to reach about 200 ng/mL (about 0.4 μM), but falls to about 20 ng/mL prior to the succeeding dose White et al. 1988, Wetsteyn et al. 1995. This
General Structure-Function Considerations for Quinoline Antimalarials
The structure-activity relationships of chloroquine and related quinoline antimalarial compounds have been reviewed extensively Coatney 1963, Thompson and Werbel 1972, Hofheinz and Merkli 1984, Sweeney 1984, Peters 1987, Slater 1993, Bray et al. 1996a, Ismail et al. 1996. In general, it can be said that active 4-aminoquinoline antimalarials contain two or more nitrogens that become protonated within the physiological pH range. The antimalarial activity is affected by chemical modifications to
Acknowledgements
We are very grateful to Professor Hagai Ginsburg, Hebrew University of Jerusalem, Israel; Dr. Geoff Pasvol, Imperial College School of Medicine, Harrow, UK; and Professor Wallace Peters, International Institute of Parasitology, St. Albans, UK, for extensive discussions and insightful input, and to Dr. Kaylene Raynes, Mr. Paul Loria, and Dr. Giovanni Ciarrocchi, La Trobe University, Australia, for help with proofreading and preparation of the diagrams.
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