Background
Malaria represents a significant global health threat, with 40% of the world's population being at risk of contracting this disease. During 2012, nearly six-hundred and thirty thousand people died from the disease, with pregnant women and children under the age of five being the most vulnerable to infection. By far the most (around 90%) deaths occur in sub-tropical and tropical Africa south of the Sahara (representing 564,300 of the total 627,000 deaths reported in 2012), indicative of the endemic proportions that malaria has reached in this region.
Malaria arises from the invasion of red blood cells (RBCs) by a protozoan of the genus, Plasmodium. Five species of the Plasmodium genus, i.e. Plasmodium falciparum, Plasmodium ovale, Plasmodium vivax, Plasmodium malariae, and Plasmodium knowlesi cause human malaria. Of these species, P. falciparum is responsible for the most severe form of malaria. The malaria parasite is transmitted to humans following the bite of an infected female Anopheles mosquito. The parasite has a complex life cycle, involving the vector and a vertebrate host. Figure 1 illustrates the malaria parasite life cycle that progresses through three different phases, with each phase comprising its own different stages.
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Figure 1.
Schematic life cycle of malaria parasite. (A) Liver phase, (B) Blood phase, (C) Mosquito phase. The cycle progresses from (A) to (B), and then to (C).
The liver phase (A): following the bite of an infected Anopheles mosquito, sporozoites (1) (infectious stage) are introduced into the bloodstream of the victim (host), from where they migrate to the liver. In the liver, each sporozoite develops into a tissue schizont (3). In P. ovale and P. vivax, the sporozoites develop into hypnozoites (2), the dormant form responsible for the relapse of the disease, months after the initial infection.
The blood phase (B): when the tissue schizont (3) ruptures in the liver, merozoites are released into the bloodstream, where they invade the RBCs. Within the RBCs, each merozoite transforms into a trophozoite (6) and later into a blood schizont (7), which multiplies asexually, giving rise to 16–32 merozoites (4). When the infected RBCs rupture, merozoites are released into the bloodstream to further invade more RBCs and hence continue asexual multiplication. The clinical manifestations of the disease (e.g. fever and chills) appear during this phase. Some of these merozoites develop into gametocytes (8).
The mosquito phase (C): when a mosquito feeds on an infected person, it ingests gametocytes with the blood. The gametocytes undergo asexual reproduction within the mosquito's mid-gut, producing thousands of sporozoites (1), which then migrate into the salivary glands of the mosquito, from where they are injected into humans during a blood meal.
Hitherto, chemotherapy has remained the sole option for malaria treatment. Quinine, an alkaloid present in the bark of Cinchona trees, was the first effective treatment for malaria. Once the structure of quinine had been established by Rabe et al., the syntheses of quinine analogues became the next focus. This led to the discovery of the quinoline chloroquine (CQ) (Figure 1) and related compounds, such as amodiaquine and piperaquine. Other quinolines bearing a benzylic hydroxyl group as in the case of quinine were also prepared, the most important of which was mefloquine. CQ turned out to be the most successful drug: it was cheap, relatively safe and was used for decades, before the parasite developed resistance to the drug. Structurally quite different drugs, as represented by Fansidar (a combination of sulphadoxine and pyrimethamine), have since been introduced, but unfortunately efficacy has also been impeded by the development of resistance.
Artemisinin and its derivatives (2, 3–6, Figure 2), referred to as the 'artemisinins', are another class of anti-malarial drugs that are fast acting and potent against all resistant strains of the malaria parasite. In an attempt to protect the artemisinins against the development of parasite resistance, the World Health Organization (WHO) recommended the use of these drugs in combination with other drugs, rather than in monotherapy. This led to the adoption of artemisinin based combination therapy (ACT) for the treatment of uncomplicated malaria in endemic countries. ACT combines an artemisinin derivative with a longer half-life anti-malarial drug. The rationale is that the fast acting artemisinin clears a larger proportion of the parasites within its short pharmacological half-life, whilst the longer half-life partner drug then continues the clearance as the artemisinin concentration falls to sub-therapeutic levels. In spite of this, tolerance to ACTs by the parasite has been reported in South-East Asia, which is indicative of emerging resistance to the artemisinins. With the recent identification of genetic markers of the resistant phenotype and the pinpointing of the rapid spread of this phenotype, the search for new anti-malarial drugs becomes of utmost importance.
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Figure 2.
Structures of chloroquine (1), artemisinin (2) and its derivatives: dihydroartemisinin (3), artemether (4), arteether (5), artesunate (6), and primaquine (7).
The anti-malarial drugs discussed above are more effective against the blood stage than any other stage of the malarial parasite. Primaquine is the only clinically proven drug that effectively kills hypnozoites (2) (the liver stage of the P. vivax parasite), and is also active against gametocytes (8) (the transmission stage of the parasite). Primaquine, however, causes fatal haemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, an adverse side effect that has significantly limited its use.
Overall, resistance and tolerance associated with currently available anti-malarial drugs have created a driving force to the search for new chemical entities having novel modes of action, being readily available and meeting the Medicines for Malaria Venture (MMV) requirements for the next generation drugs needed to eradicate malaria. According to MMV, a suitable drug candidate for malaria eradication should be able to kill gametocytes, hypnozoites and other liver stages, thereby inhibiting transmission, relapse, as well as providing prophylaxis against the disease. Ideally, such a potential candidate should also have a minimum half-life of three days, although in practice such a property may be difficult to achieve.