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Medicinal chemistry

A worthy adversary for malaria

Nature volume 430, pages 838839 (19 August 2004) | Download Citation

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A remarkable set of antimalarial drug candidates has been developed by an international collaboration of scientists, using the age-old Chinese herbal medicine artemisinin as a template.

Nearly two billion people live in areas where malaria is endemic, and the incidence of this disease is increasing dramatically, mainly because many malaria-parasite strains have become resistant to the available drugs1. The devastating spread of parasite resistance has prompted the worldwide search for new classes of effective antimalarial drugs. On page 900 of this issue, Vennerstrom and colleagues2 describe the development of a new class of synthetic drug related to the natural antimalarial product artemisinin.

Artemisinin has been used in traditional Chinese herbal fever remedies for more than 1,500 years3. It is extracted from sweet wormwood (Artemisia annua), and is used as the basis for synthesizing several modern antimalarial drugs, such as artesunate and artemether. These artemisinin derivatives are increasingly important in the treatment of drug-resistant malaria, as they are the most potent antimalarials available, rapidly killing all blood stages of the malaria parasite Plasmodium falciparum. But the overall yield of the artemisinin extraction process is poor, so that its derivatives, though inexpensive by the standards of developed countries, are relatively expensive when put in the African context. In addition, the drugs only act for a short time, so the dosage regimen can lead to patient non-compliance and subsequent treatment failure. These shortcomings have prompted medicinal chemists to try to make entirely synthetic analogues of artemisinin with improved antimalarial properties4.

Artemisinins contain a structural feature known as an endoperoxide bridge (Fig. 1a) that is key to their antimalarial activity, and one of the major challenges in the pursuit of synthetic analogues has been to introduce this bridge into candidate drugs. Incor-porating the endoperoxide ‘warhead’ is now possible, but many of the candidate analogues produced have significant drawbacks, including poor antimalarial activity and syntheses that are not stereoselective or not amenable to being scaled up5,6. So, although many research groups had focused on the problem for some fifteen years, the goal of a cheap, synthetic, endoperoxide-based antimalarial had not been realized.

Figure 1: Artemisinin and its analogues.
Figure 1

a, Chemical structure of artemisinin. The space-filled model on the right shows how the sensitive endoperoxide bridge is shielded by the ring system. b, Drug prototypes. Vennerstrom and colleagues2 fused an adamantane ring system onto the basic ozonide ring to produce a new class of antimalarial drug with superior activity to artemisinin. c, The clinical candidate, OZ277. The adamantane system protects the endoperoxide bridge, and the boxed chemical group is key to the compound's improved water solubility and pharmaceutical properties. Carbon atoms, grey; hydrogen atoms, light blue; oxygen atoms, red; nitrogen atoms, dark blue.

Vennerstrom et al.2 now provide the solutions to many of these problems. They compiled a wish-list of ideal drug properties for the target molecule and stuck strictly to it through a process of drug-optimization to create a new class of endoperoxide antimalarials that have superior properties to the artemisinin derivatives. The team consisted of chemists, parasitologists, pharmacokineticists and toxicologists.

The first stage of their drug discovery process involved a systematic examination of a chemical group known as secondary ozonides (or 1,2,4-trioxolanes; Fig. 1b). This class of compounds is well known to organic chemists as intermediates obtained by exposing alkenes to ozone. Although they have the requisite endoperoxide bridge, these molecules tend to be highly unstable — not a promising starting point, one might think. And unsurprisingly, some of the initial ozonide compounds tested turned out to be very poor antimalarials.

In artemisinin, the sensitive peroxide bridge is protected by bulky chemical rings, and the team attempted to mimic this feature by fusing a large, bulky group known as an adamantane ring onto the standard ozonide ring system (Fig. 1b). This was their first breakthrough. Remarkably, not only were the resulting compounds stable, but when tested against human strains of the malaria parasite, they also had superior parasite-killing properties even to artesunate and artemether.

The first series of the compounds were poorly soluble in water, however, so the next step was to increase the compounds’ water solubility so that they could be more easily absorbed from the gastrointestinal tract7. Many potential drugs containing chemical groups that increase water solubility were examined, and this led to the discovery of a candidate, OZ277 (Fig. 1c), that was well absorbed when administered orally to animals, and had outstanding antimalarial properties both in vitro and in vivo. Unlike the available artemisinin derivatives, OZ277 is structurally simple and its synthesis can be scaled up in a way that is economically feasible. What's more, its toxicological profiles are satisfactory. Following the development of a large-scale synthesis for OZ277, it has just entered ‘first into man’ studies.

Given the effectiveness of this new structurally simple drug, the question arises: how does it kill parasites? It seems probable that it shares a common mechanism of action with the artemisinins, where it is proposed that an interaction of the endoperoxide bridge with ferrous iron or haem from the red blood cell in which the parasite lodges generates toxic, carbon-centred free radicals8,9. Theoretically, these highly reactive molecules can modify key parasite proteins, disabling essential biological targets and killing the parasite. Using a technique known as spin-trapping, Vennerstrom and colleagues provide evidence that trioxolanes can indeed generate a carbon-centred free radical in a manner reminiscent of the artemisinins. There are several proposed protein targets for the noxious free radicals produced by artemisinin, one of which is an enzyme known as PfATP6 (ref. 10). Future studies should reveal whether OZ277 and its chemical siblings target the same proteins as the artemisinin derivatives.

The development of OZ277 is a flagship project for the Medicines for Malaria Venture11,12. It is an excellent example of how a well-managed partnership between academia and major pharmaceutical companies can have a significant impact on antimalarial product research and development.

Basing the drug development process on a chemically unstable entity such as a secondary ozonide was a daring move. And the research that enabled ozonides to be redesigned, not only to increase the chemical and metabolic stability, but also to provide phenomenal antimalarial properties, is impressive. The subsequent tailoring of the ‘ozonide’ molecule to enhance its availability to the body was hugely successful — the new synthetic analogues are more potent and act for longer in vivo than artemether and artesunate by some margin. As such, when combined with a second antimalarial, this new class could offer the best solution to date for destroying drug-resistant malaria parasites.

Nature Outlook: Malaria  More about the challenges posed by malaria appears in the collection of articles published as a Nature Outlook supplement, beginning on page 923 of this issue. The articles cover scientific, social and political problems, with the emphasis on Africa.

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  1. Paul M. O'Neill is in the Departments of Chemistry and of Pharmacology, University of Liverpool, Liverpool L69 7ZD, UK. p.m.oneill01@liverpool.ac.uk

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