Malaria Drug Design on a Dime

MEDICINAL CHEMISTRY

Using the antimalarial natural product artemisinin for inspiration, an international public-private partnership has designed a synthetic ozonide compound with potent antimalarial properties. The structurally simple, orally available drug candidate could be a cheaper and more effective alternative to current malaria drugs, its developers say.

"When combined with a second antimalarial, synthetic ozonides may offer the best solution we have seen to date for treating drug-resistant malaria parasites," comments chemist Paul M. O'Neill of the University of Liverpool.

Extracted from the bark of the sweet wormwood tree, artemisinin has been used to treat fevers in traditional Chinese herbal medicine for more than 1,500 years. Today, derivatives made from the isolated natural product are the most potent antimalarial drugs available. And as malaria strains resistant to older drugs spread at an alarming rate, the artemisinins are becoming increasingly important.

But because the artemisinins must be synthesized from a plant extract, most malaria sufferers, particularly those in Africa, can't afford them. In addition, the drugs must be administered often because they're quickly degraded in the bloodstream. Chemists have made synthetic analogs of artemisinin that incorporate the endoperoxide bridge that gives the natural product its parasite-killing properties. But poor activity and unwieldy syntheses have plagued the analogs developed so far.

The international team's new endoperoxide-containing ozonide, dubbed OZ277, has overcome these limitations: It's more potent and longer lasting than the artemisinins, it's structurally simple, and its synthesis is amenable to industrial scale-up, notes team leader Jonathan L. Vennerstrom, a medicinal chemist at the University of Nebraska Medical Center, Omaha [Nature, 430, 900 (2004)].

Vennerstrom's team systematically evaluated a variety of secondary ozonides before picking one that contained both an adamantane and a cyclohexane ring. The compound was more active than the artemisinins, but it remained too lipophilic to be administered orally. To improve solubility, Vennerstrom and his team--which included pharmacokineticists from Monash University, in Australia; parasitologists from the Swiss Tropical Institute; and toxicologists from Hoffmann-La Roche in Basel, Switzerland--derivatized the ozonide's cyclohexyl ring in various ways. OZ277 had the killer combination of good activity and attractive pharmaceutical properties.

Cost was also a key constraint. "A drug must be economical to produce to even be considered for tropical medicine," Vennerstrom says. His team's chromatography-free synthesis of OZ277 has an overall yield of 68%. The firm developing the drug, India's Ranbaxy Laboratories, is already making OZ277 on a multikilogram scale. The compound is currently in Phase I clinical trials in the U.K., and tests of its efficacy in malaria patients will begin early next year.

The development of OZ277 was funded and coordinated by Medicines for Malaria Venture, a Swiss nonprofit that has reinvigorated antimalarial R&D since its formation four years ago. The new antimalarial "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," O'Neill notes in a companion Nature commentary.