Chemists have been able to make the new compounds by figuring out how artemisinin kills the malaria parasites. The central component of the mechanism is a ring of atoms, present in artemisinin and the new compounds, that contains three oxygen atoms. The structure, called a trioxane, contains two oxygens that are bound together, a combination called a peroxide.
The researchers found that iron from blood inside the malaria parasite provides electrons that rupture the bond between the two adjacent oxygen atoms in the peroxide. The result is an oxygen free radical -- an atom with an unpaired electron. The free radical attracts a hydrogen atom, plucking it away from its bond with a carbon atom and producing an electron-hungry carbon free radical. Carbon radicals damage cells inside the parasite by stealing electrons and breaking molecular bonds, making the drug toxic to the malaria parasite.
"The parasite initiates its own self-destruction inadvertently," Posner said. "Based on that mechanistic understanding, we have designed a new series of trioxanes. We don't start with artemisinin and change its structure. Rather, we start from scratch and design a series of trioxanes so that they are in accord with our understanding, at the molecular level, of how these compounds behave."
Some of the synthetic compounds were as effective as artemisinin.
"More important, perhaps, is the fact that they are active by oral administration so you can not only administer them by injection, you can give them orally," Posner said.
For the most severe form of malaria, called cerebral malaria, the
early administration of medicine could be the difference between
life and death. That form of the disease can induce coma and
fevers as hig
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Contact: Emil Venere
emil@jhu.edu
410-516-7160
Johns Hopkins University
12-Feb-1998