Feb. 12, 1998 Chemists have developed new compounds that show promise in treating malaria by making the disease-causing parasites self-destruct.
A scientific paper about the compounds will appear in the March 12 issue of the Journal of Medicinal Chemistry, published by the American Chemical Society.
At any given time, about 300 million people suffer from malaria, and as many as 3 million of them, mostly children, will die every year. The most severe form of the infection is caused by tiny parasites called Plasmodium falciparum, which are transmitted by female mosquitos feeding on human blood.
The drug of choice to combat malaria has been chloroquine, a derivative of quinine, which comes from the bark of the Cinchona tree. But the malaria parasites began showing resistance to chloroquine nearly 40 years ago.
Chinese chemists have isolated a new anti-malarial drug from the plant Artemisia annua, which has been used for thousands of years as an herbal remedy for fever. The drug, called artemisinin, has since been proven to be effective against malaria. Chemists have developed derivatives of artemisinin, as well. But artemisinin and its derivatives remain difficult and expensive to produce, and they quickly break down in the human body.
New synthetic compounds being developed at Johns Hopkins have been shown to kill malaria parasites in test tubes and in experiments with mice. Although the synthetic compounds use the same general mechanism as artemisinin, they are not derivatives of the drug; they are a new type of compound that has a much simpler structure. Because they are simpler, they can be made in only three to five chemical steps, compared to 12 or more steps for the artemisinin derivatives.
The research is being conducted by a team of scientists led by Gary H. Posner, Scowe Professor of Chemistry in The Johns Hopkins University School of Arts and Sciences, Theresa A. Shapiro, a pharmacologist and associate professor in the School of Medicine, graduate students Jared N. Cumming and Poonsakdi Ploypradith and technician Suji Xie.
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 high as 106 degrees Fahrenheit.
"A person cannot survive more than a few hours having cerebral malaria," Posner said.
The next step will be to determine whether it is safe when administered in large doses. Preliminary safety results are encouraging, Posner said.
Malaria is a menace in regions stretching from Africa to the Caribbean islands, and from Central America to Asia and India. The disease is spread by a genus of mosquitos called Anopheles, which pick up the parasite when they bite an infected person. The insects then transmit infected blood to other people. Anopheles mosquitos are found in portions of the United States, where reports of malaria have historically been rare since the 1930s but where public health officials are increasingly concerned.
The research is being funded by the National Institutes of Health and the Burroughs Wellcome Fund.
(The scientific paper is available on-line at the following Web address: http://pubs.acs.org/hotartcl/jmcmar/jmcmar.html).
Another paper about the synthesis of similar antimalarial compounds will be published in March 1998 in Tetrahedron Letters, an international science journal published in the United Kingdom. ###
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