Johns Hopkins Gazette: October 14, 1996 Form

On Campus:
Synthetic Compound
May Lead To
Malaria Drugs

Chemical solution
based on successful
plant therapy now
in limited supply.

Emil Venere
News and Information

Hopkins chemist Gary Posner and pharmacologist Theresa A. Shapiro have developed new chemical compounds that show promise in fighting malaria, a disease that kills 2 million people a year.

Malaria is a menace in regions stretching from Africa to the Caribbean Islands, and from Central America to Asia and India. New anti-malarial agents are urgently needed. More than three decades ago the parasite that causes malaria began showing a resistance to the drug chloroquine, traditionally used to prevent malaria, and the resistance has been spreading progressively throughout the world. The anti-malarial drug artemisinin, extracted from the plant Artemisia annua, has been successful in curing malaria patients in China. But plants contain only small amounts of the substance, making the drug expensive and impractical.

The Hopkins researchers were able to synthesize the new compounds after learning how artemisinin works at the molecular level. The experimental compounds use the same mechanism to kill the parasite that causes malaria, but they are much less expensive and easier to produce than drugs presently available.

When tested in laboratory cultures of infected blood, the compounds killed Plasmodium falciparum, the species of mosquito-borne parasite that causes most malaria deaths in people. One of the compounds has been tested on malaria-infected mice, curing the animals. The researchers are working now to develop more potent compounds, leading to additional animal testing.

The scientists have previously developed synthetic versions, or analogs, of artemisinin; the synthetic drugs have been shown to cure malaria in monkeys. But the new compounds would be easier and less expensive to produce than those analogs of artemisinin.

A scientific paper about the compounds was published on Sept. 30 in Tetrahedron Letters, an international science journal published in the United Kingdom.

After figuring out artemisinin's Plasmodium-killing chemistry, the organic chemists were able to make the new compounds. The central component of the mechanism is a ring of atoms, present in artemisinin and the new compounds, that contains two oxygen atoms bound together, a structure called a peroxide.

The researchers found that iron from blood inside the malaria parasite provides a source of electrons that rupture the bond between the two adjacent oxygen atoms in the peroxide structure. 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.

"Our understanding of that mechanism has allowed us to design structurally simpler compounds that would follow that chemical mechanism," said Posner, a professor in the Department of Chemistry.

The new compounds have a similar oxygen-oxygen bond, thereby enabling the same sort of iron-induced reaction.

Malaria is spread by a genus of mosquito 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 but where public health officials are increasingly concerned.

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