Johns Hopkins University scientists have developed new chemical compounds that show promise in fighting malaria, a disease that kills 2 million people a year.
Chemists were able to synthesize the new compounds after learning how another, more expensive and difficult-to-produce malaria drug works at the molecular level. The new 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 experimental drugs 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 more animal testing.
Finding new anti-malarial agents is important because Plasmodium parasites are becoming increasingly resistant to chloroquine and other traditional drugs used to treat malaria patients. 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 have previously developed synthetic versions, or analogs, of artemisinin; the synthetic drugs have been shown to cure malaria in monkeys. The new compounds, however, 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. The research is being conducted by a team of scientists led by Gary H. Posner, Scowe Professor of Chemistry in The Johns Hopkins School of Arts and Sciences, and Theresa A. Shapiro, a pharmacologist and associate professor in the School of Medicine.
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 atemisinin 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," Posner said. The new compounds have a similar oxygen-oxygen bond, thereby enabling the same sort of iron-induced reaction.
Malaria is a menace in regions stretching from Africa to the Caribbean islands, and from Central America to Asia and India. The parasite began showing a resistance to chloroquine more than three decades ago, and its resistance is spreading progressively throughout the world.
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 but where public health officials are increasingly concerned.
The research was funded by a three-year grant, totaling $740,969, from the National Institutes of Health. That grant was recently renewed by NIH for another four years. Also involved in the work are Xueliang Tao, a postdoctoral fellow in chemistry; Jared N. Cumming, a chemistry graduate student; and Donna Klinedinst, a research assistant in the Johns Hopkins School of Medicine.