Scientists designing new anti-malaria compounds

A scientific paper about the compounds will appear in the March12 issue of the Journal of Medicinal Chemistry, published by theAmerican 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 everyyear. The most severe form of the infection is caused by tinyparasites called Plasmodium falciparum, which are transmitted byfemale mosquitos feeding on human blood.

The drug of choice to combat malaria has been chloroquine, aderivative of quinine, which comes from the bark of the Cinchonatree. But the malaria parasites began showing resistance tochloroquine nearly 40 years ago.

Chinese chemists have isolated a new anti-malarial drug from theplant Artemisia annua, which has been used for thousands of yearsas an herbal remedy for fever. The drug, called artemisinin, hassince been proven to be effective against malaria. Chemists havedeveloped derivatives of artemisinin, as well. But artemisininand 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 havebeen shown to kill malaria parasites in test tubes and inexperiments with mice. Although the synthetic compounds use thesame general mechanism as artemisinin, they are not derivativesof the drug; they are a new type of compound that has a muchsimpler structure. Because they are simpler, they can be made inonly three to five chemical steps, compared to 12 or more stepsfor the artemisinin derivatives.

The research is being conducted by a team of scientists led byGary H. Posner, Scowe Professor of Chemistry in The Johns HopkinsUniversity School of Arts and Sciences, Theresa A. Shapiro, apharmacologist and associate professor in the School of Medicine,graduate students Jared N. Cumming and Poonsakdi Ploypradith andtechnician Suji Xie.

Chemists have been able to make the new compounds by figuring outhow artemisinin kills the malaria parasites. The centralcomponent of the mechanism is a ring of atoms, present inartemisinin and the new compounds, that contains three oxygenatoms. The structure, called a trioxane, contains two oxygensthat are bound together, a combination called a peroxide.

The researchers found that iron from blood inside the malariaparasite provides electrons that rupture the bond between the twoadjacent oxygen atoms in the peroxide. The result is an oxygenfree radical -- an atom with an unpaired electron. The freeradical attracts a hydrogen atom, plucking it away from its bondwith a carbon atom and producing an electron-hungry carbon freeradical. Carbon radicals damage cells inside the parasite bystealing electrons and breaking molecular bonds, making the drugtoxic to the malaria parasite.

"The parasite initiates its own self-destruction inadvertently,"Posner said. "Based on that mechanistic understanding, we havedesigned a new series of trioxanes. We don't start withartemisinin and change its structure. Rather, we start fromscratch and design a series of trioxanes so that they are inaccord with our understanding, at the molecular level, of howthese compounds behave."

Some of the synthetic compounds were as effective as artemisinin.

"More important, perhaps, is the fact that they are active byoral administration so you can not only administer them byinjection, you can give them orally," Posner said.

For the most severe form of malaria, called cerebral malaria, theearly administration of medicine could be the difference betweenlife and death. That form of the disease can induce coma andfevers as high as 106 degrees Fahrenheit.

"A person cannot survive more than a few hours having cerebralmalaria," Posner said.

The next step will be to determine whether it is safe whenadministered in large doses. Preliminary safety results areencouraging, Posner said.

Malaria is a menace in regions stretching from Africa to theCaribbean 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. Theinsects then transmit infected blood to other people. Anophelesmosquitos are found in portions of the United States, wherereports of malaria have historically been rare since the 1930sbut where public health officials are increasingly concerned.

The research is being funded by the National Institutes of Healthand the Burroughs Wellcome Fund.

(The scientific paper is available on-line at the following Webaddress: http://pubs.acs.org/hotartcl/jmcmar/jmcmar.html).

Another paper about the synthesis of similar antimalarialcompounds will be published in March 1998 in Tetrahedron Letters,an international science journal published in the United Kingdom. ###