The team also has developed several other compounds which defeated the febrile disease in rodents after three oral doses. These peroxide compounds, containing a crucial oxygen-oxygen unit, promise not only to be more effective than today's best malaria remedies, but also potentially safer and more efficient, said research team leader Gary Posner, Scowe Professor of Chemistry in the Krieger School of Arts and Sciences at Johns Hopkins.
"Older drugs in this family of peroxide antimalarials also are known to be fast-acting, but they are unfortunately short-lived and not curative when used by themselves," Posner said. The peroxide compounds, called trioxanes mimic artemisinin, the active agent in a Chinese herbal drug used to treat malaria and other fevers for thousands of years.
The oxygen-oxygen unit in the peroxides causes malaria parasites essentially to self-destruct. The parasites digest hemoglobin, the oxygen-carrying pigment of red blood cells, and, in the process, release a substance called heme, a deep-red iron-containing blood pigment. When the heme encounters peroxides, a powerful chemical reaction occurs, releasing carbon-free radicals and oxidizing agents that eventually kill the parasites.
The first generation of trioxane drugs had a number of shortcomings, including a half-life of less than one hour. Posner and team believe that their new compounds address those disadvantages. "Our semi-synthetic artemisinin-derived compounds successfully overcome the disadvantages of their first-generation predecessors," he said. "Most important is their curative activity after a single, low dose, which is distinctly unusual. But based on our intentional design, they may also have a longer half-life in animals. We also designed them to be more lipophilic, meaning they have an enhanced ability to dissolve in fats and thus to arrive inside malaria-infected red blood cells."
In addition, the new compounds are far less likely to break down into toxic substances when they are metabolized in the test animals' bodies, making them potentially safer than their predecessors.
MEDICA.de; Source: Johns Hopkins University