MEDI 5 |
| The Plasmodium parasites that cause malaria attack and invade red blood cells and devour hemoglobin to derive amino acids necessary for their survival. Hemoglobinolysis liberates an enormous amount of free heme in the parasite's digestive vacuole. The heme is detoxified by conversion into dimers which spontaneously form an macromolecular aggregate known as “hemozoin”. We have designed and synthesized acridones that accumulate in the digestive vacuole, form soluble complexes with heme, and prevent the process of hemozoin formation. We have also built into these molecules the ability to sensitize multidrug resistant parasites to the quinolines, quinine and chloroquine. My presentation will detail pertinent structure-activity profiles of these “merged acridones” together with in vivo evidence of their efficacy alone and in combination with the quinolines in a mouse model of malaria. Studies of certain synthetic intermediates that exhibited unexpected and potent antiplasmodial activity will also be discussed. |
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Antimalarial
9:00 AM-12:40 PM, Sunday, August 19, 2007 BCEC -- 210B, Oral
Division of Medicinal Chemistry |