MEDI 4 |
| Widespread resistance has greatly diminished the utility of previously reliable antimalarial drugs. Artemisinins and related trioxanes are among the newest antimalarials, and combination therapy that includes a trioxane with at least one other drug is now usually recommended in malaria-endemic areas. Although potent and fast-acting, the clinically available monomeric trioxanes commonly fail to achieve a cure when administered alone. In an effort to improve antimalarial activity and to prevent metabolic inactivation, a series of dimeric compounds that contain two artemisinin moieties linked by a short non-hydrolyzable bridge was designed and synthesized. In contrast to the clinically used trioxane artesunate which prolongs mouse survival by 3 days or less, for several of our new trioxane dimers a single subcutaneous dose of 30 mg/kg cured P. berghei-infected mice. Other of our dimers cured after three consecutive daily oral doses of 30 mg/kg. No toxicity was noted. The result is structurally diverse new trioxane dimers, obtained in good yield in a straightforward and inexpensive few steps from plant-derived artemisinin, having potent antimalarial activity, efficacy and safety in curing malaria-infected mice. These trioxane dimers are promising candidates for further preclinical and human studies toward much-needed new drug development for antimalarial chemotherapy. |
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Antimalarial
9:00 AM-12:40 PM, Sunday, August 19, 2007 BCEC -- 210B, Oral
Division of Medicinal Chemistry |