Spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane,and 1,2,4-trioxepane pairs: Relationship between peroxide bond iron(II) reactivity,heme alkylation efficiency,and antimalarial activity |
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| Authors: | Xiaofang Wang Darren J Creek Charles E Schiaffo Yuxiang Dong Jacques Chollet Christian Scheurer Sergio Wittlin Susan A Charman Patrick H Dussault James K Wood Jonathan L Vennerstrom |
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| Institution: | 1. College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE, USA;2. Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia;3. Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE, USA;4. Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland;5. Department of Chemistry, University of Nebraska at Omaha, Omaha, NE, USA |
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| Abstract: | These data suggest that iron(II) reactivity for a set of homologous spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane peroxide heterocycles is a necessary, but insufficient, property of animalarial peroxides. Heme alkylation efficiency appears to give a more accurate prediction of antimalarial activity than FeSO4-mediated reaction rates, suggesting that antimalarial activity is not merely dependent on peroxide bond cleavage, but also on the ability of reactive intermediates to alkylate heme or other proximal targets. |
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