Abstract
Thiol-Olefin Co-Oxygenation (TOCO) methodology has been applied to the synthesis of a small library of weak base and polar 1,2,4-trioxanes. The 1,2,4-trioxane units synthesised exhibit remarkable stability as they survive base catalysed hydrolysis and mixed anhydride/amine coupling reactions. This unique stability feature has enabled a range of novel substitution patterns to be incorporated within the spiro 1,2,4-trioxane unit. Selected analogues express potent in vitro nM antimalarial activity, low cytotoxicity and oral activity in the Plasmodium berghei mouse model of malaria.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkenes / chemistry*
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Amides / chemistry
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Animals
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Antimalarials / chemical synthesis
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Antimalarials / chemistry
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Antimalarials / pharmacology*
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Crystallography, X-Ray
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Disease Models, Animal
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Heterocyclic Compounds / chemical synthesis
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Heterocyclic Compounds / chemistry
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Heterocyclic Compounds / pharmacology*
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Malaria / drug therapy*
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Mice
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Models, Molecular
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Molecular Structure
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Oxidation-Reduction
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Oxygen / chemistry
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Parasitic Sensitivity Tests
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Plasmodium berghei / drug effects
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Propanols / chemistry*
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Stereoisomerism
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Sulfhydryl Compounds / chemistry*
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Sulfides / chemistry
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Sulfones / chemistry
Substances
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1,2,4-trioxane
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Alkenes
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Amides
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Antimalarials
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Heterocyclic Compounds
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Propanols
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Sulfhydryl Compounds
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Sulfides
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Sulfones
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allyl alcohol
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Oxygen