Abstract
Trypanosoma brucei is a parasite that causes human African trypanosomiasis (HAT). The parasites depend on the cyanide-insensitive trypanosome alternative oxidase (TAO) for their vital aerobic respiration. Ascofuranone (AF), a potent and specific sub-nanomolar inhibitor of the TAO quinol oxidase, is a potential novel drug with selectivity for HAT, because mammalian hosts lack the enzyme. To elucidate not only the inhibition mechanism but also the inhibitor-enzyme interaction, AF derivatives were designed and synthesized, and the structure-activity relationship was evaluated. Here we identified the pharmacophore of AF that interacts with TAO. The detailed inhibitory profiles indicated that the 1-formyl and 6-hydroxyl groups, which might contribute to intramolecular hydrogen bonding and/or serve as hydrogen-bonding donors, were responsible for direct interaction with the enzyme.
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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Alkenes / pharmacology
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Humans
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Molecular Structure
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Oxidoreductases / antagonists & inhibitors*
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Oxidoreductases / genetics
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Oxidoreductases / metabolism
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Phenols / chemistry
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Phenols / pharmacology
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Protozoan Proteins / antagonists & inhibitors*
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Protozoan Proteins / metabolism
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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Sesquiterpenes / chemistry*
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Sesquiterpenes / pharmacology*
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Structure-Activity Relationship
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Trypanosoma brucei brucei / enzymology*
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Trypanosoma brucei brucei / genetics
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Trypanosomiasis, African / parasitology
Substances
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Alkenes
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Enzyme Inhibitors
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Phenols
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Protozoan Proteins
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Recombinant Proteins
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Sesquiterpenes
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Oxidoreductases
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duroquinol oxidase
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ubiquinol oxidase
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ascofuranone
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ascochlorin