Abstract
A series of 1-substituted and 4-substituted benzyl analogues of the known inhibitor (1S,3R,4R)-1,3,4-trihydroxy-5-cyclohexene-1-carboxylic acid has been synthesized and tested as inhibitors of Streptomyces coelicolor type II dehydroquinase. The solid-phase syntheses of 18 new analogues are reported. The most potent inhibitor, 2-nitrobenzyloxy analogue 5i, has K(i) of 8 microM, more than 30 times lower than the K(M) of the substrate and approximately 4 times more potent than the original inhibitor. The binding modes of the synthesized analogues in the active site were studied by molecular docking with GOLD 2.0.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Benzyl Compounds / chemical synthesis*
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Benzyl Compounds / chemistry
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Binding Sites
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Cyclohexanes / chemical synthesis*
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Cyclohexanes / chemistry
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Hydro-Lyases / antagonists & inhibitors*
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Hydro-Lyases / chemistry
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Models, Molecular
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Protein Binding
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Shikimic Acid / analogs & derivatives
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Shikimic Acid / chemical synthesis*
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Shikimic Acid / chemistry
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Spectrophotometry, Ultraviolet
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Streptomyces / chemistry*
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Structure-Activity Relationship
Substances
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1,3,4-trihydroxy-5-cyclohexene-1-carboxylic acid
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Benzyl Compounds
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Cyclohexanes
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Shikimic Acid
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Hydro-Lyases
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3-dehydroquinate dehydratase