Abstract
The design and two synthetic pathways to aminophosphonate 4 which mimics the ionic and steric properties of putative oxocarbenium intermediate 3 in the Kdo8P synthase-catalyzed reaction are reported. It was found that 4 is a slow-binding, most potent inhibitor of the enzyme yet tested, with a Ki value of 0.4 microM.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Aldehyde-Lyases / antagonists & inhibitors*
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / metabolism
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Anti-Bacterial Agents / pharmacology*
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology*
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Gram-Negative Bacteria / drug effects
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Gram-Negative Bacteria / metabolism
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Gram-Negative Bacteria / pathogenicity
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Hydrogen-Ion Concentration
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Kinetics
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Lipopolysaccharides / biosynthesis
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Magnetic Resonance Spectroscopy
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Mannitol / analogs & derivatives*
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Mannitol / chemical synthesis
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Mannitol / metabolism
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Mannitol / pharmacology
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Sugar Phosphates / chemical synthesis*
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Sugar Phosphates / metabolism
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Sugar Phosphates / pharmacology*
Substances
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1-deoxy-1-((N-(phosphonomethyl)-2-oxoethyl)amino)mannitol-6-phosphate
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Anti-Bacterial Agents
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Enzyme Inhibitors
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Lipopolysaccharides
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Sugar Phosphates
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Mannitol
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2-dehydro-3-deoxyphosphooctonate aldolase
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Aldehyde-Lyases