Abstract
A macrocyclic, peptidomimetic inhibitor of peptide deformylase was designed by covalently cross-linking the P1' and P3' side chains. The macrocycle, which contains an N-formylhydroxylamine side chain as the metal-chelating group, was synthesized from a diene precursor via olefin metathesis using Grubbs's catalyst. The cyclic inhibitor showed potent inhibitory activity toward Escherichia coli deformylase (K(I) = 0.67 nM) and antibacterial activity against both Gram-positive and Gram-negative bacteria (MIC = 0.7-12 microg/mL).
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amidohydrolases*
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Aminopeptidases / antagonists & inhibitors*
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology
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Chelating Agents / chemical synthesis*
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Chelating Agents / chemistry
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Chelating Agents / pharmacology
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Gram-Negative Bacteria / drug effects
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Gram-Positive Bacteria / drug effects
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Metalloendopeptidases / antagonists & inhibitors*
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Microbial Sensitivity Tests
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Models, Molecular
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Molecular Mimicry
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Peptides, Cyclic / chemical synthesis*
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Peptides, Cyclic / chemistry
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Peptides, Cyclic / pharmacology
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Structure-Activity Relationship
Substances
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Anti-Bacterial Agents
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Chelating Agents
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Enzyme Inhibitors
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Peptides, Cyclic
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Aminopeptidases
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Metalloendopeptidases
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Amidohydrolases
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peptide deformylase