Abstract
Enzymes involved in the biosynthesis of bacterial peptidoglycan represent important targets for development of new antibacterial drugs. Among them, Mur ligases (MurC to MurF) catalyze the formation of the final cytoplasmic precursor UDP-N-acetylmuramyl-pentapeptide from UDP-N-acetylmuramic acid. We present the design, synthesis and biological evaluation of a series of phosphorylated hydroxyethylamines as new type of small-molecule inhibitors of Mur ligases. We show that the phosphate group attached to the hydroxyl moiety of the hydroxyethylamine core is essential for good inhibitory activity. The IC(50) values of these inhibitors were in the micromolar range, which makes them a promising starting point for the development of multiple inhibitors of Mur ligases as potential antibacterial agents. In addition, 1-(4-methoxyphenylsulfonamido)-3-morpholinopropan-2-yl dihydrogen phosphate 7a was discovered as one of the best inhibitors of MurE described so far.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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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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Binding Sites
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Cell Wall / metabolism*
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Computer Simulation
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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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Escherichia coli / enzymology
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Ethylamines / chemical synthesis
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Ethylamines / chemistry*
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Ethylamines / pharmacology
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Peptide Synthases / antagonists & inhibitors*
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Peptide Synthases / metabolism
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Uridine Diphosphate N-Acetylmuramic Acid / analogs & derivatives
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Uridine Diphosphate N-Acetylmuramic Acid / biosynthesis
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Uridine Diphosphate N-Acetylmuramic Acid / metabolism
Substances
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Anti-Bacterial Agents
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Enzyme Inhibitors
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Ethylamines
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Uridine Diphosphate N-Acetylmuramic Acid
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UDP-N-acetylmuramic acid pentapeptide
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Peptide Synthases
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UDP-N-acetylmuramoylalanyl-D-glutamyllysine-D-alanyl-D-alanine ligase
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UDP-N-acetylmuramoyl-alanine synthetase