Abstract
We have shown that lipopolyamines bind to the lipid A moiety of lipopolysaccharide, a constituent of Gram-negative bacterial membranes, and neutralize its toxicity in animal models of endotoxic shock. In an effort to identify non-polyamine scaffolds with similar endotoxin-recognizing features, we had observed an unusually high frequency of hits containing guanylhydrazone scaffolds in high-throughput screens. We now describe the syntheses and preliminary structure-activity relationships in a homologous series of bis-guanylhydrazone compounds decorated with hydrophobic functionalities. These first-generation compounds bind and neutralize lipopolysaccharide with a potency comparable to that of polymyxin B, a peptide antibiotic known to sequester LPS.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Endotoxins / antagonists & inhibitors
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Endotoxins / chemistry
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Endotoxins / metabolism*
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Endotoxins / pharmacology*
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Guanidines / chemistry*
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Guanidines / metabolism*
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Guanidines / pharmacology
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Hydrazones / chemistry*
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Hydrazones / metabolism*
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Hydrazones / pharmacology
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Hydrophobic and Hydrophilic Interactions
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Inhibitory Concentration 50
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Lipopolysaccharides / antagonists & inhibitors
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Lipopolysaccharides / chemistry
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Lipopolysaccharides / metabolism
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Lipopolysaccharides / pharmacology
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Mice
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Molecular Structure
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Phthalic Acids / chemistry*
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Phthalic Acids / metabolism*
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Phthalic Acids / pharmacology
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Structure-Activity Relationship
Substances
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Endotoxins
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Guanidines
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Hydrazones
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Lipopolysaccharides
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Phthalic Acids