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.
Original language | English (US) |
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Pages (from-to) | 1305-1308 |
Number of pages | 4 |
Journal | Bioorganic and Medicinal Chemistry Letters |
Volume | 16 |
Issue number | 5 |
DOIs | |
State | Published - Mar 1 2006 |
Bibliographical note
Funding Information:This work was supported by NIH 1U01 AI 56476. K.K. is grateful to the Royal Thai Government for a scholarship from the Development and Promotion of Science and Technology (DPST) Project. Coordinates of models of the compounds docked on lipid A are available on request.
Keywords
- Bis-guanylhydrazones
- Endotoxin
- Lipopolysaccharide
- Sepsis