Novel endotoxin-sequestering compounds with terephthalaldehyde-bis-guanylhydrazone scaffolds |
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Authors: | Khownium Kriangsak Wood Stewart J Miller Kelly A Balakrishna Rajalakshmi Nguyen Thuan B Kimbrell Matthew R Georg Gunda I David Sunil A |
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Institution: | Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence KS 66045-7582, USA. |
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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. |
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