Novel endotoxin-sequestering compounds with terephthalaldehyde-bis-guanylhydrazone scaffolds.
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.
Khownium
Kriangsak
K
Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence KS 66045-7582, USA.
Wood
Stewart J
SJ
Miller
Kelly A
KA
Balakrishna
Rajalakshmi
R
Nguyen
Thuan B
TB
Kimbrell
Matthew R
MR
Georg
Gunda I
GI
David
Sunil A
SA
D000818:Animals; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006146:Guanidines / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D006835:Hydrazones / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D010795:Phthalic Acids / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004731:Endotoxins; D006146:Guanidines; D006835:Hydrazones; D008070:Lipopolysaccharides; D010795:Phthalic Acids