title: Novel endotoxin-sequestering compounds with terephthalaldehyde-bis-guanylhydrazone scaffolds.
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.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence KS 66045-7582, USA.
authors.forename: Kriangsak
authors.initials: K
authors.lastname: Khownium
authors.forename: Stewart J
authors.initials: SJ
authors.lastname: Wood
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Miller
authors.forename: Rajalakshmi
authors.initials: R
authors.lastname: Balakrishna
authors.forename: Thuan B
authors.initials: TB
authors.lastname: Nguyen
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Kimbrell
authors.forename: Gunda I
authors.initials: GI
authors.lastname: Georg
authors.forename: Sunil A
authors.initials: SA
authors.lastname: David
mesh_terms: 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
chemical_list: D004731:Endotoxins; D006146:Guanidines; D006835:Hydrazones; D008070:Lipopolysaccharides; D010795:Phthalic Acids