Novel endotoxin-sequestering compounds with terephthalaldehyde-bis-guanylhydrazone scaffolds

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 5; pp. 1305 - 1308
• Main Authors: Khownium, Kriangsak, Wood, Stewart J., Miller, Kelly A., Balakrishna, Rajalakshmi, Nguyen, Thuan B., Kimbrell, Matthew R., Georg, Gunda I., David, Sunil A.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.03.2006; Elsevier
• Subjects: Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Bis-guanylhydrazones; Endotoxin; Endotoxins - antagonists & inhibitors; Endotoxins - chemistry; Endotoxins - metabolism; Endotoxins - pharmacology; Guanidines - chemistry; Guanidines - metabolism; Guanidines - pharmacology; Hydrazones - chemistry; Hydrazones - metabolism; Hydrazones - pharmacology; Hydrophobic and Hydrophilic Interactions; Inhibitory Concentration 50; Lipopolysaccharide; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - chemistry; Lipopolysaccharides - metabolism; Lipopolysaccharides - pharmacology; Medical sciences; Mice; Molecular Structure; Pharmacology. Drug treatments; Phthalic Acids - chemistry; Phthalic Acids - metabolism; Phthalic Acids - pharmacology; Sepsis; Structure-Activity Relationship; Lipopolysaccharide; Bis-guanylhydrazones; Sepsis; Endotoxin; High throughput screening; Oxidative stress; Prevention; Bisguanylhydrazones; Structure activity relation; Diether; Chemical synthesis; Endotoxemia; Gram negative bacteria; Aliphatic compound; Chain length; Rodentia; Benzene derivatives; In vitro; Infection; Toxin; In vivo; Vertebrata; Biological fixation; Mammalia; Mouse; Complexing agent; Animal; Homologous series; Affinity
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.11.059

A homologous series of bis-guanylhydrazone compounds decorated with hydrophobic functionalities bind and neutralize lipopolysaccharide (LPS) with a potency comparable to that of polymyxin B, a peptide antibiotic known to sequester LPS. 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.