1. Synthesis from caffeine of a mixed N-heterocyclic carbene-silver acetate complex active against resistant respiratory pathogens.
- Author
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Kascatan-Nebioglu A, Melaiye A, Hindi K, Durmus S, Panzner MJ, Hogue LA, Mallett RJ, Hovis CE, Coughenour M, Crosby SD, Milsted A, Ely DL, Tessier CA, Cannon CL, and Youngs WJ
- Subjects
- Animals, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Antifungal Agents chemistry, Antifungal Agents pharmacology, Caffeine chemical synthesis, Caffeine pharmacology, Cells, Cultured, Crystallography, X-Ray, Cystic Fibrosis microbiology, Drug Resistance, Bacterial, Drug Resistance, Fungal, Gene Expression drug effects, Gram-Negative Bacteria drug effects, Gram-Negative Bacteria isolation & purification, Gram-Positive Bacteria drug effects, Gram-Positive Bacteria isolation & purification, Humans, Methylation, Mice, Mice, Inbred C57BL, Microbial Sensitivity Tests, Molecular Structure, Organometallic Compounds chemistry, Organometallic Compounds pharmacology, Respiratory Mucosa cytology, Respiratory Mucosa drug effects, Respiratory Mucosa metabolism, Structure-Activity Relationship, Acetates chemistry, Anti-Bacterial Agents chemical synthesis, Antifungal Agents chemical synthesis, Caffeine analogs & derivatives, Caffeine chemistry, Organometallic Compounds chemical synthesis, Respiratory Tract Infections microbiology, Silver Compounds chemistry
- Abstract
The bis(N-heterocyclic carbene) (NHC) silver complex, 3, with a methyl carbonate anion was formed from the reaction of the iodide salt of methylated caffeine, 1, with silver (I) oxide in methanol. Attempts to crystallize this complex from a mixture of common alcohols and ethyl acetate led to the formation of an NHC-silver acetate complex, 4. The more direct synthesis of 4 was accomplished by the in-situ deprotonation of 1 by silver acetate in methanol. Complex 4 demonstrated antimicrobial activity against numerous resistant respiratory pathogens from the lungs of cystic fibrosis (CF) patients including members of the Burkholderia cepacia complex that cause a high rate of mortality in patients with cystic fibrosis (CF). Application of this NHC silver complex to primary cultures of murine respiratory epithelial cells followed by microarray analysis showed minimal gene expression changes at the concentrations effective against respiratory pathogens. Furthermore, methylated caffeine without silver showed some antibacterial and antifungal activity.
- Published
- 2006
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