Synthesis from Caffeine of a Mixed N-Heterocyclic Carbene−Silver Acetate Complex Active against Resistant Respiratory Pathogens

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.

In Vitro and Murine Efficacy and Toxicity Studies of Nebulized SCC1, a Methylated Caffeine-Silver(I) Complex, for Treatment of Pulmonary Infections

“…2). As determined by curve fitting of the semilogarithmically transformed data, the 50% lethal dose of SCC1 in this model is 289 g/ml, which is 48-fold greater than the MIC 90 for all of the P. aeruginosa strains previously tested and 145-fold above the MIC for PA M57-15 (20).…”

“…1C) is composed of silver complexed to a methylated caffeine carrier (Fig. 1B) (20). SCC1 and the methylated caffeine SCC1 precursor (Fig.…”

“…Consequently, the rational design of a new silver-based antimicrobial must ideally include coordination of the use of the bioactive metal with a nontoxic carrier. We have previously reported the synthesis and in vitro antimicrobial properties of the N-heterocyclic carbene silver complex designated SCC1, for silver carbene complex 1, formed from the coupling of silver to the xanthine derivative, methylated caffeine (20). Xanthine derivatives have been used for multiple purposes, including bronchodilation.…”

Assessment of in vivo antimicrobial activity of the carbene silver(I) acetate derivative SBC3 using Galleria mellonella larvae

“…The continuous development of novel resistancedisrupting antimicrobial drugs should therefore be a prime activity of industry and academia (Rex 2014). There is significant unexplored space for antimicrobial silver-based drugs (Mijnendonckx et al 2013;Oehninger et al 2013) and it has been suggested that carbene-silver acetates derived from methylated caffeine may have the stability and antibiotic activity to become drug candidates (Kascatan-Nebioglu et al 2006;Hindi et al 2008). This idea led to the development of more lipophilic benzyl-substituted imidazole-and benzimidazole-derived carbene-silver complexes showing activity against Gram-positive and Gram-negative bacteria (Hackenberg and Tacke 2014;.…”

Behavior and changes in cell morphology ofEscherichia coliO157:H7 in liquid medium and skim milk in the presence of caffeine

“…Similarly, 1 Log reduction of Salmonella Typhimurium and Salmonella Enteritidis was observed in raw ground chicken breast meat with coffee filtrate, 0.93 mg glyoxal, and 1 mg caffeine/g chicken (Maletta & Were, 2012). In vitro antimicrobial activity of caffeine was evaluated against several bacterial strains including Escherichia coli, Pseudomonas aeruginosa, pseudomonas fluorescens, and Staphylococcus aureus (Kascatan-Nebioglu et al, 2006;Ramanaviciene et al, 2003). Thus, the addition of caffeine as a natural antimicrobial to milk, juice, and various beverages has potential, as supported by these studies showing antimicrobial activities on pathogens.…”