A theobromine derived silver N-heterocyclic carbene: synthesis, characterization, and antimicrobial efficacy studies on cystic fibrosis relevant pathogens

Abstract

The increasing incidence of multidrug-resistant (MDR) pulmonary infections in the cystic fibrosis (CF) population has prompted the investigation of innovative silver based therapeutics. The functionalization of the naturally occurring xanthine theobromine at the N1 nitrogen atom with an ethanol substituent followed by the methylation of the N9 nitrogen atom gives the N-heterocyclic carbene precursor 1-(2-hydroxyethyl)-3,7,9-trimethylxanthinium iodide. The reaction of this xanthinium salt with silver acetate produces the highly hydrophilic silver carbene complex SCC8. The in vitro antimicrobial efficacy of this newly synthesized complex was evaluated with excellent results on a variety of virulent and MDR pathogens isolated from CF patients. A comparative in vivo study between the known caffeine derived silver carbene SCC1 and SCC8 demonstrated the ability of both complexes to improve the survival rates of mice in a pneumonia model utilizing the clinically isolated infectious strain of Pseudomonas aeruginosa PA M57-15.

Ag(I) and Zn(II) isonicotinate complexes: design, characterization, antimicrobial effect, and CT-DNA binding studies

“…The research presented herein provides alternatives to some of the products on the market, to widen the spectrum of microbial pathogens susceptible to silver and also to target organisms which are resistant to current silver complexes [2][3][4][5][6] and for other biological properties [7].…”

Preparation and in Vitro Antimicrobial Activity of Silver-Bearing Degradable Polymeric Nanoparticles of Polyphosphoester-block-Poly(l-lactide)

“…designed a library of N -heterocyclic silver carbene complexes (SCCs), which improved the stability of Ag + to light and aqueous solution, allowed for the direct administration of silver-compounds via nebulization, and demonstrated the antimicrobial activity of Ag + against contemporary Gram-positive and Gram-negative pathogens. 16–24 In parallel, Cannon and Youngs et al demonstrated sustained silver release and potent in vitro and in vivo antimicrobial efficacy of SCC10-bearing L-tyrosine polyphosphate nanoparticles (LTP NPs) against the cystic fibrosis pathogen Pseudomonas aeruginosa . 25 Meanwhile, benefiting from polymeric backbone-structured building blocks with precisely controlled architectures, surface characteristics and supramolecular assembly, 26, 27 Cannon, Youngs and Wooley et al highlighted the preparation of smaller particle size and the introduction of functionalities for attachment of targeting moieties by utilizing multifunctional shell cross-linked knedel-like polymeric nanoparticles (SCK NPs) of poly(acrylic acid)- block -polystyrene (PAA- b -PS).…”

Beyond catalysis: N-heterocyclic carbene complexes as components for medicinal, luminescent, and functional materials applications

“…8 More recent efforts aimed at improving the modest water solubility of complex 2. For this purpose, theobromine rather than caffeine has been introduced as a basic structural motif, 9 since the unsubstituted nitrogen N1 in theobromine 90 allows for incorporating functional groups that increase the solubility of the silver complex in water. Insertion of an ethanol residue in theobromine, followed by nitrogen N9 alkylation and subsequent metalation affords the silver NHC complex 3.…”