Fluoro-Substituted Cationic and Neutral Antibiotic NHC* Silver Derivatives of SBC3: Continuous Flow versus Conventional Synthesis

The emergence of antibiotic resistance is an impending crisis which requires that new antibiotics possessing novel mechanisms of action are introduced into the clinical regime. Silver, which is biologically active as the Ag+ cation, has seen a resurgence in popularity as an antimicrobial agent due to its multiple antibiotic mechanisms, its relatively few reported instances of resistance, and its low human toxicity. For silver to be useful as a systemic antibiotic it must exist in a complex which is stable enough to reach the biological target before release of the silver ion. N-heterocyclic carbenes (NHCs) have become a popular choice of stabilising ligand due to their excellent s-donating abilities and the ease with which they can be functionalised. Herein, we describe the synthesis and characterisation of neutral and cationic NHC complexes of silver with ligands based on the 1,3-dibenzyl-4,5-diphenyl imidazole scaffold used in the lead compound SBC3 of the Tacke group. Eleven new imidazolium salt precursors were synthesised in moderate to excellent yields (56 - 97%). NHC silver acetate and NHC silver (trifluoromethyl)benzoate complexes were synthesised as fluorinated derivatives of the lead compound SBC3 and were achieved in moderate to good yields (53 - 68%). Fluorination was incorporated on the ligands to increase the lipophilicity of the complexes and improve cellular uptake in vivo. Cationic bis-NHC silver complexes were synthesised to improve overall stability by introduction of a second NHC ligand. The bis-NHC silver complexes with non-coordinating anions (PF6- and BF4-) were synthesised directly from their imidazolium salts in good to excellent yields (77 - 94%). We also describe a continuous flow method using anion exchange resins in a packed bed reactor to achieve bis-NHC silver complexes with non-traditional, coordinating gluconate (66 - 97% yield) and acetate (90% yield) which would not be achievable by direct synthesis in batch mode. An attempt to synthesise bis-NHC complexes with a chloride anion was unsuccessful. Instead, the complexes which have the empirical formula [(NHC)AgX], were obtained in low to moderate yield (27 - 63%). Evaluation of all novel complexes for their biological activity was carried out in vitro by Kirby-Bauer disk diffusion method. This preliminary testing method indicates that all silver complexes synthesised herein show antibacterial activity comparable to that of the lead compound SBC3.