Continuous Flow Synthesis and Antimicrobial Evaluation of NHC* Silver Carboxylate Derivatives of SBC3 in vitro and in vivo

    • Cillian O’Beirne†a
    • Magdalena E. Piatekb
    • Jen Fossenc
    • Helge Müller-Bunza
    • David R. Andesc
    • Kevin Kavanaghb
    • Siddappa A. Patild
    • Marcus Baumanna
    • Matthias Tacke†a
    • aSchool of Chemistry, University College Dublin, Belfield, Stillorgan, Dublin 4, Republic of Ireland
    • bSSPC Pharma Research Centre, Department of Biology, Maynooth University, Maynooth, W23F2H6, Co. Kildare, Republic of Ireland
    • cJ. Fossen, Prof. D. R. Andes, Department of Medicine, 600 Highland Avenue, University of Wisconsin, Madison, USA
    • dCentre for Nano and Material Sciences, Jain University, Bangalore, Karnataka, India

    N-Heterocyclic silver carbene compounds have been extensively studied and shown to be active agents against a host of pathogenic bacteria and fungi. By incorporating hypothesised virulence targeting substituents into NHC-silver systems via salt metathesis, an atom efficient complexation process can used to develop new complexes to target the passive and active systems of a microbial cell. The incorporation of fatty acids and an FtsZ inhibitor have been achieved, and creation of both the intermediate salt and subsequent silver complex has been streamlined into a continuous flow process. Biological evaluation was conducted with in vitro toxicology assays showing these novel complexes had excellent inhibition against Gram-negative strains E. coli, P. aeruginosa and K. pneumonia; further studies also confirmed the ability to inhibit biofilm formation in Methicillin-resistant S. aureus and C. Parapsilosis. In vivo testing using a murine thigh infection model showed promising inhibition of MRSA for the lead compound SBC3, which is derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene(NHC*).

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