Synthesis of Iron(II)-N-Heterocyclic Carbene Complexes: Paving the Way for a New Class of Antibiotics.

Carolina S Vinagreiro,Rita Lopes,Gabriela Jorge Da Silva,Beatriz Royo,Mariette M Pereira

doi:10.3390/molecules25122917

Abstract

The synthesis and structural modulation of five pro-ligand salts was achieved using alternative sustainable synthetic strategies, the use of microwaves being the method of choice, with an 81% yield and an E factor of 43 for 3d. After complexation with Fe3(CO)12 by direct reaction with the appropriate pro-ligands at 130 °C, a set of iron(II) N-heterocyclic carbene (NHC) complexes were isolated and fully characterized (via 1H and 13C NMR and IR spectroscopy and elemental analysis). The antibacterial activities of the iron(II)-NHC complexes were tested against standard World Health Organization priority bacterial strains: Staphylococcus aureus ATCC 29213 and Escherichia coli ATCC 25922. The results showed a significant effect of the Fe(II)-NHC side-chain on the antibacterial activity against both Gram-negative and Gram-positive bacteria. Among all compounds, the most lipophilic iron complex, 3b, was found to be the most active one, with a minimum inhibitory concentration of 8 µg/mL. Pioneering mechanistic studies suggested an alternative mechanism of action (OH· formation), which opens the way for the development of a new class of antibiotics.

Highlights

Antimicrobial resistance (AMR) against marketed antibiotics is one of the most serious public threats that our society currently faces [1]
World Health Organization (WHO) report included an urgent alert about the dramatic phenomenon of antibiotic resistance, and prioritized a group of pathogens concerning in terms of AMR, which includes
Among the approaches described in the literature, the use of organometallics is considered a great challenge, since metals can modulate the amphiphilicity of the molecules and, their interactions with membranes, but can generate reactive oxygen species that can kill bacteria by alternative mechanisms

Summary

Introduction

Antimicrobial resistance (AMR) against marketed antibiotics is one of the most serious public threats that our society currently faces [1]. World Health Organization (WHO) report included an urgent alert about the dramatic phenomenon of antibiotic resistance, and prioritized a group of pathogens concerning in terms of AMR, which includes. The development of new molecular entities or approaches capable of inactivating microorganisms without promoting drug resistance is crucial, and depends on unveiling alternative mechanisms of action for conventional drugs. Among the approaches described in the literature, the use of organometallics is considered a great challenge, since metals can modulate the amphiphilicity of the molecules and, their interactions with membranes (uptake profile), but can generate reactive oxygen species that can kill bacteria by alternative mechanisms. The synthesis of new organometallic compounds is an attractive approach to overcome the resistance issue, if the resulting compounds can offer a metal-specific mode of action that is not available from a purely organic parent molecule [3]

Methods

Results

Conclusion