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

• Main Authors: Carolina S. Vinagreiro, Rita Lopes, Beatriz Royo, Gabriela Jorge Da Silva, Mariette M. Pereira
• Format: Article
• Language: English
• Published: MDPI AG 2020-06-01
• Series: Molecules
• Subjects: <i>N</i>-heterocyclic carbene; iron(II)-NHC complexes; antibacterial activity
• Online Access: https://www.mdpi.com/1420-3049/25/12/2917

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 <b>3d</b>. 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: <i>Staphylococcus aureus</i> ATCC 29213 and <i>Escherichia coli</i> 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, <b>3b</b>, 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.