2. Academic Validation
  3. N,N'-disubstituted cinnamamide derivatives potentiate ciprofloxacin activity against overexpressing NorA efflux pump Staphylococcus aureus 1199B strains

N,N'-disubstituted cinnamamide derivatives potentiate ciprofloxacin activity against overexpressing NorA efflux pump Staphylococcus aureus 1199B strains

  • Eur J Med Chem. 2018 Apr 25:150:900-907. doi: 10.1016/j.ejmech.2018.03.028.
Sylvie Radix 1,  Anne Doléans Jordheim 2,  Luc Rocheblave 3,  Serge N'Digo 3,  Anne-Laure Prignon 3,  Carine Commun 4,  Serge Michalet 4,  Marie-Geneviève Dijoux-Franca 4,  Angélique Mularoni 3,  Nadia Walchshofer 5
Affiliations

Affiliations

  • 1 Univ Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie, EA 4446, B2MC, F-69373, Lyon Cedex 08, France. Electronic address: sylvie.radix@univ-lyon1.fr.
  • 2 Univ Lyon, Université Claude Bernard Lyon 1, VetAgro Sup, UMR CNRS 5557, Ecologie Microbienne, F-69622, Villeurbanne, France; Laboratoire de Bactériologie, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon (HCL), F-69, Bron, France.
  • 3 Univ Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie, EA 4446, B2MC, F-69373, Lyon Cedex 08, France.
  • 4 Univ Lyon, Université Claude Bernard Lyon 1, VetAgro Sup, UMR CNRS 5557, Ecologie Microbienne, F-69622, Villeurbanne, France.
  • 5 Univ Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie, EA 4446, B2MC, F-69373, Lyon Cedex 08, France. Electronic address: nadia.walchshofer@univ-lyon1.fr.
PMID: 29597171 DOI: 10.1016/j.ejmech.2018.03.028
Abstract

A multi-step procedure has been described which afforded satisfactory yields of N,N'-disubstituted cinnamamides derived from N-Boc-protected Amino acids (Boc-Gly, Boc-Val, Boc-Phe). The key step of this synthesis was a regioselective RedAl reduction of an amide function in presence of a carbamate group. Next, these cinnamamides were evaluated in co-admnistration with ciprofloxacin as efflux pump inhibitors against two S. aureus strains, NorA overexpressing SA1199B and wild type SA1199. In parallel, their intrinsic toxicity was appreciated on human lung fibroblast MRC5 cells. Therefore, the cinnamamide combining both carbamate and indol-3-yl groups, was found to be the most active and one of the less toxic EPI and constituted a promising hit.

Keywords

Antibiotic resistance; Cinnamamides; NorA efflux pump inhibitors; Regioselective RedAl-reduction; Staphylococcus aureus.

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