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

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 gr...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2018-04, Vol.150, p.900-907
Main Authors: Radix, Sylvie, Jordheim, Anne Doléans, Rocheblave, Luc, N'Digo, Serge, Prignon, Anne-Laure, Commun, Carine, Michalet, Serge, Dijoux-Franca, Marie-Geneviève, Mularoni, Angélique, Walchshofer, Nadia
Format: Article
Language:English
Subjects:
Antibiotic resistance
Chemical Sciences
Cinnamamides
Life Sciences
Medication
Medicinal Chemistry
NorA efflux pump inhibitors
Pharmaceutical sciences
Regioselective RedAl-reduction
Staphylococcus aureus
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Summary: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. [Display omitted] •Cinnamamides potentiate ciprofloxacin activity as efflux pump inhibitors.•Synthesis from N-Boc amino acids with a RedAl selective reduction as a key step.•EPI activity could be related to the presence of the NorA pump.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2018.03.028