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

Sylvie Radix (1) , Anne Doléans Jordheim , Luc Rocheblave (1) , Serge N'Digo (1) , Anne-Laure Prignon (1) , Carine Commun (2) , Serge Michalet (2) , Marie-Geneviève Dijoux-Franca (2) , Angélique Mularoni (1) , Nadia Walchshofer (1)

1 B2MC - Molécules bioactives et chimie médicinale
2 LEM - Laboratoire d'Ecologie Microbienne - UMR 5557

A multi-step procedure has been described which afforded satisfactory yields of N,N 0-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.

Mots clés: Staphylococcus aureus; Regioselective RedAl-reduction; Cinnamamides; Antibiotic resistance; NorA efflux pump inhibitors

Domaines: Chimie thérapeutique; Médicaments

Sylvie Radix, Anne Doléans Jordheim, Luc Rocheblave, Serge N'Digo, Anne-Laure Prignon, et al.. N,N′-disubstituted cinnamamide derivatives potentiate ciprofloxacin activity against overexpressing NorA efflux pump Staphylococcus aureus 1199B strains. European Journal of Medicinal Chemistry, 2018, 150, pp.900 - 907. ⟨10.1016/j.ejmech.2018.03.028⟩. ⟨hal-01763023⟩