Substituted dihydronaphthalenes as efflux pump inhibitors of Staphylococcus aureus

A new series of 3-(substituted-3,4-dihydronaphthyl)-2-propenoic acid amides has been prepared through convergent synthetic strategies and tested in combination with ciprofloxacin against NorA overexpressing Staphylococcus aureus 1199B as test strain for potentiating of the drug activity. Out of 24 compounds evaluated, 12 compounds potentiated the activity of ciprofloxacin and resulted in 2–16 fold reduction in the MIC (4–0.5 μg/mL) of the drug. The failure of these efflux pump inhibitors (EPIs) to potentiate the activity of ciprofloxacin when tested against NorA knock out S. aureus SA-K1758 established their identity as NorA inhibitors. The structure of all these newly synthesised compounds was confirmed by spectral data. The present communication describes the synthesis, bioevaluation, structure activity relationship and mechanism of action of these EPIs.

Graphical abstractDesign and synthesis of new series of 3-(substituted 3,4-dihydronaphthyl)-propenoic acid amides as efflux pump inhibitors has resulted in the MIC reduction of ciprofloxacin.Figure optionsDownload full-size imageDownload as PowerPoint slide