Structure–activity relationships of 2-aryl-1H-indole inhibitors of the NorA efflux pump in Staphylococcus aureus

The synthesis of 22 2-aryl-1H-indoles, including 12 new compounds, has been achieved via Pd- or Rh-mediated methodologies, or selective electrophilic substitution. All three methods were based on elaborations from simple indole precursors. SAR studies on these indoles and 2-phenyl-1H-indole in Staphylococcus aureus as NorA efflux pump inhibitors indicated 5-nitro-2-(3-methoxycarbonyl)phenyl-1H-indole was a slightly more potent inhibitor than the lead INF55. A promising new antibacterial lead compound against S. aureus (2-phenyl-1H-indol-5-yl)-methanol, was also found.

Graphical abstractThree new potent indole NorA pump inhibitors and an antibacterial lead compound for Staphylococcus aureus are described.Figure optionsDownload full-size imageDownload as PowerPoint slide