2,3,4,5-Tetrahydro-1H-pyrido[2,3-b and e][1,4]diazepines as inhibitors of the bacterial enoyl ACP reductase, FabI

In the search for new antibacterial agents, the enzyme FabI has been identified as an attractive target. Employing a structure guided approach, the previously reported ene-amide series of FabI inhibitors were expanded to include 2,3,4,5-tetrahydro-1H-pyrido[2,3-b and e][1,4]diazepines. These novel series incorporate additional H-bonding functions and can be more water soluble than their naphthyridinone progenitors; diazepine 16c is shown to be efficacious in a mouse infection model.

Graphical abstractUsing a structure guided approach, naphthyridionone FabI inhibitors were expanded to novel 2,3,4,5-tetrahydro-1H-pyrido[2,3-b and e][1,4]diazepines (e.g., 11d; FabI IC50 = 11 nM). Diazepinone 16c is shown to be efficacious in a mouse infection model.Figure optionsDownload full-size imageDownload as PowerPoint slide