Preparation of novel anthranilic acids as antibacterial agents. Extensive evaluation of alternative amide bioisosteres connecting the A- and the B-rings

In the past few years, a significant effort has been devoted by Pharmacia toward the discovery of novel antibiotics. We have recently described the identification of an anthranilic acid lead 1 and the optimization resulting in the advanced lead 2. In this report, we describe the preparation of several selected amide bioisosteres connecting the A- and the B-rings. The E-alkene provided a rigid analog with equal potency to the corresponding amide. This indicates that the amide is not a recognition element rather acts as an appropriate spatial linker of the two important aryl A and B rings. The work here clearly demonstrates that the amide linker can be replaced with several functionalities without significant deterioration in the MIC activity.

Graphical abstractThis paper describes the discovery of amide bioisosteres, an E-alkene and a trans cyclopropane, as potent antibacterial agents against Gram-positive organisms.Figure optionsDownload full-size imageDownload as PowerPoint slide