Design and synthesis of a library of C2-substituted sulfamidoadenosines to probe bacterial permeability

Antibiotic resistance is a major threat to public health, and Gram-negative bacteria pose a particular challenge due to their combination of a low permeability cell envelope and efflux pumps. Our limited understanding of the chemical rules for overcoming these barriers represents a major obstacle in antibacterial drug discovery. Several recent efforts to address this problem have involved screening compound libraries for accumulation in bacteria in order to understand the structural properties required for Gram-negative permeability. Toward this end, we used cheminformatic analysis to design a library of sulfamidoadenosines (AMSN) having diverse substituents at the adenine C2 position. An efficient synthetic route was developed with installation of a uniform cross-coupling reagent set using Sonogashira and Suzuki reactions of a C2-iodide. The potential utility of these compounds was demonstrated by pilot analysis of selected analogues for accumulation in Escherichia coli.