New N-phenylpyrrolamide DNA gyrase B inhibitors: Optimization of efficacy and antibacterial activity

The ATP binding site located on the subunit B of DNA gyrase is an attractive target for the development of new antibacterial agents. In recent decades, several small-molecule inhibitor classes have been discovered but none has so far reached the market. We present here the discovery of a promising new series of N-phenylpyrrolamides with low nanomolar IC₅₀ values against DNA gyrase, and submicromolar IC₅₀ values against topoisomerase IV from Escherichia coli and Staphylococcus aureus. The most potent compound in the series has an IC₅₀ value of 13 nM against E. coli gyrase. Minimum inhibitory concentrations (MICs) against Gram-positive bacteria are in the low micromolar range. The oxadiazolone derivative 11a, with an IC₅₀ value of 85 nM against E. coli DNA gyrase displays the most potent antibacterial activity, with MIC values of 1.56 microM against Enterococcus faecalis, and 3.13 microM against wild type S. aureus, methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). The activity against wild type E. coli in the presence of efflux pump inhibitor phenylalanine-arginine β-naphthylamide (PAβN) is 4.6 microM.