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The conformational preferences of b-sulfonamidopeptides in chloroform solution were investigated by variable-temperature 1 H NMR spectroscopy and FT-IR spectroscopy. The following hydrogen-bonding acceptor scale was derived from the experiments: RCON % tBuOCON b COOMe ! RS-O 2 N. An intermolecular study gave results complementary to those described above: the N ± H stretch bands of Nmethylacetamide and N-methyl methanesulfonamide in chloroform were followed during titration with excess methanesulfonylpyrrolidine and N,N-dimethylacetamide.Shifts to lower frequencies were observed which are correlated with the hydrogen-bond strengths and show that the amide is a stronger hydrogen-bond acceptor than the sulfonamide.

Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site. A detailed characterization of the lead compound highlighted the potential for treatment of the problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an intravenous-to-oral switch therapy was supported by the identification of a suitable prodrug concept. Eventually, hERG K-channel block was identified as the main limitation of this chemical series, and efforts toward its minimization are reported.

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