| Abstract
| - We describe the lead optimization and structure−activity relationship of DNA minor-groovebinding ligands, a novel class of antibacterial molecules. These compounds have been shownto target A/T-rich sites within the bacterial genome and, as a result, inhibit DNA replicationand RNA transcription. The optimization was focused on N-terminal aromatic heterocyclesand C-terminal amines and resulted in compounds with improved in vivo tolerability andexcellent in vitro antibacterial potency (MIC ≥ 0.031 μg/mL) against a broad range of Gram-positive pathogens, including drug-resistant strains such as methicillin-resistant Stapylococcusaureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant Enterococcus faecalis (VRE). In a first proof-of-concept study, a selected compound(35) showed in vivo efficacy in a mouse peritonitis model against methicillin-sensitive S. aureusinfection with an ED50 value of 30 mg/kg.
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