Rediscovering Diazaborines: Synthesis and Bioactivity Profiling of Boron-Containing FabI Inhibitors against Gram-Negative Bacteria

In this study, we investigated the potential of diazaborine compounds for antibacterial drug development. Most promising diazaborines demonstrated activity against several Gram-negative pathogens including Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Salmonella enterica ser. Typhimurium. For a subset of diazaborines, we showed inhibitory activity against isolated FabI (enoyl-acyl carrier protein reductase) enzyme aligning with antimicrobial activity, suggesting a mechanism of action via the FabI enzyme and providing early information on structure–activity relationships. Optimized diazaborine scaffold 11 features an amino group in a meta-relative position to the sulfonamide group and exhibited the most favorable bioactivity profile, showing MIC of 6.25 μM against E. coli, low cytotoxicity, and high stability in human plasma. Furthermore, diazaborine 11 had synergistic effect with colistin (FICI 0.25) and preliminary data show that it may rescue Galleria mellonella larvae from lethal E. coli infection at the therapeutic dose of 1.13 and 2.81 mg/kg, demonstrating efficacy similar to ciprofloxacin.