Second-generation 4,5,6,7-tetrahydrobenzo[ d ]thiazoles as novel DNA gyrase inhibitors.

Aim: DNA gyrase and topoisomerase IV are essential bacterial enzymes, and in the fight against bacterial resistance, they are important targets for the development of novel antibacterial drugs. Results: Building from our first generation of 4,5,6,7-tetrahydrobenzo[ d ]thiazole-based DNA gyrase inhibitors, we designed and prepared an optimized series of analogs that show improved inhibition of DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli , with IC ₅₀ values in the nanomolar range. Importantly, these inhibitors also show improved antibacterial activity against Gram-positive strains. Conclusion: The most promising inhibitor, 29 , is active against Enterococcus faecalis , Enterococcus faecium and S. aureus wild-type and resistant strains, with minimum inhibitory concentrations between 4 and 8 μg/ml, which represents good starting point for development of novel antibacterials.