Second-Generation 4,5,6,7-Tetrahydrobenzo[ <i>d</i> ]Thiazoles as Novel DNA Gyrase Inhibitors

Abstract

<b>Aim:</b> 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. <b>Results:</b> Building from our first generation of 4,5,6,7-tetrahydrobenzo[<i>d</i>]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 <i>Staphylococcus aureus</i> and <i>Escherichia coli</i>, with IC₅₀ values in the nanomolar range. Importantly, these inhibitors also show improved antibacterial activity against Gram-positive strains. <b>Conclusion:</b> The most promising inhibitor, <b>29</b>, is active against <i>Enterococcus faecalis</i>, <i>Enterococcus faecium</i> and <i>S. aureus</i> 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.