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 IC50 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.Fil: Lamut, Andraž. University of Ljubljana; EsloveniaFil: Skok, Žiga. University of Ljubljana; EsloveniaFil: Barancokova, Michaela. University of Ljubljana; EsloveniaFil: Gutierrez, Lucas Joel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Cruz, Cristina D.. University of Helsinki; FinlandiaFil: Tammela, Päivi. University of Helsinki; FinlandiaFil: Draskovits, Gábor. No especifíca;Fil: Szili, Petra Éva. University of Szeged; HungríaFil: Nyerges, Ákos. No especifíca;Fil: Pál, Csaba. No especifíca;Fil: Molek, Peter. University of Ljubljana; EsloveniaFil: Bratkovic, Tomaz. University of Ljubljana; EsloveniaFil: Ilas, Janez. University of Ljubljana; EsloveniaFil: Zidar, Nace. University of Ljubljana; EsloveniaFil: Zega, Anamarija. University of Ljubljana; EsloveniaFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Kikelj, Danijel. University of Ljubljana; EsloveniaFil: Tomasic, Tihomir. University of Ljubljana; Esloveni