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

ANDRAZ LAMUT1; ZIGA SKOK,; MICHAELA BARANCOKOVA; LUCAS GUTIERREZ; CRISTINA D CRUZ; PA¨ IVI TAMMELA; GABOR DRASKOVITS; PETER MOLEK; NACE ZIDAR; ANAMARIJA ZEGA; ENRIZ, RICARDO; DANIJEL KIKEL; TIHOMIR TOMA

future medicinal chemistry

future science

Año: 2020

1756-8919

DNA gyrase and topoisomerase IV are essential bacterial enzymes, and in the fight against bacterialresistance, 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 gyraseand topoisomerase IV from Staphylococcus aureus and Escherichia coli, with IC50 values in the nanomolarrange. Importantly, these inhibitors also show improved antibacterial activity against Gram-positivestrains. Conclusion: The most promising inhibitor, 29, is active against Enterococcus faecalis, Enterococcusfaecium and S. aureus wild-type and resistant strains, with minimum inhibitory concentrations between4 and 8 μg/ml, which represents good starting point for development of novel antibacterials.