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

Andraž Lamut, Žiga Skok, Michaela Barančoková, Lucas J. Gutierrez, Cristina D. Cruz, Päivi Tammela, Gábor Draskovits, Petra Éva Szili, Ákos Nyerges, Csaba Pál, Peter Molek, Tomaž Bratkovič, Janez Ilaš, Nace Zidar, Anamarija Zega, Ricardo D. Enriz, Danijel Kikelj, Tihomir Tomašič

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)277-297
Number of pages21
JournalFuture Medicinal Chemistry
Volume12
Issue number4
DOIs
Publication statusPublished - Feb 2020

    Fingerprint

Keywords

  • antibacterial
  • DNA gyrase
  • inhibitor
  • pyrrolamide
  • QTAIM
  • thiazole

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

Cite this

Lamut, A., Skok, Ž., Barančoková, M., Gutierrez, L. J., Cruz, C. D., Tammela, P., Draskovits, G., Szili, P. É., Nyerges, Á., Pál, C., Molek, P., Bratkovič, T., Ilaš, J., Zidar, N., Zega, A., Enriz, R. D., Kikelj, D., & Tomašič, T. (2020). Second-generation 4,5,6,7-tetrahydrobenzo[d]thiazoles as novel DNA gyrase inhibitors. Future Medicinal Chemistry, 12(4), 277-297. https://doi.org/10.4155/fmc-2019-0127