Discovery of bentzothiazole scaffold-based DNA gyrase B inhibitors

Marina Gjorgjieva, Tihomir Tomašič, Michaela Barančokova, Sotirios Katsamakas, Janez Ilaš, Päivi Tammela, Lucija Peterlin Mašič, Danijel Kikelj

Research output: Contribution to journalArticleScientificpeer-review


Bacterial DNA gyrase and topoisomerase IV control the topological state of DNA
during replication and are validated targets for antibacterial drug discovery. Starting from our recently reported 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole-based DNA gyrase B inhibitors, we replaced their central core with benzothiazole-2,6-diamine scaffold and interchanged substituents in positions 2 and 6. This resulted in equipotent nanomolar inhibitors of DNA gyrase from Escherichia coli displaying improved inhibition of Staphylococcus aureus DNA gyrase and topoisomerase IV from both bacteria. Compound 27 was the most balanced inhibitor of DNA gyrase and topoisomerase IV both from E. coli and S. aureus. The crystal structure of the
2-((2-(4,5-dibromo-1H-pyrrole-2-carboxamido)benzothiazol-6-yl)amino)-2-oxoacetic acid (24) in complex with E. coli DNA gyrase B revealed the binding mode of the inhibitor in the ATPbinding pocket. Only some compounds possessed weak antibacterial activity against Grampositive bacteria. These results provide a basis for structure-based optimization towards dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Issue number19
Pages (from-to)8941-8954
Number of pages14
Publication statusPublished - Oct 2016
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 317 Pharmacy

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