Discovery of benzothiazole scaffold-based DNA gyrase B inhibitors

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

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 ATP-binding pocket. Only some compounds possessed weak antibacterial activity against Gram-positive bacteria. These results provide a basis for structure-based optimization towards dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.

• Language: English
• Keywords: organoruthenium complexes, diketonates, anticancer drugs, ROS, cytotoxicity, cell cycle arrest
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Author Accepted Manuscript
• Year: 2016
• Number of pages: Str. 8941-8954
• Numbering: Vol. 59, iss. 19
• PID: 20.500.12556/RUL-107604
• UDC: 543:542:615
• ISSN on article: 0022-2623
• DOI: 10.1021/acs.jmedchem.6b00864
• COBISS.SI-ID: 4145265
• Publication date in RUL: 06.05.2019

Record is a part of a journal

• Title: Journal of medicinal chemistry
• Shortened title: J. med. chem.
• Publisher: American Chemical Society
• ISSN: 0022-2623
• COBISS.SI-ID: 25763328

Secondary language

• Language: Slovenian
• Keywords: bioanorganska kemija, koordinacijske spojine, organorutenijevi kompleksi, diketonati, citotoksičnost, protirakava zdravila

Projects

• Funder: EC - European Commission
• Funding programme: H2020
• Project number: 642620
• Name: Interdisciplinary Training Network for Validation of Gram-Negative Antibacterial Targets
• Acronym: INTEGRATE