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

Abstract

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.

Keywords

bioanorganska kemija;koordinacijske spojine;organorutenijevi kompleksi;diketonati;citotoksičnost;protirakava zdravila;organoruthenium complexes;diketonates;anticancer drugs;ROS;cytotoxicity;cell cycle arrest;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 543:542:615
COBISS: 4145265 Link will open in a new window
ISSN: 0022-2623
Views: 898
Downloads: 890
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Other data

Secondary language: Slovenian
Secondary keywords: bioanorganska kemija;koordinacijske spojine;organorutenijevi kompleksi;diketonati;citotoksičnost;protirakava zdravila;
Embargo end date (OpenAIRE): 2017-08-19
Pages: str. 8941-8954
Volume: ǂVol. ǂ59
Issue: ǂiss. ǂ19
Chronology: 2016
DOI: 10.1021/acs.jmedchem.6b00864
ID: 11129697