Discovery of Benzothiazole Scaffold-Based DNA Gyrase B Inhibitors

• Published in: Journal of medicinal chemistry Vol. 59; no. 19; pp. 8941 - 8954
• Main Authors: Gjorgjieva, Marina, Tomašič, Tihomir, Barančokova, Michaela, Katsamakas, Sotirios, Ilaš, Janez, Tammela, Päivi, Peterlin Mašič, Lucija, Kikelj, Danijel
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.10.2016; Amer Chemical Soc
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Benzothiazoles - chemistry; Benzothiazoles - pharmacology; Chemistry, Medicinal; Crystallography, X-Ray; DNA Gyrase - metabolism; DNA Topoisomerase IV - antagonists & inhibitors; DNA Topoisomerase IV - metabolism; Drug Design; Escherichia coli - drug effects; Escherichia coli - enzymology; Escherichia coli Infections - drug therapy; Escherichia coli Infections - microbiology; Humans; Life Sciences & Biomedicine; Models, Molecular; Pharmacology & Pharmacy; Science & Technology; Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; Structure-Activity Relationship; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; DESIGN; POTENT; ATPASE INHIBITORS; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; QUINOLONES; CYCLOTHIALIDINES; TOPOISOMERASE-IV; N-PHENYL-4,5-DIBROMOPYRROLAMIDES; N-PHENYLINDOLAMIDES
• DOI: 10.1021/acs.jmedchem.6b00864
• ISSN: 0022-2623

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 from both 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 toward dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.