Discovery of benzothiazole scaffold-based DNA gyrase B inhibitors

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

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.

• Jezik: Angleški jezik
• Ključne besede: organoruthenium complexes, diketonates, anticancer drugs, ROS, cytotoxicity, cell cycle arrest
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Recenzirani rokopis
• Leto izida: 2016
• Št. strani: Str. 8941-8954
• Številčenje: Vol. 59, iss. 19
• PID: 20.500.12556/RUL-107604
• UDK: 543:542:615
• ISSN pri članku: 0022-2623
• DOI: 10.1021/acs.jmedchem.6b00864
• COBISS.SI-ID: 4145265
• Datum objave v RUL: 06.05.2019

Gradivo je del revije

• Naslov: Journal of medicinal chemistry
• Skrajšan naslov: J. med. chem.
• Založnik: American Chemical Society
• ISSN: 0022-2623
• COBISS.SI-ID: 25763328

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: bioanorganska kemija, koordinacijske spojine, organorutenijevi kompleksi, diketonati, citotoksičnost, protirakava zdravila

Projekti

• Financer: EC - European Commission
• Program financ.: H2020
• Številka projekta: 642620
• Naslov: Interdisciplinary Training Network for Validation of Gram-Negative Antibacterial Targets
• Akronim: INTEGRATE