Synthesis and Evaluation of N-Phenylpyrrolamides as DNA GyraseB Inhibitors

ATP-competitive inhibitors of DNA gyrase and topoisomeraseIV are among the most interesting classes of antibacterial drugs that are unrepresented in the antibacterial pipeline. We developed 32 new N-phenylpyrrolamides and evaluated them against DNA gyrase and topoisomeraseIV from E.coli and Staphylo...

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Bibliographic Details
Published in:ChemMedChem 2018-01, Vol.13 (2), p.186
Main Authors: Durcik, Martina, Tammela, Päivi, Barancokova, Michaela, Tomasic, Tihomir, Ilas, Janez, Kikelj, Danijel, Zidar, Nace
Format: Article
Language:English
Subjects:
Antibacterial activity
Antibacterial materials
Bacteria
Deoxyribonucleic acid
DNA
DNA topoisomerase
Drugs
E coli
Efflux
Gram-negative bacteria
Inhibitors
Minimum inhibitory concentration
Structure-activity relationships
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Summary:ATP-competitive inhibitors of DNA gyrase and topoisomeraseIV are among the most interesting classes of antibacterial drugs that are unrepresented in the antibacterial pipeline. We developed 32 new N-phenylpyrrolamides and evaluated them against DNA gyrase and topoisomeraseIV from E.coli and Staphylococcus aureus. Antibacterial activities were studied against Gram-positive and Gram-negative bacterial strains. The most potent compound displayed an IC50 of 47nm against E.coli DNA gyrase, and a minimum inhibitory concentration (MIC) of 12.5µm against the Gram-positive Enterococcus faecalis. Some compounds displayed good antibacterial activities against an efflux-pump-deficient E.coli strain (MIC=6.25µm) and against wild-type E.coli in the presence of efflux pump inhibitor PA[beta]N (MIC=3.13µm). Here we describe new findings regarding the structure-activity relationships of N-phenylpyrrolamide DNA gyraseB inhibitors and investigate the factors that are important for the antibacterial activity of this class of compounds.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201700549