Synthesis and Evaluation of N‐Phenylpyrrolamides as DNA Gyrase B Inhibitors

• Published in: ChemMedChem 2018-01, Vol.13 (2), p.186-198
• Main Authors: Durcik, Martina, Tammela, Päivi, Barančoková, Michaela, Tomašič, Tihomir, Ilaš, Janez, Kikelj, Danijel, Zidar, Nace
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - pharmacology; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; antibacterials; Bacterial Proteins - antagonists & inhibitors; DNA gyrase; DNA Gyrase - metabolism; DNA Topoisomerase IV - antagonists & inhibitors; Escherichia coli - drug effects; Escherichia coli - enzymology; Gram-Positive Bacteria - drug effects; GyrB; Humans; inhibitors; Microbial Sensitivity Tests; Molecular Docking Simulation; Protein Binding; Protein Conformation; pyrrolamides; Pyrroles - chemical synthesis; Pyrroles - pharmacology; Staphylococcus aureus - enzymology; Structure-Activity Relationship; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - pharmacology
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201700549

ATP‐competitive inhibitors of DNA gyrase and topoisomerase IV 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 topoisomerase IV 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 47 nm against E. coli DNA gyrase, and a minimum inhibitory concentration (MIC) of 12.5 μm against the Gram‐positive Enterococcus faecalis. Some compounds displayed good antibacterial activities against an efflux‐pump‐deficient E. coli strain (MIC=6.25 μm) and against wild‐type E. coli in the presence of efflux pump inhibitor PAβN (MIC=3.13 μm). Here we describe new findings regarding the structure–activity relationships of N‐phenylpyrrolamide DNA gyrase B inhibitors and investigate the factors that are important for the antibacterial activity of this class of compounds. Don′t try to resist: New N‐phenylpyrrolamides were prepared as DNA gyrase and topoisomerase IV inhibitors, and their structure–activity relationships were studied. The most potent compounds displayed IC50 values lower than 100 nm against E. coli gyrase. A minimum inhibitory concentration of 12.5 μm was determined for compound 11 against the Gram‐positive Enterococcus faecalis. Growth inhibition of efflux‐pump‐deficient E. coli strains and wild‐type E. coli in the presence of an efflux pump inhibitor was also evaluated.