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New N-phenylpyrrolamide DNA gyrase B inhibitors: Optimization of efficacy and antibacterial activity.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2018 Jun 25; Vol. 154, pp. 117-132. Date of Electronic Publication: 2018 May 10. - Publication Year :
- 2018
-
Abstract
- The ATP binding site located on the subunit B of DNA gyrase is an attractive target for the development of new antibacterial agents. In recent decades, several small-molecule inhibitor classes have been discovered but none has so far reached the market. We present here the discovery of a promising new series of N-phenylpyrrolamides with low nanomolar IC <subscript>50</subscript> values against DNA gyrase, and submicromolar IC <subscript>50</subscript> values against topoisomerase IV from Escherichia coli and Staphylococcus aureus. The most potent compound in the series has an IC <subscript>50</subscript> value of 13 nM against E. coli gyrase. Minimum inhibitory concentrations (MICs) against Gram-positive bacteria are in the low micromolar range. The oxadiazolone derivative 11a, with an IC <subscript>50</subscript> value of 85 nM against E. coli DNA gyrase displays the most potent antibacterial activity, with MIC values of 1.56 μM against Enterococcus faecalis, and 3.13 μM against wild type S. aureus, methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). The activity against wild type E. coli in the presence of efflux pump inhibitor phenylalanine-arginine β-naphthylamide (PAβN) is 4.6 μM.<br /> (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Amides cerebrospinal fluid
Amides chemistry
Anti-Bacterial Agents chemical synthesis
Anti-Bacterial Agents chemistry
Dose-Response Relationship, Drug
Escherichia coli enzymology
Microbial Sensitivity Tests
Molecular Structure
Pyrroles cerebrospinal fluid
Pyrroles chemistry
Staphylococcus aureus enzymology
Structure-Activity Relationship
Topoisomerase II Inhibitors chemical synthesis
Topoisomerase II Inhibitors chemistry
Amides pharmacology
Anti-Bacterial Agents pharmacology
DNA Gyrase metabolism
Enterococcus faecalis drug effects
Escherichia coli drug effects
Pyrroles pharmacology
Staphylococcus aureus drug effects
Topoisomerase II Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 154
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29778894
- Full Text :
- https://doi.org/10.1016/j.ejmech.2018.05.011