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

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Durcik , M , Tammela , P S M , Barančoková , M , Tomašič , T , Ilaš , J , Kikelj , D & Zidar , N 2018 , ' Synthesis and Evaluation of N-Phenylpyrrolamides as DNA Gyrase B Inhibitors ' , ChemMedChem : chemistry enabling drug discovery. , vol. 13 , no. 2 , pp. 186-198 . https://doi.org/10.1002/cmdc.201700549

Title: Synthesis and Evaluation of N-Phenylpyrrolamides as DNA Gyrase B Inhibitors
Author: Durcik, Martina; Tammela, Päivi Sirpa Marjaana; Barančoková, Michaela; Tomašič, Tihomir; Ilaš, Janez; Kikelj, Danijel; Zidar, Nace
Contributor organization: Faculty of Pharmacy
Drug Research Program
Division of Pharmaceutical Biosciences
Bioactivity Screening Group
Date: 2018-01-22
Language: eng
Number of pages: 13
Belongs to series: ChemMedChem : chemistry enabling drug discovery.
ISSN: 1860-7179
DOI: https://doi.org/10.1002/cmdc.201700549
URI: http://hdl.handle.net/10138/313212
Abstract: 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 mu m against the Gram-positive Enterococcus faecalis. Some compounds displayed good antibacterial activities against an efflux-pump-deficient E.coli strain (MIC=6.25 mu m) and against wild-type E.coli in the presence of efflux pump inhibitor PA beta N (MIC=3.13 mu m). 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.
Subject: 317 Pharmacy
antibacterials
DNA gyrase
GyrB
inhibitors
pyrrolamides
STRUCTURE-GUIDED DESIGN
TOPOISOMERASE-IV PARE
ANTIBACTERIAL ACTIVITY
ATPASE INHIBITORS
II TOPOISOMERASE
BROAD-SPECTRUM
PYRROLOPYRIMIDINE INHIBITORS
PSEUDOMONAS-AERUGINOSA
STAPHYLOCOCCUS-AUREUS
ESCHERICHIA-COLI
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: acceptedVersion
Funder: European Commission / Horizon 2020
SUOMEN AKATEMIA
Grant number: 642620
277001


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