New N-phenylpyrrolamide DNA gyrase B inhibitors: Optimization of efficacy and antibacterial activity

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http://hdl.handle.net/10138/314743

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Durcik , M , Lovison , D , Skok , Ž , Durante Cruz , C , Tammela , P , Tomašič , T , Benetto Tiz , D , Draskovits , G , Nyerges , Á , Pál , C , Ilaš , J , Peterlin Mašič , L , Kikelj , D & Zidar , N 2018 , ' New N-phenylpyrrolamide DNA gyrase B inhibitors: Optimization of efficacy and antibacterial activity ' , European Journal of Medicinal Chemistry , vol. 154 , pp. 117-132 . https://doi.org/10.1016/j.ejmech.2018.05.011

Title: New N-phenylpyrrolamide DNA gyrase B inhibitors: Optimization of efficacy and antibacterial activity
Author: Durcik, Martina; Lovison, Denise; Skok, Žiga; Durante Cruz, Cristina; Tammela, Päivi; Tomašič, Tihomir; Benetto Tiz, Davide; Draskovits, Gábor; Nyerges, Ákos; Pál, Csaba; Ilaš, Janez; Peterlin Mašič, Lucija; Kikelj, Danijel; Zidar, Nace
Contributor: University of Helsinki, Division of Pharmaceutical Biosciences
University of Helsinki, Faculty of Pharmacy
Date: 2018-06-25
Language: eng
Number of pages: 16
Belongs to series: European Journal of Medicinal Chemistry
ISSN: 0223-5234
URI: http://hdl.handle.net/10138/314743
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 IC50 values against DNA gyrase, and submicromolar IC50 values against topoisomerase IV from Escherichia coil and Staphylococcus aureus. The most potent compound in the series has an IC50 value of 13 nM against E. coil gyrase. Minimum inhibitory concentrations (MICs) against Gram-positive bacteria are in the low micromolar range. The oxadiazolone derivative with an IC50 value of 85 nM against E. coli DNA gyrase displays the most potent antibacterial activity, with MIC values of 1.56 mu M against Enterococcus faecalis, and 3.13 mu M against wild type S. aureus, methicillinresistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). The activity against wild type E. coli in the presence of efflux pump inhibitor phenylalanine-arginine beta-naphthylamide (PA beta N) is 4.6 mu M. (C) 2018 Elsevier Masson SAS. All rights reserved.
Subject: 317 Pharmacy
Antibacterial
DNA gyrase
GyrB
Inhibitor
N-phenylpyrrolamide
ParE
Topoisomerase IV
ANTICANCER ACT IVITY
TOPOISOMERASE-IV
DISCOVERY
DESIGN
SPECTRUM
DOCKING
ANALOGS
AGENTS
BROAD
PARE
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