An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors

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Benetto Tiz , D , Skok , Ž , Durcik , M , Tomašič , T , Peterlin Mašič , L , Ilaš , J , Draskovits , G , Révész , T , Nyerges , Á , Pál , C , Cruz , C D , Tammela , P S M , Žigon , D , Kikelj , D & Zidar , N 2019 , ' An optimised series of substituted N -phenylpyrrolamides as DNA gyrase B inhibitors ' , European Journal of Medicinal Chemistry , vol. 167 , pp. 269-290 . https://doi.org/10.1016/j.ejmech.2019.02.004

Title: An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors
Author: Benetto Tiz, Davide; Skok, Žiga; Durcik, Martina; Tomašič, Tihomir; Peterlin Mašič, Lucija; Ilaš, Janez; Draskovits, Gábor; Révész, Tamás; Nyerges, Ákos; Pál, Csaba; Cruz, Cristina D.; Tammela, Päivi Sirpa Marjaana; Žigon, Dušan; Kikelj, Danijel; Zidar, Nace
Contributor: University of Helsinki, Division of Pharmaceutical Biosciences
University of Helsinki, Division of Pharmaceutical Biosciences
Date: 2019-04-01
Language: eng
Number of pages: 22
Belongs to series: European Journal of Medicinal Chemistry
ISSN: 0223-5234
URI: http://hdl.handle.net/10138/312428
Abstract: ATP competitive inhibitors of DNA gyrase and topoisomerase IV have great therapeutic potential, but none of the described synthetic compounds has so far reached the market. To optimise the activities and physicochemical properties of our previously reported N-phenylpyrrolamide inhibitors, we have synthesized an improved, chemically variegated selection of compounds and evaluated them against DNA gyrase and topoisomerase IV enzymes, and against selected Gram-positive and Gram-negative bacteria. The most potent compound displayed IC50 values of 6.9 nM against Escherichia coli DNA gyrase and 960 nM against Staphylococcus aureus topoisomerase IV. Several compounds displayed minimum inhibitory concentrations (MICs) against Gram-positive strains in the 1-50 mu M range, one of which inhibited the growth of Enterococcus faecalis, Enterococcus faecium, S. aureus and Streptococcus pyogenes with MIC values of 1.56 mu M, 1.56 mu M, 0.78 mu M and 0.72 mu M, respectively. This compound has been investigated further on methicillin-resistant S. aureus (MRSA) and on ciprofloxacin non-susceptible and extremely drug resistant strain of S. aureus (MRSA VISA). It exhibited the MIC value of 2.5 mu M on both strains, and MIC value of 32 mu M against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action. (C) 2019 Elsevier Masson SAS. All rights reserved.
Subject: 317 Pharmacy
Antibacterial
ATP competitive
DNA gyrase
GyrB
Inhibitor
N-phenylpyrrolamide
ParE
Topoisomerase IV
BIOLOGICAL EVALUATION
ATPASE INHIBITORS
ANTIBACTERIAL
ACID
TOPOISOMERASE
DESIGN
DISCOVERY
ANALOGS
N-PHENYL-4,5-DIBROMOPYRROLAMIDES
PHENYLINDOLAMIDES
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