New N-phenyl-4,5-dibromopyrrolamides as DNA gyrase B inhibitors

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Zidar , N , Macut , H , Tomašič , T , Peterlin Mašič , L , Ilaš , J , Zega , A , Tammela , P & Kikelj , D 2019 , ' New N -phenyl-4,5-dibromopyrrolamides as DNA gyrase B inhibitors ' , MedChemComm , vol. 10 , no. 6 , pp. 1007-1017 . https://doi.org/10.1039/c9md00224c

Title: New N-phenyl-4,5-dibromopyrrolamides as DNA gyrase B inhibitors
Author: Zidar, Nace; Macut, Helena; Tomašič, Tihomir; Peterlin Mašič, Lucija; Ilaš, Janez; Zega, Anamarija; Tammela, Päivi; Kikelj, Danijel
Contributor organization: Division of Pharmaceutical Biosciences
Drug Research Program
Bioactivity Screening Group
University Management
Date: 2019-06-01
Language: eng
Number of pages: 11
Belongs to series: MedChemComm
ISSN: 2040-2503
DOI: https://doi.org/10.1039/c9md00224c
URI: http://hdl.handle.net/10138/315658
Abstract: Due to the rapid development of antimicrobial resistance, the discovery of new antibacterials is essential in the fight against potentially lethal infections. The DNA gyrase B (GyrB) subunit of bacterial DNA gyrase is an excellent target for the design of antibacterials, as it has been clinically validated by novobiocin. However, there are currently no drugs in clinical use that target GyrB. We prepared a new series of N-phenyl-4,5-dibromopyrrolamides and evaluated them against DNA gyrase and against the structurally and functionally similar enzyme, topoisomerase IV. The most active compound, 28, had an IC50 of 20 nM against Escherichia coli DNA gyrase. The IC50 values of 28 against Staphylococcus aureus DNA gyrase, and E. coli and S. aureus topoisomerase IV were in the low micromolar range. However, the compounds evaluated did not show significant antibacterial activities against selected Gram-positive and Gram-negative bacteria. Our results indicate that for potent inhibition of DNA gyrase, a combination of polar groups on the carboxylic end of the molecule and substituents that reach into the 'lipophilic floor' of the enzyme is required.
Subject: 1182 Biochemistry, cell and molecular biology
116 Chemical sciences
317 Pharmacy
N-PHENYLPYRROLAMIDES
ATPASE INHIBITORS
DRUG DISCOVERY
ANTIBACTERIAL
TOPOISOMERASE
PHENYLINDOLAMIDES
OPTIMIZATION
CANDIDATE
DESIGN
Peer reviewed: Yes
Rights: unspecified
Usage restriction: openAccess
Self-archived version: acceptedVersion
Funder: SUOMEN AKATEMIA
SUOMEN AKATEMIA
Grant number: 277001


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