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

Martina Durcik, Denise Lovison, Žiga Skok, Cristina Durante Cruz, Päivi Tammela, Tihomir Tomašič, Davide Benedetto Tiz, Gábor Draskovits, Ákos Nyerges, C. Pál, Janez Ilaš, Lucija Peterlin Mašič, Danijel Kikelj, Nace Zidar

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 coli and Staphylococcus aureus. The most potent compound in the series has an IC50 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 IC50 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.

Original languageEnglish
Pages (from-to)117-132
Number of pages16
JournalEuropean Journal of Medicinal Chemistry
Volume154
DOIs
Publication statusPublished - Jun 25 2018

Fingerprint

DNA Gyrase
Topoisomerase II Inhibitors
Escherichia coli
Inhibitory Concentration 50
Microbial Sensitivity Tests
Staphylococcus aureus
DNA Topoisomerase IV
Methicillin
Enterococcus faecalis
Gram-Positive Bacteria
Vancomycin
Methicillin-Resistant Staphylococcus aureus
Phenylalanine
Arginine
Bacteria
Adenosine Triphosphate
Binding Sites
Pumps
Anti-Bacterial Agents
Derivatives

Keywords

  • Antibacterial
  • DNA gyrase
  • GyrB
  • Inhibitor
  • N-phenylpyrrolamide
  • ParE
  • Topoisomerase IV

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Durcik, M., Lovison, D., Skok, Ž., Durante Cruz, C., Tammela, P., Tomašič, T., ... Zidar, N. (2018). New N-phenylpyrrolamide DNA gyrase B inhibitors: Optimization of efficacy and antibacterial activity. European Journal of Medicinal Chemistry, 154, 117-132. https://doi.org/10.1016/j.ejmech.2018.05.011

New N-phenylpyrrolamide DNA gyrase B inhibitors : Optimization of efficacy and antibacterial activity. / Durcik, Martina; Lovison, Denise; Skok, Žiga; Durante Cruz, Cristina; Tammela, Päivi; Tomašič, Tihomir; Benedetto Tiz, Davide; Draskovits, Gábor; Nyerges, Ákos; Pál, C.; Ilaš, Janez; Peterlin Mašič, Lucija; Kikelj, Danijel; Zidar, Nace.

In: European Journal of Medicinal Chemistry, Vol. 154, 25.06.2018, p. 117-132.

Research output: Contribution to journalArticle

Durcik, M, Lovison, D, Skok, Ž, Durante Cruz, C, Tammela, P, Tomašič, T, Benedetto 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
Durcik, Martina ; Lovison, Denise ; Skok, Žiga ; Durante Cruz, Cristina ; Tammela, Päivi ; Tomašič, Tihomir ; Benedetto Tiz, Davide ; Draskovits, Gábor ; Nyerges, Ákos ; Pál, C. ; Ilaš, Janez ; Peterlin Mašič, Lucija ; Kikelj, Danijel ; Zidar, Nace. / New N-phenylpyrrolamide DNA gyrase B inhibitors : Optimization of efficacy and antibacterial activity. In: European Journal of Medicinal Chemistry. 2018 ; Vol. 154. pp. 117-132.
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