2. Academic Validation
  3. New N-phenylpyrrolamide DNA gyrase B inhibitors: Optimization of efficacy and antibacterial activity

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

  • Eur J Med Chem. 2018 Jun 25:154:117-132. doi: 10.1016/j.ejmech.2018.05.011.
Martina Durcik 1,  Denise Lovison 1,  Žiga Skok 1,  Cristina Durante Cruz 2,  Päivi Tammela 2,  Tihomir Tomašič 1,  Davide Benedetto Tiz 1,  Gábor Draskovits 3,  Ákos Nyerges 3,  Csaba Pál 3,  Janez Ilaš 1,  Lucija Peterlin Mašič 1,  Danijel Kikelj 1,  Nace Zidar 4
Affiliations

Affiliations

  • 1 Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia.
  • 2 Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5 E), 00014, Helsinki, Finland.
  • 3 Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, H-6726, Hungary.
  • 4 Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia. Electronic address: nace.zidar@ffa.uni-lj.si.
PMID: 29778894 DOI: 10.1016/j.ejmech.2018.05.011
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.

Keywords

Antibacterial; DNA gyrase; GyrB; Inhibitor; N-phenylpyrrolamide; ParE; Topoisomerase IV.

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