2. Academic Validation
  3. An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors

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

  • Eur J Med Chem. 2019 Apr 1:167:269-290. doi: 10.1016/j.ejmech.2019.02.004.
Davide Benedetto Tiz 1,  Žiga Skok 1,  Martina Durcik 1,  Tihomir Tomašič 1,  Lucija Peterlin Mašič 1,  Janez Ilaš 1,  Anamarija Zega 1,  Gábor Draskovits 2,  Tamás Révész 2,  Ákos Nyerges 2,  Csaba Pál 3,  Cristina D Cruz 3,  Päivi Tammela 3,  Dušan Žigon 4,  Danijel Kikelj 1,  Nace Zidar 5
Affiliations

Affiliations

  • 1 University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia.
  • 2 Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, H-6726, Hungary.
  • 3 Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5 E), Helsinki, FI-00014, Finland.
  • 4 Jožef Stefan Institute, Department of Environmental Science, Jamova cesta 39, 1000, Ljubljana, Slovenia.
  • 5 University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia. Electronic address: nace.zidar@ffa.uni-lj.si.
PMID: 30776691 DOI: 10.1016/j.ejmech.2019.02.004
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 μM range, one of which inhibited the growth of Enterococcus faecalis, Enterococcus faecium, S. aureus and Streptococcus pyogenes with MIC values of 1.56 μM, 1.56 μM, 0.78 μM and 0.72 μM, 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 μM on both strains, and MIC value of 32 μM against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action.

Keywords

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

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