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

Tiz, Davide Benedetto and Skok, Ziga and Durcik, Martina and Tomasic, Tihomir and Peterlin Masic, Lucija and Draskovits, Gábor and Révész, Tamás and Nyerges, Ákos and Pál, Csaba (2019) An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 167. pp. 269-290. ISSN 0223-5234

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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.

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