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 Benetto Tiz, Gábor Draskovits, Ákos Nyerges, Csaba Pál, Janez Ilaš, Lucija Peterlin Mašič, Danijel Kikelj, Nace Zidar

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

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 coil and Staphylococcus aureus. The most potent compound in the series has an IC50 value of 13 nM against E. coil gyrase. Minimum inhibitory concentrations (MICs) against Gram-positive bacteria are in the low micromolar range. The oxadiazolone derivative with an IC50 value of 85 nM against E. coli DNA gyrase displays the most potent antibacterial activity, with MIC values of 1.56 mu M against Enterococcus faecalis, and 3.13 mu M against wild type S. aureus, methicillinresistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). The activity against wild type E. coli in the presence of efflux pump inhibitor phenylalanine-arginine beta-naphthylamide (PA beta N) is 4.6 mu M. (C) 2018 Elsevier Masson SAS. All rights reserved.

Originalspråkengelska
TidskriftEuropean Journal of Medicinal Chemistry
Volym154
Sidor (från-till)117-132
Antal sidor16
ISSN0223-5234
DOI
StatusPublicerad - 25 jun 2018
MoE-publikationstypA1 Tidskriftsartikel-refererad

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