RRC ID 55802
Author 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.
Title New N-phenylpyrrolamide DNA gyrase B inhibitors: Optimization of efficacy and antibacterial activity.
Journal Eur J Med Chem
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.
Volume 154
Pages 117-132
Published 2018-6-25
DOI 10.1016/j.ejmech.2018.05.011
PII S0223-5234(18)30415-X
PMID 29778894
PMC PMC6016738
MeSH Amides / cerebrospinal fluid Amides / chemistry Amides / pharmacology* Anti-Bacterial Agents / chemical synthesis Anti-Bacterial Agents / chemistry Anti-Bacterial Agents / pharmacology* DNA Gyrase / metabolism* Dose-Response Relationship, Drug Enterococcus faecalis / drug effects* Escherichia coli / drug effects* Escherichia coli / enzymology Microbial Sensitivity Tests Molecular Structure Pyrroles / cerebrospinal fluid Pyrroles / chemistry Pyrroles / pharmacology* Staphylococcus aureus / drug effects* Staphylococcus aureus / enzymology Structure-Activity Relationship Topoisomerase II Inhibitors / chemical synthesis Topoisomerase II Inhibitors / chemistry Topoisomerase II Inhibitors / pharmacology*
IF 4.833
Times Cited 11
Prokaryotes E. coli JW5503, JD17464