Improved N-phenylpyrrolamide inhibitors of DNA gyrase as antibacterial agents for high-priority bacterial strains.

Autor: Zidar N; University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia. Electronic address: nace.zidar@ffa.uni-lj.si., Onali A; University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia., Peršolja P; University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia., Benedetto Tiz D; University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia., Dernovšek J; University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia., Skok Ž; University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia., Durcik M; University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia., Cotman AE; University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia., Hrast Rambaher M; University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia., Cruz CD; Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, Viikinkaari 5E, Helsinki, 00014, Finland., Tammela P; Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, Viikinkaari 5E, Helsinki, 00014, Finland., Senerovic L; Laboratory for Microbial Molecular Genetics and Ecology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11 042, Belgrade, Serbia., Jovanovic M; Laboratory for Microbial Molecular Genetics and Ecology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11 042, Belgrade, Serbia., Szili PÉ; Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, H-6726, Hungary., Czikkely MS; Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, H-6726, Hungary; Doctoral School of Multidisciplinary Medical Sciences, University of Szeged, Szeged, HU-6722, Hungary; Department of Forensic Medicine, Albert-Szent-Györgyi Medical School, University of Szeged, Szeged, HU-6722, Hungary., Pál C; Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, H-6726, Hungary., Zega A; University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia., Peterlin Mašič L; University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia., Ilaš J; University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia., Tomašič T; University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia., Kikelj D; University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Nov 15; Vol. 278, pp. 116823. Date of Electronic Publication: 2024 Sep 01.
DOI: 10.1016/j.ejmech.2024.116823
Abstrakt: In this work, we describe an improved series of N-phenylpyrrolamide inhibitors that exhibit potent activity against DNA gyrase and are highly effective against high-priority gram-positive bacteria. The most potent compounds show low nanomolar IC 50 values against Escherichia coli DNA gyrase, and in addition, compound 7c also inhibits E. coli topoisomerase IV in the nanomolar concentration range, making it a promising candidate for the development of potent dual inhibitors for these enzymes. All tested compounds show high selectivity towards the human isoform DNA topoisomerase IIα. Compounds 6a, 6d, 6e and 6f show MIC values between 0.031 and 0.0625 μg/mL against vancomycin-intermediate S. aureus (VISA) and Enterococcus faecalis strains. Compound 6g shows an inhibitory effect against the methicillin-resistant S. aureus strain (MRSA) with a MIC of 0.0625 μg/mL and against the E. faecalis strain with a MIC of 0.125 μg/mL. In a time-kill assay, compound 6d showed a dose-dependent bactericidal effect on the MRSA strain and achieved bactericidal activity at 8 × MIC after 8 h. The duration of the post-antibiotic effect (PAE) on the MRSA strain for compound 6d was 2 h, which corresponds to the PAE duration for ciprofloxacin. The compounds were not cytotoxic at effective concentrations, as determined in an MTS assay on the MCF-7 breast cancer cell line.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nace Zidar reports financial support was provided by Slovenian Research Agency. Cristina D. Cruz, Paivi Tammela reports financial support was provided by Research Council of Finland. Marton Simon Czikkely reports financial support was provided by Hungarian Ministry of Culture and Innovation. Nace Zidar has patent New N-phenylpyrrolamide inhibitors of DNA gyrase and topoisomerase IV with antibacterial activity pending to University of Ljubljana. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: