20.500.12556/RUL-161296 Improved N-phenylpyrrolamide inhibitors of DNA gyrase as antibacterial agents for high-priority bacterial strains 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. antibacterial agents DNA gyrase GyrB inhibitor N-phenylpyrrolamide ParE topoisomerase IV antibakterijski zaviralci DNA giraze GyrB N-fenilpirolamid ParE topoizomeraza IV farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2024-09-09 12:16:48 2024-09-09 12:16:55 2025-08-08 13:41:38 0000-00-00 00:00:00 2024 0 0 19 str. Vol. 278, art. 116823 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54 1768-3254 10.1016/j.ejmech.2024.116823 206357251 1-s2.0-S0223523424007049-main.pdf 1-s2.0-S0223523424007049-main.pdf 1 0871C69817F57D13F046800A9DF18B92 5dec5edf0f5da2a5601853194b4394b486f31d3eae41932363162831107186bf e6c6416a-6e94-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=190197 https://www.sciencedirect.com/science/article/pii/S0223523424007049 1 9b0d33fd-6e94-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=190196 Fakulteta za farmacijo 0 0 0