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

Zidar, Nace and Onali, Alessia and Persolja, Peter and Tiz, Davide Benedetto and Dernovsek, Jaka and Skok, Ziga and Durcik, Martina and Cotman, Andrej Emanuel and Rambaher, Martina Hrast and Cruz, Cristina D. and Tammela, Paivi and Senerovic, Lidija and Jovanovic, Milija and Szili, Petra and Czikkely, Márton Simon and Pál, Csaba and Zega, Anamarija and Masic, Lucija Peterlin and Ilas, Janez and Tomasic, Tihomir and Kikelj, Danijel (2024) Improved N-phenylpyrrolamide inhibitors of DNA gyrase as antibacterial agents for high-priority bacterial strains. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 278. No. 116823. ISSN 0223-5234

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Abstract

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 IC50 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 dosedependent 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.

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