New N-phenylpyrrolamide DNA gyrase B inhibitors: Optimization of efficacy and antibacterial activity

• Published in: European journal of medicinal chemistry Vol. 154; pp. 117 - 132
• Main Authors: Durcik, Martina, Lovison, Denise, Skok, Žiga, Durante Cruz, Cristina, Tammela, Päivi, Tomašič, Tihomir, Benedetto Tiz, Davide, Draskovits, Gábor, Nyerges, Ákos, Pál, Csaba, Ilaš, Janez, Peterlin Mašič, Lucija, Kikelj, Danijel, Zidar, Nace
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 25.06.2018; Elsevier
• Subjects: Amides - cerebrospinal fluid; Amides - chemistry; Amides - pharmacology; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial; Chemistry, Medicinal; DNA gyrase; DNA Gyrase - metabolism; Dose-Response Relationship, Drug; Enterococcus faecalis - drug effects; Escherichia coli - drug effects; Escherichia coli - enzymology; GyrB; Inhibitor; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Molecular Structure; N-phenylpyrrolamide; ParE; Pharmacology & Pharmacy; Pyrroles - cerebrospinal fluid; Pyrroles - chemistry; Pyrroles - pharmacology; Science & Technology; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; Structure-Activity Relationship; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; Topoisomerase IV; GyrB; ParE; GyrA; DTT; ParC; DIAD; TBTU; VRE; CDI; topo IV; Antibacterial; DNA gyrase; ATCC; MTS; CFU; FBS; MRSA; HepG2; HUVEC; Topoisomerase IV; MH; CLSI; PAβN; N-phenylpyrrolamide; NMM; RA; Inhibitor; ATR; DESIGN; ANALOGS; BROAD; DISCOVERY; IV PARE; SPECTRUM
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.05.011

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. [Display omitted] •An optimized series of N-phenylpyrrolamide DNA gyrase B inhibitors was prepared.•Low nanomolar IC50 values against DNA gyrase were obtained.•Compound 12 had an IC50 value of 13 nM against E. coli DNA gyrase.•MIC values of 11a were 1.56 μM against E. faecalis and 3.13 μM against S. aureus.•Compound 11a inhibited MRSA and VRE with MIC values of 3.13 μM.