title: Discovery of substituted oxadiazoles as a novel scaffold for DNA gyrase inhibitors.
abstract: DNA gyrase and topoisomerase IV are type IIa topoisomerases that are essential bacterial enzymes required to oversee the topological state of DNA during transcription and replication processes. Their ATPase domains, GyrB and ParE, respectively, are recognized as viable targets for small molecule inhibitors, however, no synthetic or natural product GyrB/ParE inhibitors have so far reached the clinic for use as novel antibacterial agents, except for novobiocin which was withdrawn from the market. In the present study, a series of substituted oxadiazoles have been designed and synthesized as potential DNA gyrase inhibitors. Structure-based optimization resulted in the identification of compound 35, displaying an IC50of 1.2 μM for Escherichia coli DNA gyrase, while also exhibiting a balanced low micromolar inhibition of E. coli topoisomerase IV and of the respective Staphylococcus aureus homologues. The most promising inhibitors identified from each series were ultimately evaluated against selected Gram-positive and Gram-negative bacterial strains, of which compound 35 inhibited Enterococcus faecalis with a MIC90of 75 μM. Our study thus provides further insight into the structural requirements of substituted oxadiazoles for dual inhibition of DNA gyrase and topoisomerase IV.
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia. Electronic address: ziga.jakopin@ffa.uni-lj.si.
authors.forename: Žiga
authors.initials: Ž
authors.lastname: Jakopin
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Janez
authors.initials: J
authors.lastname: Ilaš
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Michaela
authors.initials: M
authors.lastname: Barančoková
authors.affiliation: National Institute of Chemistry, Laboratory for Molecular Modeling, Hajdrihova ulica 19, 1001 Ljubljana, Slovenia.
authors.forename: Matjaž
authors.initials: M
authors.lastname: Brvar
authors.affiliation: University of Helsinki, Faculty of Pharmacy, Division of Pharmaceutical Biosciences, P.O. Box 56, FI-00014 Helsinki, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Tammela
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Marija
authors.initials: M
authors.lastname: Sollner Dolenc
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Tihomir
authors.initials: T
authors.lastname: Tomašič
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Danijel
authors.initials: D
authors.lastname: Kikelj
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D027081:DNA Gyrase / Q000187:drug effects; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D010069:Oxadiazoles; D059005:Topoisomerase II Inhibitors; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase
keywords: 1,2,4-Oxadiazoles; Antibacterial screening; Computer-aided drug design; DNA gyrase inhibition; Topoisomerase IV inhibition