title: Design, synthesis and evaluation of second generation MurF inhibitors based on a cyanothiophene scaffold.
abstract: MurF ligase is a crucial enzyme that catalyses the ultimate intracellular step of bacterial peptidoglycan biosynthesis, and thus represents an attractive target for antibacterial drug discovery. We designed, synthesized and evaluated a new series of cyanothiophene-based inhibitors of MurF enzymes from Streptococcus pneumoniae and Escherichia coli. The target compounds had increased polarity compared to the first generation of inhibitors, with demonstrated enzyme inhibitory potencies in the low micromolar range. Furthermore, the best inhibitors displayed promising antibacterial activities against selected Gram-positive and Gram-negative strains. These results represent an important step towards the development of new antibacterial agents targeting peptidoglycan biosynthesis.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Martina
authors.initials: M
authors.lastname: Hrast
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Marko
authors.initials: M
authors.lastname: Anderluh
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Damijan
authors.initials: D
authors.lastname: Knez
authors.affiliation: School of Molecular and Cellular Biology and Antimicrobial Research Centre, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Randall
authors.affiliation: Univ Paris-Sud, Enveloppes Bactériennes et Antibiotiques, IBBMC, UMR 8619 CNRS, 91405 Orsay, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Barreteau
authors.affiliation: School of Molecular and Cellular Biology and Antimicrobial Research Centre, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: O'Neill
authors.affiliation: Univ Paris-Sud, Enveloppes Bactériennes et Antibiotiques, IBBMC, UMR 8619 CNRS, 91405 Orsay, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Blanot
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia. Electronic address: stanislav.gobec@ffa.uni-lj.si.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D013876:Thiophenes; D010453:Peptide Synthases; C060628:UDP-N-acetylmuramoylalanyl-D-glutamyllysine-D-alanyl-D-alanine ligase
keywords: Antibacterials; Enzyme inhibitors; MurF; Peptidoglycan