title: Coumarin inhibitors of gyrase B with N-propargyloxy-carbamate as an effective pyrrole bioisostere.
abstract: The synthesis and biological profile in vitro of a series of coumarin inhibitors of gyrase B bearing a N-propargyloxycarbamate at C-3' of noviose is presented. Replacement of the 5-methylpyrrole-2-carboxylate of coumarin drugs with an N-propargyloxycarbamate bioisostere leads to analogues with improved antibacterial activity. Analysis of crystal structures of coumarin antibiotics with the 24 kDa N-terminal domain of the gyrase B protein provides a rational for the excellent inhibitory potency of C-3' N-alkoxycarbamates.
authors.affiliation: Medicinal Chemistry, Hoechst Marion Roussel, Romainville, France.
authors.forename: A M
authors.initials: AM
authors.lastname: Periers
authors.forename: P
authors.initials: P
authors.lastname: Laurin
authors.forename: D
authors.initials: D
authors.lastname: Ferroud
authors.forename: J L
authors.initials: JL
authors.lastname: Haesslein
authors.forename: M
authors.initials: M
authors.lastname: Klich
authors.forename: C
authors.initials: C
authors.lastname: Dupuis-Hamelin
authors.forename: P
authors.initials: P
authors.lastname: Mauvais
authors.forename: P
authors.initials: P
authors.lastname: Lassaigne
authors.forename: A
authors.initials: A
authors.lastname: Bonnefoy
authors.forename: B
authors.initials: B
authors.lastname: Musicki
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology; D027081:DNA Gyrase; D004278:DNA, Superhelical / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D011758:Pyrroles / Q000737:chemistry*; D013211:Staphylococcus aureus / Q000187:drug effects; D013237:Stereoisomerism; D059005:Topoisomerase II Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D002219:Carbamates; D003374:Coumarins; D004278:DNA, Superhelical; D004791:Enzyme Inhibitors; D011758:Pyrroles; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase