title: Glutamyl-gamma-boronate inhibitors of bacterial Glu-tRNA(Gln) amidotransferase.
abstract: Analogues of glutamyl-gamma-boronate (1) were synthesized as mechanism-based inhibitors of bacterial Glu-tRNA(Gln) amidotransferase (Glu-AdT) and were designed to engage a putative catalytic serine nucleophile required for the glutaminase activity of the enzyme. Although 1 provides potent enzyme inhibition, structure-activity studies revealed a narrow range of tolerated chemical changes that maintained activity. Nonetheless, growth inhibition of organisms that require Glu-AdT by the most potent enzyme inhibitors appears to validate mechanism-based inhibitor design of Glu-AdT as an approach to antimicrobial development.
authors.affiliation: Department of Medicinal Chemistry, DuPont Pharmaceuticals Company, Experimental Station, PO Box 80400, Wilmington, DE 19880, USA. carl.p.decicco@dupontpharma.com
authors.forename: C P
authors.initials: CP
authors.lastname: Decicco
authors.forename: D J
authors.initials: DJ
authors.lastname: Nelson
authors.forename: Y
authors.initials: Y
authors.lastname: Luo
authors.forename: L
authors.initials: L
authors.lastname: Shen
authors.forename: K Y
authors.initials: KY
authors.lastname: Horiuchi
authors.forename: K M
authors.initials: KM
authors.lastname: Amsler
authors.forename: L A
authors.initials: LA
authors.lastname: Foster
authors.forename: S M
authors.initials: SM
authors.lastname: Spitz
authors.forename: J J
authors.initials: JJ
authors.lastname: Merrill
authors.forename: C F
authors.initials: CF
authors.lastname: Sizemore
authors.forename: K C
authors.initials: KC
authors.lastname: Rogers
authors.forename: R A
authors.initials: RA
authors.lastname: Copeland
authors.forename: M R
authors.initials: MR
authors.lastname: Harpel
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D001897:Boronic Acids / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D019884:Nitrogenous Group Transferases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000890:Anti-Infective Agents; D001897:Boronic Acids; D004791:Enzyme Inhibitors; C448820:glutamyl-gamma-boronate; C412016:Asp-tRNA(Asn) amidotransferase; D019884:Nitrogenous Group Transferases