title: Structure-activity relationships of the peptide deformylase inhibitor BB-3497: modification of the methylene spacer and the P1' side chain.
abstract: Structural modifications to the peptide deformylase inhibitor BB-3497 are described. In this paper, we describe the initial SAR around this lead for modifications to the methylene spacer and the P1' side chain. Enzyme inhibition and antibacterial activity data revealed that the optimum distance between the N-formyl hydroxylamine metal binding group and the P1' side chain is one unsubstituted methylene unit. Additionally, lipophilic P1' side chains that closely mimic the methionine residue in the substrate provided compounds with the best microbiological profile.
authors.affiliation: British Biotech Pharmaceuticals Limited, Watlington Road, Oxford OX4 6LY, UK. stephen.davies@evotecoai.com
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Davies
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Ayscough
authors.forename: R Paul
authors.initials: RP
authors.lastname: Beckett
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Bragg
authors.forename: John M
authors.initials: JM
authors.lastname: Clements
authors.forename: Sheila
authors.initials: S
authors.lastname: Doel
authors.forename: Christine
authors.initials: C
authors.lastname: Grew
authors.forename: Steven B
authors.initials: SB
authors.lastname: Launchbury
authors.forename: Gemma M
authors.initials: GM
authors.lastname: Perkins
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Pratt
authors.forename: Helen K
authors.initials: HK
authors.lastname: Smith
authors.forename: Zoë M
authors.initials: ZM
authors.lastname: Spavold
authors.forename: S Wayne
authors.initials: SW
authors.lastname: Thomas
authors.forename: Richard S
authors.initials: RS
authors.lastname: Todd
authors.forename: Mark
authors.initials: M
authors.lastname: Whittaker
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006838:Hydrocarbons; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology; D019811:Hydroxylamine / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008670:Metals / Q000737:chemistry; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; C425109:BB3497; D004791:Enzyme Inhibitors; D006838:Hydrocarbons; D006877:Hydroxamic Acids; D008670:Metals; D009842:Oligopeptides; C030011:carbene; D019811:Hydroxylamine; D000581:Amidohydrolases; C084507:peptide deformylase; D008697:Methane