Structure-activity relationships of the peptide deformylase inhibitor BB-3497: modification of the methylene spacer and the P1' side chain.
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.
Davies
Stephen J
SJ
British Biotech Pharmaceuticals Limited, Watlington Road, Oxford OX4 6LY, UK. stephen.davies@evotecoai.com
Ayscough
Andrew P
AP
Beckett
R Paul
RP
Bragg
Ryan A
RA
Clements
John M
JM
Doel
Sheila
S
Grew
Christine
C
Launchbury
Steven B
SB
Perkins
Gemma M
GM
Pratt
Lisa M
LM
Smith
Helen K
HK
Spavold
Zoë M
ZM
Thomas
S Wayne
SW
Todd
Richard S
RS
Whittaker
Mark
M
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
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