Structure–activity relationships of the peptide deformylase inhibitor BB-3497: modification of the methylene spacer and the P1′ side chain

• Published in: Bioorganic & medicinal chemistry letters 2003-08, Vol.13 (16), p.2709-2713
• Main Authors: Davies, Stephen J., Ayscough, Andrew P., Beckett, R.Paul, Bragg, Ryan A., Clements, John M., Doel, Sheila, Grew, Christine, Launchbury, Steven B., Perkins, Gemma M., Pratt, Lisa M., Smith, Helen K., Spavold, Zoë M., Thomas, S.Wayne, Todd, Richard S., Whittaker, Mark
• Format: Article
• Language: English
• Subjects: Amidohydrolases - antagonists & inhibitors; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Hydrocarbons; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Hydroxylamine - chemistry; Inhibitory Concentration 50; Medical sciences; Metals - chemistry; Methane - analogs & derivatives; Methane - chemistry; Microbial Sensitivity Tests; Molecular Mimicry; Oligopeptides - chemistry; Oligopeptides - pharmacology; Pharmacology. Drug treatments; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00532-8

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. Structural modifications to the peptide deformylase inhibitor BB-3497 are described