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.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Hydroxamic Acids/chemistry , Methane/analogs & derivatives , Anti-Bacterial Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Hydrocarbons , Hydroxamic Acids/pharmacology , Hydroxylamine/chemistry , Inhibitory Concentration 50 , Metals/chemistry , Methane/chemistry , Microbial Sensitivity Tests , Molecular Mimicry , Oligopeptides/chemistry , Oligopeptides/pharmacology , Structure-Activity RelationshipABSTRACT
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 both the P2' and P3' side chains. Enzyme inhibition and antibacterial activity data revealed that a variety of substituents are tolerated at the P2' and P3' positions of the inhibitor backbone. The data from this study highlights the potential for modification at the P2' and P3' positions to optimise the physicochemical properties.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Amines/chemistry , Amino Acids/chemistry , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Enzyme Inhibitors/pharmacology , Escherichia coli/drug effects , Hydroxamic Acids/chemical synthesis , Metals/chemistry , Microbial Sensitivity Tests , Molecular Mimicry , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Oligopeptides/pharmacology , Structure-Activity RelationshipABSTRACT
A series of analogues of the potent peptide deformylase (PDF) inhibitor BB-3497 containing alternative metal binding groups was synthesised. Enzyme inhibition and antibacterial activity data for these compounds revealed that the bidentate hydroxamic acid and N-formyl hydroxylamine structural motifs represent the optimum chelating groups on the pseudopeptidic BB-3497 backbone.
