Peptide deformylase inhibitors with retro-amide scaffold: Synthesis and structure–activity relationships

• Published in: Bioorganic & medicinal chemistry letters 2010-08, Vol.20 (15), p.4317-4319
• Main Authors: Lee, Seung Kyu, Choi, Kwang Hyun, Lee, Sang Jae, Suh, Se Won, Kim, B. Moon, Lee, Bong Jin
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Amidohydrolases - antagonists & inhibitors; Amidohydrolases - metabolism; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial; Antibacterial activity; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Binding Sites; Biological and medical sciences; Crystallography, X-Ray; Cyclopentanes - chemical synthesis; Cyclopentanes - chemistry; Cyclopentanes - pharmacology; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Haemophilus influenzae; Hydroxamic Acids - pharmacology; Medical sciences; Microbial Sensitivity Tests; PDF; Pharmacology. Drug treatments; Retro-amide; SAR; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.06.088

The synthesis and structure–activity relationship studies of peptide deformylase inhibitor 7a are reported. Peptide deformylase (PDF) is a metalloprotease catalyzing the removal of a formyl group from newly synthesized proteins. Thus inhibition of PDF activity is considered to be one of the most effective antibiotic strategies. Reported herein are the synthesis and structure–activity relationship studies of retro-amide inhibitors based on actinonin, a naturally occurring PDF inhibitor. Analysis of the structure–activity relationships led to the discovery of 7a, which exhibits potent enzyme inhibition and antibacterial activity against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.