Peptide deformylase inhibitors with retro-amide scaffold: synthesis and structure-activity relationships.
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.
Lee
Seung Kyu
SK
Promeditech Ltd., College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
Choi
Kwang Hyun
KH
Lee
Sang Jae
SJ
Suh
Se Won
SW
Kim
B Moon
BM
Lee
Bong Jin
BJ
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship
D000577:Amides; D000900:Anti-Bacterial Agents; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D000581:Amidohydrolases; C084507:peptide deformylase; C010531:actinonin