Document Detail

Macrocyclic inhibitors for peptide deformylase: a structure-activity relationship study of the ring size.
MedLine Citation:
PMID:  15369398     Owner:  NLM     Status:  MEDLINE    
Peptide deformylase (PDF) catalyzes the removal of the N-terminal formyl group from newly synthesized polypeptides in eubacteria. Its essential role in bacterial cells but not in mammalian cells makes it an attractive target for antibacterial drug design. We have previously reported an N-formylhydroxylamine-based, metal-chelating macrocyclic PDF inhibitor, in which the P(1)' and P(3)' side chains are covalently joined. In this work, we have carried out a structure-activity relationship study on the size of the macrocycle and found that 15-17-membered macrocycles are optimal for binding to the PDF active site. Unlike the acyclic compounds, which are simple competitive inhibitors, the cyclic compounds all act as slow-binding inhibitors. As compared to their acyclic counterparts, the cyclic inhibitors displayed 20-50-fold higher potency against the PDF active site (K(I) as low as 70 pM), improved selectivity toward PDF, and improved the metabolic stability in rat plasma. Some of the macrocyclic inhibitors had potent, broad spectrum antibacterial activity against clinically significant Gram-positive and Gram-negative pathogens. These results suggest that the macrocyclic scaffold provides an excellent lead for the development of a new class of antibiotics.
Xubo Hu; Kiet T Nguyen; Vernon C Jiang; Denene Lofland; Heinz E Moser; Dehua Pei
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  47     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2004 Sep 
Date Detail:
Created Date:  2004-09-16     Completed Date:  2004-11-01     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4941-9     Citation Subset:  IM    
Department of Chemistry and Ohio State Biochemistry Program, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210, USA.
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MeSH Terms
Amidohydrolases / antagonists & inhibitors*,  chemistry,  metabolism
Anti-Bacterial Agents / chemistry*,  pharmacology*
Binding Sites
Drug Evaluation, Preclinical / methods
Drug Stability
Enzyme Inhibitors / chemistry*,  pharmacology*
Heterocyclic Compounds / chemistry*
Microbial Sensitivity Tests
Structure-Activity Relationship
Grant Support
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Enzyme Inhibitors; 0/Heterocyclic Compounds; EC 3.5.-/Amidohydrolases; EC deformylase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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