Document Detail


Synthesis and evaluation of 3-(dihydroxyboryl)benzoic acids as D,D-carboxypeptidase R39 inhibitors.
MedLine Citation:
PMID:  19731939     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Penicillin binding proteins (PBPs) catalyze steps in the biosynthesis of bacterial cell walls and are the targets for the beta-lactam antibiotics. Non-beta-lactam based antibiotics that target PBPs are of interest because bacteria have evolved resistance to the beta-lactam antibiotics. Boronic acids have been developed as inhibitors of the mechanistically related serine beta-lactamases and serine proteases; however, they have not been explored extensively as PBP inhibitors. Here we report aromatic boronic acid inhibitors of the D,D-carboxypeptidase R39 from Actinomadura sp. strain. Analogues of an initially identified inhibitor [3-(dihydroxyboryl)benzoic acid 1, IC(50) 400 microM] were prepared via routes involving pinacol boronate esters, which were deprotected via a two-stage procedure involving intermediate trifluorborate salts that were hydrolyzed to provide the free boronic acids. 3-(Dihydroxyboryl)benzoic acid analogues containing an amide substituent in the meta, but not ortho position were up to 17-fold more potent inhibitors of the R39 PBP and displayed some activity against other PBPs. These compounds may be useful for the development of even more potent boronic acid based PBP inhibitors with a broad spectrum of antibacterial activity.
Authors:
Steven R Inglis; Astrid Zervosen; Esther C Y Woon; Thomas Gerards; Nathalie Teller; Delphine S Fischer; André Luxen; Christopher J Schofield
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  52     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2009 Oct 
Date Detail:
Created Date:  2009-10-01     Completed Date:  2009-11-17     Revised Date:  2011-12-01    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6097-106     Citation Subset:  IM    
Affiliation:
Department of Chemistry, University of Oxford, Oxford, UK.
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MeSH Terms
Descriptor/Qualifier:
Actinomycetales / enzymology
Anti-Bacterial Agents / chemical synthesis*,  pharmacology
Bacterial Proteins / antagonists & inhibitors
Benzoic Acid / chemical synthesis,  pharmacology*
Boronic Acids
Carboxypeptidases / antagonists & inhibitors*
Enzyme Inhibitors / chemical synthesis,  pharmacology
Inhibitory Concentration 50
Structure-Activity Relationship
Grant Support
ID/Acronym/Agency:
03/08-297//Arthritis Research UK
Chemical
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Bacterial Proteins; 0/Boronic Acids; 0/Enzyme Inhibitors; 65-85-0/Benzoic Acid; EC 3.4.-/Carboxypeptidases

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


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