Document Detail

New 5-benzylidenethiazolidin-4-one inhibitors of bacterial MurD ligase: Design, synthesis, crystal structures, and biological evaluation.
MedLine Citation:
PMID:  21963114     Owner:  NLM     Status:  Publisher    
Mur ligases (MurC-MurF), a group of bacterial enzymes that catalyze four consecutive steps in the formation of cytoplasmic peptidoglycan precursor, are becoming increasingly adopted as targets in antibacterial drug design. Based on the crystal structure of MurD cocrystallized with thiazolidine-2,4-dione inhibitor I, we have designed, synthesized, and evaluated a series of improved glutamic acid containing 5-benzylidenerhodanine and 5-benzylidenethiazolidine-2,4-dione inhibitors of MurD with IC(50) values up to 28μM. Inhibitor 37, with an IC(50) of 34μM, displays a weak antibacterial activity against S. aureus ATCC 29213 and E. faecalis ATCC 29212 with minimal inhibitory concentrations of 128μg/mL. High-resolution crystal structures of MurD in complex with two new inhibitors (compounds 23 and 51) reveal details of their binding modes within the active site and provide valuable information for further structure-based optimization.
Nace Zidar; Tihomir Tomašić; Roman Sink; Andreja Kovač; Delphine Patin; Didier Blanot; Carlos Contreras-Martel; Andréa Dessen; Manica Müller Premru; Anamarija Zega; Stanislav Gobec; Lucija Peterlin Mašič; Danijel Kikelj
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-9-17
Journal Detail:
Title:  European journal of medicinal chemistry     Volume:  -     ISSN:  1768-3254     ISO Abbreviation:  -     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-10-3     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0420510     Medline TA:  Eur J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011. Published by Elsevier Masson SAS.
Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia.
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