New 5-benzylidenethiazolidin-4-one inhibitors of bacterial MurD ligase: design, synthesis, crystal structures, and biological evaluation
Zidar, Nace (Author), Tomašič, Tihomir (Author), Šink, Roman (Author), Kovač, Andreja (Author), Patin, Delphine (Author), Blanot, Didier (Author), Contreras-Martel, Carlos (Author), Dessen, Andréa (Author), Müller-Premru, Manica (Author), Zega, Anamarija (Author), Gobec, Stanislav (Author), Peterlin-Mašič, Lucija (Author), Kikelj, Danijel (Author)

URLURL - Presentation file, Visit http://www.sciencedirect.com/science/article/pii/S0223523411006775 This link opens in a new window

Mur ligases (MurCeMurF), 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 IC50 values up to 28 mM. Inhibitor 37, with an IC50 of 34 mM, displays a weak antibacterial activity against S. aureus ATCC 29213 and E. faecalis ATCC 29212 with minimal inhibitory concentrations of 128 mg/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.

Keywords:MurD ligaze, biosinteza peptidoglikana, inihbitorji, 5-benzilrodanin
Work type:Not categorized (r6)
Tipology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Number of pages:str. 5512-5523
Numbering:Vol. 46, issue 11
ISSN on article:0223-5234
DOI:10.1016/j.ejmech.2011.09.017 Link is opened in a new window
COBISS.SI-ID:3107953 Link is opened in a new window
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Record is a part of a journal

Title:European journal of medicinal chemistry
Shortened title:Eur. j. med. chem.
COBISS.SI-ID:25429760 This link opens in a new window

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