Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 46, Issue 9, Pages 3964-3975Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2011.05.070
Keywords
Antibacterial agent; Glutamic acid; Inhibitor; Mur ligase; Protein NMR; 2-Thioxothiazolidin-4-one
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Funding
- EU [LSHM-CT-2004-512138]
- Slovenian Research Agency [P1-0208]
- World Federation of Scientists
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Mur ligases are involved in cytoplasmic steps of bacterial peptidoglycan biosynthesis and are viable targets for antibacterial drug discovery. We have designed and synthesized a focused chemical library of compounds combining the glutamic acid moiety and the 2-thioxothiazolidin-4-one, thiazolidine-2,4-dione, 2-iminothiazolidin-4-one or imidazolidine-2,4-dione ring connected by a benzylidene group. These compounds were designed to target the D-Glu- and the diphosphate-binding pockets of the MurD active site and were evaluated for inhibition of MurD ligase from Escherichia coli. The most potent compounds (R)-9 and (S)-9 inhibited MurD with IC50 values of 45 mu M and 10 mu M, respectively. The specific binding mode of (R)-9 in MurD active site was established by high-resolution NMR spectroscopy. (C) 2011 Elsevier Masson SAS. All rights reserved.
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