Synthesis and biological evaluation of new glutamic acid-based inhibitors of MurD ligase

Tihomir Tomasić; Nace Zidar; Veronika Rupnik; Andreja Kovac; Didier Blanot; Stanislav Gobec; Danijel Kikelj; Lucija Peterlin Masic

doi:10.1016/j.bmcl.2008.10.129

Synthesis and biological evaluation of new glutamic acid-based inhibitors of MurD ligase

Bioorg Med Chem Lett. 2009 Jan 1;19(1):153-7. doi: 10.1016/j.bmcl.2008.10.129. Epub 2008 Nov 5.

Authors

Tihomir Tomasić¹, Nace Zidar, Veronika Rupnik, Andreja Kovac, Didier Blanot, Stanislav Gobec, Danijel Kikelj, Lucija Peterlin Masic

Affiliation

¹ University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.

PMID: 19014883
DOI: 10.1016/j.bmcl.2008.10.129

Abstract

Mur ligases catalyze the biosynthesis of the UDP-MurNAc-pentapeptide precursor of peptidoglycan, an essential polymer of bacterial cell-wall. They constitute attractive targets for the development of novel antibacterial agents. Here we report on the synthesis of a series of 2,4-diaminoquinazolines, quinazoline-2,4(1H,3H)-diones, 5-benzylidenerhodanines and 5-benzylidenethiazolidine-2,4-diones and their inhibitory activities against MurD from Escherichia coli. Compounds (R)-27 and (S)-27 showed inhibitory activity against MurD with IC(50) values of 174 and 206 microM, respectively, which makes them promising starting points for optimization.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemical synthesis*
Anti-Bacterial Agents / pharmacology
Benzylidene Compounds / chemical synthesis
Benzylidene Compounds / pharmacology
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology
Escherichia coli / enzymology
Glutamic Acid
Inhibitory Concentration 50
Peptide Synthases / antagonists & inhibitors*
Quinazolines / chemical synthesis
Quinazolines / pharmacology

Substances

Anti-Bacterial Agents
Benzylidene Compounds
Enzyme Inhibitors
Quinazolines
Glutamic Acid
Peptide Synthases
UDP-N-acetylmuramoylalanine-D-glutamate ligase