Novel 2-thioxothiazolidin-4-one inhibitors of bacterial MurD ligase targeting d-Glu- and diphosphate-binding sites

• Published in: European journal of medicinal chemistry 2011-09, Vol.46 (9), p.3964-3975
• Main Authors: Tomašić, Tihomir, Kovač, Andreja, Simčič, Mihael, Blanot, Didier, Grdadolnik, Simona Golič, Gobec, Stanislav, Kikelj, Danijel, Peterlin Mašič, Lucija
• Format: Article
• Language: English
• Subjects: 2-Thioxothiazolidin-4-one; Antibacterial agent; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Binding Sites; Biological and medical sciences; Catalytic Domain; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Escherichia coli - enzymology; Glutamic acid; Inhibitor; Inhibitory Concentration 50; Medical sciences; Models, Molecular; Mur ligase; Nuclear Magnetic Resonance, Biomolecular; Peptide Synthases - antagonists & inhibitors; Peptide Synthases - metabolism; Pharmacology. Drug treatments; Protein NMR; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Infrared; Thiazolidines - chemistry; Thiazolidines - metabolism; Thiazolidines - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.05.070

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 IC 50 values of 45 μM and 10 μM, respectively. The specific binding mode of ( R)- 9 in MurD active site was established by high-resolution NMR spectroscopy. [Display omitted] ► A new series of thiazolidin-4-ones incorporating glutamic acid as MurD ligase inhibitors was designed and synthesized. ► New low micromolar inhibitors of Escherichia coli MurD ligase were discovered. ► Structure–activity relationship was discussed. ► Binding mode of inhibitor was established by high-resolution NMR spectroscopy.