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

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 μM and 10 μM, respectively. The specific binding mode of (R)-9 in MurD active site was established by high-resolution NMR spectroscopy.

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► 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.