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

Abstract

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.