Novel Naphthalene-N-sulfonyl-D-glutamic Acid Derivatives as Inhibitors of MurD, a Key Peptidoglycan Biosynthesis Enzyme

作者：Humljan Jan; Kotnik Miha; Contreras Martel Carlos; Blanot Didier; Urleb Uros; Dessen Andrea; Solmajer Tom; Gobec Stanislav^*

来源：Journal of Medicinal Chemistry, 2008, 51(23): 7486-7494.

DOI：10.1021/jm800762u

Mur ligases have essential roles in the biosynthesis of peptidoglycan, and they represent attractive targets for the design of novel antibacterials. MurD (UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase) is the second enzyme in the series of Mur ligases, and it catalyzes the addition Of D-glutamic acid (D-Glu) to the cytoplasmic intermediate UDP-N-acetylmuramoyl-L-alanine (UMA). Because of the high binding affinity Of D-Glu toward MurD, we synthesized and biochemically evaluated a series of N-substituted D-Glu derivatives as potential inhibitors of MurD from E. coli, which allowed us to explore the structure-activity relationships. The substituted naphthalene-N-sulfonyl-D-Glu inhibitors, which were synthesized as potential transition-state analogues, displayed IC(50) values ranging from 80 to 600,mu M. In addition, the high-resolution crystal structures of MurD in complex with four novel inhibitors revealed details of the binding mode of the inhibitors within the active site of MurD. Structure-activity relationships and cocrystal structures constitute an excellent starting point for further development of novel MurD inhibitors of this structural class.

• 出版日期2008-12-11
• 单位中国地震局