Diazenedicarboxamides as inhibitors of d-alanine-d-alanine ligase (Ddl)

d-Alanine-d-alanine ligase (Ddl) catalyzes the biosynthesis of an essential bacterial peptidoglycan precursor d-alanyl-d-alanine and it represents an important target for development of new antibacterial drugs. A series of semicarbazides, aminocarbonyldiazenecarboxylates, diazenedicarboxamides, and hydrazinedicarboxamides was synthesized and screened for inhibition of DdlB from Escherichia coli. Compounds with good inhibitory activity were identified, enabling us to deduce initial structure–activity relationships. Thirteen diazenedicarboxamides were better inhibitors than d-cycloserine and some of them also possess antibacterial activity, which makes them a promising starting point for further development.

Graphical abstractA series of new inhibitors of the d-alanine-d-alanine ligase (Ddl) is presented. Thirteen diazenedicarboxamides were better inhibitors than d-cycloserine, and some of them also possess antibacterial activity, which makes them a promising starting point for further development.Figure optionsDownload full-size imageDownload as PowerPoint slide