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.
Kovac
Andreja
A
University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, Slovenia.
Majce
Vita
V
Lenarsic
Roman
R
Bombek
Sergeja
S
Bostock
Julieanne M
JM
Chopra
Ian
I
Polanc
Slovenko
S
Gobec
Stanislav
S
D000244:Adenosine Diphosphate / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry; D002384:Catalysis; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray; D003523:Cycloserine / Q000737:chemistry; D015195:Drug Design; D004926:Escherichia coli / Q000378:metabolism; D007094:Imides / Q000737:chemistry* / Q000494:pharmacology; D008956:Models, Chemical; D008968:Molecular Conformation; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation
D000900:Anti-Bacterial Agents; D002264:Carboxylic Acids; D007094:Imides; D000244:Adenosine Diphosphate; D003523:Cycloserine; D010453:Peptide Synthases; C019638:D-alanylalanine synthetase; C038867:diazene