Synthesis of sub-micromolar inhibitors of MraY by exploring the region originally occupied by the diazepanone ring in the liposidomycin structure.
The synthesis and inhibitory activity against MraY of a series of simplified analogues of liposidomycins are described. These compounds were mainly obtained by performing parallel synthesis in the 6'-position of a scaffold that gathers key features found necessary for the binding to MraY. Thus, inhibitory activity was improved from 5300 to 140 nM. This improvement was correlated with the length and lipophilicity of substituents, but was found to be independent of the nature of the chemical bond generated. In addition, some of these inhibitors presented encouraging antibacterial activities.
Dini
C
C
Aventis Pharma, Paris Research Centre, 102 route de Noisy, 93235 Cedex, Romainville, France. christophe.dini@aventis.com
Didier-Laurent
S
S
Drochon
N
N
Feteanu
S
S
Guillot
J C
JC
Monti
F
F
Uridat
E
E
Zhang
J
J
Aszodi
J
J
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001381:Azepines / Q000737:chemistry*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D014166:Transferases; D017855:Transferases (Other Substituted Phosphate Groups)
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D001381:Azepines; D001426:Bacterial Proteins; C047544:liposidomycins; D014166:Transferases; D017855:Transferases (Other Substituted Phosphate Groups); C079803:mraY protein, Bacteria