Synthesis of the nucleoside moiety of liposidomycins: elucidation of the pharmacophore of this family of MraY inhibitors.
Tunicamycins (TCMs) and liposidomycins (LPMs) are naturally occurring inhibitors of the bacterial translocase (MraY). Based on structure-activity relationship (SAR) studies, a molecular model has been proposed for their inhibitory mechanism. This study points out the importance of the nucleoside moiety of liposidomycins in the inhibition of MraY. A simplified molecule (I) based on the liposidomycin core structure has been synthesised and tested on MraY. The compound displayed a moderate inhibitory activity (IC50 = 50 microM). The validation of the molecular model was then performed by synthesising higher homologues of I, containing an additional stereocentre in the 5' position (XIV and XV). In agreement with the prediction, only the (S) isomer XV showed significant activity against MraY (IC50 = 5 microM).
Dini
C
C
Medicinal Chemistry Department. Hoechst Marion Roussel/Aventis, Romainville, France. christophe.dini@aventis.com
Collette
P
P
Drochon
N
N
Guillot
J C
JC
Lemoine
G
G
Mauvais
P
P
Aszodi
J
J
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001412:Bacillus subtilis / Q000201:enzymology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014166:Transferases / Q000037:antagonists & inhibitors*; D017855:Transferases (Other Substituted Phosphate Groups); D014529:Uridine / Q000138:chemical synthesis / Q000737:chemistry*
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; C047544:liposidomycins; D014166:Transferases; D017855:Transferases (Other Substituted Phosphate Groups); C079803:mraY protein, Bacteria; D014529:Uridine