RESUMEN
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.
Asunto(s)
Aminoglicósidos , Antibacterianos/farmacología , Azepinas/química , Proteínas Bacterianas/antagonistas & inhibidores , Transferasas , Antibacterianos/química , Transferasas (Grupos de Otros Fosfatos Sustitutos)RESUMEN
O-beta-D-ribofuranosyl nucleoside I is the minimal structural entity of liposidomycins that maintains enzyme inhibitory activity on MraY. A set of compounds with hydroxyl patterns different from I has been synthesized. The presence of a hydroxyl group in the 3" position is essential for the activity. The 3'-deoxy derivative (IV), however, shows a 5-fold improved potency.
Asunto(s)
Aminoglicósidos , Antibacterianos/síntesis química , Proteínas Bacterianas/antagonistas & inhibidores , Transferasas , Antibacterianos/farmacología , Relación Estructura-Actividad , Transferasas (Grupos de Otros Fosfatos Sustitutos)RESUMEN
The O-beta-D-ribofuranosyl nucleoside I is the minimal structural entity of liposidomycins maintaining enzyme inhibitory activity. Modifications performed on both the primary amine and the uracil moieties clearly demonstrate their major contribution to the inhibition of the bacterial translocase (MraY).
Asunto(s)
Aminoglicósidos , Antibacterianos/síntesis química , Proteínas Bacterianas/antagonistas & inhibidores , Transferasas , Antibacterianos/farmacología , Relación Estructura-Actividad , Transferasas (Grupos de Otros Fosfatos Sustitutos) , UraciloRESUMEN
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).