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 inhib itors of the bacterial translocase (MraY). Based on structure-activity rela tionship (SAR) studies, a molecular model has been proposed for their inhib itory mechanism. This study points out the importance of the nucleoside moi ety of liposidomycins in the inhibition of MraY. A simplified molecule (I) based on the liposidomycin core structure has been synthesised and tested o n MraY. The compound displayed a moderate inhibitory activity (IC50-50 mu M ). The validation of the molecular model was then performed by synthesising higher homologues of I, containing an additional stereocentre in the 5' po sition (XIV and XV). In agreement with the prediction, only the (S) isomer XV showed significant activity against MraY (IC50=5 mu M). (C) 2000 Elsevie r Science Ltd. All rights reserved.