A modified vancomycin binding pocket (D-O-E ring) incorporating a CHNHCOR function at the AA4 position is designed and synthesized. Potent bioactivities against both sensitive- and resistant-strain are found for some of these compds. (MIC 4 micro g/mL against VREF). From this preliminary SAR studies, it was speculated that the D-Ala-D-Ala binding was required for this series of compds. since the corresponding des-leucine deriv. is inactive. The presence of long aliph. chain was important for the desired activities and such hydrophobic effect is specific as no beneficial effect is obsd. when the same aliph. chain was attached to the other part of the mol. [on SciFinder (R)]