A facile and efficient strategy to prepare drug derivatives with saccharides was developed, and 12 drug-saccharide conjugates were obtained by selective enzymatic synthesis methods. When the transesterification of chlorphenesin vinyl esters with glucose was chosen as a model reaction, the influence of reaction conditions was optimized. Then, we successfully prepared a series of chlorphenesin-saccharide derivatives of three monosaccharides (glucose, mannose and galactose) and three disaccharides (maltose, lactose and sucrose). In order to study the relationship between the solubility of drug-saccharide conjugates and the structure of parent drugs, five hydrophobic drugs (chlorphenesin, mephenesin, guaifenesin, propranolol and clorprenaline) were chosen as substrates to synthesize drug-saccharide conjugates. The results indicated that the aqueous solublity of drug-saccharide derivatives was greatly improved, which was changed by different saccharides and the structure of parent drugs. (C) 2007 Elsevier Inc. All rights reserved.