Aciclovir contains several polar functional groups that can participate in hydrogen bonding. As a result, the drug is quite polar and this hinders its passagethe fatty cell membranes of the cells lining the gut wall.
One way of solving this problem would be to mask a polar group such that the molecule is less polar and can cross cell membranes more easily. The group used to mask the polar group would have to be easily removed by a metabolic reaction in order to release the active drug once it has been absorbed. There are two accessible functional groups which could be masked - the amine or the alcohol. One could mask the amine as an amide or the alcohol as an ester. Masking the alcohol is the better option since it is well known that esters are easily cleaved by esterases in the blood. Esters are also more susceptible to hydrolysis than amides. A variety of ester prodrugs could be tried out to find the best. It is also worth considering what will be released from the drug when the ester is hydrolysed. Preferably, this should be a naturally occurring chemical such as an amino acid