The involvement of central nervous system (CNS) particularly the cerebrospinal fluids and brain capillary endothelial cell (blood- brain barrier) in the pathogenesis of both DNA viruses like herpes simplex and RNA viruses like human immunodeficiency virus has been documented. Therefore, successful treatment of such neurotropic viral infections would require the delivery of antiviral agents to the CNS. However, clinically useful thymidine analogs like 5-iodo-2'-deoxy uridine (IDU) do not readily undergo transcellular transport across lipoidal brain capillary endothelium because of it polar character (due mainly to the presence of -OH groups). Moreover, the thymidine analogs can not be transported across the blood-brain-barrier by specific carrier-mediated processes because no such system is available for pyrimidine nucleosides like thymidine and cytosine. The proposed project aims at developing strategies for delivering thymidine analogs across brain capillary endothelium to the brain parenchyma by using latentiated derivatives. Using IDU as the model compound, as series of novel 5'-esters including acetyl, propionyl, butyryl, isopropyl, pivaloyl, beta-chloropivaloyl, octanoyl, palmitoyl, 1-adamantoyl, benzoyl, p-methoxy and p- chloro benzoyl, 3-quinuclidinyl, cyclobutyl and cyclohexyl derivatives will be prepared and examined for their effectiveness in enhancing brain levels of IDU. These fifteen 5'-ester derivatives have been selected for their wide range of lipophilicities and structural specificities for esterases. The latentiated analogues will undergo appreciable transport (compared to IDU itself) across the blood-brain barrier and subsequently be bioconverted to IDU by brain capillary endothelial as well as brain parenchymal esterases. In-vitro rat brain homogenate as well as plasma hydrolysis studies will provide information on the rate of bioconversion of the 5'-esters in brain parenchyma in relation to plasma. In-vivo measurements of actual brain levels of 5'-ester and IDU at different time points following intravenous injection of the 5'-esters will provide information on the pharmacokinetics of these derivatives in the brain tissue. Information on the rate of production and elimination of IDU from the brain will serve as an important tool for future brain specific analogue designated.