S-Acylthioethyl prodrugs of phosphonoformate

Due to its highly ionic nature, the antiviral phosphonoformate shows poor penetration into cells and here bioreversible prodrugs of phosphonoformate are designed in an attempt to improve its transport properties. The key step in the syntheses of tri[2-(S-acylthio)ethyl] esters of phosphonoformate 9 was the reaction between bis[2-(S-acylthio)ethyl] phosphite and 2-(S-acylthio)ethyl chloroformate in the presence of N,O-bis(trimethylsilyl)acetamide. The water soluble di[2-(S-acylthio)ethyl] esters 10 were prepared by reaction of the triesters 9 with sodium iodide. The diesters 10 showed comparable activity to phosphonoformate against herpes simplex virus-1 (HSV-1) in cell cultures, this result being consistent with their cleavage to phosphonoformate observed in rat tissue. However, phosphonoformate could not be detected in plasma following oral administration of the triesters 9 and diesters 10 to rats.