S-ACYLTHIOETHYL PRODRUGS OF PHOSPHONOFORMATE

Due to its highly ionic nature, the antiviral phosphonoformate shows p oor penetration into cells and here bioreversible prodrugs of phosphon oformate are designed in an attempt to improve its transport propertie s. 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)ethy l] 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 r at tissue. However, phosphonoformate could not be detected in plasma f ollowing oral administration of the triesters 9 and diesters 10 to rat s. (C) 1997 Elsevier Science Ireland Ltd.