Synthesis of 5-[(methylthio)methyl]-2'-deoxyuridine, the corresponding sulfoxide and sulfone, and their 5'-phosphates: antiviral effects and thymidylate synthetase inhibition

Abstract

Substitution on the .alpha. position of thymidine with methylthio (3) and methylsulfonyl (5) groups gave antiviral agents that were specific and relatively nontoxic inhibitors of herpes simplex virus replication in cell culture. The thioether (3) was effective against types 1 and 2 of herpes simplex virus, while the activity of the sulfone derivative (5) was restricted to herpes simples virus type 1. The sulfoxide derivative 1-(2-deoxy-.beta.-D-ribofuranosyl)-.alpha.-(methylsulfinyl)thymine (4) was inactive as an antiviral agent. The 5''-phosphates of these three thymidine derivatives were relatively potent inhibitors of thymidylate synthetase (Ki values range from 7.8-1.9 .mu.M). It is improbable that the inhibition of this enzyme accounts for the anti-herpes activity of compounds 3 and 5.