A series of 5-substituted 2'-deoxy-4'-thiopyrimidine nucleosides was synthesized and evaluated as potential antiviral agents. A number of analogues such as 2'-deoxy-5-propyl-4'-thiouridine (3ii), 2'-deoxy-5-isopropyl-4'-thiouridine (3iii), 5-cyclopropyl-2'-deoxy-4'-thiouridine (3iv), 2'-deoxy-4'-thio-5-vinyluridine (3viii), and 5-(2-chloroethyl)-2'-deoxy-4'-thiouridine (3xx) were found to be highly active against herpes simplex virus type-1 (HSV-1) and varicella zoster virus (VZV) in vitro with no significant cytotoxicity. The compound with the broadest spectrum of activity was 2'-deoxy-5-ethyl-4'-thiouridine (3i) which showed significant activity against HSV-1, HSV-2, and VZV.

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The antiviral activity of several nucleoside analogues is often limited by their rapid degradation by pyrimidine nucleoside phosphorylases. In an attempt to avoid this degradation, several modified nucleosides have been synthesized. A series of 4h-thio2h-deoxyuridines exhibits an anti-[herpes simplex virus (HSV)] activity significantly higher (20-600 times) than that shown by the corresponding 4h-oxy counterpart. We investigated the mode of action of these compounds and we found that : (i) several 4h-thio-2h-deoxyuridines are phosphorylated to the mono-and diphosphates by HSV-1 thymidine kinase (TK) more efficiently than their corresponding 4h-oxy counterpart ; (ii) both are inhibitors of cellular thymidylate synthase ; (iii) 4h-thio-2h-deoxyuridines are resistant to phosphorolysis by human thymidine phosphorylase ; (iv) both 4h-oxy-and 4h-thio-2h-deoxyuridines are phosphorylated to deoxyribonucleotide triphosphate in HSV-1-infected cells and are incorporated into viral DNA ; (v) 4h-thio-

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