STRUCTURE-ACTIVITY RELATIONSHIP OF THE AFFINITY OF 5-SUBSTITUTED URACIL NUCLEOSIDE ANALOGS FOR VARICELLA-ZOSTER VIRUS THYMIDINE KINASE AND THEIR ACTIVITY AGAINST VARICELLA-ZOSTER VIRUS

We investigated structure-activity relationships of 5-substituted urac il nucleoside analogues for their selective antiviral activity against varicella-zoster virus (VZV) and affinity for VZV thymidine kinase (T K). Anti-proliferative activity of the compounds was measured using hu man lymphoblastoid cells. Most 2'-deoxyribofuranosyluracil, arabinofur anosyluracil (araU) and 2'-deoxy-2'-fluoro-arabinofuranosyluracil deri vatives showed selective anti-VZV activity as well as activity against herpes simplex virus types 1 and 2 2'-Deoxyuridine derivatives showed higher affinity than the corresponding araU analogues. A correlation was seen between the 50% effective doses for VZV and the K-i values fo r VZV TK, except for 5-ethyl-2'-deoxyuridine and 5-ethyl araU that sho wed relatively high affinity for VZV TK without showing any activity a gainst VZV. 5-Halogenovinyluracil nucleosides showed the highest affin ity and the most potent and selective anti-VZV activity. 2'-Deoxy-2'-f luoro-arabinofuranosyluracil derivatives exhibited high anti-VZV poten cy though they showed relatively low affinity for VZV TK. Some 3'-deox ythymidine analogues having anti-human immunodeficiency virus activity were :inactive against herpesviruses. (C) 1997 Elsevier Science B.V.