Antiherpes activity of (E)-5-(2-bromovinyl)- and 5-vinyl-1-β-D-arabinofuranosyluracil and some other 5-substituted uracil arabinosyl nucleosides in two different cell lines

Of a series of 5-substituted 1-β-d-arabinofuranosyluracil (5-X-araU)analogues, (E)-5-(2-bromovinyl)-araU(BrVaraU)and 5-vinyl-araU(VaraU) were the most potent inhibitors of plaque formation by two herpes simplex virus type 1(HSV-1)strains in human embryonic lung fibroblast(HELF)cell cultures. They were not only more active than 5-methyl-araU (MaraU, araT)and 5-ethyl-araU (EaraU), but even more than 1000 times more potent than the 5-fluoro, 5-iodo, 5-formyl and 5-trifluoromethyl (FaraU, IaraU, faraU, CF3araU) analogues. BrVaraU and VaraU were superior to 9-(2-hydroxyethoxymethyl)guanine(Acyclovir, ACV)and comparable in potency with 2t-fluoro-5-iodoaracytosine(FIAC)and 2t-fluoro-5-methylarauracil(FMAU). Their anti-HSV-1 potency was surpassed only by (E)-5-(2-bromovinyl)-2t-deoxyuridine dine (BrVUdR). Surprisingly, in a HSV-1 plaque inhibition assay in African green monkey kidney (Vero) cells, BrVaraU and VaraU were nearly 100 times less active or even inactive. In contrast, the antiherpes activity of ACV, FIAC, FMAU and BrVUdR differed only marginally in the two cell lines. The following order of (decreasing) activity against HSV-2 in HELF cells was found: FIAC = FMAU MaraU(araT) ACV VaraU BrVUdR CF3araU IaraU FaraU = EaraU BrVaraU araU faraU. When deoxyribose is replaced by arabinose in 5-X-UdR analogues, a slight increase in anti-HSV-1-77 activity was observed for the 5-vinyl or 5-ethyl substituent, whereas the other 5-X-araU nucleosides were two to more than 100 times less active than their deoxyribosyl counterparts. However, the sugar exchange led to a strong reduction in anti-HSV-2 activity regardless of the 5-substituent.