5-Substituted deoxyuridines — Structural requirements for antiviral activity against herpes simplex virus types 1 and 2 and possible biochemical basis for relative potency

Abstract

A number of structurally related 5-substituted pyrimidine 2′-deoxyribonucleosides were tested for antiviral activity against herpes simplex virus types 1 and 2 in cell culture. A minimum inhibitory concentration was determined for each compound and from a comparison of these values a number of conclusions were drawn with regard to those molecular features which enhance or reduce antiviral activity. Analogues in which the 5-substituent was unsaturated and conjugated with the pyrimidine ring were more potent antiviral drugs than the corresponding non-conjugated and alkyl-substituted analogues. The length of the 5-substituent and the nature of any heteroatoms contained within it also affected antiviral activity. When one pair of isomers was examined in more detail, differences in antiviral activity similar to those observed in cell culture occurred in virus-infected mice. The biochemical basis for the greater antiviral activity of the preferred isomer was related to affinity both for virus thymidine kinase and virus DNA polymerase.