Structural requirements of olefinic 5-substituted deoxyuridines for antiherpes activity

A number of structurally related 5-substituted pyrimidine 2'-deoxyribonucleosides were synthesized and tested for antiviral activity against herpes simplex virus type 1 (HSV-1) 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 that enhance or reduce antiviral activity. Optimum inhibition of HSV-1 in cell culture occurred when the 5-substituent was unsaturated and conjugated with the pyrimidine ring, was not longer than four carbon atoms in length, had E stereochemistry, and included a hydrophobic, electronegative function but did not contain a branching point. Such features are contained in (E)-5-(2-bromovinyl)-2'-deoxyuridine, which was the most active of the compounds described.