Synthesis and antiviral activity of 5-ethyl-5-halo-6-alkoxy-(or azido)-5,6-dihydro-2'-deoxyuridine diastereomers as potential prodrugs to 5-ethyl-2'-deoxyuridine.

A group of 5-ethyl-5-halo-6-alkoxy (or azido)-5,6-dihydro-2'-deoxyuridines, which differ in configuration at the C-5 and C-6 positions, were synthesized by the regiospecific addition of XR (X = I, Br, Cl; R = alkoxyl, azido) to the 5,6-olefinic bond of 5-ethyl-2'-deoxyuridine (EDU). In vitro antiviral (HSV-1, HSV-2, HCMV, VZV) activities were determined. Structure-activity studies showed that the C-5 halogeno (I, Br, Cl) and C-6 alkoxy (OMe, OEt) or azido, substituents were determinants of antiviral activity where the (5R,6R)-5 and (5S,6S)-6 diastereomers of 5-ethyl-5-iodo-6-methoxy-5,6-dihydro-2'-deoxyuridine exhibited greater potency against HSV-1, HSV-2, and HCMV than the related 5-chloro-6-ethoxy and 5-bromo (or chloro)-6-azido diastereomers. The most potent antiviral agents, (+)-trans-(5R,6R)-5 and (-)-trans-(5S,6S)-6 diastereomers of 5-ethyl-5-iodo-6-methoxy-5,6-dihydro-2'-deoxyuridine were approximately 2-to-8 fold more potent than the reference drug EDU against HSV-1 and HSV-2.