| Abstract: | 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. |
