SYNTHESIS AND ANTIVIRAL ACTIVITY OF -ETHYL-5-HALO-6-ALKOXY-5,6-DIHYDRO-2'-DEOXYURIDINE OR 5-ETHYL-5-HALO-6-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'-deoxyuri dines, which differ in configuration at the C-5 and C-6 positions, wer e 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 (E DU). In vitro antiviral (HSV-1, HSV-2, HCMV, VZV) activities were dete rmined. Structure-activity studies showed that the C-5 halogeno (I, Br , Cl) and C-6 alkoxy (OMe, OEt) or azido, substituents were determinan ts of antiviral activity where the (5R,6R)-5 and (5S,6S)-6 diastereome rs of ethyl-5-iodo-6-methoxy-5,6-dihydro-2'-deoxyuridine exhibited gre ater 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 poten t antiviral agents, (+)-trans-( 5R,6R)-5 and (-)-trans-(5S,6S)-6 diast ereomers of ethyl-5-iodo-6-methoxy-5,6-dihydro-2'-deoxyuridine were ap proximately 2-to-8 fold more potent than the reference drug EDU agains t HSV-1 and HSV-2.