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The potencies of several alkoxyalkyl esters of acyclic nucleoside phosphonates against vaccinia virus and cowpox virus were evaluated in cell monolayers and three-dimensional epithelial raft cultures. Prodrugs were at least 20-fold more active than their parent compounds. Octadecycloxyethyl-(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine emerged as the most potent derivative.Smallpox has been declared eradicated since 1980 (5). However, due to the potential threat of variola virus as a weapon for bioterrorism (4) and the increasing number of infections with monkeypox virus (11), it is essential that adequate antiviral drugs be developed. Cidofovir (CDV) has already proven to be active against orthopoxviruses (9,10,14,16,18). However, this drug needs to be administered intravenously and is potentially nephrotoxic. Recently, it was shown that alkoxyalkyl and alkyl esters of CDV and cyclic cidofovir (cCDV) were more active against vaccinia virus (VV) and cowpox virus (CPV) in human foreskin fibroblasts than their parent compounds due in part to an increased penetration through the cell membrane (13,15). In vivo studies indicate that the prodrugs are highly orally bioavailable and are as effective as parenterally administered CDV for the treatment of VV-or CPV-infected mice (6,7,17).The activities of various alkoxyalkyl esters of the acyclic nucleoside phosphonate (ANP) analogues CDV [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine; HPMPC; Vistide], e Selectivity index (ratio of CC 50 to EC 50 ).

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