The preparations and antiviral activities of a series (4-17) of potential prodrug forms of the antivirals 2',3'-didehydro-2',3'-dideoxyadenosine (D4A) and 2',3'-didehydro-2',3'-dideoxycytosine (D4C) are reported. The 5'-phenyl- and 5'-methylphosphonates (4, 6, 8, and 10) and their phosphonothionate congeners (5, 7, 9, and 11), with the exception of 10, were inactive in vitro against HIV-1 and HIV-2. However, the 5'-phenyl, 5'-methyl, and 5'-(3'-thymidyl) phosphate diesters (12-17) demonstrated inhibition of the cytopathic effect of HIV-1 and HIV-2 (EC50 approximately 1-60 microM) and cytotoxicities (CC50 approximately 35-200 microM) at concentration levels comparable to those of their parent compounds, D4A and D4C. This strongly suggests that the diesters are hydrolyzed to the nucleosides D4A and D4C and/or their 5'-monophosphates. The facile hydrolysis of 12 and 13 to these products was demonstrated in a medium containing 10% fetal calf serum. The molecules can serve as ready prodrug sources of the free nucleosides and their 5'-monophosphates. Evidently, the phosphonates and phosphonothionates are not similarly cleaved, nor are they phosphorylated to form antivirally active or cytotoxic products. The importance of intracellular formation of these products in the activation of 12-17 is less clear. Potential prodrugs 4-17 are all stable in aqueous solution for hours with the exception of 14. Conjugates 4-17 showed no activity against a series of DNA and RNA viruses.