Background:  We previously reported that phosphonate derivative of thymidin—Nikavir—a potent nucleoside reverse transcriptase inhibitor (NRTI), was active against a wide spectrum of HIV-1 isolates, including a variety of laboratory and drug-resistant HIV-1 strains in vitro. Nikavir possessed both high anti-HIV activity and low cytotoxicity (6- to 8-fold less toxic as compared to other NRTI in vitro). The compound has successfully passed all clinical trials in Russia and has been approved for the treatment of HIV infection. We evaluated some groups of novel NRTI, among them the acyclic nucleoside phosphonates. The acyclic nucleoside phosphonates are well–known group of compounds, which demonstrate a broad spectrum of activity against retroviruses. Acyclic phosphonate derivatives of adenine (Z)- and (E)-9-[3-(phosphonomethoxy)prop-1-en-1yl]adenine were selected in a search for novel NRTI bearing a double bond conjugated with the adenine base.

Methods: (Z)- and (E)-9-[3-(phosphonomethoxy)prop-1-en-1yl]adenine and their diphosphates were subjected to an in vitro evaluation of antiviral potency and toxicity. Cytotoxicity of compounds was defined using T-lymphoblastoid cell lines. Antiviral activity was profiled using CEMss cells and HIV-1 strains. The level of virus reproduction in infected cells was assessed as p24 production by p24 ELISA. Pharmacokinetics was evaluated on dogs and rabbits.

Results:  Both isomers (Z)- and (E)-9-[3-(phosphonomethoxy)prop-1-en-1yl]adenine inhibited HIV replication without apparent cellular toxicity up to 3300 µM, albeit with different efficiency. Z-isomer was about 10-fold more effective inhibitor of HIV replication than E-isomer and displayed twice higher anti-HIV activity than that found for PMEA 9-[2-(phosphonometoxy)ethyl]adenine (adefovir). All compounds possessed lower cytotoxicity as compared with adefovir (ADV) and zidovudine (AZT). The selectivity index of Z-isomer exceeds that for PMEA by 2.5- to 3-fold. The T_1/2 of both isomers were greater than T_1/2 of AZT (3-10-fold).

Conclusions:  Our results demonstrate that antiviral activity of (Z)-9-[3-(phosphonomethoxy)prop-1-en-1yl]adenine is comparable or even higher than that was established for PMEA, while E-isomer was about tenfold less active than Z-isomer. Both compounds were less toxic in cell cultures as compared with adefovir. These data warrant that (Z)-9-[3-(phosphonomethoxy)prop-1-en-1yl]adenine be further developed as potential therapeutic for HIV infection and potential microbicide.