ABSTRACT
We report synthesis, in vitro antiviral activity, and stability studies in biological media of original boranophosphonate isosteres of AZT and d4T monophophates. A convenient route for the synthesis of 3'-Azido-3'-deoxythymidine-5'-boranophosphonate 8 and 2',3'-Didehydro-3'-dideoxythymidine-5'-boranophosphonate 12 is described. H-phosphinates 7 and 11, and alpha-boranophosphonates 8 and 12 exhibited no significant in vitro activity against HIV-infected cells, neither against a broad panel of viruses, up to 200 microM. The absence of activity of target compounds 8 and 12 can be partially explained by their short half-life in culture medium.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Organophosphonates/chemical synthesis , Organophosphonates/pharmacology , Stavudine/analogs & derivatives , Zidovudine/analogs & derivatives , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Cell Line , Drug Stability , Half-Life , Humans , Organophosphonates/chemistry , Organophosphonates/metabolism , Viruses/drug effectsABSTRACT
Starting from the chemical structure of the recent FDA-approved anti-HIV drug Amprenavir (Agenerase), a potent HIV-protease inhibitor, we have designed new series of Amprenavir bioisoteres in which the methylene group of the benzyl group was replaced by a sulfur atom. This structural modification has required an original multistep synthesis. Unfortunately, introduction of the sulfur atom abolished or drastically decreased both inhibitory activity on recombinant HIV protease and HIV infection protection on MT4 cell cultures.
