Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication

摘要

9-[2-(Thiophosphonomethoxy)ethyl]adenine and ( )-9-[2-(Thiophosphonomethoxy)propyl]adenine were synthesized as the first thiophosphonate nucleosides bearing a sulfur atom at the α-position of the acyclic nucleoside phosphonates PMEA and PMPA. Thiophosphonates S-PMEA and S-PMPA were evaluated for activity against HIV-1 (subtypes A to G), HIV-2 and HBV-infected cells, and found to exhibit potent antiretroviral activity. We showed that their diphosphate forms S-PMEApp and S-PMPApp are readily incorporated by wild-type (WT) HIV-1 RT into DNA and act as DNA chain terminators. Compounds and were evaluated for activity against a broad panel of DNA and RNA viruses and displayed beside HIV a moderate activity against herpes simplex virus and vaccinia viruses. In order to measure enzymatic stabilities of the target derivatives and , kinetic data and decomposition pathways were studied at 37 °C in several media.