Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication

作者：Barral Karine; Weck Clement; Payrot Nadine; Roux Loic; Durafour Celine; Zoulim Fabien; Neyts Johan; Balzarini Jan; Canard Bruno; Priet Stephane^*; Alvarez Karine

来源：European Journal of Medicinal Chemistry, 2011, 46(9): 4281-4288.

DOI：10.1016/j.ejmech.2011.06.034

• Modified nucleotide
• Thiophosphonate
• Antiviral activity
• HIV
• HBV

9-[2-(Thiophosphonomethoxy)ethyl]adenine 3 and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine 4 were synthesized as the first thiophosphonate nucleosides bearing a sulfur atom at the alpha-position of the acyclic nucleoside phosphonates PMEA and PMPA. Thiophosphonates S-PMEA 3 and S-PMPA 4 were evaluated for in vitro 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 5 and S-PMPApp 6 are readily incorporated by wild-type (WT) HIV-1 RT into DNA and act as DNA chain terminators. Compounds 3 and 4 were evaluated for in vitro 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 3 and 4, kinetic data and decomposition pathways were studied at 37 degrees C in several media.

• 出版日期2011-9
• 单位河北医科大学