Viral infections still represent a tremendous problem in public health with the emergence of resistance to known drugs and the appearance of new viruses. Acyclic nucleoside phosphonates (ANPs), pioneered by AntonínHolý and Erik De Clercq, are a key class of antiviral drugs. They represent a unique and prominent class of antiviral drugs that have attracted considerable attention. Among them, the bis (pivaloyloxymethyl) ester of adefovir (bis-(POM)-PMEA, Hepsera®) was approved for the treatment of HBV meanwhile the diisopropyloxycarbonyloxymethyl ester of tenofovir fumarate (bis-(POC)-(R)-PMPA fumarate, Viread® was licensed for the treatment of HIV and HBV.<br/>In this context, we aim to design and synthesize a new type of antiviral acyclic nucleoside phosphonates with the trans-4-phosphono-but-2’-en-1’-yl moiety. We describe organo-metallic syntheses of new modified acyclonucleoside phosphonates, on the nucleobase, the phosphonate or the acyclic spacer. Thus, the use of cross-metathesis and convergent syntheses of a broad panel of nucleic bases and modified phosphonates represents a cornerstone of our work.<br/>In conclusion, more than 30 ANPs with the trans-4-phosphono-but-2’-en-1’-yl moiety were successfully prepared through an olefin cross-metathesis reaction as key synthetic steps. All obtained compounds were evaluated in vitro assay for their antiviral activities against a broad spectrum of DNA/RNA viruses and some of them showed significant antiviral activity against a variety of DNA and RNA viruses (HSV, VZV, HIV…) in µM and nM concentration, besides lacking cytotoxicity.

Synthesis of <i>trans</i>-but-2'-enyl nucleosides phosphonates under prodrug form as potent antiviral agents

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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Synthesis of trans-but-2'-enyl nucleosides phosphonates under prodrug form as potent antiviral agents