Synthesis and Antiviral Evaluation of (1,4-Disubstituted-1,2,3-Triazol)-(<i>E</i>)-2-Methyl-but-2-Enyl Nucleoside Phosphonate Prodrugs

Abstract

A series of hitherto unknown (1,4-disubstituted-1,2,3-triazol)-(E)-2-methyl-but-2-enyl nucleosides phosphonate prodrugs bearing 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as the key synthetic step. All novel compounds were evaluated for their antiviral activities against HBV, HIV and SARS-CoV-2. Among these molecules, only compound 15j, a hexadecyloxypropyl (HDP)/(isopropyloxycarbonyl-oxymethyl)-ester (POC) prodrug, showed activity against HBV in Huh7 cell cultures with 62% inhibition at 10 μM, without significant cytotoxicity (IC50 = 66.4 μM in HepG2 cells, IC50 = 43.1 μM in HepG2 cells) at 10 μM.

Keywords

• nucleosides
• olefin cross metathesis
• ultrasound
• copper-catalyzed azide-alkyne cycloaddition (CuAAC)
• antiviral properties
• HBV