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

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 (IC ₅₀ = 66.4 μM in HepG2 cells, IC ₅₀ = 43.1 μM in HepG2 cells) at 10 μM.