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


Abuduaini T(1), Roy V(1), Marlet J(2), Gaudy-Graffin C(2), Brand D(2), Baronti C(3), Touret F(3), Coutard B(3), McBrayer TR(4), Schinazi RF(4), Agrofoglio LA(1).
Author information:
(1)Institute of Organic and Analytical Chemistry, CNRS UMR 7311, Universite d'Orléans, F-45067 Orléans, France.
(2)Inserm U1259, Université de Tours, 37032 Tours, France.
(3)Unité des Virus Émergents
(UVE: Aix-Marseille Univ, IRD 190, Inserm 1207, IHU Méditerranée Infection), 13000 Marseille, France.
(4)Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA 30222, USA.


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.