Synthesis and Antiviral Evaluation of (1,4-Disubstituted-1,2,3-Triazol)-(<i>E</i>)-2-Methyl-but-2-Enyl Nucleoside Phosphonate Prodrugs
Tuniyazi Abuduaini,
Vincent Roy,
Julien Marlet,
Catherine Gaudy-Graffin,
Denys Brand,
Cécile Baronti,
Franck Touret,
Bruno Coutard,
Tamara R. McBrayer,
Raymond F. Schinazi,
Luigi A. Agrofoglio
Affiliations
Tuniyazi Abuduaini
Institute of Organic and Analytical Chemistry, CNRS UMR 7311, Universite d’Orléans, F-45067 Orléans, France
Vincent Roy
Institute of Organic and Analytical Chemistry, CNRS UMR 7311, Universite d’Orléans, F-45067 Orléans, France
Julien Marlet
Inserm U1259, Université de Tours, 37032 Tours, France
Catherine Gaudy-Graffin
Inserm U1259, Université de Tours, 37032 Tours, France
Denys Brand
Inserm U1259, Université de Tours, 37032 Tours, France
Cécile Baronti
Unité des Virus Émergents (UVE: Aix-Marseille Univ, IRD 190, Inserm 1207, IHU Méditerranée Infection), 13000 Marseille, France
Franck Touret
Unité des Virus Émergents (UVE: Aix-Marseille Univ, IRD 190, Inserm 1207, IHU Méditerranée Infection), 13000 Marseille, France
Bruno Coutard
Unité des Virus Émergents (UVE: Aix-Marseille Univ, IRD 190, Inserm 1207, IHU Méditerranée Infection), 13000 Marseille, France
Tamara R. McBrayer
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
Raymond F. Schinazi
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
Luigi A. Agrofoglio
Institute of Organic and Analytical Chemistry, CNRS UMR 7311, Universite d’Orléans, F-45067 Orléans, France
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.
