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

• Type of Material: Article
• Authors: Tuniyazi Abuduaini, Universite d’Orléans, France; Vincent Roy, Universite d’Orléans, France; Julien Marlet, Université de Tours, France; Catherine Gaudy-Graffin, Université de Tours, France; Denys Brand, Université de Tours, France; Cécile Baronti, Aix-Marseille University, France; Franck Touret, Aix-Marseille University, France; Bruno Coutard, Aix-Marseille University, France; Tamara R McBrayer, Emory University; Raymond Schinazi, Emory University; Luigi A Agrofoglio, Universite d’Orléans, France
• Language: English
• Date: 2021-03-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2021 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/molecules26051493
• Title of Journal or Parent Work: MOLECULES
• Volume: 26
• Issue: 5
• Grant/Funding Information: T. Abuduaini thanks the China Scholarship Council for the PhD fellowship. We thank L. Bassit and O. Russell (from Pr. Raymond F. Schinazi’s laboratory) for the biological evaluations. R.F.S. is supported in part by NIH grant P30AI050409. L.A.A. thanks the LABEX SynOrg (ANR-11-LABX-0029) for support.
• Keywords: copper-catalyzed azide-alkyne cycloaddition (CuAAC); Physical Sciences; SARS-CoV-2; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Life Sciences & Biomedicine; ultrasound; Chemistry; HBV; HIV; Science & Technology; antiviral properties; nucleosides; olefin cross metathesis
• Research Categories: Chemistry, Organic; Health Sciences, Pharmacology; Chemistry, Analytical

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 uM, without significant cytotoxicity (IC50 = 66.4 uM in HepG2 cells, IC50 = 43.1 uM in HepG2 cells) at 10 uM.