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

Tuniyazi Abuduaini,Bruno Coutard,Luigi A Agrofoglio,Catherine Gaudy-Graffin,Raymond F Schinazi,Julien Marlet,Denys Brand,Franck Touret,Cécile Baronti,Tamara R Mcbrayer,Vincent Roy

doi:10.3390/molecules26051493

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.

Highlights

Accepted: 3 March 2021Acyclic nucleoside phosphonates (ANPs), such as (R)-PMPA [9-[9(R)-2-(phosphonomethoxy)propyl]adenine, 1] and PMEA [9-[2-(phosphonomethoxy)ethyl] adenine, 2] discovered by A
15a, we focused focusedour ourattention attentiononly onlyto synthesis of their
The convergent synthesis was based on olefin acyclic cross-metathesis and

Summary

Introduction

Acyclic nucleoside phosphonates (ANPs), such as (R)-PMPA [9-[9(R)-2-(phosphonomethoxy)propyl]adenine, 1] and PMEA [9-[2-(phosphonomethoxy)ethyl] adenine, 2] discovered by A. In order to improve the oral absorption of these phosphonate analogs, ANPs are delivered as prodrugs [bis(POC)-PMPA (3) or bis(POM)-PMEA (4)]; prodrug moiety [5] has previously focused on acyloxyalkylester (pivaloyloxymethyl, POM) [6,7], or ((isopropyloxycarbonyl-oxymethyl)-ester, POC) [8], alkoxyalkyl groups (hexadecyloxypropyl, HDP) [9], and more recently on phosphonoamidates (ProTides) [10,11]. In our search for antiviral compounds, we have discovered a new class of acyclic nucleoside phosphonates based on a 4phosphono-but-2-en-1-yl skeleton, with the double bond having trans stereochemistry [12,13,14]

Methods

Results

Conclusion