Design, chemical synthesis and antiviral evaluation of 2'-deoxy-2'-fluoro-2'-C-methyl-4'-thionucleosides.

Mieke Guinan, Ningwu Huang, Mark Smith, Gavin J Miller

Bioorganic & medicinal chemistry letters 2022 Apr 01

filter terms:

Nucleoside analogues represent an historically accomplished class of antiviral drug. Notwithstanding this, new molecular scaffolds are required to overcome their limitations and evolve pharmacophore space within this established field. Herein, we develop concise synthetic access to a new 2'-deoxy-2'-fluoro-2'-C-methyl-4'-thionucleoside chemotype, including the ProTide form of the uridine analogue. Biological evaluation of these materials in the Hepatitis C replicon assay shows little activity for the canonical pyrimidine forms, but the phosphoramidate of 2'-deoxy-2'-fluoro-2'-C-methyl-β-d-4'-thiouridine has an EC50 of 2.99 μM. Direct comparison to the established Hepatitis C drug Sofosbuvir shows a 100-fold drop in activity upon substituting the furanose chalcogen; the reasons for this are as yet unclear. Copyright © 2022 Elsevier Ltd. All rights reserved.

Citation

Mieke Guinan, Ningwu Huang, Mark Smith, Gavin J Miller. Design, chemical synthesis and antiviral evaluation of 2'-deoxy-2'-fluoro-2'-C-methyl-4'-thionucleosides. Bioorganic & medicinal chemistry letters. 2022 Apr 01;61:128605