Expanding the Repertoire of Low‐Molecular‐Weight Pentafluorosulfanyl‐Substituted Scaffolds

The pentafluorosulfanyl (‐SF5) functional group is of increasing interest as a bioisostere in medicinal chemistry. A library of SF5‐containing compounds, including amide, isoxazole, and oxindole derivatives, was synthesised using a range of solution‐based and solventless methods, including microwave...

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Bibliographic Details
Published in:ChemMedChem 2022-04, Vol.17 (7), p.e202100641-n/a
Main Authors: Jose, Arathy, Guest, Daniel, LeGay, Remi, Tizzard, Graham J., Coles, Simon J., Derveni, Mariliza, Wright, Edward, Marrison, Lester, Lee, Alpha A., Morris, Aaron, Robinson, Matt, Delft, Frank, Fearon, Daren, Koekemoer, Lizbé, Matviuk, Tetiana, Aimon, Anthony, Schofield, Christopher J., Malla, Tika R., London, Nir, Greenland, Barnaby W., Bagley, Mark C., Spencer, John, The Covid Moonshot Consortium
Format: Article
Language:English
Subjects:
Amides
Chemistry, Pharmaceutical
COVID-19
COVID-19, SARS-COV-2 main protease (Mpro)
Dihydroorotate dehydrogenase
Dihydroorotate Dehydrogenase - antagonists & inhibitors
DMARDs
Drugs
Functional groups
Humans
Leflunomide
Libraries
Pharmaceutical sciences
SF5 group
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Summary:The pentafluorosulfanyl (‐SF5) functional group is of increasing interest as a bioisostere in medicinal chemistry. A library of SF5‐containing compounds, including amide, isoxazole, and oxindole derivatives, was synthesised using a range of solution‐based and solventless methods, including microwave and ball‐mill techniques. The library was tested against targets including human dihydroorotate dehydrogenase (HDHODH). A subsequent focused approach led to synthesis of analogues of the clinically used disease modifying anti‐rheumatic drugs (DMARDs), Teriflunomide and Leflunomide, considered for potential COVID‐19 use, where SF5 bioisostere deployment led to improved inhibition of HDHODH compared with the parent drugs. The results demonstrate the utility of the SF5 group in medicinal chemistry. A range of molecules containing a pentafluorosulfanyl group have been made and tested versus known drug‐like entities. The SF5 functional group is of increasing interest as a bioisostere in medicinal chemistry. This library was tested against targets including human dihydroorotate dehydrogenase (HDHODH). A subsequent focused approach led to analogues of Teriflunomide and Leflunomide, considered for potential COVID‐19 treatment, where SF5 bioisostere deployment led to improved inhibition of HDHODH over the parent drugs.
ISSN:1860-7179
1860-7187
1860-7187
DOI:10.1002/cmdc.202100641