Expanding the repertoire of low-molecular-weight pentafluorosulfanyl-substituted scaffolds

DOI: 10.1002/cmdc.202100641

Authors: Arathy Jose (University of Sussex) , Daniel Guest (University of Sussex) , Remi Legay (Normandie Université) , Graham J. Tizzard (University of Southampton) , Simon Coles (University of Southampton) , Mariliza Derveni (University of Sussex) , Edward Wright (University of Sussex) , Lester Marrison (eMolecules) , Alpha A. Lee (PostEra Inc.) , Aaron Morris (PostEra Inc.) , Matt Robinson (PostEra Inc.) , Frank Von Delft (Diamond Light Source; University of Oxford; University of Johannesburg) , Daren Fearon (Diamond Light Source) , Lizbe Koekemoer (University of Oxford) , Tetiana Matviuk (Enamine) , Anthony Aimon (Diamond Light Source) , Christopher J. Schofield (University of Oxford) , Tika R. Malla (University of Oxford) , Nir London (Weizmann Institute of Science) , Barnaby W. Greenland (University of Sussex) , Mark C. Bagley (University of Sussex) , John Spencer (University of Sussex)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemmedchem , VOL 59

State: Published (Approved)
Published: February 2022
Diamond Proposal Number(s): 19301

Abstract: 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.

Journal Keywords: SF5 group; DMARDs; COVID-19; SARS-COV-2 main protease (Mpro)

Diamond Keywords: COVID-19; Viruses

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 24/02/2022 10:57

Documents:
ChemMedChem - 2022 - Jose - Expanding the Repertoire of Low%E2%80%90Molecular%E2%80%90Weight Pentafluorosulfanyl%E2%80%90Substituted Scaffolds.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)