Expanding the Repertoire of Low-Molecular-Weight Pentafluorosulfanyl-Substituted Scaffolds.
Jose A., Guest D., LeGay R., Tizzard GJ., Coles SJ., Derveni M., Wright E., Marrison L., Lee AA., Morris A., Robinson M., von Delft F., Fearon D., Koekemoer L., Matviuk T., Aimon A., Schofield CJ., Malla TR., London N., Greenland BW., Bagley MC., Spencer J., The Covid Moonshot Consortium .
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.