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

Abstract

The pentafluorosulfanyl (-SF 5 ) functional group is of increasing interest as a bioisostere in medicinal chemistry. A library of SF 5containing compounds, including amide, isoxazole, and oxindole derivatives, was synthesised using a range of solutionbased and solventless methods, including microwave and ballmill techniques. The library was tested against targets including human dihydroorotate dehydrogenase (HDHODH). A subse-quent 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 SF 5 bioisostere deployment led to improved inhibition of HDHODH compared with the parent drugs. The results demonstrate the utility of the SF 5 group in medicinal chemistry.

Expanding the toolbox of metabolically stable lipid prodrug strategies

“…To complement the -CF 3containing lipid termini, we hypothesized that the pentafluorosulfanyl (SF 5 ) motif could confer similar pharmacological profiles. The SF 5 group has found increasing utility in medicinal chemistry campaigns (Jose et al, 2022) and is largely accepted as a bioisostere of halogens, CF 3 , and t-Bu groups (Sowaileh et al, 2017). SF 5 groups impart distinct properties onto small molecules as a consequence of their octahedral geometries, unique sizes (t-Bu > SF 5 >CF 3 ), lipophilicity, and metabolic stability.…”

Recent Advances in the Chemistry and Application of SF5-Compounds

“…Since the pentafluorosulfanyl(-SF5) functional group is of growing interest as a bioisostere in medicinal chemistry, the group of Spencer support by the Covid Moonshot Consortium synthetized the same year a library of SF5-containing compounds, including amide, isoxazole, and oxindole derivatives to expand the repertoire of low-molecular-weight SF5-scaffolds. 43 All compounds were tested against targets including human dihydroorotate dehydrogenase (HDHODH) but none had any appreciable enzyme activity. A subsequent approach led to synthesis of analogues of the clinically used disease modifying anti-rheumatic drugs (DMARDs), Teriflunomide 90 and Leflunomide 91, considered for potential COVID-19 use.…”

Straightforward Pentafluorosulfanylation for Molecular Design

“…2C). 51 is the intermediate for the synthesis of the SF5-lefluamide, (34,35) which displayed two-fold greater potency than its original, commercialized CF3-version, and the antimalarial drug DSM265 (22)(23)(24) the first SF5-compound in clinical development. In order to connect this reaction to a wider set of building blocks, we next searched for suitable thiophenol derivatives that could be obtained through cross-coupling chemistry while also directly yield ArSF5 compounds in the oxidative fluorination (Fig.…”