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

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.

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

Figure 1

SF₅‐benzodiazepine and oxindole analogues previously made in our group.

Scheme 1

Synthesis of a small SF₅‐subsituted amide library.

Scheme 2

Oxindole synthesis via a Knoevenagel condensation.

Figure 2

a,b) Docking studies on VEGFR2. (Schrodinger Maestro) show Semaxinib (yellow) in complex with VEGFR2, adenine pocket, hydrophobic pocket and solvent region; c,d) 9  a (pink) in complex with VEGFR2; e) 8  a (green) in complex with VEGFR2; f) lost π–π interactions due to displaced pose. Blue dashed lines indicate aromatic π–π interactions with the DFG motif and hydrogen bonds to Tyr phenol Trp. Hydrogen bonds are shown as yellow dashes.

Scheme 3

Spirocycle formation.

Figure 3

M^Pro inhibitors based on 3‐chlorophenylacetamides.

Scheme 4

Synthesis of a small‐molecule library with CF₃/SF₅ groups.

Figure 4

Examples of CF₃‐containing DMARDs.

Figure 5

View from a crystal structure of Teriflunomide and FMN in complex with HDHODH. PDB ID: 1D3H. FMN: teal, Teriflunomide: purple.

Scheme 5

Synthesis of potential SF₅‐containing DMARDs.

Figure 6

a) SF₅‐substituted Teriflunomide in complex with HDHODH, docked using Schrödinger Maestro. b) Teriflunomide and SF₅‐Teriflunomide located in the HDHODH binding pocket. Purple: Teriflunomide, salmon pink: SF₅‐Teriflunomide Ligand interaction diagram, comparing c) SF₅‐Teriflunomide and d) Teriflunomide; showing that the bulkier SF₅ is able to fill the binding pocket better than a CF₃ group. e) BAY‐2402234, a Bayer clinical trial candidate that inhibits HDHODH with an IC₅₀ value of 1.2 nM.

Figure 7

a) Electrostatic potential of Teriflunomide; b) Electrostatic potential of SF_5‐Teriflunomide.

Figure 8

Compound 17 docked in SARS‐CoV‐2 M^pro.

Figure 9

HDHODH in complex with Teriflunomide (purple) and 17 (orange).