Small-Molecule Thioesters as SARS-CoV-2 Main Protease Inhibitors: Enzyme Inhibition, Structure-Activity Relationships, Antiviral Activity, and X-ray Structure Determination.

The main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target in coronaviruses because of its crucial involvement in viral replication and transcription. Here, we report on the design, synthesis, and structure-activity relationships of novel small-molecule thioesters as SARS-CoV-2 Mpro inhibitors. Compounds 3w and 3x exhibited excellent SARS-CoV-2 Mpro inhibition with kinac/Ki of 58,700 M-1 s-1 (Ki = 0.0141 µM) and 27,200 M-1 s-1 (Ki = 0.0332 µM), respectively. In Calu-3 and Vero76 cells, compounds 3h, 3i, 3l, 3r, 3v, 3w, and 3x displayed antiviral activity in the nanomolar range without host cell toxicity. Co-crystallization of 3w and 3af with SARS-CoV-2 Mpro was accomplished, and the X-ray structures showed covalent binding with the catalytic Cys145 residue of the protease. The potent SARS-CoV-2 Mpro inhibitors also inhibited the Mpro of other beta-coronaviruses, including SARS-CoV-1 and MERS-CoV, indicating that they might be useful to treat a broader range of coronaviral infections.

2,2,2-Trifluoroethanol-mediated hydroarylation of fluorinated alkynes with indoles: Application to diindolylmethanes.

A new mild and practically simple alkyne hydroarylation protocol for the synthesis of 3-(indol-3-yl)-3-(trifluoromethyl)acrylic acid esters by the reaction of indole derivatives with ethyl/methyl 4,4,4-trifluoro-3-(indol-3-yl)but-2-enoates in trifluoroethanol was developed. This method has the following advantages: no catalyst, atom economy, high yields, broad substrate scope, and large-scale synthesis. The potential application of this protocol was further demonstrated by the synthesis of a variety of CF3 -substituted synthons and a new class of (un)symmetrical 3,3'-diindolylmethanes with a quaternary carbon core that might be biologically active.