Publication date: Jun 29, 2026
Structure based design, synthesis and evaluation of a series of potent SARS-CoV-2 main protease inhibitors are described. We designed conformationally constrained tetrahydroisoquinoline-3-carboxamides as P2 ligands. The studies involved structure-activity relationship studies by varying P1, P2, P3, and P4 ligands, including five- and six-membered lactam rings as P1 ligands as well as nitrile and thiazole heterocycles as P1′ ligands. These new inhibitors exhibited potent SARS-CoV-2 Mpro inhibitory activity. Several inhibitors also blocked the replication of SARS-CoV-2 in VeroE6 cells with low nanomolar EC values, more potent than the approved drug, nirmatrelvir. Inhibitor 5j displayed an Mpro inhibitory K of 1. 2 nM and antiviral EC value of 360 nM. We determined several high-resolution X-ray structures of inhibitor-SARS-CoV-2 Mpro complexes which provided important insights into the ligand-binding site interactions in the active site.
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| Concepts | Keywords |
|---|---|
| Drug | Activity |
| Low | Carboxamides |
| Nanomolar | Cov |
| Protease | Design |
| Tetrahydroisoquinoline | Inhibitor |
| Inhibitors | |
| Inhibitory | |
| Ligands | |
| Mpro | |
| P1 | |
| Potent | |
| Ray | |
| Sars | |
| Synthesis | |
| Tetrahydroisoquinoline |