Design, synthesis, and X-ray structural studies of potent SARS-CoV-2 Mpro inhibitors containing...

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 EC₅₀ values, more potent than the approved drug, nirmatrelvir. Inhibitor 5j displayed an Mpro inhibitory K _i of 1.2 nM and antiviral EC₅₀ 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.