Fig. 1. Selected reported γ-lactam- and β-lactam-containing SARS-CoV-2 main protease (Mpro) inhibitors. (A) Nirmatrelvir (1);14 (B) simnotrelvir (2);15 (C) penicillin V sulfone benzyl ester 3;21 (D) β-lactam 4;21 (E) γ-lactam 5,22 derived from 3; (F) γ-lactam-derived pyrazolidinone 6;23 (G) view of the surface from the reported SARS-CoV-2 Mpro:1 complex structure active site (PDB ID: 7TE0 24), revealing that the γ-lactam group of 1 binds in the S1 subsite, whereas its bicyclic leucine mimic binds in the S2 subsite, its tert-butyl group is solvent exposed, and its trifluoroacetamide group binds in the S4 subsite. γ-Lactam, β-lactam, and pyrazolidinone groups are in green, blue, and ochre, respectively. Bn: benzyl; Ph: phenyl.
