Structure‐Activity Relationships of Benzamides and Isoindolines Designed as SARS‐CoV Protease Inhibitors Effective against SARS‐CoV‐2

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  Scheme 1. Compounds used for SAR. (A): Synthesis of benzamides 2 a–t. Reagents and conditions: X=OH a) appropriate solvent, HOBt‐hydrate, coupling reagent, (R)‐naphthylethylamine (NEA). X=Cl a’) NEA, Et2O/H2O, Na2CO3, r.t. B: Synthesis of 8. (B): Reagents and conditions: a) 1. benzene, N‐bromosuccinimide, p‐toluoenesulfonic acid monohydrate, reflux, 16 h. 2. H2O, sodium acetate trihydrate, ethanol, reflux, 2 h. 3. isopropanol, ammonia acetate, sodium cyanoborohydride, 95 °C, 1 h. b) 1. semi‐concentrated hydrochloric acid, reflux, 2 d. 2. ethyl acetate, TEA, 2‐methyl benzoyl chloride, r.t., 1 d. c) lithium hydroxide monohydrate, THF/H2O (3 : 1), reflux, 2 d. (C): Synthesis of compounds with inverted amide bond. Reagents and conditions: a) 1. MeOH, H2SO4, r.t.‐65 °C, 2 h. 2. MeI, DMSO, KOH, r.t., 10 d. 3. LiOH, THF, H2O, r.t., 16 h. b) HOBt‐hydrate, DCC, 0 °C‐r.t., 1 d. (D): Synthesis of isoindoline derivatives 14 a–b. Reagents and conditions: a) NEA, heating with a heat gun. b) THF abs., LAH, r.t.‐70 °C, 2 h. (E): Synthesis of isoindoline derivatives 14 c–l. Reagents and conditions: a) Naphthylmethylamine (NMA), EtOAc, Na2CO3, r.t.‐77 °C, 1 h. b) NEA, toluene, TEA, 120 °C, 1 h. c) SnCl2 ⋅…

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  Figure 1. Crystallographic binding modes of 2 b (A, PDB‐ID 3E9S) 13 and 20 (B, PDB‐ID 4OW0)14 in complex with SARS‐CoV PLpro. Ligand atoms are depicted as sticks with green carbon atoms, protein with white carbon atoms and transparent surface. Polar interactions are indicated as yellow dashed lines. For a clear view, only residues with direct contacts to the ligands are labeled. (C) Predicted binding modes of 2 o (magenta carbon atoms), 2 p (yellow carbon atoms) and 2 s (cyan carbon atoms) in complex with SARS‐CoV PLpro (white carbon atoms, PDB‐ID 3E9S). Crystallographic reference ligand 2 b is depicted as green sticks for orientation. (D) Predicted binding mode of 14 h (magenta carbon atoms) in complex with SARS‐CoV PLpro (white carbon atoms, PDB‐ID 4OW0). Crystallographic reference ligand 20 is depicted as green sticks for orientation.