Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors

The design and evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL(pro)) are described. Focusing on hydrophobic interactions at the S(2) site, the decahydroisoquinolin scaffold was designed by connecting the P(2) site cyclohexyl group of the substrate-based inhibitor to the main-chain at the α-nitrogen atom of the P(2) position via a methylene linker. Starting from a cyclohexene enantiomer obtained by salt resolution, trans-decahydroisoquinolin derivatives were synthesized. All decahydroisoquinolin inhibitors synthesized showed moderate but clear inhibitory activities for SARS 3CL(pro), which confirmed the fused ring structure of the decahydroisoquinolin functions as a novel scaffold for SARS 3CL(pro) inhibitor. X-ray crystallographic analyses of the SARS 3CL(pro) in a complex with the decahydroisoquinolin inhibitor revealed the expected interactions at the S(1) and S(2) sites, as well as additional interactions at the N-substituent of the inhibitor.