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 alpha-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. (c) 2014 Elsevier Ltd. All rights reserved.