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

Abstract：

: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 S2 site, the decahydroisoquinolin scaffold was designed by connecting the P2 site cyclohexyl group of the substrate-based inhibitor to the main-chain at the α-nitrogen atom of the P2 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 S1 and S2 sites, as well as additional interactions at the N-substituent of the inhibitor.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Shimamoto Y,Hattori Y,Kobayashi K,Teruya K,Sanjoh A,Nakagawa A,Yamashita E,Akaji K

doi

10.1016/j.bmc.2014.12.028

subject

Has Abstract

pub_date

2015-02-15 00:00:00

pages

876-90

issue

4

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(14)00876-1

journal_volume

23

pub_type

杂志文章

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