TY - JOUR
T1 - Fused-ring structure of decahydroisoquinolin as a novel scaffold for SARS 3CL protease inhibitors
AU - Shimamoto, Yasuhiro
AU - Hattori, Yasunao
AU - Kobayashi, Kazuya
AU - Teruya, Kenta
AU - Sanjoh, Akira
AU - Nakagawa, Atsushi
AU - Yamashita, Eiki
AU - Akaji, Kenichi
N1 - Funding Information:
This work was supported, in part, by a Grant-in-aid for Scientific Research 25460160 to K.A. from the Japan Society for the Promotion of Science and by a grant for Adaptable and Seamless Technology Transfer Program through Target-driven R&D AS251Z01976Q to Y.H. from Japan Science and Technology Agency . We thank Shimadzu Co. for the measurements of mass spectra using LCMS-IT-TOF MS.
Publisher Copyright:
©.
PY - 2015/2/15
Y1 - 2015/2/15
N2 - The design and evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CLpro) 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 3CLpro, which confirmed the fused ring structure of the decahydroisoquinolin functions as a novel scaffold for SARS 3CLpro inhibitor. X-ray crystallographic analyses of the SARS 3CLpro 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.
AB - The design and evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CLpro) 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 3CLpro, which confirmed the fused ring structure of the decahydroisoquinolin functions as a novel scaffold for SARS 3CLpro inhibitor. X-ray crystallographic analyses of the SARS 3CLpro 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.
KW - Decahydroisoquinolin
KW - Hydrophobic interaction
KW - Inhibitor
KW - SARS 3CL protease
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U2 - 10.1016/j.bmc.2014.12.028
DO - 10.1016/j.bmc.2014.12.028
M3 - Article
C2 - 25614110
AN - SCOPUS:84964199951
VL - 23
SP - 876
EP - 890
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 4
ER -