Evaluation of an octahydroisochromene scaffold used as a novel SARS 3CL protease inhibitor.
Bioorg Med Chem
; 28(4): 115273, 2020 02 15.
Article
in English
| MEDLINE | ID: covidwho-833276
ABSTRACT
An octahydroisochromene scaffold has been introduced into a known SARS 3CL protease inhibitor as a novel hydrophobic core to interact with the S2 pocket of the protease. An alkyl or aryl substituent was also introduced at the 1-position of the octahydroisochromene scaffold and expected to introduce additional interactions with the protease. Sharpless-Katsuki asymmetric epoxidation and Sharpless asymmetric dihydroxylation were employed to construct the octahydroisochromene scaffold. The introductions of the P1 site His-al and the substituent at 1-position was achieved using successive reductive amination reactions. Our initial evaluations of the diastereo-isomeric mixtures (16a-d) revealed that the octahydroisochromene moiety functions as a core hydrophobic scaffold for the S2 pocket of the protease and the substituent at the 1-position may form additional interactions with the protease. The inhibitory activities of the diastereoisomerically-pure inhibitors (3a-d) strongly suggest that a specific stereo-isomer of the octahydroisochromene scaffold, (1S, 3S) 3b, directs the P1 site imidazole, the warhead aldehyde, and substituent at the 1-position of the fused ring to their appropriate pockets in the protease.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Protease Inhibitors
/
Benzopyrans
/
Severe acute respiratory syndrome-related coronavirus
/
Coronavirus 3C Proteases
Type of study:
Experimental Studies
Language:
English
Journal:
Bioorg Med Chem
Journal subject:
Biochemistry
/
Chemistry
Year:
2020
Document Type:
Article
Affiliation country:
J.bmc.2019.115273
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