Evaluation of an octahydroisochromene scaffold used as a novel SARS 3CL protease inhibitor

Abstract

A B S T R A C TAn 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.

Discovery of Potential Flavonoid Inhibitors Against COVID-19 3CL Proteinase Based on Virtual Screening Strategy

“…Since the binding cavity of COVID-19 3CLpro and SARS 3CLpro is extremely similar ( Supplementary Figure S1 ), it is rational to make the learning model based on the data of inhibitors of above two proteins. The 66 active compounds and 66 inactive compounds were collected as the training and testing set data (patent: US7495011 B2) ( Yamamoto et al, 2004 ; Chen et al, 2006 ; Wang et al, 2007 ; Jacobs et al, 2013 ; Adedeji and Sarafianos, 2014 ; García-Fernández et al, 2016 ; Konno et al, 2017 ; Hu et al, 2020 ; Jo et al, 2020 ; Yoshizawa et al, 2020 ). The chemical structures of compounds were drawn by ChemDraw software and translated into canonical SMILES by the RDKit python package ( Shi and Borchardt, 2017 ).…”

Drug Development and Medicinal Chemistry Efforts toward SARS‐Coronavirus and Covid‐19 Therapeutics

“…All the possible diastereomers (compounds 50 – 53 , Figure ) were assayed and the results suggested that a specific configuration of the octahydroisochromene scaffold, namely the (1 S ,3 S ) as in compound 51 , could guarantee the correct positioning of the P1 imidazole and the aldehyde moiety within protease active site. Moreover, the n ‐butyl chain at 1‐position of the fused‐ring system was also found to be crucial for hydrophobic interactions …”

Potent inhibitors of SARS-CoV-2 3C-like protease derived from N-substituted isatin compounds

“…A variety of 3CL pro inhibitors have been reported in the literature over the past decade [ 4 , [9] , [10] , [11] , [12] ]. To date, several potential SARS-CoV-2 3CL pro inhibitors have been reported from compound library screening [ 8 ], rational design [ 8 , 13 , 14 ] and testing of ingredients from traditional Chinese medicine [ 15 , 16 ].…”