Evaluation of a non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold as a SARS 3CL protease inhibitor

Abstract

A non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold was evaluated as a novel inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL pro ). The decahydroisoquinolin scaffold has been demonstrated to be an effective hydrophobic center to interact with S2 site of SARS 3CL pro , but the lack of interactions at S3 to S4 site is thought to be a major reason for the moderate inhibitory activity. In this study, the effects of an additional non-prime site substituent on the scaffold as well as effects of several warheads are evaluated. For the introduction of a desired non-prime site substituent, amino functionality was introduced on the decahydroisoquinolin scaffold, and the scaffold was constructed by Pd(II) catalyzed diastereoselective ring formation. The synthesized decahydroisoquinolin inhibitors showed about 2.4 times potent inhibitory activities for SARS 3CL pro when combined with a non-prime site substituent. The present results indicated not only the expected additional interactions with the SARS 3CL pro but also the possibility of new inhibitors containing a fused-ring system as a hydrophobic scaffold and a new warhead such as thioacetal.

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

“…As an alternative non-peptide scaffold to decahydroisoquinoline 11,12 , using an octahydroisochromen scaffold has been introduced into a fused-ring type SARS 3CL protease inhibitor as a novel hydrophobic core to interact with the S2 pocket of the protease. Alkyl and aryl substituents were also introduced to the 1-position of the octahydroisochromene scaffold to form additional interactions with the protease.…”

“…To a solution of 11 (6.50 g, 29.3 mmol) in CH 2 Cl 2 (100 mL) was added DIBAL-H (1.0 M solution in hexane; 88 mL, 88 mmol) at -78°C under an argon atmosphere and the resulting mixture stirred for 1 h. The reaction was quenched with CH 3 OH, warmed to room temperature, filtered through a pad of silica gel, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ ((2R,3R)-3-((1S,2R)-2-Allylcyclohexyl) oxiran-2-yl) methanol (12) To a solution of diethyl D-tartrate (7.8 mL, 46 mmol) in CH 2 Cl 2 (100 mL) was added titanium(IV) isopropoxide (13 mL, 46 mmol) at 0°C under an argon atmosphere. After stirring for 20 min, the mixture was cooled to -20°C and added to t-butyl hydroperoxide (6.0 M solution in toluene; 15 mL, 90 mmol).…”

“…2). 12 The configuration of the octahydroisochromene ring in 3 can be easily controlled using a stereo-selective ring-closing reaction featuring the nucleophilic opening of an epoxide. The synthesis of the requisite oxygen-containing precursor used in the ring-closing reaction can be achieved using established stereo-selective reactions such as the Sharpless-Katsuki asymmetric epoxidation and Sharpless dihydroxylation reaction.…”

“…In addition, the effect of the substituent at the 1-position in the fused-ring system of 3 may also be evaluated; the effects of different substituents in this position have not been assessed in our previous studies using the decahydroisoquinoline scaffold in 2. 12 Thus, resulting ring structure in 5 can be controlled using a combination of the stereo-chemistry of the nucleophilic secondary hydroxyl group and electrophilic epoxide in 6, which make it possible to selectively form the four possible configurations of the ring system in 5. The configuration of the nucleophilic hydroxyl groups in 6 can be controlled using a Sharpless asymmetric dihydroxylation reaction 13 on the olefin in 7 and the configuration of the electrophilic epoxide in 7 can be selectively constructed using a Sharpless-Katsuki asymmetric epoxidation reaction 14 on the allylic alcohol obtained upon the functional group conversion of commercially available diol 8.…”

Finding potent inhibitors for COVID-19 main protease (Mpro): anin silicoapproach using SARS-CoV-3CL protease inhibitors for combating CORONA

“…A previous study has demonstrated that the structure and active site of human SARS-CoV 3CL protease (also known as M pro or main protease) resemble those of picornavirus 3 C protease (Anand et al, 2003). Moreover, a number of studies have reported the synthesis and in vitro experiments on SARS 3CL pro inhibitors (Chen et al, 2005;Konno et al, 2017;Ohnishi et al, 2019;Pillaiyar et al, 2016).…”