Discovery of 9,10-dihydrophenanthrene derivatives as SARS-CoV-2 3CLpro inhibitors for COVID-19

The epidemic coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now spread worldwide and efficacious therapeutics are urgently needed. 3-Chymotrypsin-like cysteine protease (3CL(pro)) is an indispensable protein in viral replication and represents an attractive drug target for fighting COVID-19. Herein, we report the discovery of 9,10-dihydrophenanthrene derivatives as non-peptidomimetic and non-covalent inhibitors of the SARS-CoV-2 3CL(pro). The structure-activity relationships of 9,10-dihydrophenanthrenes as SARS-CoV-2 3CL(pro) inhibitors have carefully been investigated and discussed in this study. Among all tested 9,10-dihydrophenanthrene derivatives, C1 and C2 display the most potent SARS-CoV-2 3CL(pro) inhibition activity, with IC50 values of 1.55 +/- 0.21 mu M and 1.81 +/- 0.17 mu M, respectively. Further enzyme kinetics assays show that these two compounds dose-dependently inhibit SARS-CoV-2 3CL(pro) via a mixed-inhibition manner. Molecular docking simulations reveal the binding modes of C1 in the dimer interface and substrate-binding pocket of the target. In addition, C1 shows outstanding metabolic stability in the gastrointestinal tract, human plasma, and human liver microsome, suggesting that this agent has the potential to be developed as an orally administrated SARS-CoV-2 3CL(pro) inhibitor. (c) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

In this study, 9,10-dihydrophenanthrene derivatives were discovered as non-peptidomimetic and non-covalent inhibitors of SARS-CoV-2 3CL(pro). Among the tested compounds, C1 and C2 showed the most potent inhibition activity. Further experiments revealed that these compounds dose-dependently inhibit SARS-CoV-2 3CL(pro) and exhibit good metabolic stability.