Design, synthesis and in vitro evaluation of novel SARS-CoV-2 3CL^pro covalent inhibitors

Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CL^pro (main coronaviruses cysteine-protease) has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CL^pro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CL^pro. We report herein our efforts in the design and synthesis of submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.