Synthesis and Structural Characterization of Covalent Fragment-like SARS-CoV-2 Mpro inhibitors by X-ray crystallography

Coronaviruses are common viruses known to cause respiratory illness in humans. The COVID-19 pandemic (2020-2023) resulted in millions of cases and deaths and socioeconomic impact in many countries. Despite the success of current treatments, the emergence of drug-resistant variants raised concerns with potential future outbreaks, highlighting the need for novel approaches and development of new small molecules. In our previous work¹, we found five fragment-like inhibitors able to inhibit SARS-CoV-2 main protease (Mpro). Based on the recently solved crystallographic structures of compound (1), we prepared the analogues (6b-f) through a Fischer indole synthesis and acquired the available compounds (7a-d) to evaluate their in vitro activity. Our results show the α-chloroketoamide role in fragment’s activity, as well as modulation of binding kinetics and selectivity by substituents on the C6 of the tetrahydro carbazole moiety. Alongside molecular docking studies, these findings may contribute to the development of novel non-peptidic inhibitors of Mpro.