Structure−Activity Relationships of New 1‐Aryl‐1H‐indole Derivatives as SARS‐CoV‐2 Nsp13 Inhibitors

: It has been more than four years since the first report of SARS-CoV-2, the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. The scientific community focused on vaccine development in an exceptionally rapid time frame, as well as the evaluation of a wide range of potential treatments in clinical trials, a few of which have also reached the market. However, these drugs are characterized by several limits (including low response to treatment in some patients, low effectiveness against the new variants, severe side effects, etc), thus underscoring the need to speed up the research. Among potential antiviral targets, the SARS-CoV-2 non-structural protein 13 (nsp13) is highly promising thanks to its pivotal role in viral replication. Pursuing our studies on the development of nsp13 inhibitors, herein we report the design, synthesis, and biological evaluation of new SARS-CoV-2 nsp13 inhibitors. In general, the newly designed dikehexenoic derivatives were proven active against both the enzymatic activities showing measurable IC50 under 30 μM concentration, while the diketobutanoic series showed less promising results. Moreover, the tested compounds were capable of blocking viral replication without exerting cytotoxicity. Docking studies predicted their binding into an allosteric pocket within the RecA2 domain.