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

## TL;DR

Researchers designed new indole compounds that inhibit a key SARS-CoV-2 protein involved in viral replication, showing antiviral activity without toxicity.

## Contribution

New 1-aryl-1H-indole derivatives are developed as SARS-CoV-2 nsp13 inhibitors with structure-activity relationships explored.

## Key findings

- Dikehexenoic derivatives show activity against SARS-CoV-2 nsp13 enzymatic activities with IC50 under 30 μM.
- Compounds block viral replication without cytotoxicity in infected cells.
- In silico docking suggests binding to an allosteric pocket in the RecA2 domain of nsp13.

## Abstract

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 is 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 nonstructural protein 13 (nsp13) is highly promising thanks to its pivotal role in viral replication. Pursuing the studies on the development of nsp13 inhibitors, herein, the design, synthesis, and biological evaluation of new SARS‐CoV‐2 nsp13 inhibitors are reported. In general, the newly designed dikehexenoic derivatives are proven active against both the enzymatic activities showing measurable IC50 under 30 μM concentration, while the diketobutanoic series shows less promising results. Moreover, the tested compounds are capable of blocking viral replication without exerting cytotoxicity. Docking studies predict their binding into an allosteric pocket within the RecA2 domain.

SARS‐CoV‐2 nsp13 is a promising target to develop effective antivirals. Pursuing the studies, new indolyl derivatives to deepen SARs are designed. The newly synthesized N‐aryl indoles are active vs both nsp13‐associated activities. They exert antiviral activity vs SARS‐CoV‐2 infected cells with no cytotoxicity. In silico studies predict their binding into an allosteric pocket.© 2025 WILEY‐VCH GmbH