<i>N</i> -alkyl and <i>N</i> -benzyl indoles are anti-SARS-CoV-2 agents and nsp13 inhibitors
COVID-19 pandemic stimulated tremendous efforts to develop therapeutic strategies targeting SARS-CoV-2, leading to the evaluation of a wide range of potential treatments in clinical trials. However, effective therapeutics remain elusive when the development of new variants and the limits of antiviral drugs is considered. Therefore, the development of antiviral drugs against SARS-CoV-2 is of paramount importance. Among potential drug targets, the SARS-CoV-2 nsp13 is highly attractive thanks to its pivotal role in viral replication. Pursuing our studies on the development of nsp13 inhibitors, in this work we describe the design, synthesis, and biological evaluation of novel inhibitors targeting SARS-CoV-2 nsp13. The newly designed <i>N</i>-benzyl indole derivatives were active against both enzymatic activities showing measurable IC<sub>50</sub> under 30 μM concentration, while <i>N</i>-alkyl derivatives showed less promising results. Interestingly, the tested compounds blocked viral replication with no cytotoxicity. Docking studies predicted their binding into an allosteric conserved site located in the RecA2 domain.
Authors
- Giuseppe Ruggieri
- Davide Ialongo (ORCID: https://orcid.org/0000-0002-4672-2936)
- Luigi Scipione (ORCID: https://orcid.org/0000-0002-2006-7005)
- Enzo Tramontano (ORCID: https://orcid.org/0000-0002-4849-0980)
- Valentina Noemi Madia (ORCID: https://orcid.org/0000-0002-5724-612X)
- Roberta Costi (ORCID: https://orcid.org/0000-0002-1314-9029)
- Roberto Di Santo (ORCID: https://orcid.org/0000-0002-4279-7666)
- Elisa Patacchini (ORCID: https://orcid.org/0000-0002-4531-3612)
- Angela Corona (ORCID: https://orcid.org/0000-0002-6630-8636)
- Francesco Saccoliti (ORCID: https://orcid.org/0000-0002-2907-5503)
- Florigio Lista (ORCID: https://orcid.org/0000-0001-5700-4772)
- Merve Arpacioglu (ORCID: https://orcid.org/0000-0003-4384-306X)
- Stefania Maloccu
- Roberta Emmolo
- Francesca Esposito (ORCID: https://orcid.org/0000-0001-9725-7977)
- Giorgia Grilli (ORCID: https://orcid.org/0009-0009-4993-6823)
- Riccardo De Santis (ORCID: https://orcid.org/0000-0002-2097-6663)
- Aurora Albano
- Donatella Amatore
Institutions
- University of Pavia (IT)
- Istituto di Scienze Marine del Consiglio Nazionale delle Ricerche (IT)
- Istituto Nazionale di Fisica Nucleare, Sezione di Cagliari (IT)
- Istituto Pasteur (IT)
- Institute of Cognitive Sciences and Technologies (IT)
- Link Campus University (IT)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- Journal of Enzyme Inhibition and Medicinal Chemistry
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1080/14756366.2025.2539445
- Primary Topic
- Computational Drug Discovery Methods
- Type
- article
- Field-Weighted Citation Impact
- 0.00