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Pyrrolo[2,3-e]indazole as a novel chemotype for both influenza A virus and pneumococcal neuraminidase inhibitors

Influenza infections are often exacerbated by secondary bacterial infections, primarily caused by Streptococcus pneumoniae. Both respiratory pathogens have neuraminidases that support infection. Therefore, we hypothesized that dual inhibitors of viral and bacterial neuraminidases might be an advanta...

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Detalles Bibliográficos
Autores principales: Egorova, Anna, Richter, Martina, Khrenova, Maria, Dietrich, Elisabeth, Tsedilin, Andrey, Kazakova, Elena, Lepioshkin, Alexander, Jahn, Birgit, Chernyshev, Vladimir, Schmidtke, Michaela, Makarov, Vadim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10282731/
https://www.ncbi.nlm.nih.gov/pubmed/37350858
http://dx.doi.org/10.1039/d3ra02895j
Descripción
Sumario:Influenza infections are often exacerbated by secondary bacterial infections, primarily caused by Streptococcus pneumoniae. Both respiratory pathogens have neuraminidases that support infection. Therefore, we hypothesized that dual inhibitors of viral and bacterial neuraminidases might be an advantageous strategy for treating seasonal and pandemic influenza pneumonia complicated by bacterial infections. By screening our in-house chemical library, we discovered a new chemotype that may be of interest for a further campaign to find small molecules against influenza. Our exploration of the pyrrolo[2,3-e]indazole space led to the identification of two hit compounds, 6h and 12. These molecules were well-tolerated by MDCK cells and inhibited the replication of H3N2 and H1N1 influenza A virus strains. Moreover, both compounds suppress viral and pneumococcal neuraminidases indicating their dual activity. Given its antiviral activity, pyrrolo[2,3-e]indazole has been identified as a promising scaffold for the development of novel neuraminidase inhibitors that are active against influenza A virus and S. pneumoniae.