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

Anna Egorova; Martina Richter; Maria Khrenova; Elisabeth Dietrich; Andrey Tsedilin; Elena Kazakova; Alexander Lepioshkin; Birgit Jahn; Vladimir Chernyshev; Michaela Schmidtke; Vadim Makarov

doi:10.1039/D3RA02895J

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

Anna Egorova,

‡^a Martina Richter,‡^b Maria Khrenova,

^ac Elisabeth Dietrich,^b Andrey Tsedilin,

^a Elena Kazakova,

^a Alexander Lepioshkin,

^a Birgit Jahn,^b Vladimir Chernyshev,

^cd Michaela Schmidtke*^b and Vadim Makarov

*^a

Author affiliations

* Corresponding authors

^a Federal Research Centre “Fundamentals of Biotechnology” of the Russian Academy of Sciences (Research Centre of Biotechnology RAS), 33-2 Leninsky Prospect, 119071 Moscow, Russia
E-mail: makarov@inbi.ras.ru

^b Department of Medical Microbiology, Section of Experimental Virology, Jena University Hospital, Hans-Knöll-Straße 2, 07745 Jena, Germany
E-mail: michaela.schmidtke@med.uni-jena.de

^c Chemistry Department, Lomonosov Moscow State University, 1-3 Leninskie Gory, 119991 Moscow, Russia

^d Frumkin Institute of Physical Chemistry and Electrochemistry of the Russian Academy of Sciences, 31-4 Leninsky Prospect, 119071 Moscow, Russia

Abstract

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.

RSC Advances

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

Abstract

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

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