2. Academic Validation
  3. Indole-core inhibitors of influenza a neuraminidase: iterative medicinal chemistry and molecular modeling

Indole-core inhibitors of influenza a neuraminidase: iterative medicinal chemistry and molecular modeling

  • Eur J Med Chem. 2024 Nov 5:277:116768. doi: 10.1016/j.ejmech.2024.116768.
Andrey Tsedilin 1,  Michaela Schmidtke 2,  Natalia Monakhova 1,  Irina Leneva 3,  Irina Falynskova 3,  Maria Khrenova 4,  Thomas R Lane 5,  Sean Ekins 5,  Vadim Makarov 6
Affiliations

Affiliations

  • 1 Federal Research Centre "Fundamentals of Biotechnology" of the Russian Academy of Sciences (Research Centre of Biotechnology RAS), Leninsky prospect, 33, build. 2, 119071, Moscow, Russia.
  • 2 Institute of Medical Microbiology, Section of Experimental Virology, Jena University Hospital, Hans-Knöll-Straße 2, 07745, Jena, Germany.
  • 3 Mechnikov Research Institute of Vaccines and Sera, Department of Virology, 105064, Moscow, Russia.
  • 4 Federal Research Centre "Fundamentals of Biotechnology" of the Russian Academy of Sciences (Research Centre of Biotechnology RAS), Leninsky prospect, 33, build. 2, 119071, Moscow, Russia; Chemistry Department, Lomonosov Moscow State University, 119991, Moscow, Russia.
  • 5 Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, NC27606, USA.
  • 6 Federal Research Centre "Fundamentals of Biotechnology" of the Russian Academy of Sciences (Research Centre of Biotechnology RAS), Leninsky prospect, 33, build. 2, 119071, Moscow, Russia. Electronic address: makarov@inbi.ras.ru.
PMID: 39163780 DOI: 10.1016/j.ejmech.2024.116768
Abstract

Influenza viruses that cause seasonal and pandemic flu are a permanent health threat. The surface glycoprotein, neuraminidase, is crucial for the infectivity of the virus and therefore an attractive target for flu drug discovery campaigns. We have designed and synthesized more than 40 3-indolinone derivatives. We mainly investigated the role of substituents at the 2 position of the core as well as the introduction of substituents or a nitrogen atom in the fused phenyl ring of the core for inhibition of Influenza Virus Neuraminidase activity and replication in vitro and in vivo. After evaluating the compounds for their ability to inhibit the viral neuraminidase, six potent inhibitors 3c, 3e, 7c, 12o, 12v, 18d were progressed to evaluate for cytotoxicity and inhibition of Influenza Virus A/PR/8/34 replication in in MDCK cells. Two hit compounds 3e and 12o were tested in an animal model of Influenza Virus infection. Molecular mechanism of the 3-indolinone derivatives interactions with the neuraminidase was revealed in molecular dynamic simulations. Proposed inhibitors bind to the 430-cavity that is different from the conventional binding site of commercial compounds. The most promising 3-indolinone inhibitors demonstrate stronger interactions with the neuraminidase in molecular models that supports proposed binding site.

Keywords

3-Indolinone; 430-Cavity; 7-Azaindole; Anti-Influenza drug discovery; Heumann cyclization; Influenza a; Neuraminidase.

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