2. Academic Validation
  3. Non-rigid Diarylmethyl Analogs of Baloxavir as Cap-Dependent Endonuclease Inhibitors of Influenza Viruses

Non-rigid Diarylmethyl Analogs of Baloxavir as Cap-Dependent Endonuclease Inhibitors of Influenza Viruses

  • J Med Chem. 2020 Sep 10;63(17):9403-9420. doi: 10.1021/acs.jmedchem.0c00565.
Andrei A Ivashchenko 1 2 3,  Oleg D Mitkin 1,  Jeremy C Jones 4,  Alexander V Nikitin 1,  Angela G Koryakova 1,  Alexey Ryakhovskiy 1,  Ruben N Karapetian 1,  Dmitry V Kravchenko 1,  Vladimir Aladinskiy 3,  Irina A Leneva 5,  Irina N Falynskova 5,  Ekaterina A Glubokova 5,  Elena A Govorkova 4,  Alexandre V Ivachtchenko 1 2 6
Affiliations

Affiliations

  • 1 Chemical Diversity Research Institute, Rabochaya Street 2a, Khimki, Moscow Region 141401, Russia.
  • 2 ChemDiv, 6605 Nancy Ridge Drive, San Diego, California 92121, United States.
  • 3 Moscow Institute of Physics and Technology (State University), 9 Institutskiy Lane, Dolgoprudny City, Moscow Region 141700, Russia.
  • 4 Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 5 I. Mechnikov Research Institute for Vaccines and Sera, 5a Malyy Kazennyy Lane, Moscow 105064, Russia.
  • 6 ASAVI LLC, 1835 E. Hallandale Beach Blvd, #442, Hallandale Beach, Florida 33009, United States.
PMID: 32787099 DOI: 10.1021/acs.jmedchem.0c00565
Abstract

4-Substituted 2,4-dioxobutanoic acids inhibit Influenza Virus cap-dependent Endonuclease (CEN) activity. Baloxavir marboxil, 4, is approved for treating Influenza Virus infections. We describe here the synthesis and biological evaluation of active compounds, 5a-5g, and their precursors (6a, 6b, 6d, and 6e) with flexible bulky hydrophobic groups instead of the rigid polyheterocyclic moieties. In silico docking confirmed the ability of 5a-5g to bind to the active site of influenza A CEN (PDB code: 6FS6) like baloxavir acid, 3. These novel compounds inhibited polymerase complex activity, inhibited virus replication in cells, prevented death in a lethal influenza A virus mouse challenge model, and dramatically lowered viral lung titers. 5a and 5e potently inhibited different influenza genera in vitro. Precursors 6a and 6d demonstrated impressive mouse oral bioavailability with 6a, providing effective in vivo protection. Thus, these novel compounds are potent CEN inhibitors with in vitro and in vivo activity comparable to baloxavir.

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