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

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.