Non-rigid Diarylmethyl Analogs of Baloxavir as Cap-Dependent Endonuclease Inhibitors of Influenza Viruses.
Ivashchenko AA, Mitkin OD, Jones JC, Nikitin AV, Koryakova AG, Ryakhovskiy A, Karapetian RN, Kravchenko DV, Aladinskiy V, Leneva IA, Falynskova IN, Glubokova EA, Govorkova EA, Ivachtchenko AV.
4-Substituted 2,4-dioxobutanoic acids inhibit influenza virus cap-dependent endonuclease (CEN) activity. Baloxavir marboxil, <b>4</b>, is approved for treating influenza virus infections. We describe here the synthesis and biological evaluation of active compounds, <b>5a</b>-<b>5g</b>, and their precursors (<b>6a</b>, <b>6b</b>, <b>6d</b>, and <b>6e</b>) with flexible bulky hydrophobic groups instead of the rigid polyheterocyclic moieties. In silico docking confirmed the ability of <b>5a</b>-<b>5g</b> to bind to the active site of influenza A CEN (PDB code: 6FS6) like baloxavir acid, <b>3</b>. 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. <b>5a</b> and <b>5e</b> potently inhibited different influenza genera in vitro. Precursors <b>6a</b> and <b>6d</b> demonstrated impressive mouse oral bioavailability with <b>6a</b>, providing effective in vivo protection. Thus, these novel compounds are potent CEN inhibitors with in vitro and in vivo activity comparable to baloxavir.