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

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.

Identification of N- and C-3-Modified Laudanosoline Derivatives as Novel Influenza PAN Endonuclease Inhibitors

“…Using general procedure A, 60 was reacted with 3-nitrobenzoic acid to give 84 as a white solid in an 82% yield. 1 (22). It was obtained as a white solid in an 80% yield.…”

Contemporary medicinal chemistry strategies for the discovery and optimization of influenza inhibitors targeting vRNP constituent proteins

“…However, in vitro studies have revealed that the mutation PA I38X were detected in 2.2%–9.7% of baloxavir-treated patients, and exhibited reduced susceptibility to BXM by 20–40 fold 65 . Therefore, in the future, the rapid emergence of drug resistance could become a significant obstacle to antiviral therapy with BXM 66 , 67 . At present, substantial efforts were devoted to developing polyheterocyclic CEN inhibitors as candidates for treating influenza infection.…”

Anno 2021: Which antivirals for the coming decade?

“… 45 However, mutations in the PA subunit associated with BMX resistance were detected during clinical trials, 46 prompting further medicinal chemistry efforts towards the exploration of alternative scaffolds. 47 , 48 , 49 …”