Structure-Based Optimization of N‑Substituted Oseltamivir Derivatives as Potent Anti-Influenza A Virus Agents with Significantly Improved Potency against Oseltamivir-Resistant N1-H274Y Variant

Due
to the emergence of highly pathogenic and oseltamivir-resistant
influenza viruses, there is an urgent need to develop new anti-influenza
agents. Herein, five subseries of oseltamivir derivatives were designed
and synthesized to improve their activity toward drug-resistant viral
strains by further exploiting the 150-cavity in the neuraminidases
(NAs). The bioassay results showed that compound 21h exhibited
antiviral activities similar to or better than those of oseltamivir
carboxylate (OSC) against H5N1, H5N2, H5N6, and H5N8. Besides, 21h was 5- to 86-fold more potent than OSC toward N1, N8,
and N1-H274Y mutant NAs in the inhibitory assays. Computational studies
provided a plausible rationale for the high potency of 21h against group-1 and N1-H274Y NAs. In addition, 21h demonstrated
acceptable oral bioavailability, low acute toxicity, potent antiviral
activity in vivo, and high metabolic stability.
Overall, the above excellent profiles make 21h a promising
drug candidate for the treatment of influenza virus infection.