1 research outputs found
Optimization of N‑Substituted Oseltamivir Derivatives as Potent Inhibitors of Group‑1 and -2 Influenza A Neuraminidases, Including a Drug-Resistant Variant
On the basis of our earlier discovery
of N1-selective inhibitors,
the 150-cavity of influenza virus neuraminidases (NAs) could be further
exploited to yield more potent oseltamivir derivatives. Among the
synthesized compounds, <b>15b</b> and <b>15c</b> were
exceptionally active against both group-1 and -2 NAs. Especially for
09N1, N2, N6, and N9 subtypes, they showed 6.80–12.47 and 1.20–3.94
times greater activity than oseltamivir carboxylate (OSC). They also
showed greater inhibitory activity than OSC toward H274Y and E119V
variant. In cellular assays, they exhibited greater potency than OSC
toward H5N1, H5N2, H5N6, and H5N8 viruses. <b>15b</b> demonstrated
high metabolic stability, low cytotoxicity in vitro, and low acute
toxicity in mice. Computational modeling and molecular dynamics studies
provided insights into the role of R group of <b>15b</b> in
improving potency toward group-1 and -2 NAs. We believe the successful
exploitation of the 150-cavity of NAs represents an important breakthrough
in the development of more potent anti-influenza agents