Discovery of N‑Substituted
Oseltamivir Derivatives
as Potent and Selective Inhibitors of H5N1 Influenza Neuraminidase
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Abstract
To
discover group-1-specific neuraminidase (NA) inhibitors that
are especially involved in combating the H5N1 virus, two series of
oseltamivir derivatives were designed and synthesized by targeting
the 150-cavity. Among these, compound <b>20l</b> was the most
potent N1-selective inhibitor, with IC<sub>50</sub> values of 0.0019,
0.0038, and 0.0067 μM against NAs from three H5N1 viruses. These
values are better than those of oseltamivir carboxylate. Compound <b>32</b> was another potent N1-selective inhibitor that exhibited
a 12-fold increase in activity against the H274Y mutant relative to
oseltamivir carboxylate. Molecular docking studies revealed that the
150-cavity was an auxiliary binding site that may contribute to the
high selectivity of these compounds. The present work is a significant
breakthrough in the discovery of potent group-1-specific neuraminidase
inhibitors, which may be further investigated for the treatment of
infection by the H5N1 virus