Elaborate Structural Modifications Yielding Novel Boron-Containing N‑Substituted Oseltamivir Derivatives as Potent Neuraminidase Inhibitors with Significantly Improved Broad-Spectrum Antiresistance Profiles

Inspired by our previous finding that targeting the 150-cavity
with a multisite-binding strategy emerged as an effective approach
to obtain more potent and selective neuraminidase (NA) inhibitors
against influenza virus, we present here the design, synthesis, and
optimization of novel boron-containing N-substituted oseltamivir (OSC)
derivatives. Exploratory structure–activity relationship (SAR)
studies led to the identification of compounds 27c and 33c as the most potent NA inhibitors, surpassing OSC in potency
against both wild-type group-1 NAs and oseltamivir-resistant NAs.
These compounds demonstrated significant antiviral activity against
several wild-type strains and H1N1pdm09 strains (EC50 =
0.03 ± 0.005 and 0.03 ± 0.0008 μM, respectively).
Additionally, these compounds did not exhibit significant toxicity
(CC50 > 200 μM in CEF cells; CC50 >
250
μM in MDCK cells). These findings highlight 27c and 33c as promising next-generation anti-influenza
agents.