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.