With the introduction of bioisosteres of the guanidinium group together with scaffold hopping, 35
zanamivir analogs with C-4-modification were synthesized, and their inhibitory activities against both
group-1 and group-2 neuraminidase (H5N1 and H3N2) were determined. Compound D26 exerts the
most potency, with IC50 values of 0.58 and 2.72 mM against N2 and N1, respectively. Further preliminary
anti-avian influenza virus (AIV, H5N1) activities against infected MDCK cells were evaluated, and D5
exerts w58% protective against AIV infection, which was comparable to zanamivir (w67%). In a rat
pharmacokinetic study, compound D5 showed an increased plasma half-life (t1/2) compared to zanamivir
following either intravenous or oral administration. This study may represent a new start point for the
future development of improved anti-AIV agents