Two phosphonate compounds la (4-amino-1-phosphono-DANA) and 1b (phosphono-zanamivir) are synthesized and shown More potent than zanamivir against the neuraminidases of avian and human influenza viruses, including the oseltamivir-resistant strains. For the first time, the practical synthesis of these phosphonate compounds is realized by conversion of sialic acid to peracetylated phosphono-DANA diethyl ester (5) as a key intermediate in three steps by a novel approach. In comparison with zanamivir, the high affinity of la and 1b can be partly attributable to the strong electrostatic interactions of their phosphonate,group'S With the three arginine residues (Arg118, Arg292, and Arg371) in the active site of neuraminidases. These phosphonates are nontoxic to the human 293T cells; they protect cells from influenza : virus infection with EC50 values. in low-nanomolar range; including the wild-type WSN (H1N1), the 2009 pandemic (H1N1), the oseltamivir-resistant H274Y (H1N1), RG14 (H5N1); and Udorn (H3N2) influenza strains.