Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors

Peramivir
is a potent neuraminidase (NA) inhibitor for treatment
of influenza infection by intravenous administration. By replacing
the carboxylate group in peramivir with a phosphonate group, phosphono-peramivir
(6a), the dehydration and deoxy derivatives (7a and 8a) as well as their corresponding monoalkyl esters
are prepared from a pivotal intermediate epoxide 12.
Among these phosphonate compounds, the dehydration derivative 7a that has a relatively rigid cyclopentene core structure
exhibits the strongest inhibitory activity (IC50 = 0.3–4.1
nM) against several NAs of wild-type human and avian influenza viruses
(H1N1, H3N2, H5N1, and H7N9), although the phosphonate congener 6a is unexpectedly less active than peramivir. The inferior
binding affinity of 6a is attributable to the deviated
orientations of its phosphonic acid and 3-pentyl groups in the NA
active site as inferred from the NMR, X-ray diffraction, and molecular
modeling analyses. Compound 7a is active to the oseltamivir-resistant
H275Y strains of H1N1 and H5N1 viruses (IC50 = 73–86
nM). The phosphonate monoalkyl esters (6b, 6c, 7b, 7c, 8b, and 8c) are better anti-influenza agents (EC50 = 19–89
nM) than their corresponding phosphonic acids (EC50 = 50–343
nM) in protection of cells from the viral infection. The phosphonate
monoalkyl esters are stable in buffer solutions (pH 2.0–7.4)
and rabbit serum; furthermore, the alkyl group is possibly tuned to
attain the desired pharmacokinetic properties.