Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors

Abstract

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.

Respiratory virus deterrence induced by modified mask filter

“…Sodium dihydrogen phosphate solution is weakly acidic (pH 4.0) and it was reported that excessive osmotic stress in such an environment can trigger damages to the virus morphology and function [ 18 , 19 ], which may have contributed to the HA activity and infectivity reductions in the present study. The inclusion of phosphonates in drugs has been reported to inhibit influenza virus infection [ 20 – 22 ]. Since phosphates are cheap, odorless, and tasteless, their application as a mask filter coating would have a great impact.…”

Green and Effective Preparation of α-Hydroxyphosphonates by Ecocatalysis

“…Among the known organophosphorus compounds, the α-hydroxyphosphonic acids, their esters (hydroxyphosphonates), and close derivatives represent an interesting class of molecules endowed with a wide range of properties. They are especially useful as biologically active compounds such as antibiotics (e.g., Valinophos I [ 13 ], and Fosfazinomycin A III [ 14 ]); enzyme inhibitors (e.g., renin inhibitors II [ 15 ], for potential treatment of hypertension and congestive heart failure or neuraminidase inhibitor [ 16 ], for treatment of influenza infection, commonly called “the flu”); antiparasitics (e.g., inhibitors of Plasmodium falciparum growth IV [ 17 ], useful in treatment of malaria that is caused by this parasite); and insecticides (e.g., trichlorfon V ) ( Figure 1 ). Additionally, α-hydroxyphosphonic acids and their esters are very useful scaffolds in organic synthesis often used to prepare more complex molecules [ 18 ], e.g., after O -allylation and subsequent RCM or isomerization/Claisen rearrangement [ 19 ], reaction with primary amines leading to α-aminophosphonates and phosphonic acids [ 20 ], phospha-Brook rearrangement [ 21 ], reduction [ 22 ], halogenation [ 23 ], and oxidation leading to ketophosphonates ( Figure 1 ) [ 24 ].…”

Development of effective anti-influenza drugs: congeners and conjugates – a review

“…Peraphosphor (PP, 33 ) is the phosphonate congener of peramivir (PE). An efficient synthetic method of peraphosphor [94] comprises a [3 + 2] cycloaddition of 2-ethylbuanenitrile oxide ( 27 ) with a cyclopentene dipolarophile 26 (Fig. 11).…”