C O M M U N I C A T I O N S
Scheme 1. Synthesis of Tamiflu 1, Oseltamivir 2, the Guanidine
Analogue 13a, and the Phosphonate Congeners 3, 3b, and 13ba
phosphonate 3 is more active than oseltamivir by 19- and 7-folds,
respectively, in the NA inhibition and antiflu assays. The phos-
phonate 3 was further evaluated at multiple concentrations to
determine the growth inhibition on the host MDCK cells. The
deduced CC50 value of phosphonate 3 was 74 µM. The phosphonate
3, showing a high selectivity index of greater than 15800, is thus
a potent antiviral agent against H1N1 virus with no toxicity to the
host MDCK cells. By replacing the amino group in 3 with a
guanidino group, the phosphonate 13b exhibits an enhanced NA
inhibition (Ki ) 0.06 nM) and antiflu activity (EC50 ) 0.09 nM).
By analogy to the previous reports,3 the guanidinium group may
exert strong electrostatic interactions with the residues of Glu119,
Asp151, and Glu227.
Before a safe and effective vaccine is available to protect the
possible pandemic avian flu, neuraminidase inhibitors are the only
therapy we have. The recent reports on the drug resistant avian flu
infections and the side effects in children receiving Tamiflu
treatments suggest that new chemical identities for neuraminidase
inhibitors are needed for our battle against the threat of the pandemic
flu. The phosphonate congeners described in this study are
significantly more potent than the carboxylate congeners against
the wild-type neuraminidases of H1N1 and H5N1. In addition,
compound 13b is an effective inhibitor at 19 nM for the H274Y
mutant of a H5N1 neuraminidase. Because the high polarity of
phosphonate and guanidinium groups may cause a problem of orally
bioavailability, further investigation of formulation and use of
prodrugs, for example, acyloxymethyl- and arylphosphonate esters,9
may eventually solve the problem in the drug development.
Supporting Information Available: Complete ref 3a and ref 7,
experimental section, computer modeling of neuraminidase inhibition,
1H, 13C, and 31P NMR spectra. This material is available free of charge
References
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