Inhibition of bacterial and viral sialidases by 3-fluoro-N-acetylneuraminic acid

Influenza neuraminidase operates via a nucleophilic mechanism and can be targeted by covalent inhibitors

“…Another electronegative group at the C-3 position should also be present to destabilize any oxocarbenium ion transition-state intermediate, thereby stabilizing the potential Tyr406-inhibitor covalent bond 26 . Fluorinated compounds have been investigated for their anti-NA activity for quite some time and are excellent choices for covalent influenza NA inhibitors [26][27][28][29][30] . Although 2b,3eq-difluoro-Neu5Ac, which has been explored as an inhibitor of parainfluenza virus, was readily available from our previous studies 30 , structural analysis clearly demonstrates that the compound should be in the a-anomeric configuration so that the …”

An O-glycoside of sialic acid derivative that inhibits both hemagglutinin and sialidase activities of influenza viruses

“…Most of the inhibitors of sialidases reported so far are derived from the 2,3-ene compound that has the half-chair conformation to mimic the transition state of the enzyme reaction (Varghese et al, 1992). Sialic acid derivatives without aglycone are also considered to mimic the transition state (Hagiwara et al, 1994). Different approaches accommodating noncleavable glycosidic linkage has been also addressed in find sialidase inhibitors, for instance, trisaccharides having Neu5Ac as thioglycoside were shown to be inhibitors (K i value of µM range) of sialidase from Arthrobacter sialophilus (Kessler et al, 1982).…”

Chemistry, biochemistry and biology of sialic acids

“…The finding that these glycosides are the first common inhibitors of both hemagglutinin and sialidase of influenza viruses may prove to be of great advantage. 3F-Neu5Ac strongly and competitively inhibits bacterial, viral and mouse spleen sialidases [442]. This mechanism-based inhibitor acts by a fluoromethylene-quinone formed spontaneously from the liberated difluoromethylphenol.…”