A sialosyl sulfonate as a potent inhibitor of influenza virus replication

Abstract

A new direction for influenza virus sialidase inhibitor development was identified using a sulfonate congener of 2-deoxy-2-β-H N-acetylneuraminic acid. Sialosyl sulfonates can be synthesised efficiently in four steps from N-acetylneuraminic acid via a microwave assisted decarboxylation. The presence of the sulfonate group significantly increases inhibition of influenza virus sialidase and viral infection when compared to the carboxylate congener, and also to the benchmark sialidase inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid, Neu5Ac2en.

A Sulfonozanamivir Analogue Has Potent Anti‐influenza Virus Activity

“…Key among the interacting substituents is a charged group, represented by the carboxylate of the natural substrate, and of 1 , which contributes significantly (≥50 % of the interaction energy) to binding of the substrate or inhibitor to the enzyme active site. We, and others, have recently reported that the sialosyl α‐sulfonate 4 , with a central, saturated pyranose ring, and in which the natural carboxylate is replaced by a sulfonate group, is an inhibitor of both viral and bacterial sialidases. The incorporation of the sulfonate as the acidic group led to significantly greater inhibitory potency relative to the corresponding carboxylate and phosphonate congeners.…”

“…We, and others, have recently reported that the sialosyl α‐sulfonate 4 , with a central, saturated pyranose ring, and in which the natural carboxylate is replaced by a sulfonate group, is an inhibitor of both viral and bacterial sialidases. The incorporation of the sulfonate as the acidic group led to significantly greater inhibitory potency relative to the corresponding carboxylate and phosphonate congeners. Sulfonate derivative 4 showed micromolar level inhibition of influenza virus sialidase activity and viral infection in vitro, and was more effective than the benchmark unsaturated sialidase inhibitor Neu5Ac2en 2 .…”

“…The incorporation of the sulfonate as the acidic group led to significantly greater inhibitory potency relative to the corresponding carboxylate and phosphonate congeners. Sulfonate derivative 4 showed micromolar level inhibition of influenza virus sialidase activity and viral infection in vitro, and was more effective than the benchmark unsaturated sialidase inhibitor Neu5Ac2en 2 . The sialidase inhibitory activity produced by 4 led us to explore the sialosyl α‐sulfonate template for development of new, high‐potency influenza virus sialidase inhibitors.…”

“…Based on our previously reported method of microwave (MW)‐mediated decarboxylation, the synthesis of glycosyl acetate derivative 9 was achieved through a three step reaction sequence. Saponification of the ester groups of 7 , followed by global reintroduction of the acetates under standard conditions (Ac 2 O/py) yielded derivative 8 , which was then subjected to MW irradiation to give 9 as an anomeric mixture (α/β 1:5).…”

“…Conversion of the glycosyl acetate 9 into the corresponding thioacyl derivative, was initially carried out following our previously reported procedure using thioacetic acid under Lewis acid catalysis in CH 3 CN . In contrast to reaction on the C3 acetate derivative, in the presence of the C3 carbamate, formation of the axial β‐thioacetate was found to predominate (α/β 1:7).…”