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Based on our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Among the synthesized compounds, 15b and 15c were exceptionally active against both group-1 and -2 NAs. Especially for 09N1, N2, N6 and N9 subtypes, they showed 6.80-12.47 and 1.20-3.94 times greater activity than oseltamivir carboxylate (OSC). They also showed greater inhibitory activity than OSC towards H274Y and E119V variant. In cellular assays, they exhibited greater potency than OSC towards H5N1, H5N2, H5N6, and H5N8 viruses. 15b demonstrated high metabolic stability, low cytotoxicity in vitro, and low acute toxicity in mice. Computational modeling and molecular dynamics studies provided insights into the role of R group of 15b in improving potency towards group-1 and -2 NAs. We believe the successful exploitation of the 150-cavity of NAs represents an important breakthrough in the development of more potent anti-influenza agents.
This article was published in the following journal.
Name: Journal of medicinal chemistry
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Amidines substituted with a benzene group. Benzamidine and its derivatives are known as peptidase inhibitors.
A group of nitrogen mustard compounds which are substituted with a phosphoramide group or its derivatives. They are usually cytotoxic and used as antineoplastic agents.
Compounds that contain the biogenic monoamine tryptamine and are substituted with one methoxy group and two methyl groups. Members of this group include several potent serotonergic hallucinogens found in several unrelated plants, skins of certain toads, and in mammalian brains. They are possibly involved in the etiology of schizophrenia.
Sulfonic acid derivatives that are substituted with an aliphatic hydrocarbon group.
Species of the genus INFLUENZAVIRUS B that cause HUMAN INFLUENZA and other diseases primarily in humans. Antigenic variation is less extensive than in type A viruses (INFLUENZA A VIRUS) and consequently there is no basis for distinct subtypes or variants. Epidemics are less likely than with INFLUENZA A VIRUS and there have been no pandemics. Previously only found in humans, Influenza B virus has been isolated from seals which may constitute the animal reservoir from which humans are exposed.
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