Synthesis of C-4-modified zanamivir analogs as neuraminidase inhibitors and their anti-AIV activities

Deju Ye; Woo Jin Shin; Ning Li; Wei Tang; Enguang Feng; Jian Li; Pei Lan He; Jian Ping Zuo; Hanjo Kim; Ky Youb Nam; Weiliang Zhu; Baik Lin Seong; Kyoung Tai No; Hualiang Jiang; Hong Liu

doi:10.1016/j.ejmech.2012.06.033

Synthesis of C-4-modified zanamivir analogs as neuraminidase inhibitors and their anti-AIV activities

Deju Ye, Woo Jin Shin, Ning Li, Wei Tang, Enguang Feng, Jian Li, Pei Lan He, Jian Ping Zuo, Hanjo Kim, Ky Youb Nam, Weiliang Zhu, Baik Lin Seong, Kyoung Tai No, Hualiang Jiang, Hong Liu

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29 Citations (Scopus)

Abstract

With the introduction of bioisosteres of the guanidinium group together with scaffold hopping, 35 zanamivir analogs with C-4-modification were synthesized, and their inhibitory activities against both group-1 and group-2 neuraminidase (H5N1 and H3N2) were determined. Compound D26 exerts the most potency, with IC₅₀ values of 0.58 and 2.72 μM against N2 and N1, respectively. Further preliminary anti-avian influenza virus (AIV, H5N1) activities against infected MDCK cells were evaluated, and D5 exerts ∼58% protective against AIV infection, which was comparable to zanamivir (∼67%). In a rat pharmacokinetic study, compound D5 showed an increased plasma half-life (t_1/2) compared to zanamivir following either intravenous or oral administration. This study may represent a new start point for the future development of improved anti-AIV agents.

Original language	English
Pages (from-to)	764-770
Number of pages	7
Journal	European Journal of Medicinal Chemistry
Volume	54
DOIs	https://doi.org/10.1016/j.ejmech.2012.06.033
Publication status	Published - 2012 Aug

Bibliographical note

Funding Information:
We gratefully acknowledge financial support from National Basic Research Program of China (Grants 2009CB918502 and 2012CB518005 ), the National Natural Science Foundation of China (Grants 20721003 and 81025017 ), National S&T Major Projects (2012ZX09103-101-072), Silver Project (260644), the R&D Program of MKE/KEIT (10031969), Translational Research Center for Protein Function Control, NSF ( 2011-0001244 ) and a grant from the Korea Healthcare Technology R&D project, Ministry for Health, Welfare Family Affairs, Republic of Korea ( A085105 ).

All Science Journal Classification (ASJC) codes

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2012.06.033

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title = "Synthesis of C-4-modified zanamivir analogs as neuraminidase inhibitors and their anti-AIV activities",

abstract = "With the introduction of bioisosteres of the guanidinium group together with scaffold hopping, 35 zanamivir analogs with C-4-modification were synthesized, and their inhibitory activities against both group-1 and group-2 neuraminidase (H5N1 and H3N2) were determined. Compound D26 exerts the most potency, with IC50 values of 0.58 and 2.72 μM against N2 and N1, respectively. Further preliminary anti-avian influenza virus (AIV, H5N1) activities against infected MDCK cells were evaluated, and D5 exerts ∼58% protective against AIV infection, which was comparable to zanamivir (∼67%). In a rat pharmacokinetic study, compound D5 showed an increased plasma half-life (t1/2) compared to zanamivir following either intravenous or oral administration. This study may represent a new start point for the future development of improved anti-AIV agents.",

author = "Deju Ye and Shin, {Woo Jin} and Ning Li and Wei Tang and Enguang Feng and Jian Li and He, {Pei Lan} and Zuo, {Jian Ping} and Hanjo Kim and Nam, {Ky Youb} and Weiliang Zhu and Seong, {Baik Lin} and {Tai No}, Kyoung and Hualiang Jiang and Hong Liu",

note = "Funding Information: We gratefully acknowledge financial support from National Basic Research Program of China (Grants 2009CB918502 and 2012CB518005 ), the National Natural Science Foundation of China (Grants 20721003 and 81025017 ), National S&T Major Projects (2012ZX09103-101-072), Silver Project (260644), the R&D Program of MKE/KEIT (10031969), Translational Research Center for Protein Function Control, NSF ( 2011-0001244 ) and a grant from the Korea Healthcare Technology R&D project, Ministry for Health, Welfare Family Affairs, Republic of Korea ( A085105 ). ",

year = "2012",

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doi = "10.1016/j.ejmech.2012.06.033",

language = "English",

volume = "54",

pages = "764--770",

journal = "European Journal of Medicinal Chemistry",

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T1 - Synthesis of C-4-modified zanamivir analogs as neuraminidase inhibitors and their anti-AIV activities

AU - Ye, Deju

AU - Shin, Woo Jin

AU - Li, Ning

AU - Tang, Wei

AU - Feng, Enguang

AU - Li, Jian

AU - He, Pei Lan

AU - Zuo, Jian Ping

AU - Kim, Hanjo

AU - Nam, Ky Youb

AU - Zhu, Weiliang

AU - Seong, Baik Lin

AU - Tai No, Kyoung

AU - Jiang, Hualiang

AU - Liu, Hong

N1 - Funding Information: We gratefully acknowledge financial support from National Basic Research Program of China (Grants 2009CB918502 and 2012CB518005 ), the National Natural Science Foundation of China (Grants 20721003 and 81025017 ), National S&T Major Projects (2012ZX09103-101-072), Silver Project (260644), the R&D Program of MKE/KEIT (10031969), Translational Research Center for Protein Function Control, NSF ( 2011-0001244 ) and a grant from the Korea Healthcare Technology R&D project, Ministry for Health, Welfare Family Affairs, Republic of Korea ( A085105 ).

PY - 2012/8

Y1 - 2012/8

N2 - With the introduction of bioisosteres of the guanidinium group together with scaffold hopping, 35 zanamivir analogs with C-4-modification were synthesized, and their inhibitory activities against both group-1 and group-2 neuraminidase (H5N1 and H3N2) were determined. Compound D26 exerts the most potency, with IC50 values of 0.58 and 2.72 μM against N2 and N1, respectively. Further preliminary anti-avian influenza virus (AIV, H5N1) activities against infected MDCK cells were evaluated, and D5 exerts ∼58% protective against AIV infection, which was comparable to zanamivir (∼67%). In a rat pharmacokinetic study, compound D5 showed an increased plasma half-life (t1/2) compared to zanamivir following either intravenous or oral administration. This study may represent a new start point for the future development of improved anti-AIV agents.

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Synthesis of C-4-modified zanamivir analogs as neuraminidase inhibitors and their anti-AIV activities

Abstract

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