Structure-based design and synthesis of C-1- and C-4-modified analogs of zanamivir as neuraminidase inhibitors

Enguang Feng, Woo Jin Shin, Xuelian Zhu, Jian Li, Deju Ye, Jiang Wang, Mingyue Zheng, Jian Ping Zuo, Kyoung Tai No, Xian Liu, Weiliang Zhu, Wei Tang, Baik Lin Seong, Hualiang Jiang, Hong Liu

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

In order to exploit the 430-cavity in the active sites of neuraminidases, 22 zanamivir analogs with C-1 and C-4 modification were synthesized, and their inhibitory activities against both group-1 (H5N1, H1N1) and group-2 neuraminidases (H3N2) were determined. Compound 9f exerts the most potency, with IC50 value of 0.013, 0.001, and 0.09 μM against H3N2, H5N1, and H1N1, which is similar to that of zanamivir (H3N2 IC50 = 0.0014 μM, H5N1 IC50 = 0.012 μM, H1N1 IC50 = 0.001 μM). Pharmacokinetic studies of compound 9f in rats showed a much longer plasma half-life (t1/2) than that of zanamivir following administration (po dose). Molecular modeling provided information about the binding model between the new inhibitors and neuraminidase, with the elongated groups at the C-1-position being projected toward the 430-loop region. This study may represent a novel starting point for the future development of improved antiflu agents.

Original languageEnglish
Pages (from-to)671-684
Number of pages14
JournalJournal of Medicinal Chemistry
Volume56
Issue number3
DOIs
Publication statusPublished - 2013 Feb 14

Fingerprint

Zanamivir
Neuraminidase
Inhibitory Concentration 50
Half-Life
Catalytic Domain
Pharmacokinetics

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Feng, Enguang ; Shin, Woo Jin ; Zhu, Xuelian ; Li, Jian ; Ye, Deju ; Wang, Jiang ; Zheng, Mingyue ; Zuo, Jian Ping ; No, Kyoung Tai ; Liu, Xian ; Zhu, Weiliang ; Tang, Wei ; Seong, Baik Lin ; Jiang, Hualiang ; Liu, Hong. / Structure-based design and synthesis of C-1- and C-4-modified analogs of zanamivir as neuraminidase inhibitors. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 3. pp. 671-684.
@article{2b78821f3654431b99c68787794c13f1,
title = "Structure-based design and synthesis of C-1- and C-4-modified analogs of zanamivir as neuraminidase inhibitors",
abstract = "In order to exploit the 430-cavity in the active sites of neuraminidases, 22 zanamivir analogs with C-1 and C-4 modification were synthesized, and their inhibitory activities against both group-1 (H5N1, H1N1) and group-2 neuraminidases (H3N2) were determined. Compound 9f exerts the most potency, with IC50 value of 0.013, 0.001, and 0.09 μM against H3N2, H5N1, and H1N1, which is similar to that of zanamivir (H3N2 IC50 = 0.0014 μM, H5N1 IC50 = 0.012 μM, H1N1 IC50 = 0.001 μM). Pharmacokinetic studies of compound 9f in rats showed a much longer plasma half-life (t1/2) than that of zanamivir following administration (po dose). Molecular modeling provided information about the binding model between the new inhibitors and neuraminidase, with the elongated groups at the C-1-position being projected toward the 430-loop region. This study may represent a novel starting point for the future development of improved antiflu agents.",
author = "Enguang Feng and Shin, {Woo Jin} and Xuelian Zhu and Jian Li and Deju Ye and Jiang Wang and Mingyue Zheng and Zuo, {Jian Ping} and No, {Kyoung Tai} and Xian Liu and Weiliang Zhu and Wei Tang and Seong, {Baik Lin} and Hualiang Jiang and Hong Liu",
year = "2013",
month = "2",
day = "14",
doi = "10.1021/jm3009713",
language = "English",
volume = "56",
pages = "671--684",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "3",

}

Feng, E, Shin, WJ, Zhu, X, Li, J, Ye, D, Wang, J, Zheng, M, Zuo, JP, No, KT, Liu, X, Zhu, W, Tang, W, Seong, BL, Jiang, H & Liu, H 2013, 'Structure-based design and synthesis of C-1- and C-4-modified analogs of zanamivir as neuraminidase inhibitors', Journal of Medicinal Chemistry, vol. 56, no. 3, pp. 671-684. https://doi.org/10.1021/jm3009713

Structure-based design and synthesis of C-1- and C-4-modified analogs of zanamivir as neuraminidase inhibitors. / Feng, Enguang; Shin, Woo Jin; Zhu, Xuelian; Li, Jian; Ye, Deju; Wang, Jiang; Zheng, Mingyue; Zuo, Jian Ping; No, Kyoung Tai; Liu, Xian; Zhu, Weiliang; Tang, Wei; Seong, Baik Lin; Jiang, Hualiang; Liu, Hong.

In: Journal of Medicinal Chemistry, Vol. 56, No. 3, 14.02.2013, p. 671-684.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Structure-based design and synthesis of C-1- and C-4-modified analogs of zanamivir as neuraminidase inhibitors

AU - Feng, Enguang

AU - Shin, Woo Jin

AU - Zhu, Xuelian

AU - Li, Jian

AU - Ye, Deju

AU - Wang, Jiang

AU - Zheng, Mingyue

AU - Zuo, Jian Ping

AU - No, Kyoung Tai

AU - Liu, Xian

AU - Zhu, Weiliang

AU - Tang, Wei

AU - Seong, Baik Lin

AU - Jiang, Hualiang

AU - Liu, Hong

PY - 2013/2/14

Y1 - 2013/2/14

N2 - In order to exploit the 430-cavity in the active sites of neuraminidases, 22 zanamivir analogs with C-1 and C-4 modification were synthesized, and their inhibitory activities against both group-1 (H5N1, H1N1) and group-2 neuraminidases (H3N2) were determined. Compound 9f exerts the most potency, with IC50 value of 0.013, 0.001, and 0.09 μM against H3N2, H5N1, and H1N1, which is similar to that of zanamivir (H3N2 IC50 = 0.0014 μM, H5N1 IC50 = 0.012 μM, H1N1 IC50 = 0.001 μM). Pharmacokinetic studies of compound 9f in rats showed a much longer plasma half-life (t1/2) than that of zanamivir following administration (po dose). Molecular modeling provided information about the binding model between the new inhibitors and neuraminidase, with the elongated groups at the C-1-position being projected toward the 430-loop region. This study may represent a novel starting point for the future development of improved antiflu agents.

AB - In order to exploit the 430-cavity in the active sites of neuraminidases, 22 zanamivir analogs with C-1 and C-4 modification were synthesized, and their inhibitory activities against both group-1 (H5N1, H1N1) and group-2 neuraminidases (H3N2) were determined. Compound 9f exerts the most potency, with IC50 value of 0.013, 0.001, and 0.09 μM against H3N2, H5N1, and H1N1, which is similar to that of zanamivir (H3N2 IC50 = 0.0014 μM, H5N1 IC50 = 0.012 μM, H1N1 IC50 = 0.001 μM). Pharmacokinetic studies of compound 9f in rats showed a much longer plasma half-life (t1/2) than that of zanamivir following administration (po dose). Molecular modeling provided information about the binding model between the new inhibitors and neuraminidase, with the elongated groups at the C-1-position being projected toward the 430-loop region. This study may represent a novel starting point for the future development of improved antiflu agents.

UR - http://www.scopus.com/inward/record.url?scp=84873916093&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873916093&partnerID=8YFLogxK

U2 - 10.1021/jm3009713

DO - 10.1021/jm3009713

M3 - Article

C2 - 23330908

AN - SCOPUS:84873916093

VL - 56

SP - 671

EP - 684

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 3

ER -