Anti-influenza drug discovery: Structure-activity relationship and mechanistic insight into novel angelicin derivatives

Jiann Yih Yeh; Mohane Selvaraj Coumar; Jim Tong Horng; Hui Yi Shiao; Fu Ming Kuo; Hui Ling Lee; In Chun Chen; Chun Wei Chang; Wen-Fang Tang; Sung Nain Tseng; Chi Jene Chen; Shin Ru Shih; John T.A. Hsu; Chun Chen Liao; Yu Sheng Chao; Hsing Pang Hsieh

doi:10.1021/jm901570x

Anti-influenza drug discovery: Structure-activity relationship and mechanistic insight into novel angelicin derivatives

Jiann Yih Yeh, Mohane Selvaraj Coumar, Jim Tong Horng, Hui Yi Shiao, Fu Ming Kuo, Hui Ling Lee, In Chun Chen, Chun Wei Chang, Wen-Fang Tang, Sung Nain Tseng, Chi Jene Chen, Shin Ru Shih, John T.A. Hsu, Chun Chen Liao, Yu Sheng Chao, Hsing Pang Hsieh^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal Article › peer-review

161 Scopus citations

Abstract

By using a cell-based high throughput screening campaign, a novel angelicin derivative 6a was identified to inhibit influenza A. (H1N1) virus induced cytopathic effect in Madin-Darby canine kidney cell culture in low micromolar range. Detailed structure-activity relationship studies of 6a revealed that the angelicin scaffold is essential for activity in pharmacophore B, while meta-substituted phenyl/2-thiophene rings are optimal in pharmacophore A and C. The optimized lead 4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo[2,3-h] chromen-2-one (8g, IC₅₀ = 70 nM) showed 64-fold enhanced activity compared to the high throughput screening (HTS) hit 6a. Also, 8g was found effective in case of influenza A (H3N2) and influenza B virus strains similar to approved anti-influenza drug zanamivir (4). Preliminary mechanistic studies suggest that these compounds act as anti-influenza agents by inhibiting ribonucleoprotein (RNP) complex associated activity and have the potential to be developed further, which could form the basis for developing additional defense against influenza pandemics.

Original language	English
Pages (from-to)	1519-1533
Number of pages	15
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	4
DOIs	https://doi.org/10.1021/jm901570x
State	Published - 25 02 2010

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Yeh, J. Y., Coumar, M. S., Horng, J. T., Shiao, H. Y., Kuo, F. M., Lee, H. L., Chen, I. C., Chang, C. W., Tang, W.-F., Tseng, S. N., Chen, C. J., Shih, S. R., Hsu, J. T. A., Liao, C. C., Chao, Y. S., & Hsieh, H. P. (2010). Anti-influenza drug discovery: Structure-activity relationship and mechanistic insight into novel angelicin derivatives. Journal of Medicinal Chemistry, 53(4), 1519-1533. https://doi.org/10.1021/jm901570x

@article{999b5ccc7cbf4cffb48f8d8d8b7e349d,

title = "Anti-influenza drug discovery: Structure-activity relationship and mechanistic insight into novel angelicin derivatives",

abstract = "By using a cell-based high throughput screening campaign, a novel angelicin derivative 6a was identified to inhibit influenza A. (H1N1) virus induced cytopathic effect in Madin-Darby canine kidney cell culture in low micromolar range. Detailed structure-activity relationship studies of 6a revealed that the angelicin scaffold is essential for activity in pharmacophore B, while meta-substituted phenyl/2-thiophene rings are optimal in pharmacophore A and C. The optimized lead 4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo[2,3-h] chromen-2-one (8g, IC50 = 70 nM) showed 64-fold enhanced activity compared to the high throughput screening (HTS) hit 6a. Also, 8g was found effective in case of influenza A (H3N2) and influenza B virus strains similar to approved anti-influenza drug zanamivir (4). Preliminary mechanistic studies suggest that these compounds act as anti-influenza agents by inhibiting ribonucleoprotein (RNP) complex associated activity and have the potential to be developed further, which could form the basis for developing additional defense against influenza pandemics.",

author = "Yeh, \{Jiann Yih\} and Coumar, \{Mohane Selvaraj\} and Horng, \{Jim Tong\} and Shiao, \{Hui Yi\} and Kuo, \{Fu Ming\} and Lee, \{Hui Ling\} and Chen, \{In Chun\} and Chang, \{Chun Wei\} and Wen-Fang Tang and Tseng, \{Sung Nain\} and Chen, \{Chi Jene\} and Shih, \{Shin Ru\} and Hsu, \{John T.A.\} and Liao, \{Chun Chen\} and Chao, \{Yu Sheng\} and Hsieh, \{Hsing Pang\}",

year = "2010",

month = feb,

day = "25",

doi = "10.1021/jm901570x",

language = "英语",

volume = "53",

pages = "1519--1533",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "4",

}

Yeh, JY, Coumar, MS, Horng, JT, Shiao, HY, Kuo, FM, Lee, HL, Chen, IC, Chang, CW, Tang, W-F, Tseng, SN, Chen, CJ, Shih, SR, Hsu, JTA, Liao, CC, Chao, YS & Hsieh, HP 2010, 'Anti-influenza drug discovery: Structure-activity relationship and mechanistic insight into novel angelicin derivatives', Journal of Medicinal Chemistry, vol. 53, no. 4, pp. 1519-1533. https://doi.org/10.1021/jm901570x

TY - JOUR

T1 - Anti-influenza drug discovery

T2 - Structure-activity relationship and mechanistic insight into novel angelicin derivatives

AU - Yeh, Jiann Yih

AU - Coumar, Mohane Selvaraj

AU - Horng, Jim Tong

AU - Shiao, Hui Yi

AU - Kuo, Fu Ming

AU - Lee, Hui Ling

AU - Chen, In Chun

AU - Chang, Chun Wei

AU - Tang, Wen-Fang

AU - Tseng, Sung Nain

AU - Chen, Chi Jene

AU - Shih, Shin Ru

AU - Hsu, John T.A.

AU - Liao, Chun Chen

AU - Chao, Yu Sheng

AU - Hsieh, Hsing Pang

PY - 2010/2/25

Y1 - 2010/2/25

N2 - By using a cell-based high throughput screening campaign, a novel angelicin derivative 6a was identified to inhibit influenza A. (H1N1) virus induced cytopathic effect in Madin-Darby canine kidney cell culture in low micromolar range. Detailed structure-activity relationship studies of 6a revealed that the angelicin scaffold is essential for activity in pharmacophore B, while meta-substituted phenyl/2-thiophene rings are optimal in pharmacophore A and C. The optimized lead 4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo[2,3-h] chromen-2-one (8g, IC50 = 70 nM) showed 64-fold enhanced activity compared to the high throughput screening (HTS) hit 6a. Also, 8g was found effective in case of influenza A (H3N2) and influenza B virus strains similar to approved anti-influenza drug zanamivir (4). Preliminary mechanistic studies suggest that these compounds act as anti-influenza agents by inhibiting ribonucleoprotein (RNP) complex associated activity and have the potential to be developed further, which could form the basis for developing additional defense against influenza pandemics.

AB - By using a cell-based high throughput screening campaign, a novel angelicin derivative 6a was identified to inhibit influenza A. (H1N1) virus induced cytopathic effect in Madin-Darby canine kidney cell culture in low micromolar range. Detailed structure-activity relationship studies of 6a revealed that the angelicin scaffold is essential for activity in pharmacophore B, while meta-substituted phenyl/2-thiophene rings are optimal in pharmacophore A and C. The optimized lead 4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo[2,3-h] chromen-2-one (8g, IC50 = 70 nM) showed 64-fold enhanced activity compared to the high throughput screening (HTS) hit 6a. Also, 8g was found effective in case of influenza A (H3N2) and influenza B virus strains similar to approved anti-influenza drug zanamivir (4). Preliminary mechanistic studies suggest that these compounds act as anti-influenza agents by inhibiting ribonucleoprotein (RNP) complex associated activity and have the potential to be developed further, which could form the basis for developing additional defense against influenza pandemics.

UR - https://www.scopus.com/pages/publications/77649210704

U2 - 10.1021/jm901570x

DO - 10.1021/jm901570x

M3 - 文章

C2 - 20092255

AN - SCOPUS:77649210704

SN - 0022-2623

VL - 53

SP - 1519

EP - 1533

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 4

ER -

Anti-influenza drug discovery: Structure-activity relationship and mechanistic insight into novel angelicin derivatives

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