標題: Anti-Influenza Drug Discovery: Structure-Activity Relationship and Mechanistic Insight into Novel Angelicin Derivatives
作者: Yeh, Jiann-Yih
Coumar, Mohane Selvaraj
Horng, Jim-Tong
Shiao, Hui-Yi
Kuo, Fu-Ming
Lee, Hui-Ling
Chen, In-Chun
Chang, Chun-Wei
Tang, Wen-Fang
Tseng, Sung-Nain
Chen, Chi-Jene
Shih, Shin-Ru
Hsu, John T. -A
Liao, Chun-Chen
Chao, Yu-Sheng
Hsieh, Hsing-Pang
生物科技學系
Department of Biological Science and Technology
公開日期: 25-Feb-2010
摘要: 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 ill pharmacophore A and C. The optimized lead 4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo[2,3-h]chromen-2-one (8g, IC(50) = 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.
URI: http://dx.doi.org/10.1021/jm901570x
http://hdl.handle.net/11536/5821
ISSN: 0022-2623
DOI: 10.1021/jm901570x
期刊: JOURNAL OF MEDICINAL CHEMISTRY
Volume: 53
Issue: 4
起始頁: 1519
結束頁: 1533
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