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 |
Appears in Collections: | Articles |
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