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, 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.
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Authors | 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 |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 53
Issue 4
Pg. 1519-33
(Feb 25 2010)
ISSN: 1520-4804 [Electronic] United States |
PMID | 20092255
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo(2,3-h)chromen-2-one
- 8-benzoyl-4,9-dimethylfuro(2,3-h)chromen-2-one
- Antiviral Agents
- Furocoumarins
- angelicin
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Topics |
- Animals
- Antiviral Agents
(chemical synthesis, chemistry, pharmacology)
- Cell Line
- Cell Survival
(drug effects)
- Dogs
- Drug Discovery
- Furocoumarins
(chemical synthesis, chemistry, pharmacology)
- Humans
- Influenza A virus
(drug effects, physiology)
- Influenza B virus
(drug effects, physiology)
- Structure-Activity Relationship
- Virus Replication
(drug effects)
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