Anti-influenza drug discovery: structure-activity relationship and mechanistic insight into novel angelicin derivatives
| Autor: | John T.A. Hsu, In Chun Chen, Jiann Yih Yeh, Fu Ming Kuo, Shin-Ru Shih, Wen Fang Tang, Hsing Pang Hsieh, Chun Wei Chang, Sung Nain Tseng, Mohane Selvaraj Coumar, Chi Jene Chen, Yu-Sheng Chao, Chun-Chen Liao, Hui Ling Lee, Jim-Tong Horng, HY Shiao |
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| Rok vydání: | 2010 |
| Předmět: |
Cell Survival
Orthomyxoviridae medicine.disease_cause Virus Replication Antiviral Agents Cell Line chemistry.chemical_compound Structure-Activity Relationship Zanamivir Dogs Angelicin Furocoumarins Drug Discovery Influenza A virus medicine Structure–activity relationship Animals Humans biology Drug discovery Influenzavirus B virus diseases biology.organism_classification Influenza B virus Biochemistry chemistry Molecular Medicine Pharmacophore medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 53(4) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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