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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, 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.
AuthorsJiann-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
JournalJournal of medicinal chemistry (J Med Chem) Vol. 53 Issue 4 Pg. 1519-33 (Feb 25 2010) ISSN: 1520-4804 [Electronic] United States
PMID20092255 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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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