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^*

来源：Journal of Medicinal Chemistry, 2010, 53(4): 1519-1533.

DOI：10.1021/jm901570x

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.

• 出版日期2010-2-25
• 单位清华大学; 长春大学