title: 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.
authors.affiliation: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Jiann-Yih
authors.initials: JY
authors.lastname: Yeh
authors.forename: Mohane Selvaraj
authors.initials: MS
authors.lastname: Coumar
authors.forename: Jim-Tong
authors.initials: JT
authors.lastname: Horng
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Shiao
authors.forename: Fu-Ming
authors.initials: FM
authors.lastname: Kuo
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Lee
authors.forename: In-Chun
authors.initials: IC
authors.lastname: Chen
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Chang
authors.forename: Wen-Fang
authors.initials: WF
authors.lastname: Tang
authors.forename: Sung-Nain
authors.initials: SN
authors.lastname: Tseng
authors.forename: Chi-Jene
authors.initials: CJ
authors.lastname: Chen
authors.forename: Shin-Ru
authors.initials: SR
authors.lastname: Shih
authors.forename: John T-A
authors.initials: JT
authors.lastname: Hsu
authors.forename: Chun-Chen
authors.initials: CC
authors.lastname: Liao
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D055808:Drug Discovery; D011564:Furocoumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000502:physiology; D009981:Influenza B virus / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: C547947:4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo(2,3-h)chromen-2-one; C547948:8-benzoyl-4,9-dimethylfuro(2,3-h)chromen-2-one; D000998:Antiviral Agents; D011564:Furocoumarins; C011659:angelicin