Anti-influenza drug discovery: structure-activity relationship and mechanistic insight into novel angelicin derivatives.
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.
Yeh
Jiann-Yih
JY
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Coumar
Mohane Selvaraj
MS
Horng
Jim-Tong
JT
Shiao
Hui-Yi
HY
Kuo
Fu-Ming
FM
Lee
Hui-Ling
HL
Chen
In-Chun
IC
Chang
Chun-Wei
CW
Tang
Wen-Fang
WF
Tseng
Sung-Nain
SN
Chen
Chi-Jene
CJ
Shih
Shin-Ru
SR
Hsu
John T-A
JT
Liao
Chun-Chen
CC
Chao
Yu-Sheng
YS
Hsieh
Hsing-Pang
HP
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
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