Anti-Influenza Drug Discovery: Structure−Activity Relationship and Mechanistic Insight into Novel Angelicin Derivatives

• Published in: Journal of medicinal chemistry Vol. 53; no. 4; pp. 1519 - 1533
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Columbus, OH American Chemical Society 25-02-2010
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Line; Cell Survival - drug effects; Dogs; Drug Discovery; Furocoumarins - chemical synthesis; Furocoumarins - chemistry; Furocoumarins - pharmacology; Humans; Influenza A virus - drug effects; Influenza A virus - physiology; Influenza B virus - drug effects; Influenza B virus - physiology; Medical sciences; Pharmacology. Drug treatments; Structure-Activity Relationship; Virus Replication - drug effects; Ribonucleoprotein; Coumarine derivatives; Orthomyxoviridae; Influenza B virus; Optimization; Research and development; Kidney; Thiophene derivatives; Structure activity relation; Antiviral; Mechanism of action; Chemical synthesis; Dog; Drug; Fissipedia; Carnivora; Furocoumarine derivatives; Lactone; In vitro; Influenzavirus; Virus; Influenzavirus B; Vertebrata; Influenzavirus A; Mammalia; Cell line; Influenza A virus
• ISSN: 0022-2623; 1520-4804
• 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 in pharmacophore A and C. The optimized lead 4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo[2,3-h]chromen-2-one (8g, IC50 = 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.