Coumarin鈭扨urine Ribofuranoside Conjugates as New Agents against Hepatitis C Virus

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• 作者：Jih Ru Hwu ; Shu-Yu Lin ; Shwu-Chen Tsay ; Erik De Clercq ; Pieter Leyssen ; Johan Neyts
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 14, 2011
• 年：2011
• 卷：54
• 期：7
• 页码：2114-2126
• 全文大小：1027K
• 年卷期：v.54,no.7(April 14, 2011)
• ISSN：1520-4804

文摘

About 3% of world鈥檚 population is infected by the hepatitis C virus (HCV), for which prophylactic vaccine is not available yet. Nowadays, pegylated interferon-伪 and ribavirin are commonly used to treat HCV; unfortunately these drugs often produce significant side effects. Upon the desperate need of anti-HCV drugs, a plan to establish a new compound library was set that included leads with high antiviral activity, good hydrophilicity, yet low toxicity. Accordingly, 26 new conjugated compounds were synthesized through the chemical coupling of various 9-(尾-d-ribofuranosyl)purine-8-thiones with 3-(chloromethyl)coumarins bearing various substituents. A 鈭扴CH₂鈭?unit was used to link the coumarin and the purine moieties. The three hydroxyl groups at the 2鈥?, 3鈥?, and 5鈥?positions were selectively protected with an acyl or acetal group in these coumarin鈭抪urine ribofuranosides. Their anti-HCV and cytostatic determination assays were performed, and the structure鈭抋ctivity relationship was established. Three conjugates in the family of 8-(coumarin-3鈥?yl)methylthio-9-(尾-d-ribofuranos-1鈥测€?yl)purine possessed an appealing ability to inhibit HCV replication with EC₅₀ between 5.5 and 6.6 渭M and EC₉₀ of 20 渭M. These data in the new compound library provide clues for the future in the development of anti-HCV leads for viral eradication.