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Coumarin−Purine Ribofuranoside Conjugates as New Agents against Hepatitis C Virus

2011; American Chemical Society; Volume: 54; Issue: 7 Linguagem: Inglês

10.1021/jm101337v

1520-4804

Jih Ru Hwu, Shu-Yu Lin, Shwu‐Chen Tsay, Erik De Clercq, Pieter Leyssen, Johan Neyts,

Biochemical and Molecular Research

About 3% of world's population is infected by the hepatitis C virus (HCV), for which prophylactic vaccine is not available yet. Nowadays, pegylated interferon-α 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-(β-d-ribofuranosyl)purine-8-thiones with 3-(chloromethyl)coumarins bearing various substituents. A −SCH2− unit was used to link the coumarin and the purine moieties. The three hydroxyl groups at the 2′-, 3′-, and 5′-positions were selectively protected with an acyl or acetal group in these coumarin−purine ribofuranosides. Their anti-HCV and cytostatic determination assays were performed, and the structure−activity relationship was established. Three conjugates in the family of 8-(coumarin-3′-yl)methylthio-9-(β-d-ribofuranos-1′′-yl)purine possessed an appealing ability to inhibit HCV replication with EC50 between 5.5 and 6.6 μM and EC90 of ∼20 μM. These data in the new compound library provide clues for the future in the development of anti-HCV leads for viral eradication.