Optimization of Potent Hepatitis C Virus NS3 Helicase Inhibitors Isolated from the Yellow Dyes Thioflavine S and Primuline

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• 作者：Kelin Li ; Kevin J. Frankowski ; Craig A. Belon ; Ben Neuenswander ; Jean Ndjomou ; Alicia M. Hanson ; Matthew A. Shanahan ; Frank J. Schoenen ; Brian S. J. Blagg ; Jeffrey Aub茅 ; David N. Frick
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 12, 2012
• 年：2012
• 卷：55
• 期：7
• 页码：3319-3330
• 全文大小：498K
• 年卷期：v.55,no.7(April 12, 2012)
• ISSN：1520-4804

文摘

A screen for hepatitis C virus (HCV) NS3 helicase inhibitors revealed that the commercial dye thioflavine S was the most potent inhibitor of NS3-catalyzed DNA and RNA unwinding in the 827-compound National Cancer Institute Mechanistic Set. Thioflavine S and the related dye primuline were separated here into their pure components, all of which were oligomers of substituted benzothiazoles. The most potent compound (P4), a benzothiazole tetramer, inhibited unwinding >50% at 2 卤 1 渭M, inhibited the subgenomic HCV replicon at 10 渭M, and was not toxic at 100 渭M. Because P4 also interacted with DNA, more specific analogues were synthesized from the abundant dimeric component of primuline. Some of the 32 analogues prepared retained ability to inhibit HCV helicase but did not appear to interact with DNA. The most potent of these specific helicase inhibitors (compound 17) was active against the replicon and inhibited the helicase more than 50% at 2.6 卤 1 渭M.