Optimization of potent hepatitis C virus NS3 helicase inhibitors isolated from the yellow dyes thioflavine S and primuline

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 Aubé, David N. Frick

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51 Scopus citations

Abstract

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 ± 1 μM, inhibited the subgenomic HCV replicon at 10 μM, and was not toxic at 100 μM. 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 ± 1 μM.

Original languageEnglish (US)
Pages (from-to)3319-3330
Number of pages12
JournalJournal of Medicinal Chemistry
Volume55
Issue number7
DOIs
StatePublished - Apr 12 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Li, K., Frankowski, K. J., Belon, C. A., Neuenswander, B., Ndjomou, J., Hanson, A. M., Shanahan, M. A., Schoenen, F. J., Blagg, B. S. J., Aubé, J., & Frick, D. N. (2012). Optimization of potent hepatitis C virus NS3 helicase inhibitors isolated from the yellow dyes thioflavine S and primuline. Journal of Medicinal Chemistry, 55(7), 3319-3330. https://doi.org/10.1021/jm300021v