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vide a novel class of arylthiourea HCV inhibitors bearing various
functionalities, such as cyclic urea, cyclic thiourea, urea, and thio-
urea, on the alkyl linker. According to our SAR investigation, varia-
tion in the ring size from five-membered to seven-membered
cyclic urea resulted in an interesting pattern of activity. The
five-membered cyclic urea 13 demonstrated moderate inhibitory
activity with an EC50 of 0.28 lM. An expansion of the ring size to
six-membered cyclic urea 14 reduced the activity. Interestingly,
further ring expansion to a seven-membered ring 15 showed six-
fold increased activity. This effect might be due to their drastically
conformational change and steric requirement between the rings
of different size. However, the underlying cause of this biological
result is not fully understood and worthy of further study. Incorpo-
ration of a methyl group at the left-hand phenyl ring resulted in
diminished activity. Increasing the alkyl chain length from five to
eight carbon atoms provided a corresponding increase in activity.
Among compounds tested, the new carbazole derivative 64, which
has an eight-carbon linkage between the phenyl and carbazole
rings and a tolyl group at the N-9 position of carbazole, was found
to possess strong anti-HCV activity (EC50 = 0.031
toxicity (CC50 >50 M), and higher selectivity index (SI >1612)
compared to its derivatives. Further mechanistic and pharmacoki-
netic studies on this class of compounds are currently under active
investigation and will be reported in due course.
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lM), lower cyto-
l
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Acknowledgments
11. Recently, structurally related acylthiourea compound ACH-806 was reported
to show potent anti-HCV activity with a unique mechanism of action. It
selectively binds to the HCV NS4A protein, resulting in altered protein
composition and inactivation of the replicase complex, see: (a) Wyles, D. L.;
Kaihara, K. A.; Schooley, R. T. Antimicrob. Agents Chemother. 2008, 52, 1862; (b)
Yang, W.; Zhao, Y.; Fabrycki, J.; Hou, X.; Nie, X.; Sanchez, A.; Phadke, A.;
Deshpande, M.; Agarwal, A.; Huang, M. Antimicrob. Agents Chemother. 2008, 52,
2043.
We gratefully acknowledge the financial support of the National
Health Research Institutes in Taiwan (ROC).
References and notes
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