Organic & Biomolecular Chemistry
Communication
Research Foundation for the Returned Overseas Chinese Scho-
lars, Ministry of Education, and Beijing Natural Science Foun-
dation (2132037).
Table 4 Anti-viral activity of 3a–l and 5a–f against HCV genotype 2a
JFH-1 virus
No. of compound
EC50 a,b (μM)
No. of compound
EC50 a,b (μM)
3a
3b
3c
3d
3e
3f
3g
3h
3i
12.0
9.9
10.3
11.1
12.0
8.2
13.8
2.6
2.8
3k
3l
5a
5b
5c
5d
5e
5f
>20
>20
>20
>20
4.1
>20
>20
>20
0.18
Notes and references
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RO8191
2 (a) N. Hamdi, W. El-Akel, M. El-Serafy, G. Esmat,
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Y. J. Hutin and B. P. Bell, J. Hepatol., 2006, 45, 529–538.
3 For representative reviews, see: (a) D. L. Ge, J. Fellay,
A. J. Thompson, J. S. Simon, K. V. Shianna, T. J. Urban,
E. L. Heinzen, P. Qiu, A. H. Bertelsen, A. J. Muir,
M. Sulkowski, J. G. McHutchison and D. B. Goldstein,
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G. Ahlenstiel, T. Berg, M. Weltman, M. L. Abate,
M. Bassendine, U. Spengler, G. J. Dore, E. Powell,
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T. Müller, M. Bahlo, G. J. Stewart, D. R. Booth and
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3j
8.2
a Inhibitory concentration that reduced viral replication by 50%. b Each
data point represents the average of three replicates in cell culture and
the values of EC50 were plotted by the GraphPad Prism 5 software.
To determine the inhibitory activities of the two series of
RO8191 analogues, we prepared a HCV cell culture system
(HCVcc-hRluc-JFH1), HCV genotype 2a JFH-1 virus containing
a humanized Rellina luciferase reporter gene (for experimental
details, see the ESI†).18 The anti-HCV activities of the syn-
thesized analogues were then evaluated using the HCV cell
culture system, with RO8191 as a positive control. The results
are summarized in Table 4. As shown, most of the single aryla-
tion products (3a–i) displayed moderate inhibitory activity
against HCV (JFH-1, genotype 2a), with EC50 values ranged
from 2.8 to 13.8 μM. Among them, 3h and 3i, which bear a
meta- or ortho-substituted aryl moiety, exhibited more potent
activities than the para-substituted compounds (3a–g). Un-
expectedly, 3j–l, which have a heterocyclic moiety on the C1
position, displayed lower or no anti-viral activity. Furthermore,
except for 5c, all of the double arylation products (5a, 5b and
5d–f) were proved to be inactive at the 20 μM concentration.
4 J. Czepiel, G. Biesiada and T. Mach, Pol. Arch. Med. Wewn.,
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Conclusion
In summary, we have developed an efficient approach for the
synthesis of two series of imidazo[1,2-α][1,8]naphthyridine
derivatives, as analogues of RO8191, a newly discovered small-
molecule IFN-α-substitute. The key element of the approach
features a novel Pd-catalyzed, regioselective, single- or double-
arylation. Preliminary biological evaluations revealed that
some of the synthesized compounds displayed promising anti-
HCV activities. Our investigations enrich the structure–activity
relationship study on RO8191, and provide informative clues
for the design and synthesis of the next generation of
RO8191’s analogues as anti-HCV agents, which are underway
in our laboratory and will be reported in due course.
8 Y. F. Tang, L. Q. Zhang, Y. G. Wang, J. Qing and
S. D. Huang, Faming Zhuanli Shenqing, CN 103333168 A,
2013.
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Acknowledgements
This work was financially supported by the National Science of
Foundation of China (21102081, 21272133), the New Teachers’
Fund for Doctor Stations (20110002120011), the Scientific
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Org. Biomol. Chem., 2014, 12, 2344–2348 | 2347