2402
J. Tang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2400–2402
Figure 2. Inhibitory modes of binding for compound 20 within (A) the NNRTI binding pocket and (B) the active site of IN CCD in complex with Mg2+ and DNA. The
electrostatic potential surface of the binding pocket is shown to highlight the hydrophobic regions (white) in both enzymes.
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Table 2
Antiviral assay results of compounds 17–24 against HIV-1
Compd
10
l
M
Dose response
% CPEa
reduction
% Cell
viability
EC50
M)
CC50
TId
b
c
(
l
(lM)
17
18
19
20
21
22
23
24
100
100
100
100
100
56
98
100
100
100
100
81
1.4
2.0
>100
>100
28
33
>100
––
>71
>50
78
540
290
––
0.36
0.061
0.34
––
100
100
100
100
2.3
94
77
41
2600
0.030
a
b
c
Viral cytopathic effect.
Concentration inhibiting viral replication by 50%.
Concentration causing 50% cell death.
d
Therapeutic index, defined by CC50/EC50
.
15. Wang, Z.; Tang, J.; Salomon, C. E.; Dreis, C. D.; Vince, R. Bioorg. Med. Chem. 2010,
18, 4202.
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W.; Kang, D. W.; Chung, S. G.; Cho, E. H. Antiviral Chem. Chemother. 2007, 18,
259.
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50, 1778.
18. Ji, L.; Chen, F.-E.; Xie, B.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Eur. J. Med.
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L.; Kim, C. U. Bioorg. Med. Chem. Lett. 2010, 20, 1585.
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RT and IN, we have synthesized an extended series of analogues
featuring a benzyol group at the C-6 position of the pyrimidine.
Through biochemical studies and cell culture antiviral assays it
was found that these new analogues inhibit RT, IN and HIV-1 at
nanomolar to low micromolar range. Molecular modeling also sug-
gests that these compounds can fit nicely into both the NNRTI
binding pocket and IN CCD. These results provide further support
on 3-hydroxypyrimidine-2,4-diones as a valid scaffold for antiviral
development.
Acknowledgments
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This research was supported by the Center for Drug Design at
the University of Minnesota, by the Center for Cancer Research, Na-
tional Cancer Institute, NIH, and by an NIH-IATAP grant to Y.P. and
K.M. We thank Roger Ptak at Southern Research Institute for anti-
viral assays and the Minnesota Supercomputing Institute for mod-
eling resources.
24. Hazuda, D. J.; Anthony, N. J.; Gomez, R. P.; Jolly, S. M.; Wai, J. S.; Zhuang, L.;
Fisher, T. E.; Embrey, M.; Guare, J. P., Jr.; Egbertson, M. S.; Vacca, J. P.; Huff, J. R.;
Felock, P. J.; Witmer, M. V.; Stillmock, K. A.; Danovich, R.; Grobler, J.; Miller, M.
D.; Espeseth, A. S.; Jin, L.; Chen, I. W.; Lin, J. H.; Kassahun, K.; Ellis, J. D.; Wong,
B. K.; Xu, W.; Pearson, P. G.; Schleif, W. A.; Cortese, R.; Emini, E.; Summa, V.;
Holloway, M. K.; Young, S. D. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11233.
25. Mustata, G. I.; Brigo, A.; Briggs, J. M. Bioorg. Med. Chem. Lett. 2004, 14, 1447.
26. Barreca, M. L.; Ferro, S.; Rao, A.; De Luca, L.; Zappala, M.; Monforte, A.-M.;
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Z.; Witvrouw, M.; Chimirri, A. Bioorg. Med. Chem. Lett. 2008, 18, 2891.
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2010, 20, 3275.
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Supplementary data
Supplementary data associated with this article can be found, in
References and notes
1. UNAIDS, 2007.