Synthesis and HIV-1 integrase inhibitory activities of caffeoylglucosides

Article abstract of DOI:10.1016/S0960-894X(00)00355-3

Caffeoylglucosides, which have a glucose ring as a central linker, were synthesized from methyl D-glucosides, and their anti-HIV-1 activities were tested. Among them, four dicaffeoylglucosides (IC₅₀=29.1-35.1 μM), 6a, 6b. 9b and 10b, showed HIV-1 integrase inhibitory activity as potent as L-chicoric acid. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00355-3

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1879±1882
Synthesis and HIV-1 Integrase Inhibitory Activities of
Ca€eoylglucosides
Sun Nam Kim,a Jae Yeol Lee,a Hyoung Ja Kim,a Cha-Gyun Shin,b Hokoon Parka
and Yong Sup Lee a,*
aDivision of Life Sciences, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, South Korea
bDepartment of Biotechnology, Chung Ang University, An-Sung 456-756, South Korea
Received 8 May 2000; accepted 21 June 2000
AbstractÐCa€eoylglucosides, which have a glucose ring as a central linker, were synthesized from methyl d-glucosides, and their
anti-HIV-1 activities were tested. Among them, four dica€eoylglucosides (IC50=29.1±35.1 mM), 6a, 6b, 9b and 10b, showed HIV-1
integrase inhibitory activity as potent as l-chicoric acid. # 2000 Elsevier Science Ltd. All rights reserved.
Human immunode®ciency virus (HIV) is the probable
causative agent of acquired immune de®ciency syn-
drome (AIDS), which is one of the world's most serious
health problems. Several biological processes in the life
cycle of this virus have been targeted for anti-HIV
therapy. Integrase (IN) catalyzes the integration of HIV
DNA copy into the host cell DNA. Such integration is
essential for the production of progeny viruses, and
therefore therapeutic agents that can inhibit this process
should be e€ective anti-HIV agents.1 3 For the past few
years, extensive e€orts have been made resulting in a
large number of HIV IN inhibitors. Recent studies
showed that l-chicoric acid (1) and dica€eoylquinic
acids (DCQAs, for example, compound 2) display
potent activity against HIV IN and can inhibit HIV
replication with moderate anti-HIV activity.4 9 To fur-
ther improve the anti-HIV e€ect in tissue culture, several
analogues of l-chicoric acid (1) and DCQAs have been
synthesized. The common structural features of reported
synthetic analogues are ca€eic acid esters separated by
aliphatic, alicyclic, or aromatic linker.10,11
In an e€ort to identify new HIV-1 IN inhibitors from
medicinal plants, we have recently isolated several HIV-1
IN inhibitory phenylpropanoid glycosides from the
extract of Clerodendron trichotomum.12 Among isolated
compounds, phenylpropanoid glycoside 3, which contains
a b-d-glucopyranoside as a basic skeleton with an l-
rhamnopyranosyl and a ca€eoyl substituent, showed
potent inhibitory activity against HIV-1 IN (IC50=7.8
mM). We envisioned that the compound 3 has a structural
similarity to DCQAs since two substituents were sepa-
rated by a glucose linker instead of a quinic acid ring of
DCQAs. Furthermore, there is no report on the synth-
esis of ca€eic acid esters separated by a sugar ring as a
central linker. In the present studies, we synthesized and
*Corresponding author. Tel.: +82-2958-5167; fax: +82-2958-5189; e-mail: yslee@kist.re.kr
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00355-3

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S. N. Kim et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1879±1882
tested a new class of compounds with HIV-1 IN inhibitory
activities, which have a glucose ring as a central linker. To
simplify the structure of parent compound 3 and exam-
ine the e€ect of the glycosidic bond on the activity,
methyl a-d-glucoside (4a) and methyl b-d-glucoside (4b)
were used as starting materials instead of 3,4-dihy-
droxyphe-nylethyl glucosides.
lar procedure as above since digalloyl-substituted tarta-
ric acid derivatives were found to be potent inhibitors of
HIV-1 IN.11
In order to investigate the in¯uence of the position of
ca€eoyl groups on the HIV-1 IN inhibitory activity, 2,6-
and 3,6-dica€eoylglucosides (9, 10) were synthesized
(Scheme 2). The selective acylation of ca€eoyl groups at
2- and 6-positions was carried out after conversion to the
tributyltin ethers. Treatment of methyl a-d-glucoside (4a)
with dibutyltin oxide in re¯uxing toluene followed by
addition of Ac2ca€eoyl-Cl at room temperature a€orded
2,6-Ac2ca€eoylglucoside 7a and 3,6-Ac2ca€eoylglucoside
8a in 16:1 ratio. On the other hand, acylation of methyl b-
d-glucoside (4b) by the same procedure was not regio-
selective resulting in the formation of 7b and 8b in 1.7:1
ratio.15 The acetyl protecting groups were removed by
re¯uxing in acetone containing aqueous HCl to provide
2,6- and 3,6-ca€eoylglucosides (9a±b, 10a±b).16
The 4- and 6-hydroxyl groups of 4a and 4b were benzyl-
ideneated with benzaldehyde dimethyl acetal in DMF
containing catalytic p-toluenesulfonic acid by heating to
80 ꢀC under reduced pressure (Scheme 1).13 The residual
2- and 3-hydroxyl groups were acylated with diace-
tylcaf-feoyl chloride (Ac2ca€eoyl-Cl) to give 5a and 5b.
The benzylidene and acetyl protecting groups were
removed concomitantly in re¯uxing acetone containing
aqueous HCl to provide 6a and 6b, respectively.11,14 2,3-
Digalloyl glucoside 6c was also synthesized from 4b by
using triacetylgalloyl chloride (Ac3galloyl-Cl) in a simi-
Scheme 1.
Scheme 2.

S. N. Kim et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1879±1882
1881
Scheme 3.
Table 1. HIV-1 integrase inhibitory activities of ca€eoylglucosides18
References and Notes
Compound
IC50 (mM)
Compound
IC50 (mM)
1. Sakai, H.; Kawamura, M.; Sakuragi, J.; Sakuragi, S.; Shi-
bata, R.; Isimoto, A.; Ono, H.; Ueda, S.; Adachi, A. J. Virol.
1993, 67, 1169.
2. Taddeo, B.; Haseltine, W. A.; Farnet, C. M. J. Virol. 1994,
68, 8401.
6a
6b
6c
9a
9b
10a
29.1
31.8
5.4
82.4
35.1
70.0
10b
12a
12b
30.5
>118.7
89.6
3
7.8
57.5
24.9
Curcumina
l-Chicoric acidb
3. Engelman, A.; Englund, G.; Orenstein, J. M.; Martin, M.
A.; Craigie, R. J. Virol. 1995, 69, 2729.
4. Robinson, W. E. Jr. Infect. Med. 1998, 15, 129.
5. Robinson, W. E. Jr.; Reinecke, M. G.; Abdel-Malek, S.; Jia,
Q.; Chow, S. A. Proc. Natl. Acad. Sci. USA 1996, 93, 6326.
6. Robinson, W. E. Jr.; Codeiro, M.; Abdel-Malek, S.; Jia, Q.;
Chow, S. A.; Reinecke, M. G.; Mitchell, W. M. Mol. Phar-
macol. 1996, 50, 846.
7. McDougall, B. R.; King, P. J.; Wu, B. W.; Hostomsk, Z.;
Reinecke, M. G.; Robinson, W. E. Jr. Antimicrob. Agents
Chemother. 1998, 42, 140.
aCurcumin was purchased from Aldrich1
bl-Chicoric acid was prepared by a known method.10
.
In order to examine the in¯uence of a number of caf-
feoyl groups on the activity, fully ca€eoylated gluco-
sides 12a and 12b were also synthesized in a similar
manner (Scheme 3).17
8. Neamati, N.; Hong, H.; Mazumder, A.; Wang, S.; Sunder,
S.; Nicklaus, M. C.; Milne, G. W. A.; Proska, B.; Pommier, Y.
J. Med. Chem. 1997, 40, 942.
9. Neamati, N.; Hong, H.; Sunder, S.; Milne, G. W. A.;
Pommier, Y. Mol. Pharmacol. 1997, 52, 1041.
10. King, P. J.; Ma, G.; Miao, W.; Jia, Q.; McDougall, B. R.;
Reinecke, M. G.; Cornell, C.; Kuan, J.; Kim, T. R.; Robinson,
W. E. Jr. J. Med. Chem. 1999, 42, 497.
The ca€eoylglucosides were tested for inhibitory activity
against HIV-1 IN (Table 1). The activities of curcumin, l-
chicoric acid and a phenylpropanoid glycoside 3, isolated
from the extract of Clerodendron trichotomum were
included for comparisons. The inhibitory activities of
2,3-dica€eoylglucosides (6a, 6b) and 3,6- and 2,6-dicaf-
feoylglucosides (9b, 10b), derived from methyl b-d-glu-
coside were more potent than that of curcumin and
comparable to l-chicoric acid. However, all ca€eoyl-
glucosides were less active than the parent compound 3
implicating the important role of l-rhamnopyranosyl or
3,4-dihydroxyphenylethyl group in the binding with HIV-
1 IN. b-Methyl glucosides, except 6b, have more enhanced
HIV-1 IN inhibitory activity than their a-anomers,
respectively. Interestingly, upon substitution of digalloyl
groups at the 2- and 3-positions of glucose (6c) instead
of ca€eoyl groups, the inhibitory activity was remark-
ably increased. More substitutions than two ca€eoyl
groups decreased the IN inhibitory activity (12a, 12b).
However, more studies on the ca€eoylglucosides would
be needed since none of the ca€eoylglucosides synthe-
sized in this study could inhibit the replication of HIV-1
at nontoxic concentration (data not shown).
11. Lin, Z.; Neamati, N.; Zhao, H.; Kiyru, Y.; Turpin, J. A.;
Abderham, C.; Strebel, K.; Kohn, K.; Witvrouw, M.; Panne-
couque, C.; Debyser, Z.; Clercq, E. D.; Rice, W. G.; Pommier,
Y.; Burke, T. R. Jr. J. Med. Chem. 1999, 42, 1401.
12. Kim, H. J.; Lee, J. S.; Shin, C.-G., Woo, E.-R.; Park, H.;
Lee, Y. S. Arch. Pharm. Res. 2000, 23, in press.
13. Yamada, H.; Harada, T.; Takahashi, T. J. Am. Chem.
Soc. 1994, 116, 7917.
1
14. The yields were not optimized. 5a; 66% yield. H NMR
(CDCl3, 300 MHz) d 7.44 (d, 1H, J=16.0 Hz), 7.41 (d, 1H,
J=16.0 Hz), 7.28±7.00 (m, 11H), 6.18 (d, 1H, J=16.0 Hz),
6.15 (d, 1H, J=16.0 Hz), 5.62 (t, 1H, J=9.7 Hz), 5.36 (s, 1H),
4.91 (dd, 1H, J=9.8, 3.7 Hz), 4.86 (d, 1H, J=3.7 Hz), 4.16
(dd, 1H, J=10.1, 4.7 Hz), 3.83 (td, 1H, J=9.8, 4.7 Hz), 3.64
(t, 1H, J=10.2 Hz), 3.59 (t, 1H, J=9.6 Hz), 3.26 (s, 3H), 2.11±
1
2.09 (m, 12H). 5b; 58% yield. H NMR (CDCl3, 300 MHz) d
7.63 (d, 1H, J=16.0 Hz), 7.60 (d, 1H, J=16.0 Hz), 7.47±7.19
(m, 11H), 6.36 (d, 1H, J=16.0 Hz), 6.35 (d, 1H, J=15.9 Hz),
5.57 (t, 1H, J=9.5 Hz), 5.57 (s, 1H), 5.25 (t, 1H, J=9.3 Hz),
4.63 (d, 1H, J=7.8 Hz), 4.45 (dd, 1H, J=10.4, 4.8 Hz), 3.92±
3.80 (m, 2H), 3.64 (td, 1H, J=9.5, 4.8 Hz), 3.57 (s, 3H), 2.33±
2.30 (m, 12H). 6a; 38% yield. 1H NMR (CD3OD, 300 MHz) d
7.55 (d, 1H, J=15.9 Hz), 7.52 (d, 1H, J=15.9 Hz), 7.00 (s,
1H), 6.99 (s, 1H), 6.90 (d, 1H, J=8.2 Hz), 6.89 (d, 1H, J=8.2
Hz), 6.74 (2d, 1H each, J=8.2 Hz), 6.25 (d, 1H, J=15.9 Hz),
6.17 (d, 1H, J=15.8 Hz), 5.53 (m, 1H), 4.98 (d, 1H, J=3.5
Hz), 4.90 (1H, overlapped with HDO signal), 3.89±3.62 (m,
4H), 3.44 (s, 3H). 6b; 10% yield. 1H NMR (CD3OD, 300
MHz) d 7.53 (d, 1H, J=15.8 Hz), 7.51 (d, 1H, J=15.9 Hz),
7.01 (2s, 2H), 9.91 (d, 2H, J=7.9 Hz), 6.10 (2d, 2H, J=8.1
Hz), 6.24 (d, 1H, J=15.8 Hz), 6.19 (d, 1H, J=15.9 Hz), 5.28
In conclusion, we have synthesized and tested the inhi-
bitory activities of new types of HIV-1 IN inhibitors
which have a glucose ring as a basic skeleton. This work
is the ®rst example of the synthesis of ca€eic acid esters
separated by a sugar ring as a central linker for the
development of HIV-1 integrase inhibitors.
Acknowledgements
This work was supported by the Ministry of Science and
Technology, Korea (2N20110).

1882
S. N. Kim et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1879±1882
(t, 1H, J=9.5 Hz), 4.98 (dd, 1H, J=9.8, 8.0 Hz), 4.62 (d, 1H,
1
J=8.1 Hz), 6.45 (d, 1H, J=15.9 Hz), 6.43 (d, 1H, J=15.9
Hz), 5.19 (t, 1H, J=9.2 Hz), 4.62 (t, 1H, J=12.0 Hz), 4.46
(dd, 1H, J=12.0, 5.0 Hz), 4.45 (d, 1H, J=7.8 Hz), 3.79±3.61
J=8.0 Hz), 4.06±3.66 (m, 4H), 3.54 (s, 3H). 5c; 16% yield. H
NMR (CDCl3, 300 MHz) d 7.75 (s, 2H), 7.74 (s, 2H), 7.43±7.40
(m, 2H), 7.37±7.32 (m, 3H), 5.71 (t, 1H, J=9.5 Hz), 5.54 (s, 1H),
5.37 (dd, 1H, J=8.9, 8.2 Hz), 4.65 (d, 1H, J=7.8 Hz), 4.44 (dd,
1H, J=10.5, 4.8 Hz), 3.91±3.84 (m, 2H), 3.65 (td, 1H, J=9.5, 4.8
1
(m, 5H), 3.51 (dd, 1H, J=9.5, 7.8 Hz) . 10a; 32% yield. H
NMR (CD3OD, 300 MHz) d 7.63 (d, 1H, J=15.9 Hz), 7.60 (d,
1H, J=15.9 Hz), 7.07 (d, 1H, J=2.1 Hz), 7.06 (d, 1H, J=2.2
Hz), 6.98 (d, 1H, J=8.1 Hz), 6.80 (d, 1H, J=8.2 Hz), 6.33 (d,
1H, J=15.9 Hz), 6.32 (d, 1H, J=15.9 Hz), 4.94 (d, 1H, J=3.7
Hz), 4.74 (dd, 1H, J=10.0, 3.7 Hz), 4.53 (dd, 1H, J=11.9, 2.1
Hz), 4.37 (dd, 1H, J=11.8, 5.7 Hz), 3.92 (t, 1H, J=9.4 Hz),
3.78 (m, 1H), 3.49 (t, 1H, J=9.3 Hz), 3.42 (s, 3H) . 10b; 59%
yield. 1H NMR (CD3OD, 300 MHz) d 7.55 (d, 1H, J=15.9
Hz), 7.53 (d, 1H, J=15.9 Hz), 7.01 (s, 2H), 6.92 (d, 2H, J=8.4
Hz), 6.74 (d, 2H, J=8.1 Hz), 6.28 (d, 1H, J=15.9 Hz), 6.26 (d,
1H, J=15.9 Hz), 4.79 (dd, 1H, J=9.3, 8.2 Hz), 4.48 (d, 1H,
J=10.4 Hz), 4.43 (d, 1H, J=8.0 Hz), 4.33 (m, 1H), 3.61±3.55
(m, 2H), 3.50±3.42 (m, 4H) .
1
Hz), 3.52 (s, 3H), 2.29±2.27 (m, 18H). 6c; 44% yield. H NMR
(CD3OD, 300 MHz) d 6.89 (s, 2H), 6.85 (s, 2H), 5.32 (t, 1H,
J=8.7 Hz), 4.98 (dd, 1H, J=9.7, 8.0 Hz), 4.54 (d, 1H, J=8.0
Hz), 3.84 (dd, 1H, J=11.9, 1.7 Hz), 3.68 (dd, 1H, J=11.9, 5.3
Hz), 3.65 (d, 1H, J=9.5 Hz), 3.43±3.41 (bs, 4H).
15. 5 (a) Ogawas. T; Nakabayashi, S.; Sasajima, K. Carbo-
hydr. Res. 1981, 96, 29. (b) Sato, K.; Yoshitomo, A. Chem.
Lett. 1995, 39.
16. The yields were not optimized. 7a; 2% yield. 1H NMR
(CDCl3, 300 MHz) d 7.74 (d, 2H, J=15.9 Hz), 7.71±7.42 (m,
4H), 7.29 (d, 1H, J=8.3 Hz), 7.27 (d, 1H, J=8.3 Hz), 6.51 (d,
2H, J=16.1 Hz), 5.27 (t, 1H, J=9.5 Hz), 4.91 (d, 1H, J=3.8
Hz), 4.72 (dd, 1H, J=12.2, 4.3 Hz), 4.49 (dd, 1H, J=12.2, 2.0
Hz), 3.95 (ddd, 1H, J=9.9, 4.0, 2.0 Hz), 3.77 (bs, 1H), 3.66 (t,
1H, J=9.5 Hz), 3.54 (s, 3H), 3.23 (bs, 1H, OH), 2.39±2.36 (m,
1
17. The yields were not optimized. 11a; 31% yield. H NMR
(CDCl3, 300 MHz) d 7.69 (d, 1H, J=15.9 Hz), 7.64 (d, 1H,
J=15.8 Hz), 7.61 (d, 1H, J=16.0 Hz), 7.56 (d, 1H, J=15.9
Hz), 7.43±7.16 (m, 12H), 6.46 (d, 1H, J=16.0 Hz), 6.38 (d,
1H, J=16.1 Hz), 6.32 (d, 1H, J=16.1 Hz), 6.28 (d, 1H,
J=16.0 Hz), 5.84 (t, 1H, J=9.8 Hz), 5.39 (t, 1H, J=9.8 Hz),
5.17 (dd, 1H, J=10.0, 3.7 Hz), 5.12 (d, 1H, J=3.5 Hz), 4.45±
4.34 (m, 2H), 4.25±4.21 (m, 1H), 3.51 (s, 3H), 2.33±2.28 (m,
24H) . 11b; 20% yield. 1H NMR (CDCl3, 300 MHz) d 7.59 (d,
1H, J=15.7 Hz), 7.53 (d, 1H, J=14.6 Hz), 7.51 (d, 1H,
J=15.7 Hz), 7.46 (d, 1H, J=14.5 Hz), 7.32±7.22 (m, 8H),
7.14±7.08 (m, 4H), 6.35 (d, 1H, J=16.0 Hz), 6.26 (d, 1H,
J=15.9 Hz), 6.22 (d, 1H, J=15.9 Hz), 6.17 (d, 1H, J=15.9
Hz), 5.48 (t, 1H, J=9.6 Hz), 5.31 (t, 1H, J=9.7 Hz), 5.20 (dd,
1H, J=9.6, 7.9 Hz), 4.54 (d, 1H, J=7.9 Hz), 4.37 (dd, 1H,
J=12.4, 3.0 Hz), 4.31 (dd, 1H, J=12.3, 5.0 Hz), 3.88 (m, 1H),
3.35 (s, 3H), 2.24±2.10 (m, 24H). 12a; 65% yield. 1H NMR
(CD3OD, 300 MHz) d 7.60 (d, 1H, J=15.7 Hz), 7.56 (d, 2H,
J=15.5 Hz), 7.51 (d, 1H, J=15.7 Hz), 7.05±7.01 (m, 3H),
6.97±6.85 (m, 5H), 6.77±6.71 (m, 4H), 6.29 (d, 1H, J=15.9
Hz), 6.22 (d, 2H, J=16.2 Hz), 6.16 (d, 1H, J=16.0 Hz), 5.78
(t, 1H, J=9.7 Hz), 5.36 (t, 1H, J=9.7 Hz), 5.14±5.11 (m, 2H),
4.37±4.36 (m, 2H), 4.15±4.08 (m, 1H), 3.52 (s, 3H) . 12b; 32%
yield. 1H NMR (CD3OD, 300 MHz) d 7.40 (d, 1H, J=15.6
Hz), 7.35 (d, 2H, J=15.5 Hz), 7.29 (d, 1H, J=15.9 Hz), 6.86±
6.65 (m, 8H), 6.58±6.52 (m, 4H), 6.10 (d, 1H, J=15.9 Hz),
6.03 (d, 1H, J=15.8 Hz), 6.02 (d, 1H, J=15.9 Hz), 5.94 (d,
1H, J=15.9 Hz), 5.41 (t, 1H, J=9.5 Hz), 5.15 (t, 1H, J=9.7
Hz), 4.98 (dd, 1H, J=9.7, 8.1 Hz), 4.53 (d, 1H, J=9.2 Hz),
4.19 (d, 2H, J=3.5 Hz), 3.89 (m, 1H), 3.35 (s, 3H) .
1
13H) . 7b; 14% yield. H NMR (CDCl3, 300 MHz) d 7.70 (d,
1H, J=15.9 Hz), 7.67 (d, 1H, J=16.0 Hz), 7.43±7.37 (m, 4H),
7.24±7.17 (m, 2H), 6.47 (d, 1H, J=16.1 Hz), 6.45 (d, 1H,
J=16.0 Hz), 5.09 (t, 1H, J=9.0 Hz), 4.61 (d, 1H, J=11.7 Hz),
4.49 (d, 1H, J=12.0 Hz), 4.34 (d, 1H, J=7.7Hz), 3.81 (s, 1H),
3.72±3.46 (m, 6H), 3.08 (d, 1H, J=2.8 Hz), 2.32±2.29 (m,
1
12H) . 8a; 34% yield. H NMR (CDCl3, 300 MHz) d 7.72 (d,
1H, J=16.0 Hz), 7.70 (d, 1H, J=16.0 Hz), 7.47±7.38 (m, 4H),
7.26 (d, 1H, J=8.4 Hz), 7.24 (d, 1H, J=8.3 Hz), 6.49 (d, 1H,
J=15.9 Hz), 6.48 (d, 1H, J=16.0 Hz), 5.03 (d, 1H, J=3.7
Hz), 4.87 (dd, 1H, J=10.0, 3.7 Hz), 4.75 (dd, 1H, J=12.2, 3.9
Hz), 4.39 (d, 1H, J=12.2 Hz), 4.10 (t, 1H, J=9.4 Hz), 3.87 (d,
1H, J=9.6 Hz), 3.52 (t, 1H, J=9.3 Hz), 3.43 (s, 3H), 3.25 (bs,
1H, OH), 2.69 (bs, 1H, OH), 2.33±2.32 (2s, 12H) . 8b; 8%
yield. 1H NMR (CDCl3, 300 MHz) d 7.68 (d, 1H, J=16.0 Hz),
7.67 (d, 1H, J=16.0 Hz), 7.44±7.34 (m, 4H), 7.25±7.21 (m,
2H), 6.46 (d, 1H, J=16.0 Hz), 6.44 (d, 1H, J=16.0 Hz), 4.95
(dd, 1H, J=9.3, 8.0 Hz), 4.60±4.48 (m, 2H), 4.44 (d, 1H,
J=8.0 Hz), 3.71±3.56 (m, 3H), 3.51 (s, 3H), 2.32±2.30 (m,
12H) . 9a; 42% yield. 1H NMR (CD3OD, 300 MHz) d 7.77 (d,
1H, J=15.9 Hz), 7.75 (d, 1H, J=15.9 Hz), 7.23±7.19 (m, 2H),
7.15±7.07 (m, 2H), 6.97±6.92 (m, 2H), 6.51 (d, 1H, J=15.9
Hz), 6.47 (d, 1H, J=15.9 Hz), 5.46 (t, 1H, J=9.5 Hz), 4.92 (d,
1H, J=3.7 Hz), 4.67 (dd, 1H, J=11.9, 2.1 Hz), 4.52 (dd, 1H,
J=11.9, 5.7 Hz), 4.07 (ddd, 1H, J=9.9, 5.6, 2.1 Hz), 3.79 (m,
2H), 3.64 (s, 3H), 3.23 (bs, 1H, OH), 2.39±2.36 (m, 13H) . 9b;
87% yield. 1H NMR (CD3OD, 300 MHz) d 7.71 (d, 1H,
J=15.9 Hz), 7.70 (d, 1H, J=15.9 Hz), 7.17 (s, 1H), 7.16 (s,
1H), 7.10±7.05 (m, 2H), 6.89 (d, 1H, J=8.1 Hz), 6.88 (d, 1H,
18. The enzyme inhibition assay of compounds against HIV-1
integrase was carried out as described previously. Oh, J.-W.;
Shin, C.-G. Mol. Cells 1996, 6, 96.