P. Wang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4574–4578
4577
Table 1 (continued)
a
Compounds
Structures
Inhibition of HIV-1 IN (IC50)
30-P (
lM)
ST (lM)
SO2NH
O
7s
7t
HO
HO
16
5
12
4
N
H
SO2NH2
O
HO
N
22 11
2
1
H
HO
OH
SO2NH
H3C
O
AcO
AcO
6h
N
>10
1.6
1.6
H
OAc
SO2NH
O
AcO
AcO
6q
N
H
8
OAc
a
HIV-1 IN inhibitory activities were measured according to the procedure described in Ref. 12.
the 30-end processing and strand transfer at micromolar concentra-
as HIV-1 integrase inhibitors. The current work represents the first
synthetic example of such structures for the development of HIV-1
integrase inhibitors. They exhibit potent inhibitory activities at
micromolar concentrations, and further research based on these
structures will be continued.
tions. Compound 7r shows a weak activity with an IC50 value of
100
l
M towards 30-end processing compared to 7s (16
5 lM),
with the only difference of a double bond between a caffeoyl and
an amide structurally. Interestingly, the introduction of a hydroxyl
at 5-position of the caffeoyl in 7r gave 7q, which exhibited high
IC50 values of both 30-end processing and strand transfer at 7
3
Acknowledgments
and 1.5 0.1 lM, respectively. These results indicate the signifi-
cance of the galloyl as a core pharmacophore, and that the aryl sub-
stitution could assist and improve the inhibitory activities.
Compound 7t, without a phenyl in the sulfonamide group, shows
This work was supported by the National Natural Science Foun-
dation of China (No. 20872082) and Shandong Natural Science
Foundation (No. Y2007C060).
a slight activity drop against 30-end processing (22 11
lM). How-
ever, an unexpected selectivity was observed although the selec-
tivity index is small (30-end processing/strand transfer = 11). A
methylene linker was introduced into 7j and 7m, leading to com-
pounds 7a and 7b. However, the presence of longer spans caused
a slight impact on their activities (Table 1).
Supplementary data
Supplementary data associated with this article can be found, in
In order to investigate the substitution effect on the phenyl ring,
electron-donating and electron-withdrawing groups were pre-
ferred and utilized (7c–p). All these compounds display significant
potent inhibitory activities (Table 1) without any marked fluctua-
tion. This observation somewhat indicates that such substitution
has no notable impact on their activities. However, compounds
7k and 7l exhibit the most potent inhibitory activities at
References and notes
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0.7 0.3
cessing, respectively. Similarly, compounds with halogenic substi-
tution (7a, 7b, 7j–p) show IC50’s in the range of 0.7–7 M without
lM to strand transfer and 3 2/2
1 l
M to 30-end pro-
l
any significant dependence on the number or position of the
substitutions.
Intrigued by the blockage from the phenolic hydroxyl group,
more substitution was studies. Surprisingly, the introduction of
an acetyl to the oxygen atom has caused no substantial loss of
the HIV-1 integrase inhibitory activities in 6h or 6q. We believe
that the oxygen atoms in phenolic hydroxyl groups are exposed
sufficiently to interact with Mg2+ or Mn2+. Meanwhile, another
possible explanation is that the carbonyl, instead of the phenolic
hydroxyl group, binds to Mg2+ or Mn2+ (Date not shown).
In conclusion, a series of novel nitrogen-containing polyhydr-
oxylated aromatics with sulfanilamide linkers have been identified
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