Bifunctional thiosialosides inhibit influenza virus

Article abstract of DOI:10.1016/j.bmcl.2013.11.077

We have synthesized a panel of bivalent S-sialoside analogues, with modifications at the 4 position, as inhibitors of influenza virus. These first generation compounds show IC₅₀ values ranging from low micromolar to high nanomolar in enzyme inhibition and plaque reduction assays with two intact viruses, Influenza H1N1 (A/California/07/2009) and H3N2 (A/Hongkong/8/68).

Full text of DOI:10.1016/j.bmcl.2013.11.077

Bioorganic & Medicinal Chemistry Letters 24 (2014) 636–643
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Bifunctional thiosialosides inhibit influenza virus
⇑
Yang Yang, Yun He, Xingzhe Li, Hieu Dinh, Suri S. Iyer
788 Petit Science Center, Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30302, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We have synthesized a panel of bivalent S-sialoside analogues, with modifications at the 4 position, as
inhibitors of influenza virus. These first generation compounds show IC50 values ranging from low micro-
molar to high nanomolar in enzyme inhibition and plaque reduction assays with two intact viruses, Influ-
enza H1N1 (A/California/07/2009) and H3N2 (A/Hongkong/8/68).
Received 17 October 2013
Revised 23 November 2013
Accepted 27 November 2013
Available online 11 December 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Influenza virus
Sialic acid
Glycoconjugates
Inhibitors
Bifunctional
Influenza is an opportunistic pathogen that causes severe respi-
ratory illnesses. The virus accounts for millions of infections world-
wide each year, leading to significant morbidity and mortality.
Senior citizens (over 65 years of age), young children, and individu-
als with underlying health problems are at increased risk for infec-
A slightly different strategy of developing inhibitors follows
Nature’s method of using multivalency that target Hemagluttinin
(HA), a surface glycoprotein that binds to cell surface sialic acid
to facilitate viral entry and NA. HA and NA are excellent targets
for inhibition, because labeling experiments have shown that an
individual viral particle has approximately 200–300 copies of tri-
meric HA and 50–100 copies of tetrameric NA, leading to over
1
tion and subsequent secondary illnesses like pneumonia. Along
Ò
Ò
Ò
with vaccines, Oseltamivir , Zanamivir , and Premavir (Fig. 1B–
2
7,8
D) are among the frontline drugs used to fight the infection. These
800 binding sites per virion. Indeed, mucins, endogenous sialy-
FDA approved transition state analogs inhibit the activity of the viral
surface enzyme, Neuraminidase (NA), from cleaving the residual
N-acetyl neuraminic acid (or sialic acid, Figure 1A) present on the in-
fected host cell, consequently arresting the virus progeny from
escaping the cell. However, some strains which include emerging,
highly virulent strains that can potentially cause pandemics, have
startedto exhibitresistance tosomeof theseinhibitors. Inone recent
surveillance study, 100% of all patients had a resistant strain to
lated proteins released by respiratory epithelial cells, capture viral
particles by virtue of their multiple sialic acid residues which bind
to HA and NA, and flush them away by the natural process of
9
–11
sneezing and coughing.
A similar approach using glycopoly-
mers and glycodendrimers with pendant sialic acids have been
generated to capture the virus. It has been demonstrated that in-
crease in the valency of the sialic acids increases the inhibitory ef-
fect significantly, from the micromolar IC50 value of a mono/di/
Ò 3
12–14
Oseltamivir , and another study identified a strain that was resis-
tri saccharide, to the micromolar/submicromolar range.
These
tant to both, ZanamivirÒ and Oseltamivir . These studies empha-
size the need for vigilance and continued development of novel
drugs. Recently, a new class of mechanism based anti-viral
compounds against NA has been reported to show broad spectrum
anti-viral activity against all strains in vitro and in animal models
Ò 4
reports have focused on the architecture of the scaffolds, leaving
the sialic acid unit unmodified.
In this Letter, we have increased the intrinsic binding affinity of
a single sialic acid unit by introducing an amine/guanidine group at
the 4 position of sialic acid. The basic amine/guanidine group fits
perfectly into the binding pocket of viral NA as it interacts with
5
,6
(
Fig. 1E, F). Unlike transition state analogs, these compounds are
2
,15
similar to natural substrate, with modifications at the 3 and 4
positions, which enhance the binding activity. All of these recent
reports are based on the natural substrate (sialic acid) with struc-
ture based drug design leading to increased and highly specific
inhibition.
the trio of amino acids present in the binding pocket.
We intro-
duced sulfur at the anomeric center, which provides additional
advantages. First, replacing the O-sialoside with an S-sialoside
makes the ligand more robust as we and others have demonstrated
1
6,17
that S-sialosides are not readily cleaved by the virus.
Second,
the thiol group reacts with triflates and/or bromides present on
multivalent scaffolds readily, thereby yielding rapid access to mul-
tivalent molecules. The combination of NA resistant sialosides
⇑
Corresponding author. Tel.: +1 404 413 3606.
E-mail address: siyer@gsu.edu (S.S. Iyer).
0
960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.11.077

Y. Yang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 636–643
637
OH OH
O
COOH
OH
2
CO Et
O
HO
AcHN
HO
OH
1
3
CO
2
H
6
8
2
9
7
O
O
AcHN
NH
NH
AcHN
5
4
HN
HO
2
H N
2
B
C
A
OH
HO
OH
OH
CH
3
2
CO H
OH
O
HO
OH
2
CO H
H
O
F
AcHN
HN
COOH
X'
O
N
H
NH
NH
AcHN
O
O
H
X
O
HO
2
NH
NH
HN
2
E, X = F, X' = H
F, X = H, X' = F
G
D
Figure 1. Structures of N-acetyl neuraminic acid (sialic acid) analogs. (A) Sialic acid with the numbering scheme. (B) OseltamivirÒ (C) Zanamivir , (D) Premavir (E–F)
Ò
Ò
Flourinated analogs of Sialic acid. (G) Fluorogenic substrate of sialic acid for obtaining IC50 values.
combined with the multivalent presentation provides easy access
to a new class of influenza virus inhibitors. Using this approach,
we constructed a panel of bivalent compounds, (Schemes 1 and
guanidinium group to yield 6 and 7, respectively. Removal of ester
moieties was conducted under basic hydrolysis conditions,
followed by removal of the acid sensitive t-butylcarbonyl groups
using trifluoroacetic acid to yield analogs of sialic acid with an
amine (SA) or guanidine group (SG) at the 4 position. While not
the focus of this report, we incorporated a thiol group at the
terminus of the alkyl spacer in SA and SG as it provides facile con-
jugation to surfaces for capture of the virus or to a scaffold/protein
to produce multivalent inhibitors.
2) that are similar to the natural substrate and evaluated their
inhibitory activities with two viral NAs, N1 and N2, and intact viral
strains. These first generation compounds show micromolar to
nanomolar inhibition and could be further elaborated into poten-
tial therapies for influenza.
The design and synthesis of the compounds is shown in
Scheme 1. Starting with the known azido compound, 1,18 hydrogen
chloride was added across the double bond to produce the
We used a series of activated homobifunctional hydrophobic
and hydrophilic linkers to produce the dimeric compounds, shown
in Scheme 2. Different spacers were used because the bivalent mol-
ecules can interact with viral NA in three ways. Briefly, the bivalent
molecules can crosslink adjacent NAs on the same tetramer or
crosslink two NAs from two different NA tetramers on the same
viral particle or crosslink NA’s from two viral particles. The mini-
mal distance between the active sites of the NAs in all three possi-
b-chloride 2, followed by SN
by a thioacetate to introduce the sulfur moiety at the anomeric
center in good yield. The -anomeric conformation in 3 was con-
2
type replacement of the chloride
a
1
13
firmed by H and C NMR spectroscopies. Reaction of 3 with a
hydrophobic six carbon spacer in the presence of diethylamine
yielded 4. Next, the azide group of 4 was reduced using triphenyl-
phospine to yield the amine 5, which was subsequently protected
with a t-butylcarbonyl group or reacted with a suitable protected
1
9
bilities are ꢀ16, 30, 50 Å, respectively. Therefore, using a series of
activated hydrophilic and hydrophobic spacers, we generated a
OAc OAc
AcO OAc
AcO OAc
OAc
O
COOMe
a
AcO OAc
OAc
OAc
Cl
b
COOMe
SAc
c
COOMe
S
SAc
6
AcO
AcHN
O
AcHN
O
COOMe
O
AcHN
AcHN
N
3
N
3
N
3
N
3
3
4
2
1
d
AcO OAc
OAc
AcO OAc
OAc
HO OH
OH
e
COOMe
S
COOH
S
g,h
COOMe
O
AcHN
O
O
AcHN
BocHN
S
SAc
SAc
6
AcHN
SH
6
2
H N
6
2
H N
5
SA
6
f
HO OH
AcO OAc
OAc
OH
COOH
S
COOMe
g,h
O
AcHN
SH
O
6
AcHN
S
SAc
6
HN
HN
NH
NBoc
7
2
H N
BocHN
SG
Scheme 1. Synthesis of SA and SG. Reagents and Conditions: (a) HCl (g), LiCl, CH
over 2 steps; (c) TosOC 12SAc, DEA, DMF, 65%; (d) PPh , THF/H O, 12 h; (e) (Boc) O, TEA, THF, 60% over 2 steps (f) MeS-(C@NBoc)NHBoc, HgCl
g) MeOH/NaOH (aq), 1 h; (h) TFA/DCM (1:1). 90% over two steps for SA and SG, respectively.
3
CN, 6 days; (b) KSAc, TBAB (Tetrabutylammonium bisulfate), CH
2
Cl
2
/H
Cl
2
O, overnight, 50%
, 80% over 2 steps;
6
H
3
2
2
2
, TEA, CH
2
2
(

6
38
Y. Yang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 636–643
OAc
OAc
OAc
OAc
OAc
OAc
AcHN
N3
N3
AcO OAc
OAc
O
O
COOMe
SAc
a
COOMe
COOMe
O
AcHN
N3
Br
x
Br
S
S
x
3
8
9
1
1
1
X= -CH2(CH2)4CH2-
X= -CH2(CH2)10CH2-
0 X= -CH CH O(CH CH O) CH CH -
2
2
2
2
2
2
2
1 X= -CH2CH2O(CH2CH2O)3CH2CH2-
2 X= -CH CH O(CH CH O) CH CH -
2
2
2
2
4
2
2
b
c
OH
OH
OH
OH
OH
OH
OAc
OAc
OAc
OAc
OAc
OAc
AcHN
H2N
AcHN
AcHN
BocN
H
BocN
H
N
N
H N
2
O
O
BocHN
O
BocHN
O
COOH
COOH
COOMe
COOMe
S
S
S
S
x
x
C6-SA
C12-SA
X= -CH2(CH2)4CH2-
X= -CH2(CH2)10CH2-
13 X= -CH2(CH2)4CH2-
14 X= -CH2(CH2)10CH2-
TetraEG-SA X= -CH CH O(CH CH O) CH CH -
15 X= -CH2CH2O(CH2CH2O)2CH2CH2-
16 X= -CH2CH2O(CH2CH2O)3CH2CH2-
17 X= -CH2CH2O(CH2CH2O)4CH2CH2-
2
2
2
2
2
2
2
PentaEG-SA X= -CH2CH2O(CH2CH2O)3CH2CH2-
HexaEG-SA X= -CH CH O(CH CH O) CH CH -
2
2
2
2
4
2
2
d
OH
OH
OH
OH
OH
OH
AcHN
AcHN
HN
H
HN
H
N
N
H2N
O
H2N
O
COOH
COOH
S
S
x
C6-SG
X= -CH2(CH2)4CH2-
X= -CH2(CH2)10CH2-
C12-SG
TetraEG-SG X= -CH CH O(CH CH O) CH CH -
2
2
2
2
2
2
2
PentaEG-SG X= -CH2CH2O(CH2CH2O)3CH2CH2-
HexaEG-SG X= -CH CH O(CH CH O) CH CH -
2
2
2
2
4
2
2
Scheme 2. Synthesis of bivalent analogs of S-Sialosides. Reagents and Conditions: (a) DEA, DMF; 76–85%; (b) (i) NaOH/CH
3 2 2
OH (aq), (ii) H /Pd(OH) ; 90–92% over 2 steps; (c)
(
i) H /Pd(OH) , (ii)MeS-(C@NBoc)NHBoc, HgCl , TEA, CH Cl . 85–89% over 2 steps; (d) NaOH/CH OH (aq), 1 h; (i) TFA/DCM (1:1), 80–85% over 2 steps.
2
2
2
2
2
3
panel of gemini compounds, 8–12 in decent yield. The synthesis of
the activated spacers for coupling are presented in the Supplemen-
tary data. The azides in 8–12 were deprotected under basic condi-
tion and hydrogenation to yield five bivalent S-sialoside analogs
with an amine at the 4 position. (C6-SA, C12-SA, TetraEG-SA,
PentaEG-SA and HexaEG-SA). We also introduced a guanidine
group at the 4 position as described with minor modifications for
the synthesis of the monomeric SG to yield five bivalent S-sialoside
analogs. (C6-SG, C12-SG, TetraEG-SG, PentaEG-SG and HexaEG-
SG). All intermediates and final compounds were characterized
by NMR and mass spectroscopies (Supplementary data).
raw data is presented in the Supplementary data. The commercial
drugs, ZanamivirÒ and OstelimivirÒ are included as controls. As ex-
pected, sialic acid exhibits millimolar inhibition and the antivirals
exhibit nanomolar inhibitory values. Introduction of an amine at
the 4 position decreases the IC50 by 1000 fold to micromolar levels
for both influenza viral enzymes, N1 and N2; the IC50 values for SA
range from 60–180 lM. The bivalent sialosides (C6-SA, C12-SA,
TetraEG-SA, PentaEG-SA and HexaEG-SA) all exhibit higher inhibi-
tion activity, approximately four to five fold increase in inhibition,
especially for the N1 enzyme, when compared to the monovalent
compound. There were exceptions, the compounds with the longer
spacers (PentaEG-SA and HexaEG-SA), were not that efficacious
compared to the monomeric compounds. With the N2 enzyme, a
similar trend was observed, with the bivalent compound exhibit-
ing a two fold higher inhibition compared to the monomeric amine
containing compound and the compounds with longer spacers not
as effective. Introduction of the guanidine group led to increased
Next, we performed NA inhibition studies using commercially
0
available 2 -(4-Methylumbelliferyl)-
a
-D-N-acetylneuraminic acid
(
MUNANA) (Fig. 1G) as the substrate. First, we used soluble viral
NA as the enzymes before testing intact viruses. Since there is an
initial binding component in the inhibitory mechanism, we pre-
mixed the compounds with NA and followed the cleavage of the
substrate over two hours to obtain the IC50s using the linear slope
between 0–35 min. The IC50 values with three independent exper-
iments for each compound are given in Table 1 and the selective
inhibition with IC50 values ranging from 0.2–25 lM for SG,
C6-SG, C12-SG, TetraEG-SG, PentaEG-SG and HexaEG-SG. The IC50
values for the bivalent compounds, irrespective of the spacers,

Y. Yang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 636–643
639
Table 1
IC50 values for the inhibition of soluble NAs and intact virus by the gemini sialoside analogs. The influenza strains used in these studies were Influenza H1N1 (A/California/07/
009) and H3N2 (A/Hongkong/8/68)
2
Name
Structure
Virus
NA from virus
H5N1 ( M)
H3N2 (
lM)
H1N1 (
l
M)
l
H3N2 (lM)
HO OH
OH
COOH
S
SA
64 ± 14
56 ± 6
127 ± 29
178 ± 20
O
AcHN
SH
2
H N
OH
OH
OH
OH
OH
OH
AcHN
AcHN
C6-SA
H
2
N
H N
11.6 ± 3.5
9.9 ± 1.8
20 ± 5
32 ± 5
2
O
O
COOH
COOH
S
S
OH
OH
OH
OH
OH
OH
AcHN
AcHN
C12-SA
H
2
N
15 ± 9
11 ± 5
21 ± 3
11 ± 1
9.8 ± 2.4
36 ± 4
31 ± 7
28 ± 3
64 ± 14
40 ± 1
2
H N
O
O
COOH
COOH
S
S
OH
OH
OH
OH
OH
OH
AcHN
AcHN
H
2
N
TetraEG-SA
H N
39 ± 14
2
O
O
COOH
COOH
S
O
S
O
O
OH
OH
OH
OH
OH
OH
AcHN
AcHN
H N
H N
2
PentaEG-SA
2
178 ± 20
216 ± 56
O
O
COOH
COOH
O
S
O
O
O
S
OH
OH
OH
OH
OH
OH
AcHN
AcHN
2
H N
HexaEG-SA
H
2
N
O
33 ± 15
45 ± 1
85 ± 12
O
COOH
COOH
S
O
O
S
O
O
O
HO OH
OH
COOH
S
O
AcHN
SG
SH
0.55 ± 0.02
0.8 ± 0.1
0.1 ± 0.02
1 ± 0.1
HN
NH
2
H N
OH
OH
OH
OH
OH
OH
AcHN
AcHN
H
H
C6-SG
N
N
0.25 ± 0.05
0.26 ± 0.03
0.2 ± 0.02
4.2 ± 1.2
HN
COOH
HN
HN
O
O
NH2
NH2
COOH
S
S
OH
OH
OH
OH
AcHN
OH
OH
AcHN
H
N
H
N
C12-SG
0.5 ± 0.3
0.8 ± 0.06
0.73 ± 0.03
12 ± 2
O
HN
NH
2
O
COOH
NH
2
COOH
S
S
(
continued on next page)

6
40
Y. Yang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 636–643
Table 1 (continued)
Name
Structure
Virus
NA from virus
H5N1 ( M)
H3N2 (
lM)
H1N1 (
l
M)
l
H3N2 (lM)
OH
OH
OH
OH
OH
OH
AcHN
AcHN
H
H
N
TetraEG-SG
N
1.78 ± 1.3
2.4 ± 0.4
2.5 ± 0.1
10 ± 1
HN
HN
HN
O
O
NH2
NH2
COOH
COOH
O
S
S
O
O
OH
OH
OH
OH
OH
OH
AcHN
H
AcHN
H
N
NH
N
NH
PentaEG-SG
HexaEG-SG
HN
1 ± 0.6
1.2 ± 0.2
0.9 ± 0.1
1.1 ± 0.1
10 ± 2
O
O
2
COOH
2
COOH
S
O
O
O
O
S
OH
OH
OH
OH
OH
OH
AcHN
AcHN
H
H
N
N
HN
0.5 ± 0.2
0.57 ± 0.06
11 ± 2
HN
O
O
NH
2
COOH
NH
2
COOH
S
O
O
S
O
O
O
OH OH
O
COOH
HO
ZanamivirÒ
ꢀ0.001
ꢀ0.008
ꢀ0.01
ꢀ0.01
ꢀ0.04
ꢀ0.05
ꢀ0.04
ꢀ0.05
AcHN
NH
NH
HN
2
CO Et
O
2
Oseltamivir Ò
AcHN
H N
2
are similar to SG, which is the monomeric compound and the val-
ues for both enzymes are similar, in the submicromolar range. This
is because the soluble NAs are not membrane bound and are pres-
ent as a mixture of monomers, dimers, trimers and some tetra-
mers. To summarize this subsection, these experiments confirm
that the compounds with amine at the 4 position (SA, C6-SA,
C12-SA, TetraEG-SA, PentaEG-SA and HexaEG-SA) are better inhib-
itors than the natural receptor. The compounds with guanidine at
the 4 position (SG, C6-SG, C12-SG, TetraEG-SG, PentaEG-SG and
HexaEG-SG) are better inhibitors than compounds with amine at
the case of the guanidine containing compounds, the monomer SG
M for both strains, which is a 50-fold de-
crease compared to SA. The bivalent compounds, C6-SG, C12-SG,
TetraEG-SG, PentaEG-SG and HexaEG-SG all show significant de-
has an IC50 value of ꢀ1
l
creases in the IC50 values, ranging from 250 nm to 2.4 lM for both
viruses, with C6-SG the best inhibitor of all compounds. However,
since the values for all bivalent compounds are similar, it is not clear
if the compounds bind to two NA’s on the same virion or different
virions. Whatis clearis thatourhypothesisofincreasingtheintrinsic
binding affinity of an individual sialoside analog coupled with biva-
lency decreases the IC50 values from the millimolar range by 10,000
fold to the nanomolar range.
We were also interested in testing the efficacy of these com-
pounds to inhibit the virus in cell based systems. Towards that
end, we performed a plaque assay for all the compounds. The virus
was introduced to the cells for 30 min, followed by addition of the
compounds to arrest the spread of the viruses. IC50 values based on
50% decrease in plaque size are given in Table 2. We were pleased
to observe a similar trend for all compounds as was seen with the
cell free system. Briefly, SA, the compound with an amine at the 4
the 4 position. We also confirmed that both classes of NA, NA
the more open binding pocket and a flexible loop that closes upon
introduction of sialic acid or an inhibitor and NA , which has a pre-
1
with
2
2
0
set binding pocket, are inhibited very well by the synthetic
compounds.
Since the compounds inhibited soluble NAs, we performed the
same assay repeated with two intact viruses, Influenza H1N1
(
A/California/07/2009) and H3N2 (A/Hongkong/8/68) to ensure that
the compounds inhibit the transmembrane NAs present on the
viruses. A similar trend as was observed for soluble NA. SA, the com-
pound with an amine at the four position exhibits an IC50 value of
position exhibited inhibition in the 10–1000 lM range for both,
6
0
l
M for both strains. The bivalent molecules, C6-SA, C12-SA, Tet-
raEG-SA, PentaEG-SAand HexaEG-SAexhibita 5-fold decrease in the
M. The lone exception is
H1N1 and H3N2 strains, and the dimers C6-SA, C12-SA, TetraEG-
SA, PentaEG-SA and HexaEG-SA, exhibiting a 10-fold decrease in
IC50s compared to the monomer to ꢀ10
l
the IC50 values (range from 1 to 100
SG, the compounds with a guanidine at the 4 position, exhibited
a 10-fold decrease in the IC50 values (1–10 M) compared to SA.
The bivalent derivatives, C6-SG, C12-SG, TetraEG-SG, PentaEG-SG
lM) in comparison to SA.
the compound with the longest oligoethylene glycol spacer, which
did not have a similar effect as the other bivalent molecules, presum-
ably because the spacer is too flexible to exhibit a bidentate effect. In
l

Y. Yang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 636–643
641
Table 2
IC50 values of influenza strains by the gemini sialosides based on 50% decrease in plaque size. The strains used in these studies were Influenza H1N1 (A/California/07/2009) and
H3N2 (A/Hongkong/8/68)
Name
Structure
Virus
H3N2 (
l
M)
H1N1 (lM)
HO OH
OH
COOH
S
SA
10–100
>100
O
AcHN
SH
H N
2
OH
OH
OH
OH
OH
OH
AcHN
AcHN
C6-SA
H
2
N
H N
1–10
100
2
O
O
COOH
COOH
S
S
OH
OH
OH
OH
OH
OH
AcHN
AcHN
C12-SA
H
2
N
1–10
1–10
1–10
100
100
100
H N
2
O
O
COOH
COOH
S
S
OH
OH
OH
OH
OH
OH
AcHN
AcHN
H N
TetraEG-SA
H N
2
2
O
O
COOH
COOH
O
S
S
O
O
OH
OH
OH
OH
OH
OH
AcHN
AcHN
H N
H N
2
PentaEG-SA
2
O
O
COOH
COOH
O
S
O
O
O
S
OH
OH
OH
OH
OH
OH
AcHN
AcHN
2
H N
HexaEG-SA
H
2
N
O
1–10
1–10
100
10
O
COOH
COOH
S
O
O
S
O
O
O
HO OH
OH
COOH
S
O
AcHN
SG
SH
HN
NH
H N
2
OH
OH
OH
OH
OH
OH
AcHN
AcHN
H
H
C6-SG
N
N
0.01–0.1
1.0
HN
COOH
HN
HN
O
O
NH2
NH2
COOH
S
S
OH
OH
OH
OH
OH
OH
AcHN
AcHN
H
N
H
N
C12-SG
0.1
1.0
O
HN
NH
2
O
COOH
NH
2
COOH
S
S
(
continued on next page)

6
42
Y. Yang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 636–643
Table 2 (continued)
Name
Structure
Virus
H3N2 (lM)
H1N1 (lM)
OH
OH
OH
OH
OH
OH
AcHN
AcHN
H
H
N
TetraEG-SG
N
0.1
1.0
HN
HN
HN
O
O
NH2
NH2
COOH
COOH
O
S
S
O
O
OH
OH
OH
OH
OH
OH
AcHN
H
AcHN
H
N
NH
N
NH
PentaEG-SG
HexaEG-SG
HN
.01–0.1
0.1–1.0
1.0
1.0
O
O
2
COOH
2
COOH
S
O
O
O
O
S
OH
OH
OH
OH
OH
OH
AcHN
AcHN
H
H
N
N
HN
HN
O
O
NH
2
COOH
NH
2
COOH
S
O
O
S
O
O
O
OH OH
O
COOH
HO
ZanamivirÒ
0.001
0.01
AcHN
NH
NH
HN
2
CO Et
O
2
Oseltamivir Ò
0.001–0.01
0.001–0.01
AcHN
H N
2
and HexaEG-SG, all exhibiting lower IC50 values (10–1000 nM)
than SG.
References and notes
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