Antiviral activity and interaction mechanisms study of novel glucopyranoside derivatives

Article abstract of DOI:10.1016/j.bmcl.2015.07.068

Novel glucopyranoside derivatives were synthesized and evaluated for their antiviral activities against tobacco mosaic virus (TMV). Bioassay results indicated that some of the target compounds exhibited good in vivo antiviral activities against TMV. Among the title compounds, f6 showed appreciable inactivation effect against TMV, with the 50% effective concentration value (EC₅₀) of 52.9 μg/mL, which was better than that of ribavirin (145.1 μg/mL). In addition, interaction between f6 and TMV-CP was characterized by fluorescence spectroscopy, isothermal titration calorimetry (ITC), and microscale thermophoresis (MST). Results showed that f6 bound to TMV-CP with micromole affinity, and thermodynamic parameters suggested that this interaction was typically endothermic and spontaneous, with 1:1.53 ratio of TMV-CP to f6. Thus, the synthesized glucopyranoside derivatives containing 1,4-pentadien-3-one moiety could be promising antiviral agents.

Full text of DOI:10.1016/j.bmcl.2015.07.068

Bioorganic & Medicinal Chemistry Letters 25 (2015) 3840–3844
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Antiviral activity and interaction mechanisms study of novel
glucopyranoside derivatives
Meihang Chen a,b, Deyu Hu a, Xiangyang Li a, Song Yang a, Weiying Zhang a, Pei Li a, Baoan Song a,
⇑
a State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of
Education, Guizhou University, Huaxi District, Guiyang 550025, China
b College of Material and Chemistry Engineering, Tongren University, Tongren, Guizhou 554300, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel glucopyranoside derivatives were synthesized and evaluated for their antiviral activities against
tobacco mosaic virus (TMV). Bioassay results indicated that some of the target compounds exhibited
good in vivo antiviral activities against TMV. Among the title compounds, f6 showed appreciable
Received 28 April 2015
Revised 19 July 2015
Accepted 21 July 2015
Available online 26 July 2015
inactivation effect against TMV, with the 50% effective concentration value (EC50) of 52.9
lg/mL, which
was better than that of ribavirin (145.1 g/mL). In addition, interaction between f6 and TMV-CP was
l
characterized by fluorescence spectroscopy, isothermal titration calorimetry (ITC), and microscale ther-
mophoresis (MST). Results showed that f6 bound to TMV-CP with micromole affinity, and thermody-
namic parameters suggested that this interaction was typically endothermic and spontaneous, with
1:1.53 ratio of TMV-CP to f6. Thus, the synthesized glucopyranoside derivatives containing 1,4-penta-
dien-3-one moiety could be promising antiviral agents.
Keywords:
Glucopyranoside derivatives
1,4-Pentadien-3-one
Synthesis
Antiviral activity
Interaction mechanisms
Ó 2015 Elsevier Ltd. All rights reserved.
Tobacco mosaic virus (TMV) is a kind of severe plant virus and
extremely difficult to control due to its absolute parasitism, which
hence endows it with another name ‘plant cancer’. So far the activ-
ities of all commercialized antiviral agents for plants are around
Glycoside, widely distributed in plants, has increasingly
aroused attention because of its various pharmacological effects,6
such as anticancer,7 antiviral,8 antiproliferative,9 anti-HBV,10 anti-
HIV,11 antihyperglycemic,12 antimicrobial,13 antioxidant,14 and
cytotoxic14 activities. Recently, a large number of natural glyco-
sides were found to exhibit outstanding antiviral activities against
TMV.15–21 Moreover, a number of synthetic glycosides derivatives
were found to exhibit antiviral activities against TMV. For example,
Dai and co-workers synthesized a series of glycosides derivatives
containing 1,5-diacetyl-2,4-dioxohexahydro-1,3,5-triazine moiety
with good antiviral activity against TMV.22 Meanwhile, Wang
et al. synthesized a series of novel glycoconjugates of phenan-
throindolizidine alkaloids, and found that these compounds exhib-
ited higher antiviral activities against TMV than commercialized
antiviral agents.23
Curcumin, a non-nutritive and non-toxic compound, was iso-
lated from the plant Curcuma longa L. A number of studies docu-
mented that curcumin and its derivatives exhibited multiple
pharmacological activities, such as antiviral,24 anti-angiogenic,25
antimicrobial,26 anticancer,27 antioxidative,28 anti-inflammatory,29
and anti-HIV30 activities. Additionally, curcumin and its derivatives
have been also found to possess fine activities against plant
virus.31–34 For example, our research group has synthesized a ser-
ies of 1,4-pentadiene-3-one derivatives containing pyrazole, oxime
ester, and quinazoline groups with good antiviral activities.32
30–50% at 500
widely used to prevent TMV disease. However, its antiviral activity
is consistently less than 50% at 500
g/mL.2 In addition, anti-plant
l
g/mL.1 Ribavirin, a successful antiviral agent, is
l
virus agent research is not like pharmaceutical research. We all
know that many targets of pharmaceutical research, such as the
structure and function of target protein, or even the signal trans-
duction pathway of target proteins are already known.3 But for
anti-plant virus agent research, only very few molecular targets
are investigated and can be used in agrochemical design and
discovering,4 which on the other hand increases the difficulty of
discovery of antiviral molecules for plants. Therefore, it’s a chal-
lenge for the development of novel, effective, and environmentally
safe antiviral agent.5
Abbreviations: EC50, 50% effective concentration; 1H NMR, 1H nuclear magnetic
resonance; 13C NMR, 13C nuclear magnetic resonance; TMV, tobacco mosaic virus;
TBAB, tetrabutylammonium bromide; PEG, polyethylene glycol; TMV-CP, tobacco
mosaic virus coat protein; ITC, isothermal titration calorimetry; MST, microscale
thermophoresis; DCM, dichloromethane; mp, melting point.
⇑
Corresponding author. Tel.: +86 (851)8362 0521; fax: +86 (851)8362 2211.
E-mail address: songbaoan22@yahoo.com (B. Song).
http://dx.doi.org/10.1016/j.bmcl.2015.07.068
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

M. Chen et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3840–3844
3841
Table 1
Notably,
a number of quinazolin-1,4-pentadien-3-one deriva-
tives33 and 4(3H)-quinazolinone-1,4-pentadien-3-one derivatives
exhibited better protection and curative effects in vivo against
TMV than Ningnanmycin.34 However, all of the synthesized com-
pounds poorly inactivated TMV. Thus, the development of an
excellent antiviral agent with a simple structure is needed.
Effect of different concentration for synthesis of f1
No
Concentration
Solvent
Temperature
(°C)
Reaction time
(h)
Yield
(%)
1
2
3
4
3% NaOH
4% NaOH
5% NaOH
6% NaOH
DCM
DCM
DCM
DCM
35
35
35
35
6
6
6
6
37
52
87
84
Based on the above finding, we aim to introduce a glucopyra-
noside fragment into the structure of 1,4-pentadien-3-one
(Fig. 1) to build a novel family of bioactive compounds inactivated
TMV. Therefore, in current work, a serial of novel glucopyranoside
derivatives containing 1,4-pentadien-3-one moiety were synthe-
sized. The activities against TMV in vivo were subsequently evalu-
ated, and the bioassays results demonstrated that compounds f5,
f6, f8, f10, f13, f14, f20, f24, f26, and f28 remarkably inactivated
TMV, with EC50 values of 59.6, 52.9, 55.3, 56.0, 62.8, 60.6, 67.4,
of 87% was achieved when the reaction mixture was stirred for 6 h
with 5% NaOH. The physical characteristics, IR, 1H NMR, 13C NMR,
and elemental analysis data for all the synthesized compounds
were reported in Supplementary data and the representative data
of f1 were shown below.
62.3, 57.1, and 57.4
l
g/mL, respectively, compared with Ribavirin
(1E,4E)-1-(2-(2,3,4,6-tert-O-acetyl-b-
phenyl-1,4-pentadien-3-one (f1): yellow solid, mp 175–178 °C,
yield, 87%; IR (KBr, cmÀ1
: 1759, 1651, 1616, 1602, 1489, 1375,
D-glucopyranosyl)phenyl)-5-
(145.1 g/mL). And as an extension of this approach, the struc-
l
ture–activity relationship (SAR) analyses of antiviral activities
were also discussed. To further study the underlying mechanisms
of inactivation effect between compound f6 and TMV-CP, their
interaction was studied by fluorescence spectroscopy, isothermal
titration calorimetry (ITC), and microscale thermophoresis (MST).
The synthetic route of glucopyranoside derivatives containing
1,4-pentadien-3-one moiety f1–f32 was shown in Scheme 1.
Using 2 or 4-hydroxybenzaldehydes as the starting materials, the
key intermediates d1–d32 were obtained via two consecutive
condensation reactions.34 Then, a mixture of the intermediates
d1–d32, compound e, tetrabutylammonium bromide and NaOH
were reacted in dichloromethane (DCM) for 6–12 h at 35 °C, and
generated the title compounds f1–f32 in 36–87% yields. To opti-
mize the reaction conditions for the preparation of compound f1,
the synthesis was carried out with different concentrations of
NaOH (3%, 4%, 5%, and 6%). As shown in Table 1, a maximum yield
) m
1228, 1074; 1H NMR (500 MHz, CDCl3, ppm) d: 7.93 (1H, d,
J = 16.50 Hz, @CH–C6H4O), 7.77–7.75 (3H, m, @CH–C6H5, ArH),
7.65 (1H, d, J = 8.05 Hz, ArH), 7.43–7.12 (5H, m, CO–CH@CH–
C6H5, ArH), 7.10–7.04 (2H, m, ArH), 7.00 (1H, d, J = 16.60 Hz,
CO–CH@CH–C6H4O), 5.51 (1H, t, J = 9.75 Hz, 3-H), 5.37 (1H, t,
J = 9.10 Hz, 2-H), 5.23 (1H, t, J = 8.30 Hz, 4-H), 5.12 (1H, d,
J = 18.35 Hz, 1-H), 4.35–4.23 (2H, m, 6-H), 4.12–4.10 (1H, m,
5-H), 2.09–2.02 (12H, 4s, 4 Â CH3CO); 13C NMR (125 MHz, CDCl3,
ppm) d: 189.58, 170.65, 170.19, 169.57, 169.44, 155.61, 143.56,
137.06, 135.10, 131.58, 130.33, 128.89, 128.73, 128.61, 124.97,
123.60, 123.40, 115.40, 99.30, 72.34, 72.17, 70.64, 61.85, 20.70,
20.67, 20.61; Anal. Calcd for C31H32O11 (580.19): C, 64.13; H,
5.56; found: C, 64.52; H, 5.72.
In this study, the inhibitory effect of the synthesized glucopyra-
noside derivatives containing 1,4-pentadien-3-one moiety were
Figure 1. Design of the target compounds.
Scheme 1. Synthesis of the target compounds f1–f32.

3842
M. Chen et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3840–3844
evaluated for their antiviral activities in vivo against TMV based on
previously described methods,35 and the commercial agent
Ribavirin was the control. Results of preliminary bioassay against
TMV were listed in Table 2 and most of the glucopyranoside
derivatives exhibited good inactivation activities against TMV with
the inhibition rates of 57.0–93.9% at 500 lg/mL. Particularly, com-
pounds f6, f8, f10, f26, and f28 showed excellent inactivation activ-
ity (93.9%, 90.6%, 91.7%, 92.3% and 91.0%, respectively) superior to
Ribavirin (72.9%) against TMV at 500 lg/mL. Compounds f1, f2, f3,
glucopyranose of derivatives. The data of antiviral activities indi-
cated that the relationships of the antiviral activities with different
Ar were deduced. Excellent TMV inactivation was observed when
Ar was substituted with 2-ClC6H4, 3-NO2C6H4, 4-NO2C6H4, 3-Py,
and 4-Py groups, whereas when Ar was substituted with
2-MeOC6H4, 4-MeOC6H4, or 4-MeC6H4, the corresponding target
compounds poorly inactivated TMV. Notably, the compounds bear-
ing electron-withdrawing (2-ClC6H4, 3-NO2C6H4, 4-NO2C6H4) and
heterocyclic groups (3-Py, 4-Py) were found to exhibit significantly
higher inactivity effects against TMV than the other groups.
Furthermore, most of title compounds bearing the same Ar along
with O-glucopyranose at C-2-position of benzene showed higher
inactivation activities against TMV than the corresponding com-
pounds with O-glucopyranose at C-4-position of benzene.
f4, f5, f7, f13, f15, f16, f20, f23, f25, and f27 had higher inhibition
rates (84.1%, 86.7%, 89.7%, 81.4%, 89.1%, 89.4%, 81.5%, 86.8%, 85.3%,
88.1%, 80.0%, 87.2% and 83.1%, respectively) against TMV than the
that of Ribavirin (72.9%) at 500
erately inactivated TMV.
lg/mL. The other compounds mod-
On the basis of previous in vivo bioassays, the title compounds
exhibited good inactivation activities against TMV. Therefore, to
further investigate their inhibitory activity in vivo, the EC50 values
for all of the synthesized compounds were calculated and summa-
rized in Table 3. Generally, the evaluated compounds favorably
inactivated TMV, notably, compounds f5, f6, f8, f10, f13, f14, f20,
f24, f26, and f28 exhibited higher antiviral activity against TMV
(the EC50 values of 52.9, 55.3, 56.0, 62.8, 60.6, 67.4, 62.3, 57.1,
The binding interactions between compound f6 and TMV-CP
were investigated using fluorescence spectroscopy, ITC, and MST
analysis to understand the underlying mechanisms. The result of
ITC analysis demonstrated that the interaction of one TMV-CP with
1.53 f6 molecules is typically endothermic (Fig. 2). The
DG value
(
D
G ꢀÀ7.63 kJ/mol) is negative, which indicated that the interac-
tion is spontaneous. The binding constant (Ka) between f6 and
TMV-CP is 1.79 Â 105 L/mol, representing a comparatively stronger
ligand-protein interaction, which is higher than those of f18
(2.07 Â 104 L/mol) and f31 (1.76 Â 103 L/mol) with moderate
57.1, and 57.4
lg/mL, respectively) than that of Ribavirin
(145.1 g/mL). SAR indicated antiviral activities of the title com-
l
pounds shown promising potency against TMV for different aryl
(117.8 lg/mL) and poor (397.1 lg/mL) anti-TMV activity, respec-
groups (style and position) were introduced into novel
tively (Table 4). Secondly, in order to verify the result of ITC, the
Table 2
Inhibitory effect of the test compounds (500
l
g/mL) against TMV in vivo
O
AcO
OAc
OAc
OAc
Ar
O
O
Compd
Concentration (
lg/mL)
Inactivation activity (%)a
Ar
O
f1
f2
f3
f4
f5
f6
f7
f8
C6H5
C6H5
2-O
4-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
/
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
84.1 4.5
86.7 2.3
89.7 2.7
81.4 3.1
89.1 1.5
93.9 2.3
89.4 2.4
90.6 2.8
76.9 2.9
91.7 + 3.5
73.1 3.2
75.5 3.6
81.5 3.6
77.0 2.9
86.8 3.2
85.3 4.1
74.5 3.6
73.2 2.6
73.2 3.3
88.1 1.8
75.7 3.6
79.8 2.9
80.0 4.0
77.0 2.9
87.2 3.3
92.3 2.4
83.1 3.1
91.0 1.7
56.3 0.7
62.1 2.3
48.7 3.6
52.4 1.5
72.9 2.4
4-FC6H4
4-FC6H4
2-ClC6H4
2-ClC6H4
3-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-NO2C6H4
2-OMeC6H4
2-OMeC6H4
2-Py
f9
f10
f11
f12
f13
f14
f15
f16
f17
f18
f19
f20
f21
f22
f23
f24
f25
f26
f27
f28
f29
f30
f31
f32
Ribavirinb
2-Py
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
2-FC6H4
2-FC6H4
2-BrC6H4
2-BrC6H4
2-Th
2-Th
3-Py
3-Py
4-Py
4-Py
4-OMeC6H4
4-OMeC6H4
4-MeC6H4
4-MeC6H4
/
a
Average of three replicates.
The commercial, agricultural, and antiviral product Ribavirin was used for comparison of activity.
b

M. Chen et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3840–3844
3843
Table 3
The EC50 values of compounds f1–f32 against to TMV in vivo
O
O
AcO
OAc
OAc
OAc
AcO
OAc
OAc
OAc
Ar
Ar
O
O
a
a
Compd
EC50
(lg/mL)
Compd
EC50 (lg/mL)
O
O
Ar
O
Ar
O
f1
f2
f3
f4
f5
f6
f7
f8
C6H5
C6H5
2-O
4-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
98.4 1.0
75.2 2.7
94.2 3.1
84.4 3.5
59.6 2.4
52.9 2.9
81.9 1.8
55.3 2.6
110.8 3.5
56.0 1.4
154.0 3.5
132.0 1.7
62.8 1.3
60.6 2.7
108.6 2.7
105.5 4.0
122.7 1.6
f18
f19
f20
f21
f22
f23
f24
f25
f26
f27
f28
f29
f30
f31
f32
Ribavirinb
/
4-BrC6H4
2-FC6H4
2-FC6H4
2-BrC6H4
2-BrC6H4
2-Th
2-Th
3-Py
3-Py
4-Py
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
4-O
2-O
/
117.8 2.5
181.1 3.1
67.4 0.9
97.0 1.1
72.6 3.5
84.5 3.5
62.3 0.8
73.5 3.2
57.1 2.7
75.0 1.8
57.4 0.9
384.1 1.2
326.3 0.9
397.1 2.1
365.6 2.7
145.1 2.6
/
4-FC6H4
4-FC6H4
2-ClC6H4
2-ClC6H4
3-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-NO2C6H4
2-OMeC6H4
2-OMeC6H4
2-Py
f9
f10
f11
f12
f13
f14
f15
f16
f17
4-Py
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
/
2-Py
4-ClC6H4
4-ClC6H4
4-BrC6H4
/
/
a
Average of three replicates.
The commercial, agricultural, and antiviral product Ribavirin was used for comparison of activity.
b
Figure 2. (A) Results of isothermal titration calorimetry for f6 binding to TMV-CP; (B) results of isothermal titration calorimetry for f18 binding to TMV-CP; (C) results of
isothermal titration calorimetry for f31 binding to TMV-CP.
Table 4
The binding constant (Ka) of f6, f18, and f31
MST and ITC. It was found that the Ka of f6 is 3.93 Â 105 L/mol,
which is higher those of f18 (5.50 Â 104 L/mol) and f31
(3.67 Â 103 L/mol) (Fig. 4 and Table 4). The result indicated that
compound f6 has a strong affinity with TMV-CP protein.
In summary, a series of novel glucopyranoside derivatives were
designed, synthesized, and evaluated for their antiviral activities
in vivo against TMV. Bioassay results indicated the title compounds
exhibited good antiviral activities against TMV. Notably, com-
pounds f6 exhibited excellent inactivation activity against TMV,
Compd
ITC (L/mol)
MST (L/mol)
Fluorescence spectroscopy (L/mol)
f6
f18
f31
1.79 Â 105
2.07 Â 104
1.76 Â 103
1.10 Â 105
1.07 Â 104
7.69 Â 103
3.93 Â 105
5.50 Â 104
3.67 Â 103
Ka between compound f6 and TMV-CP were investigated using
MST. As shown in Figure 3 and Table 4, the result of MST measure-
ments was similar to ITC findings and the Ka between f6 and TMV-
CP is 1.10 Â 105 L/mol at 25 °C, which is higher than those of f18
(1.07 Â 104 L/mol) and f31 (7.69 Â 103 L/mol). Finally, fluorescence
spectrum measurement was also further confirmed the results of
with EC50 value of 52.9
lg/mL, which was better than that of
ribavirin (145.1 g/mL). Moreover, interaction between f6 and
l
TMV-CP was characterized by fluorescence spectroscopy, ITC, and
MST. Results showed that f6 bound to TMV-CP with micromole
affinity, and thermodynamic parameters indicated that the

3844
M. Chen et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3840–3844
Figure 3. (A) MST measurements for the binding of TMV-CP and f6; (B) MST measurements for the binding of TMV-CP and f18; (C) MST measurements for the binding of
TMV-CP and f31.
Figure 4. (A) Fluorescence emission spectra of TMV-CP in the presence of f6 with different concentrations. kex = 278 nm. Inset: the linear relationship for quenching TMV-CP
by f6; (B) fluorescence emission spectra of TMV-CP in the presence of f18 with different concentrations. kex = 278 nm. Inset: the linear relationship for quenching TMV-CP by
f18; (C) fluorescence emission spectra of TMV-CP in the presence of f31 with different concentrations. kex = 278 nm. Inset: the linear relationship for quenching TMV-CP by
f31.
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1:1.53 ratio of TMV-CP to f6. Further study on the action mecha-
nism of inactivation effect is currently underway.
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The authors gratefully acknowledge the National Natural
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.07.
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