Design, Synthesis, and Antiviral Activity of Novel Chalcone Derivatives Containing a Purine Moiety

Article abstract of DOI:10.1002/cjoc.201600568

To find new antiviral agents, novel chalcone derivatives containing a purine moiety were designed and synthesized by combining bioactive substructures. The antiviral activities of the derivatives against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) were evaluated. Results showed that most of the derivatives showed antiviral activities. Compounds 3n and 3p exhibited excellent curative, protective and inactivation activities against TMV, with the EC₅₀ values of 452.4, 416.2, 241.2 and 438.7, 418.6, 261.7 μg?mL^?1, respectively, which were better than those of ribavirin (585.8, 436.0 and 268.7 μg?mL^?1). Compounds 3n and 3p showed remarkable curative and protective activities against CMV. Compound 3n showed a moderate affinity to TMV coat protein, with binding constant K_a and K_d values of 1.5 × 10⁴ L?mol^?1 and 79.8 μmol?L^?1, respectively. These findings provided an important structural insight for further designs of highly active chalcone derivatives and a basis for further study on their mechanism of action.

Full text of DOI:10.1002/cjoc.201600568

FULL PAPER
DOI: 10.1002/cjoc.201600568
Design, Synthesis, and Antiviral Activity of Novel Chalcone
Derivatives Containing a Purine Moiety
Xiuhai Gan,a,b Yanjiao Wang,a Deyu Hu,a and 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, Center for Research and
Development of Fine Chemicals, Guizhou University, Guiyang, Guizhou 550025, China
b College of Chemistry and Life Science, Guizhou Education University, Guiyang, Guizhou 550018, China
To find new antiviral agents, novel chalcone derivatives containing a purine moiety were designed and synthe-
sized by combining bioactive substructures. The antiviral activities of the derivatives against tobacco mosaic virus
(TMV) and cucumber mosaic virus (CMV) were evaluated. Results showed that most of the derivatives showed an-
tiviral activities. Compounds 3n and 3p exhibited excellent curative, protective and inactivation activities against
TMV, with the EC50 values of 452.4, 416.2, 241.2 and 438.7, 418.6, 261.7 μg•mL1, respectively, which were better
than those of ribavirin (585.8, 436.0 and 268.7 µg•mL−1). Compounds 3n and 3p showed remarkable curative and
protective activities against CMV. Compound 3n showed a moderate affinity to TMV coat protein, with binding
constant Ka and Kd values of 1.5×104 L•mol−1 and 79.8 μmol•L−1, respectively. These findings provided an im-
portant structural insight for further designs of highly active chalcone derivatives and a basis for further study on
their mechanism of action.
Keywords chalcone, purine, antiviral activity, tobacco mosaic virus, cucumber mosaic virus
Introduction
TMV. So, it is a key pathway for the development of
pesticides on the basis of the natural products.
As an important secondary metabolite in plants,[9-12]
chalcone and its derivatives have a wide range of bio-
logical properties including anticancer,[13,14] antileish-
manial,[15] tyrosinase inhibitory,[16] nematicidal,[17] and
anti-TMV.[18,19] In our previous studies, a series of
chalcone derivatives (B, Figure 1) with good bioactivi-
ties against TMV and CMV were reported.[20,21] Mean-
while, purines are endogenous inhibitory substances that
widely exist in plants and animals; these compounds
have been used as scaffolds for the development of bio-
logically functional molecules in medicine. Acyclovir
(C, Figure 1),[22] ganciclovir[23] and abacavir[24] derived
from purine exhibit remarkable antiviral activities. We
found that purine derivatives containing a 1,4-penta-
dien-3-one moiety (D, Figure 1) possess excellent anti-
viral activities against CMV,[25] but their application in
controlling TMV has not been reported.
Tobacco mosaic virus (TMV) and cucumber mosaic
virus (CMV) are serious plant viruses that are difficult
to control worldwide.[1] Traditional agrochemicals play
a critical role in controlling these diseases. As a suc-
cessfully registered plant viral inhibitor, ribavirin (A,
Figure 1) is widely used to prevent plant virus diseases,
but its inhibitory effect is less than 50% at 500 μg•mL1.
To date, no chemical treatment can absolutely inhibit
TMV and CMV once it has infected plants.[2] Mean-
while, excessive use of agrochemicals could cause ad-
verse effects, such as environmental pollution and
treatment resistance. Therefore, searching for novel,
environmentally benign and ecologically safe antiviral
agents with unique modes of action, remains a daunting
task in pesticide research.
Given their low toxicity, easy decomposition, envi-
ronmental friendliness, and unique mode of action, nat-
ural products[3,4] have attracted great attention for de-
velopment into medicines and pesticides. Some natural
products and their derivatives such as antofine and its
derivative NK-007,[5,6] phenanthroindolizidine and its
analogues,[7] and β-carboline alkaloid and its deriva-
tives,[8] display significant inhibitory activities against
Basing on studies of purines, we found that N-9 sub-
stituted purine is a core process for biological and
pharmaceutical activities,[26-29] while anti-HBV active
purine-nucleoside analogs possess amido bonds.[30] To
find new anti-TMV candidates, a series of novel chal-
cone derivatives containing a purine group (Figure 2)
*
E-mail: songbaoan22@yahoo.com; Tel.: 0086-0851-83620521; Fax: 0086-0851-8362-2211
Received September 4, 2016; accepted November 13, 2016 ; published online XXXX, 2017.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201600568 or from the author.
In Memory of Professor Enze Min.
Chin. J. Chem. 2017, XX, 1—8
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Gan et al.
FULL PAPER
Figure 1 Chemical structures of known antiviral molecules.
Figure 2 Design of target compounds.
were designed and synthesized through an amido link
by combining bioactive substructures (Scheme 1). The
anti-TMV and anti-CMV activities of these chalcone
derivatives were evaluated. Then, the interaction of the
most active compound with tobacco mosaic virus coat
protein (TMV CP) was tested through fluorescence spec-
troscopy (FT) and microscale thermophoresis (MST).
spectra were determined on a JEOL-ECX 500 NMR
spectrometer (JEOL Ltd., Japan) in DMSO-d6 at 500
and 125 MHz, using TMS as an internal standard. High
resolution mass spectrometer (HRMS) data were rec-
orded on a Thermo Scientific Q Exactive (Thermo,
USA). Melting points were recorded on an XT-4 binoc-
ular microscope melting point apparatus (Beijing Tech
Instruments Co., Beijing, China), uncorrected. All sol-
vents and reagents were of analytical reagent grade or
chemically pure, and the solvents were dried in advance
and distilled before use. Reaction progress was moni-
Scheme 1 Synthetic routes of the target compounds
Ar
O
ArCHO/NaOH
H2N
H2N
tored by thin-layer chromatography on silica gel GF254
.
C2H5OH, r.t., 12 h
O
Column chromatographic purification was carried out
using silica gel (200－300 mesh).
1a 1q
－
O
Ar
Cl
/K2CO3
Cl
General synthetic procedure
H
N
Cl
As shown in Scheme 1, intermediates 1a－1q were
prepared as previously reported,[31,32] and the corre-
sponding intermediates 2a－2q were obtained as previ-
ously described.[32] Then, anhydrous K2CO3 (0.2 g, 1.45
mmol) was added to a solution of 6-chloro-9H-purine
(0.2 g, 1.29 mmol) in DMF (4 mL), and the mixture was
stirred at room temperature for 1 h. Subsequently, a so-
lution of corresponding 2a－2q (1.29 mmol) in DMF (3
mL) was added to the mixture slowly, warmed to 50 ℃,
and then stirred for 6 h. The mixture was cooled to room
temperature and then poured into ice water. The solid
was filtered, and washed with cold water. Then, the
crude product was recrystallized from CH2Cl2/C2H5OH
(V∶V＝1∶2), filtered, washed, and dried to obtain the
title compounds 3a－3q.
CH2Cl2, r.t., 8 h
Cl
O
O
2a 2q
－
Cl
N
N
N
Ar
N
N
N
H
N
N
HN
K2CO3/DMF, 50 oC, 6 h
O
O
3a 3q
－
Ar =
a: 4-CH3-C6H4; b: 4-OCH3-C6H4; c: 2,4-(OCH3)2-C6H3;
d: 3,4,5-(OCH3)3-C6H2; e: 3-F-C6H4; f: C6H5; g: 4-Cl-C6H4;
h: 2-F-C6H4; i: 2,3-Cl2-C6H3; j: 2-Br-C6H4; k: 4-Br-C6H4;
l: 2,4-Cl2-C6H3; m: 2-Cl-C6H4; n: 2,4-F2-C6H3; o: 2,6-F2-C6H3;
p: 4-NO2-C6H4; q: 4-F-C6H4
(E)-2-(6-Chloro-9H-purin-9-yl)-N-(4-(3-(p-tolyl)-
acryloyl)phenyl)acetamide (3a): Paly yellow solid, yield
87.2%; m.p. 201 － 202 ℃ ; 1H NMR (500 MHz,
DMSO-d6) δ: 10.93 (s, 1H, NH), 8.76 (s, 1H, purine-2-
Experimental
Chemicals and instruments
Nuclear magnetic resonance (NMR) 1H and 13C
2
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© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2017, XX, 1—8

Design, Synthesis, and Antiviral Activity of Novel Chalcone Derivatives Containing a Purine Moiety
H), 8.70 (s, 1H, purine-8-H), 8.14 (d, J＝9.0 Hz, 2H,
1-Ar-2,6-H), 7.86 (d, J＝15.5 Hz, 1H, 3-H), 7.74 (d, J＝
8.5 Hz, 2H, 1-Ar-3,5-H), 7.72 (d, J＝8.5 Hz, 1H,
3-Ar-2,6-H), 7.65 (d, J＝15.5 Hz, 1H, 2-H), 7.23 (d, J＝
8.0 Hz, 2H, 3-Ar-3,5-H), 5.30 (s, 2H, CH2CO), 2.31 (s,
3H, CH3); 13C NMR (125 MHz, DMSO-d6) δ: 187.99,
165.72, 152.79, 152.31, 149.57, 148.98, 144.16, 143.20,
141.15, 133.38, 132.55, 131.06, 130.55, 130.55, 130.07,
130.07, 129.42, 129.42, 121.28, 119.14, 119.14, 46.98,
21.63; ESI-HRMS calcd for C23H19ClN5O2 [M＋H]＋
432.12273, found 432.12158.
phenyl)acryloyl)phenyl)acetamide (3e): Paly yellow
solid, yield 80.6%; m.p.＞250 ℃; 1H NMR (500 MHz,
DMSO-d6) δ: 10.94 (s, 1H, NH), 8.76 (s, 1H, purine-
2-H), 8.70 (s, 1H, purine-8-H), 8.17 (d, J＝9.0 Hz, 2H,
1-Ar-2,6-H), 7.98 (d, J＝15.5 Hz, 1H, 3-H), 7.82 (d, J＝
10.5 Hz, 1H, 3-Ar-6-H), 7.73 (d, J＝8.5 Hz, 2H,
1-Ar-3,5-H), 7.68 (d, J＝16.0 Hz, 1H, 2-H), 7.65 (s, 1H,
3-Ar-2-H), 7.48－7.37 (m, 1H, 3-Ar-5-H), 7.29－7.21
(m, 1H, 3-Ar-4-H), 5.30 (s, 2H, CH2CO); 13C NMR
(125 MHz, DMSO-d6) δ: 187.93, 165.76, 164.00,
162.06, 152.80, 152.31, 149.57, 148.97, 143.41, 142.59,
137.89, 133.12, 131.41, 131.06, 130.72, 130.72, 126.11,
123.83, 119.16, 119.16, 117.82, 115.22; ESI-HRMS
calcd for C22H15O2N5ClFNa [M＋Na]＋ 458.07905,
found 458.07849.
(E)-2-(6-Chloro-9H-purin-9-yl)-N-(4-(3-(4-methoxy-
phenyl)acryloyl)phenyl)acetamide (3b): Paly yellow
1
solid, yield 85.1%; m.p. 208－209 ℃; H NMR (500
MHz, DMSO-d6) δ: 10.92 (s, 1H, NH), 8.77 (s, 1H, pu-
rine-2-H), 8.70 (s, 1H, purine-8-H), 8.13 (d, J＝8.5 Hz,
2H, 1-Ar-2,6-H), 7.81 (d, J＝9.0 Hz, 2H, 1-Ar-3,5-H),
7.78 (d, J＝15.5 Hz, 1H, 3-H), 7.71 (d, J＝8.5 Hz, 1H,
3-Ar-2,6-H), 7.66 (d, J＝15.5 Hz, 1H, 2-H), 6.98 (d, J＝
8.0 Hz, 2H, 3-Ar-3,5-H), 5.29 (s, 2H, CH2CO), 3.78 (s,
3H, OCH3); 13C NMR (125 MHz, DMSO-d6) δ: 187.90,
165.69, 161.84, 152.80, 152.32, 149.56, 148.99, 144.08,
143.07, 133.56, 131.29, 131.29, 131.06, 130.46, 130.46,
127.91, 119.83, 119.13, 119.13, 114.93, 114.93, 55.92,
46.98; ESI-HRMS calcd for C23H18O3N5ClNa [M＋
Na]＋ 470.09904, found 470.09888.
(E)-2-(6-Chloro-9H-purin-9-yl)-N-(4-cinnamoyl-
phenyl)acetamide (3f): Paly yellow solid, yield 85.1%;
1
m.p. 198－200 ℃; H NMR (500 MHz, DMSO-d6) δ:
10.93 (s, 1H, NH), 8.77 (s, 1H, purine-2-H), 8.70 (s, 1H,
purine-8-H), 8.16 (d, J＝8.5 Hz, 2H, 1-Ar-2,6-H), 7.92
(d, J ＝ 15.5 Hz, 1H, 3-H), 7.88 － 7.82 (m, 2H,
3-Ar-2,6-H), 7.73 (d, J＝9.0 Hz, 2H, 1-Ar-3,5-H), 7.69
(d, J ＝ 16.0 Hz, 1H, 2-H), 7.48 － 7.39 (m, 3H,
3-Ar-3,4,5-H), 5.30 (s, 2H, CH2CO); 13C NMR (125
MHz, DMSO-d6) δ: 188.04, 165.73, 152.80, 152.32,
148.99, 144.09, 143.28, 135.27, 133.29, 131.09, 130.62,
130.62, 129.45, 129.45, 129.40, 129.40, 122.39, 119.17,
119.17, 46.99; ESI-HRMS calcd for C22H16O2N5ClNa
[M＋Na]＋ 440.08847, found 440.08801.
(E)-2-(6-Chloro-9H-purin-9-yl)-N-(4-(3-(2,4-dime-
thoxyphenyl)acryloyl)phenyl)acetamide (3c): Yellow
1
solid, yield 80.5%; m.p. 190－192 ℃; H NMR (500
MHz, DMSO-d6) δ: 10.90 (s, 1H, NH), 8.77 (s, 1H, pu-
rine-2-H), 8.70 (s, 1H, purine-8-H), 8.09 (d, J＝9.0 Hz,
2H, 1-Ar-2,6-H), 7.94 (d, J＝15.5 Hz, 1H, 3-H), 7.88 (d,
J＝9.0 Hz, 1H, 3-Ar-6-H), 7.73 (d, J＝15.0 Hz, 1H,
2-H), 7.71 (d, J＝8.5 Hz, 2H, 1-Ar-3,5-H), 6.60 (d, J＝
2.5 Hz, 1H, 3-Ar-3-H), 6.59 (dd, J＝8.5, 2.5 Hz, 1H,
3-Ar-5-H), 5.29 (s, 2H, CH2CO), 3.87 (s, 3H, OCH3),
3.81 (s, 3H, OCH3); 13C NMR (125 MHz, DMSO-d6) δ:
188.03, 165.66, 163.58, 160.43, 152.80, 152.31, 149.56,
148.99, 142.94, 138.77, 133.75, 131.06, 130.52, 130.33,
130.33, 119.31, 119.14,119.14, 116.46, 106.86, 98.80,
56.36, 56.08, 46.98; ESI-HRMS calcd for C24H20O4-
N5ClNa [M＋Na]＋ 500.10960, found 500.10928.
(E)-2-(6-Chloro-9H-purin-9-yl)-N-(4-(3-(4-chloro-
phenyl)acryloyl)phenyl)acetamide (3g): Paly yellow
solid, yield 89.5%; m.p. 188－190 ℃; H NMR (500
1
MHz, DMSO-d6) δ: 10.94 (s, 1H, NH), 8.76 (s, 1H, pu-
rine-2-H), 8.70 (s, 1H, purine-8-H), 8.16 (d, J＝9.0 Hz,
2H, 1-Ar-2,6-H), 7.95 (d, J＝15.5 Hz, 1H, 3-H), 7.89 (d,
J＝8.5 Hz, 2H, 1-Ar-3,5-H), 7.73 (d, J＝8.5 Hz, 2H,
3-Ar-2,6-H), 7.68 (d, J＝15.5 Hz, 1H, 2-H), 7.49 (d, J＝
8.0 Hz, 2H, 3-Ar-3,5-H), 5.30 (s, 2H, CH2CO); 13C
NMR (125 MHz, DMSO-d6) δ: 187.93, 165.74, 152.80,
152.31, 149.57, 148.98, 143.35, 142.60, 135.54, 134.27,
133.19, 131.08, 131.08, 130.66, 130.66, 129.48, 129.48,
123.15, 119.17, 119.17, 46.99; ESI-HRMS calcd for
C22H16O2N5Cl2 [M＋H]＋ 452.06717, found 452.06756.
(E)-2-(6-Chloro-9H-purin-9-yl)-N-(4-(3-(2-fluoro-
phenyl)acryloyl)phenyl)acetamide (3h): Paly yellow
solid, yield 90.3%; m.p.＞250 ℃; 1H NMR (500 MHz,
DMSO-d6) δ: 10.99 (s, 1H, NH), 8.81 (s, 1H, pu-
rine-2-H), 8.74 (s, 1H, purine-8-H), 8.19 (d, J＝9.0 Hz,
2H, 1-Ar-2,6-H), 8.14 (d, J＝8.5, 2.0 Hz, 1H, 3-Ar-6-H),
8.01 (d, J＝16.0 Hz, 1H, 3-H), 7.83 (d, J＝15.5 Hz, 1H,
2-H), 7.78 (d, J＝8.5 Hz, 2H, 1-Ar-3,5-H), 7.55－7.48
(m, 1H, 3-Ar-3-H), 7.37－7.31 (m, 2H, 3-Ar-4,5-H),
5.35 (s, 2H, CH2CO); 13C NMR (125 MHz, DMSO-d6)
δ: 187.87, 165.76, 162.43, 152.81, 152.31, 149.57,
148.98, 143.45, 135.15, 133.03, 131.06, 130.69, 130.69,
129.59, 125.49, 124.50, 122.84, 119.23, 119.23, 116.72,
116.55, 46.99; ESI-HRMS calcd for C22H15O2N5ClFNa
[M＋Na]＋ 458.07905, found 458.07880.
(E)-2-(6-Chloro-9H-purin-9-yl)-N-(4-(3-(3,4,5-tri-
methoxyphenyl)acryloyl)phenyl)acetamide (3d): Yellow
1
solid, yield 88.4%; m.p. 169－171 ℃; H NMR (500
MHz, DMSO-d6) δ: 10.94 (s, 1H, NH), 8.76 (s, 1H, pu-
rine-2-H), 8.70 (s, 1H, purine-8-H), 8.17 (d, J＝8.5 Hz,
2H, 1-Ar-2,6-H), 7.87 (d, J＝15.5 Hz, 1H, 3-H), 7.74 (d,
J＝8.5 Hz, 2H, 1-Ar-3,5-H), 7.65 (d, J＝15.5 Hz, 1H,
2-H), 7.19 (s, 2H, 3-Ar-2,6-H), 5.30 (s, 2H, CH2CO),
3.83 (s, 6H, OCH3), 3.67 (s, 3H, OCH3); 13C NMR (125
MHz, DMSO-d6) δ: 187.93, 165.73, 153.62, 153.62,
152.79, 152.31, 149.57, 148.98, 144.63, 140.14, 133.38,
132.55, 131.06, 130.83, 130.60, 130.60, 121.47, 119.12,
119.12, 106.97, 106.97, 60.66, 56.64, 56.64, 46.98;
ESI-HRMS calcd for C25H22O5N5ClNa [M ＋ Na] ＋
530.12017, found 530.12000.
(E)-2-(6-Chloro-9H-purin-9-yl)-N-(4-(3-(3-fluoro-
Chin. J. Chem. 2017, XX, 1—8
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Gan et al.
FULL PAPER
(E)-2-(6-Chloro-9H-purin-9-yl)-N-(4-(3-(2,3-dichlo-
rophenyl)acryloyl)phenyl)acetamide (3i): Paly yellow
solid, yield 88.3%; m.p. 154－156 ℃; H NMR (500
119.17, 119.17, 46.99; ESI-HRMS calcd for C22H14-
O2N5Cl3Na [M＋Na]＋ 508.01053, found 508.01031.
(E)-2-(6-Chloro-9H-purin-9-yl)-N-(4-(3-(2-chloro-
phenyl)acryloyl)phenyl)acetamide (3m): Paly yellow
1
MHz, DMSO-d6) δ: 10.96 (s, 1H, NH), 8.76 (s, 1H, pu-
rine-2-H), 8.70 (s, 1H, purine-8-H), 8.17 (d, J＝8.5 Hz,
2H, 1-Ar-2,6-H), 8.14 (dd, J ＝ 8.0, 1.0 Hz, 1H,
3-Ar-4-H), 7.98 (s, 2H, 2,3-H), 7.74 (d, J＝9.0 Hz, 2H,
1-Ar-3,5-H), 7.69 (dd, J＝8.0, 1.5 Hz, 1H, 3-Ar-6-H),
7.44 (t, J＝8.0 Hz, 1H, 3-Ar-5-H), 5.30 (s, 2H, CH2CO);
13C NMR (125 MHz, DMSO-d6) δ: 187.71, 165.79,
152.79, 152.31, 149.57, 148.97, 143.60, 138.48, 135.47,
133.06, 132.82, 132.53, 132.46, 131.06, 130.86, 130.86,
128.97, 127.73, 126.52, 119.19, 119.19, 46.99; ESI-
HRMS calcd for C22H15O2N5Cl3 [M＋H]＋ 486.02858,
found 486.02817.
1
solid, yield 81.0%; m.p. 186－188 ℃; H NMR (500
MHz, DMSO-d6) δ: 10.94 (s, 1H, NH), 8.76 (s, 1H, pu-
rine-2-H), 8.69 (s, 1H, purine-8-H), 8.21－8.15 (m, 3H,
1-Ar-2,6-H, 3-Ar-6-H), 7.97 (s, 2H, 2,3-H), 7.73 (d, J＝
8.5 Hz, 2H, 1-Ar-3,5-H), 7.53 (d, J＝8.0 Hz, 1H, 3-Ar-
3-H), 7.47－7.41 (m, 2H, 3-Ar-4,5-H), 5.30 (s, 2H,
CH2CO); 13C NMR (125 MHz, DMSO-d6) δ: 187.87,
165.77, 152.80, 152.31, 149.58, 148.97, 143.49, 138.60,
134.85, 132.99, 132.86, 132.49, 131.06, 130.77, 130.77,
130.57, 129.09, 128.22, 125.16, 119.21, 119.21, 46.99;
ESI-HRMS calcd for C22H15O2N5Cl2Na [M ＋ Na] ＋
474.04950, found 474.04929.
(E)-N-(4-(3-(2-Bromophenyl)acryloyl)phenyl)-2-(6-
chloro-9H-purin-9-yl)acetamide (3j): Paly yellow solid,
(E)-2-(6-Chloro-9H-purin-9-yl)-N-(4-(3-(2,4-difluo-
rophenyl)acryloyl)phenyl)acetamide (3n): Paly yellow
1
yield 89.2%; m.p. 198－200 ℃; H NMR (500 MHz,
1
DMSO-d6) δ: 10.94 (s, 1H, NH), 8.77 (s, 1H, pu-
rine-2-H), 8.70 (s, 1H, purine-8-H), 8.17 (d, J＝9.0 Hz,
2H, 1-Ar-2,6-H), 8.16 (dd, J ＝ 8.5, 2.0 Hz, 1H,
3-Ar-6-H), 7.94 (s, 2H, 2,3-H), 7.73 (d, J＝8.5 Hz, 2H,
1-Ar-3,5-H), 7.71 (d, J＝8.0 Hz, 1H, 3-Ar-3-H), 7.47－
7.41 (m, 1H, 3-Ar-5-H), 7.39－7.34 (m, 1H, 3-Ar-4-H),
5.30 (s, 2H, CH2CO); 13C NMR (125 MHz, DMSO-d6)
δ: 187.84, 165.77, 152.81, 152.31, 149.57, 148.98,
143.49, 141.35, 134.55, 133.83, 132.98, 132.66, 131.06,
130.78, 130.78, 129.27, 128.77, 125.87, 125.32, 119.20,
119.20, 47.00; ESI-HRMS calcd for C22H16O2N5BrCl
[M＋H]＋ 496.01704, found 496.01706.
solid, yield 85.4%; m.p. 191－193 ℃; H NMR (500
MHz, DMSO-d6) δ: 10.96 (s, 1H, NH), 8.76 (s, 1H, pu-
rine-2-H), 8.69 (s, 1H, purine-8-H), 8.19 (d, J＝8.5 Hz,
1H, 3-Ar-6-H), 8.14 (d, J＝8.5 Hz, 2H, 1-Ar-2,6-H),
7.94 (d, J＝16.0 Hz, 1H, 3-H), 7.73 (d, J＝8.5 Hz, 2H,
1-Ar-3,5-H), 7.72 (d, J＝15.0 Hz, 1H, 2-H), 7.57－7.51
(m, 1H, 3-Ar-3-H), 7.39－7.34 (m, 1H, 3-Ar-5-H), 5.30
(s, 2H, CH2CO); 13C NMR (125 MHz, DMSO-d6) δ:
187.75, 165.77, 163.12, 160.65, 152.79, 152.31, 149.57,
148.97, 143.46, 134.22, 132.98, 131.21, 130.68, 130.68,
130.51, 124.20, 119.82, 119.21, 119.21, 113.17, 105.37,
46.98; ESI-HRMS calcd for C22H15O2N5ClF2 [M＋H]＋
454.08769, found 454.08749.
(E)-2-(6-Chloro-9H-purin-9-yl)-N-(4-(3-(2,6-difluo-
rophenyl)acryloyl)phenyl)acetamide (3o): Paly yellow
solid, yield 80.2%; m.p.＞250 ℃; 1H NMR (500 MHz,
DMSO-d6) δ: 10.95 (s, 1H, NH), 8.76 (s, 1H, pu-
rine-2-H), 8.69 (s, 1H, purine-8-H), 8.04 (d, J＝9.0 Hz,
2H, 1-Ar-2,6-H), 7.84 (d, J＝16.0 Hz, 1H, 3-H), 7.74 (d,
J＝9.0 Hz, 2H, 1-Ar-3,5-H), 7.64 (d, J＝16.0 Hz, 1H,
2-H), 7.57－7.51 (m, 1H, 3-Ar-4-H), 7.25－7.18 (m, 2H,
3-Ar-3,5-H), 5.30 (s, 2H, CH2CO); 13C NMR (125 MHz,
DMSO-d6) δ: 187.95, 165.77, 162.62, 160.55, 152.79,
152.30, 149.57, 148.96, 143.57, 133.05, 132.74, 131.05,
130.59, 130.59, 129.38, 127.82, 119.35, 119.35, 113.04,
112.84, 112.58, 46.99; ESI-HRMS calcd for C22H14O2-
N5ClF2Na [M＋Na]＋ 476.06963, found 476.06918.
(E)-2-(6-Chloro-9H-purin-9-yl)-N-(4-(3-(4-nitro-
phenyl)acryloyl)phenyl)acetamide (3p): Paly yellow
solid, yield 85.7%; m.p.＞250 ℃; 1H NMR (500 MHz,
DMSO-d6) δ: 10.96 (s, 1H, NH), 8.77 (s, 1H, pu-
rine-2-H), 8.70 (s, 1H, purine-8-H), 8.25 (d, J＝9.0 Hz,
2H, 3-Ar-3,5-H), 8.19 (d, J＝8.5 Hz, 2H, 3-Ar-2,6-H),
8.14 (d, J＝8.5 Hz, 2H, 1-Ar-2,6-H), 8.13 (d, J＝16.0
Hz, 1H, 3-H), 7.77 (d, J＝16.0 Hz, 1H, 2-H), 7.74 (d,
J＝9.0 Hz, 2H, 1-Ar-3,5-H), 5.30 (s, 2H, CH2CO); 13C
NMR (125 MHz, DMSO-d6) δ: 187.86, 165.79, 152.80,
152.32, 149.57, 148.98, 148.57, 143.60, 141.81,141.23,
132.92, 131.06, 130.86, 130.86, 130.38, 130.38, 126.48,
124.48, 124.48, 119.20, 119.20, 47.00; ESI-HRMS
(E)-N-(4-(3-(4-Bromophenyl)acryloyl)phenyl)-2-(6-
chloro-9H-purin-9-yl)acetamide (3k): Paly yellow solid,
1
yield 75.2%; m.p. 176－178 ℃; H NMR (500 MHz,
DMSO-d6) δ: 10.94 (s, 1H, NH), 8.76 (s, 1H, pu-
rine-2-H), 8.70 (s, 1H, purine-8-H), 8.15 (d, J＝8.5 Hz,
2H, 1-Ar-2,6-H), 7.95 (d, J＝15.5 Hz, 1H, 3-H), 7.82 (d,
J＝8.5 Hz, 2H, 1-Ar-3,5-H), 7.72 (d, J＝8.5 Hz, 2H,
3-Ar-2,6-H), 7.66 (d, J＝16.0 Hz, 1H, 2-H), 7.62 (d, J＝
8.5 Hz, 2H, 3-Ar-3,5-H), 5.30 (s, 2H, CH2CO); 13C
NMR (125 MHz, DMSO-d6) δ: 187.94, 165.75, 152.79,
152.32, 149.57, 148.98, 143.35, 142.71, 134.58, 133.17,
132.41, 132.41, 131.30, 131.30, 131.06, 130.67, 130.67,
124.44, 123.18, 119.17, 119.17, 46.98; ESI-HRMS
calcd for C22H16O2N5BrCl [M＋H]＋ 496.01704, found
496.01675.
(E)-2-(6-Chloro-9H-purin-9-yl)-N-(4-(3-(2,4-dichlo-
rophenyl)acryloyl)phenyl)acetamide (3l): Paly yellow
1
solid, yield 83.5%; m.p. 221－222 ℃; H NMR (500
MHz, DMSO-d6) δ: 10.96 (s, 1H, NH), 8.77 (s, 1H, pu-
rine-2-H), 8.70 (s, 1H, purine-8-H), 8.23 (d, J＝8.5 Hz,
1H, 3-Ar-6-H), 8.17 (d, J＝9.5 Hz, 2H, 1-Ar-2,6-H),
8.01 (d, J＝15.5 Hz, 1H, 3-H), 7.91 (d, J＝15.0 Hz, 1H,
2-H), 7.73 (d, J＝8.5 Hz, 2H, 1-Ar-3,5-H), 7.72 (d, J＝
1.5 Hz, 1H, 3-Ar-3-H), 7.52 (dd, J＝8.5, 2.0 Hz, 1H,
3-Ar-5-H), 5.30 (s, 2H, CH2CO); 13C NMR (125 MHz,
DMSO-d6) δ: 187.67, 165.79, 152.80, 152.31, 149.57,
148.98, 143.57, 137.32, 136.08, 135.65, 132.88, 131.94,
131.06, 130.83, 130.83, 130.33, 130.04, 128.48, 125.69,
4
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Chin. J. Chem. 2017, XX, 1—8

Design, Synthesis, and Antiviral Activity of Novel Chalcone Derivatives Containing a Purine Moiety
calcd for C22H15O4N6ClNa [M ＋ Na] ＋ 485.07355,
found 485.07327.
conducted in triplicate.
The in vivo inhibiton rates of the compounds were
calculated using the following formula (“av” means av-
erage). Inhibition rate＝[(av number of local lesionsin-
controlav number of local lesions smeared with drugs)/
av number of local lesions of control]×100%.
(E)-2-(6-Chloro-9H-purin-9-yl)-N-(4-(3-(4-fluoro-
phenyl)acryloyl)phenyl)acetamide (3q): Paly yellow
1
solid, yield 87.2%; m.p. 181－182 ℃; H NMR (500
MHz, DMSO-d6) δ: 10.92 (s, 1H, NH), 8.77 (s, 1H, pu-
rine-2-H), 8.70 (s, 1H, purine-8-H), 8.15 (d, J＝8.5 Hz,
2H, 3-Ar-3,5-H), 7.97－7.90 (m, 2H, 3-Ar-2,6-H), 7.89
(d, J＝15.5 Hz, 1H, 3-H), 7.73 (d, J＝8.5 Hz, 2H,
1-Ar-2,6-H), 7.69 (d, J＝15.5 Hz, 1H, 2-H), 7.29－7.24
(m, 2H, 1-Ar-3,5-H), 5.30 (s, 2H, CH2CO); 13C NMR
(125 MHz, DMSO-d6) δ: 187.98, 165.72, 164.89,
162.91, 152.80, 152.30, 149.58, 148.96, 143.27, 142.84,
133.29, 131.98, 131.75, 131.06, 130.60, 130.60, 122.33,
Binding constant of compound 3n to TMV CP
In order to study the interactions of compound 3n to
TMV CP, the binding constant (Ka and Kd) of compound
3n with TMV CP was measured through FT and MST.
The TMV CP was cloned, expressed and purified as
previously described[35] with a solution containing 50
mmol•L−1 phosphate at pH 7.4 for buffer. 500 μL 10
μmol•L−1 TMV-CP SEC buffer solution (20 mmol•L−1
PBS, 100 mmol•L−1 sodium chloride (pH 7.4)) was
added to a 1.0 cm quartz cell. Then, the buffer solution
was titrated with compound 3n solution (1 mmol•L−1).
The ultimate antiviral 3n concentrations were 0, 2.0, 4.0,
6.0, 8.0, 10.0, 12.0, 14.0, 16.0, 18.0 and 20.0 μmol•L−1.
Fluorescence spectra were collected on a FluoroMax-4
spectrofluorometer at an excitation wavelength of 278
nm and the excitation and emission bandwidths were 5
nm. Then, the data emission spectra were recorded from
280 to 400 nm at 25 ℃. In addition, the Kd of com-
pound 3n to TMV CP labelled according to the recom-
mended methods of the manufacturer, was determined
on a NanoTemper Monolith NT.115 at 40% MST power
and 90% LED. Compound 3n (from 0.22 to 1000 μm)
was diluted at 25 ℃ in the SEC buffer, with the ratio
of 3n and TMV CP at 1∶1 (V∶V).
119.18, 119.18, 116.54, 116.37, 47.00; ESI-HRMS calcd
＋
for C22H16O2N5ClF [M ＋ H]
436.09711, found
436.09647.
Antiviral biological assay
Purification of TMV and CMV TMV and CMV
were inoculated in Nicotiana. tabacum cv. K326, and
purified by the Gooding method.[33] The concentration
of virus was determined through an ultraviolet spectro-
photometer at 260 nm.
E0.1%,260 nm
dilution ratio)/
Virus conc. (A
＝
260
1cm
Curative activities of compounds against TMV
and CMV in vivo Growing leaves of N. tabacum L. of
the same ages were selected. TMV and CMV (6
μg•mL1) were inoculated on the whole leaves with a
brush, which were previously scattered with silicon car-
bide. After 1 h, the leaves were washed with water and
dried. Then the compound solution was smeared on the
left side, and the solvent was smeared on the right side
for control. The local lesion numbers were recorded 3 to
4 d after inoculation.[25,34] Experiments for each com-
pound were conducted in triplicate.
Protective activities of compounds against TMV
and CMV in vivo The solution of the compound was
smeared on the left side, whereas the solvent was
smeared on the right side of the growing N. tabacum L.
leaves and served as the control. The leaves, which were
previously scattered with silicon carbide, were inocu-
lated with 6 μg•mL1 TMV and CMV after 12 h. Then,
the leaves were washed with water. At 3－4 d after in-
oculation, the number of local lesions was counted.[25,34]
All experiments for each compound were conducted in
triplicate.
Results and Discussion
Synthesis
As shown in Scheme 1, the compounds 1a－1q were
synthesized through Claisen-Schmidt condensation be-
tween 4-aminoacetophenone and aryl aldehyde. Then,
1a－1q containing amide bond chalcones were obtained
using chloroacetyl chloride. To obtain title compounds
with a high yield, the reaction conditions (including re-
action solvent, catalyst, and temperature) for the prepa-
ration of compound 3a were optimized. Meanwhile, the
molar ratio of 6-chloro-9H-purine/catalyst is 1∶1.15
and the reaction time is 6 h. The results showed that a
maximum yield of 3a up to 87.2% was achieved when
the solvent, catalyst and temperature was DMF, K2CO3
and 50 ℃, respectively (Table 1). Other compounds
with yield ranging from 75.2% to 90.3% were synthe-
sized under these conditions.
Inactivation activities of compounds against TMV
and CMV in vivo The virus was inhibited by mixing
with the compound solution at the same volume for 30
min and inoculated on the left side of N. tabacum L.
leaves, and the solvent and virus mixture was smeared
on the right side of the leaves as the control. The num-
ber of local lesions was recorded 3 to 4 d after inocula-
tion.[25,34] Every experiment for each compound was
Antiviral activity assay and structure-activity rela-
tionships
The antiviral activities of compounds 3a － 3q
against TMV and CMV were assayed through the half
leaf blight spot method, which was performed in tripli-
cate (Tables 2 and 3). Ribavirin was used as a reference
antiviral agent.
Chin. J. Chem. 2017, XX, 1—8
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

Gan et al.
FULL PAPER
Table 1 Effect of different conditions for the synthesis of 3aa
Continued
No. Solvent
Catalyst
Et3N
Temperature/℃
Yieldb/%
Compound
Curative
31.2±1.8
38.6±2.5
43.5±1.1
36.7±2.1
47.8±2.7
39.1±2.0
44.8±1.9
41.1±2.7
41.2±1.6
Protective
41.5±3.7
48.2±2.8
52.1±2.4
47.9±2.3
52.8±2.5
48.5±1.1
55.9±1.7
48.5±1.2
52.1±3.5
Inactivation
1
2
3
4
5
6
7
8
acetone
THF
25
25
25
25
25
25
25
50
0
3j
42.5±2.3
47.2±3.6
51.9±1.7
54.3±3.3
65.1±1.9
56.3±1.2
59.0±1.8
57.1±2.5
68.2±2.4
Et3N
0
3k
DMF
Et3N
0
3l
3m
acetone
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
25.5
30.2
35.6
43.8
87.2
3n
CH3CN
DMF
3o
3p
DMF
a
3q
General conditions: reactions were performed with the molar
ratio of 6-chloro-9H-purine to catalyst 1∶1.15. b Yields of iso-
Ribavirin
lated products.
a All results are expressed as mean±SD; n＝3 for all groups.
Table 2 Inhibition rates of the compounds against TMV in vivo
at 500 μg•mL1 (I/%)a
As shown in Tables 2 and 3, most of the title com-
pounds exhibited inhibitory activities against TMV in
vivo. Compounds 3e, 3i, 3n, 3o, 3p, and 3q exhibited
remarkable curative, protective and inactivation activi-
ties at 500 μg•mL1, with the values of 42.5%, 43.8%,
52.4%, 48.9%, 54.5%, 53.9%; 59.4%, 53.9%, 56.8%,
55.1%, 56.8%, 52.8% and 73.5%, 85.1%, 88.9%, 80.5%,
84.1%, 79.5%, respectively, which were better than
those of ribavirin (37.9%, 51.8%, and 72.9%). Mean-
while, compounds 3a－3q exhibited moderate antiviral
activities against CMV. Compounds 3f, 3g, 3n, 3p
showed better curative and protective activities with the
values of 45.9%, 48.6%, 47.8%, 44.8% and 58.9%,
57.3%, 53.8%, 55.9%, respectively, than those of rib-
avirin (41.2% and 52.1%) at 500 μg•mL1. In order to
confirm antiviral activities against TMV, the EC50 val-
ues of curative, protective and inactivation activities of
compounds 3e, 3i, 3n, 3o, 3p, and 3q were investigated
and summarized in Table 4, the results showed that
compounds 3n and 3p exhibited remarkable curative,
protective and inactivation activities against TMV, with
EC50 values of 452.4, 416.2, 241.2 and 438.7, 418.6,
261.7 μg•mL1, respectively, which were better than
those of ribavirin (585.8, 436.0 and 268.7 μg•mL1).
Compound
Curative
41.2±1.9
45.8±2.3
42.3±2.2
35.7±2.6
42.5±3.3
42.5±2.1
53.7±2.2
39.8±1.7
43.8±1.9
52.4±3.1
46.3±1.2
43.7±2.7
42.5±2.9
52.4±2.3
48.9±2.1
54.5±1.8
53.9±2.5
37.9±1.9
Protective
43.8±1.5
51.2±2.8
44.3±2.1
16.8±3.2
59.4±1.3
30.6±1.5
45.9±1.9
35.2±3.2
53.9±3.1
49.8±2.4
21.4±1.1
41.9±1.8
47.5±2.3
56.8±1.8
55.1±1.7
56.8±2.7
52.8±1.4
51.8±2.3
Inactivation
80.8±1.9
70.9±2.1
56.3±3.3
45.6±1.4
73.5±2.6
57.9±2.2
75.1±1.8
79.8±2.0
85.1±3.7
81.2±1.7
45.8±2.3
75.9±3.9
71.3±2.4
88.9±0.9
80.5±3.1
84.1±2.5
79.5±2.3
72.9±2.4
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
Ribavirin
a All results are expressed as mean±SD; n＝3 for all groups.
Table 4 EC50 values of the compounds against TMV in vivo
(μg•mL1)a
Table 3 Inhibition rates of the compounds against CMV in vivo
at 500 μg•mL1 (I/%)a
Compound
Curative
Protective
405.8±3.3
481.5±5.4
416.2±3.9
455.1±2.8
418.6±3.3
442.8±4.1
436.0±4.3
Inactivation
312.5±8.6
258.8±5.7
241.2±4.9
278.4±3.8
261.7±7.5
299.5±3.9
268.7±5.1
Compound
Curative
24.5±2.5
28.6±1.4
34.8±2.7
45.2±1.0
35.7±1.6
45.9±2.2
48.6±2.3
35.1±1.9
39.8±2.3
Protective
52.6±1.9
45.8±1.2
51.2±2.5
48.9±1.9
49.8±2.7
58.9±1.7
57.3±2.8
23.5±2.3
48.6±2.3
Inactivation
31.9±3.1
38.2±1.7
38.9±2.9
56.9±3.3
54.5±1.9
44.4±2.9
54.8± 3.1
34.9±1.5
51.2±2.8
3e
3i
612.1±3.5
603.2±2.0
452.4±3.7
567.4±2.8
438.7±3.5
501.3±2.9
585.8±4.1
3a
3b
3c
3d
3e
3f
3n
3o
3p
3q
Ribavirin
a All results are expressed as mean±SD; n＝3 for all groups.
3g
3h
3i
On the basis of the antiviral activities against TMV,
the preliminary structure-activity relationships were also
6
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Chin. J. Chem. 2017, XX, 1—8

Design, Synthesis, and Antiviral Activity of Novel Chalcone Derivatives Containing a Purine Moiety
observed. Electron-withdrawing groups favored antivi-
ral activities at the same position, this finding is evi-
denced by the activity order of 3n (Ar＝2,4-F2-C6H3)＞
3c [Ar＝2,4-(OCH3)2-C6H3] and 3p (Ar＝4-NO2-C6H4)
＞3a (4-CH3-C6H4). Meanwhile, the bulky group of
aromatic ring did not favor, for example 3b (Ar＝
4-OCH3-C6H4) ＞ 3c (Ar ＝ 2,4-(OCH3)2-C6H3) ＞ 3d
[Ar＝3,4,5-(OCH3)3-C6H2] and 3q (Ar＝4-F-C6H4)＞3g
(Ar ＝ 4-Cl-C6H4) ＞ 3k (Ar ＝ 4-Br-C6H4). However,
when 2-substituted compound with different electron-
withdrawing groups was introduced, the bulky group
favored antiviral activities, for example, 3j (Ar ＝
2-Br-C6H4) ＞ 3m (Ar ＝ 2-Cl-C6H4) ＞ 3h (Ar ＝
2-F-C6H4). Notably, the 4-substituted compound with
the same group showed better antiviral activities than
the 2-substituted compound, such as 3q (Ar＝4-F-C6H4)
＞3h (Ar＝2-F-C6H4), 3g (Ar＝4-Cl-C6H4)＞3m (Ar＝
2-Cl-C6H4), and 3k (Ar ＝ 4-Br-C6H4) ＞ 3j (Ar ＝
2-Br-C6H4). This finding indicates that appropriate
compact electron-withdrawing groups favor antiviral
activities against TMV, which is an important structural
insight for further design of chalcone derivatives with
highly active properties.
TMV to infect the host.[36,37] Binding constant is an im-
portant parameter for studying the interaction between
the ligand (molecule) and the receptor (protein). Under
the optimal conditions, the SEC buffer is PBS (20
mmol•L−1 phosphate pH 7.4, 100 mmol•L−1 sodium
chloride), the temperature is 25 ℃, the LED and MST
power is 90% and 40% respectively. The Ka vaules of
compound 3n were determined through FT and MST.
The binding constant of 3n to TMV CP is listed in Table
5 and Figure 3. Compound 3n showed a moderate affin-
ity to TMV CP, with a Ka value of 1.5×104 L•mol−1,
which was better than that of ribavirin (2.5 × 103
L•mol−1, indicating weak affinity). Meanwhile, the re-
sult of Kd through MST was similar to the FT finding,
with a Kd between 3n and TMV CP of 79.8 μmol•L−1,
which was better than that of ribavirin (112.5 μmol•L−1).
Thus, compound 3n exhibited a moderate affinity to
TMV CP, which is consistent with the inactivation ac-
tivity. Therefore, the binding constant of the compound
to TMV CP plays significant roles in antiviral capacity.
Table 5 Binding constant (Ka and Kd) of compound 3n
Ka of FT/ Kd of MST/
(L•mol−1) (μmol•L−1)
EC50 of inactivation/
Compound
(μg•mL1)
Binding constant of compound 3n to TMV CP
3n
1.5×104 79.8±2.8
241.2±4.9
268.7±5.1
TMV CP, which is necessary for virus assembly ini-
tiation and elongation, is a key functional protein for
Ribavirin 2.5×103 112.5±3.7
Figure 3 Binding affinity of 3n and Ribavirin to TMV CP. (A) Fluorescence emission spectra of TMV CP in the presence of 3n, (B)
fluorescence emission spectra of TMV CP in the presence of Ribavirin, (C) binding of TMV-CP and 3n through MST and (D) binding of
TMV-CP and Ribavirin through MST.
Chin. J. Chem. 2017, XX, 1—8
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
7

Gan et al.
FULL PAPER
[12] Xu, H.; Wang, X. M.; Wei, X.; Li, J. Y.; Liu, K. Chin. Chem. Lett.
2009, 20, 576.
Conclusions
A series of novel chalcone derivatives containing a
purine moiety was designed and synthesized through an
amido link by combining bioactive substructures. Their
anti-TMV and anti-CMV activities were evaluated.
Compounds 3n and 3p exhibited excellent curative,
protective and inactivation activities against TMV and
showed remarkable curative, and protective activities
against CMV in vivo. The introduction of appropriate
compact electron-withdrawing groups to the aromatic
ring strengthened antiviral activities against TMV.
Compound 3n showed a moderate affinity to TMV CP,
which is consistent with the inactivation activity. These
findings provide an important structural insight for the
design of highly active chalcone derivatives and serve
as a basis for further study on their mechanisms of ac-
tion.
[13] Konieczny, M. T.; Konieczny, W.; Sabisz, M.; Skladanowski, A.;
Augustynowicz-Kopec, E.; Wakiec, R.; Zwolska, Z. Chem. Pharm.
Bull. 2007, 55, 817.
[14] Lin, Y. P.; Hu, C. Y.; Zheng, X.; Wang, X. L.; Wan, C. P.; Mao, Z. W.
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Acknowledgement
This study was supported by the National Natural
Science Foundation of China (No. 21562013), the Na-
tional Key Technology R&D Program of China (No.
2011BAE06B05-6) and the Collaborative Innovation
Center for Natural Products and Biological Drugs of
Yunnan.
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(Zhao, C.)
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