Synthesis, structure-activity relationships and biological evaluation of dehydroandrographolide and andrographolide derivatives as novel anti-hepatitis B virus agents

Article abstract of DOI:10.1016/j.bmcl.2014.03.060

Dehydroandrographolide and andrographolide, two natural diterpenoids isolated from Andrographis paniculata possessed activity against HBV DNA replication with IC₅₀ values of 22.58 and 54.07 μM and low SI values of 8.7 and 3.7 in our random assay. Consequently, 48 derivatives of dehydroandrographolide and andrographolide were synthesized and evaluated for their anti-HBV properties to yield a series of active derivatives with lower cytotoxicity, including 14 derivatives against HBsAg secretion, 19 derivatives against HBeAg secretion and 38 derivatives against HBV DNA replication. Interestingly, compound 4e could inhibit not only HBsAg and HBeAg secretions but also HBV DNA replication with SI values of 20.3, 125.0 and 104.9. Furthermore, the most active compound 2c with SI value higher than 165.1 inhibiting HBV DNA replication was revealed with the optimal log P value of 1.78 and log D values. Structure-activity relationships (SARs) of the derivatives were disclosed for guiding the future research toward the discovery of new anti-HBV drugs.

Full text of DOI:10.1016/j.bmcl.2014.03.060

Bioorganic & Medicinal Chemistry Letters 24 (2014) 2353–2359
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, structure–activity relationships and biological evaluation
of dehydroandrographolide and andrographolide derivatives as
novel anti-hepatitis B virus agents
Hao Chen a,b, Yun-Bao Ma a, Xiao-Yan Huang a, Chang-An Geng a, Yong Zhao a,b, Li-Jun Wang a,
Rui-Hua Guo a, Wen-Juan Liang a,b, Xue-Mei Zhang a, Ji-Jun Chen a,
⇑
a State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, PR China
b University of Chinese Academy of Sciences, Beijing 100049, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Dehydroandrographolide and andrographolide, two natural diterpenoids isolated from Andrographis pan-
Received 2 February 2014
Revised 10 March 2014
Accepted 19 March 2014
Available online 28 March 2014
iculata possessed activity against HBV DNA replication with IC50 values of 22.58 and 54.07 lM and low SI
values of 8.7 and 3.7 in our random assay. Consequently, 48 derivatives of dehydroandrographolide and
andrographolide were synthesized and evaluated for their anti-HBV properties to yield a series of active
derivatives with lower cytotoxicity, including 14 derivatives against HBsAg secretion, 19 derivatives
against HBeAg secretion and 38 derivatives against HBV DNA replication. Interestingly, compound 4e
could inhibit not only HBsAg and HBeAg secretions but also HBV DNA replication with SI values of
20.3, 125.0 and 104.9. Furthermore, the most active compound 2c with SI value higher than 165.1 inhib-
iting HBV DNA replication was revealed with the optimal logP value of 1.78 and logD values. Structure–
activity relationships (SARs) of the derivatives were disclosed for guiding the future research toward the
discovery of new anti-HBV drugs.
Keywords:
Anti-HBV activity
Dehydroandrographolide and
andrographolide derivatives
Structure–activity relationships
Octanol–water partition coefficients
Ó 2014 Elsevier Ltd. All rights reserved.
Diseases caused by hepatitis B virus (HBV) are serious problems
worldwide, which have affected more than 2 billion people. There
are about 360 million chronically infected individuals suffering
from liver cirrhosis and hepatocellular carcinoma.1 The current
paniculata, a well-known Chinese medicine Chuan-Xin-Lian docu-
mented in each edition of Chinese Pharmacopoeia, is widely used
for anti-inflammatory, antipyretic and detoxifying purposes.18
Dehydroandrographolide (1a) and andrographolide (1b, Fig. 1),
the main active constituents in Andrographis paniculata, exhibited
various biological activities including antiinflammation, antivirus,
antitumor, antibacterium, hepatoprotection and analgesia.19–27
Although some derivatives of dehydroandrographolide (1a) and
andrographolide (1b) were synthesized for treatment of influenza
A virus, HIV, viral pneumonia and upper respiratory tract infec-
tion,29–31 no investigation was concerned with anti-HBV activity.
As our ongoing search for anti-HBV inhibitors from natural prod-
ucts, dehydroandrographolide (1a) and andrographolide (1b) were
firstly revealed to be active against HBV DNA replication with 50%
therapies including vaccines, immunomodulators, interferon-
a,
polyethylene glycol interferon- and nucleoside drugs for treating
a
HBV are still unsatisfactory, due to high recurrence, drug resistance
and inevitable side effects including influenza-like illness, myalgia,
headache, reduction of neutrophilic granulocyte and blood platelet,
etc.2–5 Therefore, it is interesting to explore novel classes of drugs
with different antiviral targets and mechanisms for anti-HBV
purposes.
Natural products possess various skeletons and diverse bioactiv-
ities, which provide prolific candidates with new targets and mech-
anisms for anti-HBV drug discovery.6–10 Our recent investigations
revealed a series of natural products and their derivatives with
promising anti-HBV activity, such as dihydrochelerythrine from
Corydalis saxicola,11 alisol F from Alisma orientalis,12 swerilactones
H-K from Swertia mileensis,13 as well as derivatives of alisol A,14
caudatin,15 glycyrrhetinic acid16 and hemslecin A.17 Andrographis
inhibitory concentration (IC50) values of 22.6 and 54.1 lM but
low selectivity index (SI) values of 8.7 and 3.7 in our random assay.
Thus, 48 dehydroandrographolide and andrographolide analogues
were synthesized by modifying on rings A, B and C to increase their
anti-HBV activity and decrease cytotoxicity. Herein, we described
the synthesis, structure–activity relationships (SARs) and in vitro
anti-HBV activity of these derivatives, as well as the octanol–water
partition coefficients of dehydroandrographolide, andrographolide
and the most potent derivative 2c.
⇑
Corresponding author. Tel.: +86 871 65223265; fax: +86 871 65227197.
E-mail address: chenjj@mail.kib.ac.cn (J.-J. Chen).
http://dx.doi.org/10.1016/j.bmcl.2014.03.060
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

2354
H. Chen et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2353–2359
concentration (CC50) value of 183 lM. After the introduction of
methoxyl group into cinnamoyl group at the C-19 position, the
cytotoxicity of analogues 2b and 2c decreased obviously (CC50
>1970 and 1706 lM) compared with compound 2a, indicating that
the methoxyl group play a crucial role in reducing cytotoxicity. The
above conclusion was further supported by 19-O-(20-methoxy) nic-
otinyl analogue 2f with lower cytotoxicity than 19-O-nicotinyl
analogue 2e. Compound 2c with 3,4,5-trimethoxycinnamic group
at C-19 possessed noticeable inhibition on HBV DNA replication
15
15
O
O
16
C
8
14
O
HO
O
11
12
17
HO
3
A
B
3
HO
19
19
with the IC50 value of 10.3 lM and lower cytotoxicity resulting in
HO
HO
a SI value higher than 165.1, demonstrating that both m-methoxyl
and p-methoxyl groups could enhance activity against HBV DNA
replication. However, 19-O-(30-chloro) cinnamoyl analogue 2d
exhibited higher cytotoxicity and weaker activity due to the intro-
duction of halogen into the substituent. The heteroatomic rings at
C-19 position play an important role in suppressing HBV DNA rep-
lication and secretions of HBsAg and HBeAg in agreement with the
high activities of compounds 2e, 2g and 2h with the IC50 values of
1b
1a
Figure 1. Compounds 1a and 1b.
According to molecular hybridization principle,32 esterification
of natural compounds is an effective approach for achieving
promising derivatives, by which two active parts can be easily
hybridized to enhance activity. For example, a series of active
derivatives of caudatin15 and hemslecin A17 were obtained by
esterification in our previous investigations, which showed obvi-
ously enhanced activity compared with the parent compounds.
To increase anti-HBV activity and decrease cytotoxicity, derivatives
of dehydroandrographolide and andrographolide were obtained by
the Steglich esterification to incorporate cinnamoyl groups and
heterocyclic rings with nitrogen, oxygen and sulfur atom, which
offered appreciable inhibition of HBV DNA replication.6,7,33 Com-
pound 1a was esterified with acids in the presence of 4-dimethyl-
aminopyridine (DMAP) and N0,N0-dicyclohexylcarbodiimide (DCC)
in anhydrous dichloromethane (Scheme 1). Generally, 19-O-subsi-
tuted derivatives were the main products; 3, 19-O-disubsituted
derivatives were obtained with low yields at the same time. Posi-
tions of the substituents can be determined by the changes of
the chemical shifts of H-3 and H-19 in 1H NMR spectrum. For
example, the chemical shifts of H-3 and H-19a of 19-O-substituted
derivative 2e appeared at dH 3.33 and 4.37 in contrast to dH 4.88
and 4.40 of 3, 19-O-disubstituted derivative 3a. When compound
1b was treated under the Steglich esterification conditions, deriva-
tives 4a–6f were obtained by losing hydroxyl group at C-14 and
forming carbon–carbon double bond between C-14 and C-15
(Scheme 2).28 Other acylation products 2j, 3d–3g, 4g, 5g, 6c, 6e
and 6f were achieved with anhydrides and catalytic amount of
DMAP in anhydrous pyridine. Compounds 1a and 1b were treated
under Pfitzner–Moffatt oxidation condition with DCC, dimethyl
sulfoxide (DMSO), trifluoroacetic acid (TFA) in anhydrous pyridine
and dichloromethane to reveal effects of transforming hydroxyl
groups at C-3 and C-19 into carbonyl groups (Scheme 3). On the
ring C, compounds 9a and 9b were obtained in the presence of
formaldehyde or acetone under sodium carbonate (Scheme 4). To
investigate the influence of lactone ring on anti-HBV activity, com-
pound 1b was dealt with sodium hydroxide in water to obtain
product 10 with lactone ring opened. On the ring B, carbon–carbon
double bond between C-8 and C-17 was epoxidized by the m-chlo-
roperoxybenzoic acid (m-CPBA) in dichloromethane at room tem-
perature to produce compound 11.34 The purity (higher than
90%) of all the derivatives was determined by HPLC (normalization
method with no obvious impurity peak) or TLC with three different
solvent systems (only one spot under UV detection and sprayed
with 10% H2SO4).
22.1, 9.3 and 22.1 lM. In contrast to 19-O-substituted analogues,
the 3, 19-O-disubstituted compounds 3a–3g showed dramatic de-
crease of anti-HBV activity resulting from the disubstituents at C-3,
and C-19.
For further investigation, 23 andrographolide derivatives were
obtained. 19-O-Cinnamoyl and 19-O-(30,40,50-trimethoxy) cinnam-
oyl derivatives 4a and 4b exhibited increased activity with the
IC50 values of 46.58 and 22.25 lM against HBV DNA replication.
19-O-Nicotinoyl (4c), 19-O-20-furoyl (4d) and 19-O-20-thenoyl
(4e) derivatives showed significant inhibition on HBV DNA replica-
tion with higher SI values of 126.0, 100.5, and 104.9, and lower
cytotoxicity than derivatives 2e, 2g and 2h with the same substit-
uents, inferring that the cytotoxicity of these derivatives is closely
related to the conjugated double bonds between C-12 and C-15 or
C-11 and C-14. According to the principle of bioisosteric replace-
ment, 19-O-benzoyl analogue 4f was prepared and exhibited sim-
ilar activity against HBV DNA replication with the IC50 value of
20.6 lM and lower SI value compared with compounds 4c, 4d
and 4e, indicating that heteroatomic rings containing N, O and S
are profitable for decreasing cytotoxicity. In contrast to 19-O-vale-
ryl analogue 4h, the obviously enhanced activity of 19-O-acetyl
analogue 4g suggested that the length of alkyl chain could influ-
ence the anti-HBV activity. Compounds 2a–2j and 4a–4g showed
different cytotoxicity, suggesting that the conjugated double bonds
are closely related to their cytotoxicity but varied with the substit-
uents at C-19. The high cytotoxicity of 3-O-substituted ones (5a–
5h) indicated that the substituent at C-19 and free hydroxyl group
at C-3 are necessary for maintaining low cytotoxicity. Among 3, 19-
disubstituted derivatives, 3, 19-O-disuccinyl (6e) and 3, 19-O-di
(20-carboxyl) benzoyl (6f) analogues exhibited the improvement
of activity, which indicated the importance of free carboxyl group
for anti-HBV activity.
In comparison with oxidative products 7a, 8a and 8b, the IC50
value of compound 7b was improved to 13.4 lM due to the pres-
ence of a free hydroxyl group at C-3. The decreased activity of
derivatives 9a and 9b supported the importance of methylene at
C-15. Derivative 10 with the lactone ring opened showed the
similar activity and cytotoxicity to the parent compound 1b, sug-
gesting that the lactone ring plays little role in anti-HBV activity.
Double bond between C-8 to C-17 in ring B was indispensable
owing to the reduced inhibition on HBV DNA replication of epoxide
11.
Although dehydroandrographolide 1a and andrographolide 1b
were inactive against the secretions of HBsAg and HBeAg, 14
derivatives with inhibitory activity on HBsAg secretion and 19
derivatives inhibited HBeAg secretion were obtained. Compounds
2a, 4e and 9a inhibited HBsAg secretion with the SI values in the
range of 10.2–20.3, and compounds 2h and 4e suppressed HBsAg
Derivatives of dehydroandrographolide (1a) and andrographo-
lide (1b) were evaluated for their anti-HBV activity, namely inhib-
iting the secretions of HBsAg and HBeAg, and HBV DNA replication
on HepG 2.2.15 cells in vitro with tenofovir as the positive con-
trol.13 The anti-HBV activity and cytotoxicity were summarized
in Table 1.
19-O-Cinnamoyl analogue 2a showed high activity against HBV
DNA replication with IC50 value of 14.6 lM and 50% cytotoxicity

H. Chen et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2353–2359
2355
Table 1
Anti-HBV activity and cytotoxicity of dehydroandrographolide and andrographolide derivatives in vitroa
O
O
O
O
O
O
O
O
O
O
HO
RO
RO
HO
RO
6
4
2
3
5
RO
HO
RO
HBeAgd
M)
RO
RO
HBsAgc
DNA replication
b
Compd
R
CC50
(l
M)
e
e
e
IC50
(l
M)
SIf
IC50
(l
SIf
IC50
(l
M)
SIf
g
1a
1b
197
198
—
—
—
—
—
—
—
—
22.6
54.1
8.7
3.7
O
2a
2b
183
18.0
10.2
—
28.9
6.3
—
14.6
15.5
—
O
O
MeO
>1970
>1706
>1970
—
1476
>513
MeO
MeO
2c
—
201
>8.5
10.3
>165.1
OMe
O
Cl
N
2d
2e
147
113
207
—
59.8
63.5
2.5
1.8
136
5.5
5.1
O
40.0
2.8
22.1
O
N
2f
1339
92
>2313
19.2
—
217
77.5
29.2
6.2
>584
9.3
—
MeO
O
O
O
2g
2h
4.6
3.4
1.2
9.9
25.2
S
557
162
19.1
22.1
O
O
2i
171
—
—
177
1.0
36.6
4.7
O
O
2j
225
565
—
—
2233
—
—
69.5
3.2
—
Me
O
3a
>1919
>1919
>1919
1864
822
>664
N
O
O
S
3b
3c
1112
1407
1448
—
—
242
185
4.6
O
>1537
>1.0
>1.8
>8.3
O
3d
3e
757
1010
—
—
1390
—
—
455
—
—
Me
HO
O
O
>1714
>1714
>1714
>429
(continued on next page)

2356
H. Chen et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2353–2359
Table 1 (continued)
b
Compd
R
CC50
(lM)
HBsAgc
M)
HBeAgd
M)
DNA replication
e
e
e
IC50
(l
SIf
—
IC50
(l
SIf
—
IC50
(l
M)
SIf
O
O
3f
>1933
>1624
>1933
—
>1933
—
>483
104
—
O
HO
O
O
3g
—
—
—
—
—
—
>15.6
5.8
OH
O
4a
4b
271
325
210
—
516
—
46.6
22.3
O
MeO
MeO
14.6
OMe
O
4c
2054
>1137
—
—
—
>974
>949
—
—
16.3
21.4
126.0
N
O
O
O
4d
>2150
>100.5
S
4e
4f
2466
82
121
880
20.3
—
19.7
123
125
—
23.5
20.6
104.9
4.0
O
O
4g
4h
334
225
280
565
1.2
—
289
1.1
—
44.1
69.5
7.6
3.2
Me
O
2233
O
O
4i
450
179
211
1317
466
—
—
—
293
1.5
—
39.4
30.7
53.1
11.4
5.8
OH
O
5a
5b
1169
518
O
MeO
MeO
753
1.6
3.0
OMe
O
5c
337
42
261
777
1.3
—
714
586
—
—
38.4
25.2
8.8
1.7
N
O
O
O
5d
S
5e
5f
257
103
41
6.2
—
>2196
118
—
—
8.1
31.8
4.8
O
877
21.6
O
5g
5h
872
126
318
625
2.7
—
241
208
3.6
—
44.4
69.8
19.6
1.82
Me
O

H. Chen et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2353–2359
2357
Table 1 (continued)
b
Compd
R
CC50
(l
M)
HBsAgc
M)
HBeAgd
M)
DNA replication
e
e
e
IC50
(l
SIf
—
IC50
(l
SIf
—
IC50
(
l
M)
SIf
O
MeO
MeO
6a
6b
>1831
1374
>1831
1641
>253
1217
>458
—
—
OMe
O
S
—
1.1
—
O
6c
297
757
251
1.2
—
260
1.1
—
39.6
455
7.6
—
Me
O
6d
1010
1390
O
HO
6e
6f
32
1158
—
—
—
243
218
—
47.6
22.0
—
O
O
>2042
>9.4
>92.8
OH
O
7a
7b
8a
8b
9a
9b
10
11
Tfh
275
122
964
155
954
122
182
1839
>1716
394
1840
518
951
74
—
—
1294
1389
—
—
1.9
—
13.0
—
—
1.4
>1.2
—
1948
—
815
860
562
—
—
—
—
—
1.1
—
—
—
>1.4
263
13.4
169
51.3
154
394
23.2
78.0
0.71
1.1
9.1
5.7
3.0
6.2
—
7.8
23.6
>2417.3
—
1238
a
Values are means of two independent experiments.
b
c
d
e
f
CC50 is 50% cytotoxicity concentration in HepG 2.2.15 cells.
HBsAg: hepatitis B surface antigen.
HBeAg, hepatitis B e antigen.
IC50 is 50% inhibitory concentration.
SI (selectivity index) = CC50/IC50
No SI can be obtained.
.
g
h
Tenofovir as the positive control.
Figure 2. Octanol-buffer distribution coefficients of dehydroandrographolide, andrographolide and compound 2ca. aValues are means of two independent experiments. LogD
bis value for log octanol-buffer distribution coefficients at pH 1–9.
secretion with the SI values of 19.1 and 125.0. The most active
compounds 2a, 2h and 4e were all 19-O-substituted derivatives,
suggesting that modification on C-19 is preferable for inhibiting
HBsAg and HBeAg secretions.
The logarithm of the octanol–water partition coefficient (logP)
is an important pharmaceutical parameter in evaluating solvency,
absorption and transport of drugs. According to Lipinski’s rule, the
preferred logP value is less than 5, and higher logP will lead to poor
absorption and permeation.35 Ghose’s analysis of different classes
of drug molecules suggested that the qualifying range of the logP
value is between ꢀ0.4 and 5.6, with an average of 2.52.36 The log-
arithm of the octanol-buffer distribution coefficient (logD) is the
ratio of the concentrations of all forms of the compound (ionized
plus un-ionized) in each of the two phases at different pH. Com-
pounds 1a, 1b and the most potent compound 2c were measured
for values of logP and logD. Solutes were equilibrates between oct-
anol and water, or octanol and buffer using the shake-flask
method.37 The concentration of each compound in octanol was

2358
H. Chen et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2353–2359
O
expressed the highest logD value near pH 7.0, indicated the easier
absorption in the small intestine than in the stomach.
O
O
O
O
O
In summary, 48 derivatives of dehydroandrographolide and
andrographolide were synthesized and evaluated for their anti-
HBV activity, which provided 14 active derivatives inhibiting
HBsAg secretion, 19 active derivatives suppressing HBeAg secre-
tion and 38 active derivatives inhibiting HBV DNA replication.
Interestingly, compound 4e could inhibit not only HBsAg and
HBeAg secretions but also HBV DNA replication with SI values of
20.3, 125.0 and 104.9. Furthermore, the most potent compound
2c with SI value higher than 165.1 inhibiting HBV DNA replication
was revealed to possess the optimal logP value of 1.78 and logD
values, which is deserved to be further investigated.
a or b
A
3
HO
HO
RO
19
1a
2
3
HO
RO
RO
Scheme 1. Reagents and conditions: (a) corresponding acids, DMAP, DCC, CH2Cl2,
rt, 47–62% for 2a–2i, 26–28% for 3a–3c; (b) anhydride, DMAP, anhydrous pyridine,
reflux, 40% for 2j, 55–57% for 3d–3g.
According to the results mentioned above, SARs were summa-
rized in Figure 3 and following conclusion could be drawn: (1)
19-O-substituted compounds with the free hydroxyl group at C-3
could provide higher anti-HBV activity than other analogues. (2)
3,4,5-Trimethoxycinnamoyl, nicotinoyl, 2-furoyl and 2-thenoyl
groups are favorable to enhance anti-HBV activity. (3) The double
determined by HPLC method.38,39 The logP values of compounds
1a, 1b and 2c were determined to be 1.44, 0.52, and 1.78 at
30 °C. Among these compounds, compound 2c may have the high
absorption and permeation for its logP value was closed to the
average value of 2.52. As shown in Figure 2, compound 2c
O
O
O
O
O
HO
O
O
O
a or b
RO
HO
RO
HO
6
4
5
1b
HO
HO
RO
RO
Scheme 2. Reagents and conditions: (a) corresponding acids, DMAP, DCC, CH2Cl2, rt, 31–50% for 4a–4f and 4h, 10–12% for 5a–5f and 5h, 13–23% for 6a, 6b and 6d; (b)
anhydride, DMAP, anhydrous pyridine, reflux, 21–31% for 4g and 4i, 25% for 5g, 20–23% for 6c, 6e and 6f.
O
O
O
O
O
O
O
O
O
b
HO
HO
O
HO
CHO
HO
CHO
7a
11
7b
HO
1a
HO
a
O
O
O
HO
HO
OH
O
O
HO
O
O
c
O
O
HO
HO
CHO
CHO
8b
8a
HO
HO
10
1b
Scheme 3. Reagents and conditions: (a) DCC, DMSO, TFA, anhydrous pyridine, CH2Cl2, rt, 34–61%; (b) m-CPBA, CH2Cl2, rt, 63%; (c) NaOH, H2O, reflux, 86%.
HO
OH
O
O
O
O
HO
O
O
a
HO
HO
HO
HO
9b
HO
9a
HO
Scheme 4. Reagents and conditions: (a) methyl aldehyde or acetone, sodium carbonate, reflux, 79–80%.

H. Chen et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2353–2359
2359
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15
14
O
No influence
Conjugateddouble bond between
C-11 and C-14, or C-12 and C-15
O
12
11
Epoxidation
11. Wu, Y. R.; Ma, Y. B.; Zhao, Y. X.; Yao, S. Y.; Zhou, J.; Zhou, Y.; Chen, J. J. Planta
Med. 2007, 73, 787.
Crucial for anti-HBV
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HO
3,4,5-trimethoxycinnamic acetyl group
nitrogen, oxygen and
13. Geng, C. A.; Wang, L. J.; Zhang, X. M.; Ma, Y. B.; Huang, X. Y.; Luo, J.; Guo, R. H.;
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Oxidation
HO
sulfur aromatic moieties
:Anti-HBV activity increased
:Anti-HBV activity decreased
Figure 3. Structure–activity relationships of dehydroandrographolide and androg-
rapholide derivatives anti-HBV activity.
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bond between C-8 and C-17, and the conjugated double bonds
between C-11 and C-14, or C-12 and C-15 are necessary for main-
taining anti-HBV activity and decreasing cytotoxicity. (4) The
methylene at C-15 is necessary for anti-HBV activity. This study
indicated that dehydroandrographolide and andrographolide
derivatives had potent anti-HBV activity, and offered valuable
information for seeking non-nucleoside anti-HBV drug candidates.
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Acknowledgment
The work was supported by the National Natural Science Foun-
dation of China for Distinguished Young Scholars (No. 81025023),
the National Natural Science Foundation of China (81202436),
the West Light Foundation of the Chinese Academy of Sciences,
and the Youth Innovation Promotion Association, CAS.
Supplementary data
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Supplementary data associated with this article can be found, in
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