Chemical investigation of an antimalarial Chinese medicinal herb Picrorhiza scrophulariiflora

Article abstract of DOI:10.1016/j.bmcl.2013.08.077

An antimalarial medicinal plant Picrorhiza scrophulariiflora was chemically investigated as part of our ongoing research in traditional chinese medicines (TCM). Mass directed fractionation of the active part of the crude extract led to the isolation of ten main components, three new compounds (1-3) and seven known compounds (4-10). Compound 10 inhibited the growth of the Plasmodium falciparum 3D7 malarial parasite line, with an IC₅₀ value of 8.3 μM. This compound accounted for ～95% of P. falciparum growth inhibitory activity in the crude extract confirming, for this TCM, that a single compound was responsible for the antimalarial activity.

Full text of DOI:10.1016/j.bmcl.2013.08.077

Bioorganic & Medicinal Chemistry Letters 23 (2013) 5915–5918
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Chemical investigation of an antimalarial Chinese medicinal herb
Picrorhiza scrophulariiflora q
Hongmin Wang a, Weimin Zhao a, Vanida Choomuenwai b, Katherine T. Andrews b, Ronald J. Quinn b,
,
⇑
Yunjiang Feng b,
⇑
a Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China
b Eskitis Institute, Griffith University, Brisbane, QLD 4111, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 July 2013
Revised 16 August 2013
Accepted 19 August 2013
Available online 27 August 2013
An antimalarial medicinal plant Picrorhiza scrophulariiflora was chemically investigated as part of our
ongoing research in traditional chinese medicines (TCM). Mass directed fractionation of the active part
of the crude extract led to the isolation of ten main components, three new compounds (1–3) and seven
known compounds (4–10). Compound 10 inhibited the growth of the Plasmodium falciparum 3D7 malar-
ial parasite line, with an IC50 value of 8.3
inhibitory activity in the crude extract confirming, for this TCM, that a single compound was responsible
for the antimalarial activity.
l
M. This compound accounted for ꢀ95% of P. falciparum growth
Keywords:
Traditional Chinese medicine
Antimalarial
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Picrorhiza scrophulariiflora
Malaria is one of the worlds’ most significant human infectious
diseases, with 216 million cases leading to an estimated 655,000
deaths in 2010.1,2 Most morbidity and mortality is caused by par-
asites of the genus Plasmodium, which like other malaria parasites
is transmitted by the bite of female Anopheles mosquitoes.1
Although several drugs are currently available for the prevention
and treatment of malaria, all are now susceptible to parasite drug
resistance or reduced clinical efficacy, including the gold standard
artemisinin combination therapies.3 The increasing problem of
drug-resistant Plasmodium strains means that new therapies are
urgently needed to treat this devastating disease.3
Historically, natural products have played a major role in the
treatment of malaria.4–7 For centuries the indigenous people from
South America have used the bark from the ‘fever tree’, Cinchona
succiruba for the treatment of malaria. Similarly, the Chinese
medicinal plant, Artemisia annua, commonly known as Qinghao,
has been used in China as an antimalarial herbal remedy for hun-
dreds of years.4–7 Subsequent chemical investigations of Cinchona
succiruba and Artemisia annua identified the major active metabo-
lites to be quinine and artemisinin (Qinghaosu), respectively.4–7
Artemisinin is considered one of the most important discoveries
in contemporary herbal research.
Traditional Chinese medicine (TCM) has been regarded as a na-
tional heritage for centuries. Approximately 13,000 kinds of medic-
inal plants have been recorded in China.8 Among them, over 300
are commonly used for antimalarial remedies. In our ongoing effort
in understanding TCM and its action, a collaborative research pro-
ject was established to investigate antimalarial traditional Chinese
medicinal plants. The objective of the project was not only to iden-
tify antimalarial natural products, but also to investigate whether a
TCM’s action is solely associated with a single active component,
an underlying philosophy of western medicine. One hundred anti-
malarial Chinese medicinal herbs recorded in the Chinese Pharma-
copeia were selected and tested in vitro against the malaria
parasite Plasmodium falciparum 3D7 for antimalarial activity. Of
these, 82 extracts showed >50% inhibition at 10 mg/mL, while 35
had >90% inhibition at the same concentration. These results lar-
gely confirmed the traditional knowledge of the antimalarial activ-
ity of the herbal medicines recorded in the Chinese Pharmacopiea.
The crude extract from the rhizomes of a Tibetan Picrorhiza scro-
phulariiflora Pennell showed potent activity and was chemically
investigated. Flash chromatography of the crude extract followed
by mass-directed fractionation of the active fraction led to the iso-
lation of three new compounds, scrophuloside C–D (1–2), and heb-
itol III (3), along with seven known compounds, namely, hebitol II
(4),8 scrophuloside B (5),9 scrophenoside B (6),10 scroneoside A
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original author and source are credited.
⇑
Corresponding authors. Tel.: +61 7 37356000; fax: +61 7 37356001 (R.J.Q); tel.:
+61 7 37356014; fax: +61 7 37356001 (Y.F.).
(7),11 picroside-I (8),12 25-(acetyloxy)-2-(b-
3,16,20-trihydroxy-9-methyl-19-norlanost-5-en-22-one (9),13 and
D-glucopyranosyloxy)-
E-mail addresses: r.quinn@griffith.edu.au (R.J. Quinn), y.feng@griffith.edu.au (Y.
Feng).
0960-894X/$ - see front matter Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.08.077

5916
H. Wang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5915–5918
25-(acetyloxy)-2-(b-
D
-glucopyranosyloxy)-3,16-dihydroxy-9-methyl-
group was attached at C-3 position of the benzene ring. The con-
19-norlanosta-5,23-dien-22-one (10).13
nectivity was confirmed by the HMBC correlations from the aro-
matic protons (dH 7.17 and 7.45) to the aromatic carbons (dC
123.0, 131.4, 149.2 and 150.9). The HMBC correlation from the glu-
cose H-60 (dH 4.44 and 4.24) to the cinnamoyl carbonyl carbon (dC
166.4) suggested the formation of an ester bond between these
two functional groups. The formation of an ether bond between
the glucose moiety and the tri-substituted benzene ring was deter-
mined by the HMBC correlation from the anomeric proton
(dH 5.12) to the C-4 aromatic carbon (dC 150.9). The planar struc-
ture of 1 was therefore elucidated as 1-O-phenyl-6-O-cinnamoyl-
b-glucopyranoside.
Picrohiza scrophulariiflora (Scrophulariaceae) is a perennial dis-
tributed throughout the high altitude region (over 4,400 m) in the
southeast of Tibet and the northwest of Yunnan, China. The plant
has been traditionally used for diarrhea, jaundice and malaria.
The rihizomes of Picrorhiza scrophulariiflora (Scrophulariaceae) in
this study collected from Tibet Autonomous Region, China, were
purchased from Bozhou Herbal Medicine Market, Anhui Province
in July, 2011. The dried and ground plant material (300 g) was
exhaustively extracted by MeOH, and then partitioned between
petroleum ether, EtOAc and n-BuOH. Silica gel flash chromatogra-
phy of the EtOAc layer yielded one active fraction which was sub-
jected to LC-MS analysis. Mass-directed purification by reverse
phase C18 HPLC led to the isolation of nine major components,
including three new metabolites, scrophuloside C (1, 4.4 mg,
0.0015% dry weight), scrophuloside D (2, 3.3 mg, 0.0011% dry
weight) and hebitol III (3, 1.1 mg. 0.0004% dry weight), along with
seven known compounds, namely, hebitol II (4, 3.2 mg, 0.0011%
dry weight), scrophuloside B (5, 12.5 mg, 0.0042% dry weight),
scrophenoside B (6, 13.3 mg, 0.0044% dry weight), scroneoside A
(7, 3.5 mg, 0.0012% dry weight), picroside-I (8, 63.0 mg, 0.021%
The absolute configuration of the glucose moiety in 1 was deter-
mined by gas chromatography of sugar enantiomers as acetylated thi-
azolidine derivative.15,16 Acid hydrolysis of
1
followed by
-cysteine methyl ester gave a GCMS peak at
17.92 min, same as that of a standard -glucose derivative, namely
methyl 3-acetyl-2R-(10R,20S,30R,40R,5-pentaacetoxypenta-1-yl)-thia-
zolidine-4R-carboxylate (17.97 min, while -glucose derivative methyl
3-acetyl-2R-(10S, 20R, 30S, 40S, 5-pentaacetoxypenta-1-yl)-thiazolidine-
4R-carboxylate at 18.48 min), indicating a -glucose in the molecule.
derivatization with
L
D
L
D
Scrophuloside C (1) was therefore identified as 1-O-(2-methoxy-4-
acetylphenyl)-6-O-(E-cinnamoyl)-ß-D-glucopyranoside.
dry weight), 25-(acetyloxy)-2-(b-
trihydroxy-9-methyl-19-norlanost-5-en-22-one (9, 435.0 mg,
0.145% dry weight), and 25-(acetyloxy)-2-(b- -glucopyranosyl-
oxy)-3,16-dihydroxy-9-methyl-19-norlanosta-5,23-dien-22-one (10,
485.3 mg, 0.167% dry weight).
D-glucopyranosyloxy)-3,16,20-
Scrophuloside D (2)17 was also isolated as an optically active
D
colorless solid, with an [
a
]
value of ꢁ17.6. Its molecular formula
D
was determined as C23H24O10 by HRESIMS (m/z 459.1286 [MꢁH]ꢁ),
indicating 2 mass unit more than that of 2. The comparison of the
1H and 13C NMR data between 2 and 1 suggested that the two com-
pounds possessed similar structural features, the differences being
the absence of an acetyl methyl signal in 2 and a up-field shift of
the carbonyl carbon (dC 196.7 in 1 to dC 167.8 in 2). These changes
suggested that the acetyl functionality in 1 was replaced by a car-
boxylic acid in 2, which was supported by the molecular formula of
2. Using the same GCMS method as that for compound 1, the abso-
1
HO
HO
HO
R
O
O
8
O
7"
7"
1
R
R
3"
1"
1"
O
OH
OH
O
9"
9"
5
6'
6'
3
O
O
O
HO
HO
HO
HO
1'
1'
O
O
6
OH
7
3
4
R=H
1 R = CH3
2 R = OH
R=OH
O
O
O
O
lute configuration of the glucose in 2 was determined as b- -glu-
D
R2
O
cose (with a retention time of 17.96 min). The structure of
scrophuloside D (2) was therefore elucidated as 1-O-(2-methoxy-
H
O
O
OH
H
H
O
HO
HO
O
O
R1
HO
HO
HO
O
OH
4-carboxylphenyl)-6-O-(E-cinnamoyl)-ß-
Hebitol III (3)18 was isolated as an amorphous solid with a neg-
ative optical rotation ([ –38). Its molecular formula, C21H30O12,
D-glucopyranoside.
R1 = OCH3, R2 = H
OH
5
6
OH
8
R
1 = R2 = H
7 R1 = R2 = OCH3
O
O
HO
a]
HO
D
OH
OH
was deduced by HRESIMS, indicating seven degrees of unsatura-
tion. The 1H NMR spectrum of 3 (Table 1) displayed signals for a
cinnamoyl group and sugar moieties (dH 3.04–4.41). The double
bond in the cinnamoyl group was determined as trans based on
its large coupling constant (dH 7.65 and 6.65, J 16.0 Hz). Twenty
one carbon resonances were observed in 13C NMR spectrum in
combination with HSQC and HMBC correlation data. Nine carbon
resonances (dC 166.7, 145.2, 134.5, 129.4 ꢂ 2, 129.1, 128.9 ꢂ 2,
and 118.4) were consistent with the presence of a cinnamoyl
group. Six carbon signals (dC 104.2, 74.1, 76.5, 70.4, 74.2 and
64.3) along with their corresponding 1H NMR signal (dH 3.04–
4.41) indicated the presence of a glucopyranoside unit. The large
coupling constant of the anomeric proton (dH 4.23, J 8.0 Hz) indi-
cated that the glucose unit had a ß-configuration. The remaining
6 carbon resonances (dC 73.4–64.3) were assigned to a mannitol
functionality based on the absence of a low field anomeric carbon
(ꢀdC 100), and lack of double bond equivalence. Further analysis of
the HSQC and HMBC correlation data confirmed the assignment.
The HMBC correlations from the glucose H-60 (dH 4.41 and 4.17)
to the cinnamoyl C-900 (dC 166.7) suggested the formation of an es-
ter bond between the two functional groups. Further HMBC corre-
lation from the glucose H-10 (dH 4.23) to the mannityl C-6 (dC 73.4)
indicated an ether linkage between the glucose and the mannityl
sub-units. The comparison of the carbon chemical shifts between
compound 3 and the known compound, hebitol II, confirmed the
sugar moiety b-glucopyrannosyl-(1 ? 6)mannitol.
O
OH
O
OH
O
O
O
O
HO
O
HO
HO
O
HO
OH
OH
HO
HO
9
10
Scrophuloside C (1)14 was obtained as an optically active color-
less solid with an [
value of ꢁ74.0. The molecular formula of 1
a
]
D
was determined to be C24H26O9 by HRESIMS (m/z 481.1461
[M+Na]+), with twelve degrees of unsaturation. The 1H NMR spec-
trum of 1 (Table 1) indicated the presence of a cinnamoyl function-
ality, a sugar moiety (dH 3.5–5.5), a 1, 2, 4-trisubstituted benzene
ring, a methyl group (dH 2.34), and a methoxyl group (dH 3.83).
The double bond in the cinnamoyl group was determined as trans
based on its coupling constant (dH 7.64 and 6.63, J 16.0 Hz) (Ta-
ble 1). Twenty three carbon resonances were deduced from the
HSQC and HMBC correlation data. Nine carbon resonances (dC
166.4, 145.2, 134.4, 131.0 ꢂ 3, 128.9 ꢂ 2, and 118.6) were consis-
tent with the presence of a cinnamoyl group. The sugar moiety
was assigned as b-glucose based on its 1H and 13C NMR data and
the coupling constant of the anomeric proton (dH 5.12, J 7.6 Hz).
The formation of the acetyl group and its attachment on C-1 posi-
tion of the tri-substituted benzene ring were established by the
HMBC correlations from the methyl singlet (dH 2.34) to a ketone
carbonyl (dC 196.7) and an aromatic carbon (dC 131.4). Further
HMBC correlation was observed from the methoxyl singlet (dH
3.83) to a aromatic carbon (dC 149.2), indicating the methoxyl

H. Wang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5915–5918
5917
Table 1
1H and 13C NMR Data for Compounds 1–3 in DMSO-d6
Compound 1a,b
Compound 2b,c
Compound 3a
Position dC
dH (J in Hz)
HMBC
dC
dH (J in Hz)
HMBC
dC
dH (J in Hz)
HMBC
1
131.4
124.9
64.3
3.58, dd (11.5, 2.3)
3.36, dd (11.5, 5.8)
3.43d
3.62, dd (3.8, 11.5)
3.52, d (8.9)
2
3
4
5
6
7
8
9
10
20
30
40
50
60
111.4 7.45d
149.2
150.9
C-1, C-3, C-4, C-6
113.5 7.47, d (1.9)
149.0
150.6
115.0 7.18, d (8.3)
123.3 7.50, dd (8.3, 1.9)
56.4
C-3, C-4, C-6, C-8
71.7
70.0
70.1
70.1
73.4
C-4
C-2, C-5
114.7 7.17, d (8.0)
C-1, C-3
C-2, C-4
C-3
C-1, C-3, C-4
C-2, C-4, C-8
C-3
3.53, d (8.9)
123.0 7.45d
4.03, dd (10.5, 1.3), 3.40d C-10
56.1
196.7
26.5
99.7
73.5
77.3
70.7
74.3
63.9
3.83, s
3.81, s
167.8
2.34, s
5.12, d (7.6)
3.38d
C-1, C-8
C-4
99.7
73.5
77.2
70.5
74.5
63.8
5.12, d,(7.6)
3.33d
C-4
C-30
C-20
104.2 4.23, d (8.0)
C-6
74.1
76.5
70.4
74.2
64.3
3.04, t (8.5)
C-10, C-30
C-50
3.37d
C-20, C-40
3.34d
3.18d
3.37d
3.23d
3.15d
C-60
3.76, m
C-10
3.74 m
3.41d
C-10
4.44, dd (10.3,1.9) C-50, C-900
4.24, dd (10.3, 6.1)
4.45, dd (11.8, 1.9) C-50, C-900
4.19, dd (11.8, 6.7)
4.41, d (10.3)
4.17, dd (10.3, 6.1)
C-50, C-900
100
200
300
400
500
600
700
800
900
134.4
134.5
134.5
128.9 7.72, m
C-300, C-600, C-700
C-100, C-200
128.6 7.69, m
C-300, C-400
C-100
128.9 7.72d
129.4 7.41d
129.1 7.40d
129.4 7.41d
128.9 7.72d
145.2 7.65, d (16.0)
118.4 6.65, d (16.0)
166.7
C-100,C-700
C-100,C-200
131.0 7.45d
129.6 7.43d
131.0 7.45d
130.8 7.43d
131.0 7.45d
C-100, C-600
129.6 7.43d
C-100
C-100
128.9 7.72, m
145.2 7.64, d (16.0)
118.6 6.63, d (16.0)
166.4
C-200, C-400, C-700
C-200, C-800, C-900
C-100, C-900
128.6 7.69, m
145.6 7.61, d (16.0)
118.5 6.60, d (16.0)
166.5
C-400, C-500
C-200, C-800, C-900
C-100, C-900
C-100,C-700
C-200,C-800, C-900
C-100, C-900
a
b
c
Spectra were recorded at 600 MHz for 1H and 150 MHz for 13C using d6-DMSO as solvent at 30 °C.
The 13C NMR spectra were observed from the HSQC and HMBC experiments.
Spectra were recorded at 500 MHz for 1H and 125 MHz for 13C using d6-DMSO as solvent at 30 °C.
Signals were overlapping.
d
The planar structure of compound 3 was therefore determined
to be 1-O-mannityl-6-O-cinnamoyl-ß-glucopyranose.
The crude extract of Picrorhiza scrophulariiflora had 95% inhibi-
tion against P. falciparum 3D7 malaria parasites at the concentra-
The GCMS analysis of a peracetylated thiazolidine derivative of
tion of 10 mg/mL. A calculated IC95 for compound 10 was
the hydrolyzed 3 established a
D-glucose moiety (with a retention
obtained based on the activity of the crude extract, the percentage
time of 17.93 min) as in 1 and 2. The attempt to isolate the manni-
tol moiety form the hydrolyzed mixture, measure its optical rota-
tion, and therefore determine the absolute configuration of
mannitol was hindered by the small quantity of compound 3. Heb-
itol III (3) was therefore determined as 1-O-mannityl-6-O-(E-cin-
yield of compound 10 and its molecular weight. The results
showed that the calculated IC95 (23.5
lM) of 10 was comparable
with that of the experimental IC90 (17.3
l
M), suggesting that the
antimalarial activity of this TCM, Picrorhiza scrophulariiflora, was
contributed mainly by a single component. Given artemisinin (Qin-
ghaosu) was also the single major antimalarial component identi-
fied from Artemisia annua, perhaps the anti-parasitic activity of
TCM is controlled by singlecompounds rather than multiple com-
ponents in TCMs effective against other diseases. Further isolation
and activity evaluation of antimalarial Chinese herbal medicines is
currently ongoing. Results will not only lead to some interesting
bioactive natural products, but also shed light on whether antima-
larial TCMs contain single or multiple active constituents.
namoyl)-ß-D-glucopyranose.
Seven known compounds, namely hebitol II (4),8 scrophuloside
B (5),9 scrophenoside B (6),10 scroneoside A (7),11 picroside-I (8),12
25-(acetyloxy)-2-(b-
D-glucopyranosyloxy)-3,16,20-trihydroxy-9-
methyl-19-norlanost-5-en-22-one (9),13 and 25-(acetyloxy)-2-(b-
D
-glucopyranosyloxy)-3,16-dihydroxy-9-methyl-19-norlanosta-5,
23-dien-22-one (10),13 were also isolated from the active fraction
of Picrorhiza scrophulariiflora. These compounds were previously
reported from the plants Picrorhiza scrophulariiflora and Picrorhiza
kurroa and their 1H and 13C NMR data were identical to those re-
ported in the literature.
Acknowledgments
The antimalarial activity of the crude extracts and the isolated
pure compounds (1–10) were evaluated in vitro against P. falcipa-
rum 3D7 malaria parasites. Chloroquine was used as positive con-
We thank the Queensland government, Australia, for an Inter-
national Fellowship (Y.F.), and Chinese National Science & Technol-
ogy Major Project ‘Key New Drug Creation and Manufacturing
Program’ (2009ZX09103-413). We thank H. T. Vu from Griffith Uni-
versity for acquiring the HRESIMS measurements. We thank Xiqu
Wang from the Institute of Botany, Jiangsu Province and Chinese
Academy of Sciences for authenticating the plant material. We
thank the Australian Research Council (ARC) for support toward
NMR and MS equipment (LE0668477 and LE0237908).
trol which had an IC50 value of 0.018 0.002
all had IC50 > 25 M, while 10 had an IC50 value of 8.3 0.6
and an IC90 value of 17.3 1.6 M. Compounds 9 and 10 were
lM. Compounds 1–9
l
lM,
l
the two main components in the active fraction, and the only
structural difference is a double bond between C-23 and C-24.
Accordingly, the presence of a a,ß-unsaturated carbonyl group in
compound 10 may be important for its antimalarial activity. Since
compound 10 has a Michael acceptor functionality,19,20 we also
tested its activity against a noncancer cell line, neonatal foreskin
fibroblast (NFF). It showed no cytotoxicity to NFF cells at the con-
Supplementary data
Supplementary data (Copy of 1H, 13C, COSY, HSQC and HMBC
NMR spectra of 1–3, GC–MS traces of sugar derivatives of hydro-
centration of up to 100 lM.

5918
H. Wang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5915–5918
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Y. Chem. Pharm. Bull. 2006, 54, 275.
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lyzed 1–3, detailed experimental procedures including general
experiment procedure, plant material, extraction and isolation pro-
cedure for compounds 1–10, acid hydrolysis and derivatisation,
GCMS analysis, antimalarial assay and cytotoxicity assay. This
material can be found in the online version.) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.bmcl.2013.08.077.
13. Stuppner, H.; Muller, E. P.; Wagner, H. Phytochemistry 1991, 30, 305.
14. Scrophuloside C (1): colorless solid; [
kMax (log
a]Dꢁ74.0 (c 0.09, CH3OH); UV (CH3OH)
e
) 270 (sh) (3.41) nm; 1H and 13C NMR data (DMSO-d6) see Table 1;
(+)-HRESIMS m/z 481.1461 [M+Na]+ (calcd. for C24H26O9Na, 481,1490).
15. Hara, S.; Okabe, H.; Mihashi, K. Chem. Pham. Bull. 1987, 35, 501.
16. Zhao, W. M.; Ye, Q. H.; Tan, X. J.; Jiang, H. L.; Li, X. Y.; Chen, K. X.; Kinghorn, A. D.
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17. Scrophuloside D (2): colorless solid; [a]D–17.6 (c 0.125, CH3OH); UV (CH3OH)
kMax (log e
) 229(3.59), 204 (sh) (3.81) nm; 1H and 13C NMR data (DMSO-d6) see
Table 1; (ꢁ)-HRESIMS m/z 459.1286 [MꢁH]ꢁ (calcd for C23H23O10, 459.1291).
18. Hebitol III (3): colorless solid; [a]D–38.0 (c 0.1, CH3OH); UV (CH3OH) kMax (log
e
) 259 (sh) (3.55), 204 (sh) (3.55) nm; 1H and 13C NMR data (DMSO-d6) see
Table 1; (+)-HRESIMS m/z 497.1643 [M+Na]+ (calcd for C21H30O12Na,
497.1629).
19. ElSubbagh, H. I.; Abu-Zaid, S. M.; Mahran, M. A.; Badria, F. A.; Al-Obaid, A. M. J.
Med. Chem. 2000, 43, 2915.
6. Schwikkard, S.; van Heerden, F. R. Nat. Prod. Rep. 2002, 19, 675.
7. Kaur, K.; Jain, M.; Kaur, T.; Jain, R. Bioorg. Med. Chem. 2009, 17, 3229.
8. Taskova, R. M.; Kokubun, T.; Ryan, K. G.; Garnock-Jones, P. J.; Jensen, S. R. J. Nat.
Prod. 2011, 74, 1477.
20. Jiang, C. S.; Guo, X. J.; Gong, J. X.; Zhu, T. T.; Zhang, H. Y.; Guo, Y. W. Bioorg. Med.
Chem. Lett. 2012, 22, 2226.