Synthesis and antiviral, insecticidal, and fungicidal activities of gossypol derivatives containing alkylimine, oxime or hydrazine moiety

Article abstract of DOI:10.1016/j.bmc.2015.08.015

Gossypol is a part of the cotton plant's defense system against pathogens and herbivorous insects. To discover gossypol analogs with broad spectrum and high activity, a series of gossypol alkylamine Schiff base, oxime and hydrazone derivatives were synthesised and bioassayed. The biological results indicated that most of these derivatives exhibited higher anti-TMV activity than gossypol. Interestingly, the activities of compounds 10, 15, 18, 20, 23 and 26 were much higher than that of ribavirin. Furthermore, compound 26, which was low toxicity to rat, showed better activity than control plant virus inhibitors in the field. Additionally, allyl amine Schiff base (9) displayed remarkable insecticidal activities against Mythimna separata, Helicoverpa armigera and Ostrinia nubilalis, whereas (pyridin-3-yl)methanamine Schiff base (13) showed excellent activity against Culex pipiens pallens. The fungicidal results revealed that all of compounds exhibited good activity against Physalospora piricola.

Full text of DOI:10.1016/j.bmc.2015.08.015

Bioorganic & Medicinal Chemistry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and antiviral, insecticidal, and fungicidal activities
of gossypol derivatives containing alkylimine, oxime or hydrazine
moiety
⇑
⇑
⇑
Ling Li, Zheng Li, Kailiang Wang, Yuxiu Liu , Yongqiang Li , Qingmin Wang
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Nankai University, Tianjin 300071, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Gossypol is a part of the cotton plant’s defense system against pathogens and herbivorous insects. To dis-
cover gossypol analogs with broad spectrum and high activity, a series of gossypol alkylamine Schiff base,
oxime and hydrazone derivatives were synthesised and bioassayed. The biological results indicated that
most of these derivatives exhibited higher anti-TMV activity than gossypol. Interestingly, the activities of
compounds 10, 15, 18, 20, 23 and 26 were much higher than that of ribavirin. Furthermore, compound
Received 17 June 2015
Revised 3 August 2015
Accepted 13 August 2015
Available online xxxx
2
6, which was low toxicity to rat, showed better activity than control plant virus inhibitors in the field.
Keywords:
Gossypol
Schiff base
Oxime
Additionally, allyl amine Schiff base (9) displayed remarkable insecticidal activities against Mythimna
separata, Helicoverpa armigera and Ostrinia nubilalis, whereas (pyridin-3-yl)methanamine Schiff base
(13) showed excellent activity against Culex pipiens pallens. The fungicidal results revealed that all of
Hydrazone
compounds exhibited good activity against Physalospora piricola.
Anti-TMV activity
Structure–activity relationships
Ó 2015 Elsevier Ltd. All rights reserved.
3
1
. Introduction
such as cancer, HIV, and malaria. Moreover, as a part of the plant’s
defense system against pathogenic fungi and insects,4 gossypol is
also endowed with great agricultural implication. However, the
research based on gossypol as botanical pesticide is still rare.
Additionally, Schiff bases, usually synthesized by the condensa-
tion of amines with active carbonyl groups, exhibit a broad range
of biological activities, including antifungal, insecticidal,6 antivi-
Botanical pesticides refer to the plants, crude plant extracts or
the derivatives of the active ingredients for the protection of crops
and stored products from insect pests. It can be recommended as
an ecochemical and sustainable strategy for the management of
agricultural pests, due to their biodegradable nature, systemicity
after application, capacity to alter the behavior of target pests
and favorable safety profile.1 Naturally active substances are fea-
tured by structural diversity and complexity, more stereogenic
centers, but some deficiencies, such as the limited quantity
available, being too complex to synthesize and being easy to
decompose, inevitably limit the widespread use. Therefore, they
usually are good lead compounds, and unlikely meet the demands
5
7
8
ral and herbicidal activities. Significantly, it is expected that
various natural products with the different imine groups could
demonstrate distinctly pharmacological efficacy. Taking our pre-
9
1
0
vious work as an example, the anti-TMV activities of aromatic
gossypol Schiff bases revealed the substituent groups of amine
had great effect on the anti-TMV activities. As a continuous
exploitation of the concept of the SAR, a series of gossypol alky-
lamine Schiff bases (Fig. 1) with the modification of the functional
groups have been synthesized. Some compounds that displayed
promising antiviral activity against TMV were identified. Further
field trials showed that compound 26 displayed higher anti-TMV
activity than did the control plant virus inhibitors.
It is also reported that oximes and hydrazones frequently
exhibit satisfactory insecticidal, fungicidal, herbicidal and antiviral
activity. And the majority of these compounds have characteristics
of low toxicity and residue. As a result, the study on molecular
design, synthesis and biological activity of oximes and hydrazones
has attracted more and more attention in recent years. It is well
2
as pesticides. So, it is necessary to modify and optimize these
structural frameworks.
Gossypol is the secondary metabolite of Gossypium and mainly
embedded in the cottonseed pigment glands. The investigations on
gossypol and its derivatives have been given considerable atten-
tion since the discovery of its impressive application in antifertility
activity. It is also well known that gossypol displays great medical
activities, providing an opportunity in struggling with the diseases
1
1
12
⇑
Corresponding authors. Tel./fax: +86 22 23503952.
E-mail address: wangqm@nankai.edu.cn (Q. Wang).
http://dx.doi.org/10.1016/j.bmc.2015.08.015
968-0896/Ó 2015 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Li, L.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.08.015

2
L. Li et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
1
1
11'
of the N-alkylphthalimide M-3 or M-4, and then acidification could
HO
CHO
OHC 8' OH
8
afford amine-17 or amine-22. Ammonolysis of o-phthalic anhy-
dride with taurine produced M-6, which was converted to sulfonyl
chloride M-7. Sulfamide M-8 or M-9 could be obtained via the
reactions of M-7 and dimethylamine or ammonia. Finally, the same
process as M-3 could provide amine-19 and amine-20.
7
OH HO
7'
9
'
9'
HO
1
1
OH
6
6'
10' 5'
5
10
2
2'
4
3
3' 4'
gossypol
R
R
1
3
The derivatives 1–33 could be synthesized by condensation of
gossypol and corresponding amines in different conditions
(Scheme 3). Most of the compounds were prepared by treating
gossypol acetic acid with the corresponding amines in ethanol,
and then collected by filtration. For the derivatives with sodium
salt group (18, 25 and 26), the corresponding amines were firstly
prepared from homologous substituted-sulfonic acid and NaOH,
which was used 3 equiv of gossypol to ensure the derivatives with
sodium salt group. MeOH is employed as the solvent in the prepa-
ration of Schiff base 26 due to the poor solubility of sodium
aminomethylsulfonate in ethanol. However, the product can be
well dissolved in MeOH, making it difficult to be precipitated.
Therefore, MeOH should be evaporated before Schiff base is recrys-
tallized from isopropanol. The amine materials of compounds 17,
19–22 and 28 were the hydrochloride salt of corresponding
amines, therefore they were deacidized before reaction with
gossypol. The oxime 27 could not be well obtained under the above
conditions. After screening various conditions, NaOAc was the best
base and the yield of oxime reached up to 97.6%.
Alkyl
Alkyl 13'
12'NH
13
X
N
X
13'
HN12
12 X = O or N 12'
11
N
O
7
11'
O
HO
11'
OH
11
8
8'
8
8'
OH HO
7'
7
OH HO
1
7'
9
9'
9
9'
'
'
HO
1
1
OH HO
1
OH
6'
6
6'
6
5
10
2
2'
10' 5'
5
10
2
2'
10' 5'
4
3
3' 4'
4
3
3' 4'
gossypol alkylamine Schiff bases
gossypol oximes and hydrazones
Figure 1. The structure of gossypol and its derivatives.
known that gossypol can exist in three symmetrical tautomeric
forms: aldehyde–aldehyde, lactol–lactol, and ketol–ketol whereas
oximes or hydrazones and amine Schiff bases of gossypol can be
present in the two tautomeric forms that are analogous to the alde-
9
hyde–aldehyde and ketol–ketol tautomeric forms of gossypol. As
a further investigation on the influence of biological activity by
the form of oximes and hydrazones and the improvement of their
biological activities, a series of gossypol oxime and hydrazone
derivatives (Fig. 1) have been synthesized and characterized in
detail. Their biological activities in the field of pesticides have been
performed as well.
All of our synthetic gossypol alkylamine Schiff bases exist in the
enamine-enamine form, whereas the imine-imine tautomer was
observed for oximes and hydrazones of gossypol in solution.
Taking compounds 8 and 32 for example, the structures can be
1
interpreted by the H NMR spectrum. The signal peaks of symmet-
2
2
. Results and discussion
rical protons should appear at the same position and have identical
coupling constant due to axial symmetry of the structure. For
compound 8, the presence of doublet peaks with the coupling
.1. Chemistry
1
constant of 13.3 Hz in the H NMR spectrum can be attributed to
The synthesis of intermediates amine-17, amine-19, amine-20
t
the signals of HAC@C proton and HANA C proton. This behavior
and amine-22 was shown in Schemes 1 and 2. Nucleophilic substi-
tution of phthalimide potassium with 1,2-dibromoethane provided
M-2. And M-2 further was reacted with sodium cyanide and tri-
ethyl phosphate respectively, to give M-3 and M-4. Hydrazinolysis
can be rationally explained by the fact that two protons are adja-
cent and coupled with each other. The signal assigned to HAC11
1
in the H NMR spectrum of compound 32 appears as a singlet at
9
.64 ppm, indicating the absence of a proton at the ortho N atom.
This result suggests the existence of the imine–imine tautomeric
O
O
O
form of compound 32 in the solution.
Br
Br
R
Br
N
K
N
N
2
.2. Antiviral biological assay
O
M-1
O
M-2
O
M-3: R = CN
The gossypol derivatives of alkylimine, oxime and hydrazone
M-4: R = PO(OEt)
2
were evaluated for their antiviral activities against TMV in the lab-
oratory (Table 1). Gossypol and ribavirin were used as controls.
Overall, compared with gossypol and ribavirin, most of the newly
designed compounds exhibited desirable anti-TMV activities.
Compounds 10, 15, 18, 20, 23, and 26 showed much higher inhibi-
tion than that of ribavirin and gossypol both in vitro and in vivo at
N H • H O
2
4
2
R
•
HCl
H N
2
amine-17: R = CN
amine-22: R = PO(OEt)2
Scheme 1. Synthetic route for intermediates amine-17 and amine-22.
O
O
O
SO H
3
H N
PCl
toluene
5
2
O
N
N
AcOK, AcOH
SO K
SO Cl
2
3
O
O
M-6
O
M-7
M-5
O
O
R
•
N H •H O
HCl
2
4
2
S
N
H N
2
O
SO R
2
O
M-8: R = N(CH )
amine-19: R = N(CH )
3 2
3
2
M-9: R = NH2
amine-20: R = NH2
Scheme 2. Synthetic route for intermediates amine-19 and amine-20.
Please cite this article in press as: Li, L.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.08.015

L. Li et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
3
OH
CHO OH
HO
•
AcOH
OH
OH CHO
R-NH2
HO
R
HN
R
N
OH
O
OH
OH
OH
OH
O
or HO
HO
OH
OH
27-33
HO
NH
N
R
R
1-26
Compd.
R
Compd.
12
R
Compd.
23
R
HO
1
2
3
4
H C
3
N
13
24
MeO C
N
2
14
25
NaO C
2
O
15
HO
HS
26
NaO S
3
5
16
27
7
HO
6
7
17
18
NC
28
29
30
H CO
3
NaO3S
H N
2
O
N
8
9
19
20
21
22
S
N
H
O
O
2
H N
3
3
3
1
2
3
S
N
O
O
1
1
0
1
S
O
N
H
OEt
EtO
O
P
S
O
O
N
H
Scheme 3. Synthesis of the target compounds 1–33.
5
2
00 and 100
l
g/mL. Especially, the activities of compounds 18 and
length of the aliphatic chain and the number of branched chains
had a little effect on their activity level.
6 at 100 g/mL were close to that of ribavirin at 500 l
l
g/mL in all
of the test modes.
The SAR of aromatic gossypol Schiff bases indicated that the
introduction of different functional groups on the aromatic ring
could adjust the anti-TMV activities. A series of alkylamine Schiff
bases with various substituent groups on aliphatic chains (9–26)
herein were synthesized and displayed distinctly different
activity levels against TMV. Among these compounds (9–13) with
unsaturated hydrocarbons substituent groups on methylene, the
propynylamine Schiff base (10) exhibited the best activities, which
were obviously higher than them of ribavirin and gossypol. The
Compounds 1–8 with aliphatic substituent groups displayed
different anti-TMV activities in the four test modes. For example,
gossypol iso-propylamine Schiff base (6) exhibited good in vitro
curative activity (45.7%), in vivo curative and protection activities
(
40.7% and 53.1%) against TMV in 500 lg/mL, whereas the in vivo
inactivation activity was very low (17.5%) in the same concentra-
tion. On the whole, the anti-TMV activities of them were not signif-
icantly improved relative to that of gossypol. Therefore, both the
Please cite this article in press as: Li, L.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.08.015

4
L. Li et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
Table 1
Table 2
The antiviral activity of compounds 1–33 against TMV in the lab
Results of anti-TMV activities of field trial in 2014
0
a
a
Compd
Conc
g/mL)
In vitro
curative
effect (%)
In vivo activity
Compd
Conc
(g ai/ha)
I
eq
I
eq
Controlled
effect (%)
(
l
Inactivation
effect (%)
Curative
effect (%)
Protection
effect (%)
26 (1% ME)
100
4.59
2.46
0.40
2.94
4.40
4.51
77.15
67.11
66.28
5
1
0
0
1
2
3
4
5
6
7
8
9
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
43.9
12.1
33.3
0
24.1
0
36.1
0
30.0
0
45.7
15.0
45.0
7.5
28.9
0
45.6
20.4
48.8
22.0
23.5
0
18.7
0
37.6
0
21.8
0
47.5
34.3
28.8
0
49.2
12.8
61.2
34.7
34.9
0
50.4
15.8
38.7
0
41.7
12.1
48.7
23.2
28.4
8.6
35.2
0
62.8
31.1
42.6
7.5
38.9
16.7
40.0
17.5
40.0
7.5
42.3
7.8
20.5
0
32.6
0
27.6
0
37.5
9.8
40.7
0
32.5
0
32.0
10.0
36.6
0
17.5
0
20.4
10.2
32.7
0
42.0
10.1
57.8
16.9
10.3
0
23.9
0
41.0
16.9
25.4
0
42.5
14.2
34.4
0
46.1
11.5
65.3
28.6
41.5
21.1
54.4
25.7
44.4
18.2
49.3
16.8
51.9
25.2
31.2
10.3
45.9
19.8
61.2
25.7
38.4
17.1
47.8
11.4
42.1
16.3
32.3
5.6
38.2
5.2
25.0
0
31.1
6.2
38.3
8.6
33.3
0
40.7
0
41.3
0
26.5
0
36.8
15.2
52.4
20.3
18.0
0
22.5
0
40.6
0
28.9
0
38.4
28.3
25.1
0
24.4
20.5
38.7
30.5
33.4
0
40.7
14.2
32.8
6.4
53.1
25.3
48.9
20.2
28.0
0
41.5
11.3
49.5
21.7
19.4
10.5
30.4
0
38.1
15.3
27.1
0
52.3
37.3
29.3
0
47.6
22.8
56.8
25.2
37.0
8.9
44.7
26.0
40.2
15.7
42.3
19.5
55.6
20.4
37.1
7.7
31.7
16.4
57.9
21.7
40.3
15.4
40.0
21.8
41.2
28.9
59.5
35.9
45.0
13.1
29.4
12.6
60.5
36.2
33.3
0
1
Blank control
5% amino glycan
20% moroxydine
hydrochlorideꢀ cupric acetate
2.81
3.33
1.23
16.86
5.42
5.72
—
65.70
66.57
1
100
600
1
a
0
I
eq , the average disease index of the spraying area before spraying. Ieq, the
average disease index of the spraying area 10 days after the third time spraying.
1
1
1
benzylamine Schiff base (11) showed the lowest activities. In order
to investigate the influence of functional groups with heteroatoms,
compounds 14–26 were designed and synthesized. Only com-
pounds 14 (tetrahydrofuran), 16 (thiol) and 24 (ester) displayed
lower activities than ribavirin and were similar to gossypol at
1
1
1
5
00 lg/mL. Especially, the introduction of sodium sulfonate group
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
1
(18 and 26) increased tremendously the anti-TMV activities. These
indicated that the introduction of different functional groups with
heteroatoms, which included hydroxyl, cyano, sodium sulfonate,
sulfamide and phosphate, was benefit to the increasement of the
anti-TMV activities.
Most of gossypol derivatives of oxime and hydrazone (27–33)
exhibited higher activities than gossypol itself and were similar
to ribavirin. Gossypol t-butyl hydrazine (30) and gossypol tosylhy-
drazone (33) further showed excellent in vivo protection effect and
1
1
1
1
1
the antiviral activities at 100
lg/mL, even reach the level of
ribavirin at 500 g/mL. Compared with 7 and 11, the position 13
1
l
50.8
9.6
and 13’ in the structures of 31 and 32 is nitrogen atom rather than
the carbon atom. They exist in different tautomers. Interestingly,
they showed similar anti-TMV activities of in vitro curative effect
and in vivo curative effect. However, the in vivo inactivation effect
of 7 and 11 is different from that of 31 and 32. It should be men-
tioned that the in vivo protection effect of 7 is similar to that of
1 but the in vivo protection effect of 11 is rather different from
that of 32.
Compound 26, which is one of the compounds with the best
anti-TMV activity in the lab-scale experiment, was employed to
evaluate the antiviral activity in the field. The results of the field
trials are shown in Table 2. Compound 26 exhibited better
activities than amino glycan and moroxydine hydrochloride-cupric
acetate. Therefore, it was suggested that 26 could be considered as
an alternative to the employed plant virus inhibitor for further
development on the basis of the field trials.
To balance the toxicity versus efficacy of compound 26, we next
explored the tolerated dose of 26 using a group of rats. They were
treated with 500 and 50 mg/kg and observed for a period of
1
63.4
30.0
43.2
12.2
46.2
20.3
36.2
10.3
44.6
10.7
54.1
18.6
37.8
0
1
1
1
3
1
1
1
1
38.3
5.6
1
62.3
26.2
35.8
12.6
45.2
22.4
35.9
0
44.8
0
37.8
9.7
22.1
0
30.9
0
30.0
0
1
1
1
1
4 days monitoring morbidity and mortality. All rats were alive
after 14 days and there was not any toxic symptom. The weight
changes of the rats (Fig. 2) had no obvious difference at 500 and
0 mg/kg and major organs had no significant pathological
changes. Therefore, compound 26 are low toxicity to rats.
1
1
5
34.7
14.6
39.4
8.2
34.1
0
1
1
2.3. Insecticidal activities
1
500
100
The insecticidal activities of the compounds against Mythimna
separata, Helicoverpa armigera, Ostrinia nubilalis and Culex pipiens
pallens were listed in Table 3. It could be seen that all of the target
compounds showed insecticidal activities. Interestingly, allyl
Gossypol
acetic
acid
31.7
0
Gossypol
500
32.4
0
38.4
14.3
35.3
7.7
37.5
12.1
29.1
0
37.2
16.6
28.6
0
39.5
18.2
1
00
500
00
amine Schiff base
M. separata, H. armigera and O. nubilalis. What is more, (pyridin-
-yl) methanamine Schiff base (13), which had 100% mortality
9 displayed remarkable activities against
Ribavirin
1
3
Please cite this article in press as: Li, L.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.08.015

L. Li et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
5
tendency. The Schiff base of hexylamine (4), tert-butylamine (8)
and benzylamine (11–14) exhibited high activities. The gossypol
derivatives of oxime and hydrazine (27–31) also displayed excel-
lent fungicidal activities.
3
. Conclusion
In summary, a series of gossypol alkylamine Schiff bases, oxi-
mes and hydrazones derivatives were synthesized and systemati-
cally evaluated for their biological activities in the field of
botanical pesticides for the first time. Gossypol alkylamine Schiff
bases exist in the enamine-enamine form, whereas the imine-
imine tautomer was observed for oximes and hydrazones. The tar-
get compounds exhibited good anti-TMV activity in the laboratory;
especially, compounds 18 and 26 showed the highest inhibition.
Field trials of compound 26 further demonstrated the antiviral
efficacy against TMV, and it is low toxicity to rat. The introduction
of different functional groups on alkyl chains, which included
hydroxyl, cyano, sodium sulfonate, sulfamide and phosphate, was
very benefit to the anti-TMV activities. In addition, all of the target
Figure 2. Average weight change of rats. 26-L, dosage of 26 is 50 mg/kg; 26-H,
dosage of 26 is 500 mg/kg.
on C. pipiens pallens at 1 mg/kg and 40% mortality at 0.5 mg/kg,
showed excellent insecticidal activity.
2
.4. Fungicidal activities
compounds also showed insecticidal activities. Compound 9
displayed remarkable activities against M. separata, H. armigera
and O. nubilalis. What is more, (pyridin-3-yl) methanamine Schiff
base (13) exhibited excellent insecticidal activity against C. pipiens
pallens. Moreover, these compounds also showed broad-spectrum
fungicidal activities and all of them exhibited excellent fungicidal
activity against Physalospora piricola. Further studies on structural
optimization and mechanism of action are currently underway in
our laboratory.
The fungicidal results are listed in Table 4. Most of the com-
pounds exhibited higher fungicidal activities against Alternaria
solani, Fusarium graminearum, Phytophthora capsici, Cercospora
arachidicola Hori, and Physalospora piricola than others. Especially,
all of the compounds showed excellent fungicidal activities against
Physalospora piricola. The SAR of those compounds against
Fusarium graminearum and Phytophthora capsici showed the same
Table 3
Insecticidal activities of compounds 1–14, 16–23, 25, 28 and 31
Compd
Ca (mg/kg)
M. separata
H. armigera
O. nubilalis
Ca (mg/kg)
C. pipiens pallens
a
a
a
a
P
(%)
P
(%)
P
(%)
P
(%)
1
2
3
4
5
6
7
8
9
600
600
600
600
600
600
600
600
600
10
15
5
15
15
10
10
10
10
10
10
10
10
10
30
20
5
15
55
25
5
35
25
10
15
25
45
20
5
10
25
25
55
20
5
5
20
25
5
15
35
55
100
100
20
10
10
5
100
50
—
15
15
5
100
60
—
15
15
15
50
2
1
00
00
1
1
1
1
0
1
2
3
600
600
600
600
10
10
10
10
5
15
15
15
100
100
100
100
40
45
15
20
50
50
45
25
5
70
55
20
100
40
30
50
2
1
0
10
10
10
10
10
10
10
10
10
10
10
10
5
.5
1
1
1
1
1
2
2
2
2
2
2
3
4
6
7
8
9
0
1
2
3
5
8
1
600
600
600
600
600
600
600
600
600
600
600
600
25
5
30
10
45
55
30
35
5
20
55
65
15
50
60
20
55
65
50
35
15
30
65
40
20
60
25
10
30
30
10
15
55
15
10
45
Gossypol
Acetic
Acid
600
65
25
30
10
5
100
30
a
C, concentration; P, larvicidal activity.
Please cite this article in press as: Li, L.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.08.015

6
L. Li et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
Table 4
Fungicidal activities of gossypol alkylamine schiff bases, oximes and hydrazones derivatives against 9 kinds of fungus
Compd
Fungicidal activity (%)/50 mg/kg
A.S.a
F.G.b
P.C.c
B.C.d
S.S.e
C.H.f
P.P.g
F.M.h
R.C.i
1
2
3
4
5
6
7
8
78.6
71.4
57.1
33.3
16.7
57.1
28.6
16.7
64.3
33.3
50.0
33.3
28.6
16.7
71.4
33.3
50.0
33.3
33.3
33.3
25.0
57.1
50.0
57.1
71.4
14.7
38.2
35.3
66.7
62.5
35.3
38.2
83.3
73.5
70.8
50.0
70.8
35.3
41.7
41.2
50.0
32.4
50.0
70.8
66.7
66.7
79.4
23.5
32.4
41.2
42.3
34.6
53.8
66.7
44.4
42.3
46.2
66.7
61.5
55.6
72.2
66.7
30.8
50.0
46.2
44.4
34.6
50.0
66.7
55.6
61.1
53.8
34.6
50.0
53.8
13.2
17.0
13.2
22.7
9.1
6.8
45.2
21.9
59.0
87.2
23.3
16.4
33.3
37.0
59.0
33.3
71.8
30.1
30.8
64.4
59.0
23.3
69.2
30.8
7.7
54.5
63.6
36.4
36.4
45.5
36.4
45.5
45.5
45.5
54.5
36.4
0
45.5
81.8
45.5
54.5
45.5
54.5
45.5
54.5
45.5
45.5
45.5
54.5
54.5
80.4
87.0
54.3
47.8
87.0
54.3
65.2
65.2
76.1
71.7
65.2
65.2
65.2
58.7
76.1
95.7
54.3
69.6
65.2
76.1
87.0
76.1
65.2
65.2
87.0
33.3
27.8
27.8
33.3
33.3
22.2
22.2
33.3
22.2
38.9
38.9
33.3
33.3
38.9
33.3
33.3
33.3
33.3
50.0
38.9
33.3
33.3
27.8
44.4
33.3
32.3
22.6
41.9
32.3
32.3
25.8
12.9
16.1
35.5
25.8
38.7
35.5
9.7
22.6
29.0
22.6
48.4
35.5
61.3
29.0
29.0
19.4
77.4
48.4
32.3
32.1
22.6
27.3
20.8
13.6
27.3
40.9
32.1
18.2
66.0
36.4
35.8
13.6
18.2
22.7
22.7
24.5
22.6
22.6
22.6
11
12
13
14
15
16
18
24
25
27
28
29
30
31
33
28.2
53.4
15.1
21.9
23.3
Gossypol acetic acid
Gossypol
a
b
c
d
e
f
A.S., Alternaria solani.
F.G., Fusarium graminearum.
P.C., Phytophthora capsici.
S.S., Sclerotinia sclerotiorum.
R.S., Rhizoctonia solani.
C.H., Cercospora arachidicola Hori.
P.P., Physalospora piricola.
F.M., Fusarium moniliforme.
R.C., Rhizoctonia cerealis.
g
h
i
4
4
. Materials and methods
.1. Chemistry
white slurry was filtered, and the cake was recrystallized with
ethanol and water to afford M-3 (1.95 g, 9.74 mmol). Yield:
1
82.6%; H NMR (400 MHz, CDCl
3
) d 7.92–7.86 (m, 2H), 7.80–7.74
(
m, 2H), 4.02 (t, J = 6.9 Hz, 2H), 2.82 (t, J = 6.9 Hz, 2H).
To a solution of M-3 (0.80 g, 4.00 mmol) in ethanol (30 mL),
General: Reagents were purchased from commercial sources
and were used as received. Reaction progress was monitored by
thin-layer chromatography on silica gel GF-254 with detection by
UV. Melting points were determined on an X-4 binocular micro-
scope melting point apparatus (Beijing Tech Instruments Co.,
hydrazine hydrate (80%, 0.30 g, 4.80 mmol) was added. After
refluxed for 7 h, a white precipitate formed that was removed by
filtration. The filtrate was evaporated to dryness and added to
water (100 mL). The aqueous suspension was acidified with conc.
HCl, and residual insoluble material was filtered off. The clear fil-
1
13
Beijing, China) and are uncorrected. H NMR and C NMR spectra
were recorded on a Bruker Ascend 300/400 MHz spectrometer.
Chemical shift values (d) are given in ppm and downfield from
internal tetramethylsilane. High-resolution mass spectra (HRMS)
were recorded on FT-ICR MS (Ionspec, 7.0 T).
trate was evaporated to give amine-17 (0.42 g, 3.91 mmol). Yield:
1
97.7%; H NMR (400 MHz, D
2
O) d 3.25 (t, J = 6.8 Hz, 2H), 2.85
O) d 117.58, 35.22, 15.74.
1
3
(t, J = 6.8 Hz, 2H); C NMR (100 MHz, D
2
To M-2 (4.00 g, 15.74 mmol), triethyl phosphite (26.16 g,
27.5 mL, 160.00 mmol) was added. After refluxed for 20 h, excess
triethyl phosphite was removed from the reaction mixture under
reduced pressure. The residue was recrystallized with diethyl
ether and n-hexane (20 mL, v/v = 30:1) to obtain M-4 (4.60 g,
Synthesis of amine-17 and amine-22.
To phthalimide potassium (10.00 g, 54.00 mmol) in DMF
(
50 mL), 1,2-dibromoethane (30.45 g, 14 mL, 162.00 mmol) was
added. After stirred at room temperature for 24 h, H O (300 mL)
and CH Cl (100 mL) were added. The aqueous phase was sepa-
rated and extracted with CH Cl
(150 mL ꢁ 2). The organic layer
was washed with brine, dried over anhydrous MgSO , and concen-
2
1
14.78 mmol) as a yellow solid. Yield: 93.9%; H NMR (400 MHz,
2
2
3
CDCl ) d 7.85–7.80 (m, 2H), 7.74–7.68 (m, 2H), 4.17–4.03 (m,
2
2
4H), 3.99–3.90 (m, 2H), 2.26–2.14 (m, 2H), 1.31–1.25 (m, 6H).
To a solution of M-4 (1.50 g, 4.82 mmol) in ethanol (30 mL),
hydrazine hydrate (80%, 0.36 g, 5.78 mmol) was added. After
refluxed for 5.5 h, a white precipitate formed that was removed
by filtration. The filtrate was evaporated to dryness and added to
water (100 mL). The aqueous suspension was acidified with conc.
HCl, and residual insoluble material was filtered off. The clear
4
trated under reduced pressure. The residue was purified by column
chromatography on silica gel and eluted with petroleum ether
(
(
7
(
60ꢂ90 °C) and ethyl acetate to give M-2 as a white solid
12.20 g, 48.02 mmol). Yield: 88.9%; 1H NMR (300 MHz, CDCl
) d
.92–7.84 (m, 1H), 7.79–7.70 (m, 1H), 4.12 (t, J = 6.7 Hz, 1H), 3.62
3
t, J = 6.7 Hz, 1H).
To a solution of M-2 (3.00 g, 11.81 mmol) in DMSO (20 mL),
NaCN (0.58 g, 11.81 mmol) was added. The resulting solution was
filtrate was evaporated to get amine-22 (0.88 g, 4.04 mmol), yield:
1
83.9%; H NMR (300 MHz, D
2
O) d 4.16–4.00 (m, 4H), 3.23–3.10
heated at 65 °C for 7 h, then poured into ice water (100 mL). The
(m, 2H), 2.32–2.14 (m, 2H), 1.23 (t, J = 7.1 Hz, 6H).
Please cite this article in press as: Li, L.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.08.015

L. Li et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
7
Synthesis of amine-19 and amine-20.
the residue was taken into H
2
O (20 mL) and EtOAc (30 mL), and
After the mixture of taurine (21.00 g, 167.66 mmol), potassium
acetate (18.10 g, 148.43 mmol) and acetic acid (70 mL) were
refluxed for 10 min, phthalic anhydride (27.32 g, 184.44 mmol)
was added. The resulting solution continued to reflux for 3.5 h.
After cooling, the reaction slurry was filtered, and washed with
ethanol to obtain M-6 as a white solid.
extracted with EtOAc (30 mL ꢁ 2). The organic layer was washed
with brine, dried over anhydrous MgSO , and concentrated under
4
reduced pressure to give the desired gossypol derivatives.
Data for 1: General procedure A; light yellow solids; yield,
1
95.7%; mp, 258–259 °C; H NMR (400 MHz, DMSO-d
6
) d 13.04
(dd, J = 13.0, 4.6 Hz, 2H), 9.73 (d, J = 13.0 Hz, 2H), 8.39 (s, 2H),
After the solution of M-6 (5.00 g, 17.05 mmol) in toluene
7.84 (s, 2H), 7.45 (s, 2H), 3.75–3.66 (m, 2H), 3.27 (d, J = 4.6 Hz,
1
3
(
(
25 mL) was heated to reflux under an argon atmosphere, PCl
6.40 g, 30.74 mmol) was added in batches within 1 h. After contin-
5
6H), 1.93 (s, 6H), 1.43 (t, J = 6.4 Hz, 12H); C NMR (100 MHz,
DMSO-d ) d 171.47, 163.60, 149.58, 146.22, 131.07, 126.74,
126.13, 119.96, 116.44, 115.81, 103.08, 36.84, 26.46, 20.34, 20.31,
6
ued to reflux for 2 h, toluene was evaporated in vacuo. The residue
+
was taken into ice water (80 mL) and filtered to give M-7 as a white
20.17; HRMS (ESI) calcd for C32
545.2645.
37 2 6
H N O (M+H) 545.2646, found
1
solid. Yield: 77.5%; H NMR (400 MHz, CDCl
3
) d 7.92–7.87 (m, 2H),
7
.80–7.74 (m, 2H), 4.37 (t, J = 6.5 Hz, 2H), 4.09 (t, J = 6.5 Hz, 2H).
To stirred mixture of dimethylamine hydrochloride
3.42 g, 41.91 mmol) and CH Cl (130 mL), Et N (9.7 mL, 7.07 g,
9.85 mmol) was added in batches. After 10 min, M-7 was added
in portion and then stirred for 5 h at room temperature. 2 M HCl
60 mL) was added and extracted with CH Cl
(100 mL ꢁ 2). The
organic layer was washed with brine, dried over anhydrous MgSO
Data for 2: General procedure A; yellow solids; yield, 96.1%; mp,
240–241 °C; H NMR (400 MHz, CDCl ) d 13.38–13.35 (m, 2H), 9.64
3
(d, J = 12.7 Hz, 2H), 8.01 (s, 2H), 7.60 (s, 2H), 5.57 (s, 2 H), 3.71–3.75
1
a
(
6
2
2
3
(m, 2H), 3.52–3.43 (m, 4H), 2.12 (s, 6H), 1.69–1.78 (m, 4H), 1.50–
1
3
3
1.55 (m, 12H), 1.00 (t, J = 7.2 Hz, 6H); C NMR (100 MHz, CDCl )
(
2
2
d 172.44, 163.03, 148.91, 147.19, 131.70, 128.89, 127.15, 118.16,
4
,
115.63, 114.72, 103.02, 52.50, 27.42, 23.91, 20.40, 20.34, 20.07,
+
and concentrated under reduced pressure. The residue was puri-
fied by column chromatography on silica gel to give M-8 as a white
solid (2.16 g, 7.65 mmol). Yield: 54.8%; H NMR (400 MHz, CDCl
11.14; HRMS (ESI) calcd for C36
601.3271.
H
45
N
2
O
6
(M+H) 601.3272, found
1
3
) d
Data for 3: General procedure A; light yellow solids; yield,
1
3
1
7
.90–7.84 (m, 2H), 7.77–7.72 (m, 2H), 4.17–4.12 (m, 2H), 3.37–3.32
3
89.6%; mp, 234–235 °C (lit. 223 °C); H NMR (400 MHz, CDCl )
(
m, 2H), 2.91 (s, 6H).
d 13.41–13.31 (m, 2H), 9.64 (d, J = 12.8 Hz, 2H), 8.01 (s, 2H), 7.60
(s, 2H), 5.59 (s, 2H), 3.74–3.71 (m, 2H), 3.49 (q, J = 6.5 Hz, 4H),
2.11 (s, 6H), 1.72–1.65 (m, 4H), 1.56–1.51 (m, 12H), 1.47–1.38
Amine-19 was synthesized as the same procedure of amine-17.
1
Yield: 90.3%; H NMR (400 MHz, D
2
O) d 3.45–3.40 (m, 4H), 2.82
1
3
(
s, 6H).
(m, 4H), 0.94 (t, J = 7.3 Hz, 6H);
3
C NMR (100 MHz, CDCl )
To the solution of ammonia in dioxane (50 mL), M-7 (2.00 g,
d 172.40, 162.99, 148.92, 147.20, 131.71, 128.88, 127.15, 118.16,
7
.31 mmol) was added. After stirred at room temperature for 5 h,
115.65, 114.72, 103.04, 50.56, 32.58, 27.43, 20.41, 20.35, 20.10,
19.78, 13.61; HRMS (ESI) calcd for C38
found 629.3586.
2
O (100 mL) was added. The aqueous phase was separated and
extracted with EtOAc (100 mL ꢁ 2). The organic layer was washed
with brine, dried over anhydrous MgSO , and concentrated under
reduced pressure to give M-9 (1.10 g, 4.33 mmol) as a white solid.
49 2 6
H N O
(M+H)+ 629.3585,
H
4
Data for 4: General procedure A; light yellow solids; yield,
1
3
1
3
89.6%; mp, 234–235 °C (lit. 201 °C); H NMR (400 MHz, CDCl )
1
Yield: 54.8%; H NMR (400 MHz, DMSO-d
.05 (s, 2H), 4.00–3.93 (m, 2H), 3.37–3.30 (m, 2H).
Amine-20 was synthesized as the same procedure of amine-17.
6
) d 7.91–7.81 (m, 4H),
d 13.40–13.31 (m, 2H), 9.63 (d, J = 12.7 Hz, 2H), 8.01 (s, 2H), 7.59
(s, 2H), 5.58 (s, 2H), 3.77–3.69 (m, 2H), 3.48 (dd, J = 12.4, 6.2 Hz,
7
4H), 2.11 (s, 6H), 1.74–1.65 (m, 4H), 1.56–1.51 (m, 12H), 1.42–
1
13
Yield: 49.3%; H NMR (400 MHz, D
2
O) d 3.51 (t, J = 6.3 Hz, 1H), 3.40
3
1.27 (m, 12H), 0.90–0.84 (m, 6H); C NMR (100 MHz, CDCl )
1
3
(
t, J = 6.3 Hz, 1H); C NMR (100 MHz, D O) d 51.00, 34.28.
2
d 172.39, 162.96, 148.93, 147.21, 131.70, 128.87, 127.13, 118.15,
Synthesis of the target compounds 1–33.
115.65, 114.72, 103.04, 50.90, 31.31, 30.58, 27.43, 26.26, 22.47,
General procedure A: A solution of gossypol acetic acid (0.50 g,
.86 mmol), amine (1.73 mmol) and ethanol (50 mL) was stirred
20.41, 20.36, 20.09, 14.00; HRMS (ESI) calcd for C42
+H) 685.4211, found 685.4218.
H
57
N
2
O
6
(M
+
0
and heated to reflux for 5 h, and then the reaction mixture was
cooled to room temperature. The resulting solid was filtered,
washed with ethanol, recrystallized with pyridine and ethanol or
chloroform and ethanol to give the desired gossypol derivatives.
General procedure B: A mixture of amine (1.73 mmol), NaOH
Data for 5: General procedure A; light yellow solids; yield,
80.3%; mp, 159–160 °C; H NMR (400 MHz, CDCl ) d 13.39–13.31
3
1
(m, 2H), 9.63 (d, J = 12.8 Hz, 2H), 8.01 (s, 2H), 7.59 (s, 2H), 5.58
(s, 2H), 3.77–3.69 (m, 2H), 3.47 (q, J = 6.8 Hz, 4H), 2.11 (s, 2H),
1.73–1.65 (m, 4H), 1.55–1.51 (m, 12H), 1.40–1.21 (m, 36H), 0.87
1
3
(
0.10 g, 2.59 mmol) and ethanol (50 mL) was stirred and heated
3
(t, J = 6.8 Hz, 6H); C NMR (100 MHz, CDCl ) d 172.39, 162.96,
to reflux for 1 h. Then gossypol acetic acid (0.50 g, 0.86 mmol)
was added and the reaction liquid continued to reflux for 5 h.
The reaction mixture was cooled to room temperature and then
the resulting solid was filtered, washed with ethanol and then
recrystallized with isopropanol and methanol to give the desired
gossypol derivatives.
148.92, 147.20, 131.69, 128.88, 127.13, 118.16, 115.63, 114.72,
103.03, 50.92, 31.92, 30.62, 29.61, 29.55, 29.43, 29.34, 29.16,
27.44, 26.60, 22.70, 20.41, 20.36, 20.10, 14.14; HRMS (ESI) calcd
+
for C54
H
81
N
2
O
6
(M+H) 853.6089, found 853.6073.
Data for 6: General procedure A; brown solids; yield, 92.3%; mp,
1
3
182–183 °C; H NMR (400 MHz, CDCl ) d 13.40–13.35 (m, 2H), 9.71
General procedure C:
1.73 mmol), NaOH (0.10 g, 2.59 mmol) and ethanol (50 mL) was
stirred and heated to reflux for 1 h. Then gossypol acetic acid
0.50 g, 0.86 mmol) was added and the reaction liquid continued
A
mixture of amine hydrochloride
(d, J = 12.9 Hz, 2H), 8.00 (s, 2H), 7.60 (s, 2 H), 5.57 (s, 2H), 3.70–3.75
(
(m, 4H), 2.12 (s, 6H), 1.53 (d, J = 5.7 Hz, 12H), 1.37 (d, J = 6.1 Hz,
1
3
12H);
3
C NMR (100 MHz, CDCl ) d 172.21, 160.77, 148.87,
(
147.20, 131.67, 128.89, 127.16, 118.17, 115.63, 114.78, 102.89,
to reflux for 5 h. The reaction mixture was cooled to room temper-
ature and then the resulting solid was filtered, washed with
ethanol and then recrystallized with pyridine and ethanol or
chloroform and ethanol to give the desired gossypol derivatives.
General procedure D: A mixture of gossypol acetic acid (0.50 g,
52.05, 27.43, 23.39, 20.39, 20.35, 20.09; HRMS (ESI) calcd for
+
C
36
45
H N
2
O
6
(M+H) 601.3272, found 601.3272.
Data for 7: General procedure A; brown solids; yield, 96.6%; mp,
1
3
214–216 °C; H NMR (400 MHz, CDCl ) d 13.48–13.36 (m, 2H), 9.70
(d, J = 13.0 Hz, 2H), 8.02 (s, 2H), 7.59 (s, 2H), 5.58 (s, 2H), 3.75–3.71
(m, 2H), 3.40–3.32 (m, 2H), 2.12 (s, 6H), 2.09–2.01 (m, 4H), 1.83–
1.81 (m, 4H), 1.57–1.49 (m, 16H), 1.40–1.25 (m, 8H); 13C NMR
0
.86 mmol), hydroxylamine hydrochloride (0.18 g, 2.59 mmol),
sodium acetate (0.28 g, 3.45 mmol) and ethanol (50 mL) was stir-
red at room temperature for 2 h. After ethanol evaporated in vacuo,
3
(100 MHz, CDCl ) d 172.14, 160.88, 148.87, 147.23, 131.61,
Please cite this article in press as: Li, L.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.08.015

8
L. Li et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
1
2
28.87, 128.35, 127.09, 115.61, 114.81, 103.01, 59.07, 33.61, 27.41,
5.09, 24.38, 20.40, 20.35, 20.08; HRMS (ESI) calcd for C42
Data for 15: General procedure A; yellow solids; yield, 92.3%;
1
54
H N
2
O
6
3
mp, 229–231 °C; H NMR (400 MHz, CD OD) d 9.90 (s, 2H), 7.59
+
(
M+H) 681.3898, found 681.3898.
Data for 8: General procedure A; yellow solids; yield, 71.7%; mp,
(s, 2H), 3.76–3.81 (m, 6H), 3.64–3.69 (m, 4H), 2.06 (s, 6H), 1.55–
1
3
3
1.50 (m, 12H); C NMR (100 MHz, CDCl ) d 172.63, 163.61,
1
3
1
2
69–271 °C (lit. 270 °C); H NMR (400 MHz, CDCl
3
) d 13.65
148.83, 146.96, 131.85, 128.86, 127.56, 118.07, 115.70, 114.51,
(
d, J = 13.3 Hz, 2H), 9.81 (d, J = 13.3 Hz, 2H), 8.04 (s, 2H), 7.61 (s,
103.28, 61.61, 52.61, 27.31, 20.23, 20.18, 19.93; HRMS (ESI) calcd
+
2
1
1
1
H), 5.59 (s, 2H), 3.95–3.56 (m, 2H), 2.12 (s, 6H), 1.56–1.51(m,
for C34
H
41
N
2
O
8
(M+H) 605.2858, found 605.2856.
2H), 1.44 (s, 18H); 1 C NMR (100 MHz, CDCl
3
Data for 16: General procedure A; orange solids; yield, 84.9%;
3
) d 171.96, 158.91,
1
3
1
48.86, 147.29, 131.58, 128.89, 127.03, 118.17, 115.60, 114.91,
3
mp, 249 °C dec (lit. 256 °C); H NMR (400 MHz, CDCl ) d 13.47–
02.84, 54.40, 29.80, 27.44, 20.41, 20.36, 20.13; HRMS (ESI) calcd
13.35 (s, 2H), 9.65 (d, J = 12.1 Hz, 2H), 7.94 (s, 2H), 7.60 (s, 2H),
+
for C38
H
49
N
2
O
6
(M+H) 629.3585, found 629.3598.
5.59 (s, 2H), 3.80–3.61 (m, 6H), 2.81 (dd, J = 14.8, 6.4 Hz, 4H),
1
3
Data for 9: General procedure A; yellow solids; yield, 74.2%; mp,
3
2.12 (s, 6H), 1.55–1.52 (m, 12H); C NMR (100 MHz, CDCl ) d
1
2
56–258 °C; H NMR (400 MHz, CDCl
3
) d 13.36–13.18 (m, 2H), 9.64
173.18, 163.07, 149.00, 147.10, 132.05, 129.13, 127.74, 118.31,
(
d, J = 5.2 Hz, 2H), 7.60 (s, 2H), 5.95–5.92 (m, 2H), 5.56 (s, 2H),
115.82, 114.57, 103.37, 53.59, 27.46, 25.56, 20.36, 20.31, 20.07;
+
5
2
1
1
2
5
.36–5.26 (m, 4H), 4.11 (d, J = 4.2 Hz, 4H), 3.79–3.69 (m, 2H),
.11 (s, 6H), 1.56–1.50 (m, 12H); 13C NMR (100 MHz, CDCl
) d
HRMS (ESI) calcd for C34
637.2390.
41
H N
2
O
S
6 2
(M+H) 637.2401, found
3
72.92, 163.04, 148.94, 147.14, 132.66, 131.90, 129.01, 127.45,
Data for 17: General procedure C; light yellow solids; yield,
1
18.47, 118.22, 115.73, 114.62, 103.39, 52.53, 27.44, 20.38, 20.33,
3
53.1%; mp, 231–233 °C; H NMR (400 MHz, CDCl ) d 13.49 (s,
ꢂ
0.08; HRMS (ESI) calcd for C36
95.2816.
H
39
N
2
O
6
(MꢂH) 595.2814, found
2H), 9.67 (s, 2H), 7.78 (s, 2H), 7.59 (s, 2H), 5.66 (s, 2H), 3.80–3.66
(m, 6H), 2.74 (t, J = 6.5 Hz, 4H), 2.11 (s, 6H), 1.54–1.50 (m, 12H);
1
3
Data for 10: General procedure A; yellow solids; yield, 71.0%;
3
C NMR (100 MHz, CDCl ) d 173.82, 162.79, 149.11, 146.85,
1
mp, 240–242 °C; H NMR (400 MHz, CDCl
3
) d 13.62–13.48 (m,
H), 9.84 (d, J = 5.6 Hz, 2H), 7.90 (s, 2H), 7.60 (s, 2H), 5.60 (s, 2H),
.30 (s, 4H), 3.77–3.67 (m, 2H), 2.48 (s, 2H), 2.11 (s, 6H), 1.55–
132.52, 129.33, 128.52, 118.42, 116.56, 116.09, 114.30, 103.98,
2
4
1
1
1
46.20, 27.49, 20.31, 20.27, 20.07; HRMS (ESI) calcd for
ꢂ
C
36
H
37
N
4
O
6
(MꢂH) 621.2705, found 621.2708.
1
3
.51 (m, 12H); C NMR (100 MHz, CDCl
3
) d 173.19, 162.23,
Data for 18: General procedure B; brown solids; yield, 94.0%;
1
5
1
49.08, 147.01, 132.21, 129.15, 127.97, 118.27, 115.91, 114.50,
mp, >300 °C (lit.
6
300 °C); H NMR (400 MHz, DMSO-d ) d
03.78, 76.45, 75.80, 38.89, 27.48, 20.35, 20.31, 20.09; HRMS
13.07–12.95 (m, 2H), 10.03 (d, J = 11.2 Hz, 2H), 8.51 (s, 2H), 7.28
ꢂ
(
ESI) calcd for C36
H
35
N
2
O
6
(MꢂH) 591.2501, found 591.2515.
(s, 2H), 3.78 (d, J = 3.8 Hz, 4H), 3.72–3.62 (m, 2H), 2.82 (t,
13
Data for 11: General procedure A; yellow solids; yield, 93.3%;
J = 5.5 Hz, 4H), 1.95 (s, 6H), 1.46–1.41 (m, 12H);
(100 MHz, DMSO-d ) d 171.33, 161.82, 152.46, 146.34, 131.01,
126.79, 126.29, 121.87, 116.34, 114.78, 103.88, 50.73, 47.48,
C NMR
1
4
1
mp, 243–244 °C (lit. 241.5 °C); H NMR (400 MHz, CDCl
3.66–13.55 (m, 2H), 9.72 (d, J = 12.4 Hz, 2H), 7.95 (s, 2H), 7.59
s, 2H), 7.28–7.38 (m, 10H), 5.56 (s, 2H), 4.67 (d, J = 4.9 Hz, 4H),
.77–3.67 (m, 2H), 2.11 (s, 6H), 1.55–1.50 (m, 12H); 13C NMR
100 MHz, CDCl 173.04, 162.99, 148.98, 147.11, 136.23,
3
) d
6
1
(
3
(
1
1
C
26.54, 20.46, 20.37, 20.34; HRMS (ESI) calcd for C34
H
39
N
2
O
12
S
2
ꢂ
(Mꢂ2Na+H) 731.1950, found 731.1927.
3
)
d
Data for 19: General procedure C; yellow solids; yield, 61.0%;
1
31.97, 129.06, 128.24, 127.56, 127.36, 118.27, 115.76, 114.62,
3
mp, 235–237 °C; H NMR (400 MHz, CDCl ) d 13.47–13.37 (m,
03.43, 54.50, 27.44, 20.36, 20.31, 20.09; HRMS (ESI) calcd for
2H), 9.64 (d, J = 12.2 Hz, 2H), 7.89 (s, 2H), 7.59 (s, 2H), 5.61
(s, 2H), 3.95 (dd, J = 11.8, 6.5 Hz, 4H), 3.76–3.66 (m, 2H), 3.26
ꢂ
44
H
43
N
2
O
6
(MꢂH) 695.3127, found 695.3125.
Data for 12: General procedure A; yellow solids; yield, 71.2%;
(t, J = 6.5 Hz, 4H), 2.88 (s, 12H), 2.11 (s, 6H), 1.55–1.50 (m, 12H);
1
3
1
13
mp, 236–237 °C (lit.
251 °C); H NMR (400 MHz, CDCl
3
) d
3
C NMR (100 MHz, CDCl ) d 173.51, 162.80, 149.02, 146.96,
1
3.84–13.59 (m, 2H), 9.77 (d, J = 12.4 Hz, 2H), 8.60 (d, J = 4.4 Hz,
132.25, 129.22, 128.09, 118.37, 115.97, 114.40, 103.70, 48.57,
2
H), 7.96 (s, 2H), 7.69 (t, J = 7.7 Hz, 2H), 7.59 (s, 2H), 7.30 (d,
45.17, 37.28, 27.45, 20.34, 20.29, 20.07; HRMS (ESI) calcd for
ꢂ
J = 8.0 Hz, 2H), 7.25–7.20 (m, 2H), 5.60 (s, 2H), 4.79 (d, J = 5.2 Hz,
4
NMR (100 MHz, CDCl
C
38
H
49
N
4
O
10
S
2
(MꢂH) 785.2896, found 785.2873.
1
3
H), 3.76–3.68 (m, 2H), 2.11 (s, 3H), 1.54–1.51 (m, 12H);
C
Data for 20: General procedure C; brown solids; yield, 66.7%;
1
3
) d 173.27, 163.26, 155.86, 149.95, 149.00,
6
mp, 250–252 °C; H NMR (400 MHz, DMSO-d ) d 13.08–12.98 (m,
1
1
47.11, 137.16, 136.31, 132.01, 127.65, 122.96, 121.37, 118.33,
15.81, 114.62, 103.65, 55.85, 27.43, 20.34, 20.29, 20.08; HRMS
2H), 9.72 (d, J = 12.5 Hz, 2H), 8.40 (s, 2H), 7.88 (s, 2H), 7.43 (s,
2H), 7.08 (s, 4H), 3.91 (dd, J = 11.7, 5.8 Hz, 4H), 3.69 (dt, J = 13.1,
6.7 Hz, 2H), 3.43–3.36 (m, 4H), 1.93 (s, 6H), 1.45–1.41 (m, 12H);
+
(
ESI) calcd for C42
43 4 6
H N O (M+H) 699.3177, found 699.3168.
1
3
Data for 13: General procedure A; yellow solids; yield, 72.3%;
C NMR (100 MHz, DMSO-d
6
) d 172.71, 162.75, 150.02, 146.71,
1
3
1
mp, 273 °C (lit. 248 °C); H NMR (400 MHz, CDCl
3
) d 13.69–
131.74, 127.41, 127.10, 121.12, 117.08, 116.51, 103.78, 55.03,
1
7
5
6
1
1
2
3.57 (m, 2H), 9.72 (d, J = 12.1 Hz, 2H), 8.56 (s, 4H), 7.87 (s, 2H),
46.02, 26.97, 20.80, 20.77, 20.69; HRMS (ESI) calcd for C34
H
41
N
4
-
ꢂ
.64 (d, J = 7.7 Hz, 2H), 7.59 (s, 2H), 7.30 (dd, J = 7.7, 5.0 Hz, 2H),
.67 (s, 2H), 4.67 (d, J = 4.9 Hz, 2H), 3.85–3.64 (m, 2H), 2.11 (s,
O
10
S
2
(MꢂH) 729.2270, found 729.2227.
Data for 21: General procedure C; yellow solids; yield, 86.8%;
H), 1.55–1.48 (m, 12H); 13C NMR (100 MHz, CDCl
) d 173.42,
1
3
3
mp, 234–236 °C; H NMR (400 MHz, CDCl ) d 13.54–13.43 (m,
62.84, 149.72, 149.03, 148.87, 146.96, 135.08, 132.23, 131.93,
29.16, 128.01, 123.86, 118.33, 115.98, 114.43, 103.73, 51.72,
7.45, 20.32, 20.27, 20.08.
2H), 9.66 (d, J = 11.4 Hz, 2H), 7.82 (s, 2H), 7.59 (s, 2H), 5.63 (s,
2H), 4.06–3.99 (m, 4H), 3.76–3.66 (m, 2H), 3.40 (t, J = 6.1 Hz, 4H),
13
2.96 (s, 6H), 2.11 (s, 6H), 1.54–1.49 (m, 12H);
C NMR
Data for 14: General procedure A; light yellow solids; yield,
(100 MHz, CDCl 173.71, 162.92, 149.07, 146.87, 132.48,
129.28, 128.49, 118.42, 116.09, 114.28, 103.87, 54.83,
3
) d
1
9
1
7
6
1
2.2%; mp, 260–262 °C; H NMR (400 MHz, DMSO-d
6
) d 13.34–
3.23 (m, 2H), 9.74 (d, J = 12.8 Hz, 2H), 8.43 (s, 2H), 7.82 (s, 2H),
.44 (s, 2H), 4.06–4.00 (m, 2H), 3.81–3.74 (m, 2H), 3.72–3.61 (m,
H), 3.55–3.43 (m, 2H), 2.01–1.91 (m, 8H), 1.85–1.77 (m, 4H),
44.34, 42.52, 27.46, 20.30, 20.26, 20.09; HRMS (ESI) calcd for
ꢂ
C
36
H
43
N
2
O
10
S
2
(MꢂH) 727.2365, found 727.2337.
Data for 22: General procedure C; brown solids; yield, 42.6%;
.63–1.51 (m, 2H), 1.46–1.40 (m, 12H); 13C NMR (100 MHz, CDCl
)
1
3
3
mp, 113–115 °C; H NMR (400 MHz, CDCl ) d 13.41–13.29 (m,
d 172.80, 163.64, 148.98, 147.19, 131.81, 128.94, 127.25, 118.13,
2H), 9.62 (d, J = 10.5 Hz, 2H), 7.96 (s, 2H), 7.58 (s, 2H), 5.60 (s,
1
2
C
15.70, 114.71, 103.29, 77.45, 77.42, 68.70, 68.68, 54.42,
2H), 4.17–4.05 (m, 8H), 3.82–3.65 (m, 6H), 2.23–2.04 (m, 10H),
1
3
8.65, 27.41, 25.91, 20.39, 20.33, 20.09; HRMS (ESI) calcd for
1.55–1.50 (m, 12H), 1.31 (t, J = 7.1 Hz, 12H); C NMR (100 MHz,
CDCl ) d 173.13, 162.57, 148.94, 147.05, 131.96, 129.09, 127.59,
+
40
49
H N
2
O
8
(M+H) 685.3483, found 685.3489.
3
Please cite this article in press as: Li, L.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.08.015

L. Li et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
9
1
2
18.27, 115.80, 114.55, 103.30, 62.16, 62.10, 45.09, 45.06, 28.34,
31.18, 27.77, 20.60, 20.56, 20.32; HRMS (ESI) calcd for
+
7.44, 26.94, 20.36, 20.31, 20.04, 16.44, 16.38; HRMS (ESI) calcd
C
38
51
H N
4
O
6
(M+H) 659.3803, found 659.3803.
ꢂ
for C42
H
57
N
2
O
12
P
2
(MꢂH) 843.3392, found 843.3384.
Data for 31: General procedure B; brown solids; yield, 92.2%;
1
Data for 23: General procedure A; orange solids; yield, 69.2%;
3
mp, 253–254 °C; H NMR (400 MHz, CDCl ) d 14.60 (s, 2H), 9.67
1
mp, 258–260 °C; H NMR (400 MHz, DMSO-d
6
) d 13.23–13.14 (m,
(s, 2H), 7.64 (s, 2H), 7.30 (s, 2H), 5.59 (s, 2H), 3.84–3.77 (m, 2H),
2
2
3
H), 9.76 (d, J = 12.9 Hz, 2H), 9.23 (s, 2H), 8.39 (s, 2H), 7.82 (s,
3.02–2.98 (m, 8H), 2.12 (s, 6H), 1.74–1.68 (m, 8H), 1.55–1.52 (m,
12H), 1.50–1.46 (m, 4H); C NMR (100 MHz, CDCl ) d 161.00,
3
152.95, 149.66, 145.70, 132.00, 129.49, 126.64, 117.80, 114.76,
1
3
H), 7.42 (s, 2H), 7.05 (d, J = 8.4 Hz, 4H), 6.67 (d, J = 8.4 Hz, 4H),
.76–3.65 (m, 6H), 2.84 (t, J = 7.0 Hz, 4H), 1.92 (s, 6H), 1.47–1.38
1
3
(
m, 12H);
C
NMR (100 MHz, DMSO-d
6
)
d 171.71, 162.29,
114.61, 104.84, 55.50, 27.35, 25.04, 23.41, 20.54, 20.49, 20.23;
+
1
1
2
55.87, 149.74, 146.20, 131.11, 129.63, 128.03, 126.77, 126.33,
HRMS (ESI) calcd for
683.3795.
C
H
40 51
N
4
O
6
(M+H) 683.3803, found
20.14, 116.40, 115.82, 115.25, 103.13, 51.63, 35.40, 26.47, 20.33,
ꢂ
0.29, 20.18; HRMS (ESI) calcd for C46
H
47
N
2
O
8
(MꢂH) 755.3338,
Data for 32: General procedure A; yellow solids; yield, 66.7%;
1
found 755.3341.
Data for 24: General procedure A; yellow solids; yield, 82.5%;
3
mp, 192–193 °C; H NMR (400 MHz, CDCl ) d 13.83 (s, 2H), 9.64
(s, 2H), 7.75 (s, 2H), 7.35–7.29 (m, 6H), 7.00–6.90 (m, 6H), 6.60
1
6
1
mp, 245–247 °C (lit. 205–210 °C dec.); H NMR (400 MHz, CDCl
d 13.47–13.35 (m, 2H), 9.57 (d, J = 11.2 Hz, 2H), 7.91 (s, 2H), 7.58 (s,
H), 5.58 (s, 2H), 4.24 (s, 4H), 3.80 (s, 6H), 3.74–3.66 (m, 2H), 2.10
s, 6H), 1.54–1.50 (m, 12H); 13C NMR (100 MHz, CDCl
) d 173.85,
3
)
(s, 2H), 5.63 (s, 2H), 4.00–3.85 (m, 2H), 2.14 (s, 6H), 1.62–1.55
1
3
(m, 12H); C NMR (75 MHz, DMSO) d 151.08, 147.35, 145.19,
2
(
1
1
144.59, 143.69, 132.49, 129.38, 128.87, 126.05, 118.94, 118.11,
3
115.73, 115.67, 111.39, 108.63, 26.51, 20.67, 20.55; HRMS (ESI)
+
68.54, 163.15, 149.05, 147.01, 132.30, 129.28, 128.08, 118.32,
calcd for C42
H
43
N
4
O
6
(M+H) 699.3177, found 699.3180.
16.00, 114.44, 104.00, 52.85, 50.90, 27.45, 20.31, 20.27, 20.05;
Data for 33: General procedure A; purple solids; yield, 97.2%;
+
1
HRMS (ESI) calcd for C36
H
41
N
2
O
10 (M+H) 661.2756, found 661.2750.
3
mp, 190–192 °C; H NMR (400 MHz, CDCl ) d 13.08 (s, 2H), 9.65
Data for 25: General procedure B; brown solids; yield, 87.2%;
(s, 2H), 7.76 (d, J = 7.8 Hz, 4H), 7.68 (s, 2H), 7.56 (s, 2H), 7.28 (d,
J = 7.8 Hz, 4H), 6.55 (s, 2H), 5.51 (s, 2H), 3.87–3.81 (m, 2H), 2.39
1
mp, >300 °C; H NMR (400 MHz, DMSO-d
6
) d 13.01 (s, 2H), 9.78
(
s, 2H), 8.47 (s, 2H), 7.34 (s, 2H), 3.87 (s, 4H), 3.72–3.63 (m, 2H),
(s, 6H), 2.05 (s, 6H), 1.54–1.50 (m, 12H); HRMS (ESI) calcd for
.93 (s, 6H), 1.48–1.37 (m, 12H); 13C NMR (100 MHz, DMSO-d
C
44
S
2
(M+H) 855.2728, found 855.2728.
+
1
1
1
C
6
) d
47
H N
4
O
10
71.33, 170.48, 161.81, 146.76, 131.17, 126.74, 126.15, 122.07,
17.16, 116.04, 103.85, 53.96, 26.97, 20.87; HRMS (ESI) calcd for
4.2. Biological assay
ꢂ
34
H
33
N
2
Na
2
O
6
(MꢂH) 675.1936, found 675.1951.
Data for 26: General procedure B; brown solids; yield, 92.3%;
The anti-TMV, insecticidal and fungicidal activities of the
compounds have been performed using our previous reported
1
mp, >300 °C; H NMR (400 MHz, DMSO-d
H), 9.71 (d, J = 12.6 Hz, 2H), 8.43 (s, 2H), 7.41 (s, 2H), 4.19 (d,
J = 5.9 Hz, 4H), 3.73–3.64 (m, 2H), 1.92 (s, 6H), 1.46–1.39 (m,
6
) d 13.43–13.32 (m,
1
9–21
2
methods.
The field trials of antiviral efficacy against TMV were
carried out between June and July in 2014. 1% microemulsion (ME)
of compound 26 was prepared in our research group. It was diluted
to 750 L/ha before used.
The rat oral gavage acute toxicity of pesticides was performed
in Xu He (Tianjin) Pharmaceutical Technology Co., Ltd. in August,
2014. Eight rats with half males and half females were divided
randomly into 2 groups. The sample was respectively configured
to 5 mg/mL and 50 mg/mL.
1
3
1
1
6
C
6
2H); C NMR (100 MHz, DMSO-d ) d 172.30, 162.81, 146.22,
43.82, 131.26, 126.90, 126.64, 120.28, 116.24, 115.79, 103.74,
5.61, 26.49, 20.31, 20.28, 20.21; HRMS (ESI) m/z calcd for
ꢂ
32
H
35
N
2
O
12
S
2
(Mꢂ2Na+H) 703.1637, found 703.1642.
Data for 27: General procedure D; brown solids; yield, 97.6%;
1
7
1
mp, 223–224 °C (lit. 225 °C); H NMR (400 MHz, DMSO-d
1
7
6
) d
2.54 (s, 2H), 11.27 (s, 2H), 9.84 (s, 2H), 8.71 (s, 2H), 8.08 (s, 2H),
1
3
.57 (s, 2H), 3.88 (s, 2H), 1.93 (s, 6H), 1.48–1.44 (m, 12H);
C
NMR (100 MHz, DMSO-d
6
) d 154.72, 151.37, 148.02, 144.07,
Acknowledgments
1
2
33.06, 129.46, 127.41, 118.37, 116.22, 116.00, 106.99, 27.05,
1.04, 20.96; HRMS (ESI) calcd for C30H N O (M+H) 549.2231,
33 2 8
+
We are grateful to the National Natural Science Foundation of
China (21132003, 21421062, 21372131) and the Specialized
Research Fund for the Doctoral Program of Higher Education
found 549.2219.
Data for 28: General procedure B; yellow solids; yield, 77.1%;
1
mp, 243–244 °C; H NMR (400 MHz, CDCl
3
) d 12.42 (s, 2H), 9.81
(
20120031110010) and ‘111’ Project of Ministry of Education of
(
s, 2H), 7.72 (s, 2H), 6.46 (s, 2H), 5.54 (s, 2H), 3.97 (s, 6H), 3.93–
China (B06005) for generous financial support for our programs.
1
3
3
(
.85 (m, 2H), 2.11 (s, 6H), 1.56–1.53 (m, 12H);
100 MHz, CDCl 154.21, 150.35, 147.56, 143.87, 132.84,
30.32, 127.68, 117.51, 114.67, 114.06, 105.88, 62.34, 27.41,
C NMR
3
) d
Supplementary data
1
2
5
+
0.59, 20.56, 20.35; HRMS (ESI) calcd for C32
77.2544, found 577.2545.
37 2 8
H N O (M+H)
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2015.08.015.
Data for 29: General procedure A; purple solids; yield, 93.6%;
1
8
1
mp, 293–295 °C (lit. 285 °C); H NMR (400 MHz, DMSO-d
6
) d
4.71 (s, 2H), 9.55 (s, 2H), 8.42 (s, 2H), 7.89 (s, 2H), 7.52 (s, 2H),
.57 (s, 4H), 3.86–3.80 (m, 2H), 1.94 (s, 6H), 1.47–1.43 (m, 12H);
1
References and notes
6
1
3
1.
2.
3.
Dubey, N. K.; Shukla, R.; Kumar, A.; Singh, P.; Prakash, B. Curr. Sci. 2010, 98, 479.
Guo, Z. Acta Pharm. Sinica 2012, 47, 144.
Dodou, K. Expert Opin. Inv. Drug 2005, 14, 1419.
C NMR (100 MHz, DMSO-d
6
) d 150.80, 150.57, 148.96, 143.90,
1
2
31.68, 128.11, 124.83, 117.64, 115.43, 115.41, 107.47, 26.46,
0.71, 20.50; HRMS (ESI) calcd for C32
+
H
37
N
2
O
8
(M+H) 547.2551,
4. Wang, X.; Howell, C. P.; Chen, F.; Yin, J.; Jiang, Y. Adv. Food Nutr. Res. 2009, 58,
found 547.2553.
Data for 30: General procedure A; purple solids; yield, 84.2%;
215.
5.
(a) Aggarwal, N.; Kumar, R.; Dureja, P.; Diwan, S.; Rawat, D. S. J. Agric. Food
Chem. 2009, 57, 8520; (b) Wang, B. L.; Shi, Y. X.; Ma, Y.; Liu, X. H.; Li, Y. H.; Song,
H. B.; Li, B. J.; Li, Z. M. J. Agric. Food Chem. 2010, 58, 5515.
1
mp, 249–251 °C; H NMR (400 MHz, CDCl
3
) d 14.55 (s, 2H), 9.57
(
s, 2H), 7.66 (s, 2H), 7.00 (s, 2H), 5.66 (s, 2H), 4.53 (s, 2H),
6. DeMilo, A. B.; Redfern, R. E. J. Agric. Food Chem. 1979, 27, 760.
7.
Sriram, D.; Yogeeswari, P.; Myneedu, N. S.; Saraswat, V. Bioorg. Med. Chem. Lett.
006, 16, 2127.
3
.86–3.82 (m, 2H), 2.10 (s, 6H), 1.56–1.53 (m, 12H), 1.22(s, 18H);
C NMR (100 MHz, CDCl
2
1
3
3
) d 154.03, 150.24, 145.32, 132.33,
8.
Ward, C. E.; Berthold, R. V.; Koerwer, J. F.; Tomlin, J. B.; Manning, D. T. J. Agric.
Food Chem. 1986, 34, 1005.
1
29.41, 126.53, 117.53, 116.27, 114.97, 114.49, 105.66, 54.42,
Please cite this article in press as: Li, L.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.08.015

1
0
L. Li et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
9
.
Przybylski, P.; Huczynski, A.; Pyta, K.; Brzezinski, B.; Bartl, F. Curr. Org. Chem.
009, 13, 124.
16. Alley, P. W.; Shirley, D. A. J. Am. Chem. Soc. 1959, 24, 1534.
17. Clark, E. P. J. Bid. Chem. 1927, 75, 725.
2
1
1
0. Li, L.; Li, Z.; Wang, K.; Zhao, S.; Feng, J.; Li, J.; Yang, P.; Liu, Y.; Wang, L.; Li, Y.;
Shang, H.; Wang, Q. J. Agric. Food Chem. 2014, 62, 11080.
1. Song, B.; Liu, X.; Yang, S.; Hu, D.; Jin, L.; Zhang, Y. Chin. J. Org. Chem. 2005, 25,
18. Karrer, P.; Tobler, E. Helv. Chim. Acta 1932, 15, 1204.
19. Wang, K. L.; Su, B.; Wang, Z. W.; Wu, M.; Li, Z.; Hu, Y. N.; Fan, Z. J.; Mi, N.; Wang,
Q. M. J. Agric. Food Chem. 2010, 58, 2703.
5
07.
20. Zhao, H. P.; Liu, Y. X.; Cui, Z. P.; Beattie, D.; Gu, Y. C.; Wang, Q. M. J. Agric. Food
Chem. 2011, 59, 11711.
1
1
2. Kang, S.; Hu, D.; Wu, J.; Song, B. Agrochemicals 2012, 51, 238.
3. Correa, O. G.; Cappi, H. M.; Salem, M.; Staffa, C. J. Am. Oil Chem. Soc. 1966, 43,
21. (a) Huang, W.; Zhao, P. L.; Liu, C. L.; Chen, Q.; Liu, Z. M.; Yang, G. F. J. Agric. Food
Chem. 2007, 55, 3004; (b) Zhao, P. L.; Wang, F.; Zhang, M. Z.; Liu, Z. M.; Huang,
W.; Yang, G. F. J. Agric. Food Chem. 2008, 56, 10767; (c) Chen, Q.; Zhu, X. L.;
Jiang, L. L.; Liu, Z. M.; Yang, G. F. Eur. J. Med. Chem. 2008, 43, 595.
6
78.
1
1
4. Shirley, D. A.; Sheehan, W. C. J. Org. Chem. 1956, 21, 251.
5. Baram, N. I.; Biktimirov, L.; Dzhurabekova, S. B.; Kamaev, F. G.; Ismailov, A. I.
Chem. Nat. Compd. 1991, 27, 309.
Please cite this article in press as: Li, L.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.08.015