Synthesis and insecticidal activity of novel hydrazone compounds derived from a naturally occurring lignan podophyllotoxin against Mythimna separata (Walker)

Article abstract of DOI:10.1016/j.bmcl.2014.04.074

In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, a series of novel hydrazone derivatives of podophyllotoxin, which is a naturally occurring aryltetralin lignan and isolated as the main secondary metabolite from the roots and rhizomes of Podophyllum species, were synthesized and evaluated as insecticidal agents against the pre-third-instar larvae of oriental armyworm, Mythimna separata (Walker) in vivo at 1 mg/mL. Especially compounds 8i, 8j, 8t, and 8u showed the more potent insecticidal activity with the final mortality rates greater than 60%.

Full text of DOI:10.1016/j.bmcl.2014.04.074

Bioorganic & Medicinal Chemistry Letters 24 (2014) 2621–2624
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and insecticidal activity of novel hydrazone compounds
derived from a naturally occurring lignan podophyllotoxin against
Mythimna separata (Walker)
Yi Wang a,b, Xiang Yu a, Xiaoyan Zhi a, Xiao Xiao a, Chun Yang a, Hui Xu a,
⇑
a Laboratory of Pharmaceutical Design & Synthesis, College of Sciences, Northwest A&F University, Yangling 712100, Shaanxi Province, People’s Republic of China
b College of Agriculture, Shanxi Agriculture University, Taigu 030801, Shanxi Province, 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:
In continuation of our program aimed at the discovery and development of natural-product-based insec-
ticidal agents, a series of novel hydrazone derivatives of podophyllotoxin, which is a naturally occurring
aryltetralin lignan and isolated as the main secondary metabolite from the roots and rhizomes of Podo-
phyllum species, were synthesized and evaluated as insecticidal agents against the pre-third-instar larvae
of oriental armyworm, Mythimna separata (Walker) in vivo at 1 mg/mL. Especially compounds 8i, 8j, 8t,
and 8u showed the more potent insecticidal activity with the final mortality rates greater than 60%.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 20 March 2014
Revised 18 April 2014
Accepted 19 April 2014
Available online 29 April 2014
Keywords:
Podophyllotoxin
Insecticidal activity
Botanical insecticide
Structural modification
Mythimna separata Walker
Nowadays, synthetic chemical insecticides have played an
important role in modern agricultural pest management, however,
repeat application of those agrochemicals over the years has led to
the development of resistance in insect pest populations and
environmental problems.1–3 On the other hand, as plant secondary
metabolites result from the interaction between plants and envi-
ronment (life and non-life) during the long period of evolution,
pesticides produced from plant secondary metabolites may result
in less or slower resistance development and lower pollution.4
Recently, the discovery of new pesticidal agents from plant second-
ary metabolites, or by using them as the lead compounds for
further structural modification, have been one of the important
procedures for research and development of new insecticides.5–10
Some pesticides from natural products such as nicotine, avermec-
tins, azadirachtin, pyrethrum and neem extracts are characteristic
examples as defenses against pests.11–13
Podophyllotoxin (1, Fig. 1), a naturally occurring aryltetralin lig-
nan, is isolated from the roots and rhizomes of Podophyllum hexan-
drum such as P. hexandrum and Podophyllum peltatum. Besides its
use as the lead compound for the preparation of potent anticancer
drugs such as etoposide, teniposide and etopophos,14–17 compound
1 has also received much research attention for its interesting
insecticidal and antifungal activities.18–23 More recently, we found
OH
5
6
4
11
3
O
10
O
9
A
B
8
C
D
O
7
2
1
1'
O
2'
3'
6'
E
5'
O
O
4'
O
1
Figure 1. The chemical structure of podophyllotoxin (1).
that introduction of hydrazone fragments into fraxinellone or
piperine could lead to more pronounced derivatives as compared
with toosendanin, a commercial botanical insecticide isolated from
Melia azedarach.24,25 Encouraged by the above-mentioned interest-
ing results, and in continuation of our program aimed at the
discovery and development of novel natural-product-based pesti-
cidal agents,26–29 in this Letter we synthesized a series of novel
podophyllotoxin-based hydrazone derivatives by introduction of
hydrazone fragments at the C-9 position on the podophyllotoxin
skeleton. Their insecticidal activity was tested against the
pre-third-instar larvae of oriental armyworm, Mythimna separata
(Walker) in vivo. In addition, their structure–activity relationships
(SARs) were also described.
⇑
Corresponding author. Tel./fax: +86 (0)29 87091952.
E-mail address: orgxuhui@nwsuaf.edu.cn (H. Xu).
http://dx.doi.org/10.1016/j.bmcl.2014.04.074
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

2622
Y. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2621–2624
HO
N
O
O
O
O
O
O
O
O
O
O
NH2OH.HCl
EtOH/Py
CrO3/Py
CH2Cl2
O
3
(7.7%)
COOH
O
1
O
N
O
N
3 h, 85%
72 h
O
O
O
O
MeOH/DIC
DMAP/CH2Cl2
O
O
O
O
2
13 h, 86%
O
O
O
O
O
O
4
(79%)
O
O
N
5
LiAlH4/THF
3 h, 80%
O
O
N
N
hydrazines, hydrazides
or sulfonyl hydrazides
HOAc,ethanol, reflux
O
O
O
O
O
O
CrO3/ Py
N
R
CH2Cl2
H
OH
N
H
2-5 h, 62-98%
4 h, 80%
O
O
O
O
O
O
O
O
8a-v
O
7
O
6
R
O
O
O
O
S
O
NO2
a
f
CH3
q
l
NO2
O
S
CH2CH3
NO2
Cl
O
g
h
b
c
O2N
O
m
r
OCH3
CH3
O
O
OCH3
OCH3
S
O
O
s
CN
S
n
o
Cl
O O
S
O
O
Cl
Cl
i
t
O
O
O
d
S
Br
NO2
Cl
O
j
O
u
S
S
S
Cl
O
O
O
e
S
O
p
O
v
k
Br
CH3
NO2
Scheme 1. The synthetic route for the preparation of 8a–v.
As shown in Scheme 1, firstly oxidation of 1 in the presence of
chromium trioxide (CrO3) and pyridine afforded podophyllone (2).
When 2 reacted with hydroxylamine hydrochloride, besides oxime
of podophyllotoxone (3, 7.7% yield), isoxazolopodophyllic acid (4)
was obtained as the major product in 79% yield. Then isoxazolop-
odophyllic acid-based ester (5) was obtained by the reaction of 4
with methanol in the presence of DIC and DMAP. Reduction of 5
in the presence of LiAlH4 gave isoxazolopodophyllol (6), which
was oxidized by CrO3 and pyridine to afford 7. Finally, 7 reacted
with hydrazines, hydrazides or sulfonyl hydrazides to give podo-
phyllotoxin-based hydrazone derivatives 8a–v. Among them, the
single-crystal structure of 8a was illustrated in Figure 2. It clearly
demonstrated that the substituents on the C@N double bond of
8a adopted E configuration.30
The insecticidal activity of compounds 8a–v against the
pre-third-instar larvae of M. separata in vivo was tested by the
leaf-dipping method at a concentration of 1 mg/mL.31 Toosenda-
nin, a commercial botanical insecticide isolated from Melia azed-
arach, was used as the positive control at 1 mg/mL. Leaves
treated with acetone alone were used as a blank control group.
As described in Table 1, the corresponding mortality rates of tested
compounds after 35 days were generally higher than those after 10
and 20 days. Therefore, these compounds exhibited the delayed
insecticidal activity. Moreover, the symptoms of the tested M. sep-
arata were also characterized by the same way as our previous
reports.24–29 Compared to toosendanin, especially compounds 8i,
8j, 8t, and 8u showed the more potent insecticidal activity with
the final mortality rates greater than 60%. Interestingly,

Y. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2621–2624
2623
Figure 2. The X-ray crystal structure of 8a.
Table 1
63.3% for 8i vs 36.7% for 8h). Introduction of 2-thienylacyl
hydrazones could result in more potent derivatives compared to
toosendanin (e.g., 60% for 8t and 63.3% for 6c). It suggested that
such hydrazides containing different heterocycles could be consid-
ered to introduce at the C-9 position of podophyllotoxin to prepare
the hydrazones as insecticidal agents. However, introduction of
acetyl or cyanoacetyl hydrazone led to less active derivatives
(e.g., 8r and 8s).
In conclusion, a series of novel podophyllotoxin-based hydra-
zone derivatives were synthesized, and evaluated for their insecti-
cidal activity against the pre-third-instar larvae of M. separata
in vivo. Especially compounds 8i, 8j, 8t, and 8u exhibited the more
potent insecticidal activity with the final mortality rates greater
than 60%. It demonstrated that the hydrazides containing different
heterocycles could be introduced at the C-9 position of podophyl-
lotoxin to prepare the hydrazones as insecticidal agents in the
future.
Insecticidal activity of 8a–v against M. separata on leaves treated with a concentration
of 1 mg/mLa
Compound
Corrected mortality rate (%)
20 days
10 days
35 days
1
2
3
4
5
6
7
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
8s
8t
8u
6.7 4.7
10.0 8.2
6.7 9.4
13.3 4.7
16.7 4.7
16.7 12.5
20.0 8.2
16.7 4.7
26.7 4.7
26.7 4.7
16.7 9.4
40.0 8.2
23.3 4.7
36.7 4.7
40.0
0
36.7 4.7
40.0 8.2
10.0
0
10.0 8.2
3.3 4.7
3.3 4.7
3.3 4.7
16.7 4.7
3.3 4.7
16.7 4.7
23.3 9.4
30.0
0
40.0
0
16.7 9.4
16.7 4.7
16.7 12.5
46.7 4.7
20.0 8.2
20.0 8.2
36.7 4.7
23.3 12.5
30.0 8.2
40.0 8.2
13.3 4.7
30.0 8.2
26.7 9.4
3.3 4.7
46.7 4.7
16.7 4.7
16.7 4.7
16.7 9.4
10.0 8.2
36.7 4.7
46.7 4.7
23.3 9.4
23.3 4.7
30.0 8.2
23.3 12.5
30.0 8.2
53.3 4.7
23.3 4.7
50.0 8.2
56.7 4.7
36.7 9.4
63.3 4.7
10.0
0
20.0 8.2
20.0 8.2
3.3 4.7
13.3 4.7
16.7 4.7
3.3 4.7
16.7 9.4
3.3 4.7
Acknowledgments
60.0
0
46.7 9.4
53.3 9.4
33.3 4.7
36.7 4.7
53.3 4.7
43.3 4.7
30.0 8.2
46.7 9.4
The present research was supported by National Natural
Science Foundation of China (No. 31071737), and Special Funds
of Central Colleges Basic Scientific Research Operating Expenses
(YQ2013008).
0
0
6.7 4.7
3.3 4.7
6.7 4.7
26.7 4.7
20.0 8.2
Supplementary data
30.0
60.0
0
0
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.04.
074.
63.3 4.7
36.7 9.4
43.3 4.7
8v
Toosendaninb
10.0
0
a
Values are means SD of three replicate.
Toosendanin was used as a positive control at 1 mg/mL.
b
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and C is the mortality rate in the untreated group expressed as a percentage.