Synthesis and biological activities of (E)-β-farnesene analogues containing 1,2,3-thiadiazole

Article abstract of DOI:10.1016/j.cclet.2016.10.030

In order to discover novel compounds with high-activity to control aphid, a series of novel (E)-β-farnesene analogues containing 1,2,3-thiadiazole were designed and synthesized, and their structures were confirmed by IR,¹H NMR,¹³C NMR, and HRMS (ESI). The stability of representative compounds was studied by HPLC and¹H NMR techniques. Repellent activity results indicated that compounds 8h and 8j displayed 60.3% and 62.0% repellent rates, respectively. The aphicidal bioassay results showed that most analogues exhibited considerable aphicidal activity against Myzus persicae. Especially, analogues 8l, 8s and 8t exhibited high activity with LC₅₀values of 33.4?μg/mL, 50.2?μg/mL and 61.8?μg/mL, respectively, which were higher than the lead compound (E)-β-farnesene, but lower than commercial insecticide pymetrozine with a LC₅₀of 7.1?μg/mL.

Full text of DOI:10.1016/j.cclet.2016.10.030

G Model
CCLET 3865 1–5
Chinese Chemical Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
2
Original article
3
4
Synthesis and biological activities of (E)-b-farnesene analogues
containing 1,2,3-thiadiazole
5
6
Q1 Jing-Peng Zhang a, Yao-Guo Qin a, Ya-Wen Dong a, Dun-Lun Song b, Hong-Xia Duan a,
Xin-Ling Yang a,
*
7
8
Q2 a Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China
b Department of Entomology, College of Plant Protection, China Agricultural University, Beijing 100193, China
A R T I C L E I N F O
A B S T R A C T
Article history:
In order to discover novel compounds with high-activity to control aphid, a series of novel (E)-b-
Received 25 July 2016
farnesene analogues containing 1,2,3-thiadiazole were designed and synthesized, and their structures
were confirmed by IR, 1H NMR, 13C NMR, and HRMS (ESI). The stability of representative compounds was
studied by HPLC and 1H NMR techniques. Repellent activity results indicated that compounds 8h and 8j
displayed 60.3% and 62.0% repellent rates, respectively. The aphicidal bioassay results showed that most
analogues exhibited considerable aphicidal activity against Myzus persicae. Especially, analogues 8l, 8s
Received in revised form 12 September 2016
Accepted 6 October 2016
Available online xxx
Keywords:
and 8t exhibited high activity with LC50 values of 33.4
which were higher than the lead compound (E)- -farnesene, but lower than commercial insecticide
pymetrozine with a LC50 of 7.1 g/mL.
mg/mL, 50.2 mg/mL and 61.8 mg/mL, respectively,
Ebf analogues
1,2,3-Thiadiazole
Synthesis
b
m
ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Stability
Published by Elsevier B.V. All rights reserved.
Repellent activity
Aphicidal activity
9
10
1. Introduction
bonds [10]. Therefore, it is necessary to find new E
that are more stable and efficient.
b
f analogues 30
31
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Aphids are important agricultural pests throughout the world,
often causing major economic losses. Their abilities of fast
breeding and easily developing resistance to insecticides make
their population control challenging [1]. Recently, the eco-toxicity
of some neonicotinoid insecticides to bees has led to call for
restrictions on their use in agriculture [2]. Therefore, it becomes
necessary to find eco-friendly chemicals with new strategy. The
As an important class of nitrogen-containing compounds, 1,2,3- 32
thiadiazole with various interesting properties is becoming a 33
rapidly growing and independent branch of the heterocyclic 34
chemistry [11]. It is widely used in chemicals discovery, and has 35
increasingly aroused attention because of its versatile biological 36
activities, such as insecticidal, systemic acquired resistance, 37
fungicidal, herbicidal and antiviral activities [12–19]. Recently, a 38
large number of 1,2,3-thiadiazole derivatives were found to exhibit 39
insecticidal activities. For example, Fan found that a series of 1,2,3- 40
thiadiazole derivatives containing diacylhydrazine moiety pos- 41
sessed superior insecticidal activities against Plutella xylostella L. 42
and Culex pipiens pallens [20]. More significantly, the structure of 43
1,2,3-thiadiazole can be easily decomposed into lower molecular 44
weight compounds by releasing N2, which favours the use of its 45
derivatives as eco-friendly pesticides with low toxicity and 46
suitable duration of efficiency to the target biology and half-life 47
major component of aphid alarm pheromone, (E)-
b-farnesene
(E f, Fig. 1), is released when aphids are attacked by natural
b
enemies and is also repellent to other aphids, causing avoidance
behaviour when detected [3–6]. Moreover, its insecticidal activity
at high doses has also been demonstrated [7]. Parasitoid and
predators, on the other hand, eavesdrop on aphid communication
and utilize Ebf as a kairomone, which attracts aphid predators and
enhances foraging behaviour of parasitoids [8,9]. Therefore, it is a
potentially valuable tool in the development of new aphid control
strategies. However, field application of this pheromone presents
some disadvantages for its relative volatility and instability in the
environment caused by easy oxidation of its conjugated double
in the agroecosystem [11].
48
In our previous studies, some E
b
f analogues with good stability 49
and biological activity were obtained by introducing a variety of 50
aromatic ring skeleton to replace the conjugated double bonds in 51
Eb
f [1,21,22]. These studies inspired our current hypothesis that 52
the introduction of 1,2,3-thiadizole moiety into the lead compound 53
f may favour the biological activity of E f. Here we designed and 54
*
Corresponding author.
Eb
b
E-mail address: yangxl@cau.edu.cn (X.-L. Yang).
http://dx.doi.org/10.1016/j.cclet.2016.10.030
1001-8417/ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: J.-P. Zhang, et al., Synthesis and biological activities of (E)-b-farnesene analogues containing 1,2,3-
thiadiazole, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.10.030

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J.-P. Zhang et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
Fig. 1. Design strategy of the target compounds.
55
56
57
58
59
60
61
62
63
64
65
synthesized a series of E
(Fig. 1) thanks to its superior properties as described above.
Accordingly, the designed compounds contain the geranyl group,
b
f analogues containing 1,2,3-thiadiazole
compounds were readily obtained in 34–92% yields through the
condensation reaction between compound 5 and compounds 7a–
7t at room temperature in the presence of the condensation
reagent N,N0-dicyclohexyl-carbodiimide (DCC) and the promoter
4-dimethy-lamino-pryidine (DMAP).
The structures of the synthesized compounds (8a–8t) were
established on the basis of their spectroscopic data of NMR, IR and
HRMS (Supporting information). As indicated by 1H NMR, all aryl
84
85
86
87
88
89
90
91
mimicking the terpene structure of E
ring. Especially, the conjugated double bonds of E
aromatic ring in the analogues. The good stability and biological
activities of these E f analogues were expected. The stability of
b
f, linked to 1,2,3-thiadizole
b
f are part of the
b
representative compounds was studied by HPLC and 1H NMR
technologies. Their aphicidal and repellent activities against Myzus
persicae (Sulzer) were evaluated. It is expected that this study may
be valuable for the discovery of eco-friendly aphid control agents.
protons showed multiplets at
the two double bonds’ protons were showed multiplet at
5.02 and triplet at about 5.26 respectively. Signals corresponding
d
6.78 to
d
8.20, and the positions of
92
93
94
d
4.91 to
d
d
to the –CH3 of the 1,2,3-thiadiazole ring were observed at about
2.82 and signals for the C–CH2–CH2–C protons were observed at
d
d
95
96
97
98
66
67
2. Results and discussion
1.92 to
about
d
2.05. Three –CH3 absorption peaks showed singlet at
2.1. Chemistry
d
1.48, 1.59 and 1.68, respectively. Interestingly, the
d
d
signal of CH2–N protons is change along with the substituent in
different position of phenyl. Normally, this absorption peak is a
doublet at about d 4.46 with coupling constants 7.20 Hz. However,
99
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
The synthetic route for the title compounds 8a–8t was
illustrated in Scheme 1. First, the key intermediate 4-methyl-
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
1,2,3-thiadiazole-5-carboxylic acid
5
was synthesized from
when the substituent is at the ortho of phenyl ring, the signal will
split two quartets in average (Supporting information). We
considered that this phenomenon is from the existing steric
hindrance of R at the ortho position. Therefore, the conformational
switching of corresponding compound is slowly at room tempera-
ture (low energy), and this led to the compound not existed with
only one preferential conformation. In order to verify this
deduction, we further chose compound 8n (R = 2-OCH3) as
example to study by dynamic 1H NMR spectroscopy. As a result,
the ‘abnormal split’ of the signal of CH2–N protons was vanish and
dimethyl carbonate through four steps: Hydrazidation, condensa-
tion, cyclization, and saponification with the total yield 68.2%.
Second, the synthetic method of compounds 7a–7t have been
reported in Ref. [22], when geranyl chloride as alkylating agents
reacted with aniline only in the present of K2CO3, the reaction
proceeded slowly and dialkylation by-products are observed. In
order to improve the selectivity and reaction yield, we choose one
optimized reaction condition: 3 equiv of aniline and a catalytic
amount of KI (0.1 equiv) in acetonitrile, additional 1 equiv K2CO3
and 3 equiv N,N-dimethyldodecylamine-N-oxide (DDAO), at room
temperature for 4 h. And we successfully obtained 7b–7t in this
condition through the reaction of geranyl chloride with different
substituted aniline in the yields of 39–83%. Finally, the target
replaced with a singlet at
d
4.37 in the 100 8C 1H NMR spectrum
(Supporting information). This result is identical with our guess, in
which the conformational switching of compound 8n is quickly at
high temperature (high energy).
Scheme 1. Synthetic route of the designed compounds. Reagents and conditions: (a) hydrazine hydrate, ethanol, r.t. 24 h; (b) ethyl acetoacetate, ethanol, r.t. 10 h; (c) SOCl2,
CH2Cl2, 0 8C–r.t. 24 h; (d) CH3OH/NaOH, HCl/H2O, r.t. 12 h; (e) substituted anilines, K2CO3, KI, DDAO, CH3CN, r.t. 4 h; (f) 4-methy-1,2,3-thiadizole-5-carboxylic acid 5, DCC,
DMAP, CH2Cl2, r.t. 6–10 h.
Please cite this article in press as: J.-P. Zhang, et al., Synthesis and biological activities of (E)-b-farnesene analogues containing 1,2,3-
thiadiazole, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.10.030

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3
Table 1
Stability data of representative compounds.
Compd.
Content/% (0 h)
Content/% (48 h)
Compd.
Content/% (0 h)
Content/% (48 h)
8a
8b
8g
8h
100.00
98.42
100.00
98.45
8l
98.18
98.88
99.66
99.14
97.99
98.80
99.48
99.06
8n
8q
8s
99.08
98.51
100.00
100.00
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
These compounds were found to be stable at room temperature.
In particular, we checked the contents change of eight compounds
by HPLC technique, and these data were shown in Table 1. The Ebf
is easy oxidation because of its conjugated double bonds, and it
degrades 77% and 94% after exposure to air for 24 h and 45 h at
room temperature, respectively [23]. We have found the accordant
weak electron-withdrawing groups (such as 4-F, 4-Br) were more 143
effective than those with electron-donating groups (such as 4-CH3, 144
4-OCH3). Additionally, compounds with di-substituents on the 145
phenyl showed lower effectiveness than those with mono- 146
substituent. For example, the repellent rate of compound 8h 147
(with a 2-F substituent) was much higher than those of 8r (with a 148
2,6-F2 substituent) and 8s (with a 2,4-F2 substituent). Furthermore, 149
the position of the substituent R on the phenyl interestingly 150
affected the repellent activity. Amongst the analogues containing a 151
halogen substituent, the order of the repellent activities of 152
compounds 8k (2-Br), 8l (3-Br), and 8m (4-Br) could be placed 153
as following: 8m > 8k > 8l. Also, compounds 8e, 8f, 8g, and 8h, 8i, 154
8j, had the similar results. However, the analogues with electron- 155
donating groups on the benzene ring exhibited another rule, for 156
instance, the repellent activities of compounds 8n (2-OCH3), 8o (3- 157
OCH3), and 8p (4-OCH3) could be found as following: 8p > 8o > 8n. 158
The aphicidal activity of the lead compound, the target 159
compounds, and pymetrozine against M. persicae was shown in 160
Table 3. The preliminary bioassay results (at a concentration of 161
result in our previous study that Ebf was decomposed absolutely
after leaving it at room temperature and in contact with air for
periods up to 48 h [21]. As indicated in Table 1, in such conditions
the degradation of the candidate compounds could not be
detected. Moreover, we took 1H NMR technique to study the
protons change of compound 8a, and Fig. 2 illustrated the 1H NMR
spectrums of compound 8a after exposure to air for 1 day, 3 days,
5 days and 7 days. As a result, there was neither proton signals
disappeared nor new proton signals appeared. On the basis of the
above results, the stability of the title compounds is much better
than that of the lead compound Ebf.
133
2.2. Biological activity
200
mg/mL, 48 h) indicated that all the target compounds 162
134
135
136
137
138
139
140
141
142
The repellent effects of analogues on M. persicae were evaluated
and listed in Table 2. The results indicated that except for 8n,
compounds 8a–8t displayed certain repellent activities against M.
exhibited aphicidal activity. The aphicidal activities of analogues 163
8d, 8e, 8f, 8h, 8j, 8l, 8o, 8p, 8r, 8s, and 8t are comparable to or even 164
better than that of the lead compound Ebf. Unluckily, the aphicidal 165
activities of all the compounds are weaker than that of 166
pymetrozine. On the basis of the primary experimental results, 167
analogues showing a mortality rate higher than 70% were chosen 168
to determine the LC50 values. As shown in Table 4, compounds 8l, 169
8s, and 8t exhibited high aphicidal activity against M. persicae with 170
persicae at 5
m
g dose. Some of them displayed promising repellent
effect with values of 18.7–62.0%. Particularly, compounds 8h and
8j showed 60.3% and 62.0% repellent rates, respectively. Repellent
activities of target compounds were affected by both variation of
the substitute’s type and position on the phenyl. When the
substituent R was at para position of phenyl, compounds with
LC50 values of 33.4, 50.2 and 61.8
mg/mL, respectively. However, 171
Fig. 2. The 1H NMR spectrums of compound 8a.
Please cite this article in press as: J.-P. Zhang, et al., Synthesis and biological activities of (E)-b-farnesene analogues containing 1,2,3-
thiadiazole, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.10.030

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Table 2
The repellent activities of title compounds 8a–8t (5
m
g/test, Myzus persicae).
Compd.
R
Repellent rate (%)a
Compd.
R
Repellent rate (%)
8a
8b
8c
8d
8e
8f
H
55.6 ꢀ 5.9
31.2 ꢀ 4.9
34.7 ꢀ 1.9
42.5 ꢀ 5.0
50.8 ꢀ 6.4
39.1 ꢀ 4.2
58.2 ꢀ 2.4
60.3 ꢀ 2.3
43.4 ꢀ 0.7
62.0 ꢀ 1.4
87.4 ꢀ 2.3
8k
8l
2-Br
51.8 ꢀ 5.5
33.2 ꢀ 4.6
59.0 ꢀ 3.0
0.0
2-CH3
3-CH3
4-CH3
2-Cl
3-Cl
4-Cl
2-F
3-Br
8m
8n
8o
8p
8q
8r
4-Br
2-OCH3
3-OCH3
4-OCH3
4-NO2
2,6-F2
2,4-F2
3-Cl-4-CH3
18.7 ꢀ 4.2
49.3 ꢀ 2.5
36.6 ꢀ 2.3
21.9 ꢀ 2.8
24.5 ꢀ 3.0
32.7 ꢀ 3.6
8g
8h
8i
3-F
8s
8j
4-F
8t
E
b b
f
–
a
Average of three replicates.
b
Ebf was used as a positive control.
Table 3
The aphicidal activity against Myzus persicae of title compounds 8a–8t (200
mg/mL, 48 h).
Compd.
R
Screening mortality (%)a
Compd.
R
Screening mortality (%)
8a
8b
8c
8d
8e
8f
H
44.9ꢀ 6.6
38.4ꢀ 6.8
34.3ꢀ 3.7
59.7ꢀ 5.6
59.5ꢀ 7.4
65.2ꢀ 6.8
50.3 ꢀ 7.9
69.1ꢀ 5.7
52.8ꢀ 2.7
60.4 ꢀ 3.6
36.4ꢀ 4.5
8l
3-Br
73.3 ꢀ 8.5
57.4 ꢀ 9.0
54.4 ꢀ 5.4
58.0 ꢀ 6.2
61.9 ꢀ 9.1
45.1 ꢀ 8.3
71.2 ꢀ 5.1
67.1 ꢀ 8.3
72.6 ꢀ 3.6
58.8 ꢀ 2.9
87.1 ꢀ 2.1
2-CH3
3-CH3
4-CH3
2-Cl
3-Cl
4-Cl
2-F
8 m
8n
8o
8p
8q
8r
4-Br
2-OCH3
3-OCH3
4-OCH3
4-NO2
2,6-F2
2,4-F2
3-Cl-4-CH3
–
8g
8h
8i
8s
8t
Ebf
3-F
8j
4-F
8k
2-Br
Pymetrozineb
–
a
Average of three replicates.
b
Pymetrozine was used as a positive control.
Table 4
4. Experimental
194
195
The LC50 of compounds 8l, 8r and 8t.
4.1. Synthesis
Compd.
LC50 (95% FL),
m
g/mL
Toxic regression equation
R
8l
33.4 (20.6–53.5)
50.2 (30.4–84.5)
y = 1.619x ꢁ 2.467
y = 1.465x ꢁ 2.492
y = 1.465x ꢁ 2.492
y = 1.770x ꢁ 1.502
0.958
0.983
0.918
0.950
Melting points of some compounds were determined on an X-4
binocular microscope (Fukai Instrument Co., Beijing, China), with
an uncorrected thermometer. 1H NMR spectra and 13C NMR
spectra were recorded on Bruker AM-300 (300 MHz, 75 MHz
respectively) spectrometer with CDCl3 as the solvent and TMS as
the internal standard. High resolution mass spectrometry (HRMS)
data were obtained on an FTICR-MS Varian 7.0 T FTICR-MS
instrument. Purity was analysed by high performance liquid
chromatography (HPLC) on a LC-1AT HPLC instrument (Shimadzu).
All the reagents were obtained commercially and used after further
purification. Column chromatography purification was carried out
by using silica gel (Merck 60, 200–300 mesh).
The general synthetic scheme for representative compounds
8a–8t is shown in Scheme 1. Key intermediate 5 was prepared from
dimethyl carbonate according to Ref. [12]. Compounds 7a–7t were
obtained through N-alkylation reaction between geranyl chloride
and different substituted aniline according to the reported method
[22,24–26]. The general procedures of 5 and 7a–7t are described in
the Supporting information.
The target compounds 8a–8t were prepared using condensa-
tion reaction between compounds 5 and 7a–7t. The general
procedure was described as below. To a solution of 5 (0.87 g,
6 mmol), DMAP (0.15 g, 1.2 mmol) and dichloromethane (20 mL),
DCC (1.36 g, 6.6 mmol) was added in batches. And then solution of
compounds 7a–7t (6.0 mmol) in dichloromethane was dropped
slowly, the resulted mixture was stirred for 6–10 h. After the
reaction completed, filtered, the filtrate was washed with water.
The organic layer was dried over anhydrous Na2SO4 and
concentrated in vacuo. Then the residue was purified by
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
8r
8t
61.8 (37.9–103.5)
7.1 (4.3–10.7)
Pymetrozine
172
173
the aphicidal activities of analogues 8l, 8s, and 8t are lower than
pymetrozine with a LC50 of 7.1
mg/mL.
174
3. Conclusion
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
In summary, a series of novel (E)-
containing 1,2,3-thiadiazole were designed and synthesized by
replacing unstable conjugated double bonds of E f with1,2,3-
b-farnesene analogues
b
thiadiazole ring according to the principle of linking bioactive
substructures. The stability of representative compounds is much
better than the lead Eb
f based on the results made by HPLC and 1H
NMR techniques. Behaviour experiment results indicated that
compounds 8h and 8j displayed 60.3% and 62.0% repellent rate,
respectively. Interestingly, compounds with weak electron-with-
drawing groups (such as 4-F, 4-Br) were more effective than those
with electron-donating groups (such as 4-CH3, 4-OCH3) when the
substituent is at para position of phenyl. The aphicidal bioassay
results showed that most analogues exhibited considerable
aphicidal activity against M. persicae, especially analogues 8l, 8s
and 8t exhibited high aphicidal activity against M. persicae with
LC50 values of 33.4, 50.2 and 61.8
exhibited improved aphicidal activity compared with the lead E
m
g/mL, respectively, which
f.
b
This work could afford some valuable information on the discovery
of eco-friendly aphid control agent.
Please cite this article in press as: J.-P. Zhang, et al., Synthesis and biological activities of (E)-b-farnesene analogues containing 1,2,3-
thiadiazole, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.10.030

G Model
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J.-P. Zhang et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
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4.2. Stability test
331–342.
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(2-F), 8l (3-Br), 8n (2-OCH3), 8q (4-NO2) and 8s (2,4-F2) were
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Please cite this article in press as: J.-P. Zhang, et al., Synthesis and biological activities of (E)-b-farnesene analogues containing 1,2,3-
thiadiazole, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.10.030