Synthesis and insecticidal activity of the fluorinated galegine analogues

Article abstract of DOI:10.1080/14786419.2020.1836631

The introduction of fluorine atom can increase the biological activities of the target compounds remarkably. To find more safe and efficient insecticides, natural product galegine as lead compound, a series of novel fluorinated galegine analogues were designed and synthesized. The bioassay results indicate that all the target compounds have moderate to high insecticidal activities against Hyalopterus pruni Geoffroy and Aphis gossypii Glover, in particular, compounds IIa-05, IId-02 and IIe-03 show the best insecticidal activities against Hyalopterus pruni with the mortality of 100%, 100% and 96.6%, respectively. And compounds IIa-02, IId-02, IId-04, IIc-01, IIc-02 and IId-01 show 0.6-7 times insecticidal activities against Aphis gossypii as Imidacloprid with their LC₅₀ values are 0.28 mg/L, 0.38 mg/L, 0.33 mg/L, 0.09 mg/L, 0.03 mg/L and 0.12 mg/L, respectively The analysis of structure-activity relationship indicates that the compounds with difluoro-substituted benzene ring have more potent insecticidal activities than the single fluoro-substituted compounds.

Full text of DOI:10.1080/14786419.2020.1836631

Natural Product Research
Formerly Natural Product Letters
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Synthesis and insecticidal activity of the
fluorinated galegine analogues
Qinglai Wu , Jinlong Cai , Fenghai Zhao , Ziyuan Zhou , Dongyan Yang &
Zhaohai Qin
To cite this article: Qinglai Wu , Jinlong Cai , Fenghai Zhao , Ziyuan Zhou , Dongyan Yang &
Zhaohai Qin (2020): Synthesis and insecticidal activity of the fluorinated galegine analogues,
Natural Product Research, DOI: 10.1080/14786419.2020.1836631
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2020.1836631
Synthesis and insecticidal activity of the fluorinated
galegine analogues
a
a
b
b
b
Ã
Ã
Qinglai Wu , Jinlong Cai , Fenghai Zhao , Ziyuan Zhou , Dongyan Yang and
Zhaohai Qina,b
b
aCollege of Agriculture, Yangtze University, Jinzhou, China; Department of Chemistry, College of
Science, China Agricultural University, Beijing, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 23 June 2020
Accepted 27 September 2020
The introduction of fluorine atom can increase the biological
activities of the target compounds remarkably. To find more safe
and efficient insecticides, natural product galegine as lead com-
pound, a series of novel fluorinated galegine analogues were
designed and synthesized. The bioassay results indicate that all
the target compounds have moderate to high insecticidal activ-
ities against Hyalopterus pruni Geoffroy and Aphis gossypii Glover,
in particular, compounds IIa-05, IId-02 and IIe-03 show the best
insecticidal activities against Hyalopterus pruni with the mortality
of 100%, 100% and 96.6%, respectively. And compounds IIa-02,
IId-02, IId-04, IIc-01, IIc-02 and IId-01 show 0.6-7 times insecticidal
activities against Aphis gossypii as Imidacloprid with their LC50 val-
ues are 0.28 mg/L, 0.38 mg/L, 0.33 mg/L, 0.09 mg/L, 0.03 mg/L and
0.12 mg/L, respectively The analysis of structure-activity relation-
ship indicates that the compounds with difluoro-substituted ben-
zene ring have more potent insecticidal activities than the single
fluoro-substituted compounds.
KEYWORDS
Galegine; fluorine atom;
insecticidal activity;
aphids; synthesis
1. Introduction
In our previous study (Wu et al. 2019), a series of hydrocarbylidene nitrohydrazinecar-
boximidamides I (Figure 1) were synthesized with the natural product galegine
CONTACT Zhaohai Qin
These authors contributed equally to this work.
qinzhaohai@263.net
College of Agriculture, Yangtze University, Jinzhou 434023, China
Ã
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14786419.2020.1836631.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
Q. WU ET AL.
Figure 1. The structures of galegine and hydrocarbylidene nitrohydrazinecarboximidamides I, and
LC50 (mg/L) of the compoundI-01 and compoundI-02.
(Figure 1) as scaffold and most coumpounds showed excellent insecticidal activities
against Aphis gossypii Glover. It is noteworthy that the insecticidal activities of the
compound I-02 (Figure 1, LC50: 0.46 mg/L), which obtained from substituting CH3O of the
compound I-01 (Figure 1, LC50: > 200 mg/L) with CF3O, increased more than 400 times.
As we well know, fluorine atom has special physicochemical property, and is widely
applied in molecular design as a bioisostere of hydrogen atom (Purser et al. 2008; Kirk
2008; Jeschke 2004). The introduction of fluorine atom can improve the solubility, sta-
bility, permeability and other molecular biological properties of molecules that often
can increase the biological activities of the target compounds remarkably (Kirk 2006).
The fluorine atom can also change the molecular conformation to enhance the bio-
logical properties of the compound, such as the ability to bind to target receptors and
enzymes, the ability to transport in organisms, and the rate of metabolism.
(Theodoridis 2006; Smart 2001; Hagmann 2008). To find more efficient insecticides, we
designed and synthesized 26 new compounds (II) (Figure 2) by the introduction of
fluorine atom. The leaf dip method was used to determine the insecticidal activity of
all compounds against aphids, calculated the Log Kow value of the target compounds
by the ALOGPS 2.1 program and the structure-activity relationship was discussed.
2. Results and discussion
2.1. Chemistry
The synthetic route of the target compounds was achieved in Figure 2. Treatment of
2-methyl-2-thiopseudourea sulfate with nitric acid and sulfuric acid at À10 ꢀC for
1 hour afforded intermediate 2, which reacted with phthaloyl dichloride and pyridine
at 0 ꢀC gave intermediate 3. Subjecting intermediate 3 to the corresponding fluori-
nated benzylamines at 0–5 ꢀC led to compounds 4a~4e which were reacted with
hydrazine hydrate under reflux for 1 hour afforded the intermediate 5a~5e. Then, the
target compound IIa-01ꢁIIf-04 was synthesized by the reaction of compound 5 with
aldehydes and ketones using glacial acetic acid as catalyst (Xu et al. 2017). Their struc-
tures were confirmed by 1H-NMR, high resolution mass spectrum (HR-MS). (Analysis
data of all the synthesized compounds are available in Supplementary Information).
2.2. Insecticidal activity
First, all the target compounds were screened for their insecticidal activities against
Hyalopterus pruni Geoffroy at 200 mg/L (Zhang et al. 2015), and the results are shown

NATURAL PRODUCT RESEARCH
3
Figure 2. Synthetic route of target compounds and the structures of fluorinated gale-
gine analogues.
in Table 1. The results indicate that all the target compounds have moderate to high
insecticidal activities against H.pruni at the concentration of 200 mg/L, but lower than
Guadipyr. In particular, compounds IIa-05, IId-02 and IIe-03 show the best insecticidal
activities against H.pruni with the mortality of 100%, 100% and 96.6%, respectively,
that equal to insecticidal activities of guadipyr at the concentration of 12.5 mg/L. As
fluorine atom can improve the lip solubility of the compounds, we calculated the Log
Kow value of the target compounds by the ALOGPS 2.1 program, and find that the
Log Kow of the target compounds with the high insecticidal activities most ranged
in 2.90–3.50.
In previous studies, we found that compound II showed remarkable insecticidal
activities against A. gossypii (Xu et al. 2017). So, A. gossypii was selected as the target
for further evaluation, and the results are listed in Table 2. All the compounds exhib-
ited excellent insecticidal activities against A. gossypii at the concentration of 200 mg/

4
Q. WU ET AL.
Table 1. Insecticidal activity of compounds II against third-instar nymphs of Hyalopterus pruni
Geoffroy at the concentration of 200 mg/L.
Compd.
Log Kow
DN/TN
CM (%)
Compd.
Log Kow
DN/TN
CM (%)
CK
–
0/68
76/78
28/52
42/114
32/93
30/40
26/26
15/33
10/44
27/133
23/35
16/19
81/108
37/45
0
IIc-02
IIc-03
IIc-04
IIc-05
IId-01
IId-02
IId-03
IId-04
IId-05
IIe-01
IIe-02
IIe-03
IIe-04
IIe-05
3.00
2.60
3.04
3.25
2.75
3.44
2.92
3.02
4.19
2.73
3.49
2.97
3.18
4.20
13/22
42/74
100/118
75/95
21/29
45/45
30/53
43/76
15/27
46/56
31/49
57/59
22/26
25/69
59.1
56.8
84.8
79.0
72.4
100
56.6
56.6
55.6
82.1
63.3
96.6
84.6
36.2
Guadipyra
IIa-01
IIa-02
IIa-03
IIa-04
IIa-05
IIa-06
IIa-07
IIa-08
IIb-01
IIb-02
IIb-03
IIc-01
2.95
2.96
2.59
3.27
3.13
3.02
3.81
3.11
5.03
2.60
3.05
3.88
2.31
97.4
53.9
36.8
34.4
75.0
100
45.5
22.7
20.3
65.7
84.2
75.0
82.2
CK(dimethylformamide and Triton X-100 mixed solution without compounds);
aGuadipyr was used at 12.5 mg/L; DN( Death number), TN (Total worm number), CM (Corrected mortality)
Table 2. LC50 (mg/L) of the compounds II against Aphis gossypii Glover.
Compd.
LC50(mg/L)
95%FL
Compd.
LC50(mg/L)
95%FL
Imidacloprid
IIa-01
IIa-02
IIa-03
IIa-04
IIa-05
IIa-06
IIa-07
IIa-08
IIb-01
IIb-02
IIb-03
IIc-01
0.21
0.62
0.28
4.70
1.04
19.59
2.53
25.95
1.01
0.49
3.09
1.56
0.09
0.03
0.14-0.27
0.23-1.08
0.05-0.69
0.24-10.72
0.10-2.48
13.56-25.55
1.72-3.54
11.44-40.00
0.52-1.59
0.001-1.48
1.31-5.78
0.79-2.41
0.001-0.50
0.001-0.15
IIc-03
IIc-04
IIc-05
IId-01
IId-02
IId-03
IId-04
IId-05
IIe-01
IIe-02
IIe-03
IIe-04
IIe-05
0.68
1.14
1.12
0.12
0.38
0.75
0.33
1.65
0.61
0.80
0.86
0.48
3.01
0.11-1.26
0.22-2.20
0.56-1.68
0.04-0.25
0.01-0.89
0.25-1.26
0.004-0.79
0.51-3.62
0.24-1.18
0.001-2.18
0.47-7.04
0.13-0.89
1.91-4.36
IIc-02
L, particularly, compounds IIa-02, IId-04 and IId-02 showed the same insecticidal activ-
ities as Imidacloprid with the LC50 values of 0.28 mg/L, 0.38 mg/L and 0.33 mg/L,
respectively. Compounds IIc-01, IIc-02and IId-01 indicated the best insecticidal
activities with the LC50 values of 0.09 mg/L, 0.03 mg/L and 0.12 mg/L, respectively,
higher than Imidacloprid (LC50: 0.21 mg/L). The structure-activity relationship of the
target compounds reveal that when the fluorine atom substituted the hydrogen
atom on benzene ring of R, the insecticidal activities display p-F > m-F and difluoro-
substituted > single fluoro-substituted. As R is the same group, the compound with R1
and R2 being the minor group, such as H, CH3, i-Pr and n-Pr,.have the better insecti-
cidal activity against A. gossypii.
3. Conclusion
In summary, a series of novel hydrocarbylidene nitrohydrazinecarboximidamides con-
taining fluorine atom were designed and synthesized, and their insecticidal activities
against A. gossypii and H. pruni were detected. The results show that most compounds
have moderate to high insecticidal activities against H.pruni at the concentration of

NATURAL PRODUCT RESEARCH
5
200 mg/L, the Log Kow of the target compounds play an important role in insecticidal
activities, the optimum value ranged in 2.90–3.50. And all the compounds exhibit
excellent insecticidal activities against A.gossypii, in particular, compounds IIa-02, IId-
02, IId-04, IIc-01, IIc-02 and IId-01 show 0.6 À 7 times insecticidal activities as
Imidacloprid. The analysis of structure-activity relationship indicates that the com-
pounds with difluoro-substituted benzene ring have more potent insecticidal activities
than the single fluoro-substituted compounds.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by the National Technology R&D Program in the 13th Five year plan
of China (grant No. 2016YFD0300709).
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