Novel 1,3,4-oxadiazole thioether derivatives containing flexible-chain moiety: Design, synthesis, nematocidal activities, and pesticide-likeness analysis

Article abstract of DOI:10.1016/j.bmcl.2020.127028

Seventy-two novel 1,3,4-oxadiazole thioether derivatives containing different flexible-chain moieties were designed and synthesized. The nematicidal activities of all the title compounds were evaluated, and some compounds showed excellent nematicidal acti

Full text of DOI:10.1016/j.bmcl.2020.127028

Journal Pre-proofs
Novel 1,3,4-oxadiazole thioether derivatives containing flexible-chain moiety:
Design, synthesis, nematocidal activities, and pesticide–likeness analysis
Jixiang Chen, Chengqian Wei, Sikai Wu, Yuqin Luo, Rong Wu, Deyu Hu,
Baoan Song
PII:
S0960-894X(20)30098-6
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127028
BMCL 127028
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
3 January 2020
5 February 2020
11 February 2020
Please cite this article as: Chen, J., Wei, C., Wu, S., Luo, Y., Wu, R., Hu, D., Song, B., Novel 1,3,4-oxadiazole
thioether derivatives containing flexible-chain moiety: Design, synthesis, nematocidal activities, and pesticide–
likeness analysis, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.
2020.127028
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Novel 1,3,4-oxadiazole thioether derivatives containing flexible-chain moiety:
Design, synthesis, nematocidal activities, and pesticide–likeness analysis
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Jixiang Chen, Chengqian Wei, Sikai Wu, Yuqin Luo, Rong Wu, Deyu Hu, Baoan Song*
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State Key Laboratory Breeding Base of Green Pesticide and Agricultural
Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering,
Ministry of Education, Research and Development Center for Fine Chemicals,
Guizhou University, Huaxi District, Guiyang 550025, China
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*CORRESPONDING AUTHOR FOOTNOTE
To whom correspondence should be addressed. Tel.: +86(851)8362-0521; fax:
+86(851)8362-2211. E-mail: basong@gzu.edu.cn.
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ABSTRACT: Seventy-two novel 1,3,4-oxadiazole thioether derivatives containing
different flexible-chain moieties were designed and synthesized. The nematicidal
activities of all the title compounds were evaluated, and some compounds showed
excellent nematicidal activities against citrus nematodes. The compounds 15, 16, 18,
27, 41, 42, 44, 53, and 71 had the mortality to citrus nematodes of 92.5, 93.7, 90.3,
91.5, 92.6, 92.8, 93.5, 91.3, and 91.0% at the concentration of 100 mg/L, which were
better than the control agent of avermectin (85.9%). After the test concentration was
reduced to 50 mg/L, the nematicidal activities of the compounds 16, 42, 44, 53, and
71 were still superior to avermectin (65.1%), with the mortality of 72.3, 71.3, 70.6,
71.1, and 73.9%, respectively. The LC50 values of the compounds 16, 42, 44, 53, and
71 were 16.3, 18.8, 20.8, 17.5, and 14.7 mg/L, which were better than the commercial
positive control agent of avermectin (24.8 mg/L). Meanwhile, the qualitative and
quantitative analysis of the pesticide-likeness shows that compound 71 exhibits the
potential insecticide-likeness. This work indicates that novel 1,3,4-oxadiazole
thioether derivatives containing flexible-chains deserve further research as potential
nematicides to protect citrus crops in the future.
Keywords: 1,3,4-Oxadiazole, Nematicidal activity, Thioether derivatives,
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Flexible-chain, Pesticide-likeness
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The citrus nematodes (Tylenchulus semipenetrans Cobb) are an important
plant-parasitic nematode with the high degree of specialization and a small range of
host plants, which mainly harm to citrus plants.1,2 There are many obvious
manifestations that serve as the warning when the roots of citrus tree were attacked,
such as, the yellowing of the leaves, short planting, poor growth, and falling flowers
and fruits.3,4 What is more, the fruit cannot bear and the tree may be die when the
trees are seriously endangered by the citrus nematodes, which caused huge losses for
the citrus production.5
In the past ten years, the application of chemical nematicides has played an extreme
important role in the control of nematodes, which greatly reduce the economic losses
caused by the nematodes.6 However, the problems of serious environmental pollution
and drug resistance are raised with the long-term reuse of the high toxic nematicides,
such as dibromochloropropane, methyl bromide, oxamide, and aldicarb.7 Meanwhile,
many high toxic nematicides are restricted or banned in recent years as people
become more aware of human health and environmental protection.8 Therefore, to
meet the requirements of modern agricultural development, many researches were
conducted to discover and develop the nematicides with the merits of high-efficiency,
low-toxicity, and environmentally friendly.9
The five-membered heterocyclic compounds play a very important role in the
development of nematicides. For example, the tioxazafen and fluensulfone (Fig. 1A)
containing the 1,2,4-oxadiazole or thiazole ring have been successfully marketed as
new generation nematicides.10,11 As one of the most important members of the
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five-membered heterocyclic family, many varieties of derivatives were synthesized
based on the 1,3,4-oxadiazole ring, and they have a broad spectrum of the biological
activities, such as, nematicidal,12 antifungal,13 antibacterial,14 insecticidal.15
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Fig. 1. The structures of the commercial pesticides. (A) The structures of the commercial
nematicides. (B) The structures of the commercial pesticides containing thioether groups. (C) The
structures of the commercial pesticides containing pyridine groups.
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71
The thioether groups exhibit a broad spectrum of the biological activities, and
receive more and more attention from many researchers.16 The biological activities
and the hydrophilicity of the 1,3,4-oxadiazole compounds can be increased by
introducing the thioether groups.17-19 The flutianil, pyrithiobac-sodium, metribuzin,
and allicin containing thioether groups (Fig. 1B) are the representative commercial
pesticides, which play an important role in plant protection.
In our previous research, a series of 1,3,4-oxadiazole thioether derivatives
containing the trifluorobutene moiety were designed and synthesized based on the
lead compound of fluensulfone, and some compounds showed moderate nematicidal
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activities against citrus nematodes.12 Subsequently, a series of 1,3,4-oxadiazole
bisthioether derivatives were designed and synthesized through introducing the sulfur
atom and methylene group to linked the benzene ring and the 1,3,4-oxadiazole ring,
and some compounds show good nematicidal activities against Caenorhabditis
elegans.20 In addition, some studies show that biological activity of the pyridine
moiety is fully reflected in many pesticides,21,22 such as boscalid, pyriofenone,
sulfoxaflor, and halauxifen-methyl (Fig. 1C). In present work, the pyridine ring was
used to instead of the benzene ring, and the methylene group connected to the sulfur
or oxygen atom was used as the flexible chain to link the pyridine ring and the
1,3,4-oxadiazole ring (Fig. 2).
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Fig. 2. The design idea of target compounds.
Therefore, the novel 1,3,4-oxadiazole compounds 1–51 containing the different
flexible linker were synthesized (Fig. 3 and 4) according to our previously reported
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method,12,23 and the structures of all target compounds were characterized by H
NMR, 13C NMR and HRMS spectra.
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Fig. 3. The synthesis route of target compounds 1-22.
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Fig. 4. The synthesis route of target compounds 23-51.
The nematicidal activities of the target compounds 1–51 were evaluated by
reported methods,12,24 and the commercial nematicide of avermectin was used as the
positive control. The nematicidal activities of the compounds 1–51 against citrus
nematodes were listed in Tables 1 and 2. Some target compounds showed better
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nematicidal activities compared to positive control agents. For example, The
compounds 15, 16, 18, 27, 41, 42, and 44 showed excellent nematicidal activities
against citrus nematodes, with the mortality of 92.5, 93.7, 90.3, 91.5, 92.6, 92.8, and
93.5% at the concentration of 100 mg/L, which were better than the control agent of
avermectin (85.9%). When the test concentration was reduced to 50 mg/L, some
compounds still showed good nematicidal activities against citrus nematodes, which
were better than the control agent of avermectin (65.1%). For example, the mortality
of the compounds 16, 42, and 44 were 72.3, 71.3, and 70.6% against citrus
nematodes, respectively.
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Table 1. The nematicidal activities of the compounds 1−22 against citrus nematodes.
mortality/%a
Compound
R2
R3
100 mg/L
71.3±1.9
71.6±1.9
64.2±2.5
74.0±1.0
70.4±1.6
50.4±1.8
43.1±2.0
59.8±1.9
43.0±2.3
66.2±1.6
63.3±1.4
51.3±1.4
33.1±2.0
82.2±2.3
92.5±1.0
50 mg/L
43.0±1.9
40.4±2.1
33.1±2.5
48.7±2.1
39.1±2.8
27.6±0.7
27.7±1.3
29.7±1.1
26.2±2.0
40.5±3.0
38.9±1.1
31.3±1.6
14.6±1.1
53.4±3.6
69.4±1.2
1
2
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
5-CF3
CH3
CH2CH3
CH2CN
3
4
CH2CH2F
CH2CH2Br
(CH2)3CH3
(CH2)4CH3
CH3
5
6
7
8
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5-CF3
CH2CN
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12
13
14
15
5-CF3
CH2CH2F
CH2CH2Cl
CH(CH3)2
(CH2)4CH3
CH3
5-CF3
5-CF3
5-CF3
5-F
5-F
CH2CH3
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5-F
5-Cl
CH2CH2F
CH3
93.7±1.4
79.9±1.6
90.3±1.8
35.9±1.5
47.7±3.1
56.5±2.1
45.2±2.6
85.9±2.5
72.3±0.7
57.6±2.4
65.2±0.6
15.7±1.5
22.3±0.8
32.7±1.3
21.0±1.8
65.1±1.6
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18
5-Cl
CH2CH3
CH3
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3,5,6-triCl
3,5,6-triCl
3,5,6-triCl
3,5,6-triCl
-
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CH2CH3
CH2CH2F
CH2CH2Cl
-
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Avermectinb
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a The average of three tests.
b The commercial nematicide avermectin was used as a positive control.
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Table 2. The nematicidal activities of the compounds 23−51 against citrus nematodes.
mortality/%a
Compound
R2
R3
CH3
100 mg/L
50 mg/L
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3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
77.9±2.5
46.4±3.8
CH2Cl
CH2CH3
83.7±3.0
83.0±2.1
71.4±3.1
91.5±3.6
89.1±2.6
85.0±3.3
72.0±2.1
58.1±2.0
75.2±3.2
54.4±2.8
50.9±2.5
48.6±2.9
35.2±3.1
18.8±1.8
15.4±1.3
16.3±2.0
36.5±2.8
54.3±2.8
51.0±3.1
29.7±1.7
62.7±3.2
60.3±1.4
50.4±2.9
30.7±1.8
34.6±2.9
23.1±2.3
36.8±3.0
25.9±2.7
17.5±2.6
14.9±2.1
6.6±1.8
CH2CN
CH2CH2F
CH2CH2Cl
CH2CH2Br
(CH2)2CF3
(CH2)2CH3
(CH2)2CN
CH(CH3)2
(CH2)3CH3
(CH2)3CN
(CH2)4CH3
CH2Ph(2-F)
CH2Ph(2-Cl)
CH2Ph(2-CN)
6.4±2.0
5.8±0.9
CH2Ph(2-CH3)
16.4±2.0
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5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
-
CH3
CH2CH3
92.6±2.2
92.8±2.9
75.0±3.3
93.5±2.8
83.3±2.4
78.5±2.7
66.0±5.4
42.5±2.9
28.2±3.1
22.6±3.2
26.1±2.4
85.9±2.5
64.2±4.1
71.3±2.6
38.2±3.6
70.6±2.7
62.6±2.2
41.3±3.2
33.0±2.7
16.6±2.6
11.3±3.0
10.1±2.3
12.1±1.7
65.1±1.6
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43
CH2CN
44
CH2CH2Cl
CH2CH2Br
(CH2)2CF3
(CH2)3CH3
(CH2)3CN
CH2Ph(2-F)
CH2Ph(2-Cl)
CH2Ph(2-CN)
-
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50
51
Avermectinb
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a The average of three tests.
b The commercial nematode avermectin was used as a positive control.
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The preliminary structure-activity relationship of the compounds 1–51 showed that
R3 is the small alkyl chain or halogen-substituted alkyl chain, the compound has a
good nematicidal activity. On the contrary, the large groups, such as benzyl and
pentyl, are not conducive to improving the nematicidal activity of the compound.
Therefore, the compounds 52–72 were designed and synthesized based on the
structure-activity relationship (Fig. 5, 6 and 7).
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Fig. 5. The synthesis route of target compounds 52−66.
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Fig. 6. The synthesis route of target compounds 67−69.
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Fig. 7. The synthesis route of target compounds 70−72.
The nematicidal activities of compounds 52−72 is shown in Tables 3 and 4. The
compounds 53 and 71 showed excellent nematicidal activities against citrus
nematodes, with the mortality of 91.3 and 91.0% at the concentration of 100 mg/L,
which were better than the control agent of avermectin (85.9%). When the test
concentration was reduced to 50 mg/L, the compounds 53 and 71 still showed good
nematicidal activities against citrus nematodes, with the mortality of 71.1 and 73.9%,
respectively.
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Table 3. The nematicidal activities of the compounds 52−66 against citrus nematodes.
mortality/%a
Compound
R3
X
n
100 mg/L
82.6±5.1
50 mg/L
67.6±3.5
52
53
54
CH3
S
S
S
2
2
2
CH2CH3
(CH2)2CH3
91.3±1.7
84.1±3.3
71.1±2.1
65.2±5.8
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CH(CH3)2
CH2CH(CH3)2
CH3
S
S
S
S
S
S
S
S
S
O
O
2
2
3
3
3
3
3
3
3
3
3
80.5±3.3
73.7±3.6
77.4±4.3
83.9±3.3
86.5±4.2
85.1±3.8
82.3±4.3
78.1±3.2
63.1±2.7
79.4±4.8
89.6±4.1
82.6±5.1
85.9±2.5
36.1±2.9
31.6±5.0
57.1±6.5
64.9±7.0
61.3±3.8
64.1±3.7
62.7±2.2
35.7±2.8
43.4±3.8
63.9±3.2
68.7±5.8
67.6±3.5
65.1±1.6
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57
58
CH2CH3
CH2CH3F
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CH2CH3Cl
CH2CH3Br
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61
(CH2)2CH3
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CH(CH3)COCH3
63
64
CH3
65
66
CH2CH3
(CH2)2CH3
-
O
-
3
-
Avermectinb
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a The average of three tests.
b The commercial nematicide avermectin was used as a positive control.
Table 4. The nematicidal activities of the compounds 67−72 against citrus nematodes.
mortality/%a
Compound
R3
100 mg/L
78.0±4.4
50 mg/L
57.3±7.1
CH3
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68
CH2CH2F
CH2CH2Cl
CH3
89.4±2.1
81.3±4.9
85.0±3.4
91.0±2.7
86.4±4.7
85.9±2.5
50.7±6.8
48.2±1.4
68.1±7.1
73.9±4.7
68.0±2.6
65.1±1.6
69
70
71
72
CH2CH3
(CH2)2CH3
-
Avermectinb
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a The average of three tests.
b The commercial nematicide avermectin was used as a positive control.
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The some LC50 values of compounds 1−72 were tested to further evaluate the
nematicidal activities (Table 5). The compounds 16, 42, 44, 53, and 71 showed
excellent nematicidal activities, with the LC50 of 16.3, 18.8, 20.8, 17.5, and 14.7
mg/L, respectively, which were superior to the control agent of avermectin (24.8
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mg/L). Meanwhile, the nematicidal activities of the compounds 16 and 71 were also
evaluated at different times and concentrations (Fig. 8). The nematicidal activities of
the compounds 16 and 71 against citrus nematodes were lower than that of the
avermectin at 1 and 10 h at the concentration of 100 mg/L, but after 10 h, the
nematicidal activities of the compounds 16 and 71 were better than that of the
avermectin. At the same time, the nematicidal activities of the compounds 16 and 71
against citrus nematodes were consistently higher than that of avermectin at 48 h at
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different concentrations.
Table 5. The LC50 of some compounds against citrus nematodes.
Compound
LC50/mg/La
23.9±3.9
16.3±1.3
18.8±3.1
24.8±5.7
Compound
LC50/mg/La
20.8±7.4
17.5±5.2
14.7±2.2
-
15
16
42
44
53
71
-
Avermectinb
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150
a The average of three tests.
b The commercial nematicide avermectin was used as a positive control.
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Fig. 8 (A) The changes of the nematicidal activities for the compounds 16 and 17 at different
times when the concentration was 100 mg/L. (B) The changes of the nematicidal activities for the
compounds 16 and 17 at different concentrations when the time was 48 h.
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The overall structure-activity relationship of the compounds 1–72 against citrus
nematodes at the concentration of 100 mg/L is as follows: (a) When R2 = -Cl, and R3
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= -CH3, the nematicidal activities of those compounds decreased gradually with Y =
-SCH2-, -SCH2CH2-, -OCH2-, -OCH2CH2CH2-, and -SCH2CH2CH2-. Such as the
nematicidal activities of the compounds 41 (Y = -SCH2-, R2 = -Cl, R3 = -CH3) > 52
(Y = -SCH2CH2-, R2 = -Cl, R3 = -CH3) > 17 (Y = -OCH2-, R2 = -Cl, R3 = -CH3) > 64
(Y = -OCH2CH2CH2-, R2 = -Cl, R3 = -CH3) > 57 (Y = -SCH2CH2CH2-, R2 = -Cl, R3 =
-CH3). (b) When R2 and Y are unchanged, the nematicidal activities of those
compounds with R3 = -CH3 is less the compounds with R3 = -CH2CH3. Such as the
nematicidal activities of the compounds 18 (Y = -OCH2-, R2 = -Cl, R3 = -CH2CH3) >
17 (Y = -OCH2-, R2 = -Cl, R3 = -CH3). (c) If R2 and Y have not changed, the
nematicidal activities of those compounds can be improved when the R3 is ethyl, and
a H atom on ethyl is substituted by a F atom. such as the nematicidal activities of the
compounds 27 (Y = -SCH2-, R2 = 3-Cl-5-CF3, R3 = -CH2CH2F) > 25 (Y = -SCH2-, R2
= -3-Cl-5-CF3, R3 = -CH2CH3). In general, changes in the flexible chains (Y =
-SCH2-, -SCH2CH2-, -OCH2-, -OCH2CH2CH2-, or -OCH2CH2CH2-) have little effect
on the nematicidal activities of those compounds. However, the changes of the
substituents R2 and R3 can significantly affect the nematicidal activities of those
compounds. Meanwhile, when the para-position of those compounds are substituted
by a F or Cl atom, and R3 are substituted by a short-chain alkyl chain containing an
electronegative atom, those are beneficial to the improvement of the nematicidal
activities.
The platform named Insecticide Physicochemical-properties Analysis Database
(InsectiPAD) (http://chemyang.ccnu.edu.cn/ccb/database/InsectiPAD/), which covers
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495 approved insecticides and over 22,200 related physicochemical properties, was
used to evaluate the insecticide-likeness of the compound 71 and positive control
avermectin based on previously reported methods.25,26 The insecticide-likeness
qualitative and quantitative analysis of the compound 71 and positive control
avermectin were illustrated in Fig. 9. The scores of Relative drug likelihood (RDL),27
Quantitative estimate of insecticide-likeness (QEI),26 Gaussian scoring function
(GAU),28 for the avermectin (Fig.9A) and compound 71 (Fig.9B) and were 1.884,
0.112, 1.259, and 1.632, 0.751, 6.027, respectively. The values of molecular weight
(MW), log of the octanol−water partition coefficient (ALogP), number of hydrogen
bond acceptors (nHBAcc), number of hydrogen bond donors (nHBDon), number of
rotatable bonds (nRotB), number of aromatic rings (nAromBond) for the compound
71 were 220-320, 1-3, 2, 0, 4-6, 10-15, respectively, which coincide with Lipinski’s
Ro5 approach.29-31
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Fig. 9 (A) The insecticide-likeness qualitative and quantitative analysis of the commercial
nematicide avermectin. (B) The insecticide-likeness qualitative and quantitative analysis of the
compound 71. RDL, Relative drug likelihood, QEI, Quantitative estimate of insecticide-likeness,
GAU, Gaussian scoring function, MW, molecular weight, ALogP, log of the octanol-water
partition coefficient, nHBAcc, number of hydrogen bond acceptors, nHBDon, number of
hydrogen bond donors, nRotB, number of rotatable bonds, nAromBond, number of aromatic rings.
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It can be known from the analysis of insecticide-likeness that the avermectin has
lower QEI (0.112) and GAU (1.259), but it has a higher RDL (1.884), which may be
caused by the characteristics of the avermectin (large molecular weight, lower AlogP
and nAromBond, high nRotB, nHBDon, and nHBAcc). Meanwhile, the compound 71
exhibits potential insecticide-likeness, with the RDL, QEI, and GAU of 1.632, 0.751,
6.027, respectively, which may be determined by the better AlogP, nAromBond, and
nRotB.
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208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
In summary, seventy-two novel 1,3,4-oxadiazole thioether derivatives containing
flexible-chain moieties were designed and synthesized. The results of the nematicidal
activity assay showed that compounds 16, 42, 44, 53, and 71 had the better
nematicidal activities against citrus nematodes than the positive control agent of
avermectin. The structure-activity relationship of the compounds was analyzed and
the compound 71 exhibits the potential insecticide-likeness. This work demonstrates
that novel 1,3,4-oxadiazole sulfide derivatives containing flexible chain moieties have
the potential to protect citrus trees, and deserve further consideration in future
research.
Acknowledgments
The authors are grateful to the National Key Research and Development Program of
China (2018YFD0200100) and National Natural Science Foundation of China (No.
21672044) for supporting the project.
Abrreviations
LC50, Median lethal concentration, RDL, Relative drug likelihood, QEI, Quantitative
estimate of insecticide-likeness, GAU, Gaussian scoring function, MW, molecular weight, ALogP,
log of the octanol-water partition coefficient, nHBAcc, number of hydrogen bond acceptors,
nHBDon, number of hydrogen bond donors, nRotB, number of rotatable bonds, nAromBond,
number of aromatic rings.
Declaration of interest
The authors declare no competing financial interest.
Supporting information
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The Materials and Methods of this article can be found online at https://doi.org/.
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Declaration of interests
☑ The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:
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32.
1. Seventy-two 1,3,4-oxadiazole thioether derivatives containing flexible-chain
moieties were designed and synthesized.
2. The LC50 values of the compounds 16, 42, 44, 53, and 71 were 16.3, 18.8, 20.8,
17.5, and 14.7 mg/L.
3. The structure-activity relationship of the series of the compounds was analyzed.
334
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4. The pesticide-likeness analysis shows that the compound 71 exhibits the potential
insecticide-likeness.
336
33.
21

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34.
338
35.
22

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36.
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37.
341
38.
23

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39.
343
344
40.
41.
24

345
346
42.
Table 1. The nematicidal activities of the compounds 1−22 against citrus nematodes.
mortality/%a
Compound
R2
R3
100 mg/L
71.3±1.9
71.6±1.9
64.2±2.5
74.0±1.0
70.4±1.6
50.4±1.8
43.1±2.0
59.8±1.9
43.0±2.3
66.2±1.6
63.3±1.4
51.3±1.4
33.1±2.0
50 mg/L
43.0±1.9
40.4±2.1
33.1±2.5
48.7±2.1
39.1±2.8
27.6±0.7
27.7±1.3
29.7±1.1
26.2±2.0
40.5±3.0
38.9±1.1
31.3±1.6
14.6±1.1
1
2
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
5-CF3
CH3
CH2CH3
CH2CN
3
4
CH2CH2F
CH2CH2Br
(CH2)3CH3
(CH2)4CH3
CH3
5
6
7
8
9
5-CF3
CH2CN
10
11
12
13
5-CF3
CH2CH2F
CH2CH2Cl
CH(CH3)2
(CH2)4CH3
5-CF3
5-CF3
5-CF3
25

14
5-F
5-F
CH3
CH2CH3
CH2CH2F
CH3
82.2±2.3
92.5±1.0
93.7±1.4
79.9±1.6
90.3±1.8
35.9±1.5
47.7±3.1
56.5±2.1
45.2±2.6
85.9±2.5
53.4±3.6
69.4±1.2
72.3±0.7
57.6±2.4
65.2±0.6
15.7±1.5
22.3±0.8
32.7±1.3
21.0±1.8
65.1±1.6
15
16
5-F
17
5-Cl
18
5-Cl
CH2CH3
CH3
19
3,5,6-triCl
3,5,6-triCl
3,5,6-triCl
3,5,6-triCl
-
20
CH2CH3
CH2CH2F
CH2CH2Cl
-
21
22
Avermectinb
347
348
a The average of three tests.
b The commercial nematicide avermectin was used as a positive control.
349
350
351
Table 2. The nematicidal activities of the compounds 23−51 against citrus nematodes.
mortality/%a
Compound
R2
R3
CH3
100 mg/L
50 mg/L
23
24
25
26
27
28
29
30
31
32
33
34
35
36
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
77.9±2.5
46.4±3.8
CH2Cl
83.7±3.0
83.0±2.1
71.4±3.1
91.5±3.6
89.1±2.6
85.0±3.3
72.0±2.1
58.1±2.0
75.2±3.2
54.4±2.8
50.9±2.5
48.6±2.9
35.2±3.1
54.3±2.8
51.0±3.1
29.7±1.7
62.7±3.2
60.3±1.4
50.4±2.9
30.7±1.8
34.6±2.9
23.1±2.3
36.8±3.0
25.9±2.7
17.5±2.6
14.9±2.1
CH2CH3
CH2CN
CH2CH2F
CH2CH2Cl
CH2CH2Br
(CH2)2CF3
(CH2)2CH3
(CH2)2CN
CH(CH3)2
(CH2)3CH3
(CH2)3CN
(CH2)4CH3
26

37
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
3-Cl-5-CF3
5-Cl
CH2Ph(2-F)
CH2Ph(2-Cl)
CH2Ph(2-CN)
CH2Ph(2-CH3)
CH3
18.8±1.8
15.4±1.3
16.3±2.0
36.5±2.8
92.6±2.2
92.8±2.9
75.0±3.3
93.5±2.8
83.3±2.4
78.5±2.7
66.0±5.4
42.5±2.9
28.2±3.1
22.6±3.2
26.1±2.4
85.9±2.5
6.6±1.8
6.4±2.0
38
39
5.8±0.9
40
16.4±2.0
64.2±4.1
71.3±2.6
38.2±3.6
70.6±2.7
62.6±2.2
41.3±3.2
33.0±2.7
16.6±2.6
11.3±3.0
10.1±2.3
12.1±1.7
65.1±1.6
41
42
5-Cl
CH2CH3
43
5-Cl
CH2CN
44
5-Cl
CH2CH2Cl
CH2CH2Br
(CH2)2CF3
(CH2)3CH3
(CH2)3CN
CH2Ph(2-F)
CH2Ph(2-Cl)
CH2Ph(2-CN)
-
45
5-Cl
46
5-Cl
47
5-Cl
48
5-Cl
49
5-Cl
50
51
5-Cl
5-Cl
Avermectinb
-
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
a The average of three tests.
b The commercial nematode avermectin was used as a positive control.
27

372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
392
Table 3. The nematicidal activities of the compounds 52−66 against citrus nematodes.
mortality/%a
Compound
R3
X
n
100 mg/L
82.6±5.1
50 mg/L
67.6±3.5
52
53
54
55
56
57
58
59
60
61
62
63
64
65
CH3
CH2CH3
S
S
S
S
S
S
S
S
S
S
S
S
O
O
2
2
2
2
2
3
3
3
3
3
3
3
3
3
91.3±1.7
84.1±3.3
80.5±3.3
73.7±3.6
77.4±4.3
83.9±3.3
86.5±4.2
85.1±3.8
82.3±4.3
78.1±3.2
63.1±2.7
79.4±4.8
89.6±4.1
71.1±2.1
65.2±5.8
36.1±2.9
31.6±5.0
57.1±6.5
64.9±7.0
61.3±3.8
64.1±3.7
62.7±2.2
35.7±2.8
43.4±3.8
63.9±3.2
68.7±5.8
(CH2)2CH3
CH(CH3)2
CH2CH(CH3)2
CH3
CH2CH3
CH2CH3F
CH2CH3Cl
CH2CH3Br
(CH2)2CH3
CH(CH3)COCH3
CH3
CH2CH3
28

66
(CH2)2CH3
-
O
-
3
-
82.6±5.1
85.9±2.5
67.6±3.5
65.1±1.6
Avermectinb
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
a The average of three tests.
b The commercial nematicide avermectin was used as a positive control.
Table 4. The nematicidal activities of the compounds 67−72 against citrus nematodes.
mortality/%a
Compound
R3
100 mg/L
78.0±4.4
50 mg/L
57.3±7.1
CH3
67
68
CH2CH2F
CH2CH2Cl
CH3
89.4±2.1
81.3±4.9
85.0±3.4
91.0±2.7
86.4±4.7
85.9±2.5
50.7±6.8
48.2±1.4
68.1±7.1
73.9±4.7
68.0±2.6
65.1±1.6
69
70
71
72
CH2CH3
(CH2)2CH3
-
Avermectinb
411
412
413
414
415
416
417
418
419
420
421
a The average of three tests.
b The commercial nematicide avermectin was used as a positive control.
29