Synthesis and Nematicidal Activities of 1,2,3-Benzotriazin-4-one Derivatives against Meloidogyne incognita

Article abstract of DOI:10.1021/acs.jafc.5b01762

A series of novel 1,2,3-benzotriazin-4-one derivatives were synthesized by the reaction of 3-bromoalkyl-1,2,3-benzotriazin-4-ones with potassium salt of 2-cyanoimino-4-oxothiazolidine in the presence of potassium iodide. Nematicidal assays in vivo showed that some of them exhibited good control efficacy against the cucumber root-knot nematode disease caused by Meloidogyne incognita, up to 100% at the concentration of 10.0 mg L^-1, which indicated that 1,2,3-benzotriazin-4-one derivatives might be potential for novel promising nematicides. The nematicidal activity was influenced by the combination of substituent type, substituted position, and linker length in the molecule. The inhibition rate data at the concentrations of 5.0 and 1.0 mg L^-1 for the compounds with high inhibitory activities were also provided. When tested in vitro, none of them showed direct inhibition against M. incognita. The investigation of a significant difference between in vivo and in vitro data is in progress.

Full text of DOI:10.1021/acs.jafc.5b01762

Page 1 of 34
Journal of Agricultural and Food Chemistry
Synthesis
and
Nematicidal
Activities
of
1
,2,3-Benzotriazin-4-one Derivatives against Meloidogyne
incognita
§
§
§
§,#
*,§,#
Gaolei Wang, Xiulei Chen, Yayun Deng, Zhong Li, and Xiaoyong Xu
§
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China
University of Science and Technology, Shanghai 200237, China
#
Shanghai Collaborative Innovation Center for Biomanufacturing Technology, 130
Meilong Road, Shanghai 200237, China
*
Corresponding author:
Tel: +86ꢀ21ꢀ64252945; Fax: +86ꢀ21ꢀ64252603
Eꢀmail: xyxu@ecust.edu.cn (X. Xu)
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ABSTRACT: A series of novel 1,2,3ꢀbenzotriazinꢀ4ꢀone derivatives were
synthesized by the reaction of 3ꢀbromoalkylꢀ1,2,3ꢀbenzotriazinꢀ4ꢀones with
potassium salt of 2ꢀcyanoiminoꢀ4ꢀoxothiazolidine in the presence of potassium
iodide. Nematicidal assays in vivo showed that some of them exhibited good control
efficacy against the cucumber rootꢀknot nematode disease caused by Meloidogyne
ꢀ1
incognita, up to 100% at the concentration of 10.0 mg L , which indicated that
1,2,3ꢀbenzotriazinꢀ4ꢀone derivatives might be potential for novel
promising nematicides. The nematicidal activity was influenced by the combination
of substituent type, substituted position and linker length in the molecule. The
ꢀ1
1
1
1
1
1
1
inhibition rate data at the concentrations of 5.0 and 1.0 mg L for the compounds
with high inhibitory activities were also provided. When tested in vitro, none of
them showed direct inhibition against M. incognita. The investigation of significant
difference between in vivo and in vitro data is in progress.
KEYWORDS:
1,2,3ꢀbenzotriazinꢀ4ꢀone,
2ꢀcyanoiminothiazolidinꢀ4ꢀone,
nematicide, Meloidogyne incognita, in vivo
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INTRODUCTION
Plantꢀparasitic nematodes cause an annual loss of $157 billion to world crops.
Rootꢀknot nematodes (Meloidogyne spp.) are one of the most severe plantꢀdamaging
1
2
,3
parasitic nematodes, attacking over 3000 plant species throughout the world. Four
major species among them, namely M. incognita, M. javanica, M. arenaria, and M.
4
hapla, are responsible for approximately 95% of all damages caused by RKN. M.
5
incognita, as one of the most important plantꢀparasitic species, cause the formation
of large galls or ‘knots’ in roots of infected plants, and sequential physiological plant
6
disorders.
For decades, chemical nematicides have played a prominent role in the
7
8
management of nematodes, which are efficacious, easy to apply and rapidꢀonset.
Dibromochloropropane (DBCP), known as an effective organochlorine nematicide,
has been banned since 1979 because of its mutagenicity, carcinogenicity and
9
reproductive effects on human. Methyl bromide has been used widely as a fumigant
10
nematicide before it is restricted owing to its detrimental effects on ozonosphere.
Albeit with a long and controversial history in terms of environmental
contamination and adverse impacts on human health, the development of chemical
nematicides have never stopped. To date, a few commercial organophosphorous and
carbamate nematicides are mainly applied for the control of rootꢀknot nematodes,
11
such as ethoprophos, fosthiazate, and oxamyl, and their repeated application has
12
given rise to the resistance development in the target pathogens. The macrocyclic
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lactone avermectin is commonly utilized as seed treatment nematicide because of its
13,14
low water solubility and light unstability.
Recently, the newly developed
trifluorobutenesulfanyl nematicide fluensulfone has been released to the market,
which exhibits high nematicidal activity against rootꢀknot nematodes and a different
15ꢀ17
mode of action compared to conventional nematicides (Figure 1, compound 1).
Tioxazafen, new class of 1,2,4ꢀoxadiazole nematicide with excellent
broadꢀspectrum activity, is still undergoing worldwide development (Figure 1,
a
1
8
compound 2). And some other nitrogenꢀcontaining heterocyclic compounds having
19ꢀ23
certain nematicidal potential are also reported (Figure 1, compounds 3–7).
Besides, botanical nematicides based on plant secondary metabolites have gained
much scientific interest throughout the world. The majority of them are natural
5,6,24,25
product extracts or their simple derivatives,
and none has proven to be very
effective and used in the field. With the growing awareness of the adverse impact on
5,6,17
environment and human health,
organophosphorous and carbamate nematicides
will not adapt to the sustainable development of modern agriculture any more, and
the number of nematicidal agents available to effectively control nematodes will
become more limited. Therefore, the search for novel chemotypes of nematicides,
which are safer, environmentally friendly, and nematodeꢀspecific, has become
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increasingly urgent.
Triazinone, as a heterocyclic skeleton associated with a wide range of pesticide
27ꢀ31
activities (Figure 2, compounds 8–12),
has attracted much attention. Metribuzin
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is wellꢀknown as a widely used triazinone herbicide (Figure 2, compound 8).
Compounds 9 and 10 exhibited plantꢀgrowth regulatory and insecticidal activities,
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respectively.
The 1,2,3ꢀbenzotriazinꢀ4ꢀone derivative 11 was first reported to
3
0
have nematicidal activity against Anguillula nematodes in 1960, and compound 12
3
1
had certain nematicidal activity against Caenorhabditis elegans. However, little
work has been done on nematicidal 1,2,3ꢀbenzotriazinꢀ4ꢀone derivatives against
plantꢀparasitic nematodes.
During the design of 1,2,3ꢀbenzotriazinꢀ4ꢀone derivatives, we found that
thiazolidinꢀ4ꢀone compounds exhibited good inhibitory activities against M.
20
incognita and the neonicotinoid derivative 3 had significant nematicidal activity
ꢀ1 19
against M. incognita at the concentration of 20.0 mg L . Hence, we attempted to
introduce 2ꢀcyanoiminothiazolidinꢀ4ꢀone moieties into the 1,2,3ꢀbenzotriazinꢀ4ꢀone
structure, while the active fragment of compound 3 was also considered, aiming to
obtain more active compounds against M. incognita (Figure 3).
In the present study, we reported for the first time 1,2,3ꢀbenzotriazinꢀ4ꢀone
derivatives containing 2ꢀcyanoiminothiazolidinꢀ4ꢀone moieties and their in vivo and
in vitro biological activities against M. incognita. We also discussed the relationship
between structure and nematicidal activity preliminarily and tried to illuminate the
mechanism of our compounds against nematodes.
MATERIALS AND METHODS
Chemicals. Anthranilic acids (I-1–13) and triphosgene were purchased from
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Shanghai Darui Fine Chemicals Co., Ltd. Ammonium carbonate, sodium nitrite,
hydrochloric acid, potassium hydroxide, potassium carbonate, anhydrous sodium
sulfate and all solvents were purchased from Shanghai Lingfeng Chemical Reagent
Co., Ltd. Nꢀcyanodithiocarbonimidate, 1,2ꢀdibromoethane, 1,3ꢀdibromopropane,
1,4ꢀdibromobutane, 1,5ꢀdibromopentane, 1,6ꢀdibromohexane and potassium iodide
were purchased from Shanghai Aladdin Chemistry Co., Ltd. All reagents and
solvents were of reagent grade without further purification.
Instrumental Analysis. Analytical thinꢀlayer chromatography (TLC) was
performed on precoated glass plates (silica gel 60 F254), visualizing the spots by a
UV lamp (254 nm). All melting points were determined on a Büchi Melting Point
B540 apparatus (Büchi Labortechnik AG, Flawil, Switzerland) and are uncorrected.
1
13
19
6
H, C, and F NMR spectra were recorded in DMSOꢀd on a Bruker AMꢀ400 (400
MHz) spectrometer at ambient temperature. Chemical shifts are reported in δ (parts
per million) values with tetramethylsilane (TMS) as the internal standard. Coupling
constants (J) are reported in hertz. Highꢀresolution mass spectra (HRꢀMS) were
recorded under electroꢀspray ionization condition on a Waters Micromass LCꢀTOF
spectrometer.
3
2
General Procedures. Synthesis of Isatoic Anhydrides (II-1–13). A mixture of
anthranilic acid (I-1–13, 40 mmol) and tetrahydrofuran (THF, 100 mL) was stirred
at ꢀ10 ºC for 30 min. Then a solution of triphosgene (BTC, 40 mmol) in THF (20
mL) was added dropwise to the above mixture. After that, the mixture was stirred for
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1 h at ꢀ10 ºC – ꢀ5 ºC, followed by 18 h at room temperature. The solvent was
removed under reduced pressure, and anhydrous ether (150 mL) was added to the
obtained residue with vigorous stirring. The precipitate was collected by filtration,
washed with anhydrous ether, and dried to afford II-1–13 in yields of 85–95%.
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Synthesis of Anthranilamides (III-1–13). A suspension of isatoic anhydride
(II-1–13, 35 mmol), ammonium carbonate (140 mmol) and 1,4ꢀdioxane (150 mL)
was heated at 60 ºC. After stirring for 5–8 h, the reaction mixture was cooled to
room temperature, evaporated under reduced pressure, and then water (200 mL) was
added to the residue, which was extracted with EtOAc (80 mL × 3). The organic
2 4
layer was washed with brine (80 mL), dried over anhydrous Na SO , and
concentrated to give III-1–13 in yields of above 73–94%.
3
4
Synthesis of 1,2,3ꢀBenzotriazinꢀ4ꢀones (IV-1–13). A solution of sodium nitrite
(4.14 g, 60 mmol) in 0.5 N HCl (240 mL) was stirred at 0 ºC for 20 min. Then
anthranilamide (III-1–13, 30 mmol) dissolved in N, Nꢀdimethylformamide (DMF,
15 mL) was added dropwise to the above solution for 40 min. After another 1 h of
stirring at 0 ºC, 30% aqueous ammonia was added slowly to adjust the pH to 10.0.
The reaction mixture was allowed to stir vigorously for 15 min, and then reacidified
to pH 2.0. After stirring for 30 min, the precipitated product was filtered off with
suction, washed with water (200 mL) and dried to afford IV-1–13 in yields of above
84–92%.
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Synthesis of Potassium Salt of 2ꢀCyanoiminoꢀ4ꢀoxothiazolidine. A stirring
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mixture of dimethyl Nꢀcyanodithiocarbonimidate (11.68 g, 80 mmol), ammonium
carbonate (4.22 g, 44 mmol) and EtOH (120 mL) was heated at 60 ºC for 3 h. To this,
methyl thioglycolate (7.15 mL, 80 mmol) and 50% KOH (aq, 8.96 g, 80 mmol) were
added separately in one portion. The reaction mixture was heated to reflux for 5 h,
and then cooled to room temperature. The precipitate was collected by filtration,
washed with cold EtOH, and dried to give the desirable potassium salt as a light
yellow solid, yield 73%.
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Synthesis of 3ꢀBromoalkylꢀ1,2,3ꢀbenzotriazinꢀ4ꢀones
(V-1–23). A stirring
suspension of 1,2,3ꢀbenzotriazinꢀ4ꢀone (IV-1–13, 6 mmol), dibromoalkane (30
mmol), potassium carbonate (1.66 g, 12 mmol) and acetone (50 mL) was refluxed
for 5–8 h, and then cooled to room temperature. The reaction mixture was
evaporated under reduced pressure, and water (100 mL) was added to the residue,
2 2
which was extracted with CH Cl (50 mL × 2). The organic layer was dried over
anhydrous Na SO , concentrated and purified with flash chromatography on silica
2
4
gel, eluting with petroleum ether (60–90 ºC)/EtOAc to afford V-1–23 in yields of
46–62%.
General Synthetic Procedure for Title Compounds (VI-1–23). To a mixture of V
(2 mmol), potassium iodide (0.332 g, 2 mmol) and DMF (10 mL), potassium salt of
2ꢀcyanoiminoꢀ4ꢀoxothiazolidine (0.358 g, 2 mmol) was added, and then the mixture
was stirred at 100 ºC. The reaction process was monitored by TLC. After the
complete consumption of V, the reaction was cooled to room temperature. The
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solvent was removed under reduced pressure, and water (50 mL) was added to the
residue, which was extracted with CH
2 2
Cl (30 mL × 2). The organic layer was dried
over anhydrous Na SO , concentrated and purified with flash chromatography on
2
4
silica gel, eluting with petroleum ether (60–90 ºC)/EtOAc to afford VI-1–23. The
data of VI-1–10 are shown as follows, whereas data of VI-11–23 are deposited in
Supporting Information.
Nꢀ(4ꢀOxoꢀ3ꢀ(3ꢀ(4ꢀoxobenzo[d][1,2,3]triazinꢀ3(4H)ꢀyl)propyl)thiazolidinꢀ2ꢀyliden
1
e)cyanamide (VI-1): yield, 41%; mp 156.9–157.6 ºC; H NMR (400 MHz,
DMSOꢀd ) δ 8.26 (d, J = 7.6 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.10 (t, J = 7.6 Hz,
6
1H), 7.94 (t, J = 7.6 Hz, 1H), 4.41 (t, J = 7.2 Hz, 2H), 4.30 (s, 2H), 3.74 (t, J = 7.2
13
6
Hz, 2H), 2.21–2.09 (m, 2H); C NMR (100 MHz, DMSOꢀd ) δ 179.6, 173.0, 155.3,
144.1, 135.9, 133.4, 128.5, 125.0, 119.7, 114.1, 47.1, 40.8, 36.1, 26.1. HRMS (ES+)
+
calcd for C14
H
13
N
4
O
2
S (M + H) , 329.0821, found, 329.0823.
Nꢀ(3ꢀ(3ꢀ(7ꢀChloroꢀ4ꢀoxobenzo[d][1,2,3]triazinꢀ3(4H)ꢀyl)propyl)ꢀ4ꢀoxothiazolidin
1
ꢀ2ꢀylidene)cyanamide (VI-2): yield, 52%; mp 163.4–164.2 ºC; H NMR (400 MHz,
DMSOꢀd ) δ 8.35 (d, J = 2.0 Hz, 1H), 8.25 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 7.97
6
1
2
(dd, J
1
2
= 8.4 Hz, J = 2.0 Hz, 1H), 4.40 (t, J = 7.2 Hz, 2H), 4.29 (s, 2H), 3.74 (t, J =
13
7.2 Hz, 2H), 2.20–2.09 (m, 2H); C NMR (100 MHz, DMSOꢀd
6
) δ 179.6, 172.9,
154.8, 144.9, 140.3, 133.6, 127.7, 127.3, 118.6, 114.0, 47.3, 40.8, 36.1, 26.0. HRMS
3
5
+
(ES+) calcd for C14
H
11
N
6
O
2
NaS Cl (M + Na) , 385.0250, found, 385.0258; calcd
37
+
for C14
H
11
N
6
O
2
NaS Cl (M + Na) , 387.0221, found, 387.0232.
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Nꢀ(3ꢀ(3ꢀ(8ꢀBromoꢀ4ꢀoxobenzo[d][1,2,3]triazinꢀ3(4H)ꢀyl)propyl)ꢀ4ꢀoxothiazolidin
1
ꢀ2ꢀylidene)cyanamide (VI-3): yield, 35%; mp 159.7–160.6 ºC; H NMR (400 MHz,
DMSOꢀd
6
) δ 8.38 (d, J = 7.6 Hz, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.82 (t, J = 7.6 Hz,
1H), 4.41 (t, J = 6.8 Hz, 2H), 4.30 (s, 2H), 3.75 (t, J = 6.8 Hz, 2H), 2.26–2.07 (m,
13
2H); C NMR (100 MHz, DMSOꢀd
6
) δ 179.6, 173.0, 154.5, 141.4, 139.4, 134.2,
124.9, 122.9, 121.8, 114.1, 47.5, 40.8, 36.1, 26.0. HRMS (ES+) calcd for
7
9
+
81
C
14
H
12
N
6
O
2
S Br (M + H) , 406.9926, found, 406.9927; calcd for C14
12 6 2
H N O S Br
+
(M + H) , 408.9905, found, 408.9908.
Nꢀ(3ꢀ(3ꢀ(7ꢀFluoroꢀ4ꢀoxobenzo[d][1,2,3]triazinꢀ3(4H)ꢀyl)propyl)ꢀ4ꢀoxothiazolidin
1
ꢀ2ꢀylidene)cyanamide (VI-4): yield, 32%; mp 171.1–171.6 ºC; H NMR (400 MHz,
DMSOꢀd
Hz, 1H), 7.82 (td, J
3.74 (t, J = 7.2 Hz, 2H), 2.23–2.07 (m, 2H); F NMR (376 MHz, DMSOꢀd
6
) δ 8.34 (dd, J
1 2 1 2
= 8.8 Hz, J = 6.0 Hz, 1H), 8.09 (dd, J = 9.2 Hz, J = 2.4
1
= 8.8 Hz, J = 2.4 Hz, 1H), 4.41 (t, J = 7.2 Hz, 2H), 4.29 (s, 2H),
2
19
6
) δ
1 2 10 6 2
ꢀ101.8 (td, J = 9.0 Hz, J = 5.6 Hz). HRMS (ES–) calcd for C14H N O
FS (M –
–
H) , 345.0570, found, 345.0570.
Nꢀ(3ꢀ(3ꢀ(6ꢀ(Trifluoromethyl)ꢀ4ꢀoxobenzo[d][1,2,3]triazinꢀ3(4H)ꢀyl)propyl)ꢀ4ꢀoxot
1
hiazolidinꢀ2ꢀylidene)cyanamide (VI-5): yield, 31%; mp 174.6–175.4 ºC; H NMR
6
(400 MHz, DMSOꢀd ) δ 8.50 (s, 1H), 8.46–8.38 (m, 2H), 4.44 (t, J = 7.2 Hz, 2H),
1
9
4.30 (s, 2H), 3.75 (t, J = 7.2 Hz, 2H), 2.23–2.11 (m, 2H); F NMR (376 MHz,
+
DMSOꢀd
6
) δ ꢀ61.5 (s). HRMS (ES+) calcd for C15
H
11
N
6
O
2
F
3
NaS (M + Na) ,
419.0514, found, 419.0519.
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Nꢀ(3ꢀ(3ꢀ(8ꢀMethylꢀ4ꢀoxobenzo[d][1,2,3]triazinꢀ3(4H)ꢀyl)propyl)ꢀ4ꢀoxothiazolidin
1
ꢀ2ꢀylidene)cyanamide (VI-6): yield, 34%; mp 166.5–167.3 ºC; H NMR (400 MHz,
DMSOꢀd
6
) δ 8.07 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.80 (t, J = 7.6 Hz,
1H), 4.41 (t, J = 7.2 Hz, 2H), 4.29 (s, 2H), 3.73 (t, J = 7.2 Hz, 2H), 2.77 (s, 3H),
13
6
2.23–2.09 (m, 2H); C NMR (100 MHz, DMSOꢀd ) δ 179.6, 172.9, 155.4, 142.4,
137.7, 136.5, 133.1, 122.6, 119.8, 114.0, 47.1, 40.9, 36.1, 26.1, 17.1. HRMS (ES+)
+
calcd for C15
H
15
N
6
O
2
S (M + H) , 343.0977, found, 343.0979.
Nꢀ(3ꢀ(3ꢀ(8ꢀMethoxyꢀ4ꢀoxobenzo[d][1,2,3]triazinꢀ3(4H)ꢀyl)propyl)ꢀ4ꢀoxothiazolidi
1
nꢀ2ꢀylidene)cyanamide (VI-7): yield, 40%; mp 190.0–190.9 ºC; H NMR (400 MHz,
DMSOꢀd
6
) δ 7.86 (t, J = 8.0 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 8.0 Hz,
1H), 4.39 (t, J = 7.2 Hz, 2H), 4.29 (s, 2H), 4.04 (s, 3H), 3.72 (t, J = 7.2 Hz, 2H),
13
6
2.22–2.04 (m, 2H); C NMR (100 MHz, DMSOꢀd ) δ 179.6, 172.9, 155.9, 155.1,
134.5, 134.4, 120.8, 116.8, 115.5, 114.1, 57.0, 47.1, 40.8, 36.1, 26.1. HRMS (ES–)
–
calcd for C15
H
13
N
6
O
3
S (M – H) , 357.0770, found, 357.0769.
Nꢀ(3ꢀ(3ꢀ(5ꢀBromoꢀ4ꢀoxobenzo[d][1,2,3]triazinꢀ3(4H)ꢀyl)propyl)ꢀ4ꢀoxothiazolidin
1
ꢀ2ꢀylidene)cyanamide (VI-8): yield, 39%; mp 201.5–202.5 ºC; H NMR (400 MHz,
DMSOꢀd
6
) δ 8.18 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 7.2 Hz, 1H), 7.91 (t, J = 8.0 Hz,
1H), 4.35 (t, J = 7.2 Hz, 2H), 4.31 (s, 2H), 3.75 (t, J = 7.2 Hz, 2H), 2.22–2.07 (m,
13
2H); C NMR (100 MHz, DMSOꢀd ) δ 179.6, 173.0, 153.5, 145.7, 138.7, 136.1,
6
128.7, 119.2, 118.1, 114.1, 47.6, 40.9, 36.1, 25.9. HRMS (ES–) calcd for
7
9
–
81
14 10 6 2 10 6 2
C H N O S Br (M – H) , 404.9769, found, 404.9773; calcd for C14H N O S Br
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(M – H) , 406.9749, found, 406.9753.
Nꢀ(3ꢀ(3ꢀ(6ꢀNitroꢀ4ꢀoxobenzo[d][1,2,3]triazinꢀ3(4H)ꢀyl)propyl)ꢀ4ꢀoxothiazolidinꢀ2
1
ꢀylidene)cyanamide (VI-9): yield, 46%; mp 186.0–187.8 ºC; H NMR (400 MHz,
DMSOꢀd
6 1 2
) δ 8.86 (d, J = 2.4 Hz, 1H), 8.78 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 8.47
(d, J = 9.2 Hz, 1H), 4.45 (t, J = 6.8 Hz, 2H), 4.30 (s, 2H), 3.76 (t, J = 6.8 Hz, 2H),
13
2.27–2.12 (m, 2H); C NMR (100 MHz, DMSOꢀd ) δ 179.7, 173.0, 154.6, 149.2,
6
146.4, 130.8, 129.8, 121.0, 120.6, 114.1, 47.7, 40.8, 36.1, 26.0. HRMS (ES–) calcd
–
for C14
H
10
N
7
O
4
S (M – H) , 372.0515, found, 372.0519.
Nꢀ(3ꢀ(3ꢀ(7ꢀBromoꢀ4ꢀoxobenzo[d][1,2,3]triazinꢀ3(4H)ꢀyl)propyl)ꢀ4ꢀoxothiazolidin
1
ꢀ2ꢀylidene)cyanamide (VI-10): yield, 41%; mp 180.9–181.0 ºC; H NMR (400 MHz,
DMSOꢀd
6 1 2
) δ 8.49 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.10 (dd, J = 8.4 Hz, J = 1.6
Hz, 1H), 4.40 (t, J = 7.2 Hz, 2H), 4.29 (s, 2H), 3.73 (t, J = 7.2 Hz, 2H), 2.20–2.08
13
(m, 2H); C NMR (100 MHz, DMSOꢀd
6
) δ 179.6, 173.0, 154.9, 144.9, 136.3, 130.7,
129.2, 127.3, 118.9, 114.1, 47.3, 40.8, 36.1, 26.0. HRMS (ES–) calcd for
7
9
–
81
C
14
H
10
N
6
O
2
S Br (M – H) , 404.9769, found, 404.9780; calcd for C14
10 6 2
H N O S Br
–
(M – H) , 406.9749, found, 406.9760.
Assay of Nematicidal Activity. The secondꢀstage juveniles (J2) of M. incognita
used in all tests were cultured by Huzhou Modern Agricultural Biotechnology
Innovation Center, Chinese Academy of Sciences, China.
In vivo. All compounds (VI-1–23) were dissolved with DMF and diluted with
ꢀ1
distilled water to obtain series concentrations of 40.0, 25.0, 10.0, 5.0, and 1.0 mg L
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for bioassays. The final concentration of DMF in each treatment never exceeded 1%
v/v. The oneꢀweek age cucumber seedlings were replanted in sterilized sand in test
tubes (one seedling per test tube, tube size: 20 × 250 mm), and the roots of each
seedling were treated with 3 mL of test solution. Then approximately 2000 living J2
nematodes were inoculated into the rhizosphere sand of each host plant. Fenamiphos
ꢀ1
and avermectin (B1) at concentrations of 5.0 and 1.0 mg L served as positive
control, and the negative control group was prepared in the same way but lacked the
tested compound. Distilled water without nematodes served as blank control. Each
treatment was replicated four times and the experiment was repeated three times. All
the above test tubes were incubated at 20–25 ºC for 20 days, with 10 h in the
daylight and 14 h in the dark per day. The number of root knots in each test tube was
counted and recorded a score. The inhibition rate on J2 of M. incognita was
calculated by comparison with the negative control group:
Inhibition rate (%) = [(score of negative control – score of treatment) / (score of
negative control)] × 100.
Scoring criteria:
0: 0–5 knots; 5: 6–10 knots; 10: 11–20 knots; 20: more than 20 knots.
In vitro. Pure compounds (VI-1–23) were dissolved in DMF and diluted with
distilled water to obtain stock solutions of double the treatment concentration. Then
2 mL of J2 aqueous suspension containing approximately 200 living nematodes was
added onto a 6 cm diameter Petri dish, and treated with 2 mL of the above solution,
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providing series concentrations of 50.0, 25.0, 10.0, 5.0 and 1.0 mg L in the
meanwhile. The final concentration of DMF in each treatment never exceeded 1%
v/v. Avermectin (B1) at the above same treatment concentrations served as positive
control, and the negative control group was prepared in the same way but lacked the
tested compound. Distilled water served as blank control. All the above test dishes
were covered with the laboratory parafilm to avoid the possible evaporation or
pollution. Each treatment was incubated at 25 ºC for 24 hours and had three
repetitions. Nematodes in each test dish were collected after washing in sterile water
through a 500ꢀmesh sieve, and finally the activities of tested compounds were
monitored under a microscope by recording the death rates of tested nematodes.
Nematodes that did not move when prodded with a needle were considered to be
dead. The LC50 values of tested compounds were calculated using the probit method.
RESULTS AND DISCUSSION
Synthesis. Starting from anthranilic acids (I-1–13), the desired isatoic anhydrides
32
(II-1–13) were readily prepared via the annulation reaction with BTC. As shown in
Figure 4, various substituents at nearly every position of the benzene ring were well
2 2 2 2
tolerated except 5ꢀNO and 8ꢀNO . 5ꢀNO or 8ꢀNO isatoic anhydride could not be
obtained from the corresponding anthranilic acid due to the possible formation of
intramolecular hydrogen bond between NO and adjacent carboxyl or amino.
2
3
3
Subsequently, II-1–13 reacted with ammonium to afford anthranilamides (III-1–
13). Notably, ammonium carbonate was utilized here as ammonium source, which
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made synthetic manipulation relatively easier. 1,2,3ꢀBenzotriazinꢀ4ꢀones (IV-1–13)
were synthesized from III-1–13 through the combination of diazotization,
34
nucleophilic addition and cyclization in one pot.
The synthesis of 3ꢀbromoalkylꢀ1,2,3ꢀbenzotriazinꢀ4ꢀones (V-1–13) was carried
out through Nꢀalkylation of IV-1–13 at 3ꢀposition, using dibromoalkane as
3
6
alkylation agent (Figure 6). To minimize the ‘bisꢀ’ product, 5 equiv. of
dibromoalkane was necessary, owing to the existing two reaction sites of
dibromoalkane. Potassium salt of 2ꢀcyanoiminoꢀ4ꢀoxothiazolidine was prepared
35
following the procedure reported in the literature (Figure 5). The potassium salt of
2ꢀcyanoiminoꢀ4ꢀoxothiazolidine has higher nucleophilic activity than
2ꢀcyanoiminoꢀ4ꢀoxothiazolidine, which promoted the nucleophilic substitution.
Then the title compounds (VI-1–23) were synthesized by the reaction of
3ꢀbromoalkylꢀ1,2,3ꢀbenzotriazinꢀ4ꢀones
with
potassium
salt
of
2ꢀcyanoiminoꢀ4ꢀoxothiazolidine in the presence of potassium iodide (Figure 6). The
1
13
structures of the title compounds were well characterized by H NMR, C NMR and
HRꢀMS (ESI).
Nematicidal Activity. As shown in Table 1, the in vivo nematicidal activities of
title compounds (VI-1–23) against M. incognita were initially evaluated at the
ꢀ1
concentration of 40.0 mg L . Some compounds such as VIꢀ1, VIꢀ3, VIꢀ6 and VIꢀ7
showed high nematicidal activities with inhibition rates of 100%, whereas others
were severely toxic to plants with a symptom of root rot. To minimize the
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phytotoxicity of test compounds, a lower treatment concentration was tried. When
ꢀ1
treated at the concentration of 25.0 mg L , the phytotoxicity was significantly
improved and quite a few compounds exhibited moderate to high nematicidal
activities. Among them, compounds VI-2, VI-5, VI-8, VI-14, VI-20, and VI-23
were 100% inhibitory against M. incognita. When the treatment concentration was
ꢀ1
reduced further to 10.0 mg L , all compounds were nematicidal without
phytotoxicity, and compounds VI-2, VI-9, VI-14, VI-20, and VI-23 still keep 100%
inhibitory activities.
ꢀ1
On the basis of the in vivo data at 10.0 mg L in Table 1, it was found that
compounds VI-2 (7ꢀCl, n=1), VI-9 (6ꢀNO , n=1), VI-14 (7ꢀCl, n=0), VI-20 (7ꢀNO
n=4), and VI-23 (7ꢀOCH , n=4) still exhibited 100% inhibitory rates. But we did not
observe the obvious trend with electron withdrawing or donating substituents. When
2
2
,
3
2
Cl, NO , OCH
3
were located at 7ꢀposition (VI-2, VI-14, VI-19, VI-20, and VI-23)
and CF
3
, NO
2
at 6ꢀposition (VI-5, VI-9), or Br at 5ꢀposition (VI-8) on the
1,2,3ꢀbenzotriazinꢀ4ꢀone ring, compounds with proper linkers displayed >90%
inhibitory activities. It indicated that high inhibitory activity seemed not to depend
upon the type of substituents on the 1,2,3ꢀbenzotriazinꢀ4ꢀone ring. When the linker
was fixed as a threeꢀcarbon chain, the activity of compound VI-2 (7ꢀCl) was the
highest among the compounds (VI-1–13) considering that compound VI-9 (6ꢀNO2)
ꢀ1
had the phytotoxicity at 25.0 mg L . Moreover, for other compounds with a
threeꢀcarbon chain, it showed that compound VI-8 (5ꢀBr) had higher activity than
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compounds VI-3 (8ꢀBr) and VI-10 (7ꢀBr), and compounds VI-6 (8ꢀCH
3
), VI-7
),
), respectively. Thus it seemed that the inhibitory
(8ꢀOCH
3
) and VI-9 (6ꢀNO
2
) were more active than compounds VI-11 (6ꢀCH
3
VI-13 (7ꢀOCH
3
) and VI-12 (7ꢀNO
2
activity was affected by the coꢀeffect of substituent type and substituted position on
the premise that the length of flexible linker was fixed.
Furthermore, when the NO or OCH group was fixed at 7ꢀposition, the effect of
2
3
linker length on inhibitory activity was investigated. It was observed that the
activities of compounds did not present a certain regularity with the increasing of
linker length, except compound VI-13. But for Cl at the same substituted position,
the activities did not present a certain regularity with the increasing of linker length.
Thus, it also suggested that inhibitory activities indeed had no positive correlation
with linker length. From the results above, it can be concluded preliminarily that the
inhibitory activity of our synthesized compounds was influenced by the combination
of substituent type, substituted position and linker length, not relying on only one
37,38
factor. It is different from the results reported by Che et al and Li et al.
Che et al
3
reported that a shorter chain length of R and electron deficiency of the indolyl ring
37
were favorable to nematicidal activity, while Li et al reported that electron richness
38
of the benzyl ring was favorable to nematicidal activity.
To determine the strength of activity of title compounds, the nematicidal
ꢀ1
evaluation of the compounds with >90% inhibitory activities at 10.0 mg L such as
VI-2, VI-5, VI-8, VI-9, VI-14, VI-19, VI-20 and VI-23 was continued at lower
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concentrations of 5.0 and 1.0 mg L , but it was found that the inhibitory activities
decreased very quickly with the decreasing of the treatment concentration. All of the
inhibitory rates were less than 41% at these two concentrations. The reason why the
inhibitory rates decreased so quickly still needs to be investigated further.
In addition, the in vitro nematicidal evaluation of compounds VI-1–23 against M.
incognita was conducted. As positive control, avermectin had the LC of 1.0 ± 0.1
50
ꢀ
1
mg L . Unexpectedly, all synthesized compounds showed only ˂5% corrected
ꢀ1
mortalities at 50.0 mg L (not listed here), which indicated that these compounds
had no direct inhibition against M. incognita. The significant difference between in
vivo and in vitro data attracted our attention. One possible reason is that these
compounds could not kill the nematodes directly like some nervous toxicants such
3
9,40
as avermectin but affect the movement and host finding of nematodes,
or they
could change the plant’s rhizosphere microbiology strengthening antagonism against
41
nematodes, somewhat like the DiTera nematicide. Further research is still needed
to verify the possible mechanism.
In conclusion, a series of novel 1,2,3ꢀbenzotriazinꢀ4ꢀone derivatives bearing
2ꢀcyanothiazolidinꢀ4ꢀone were synthesized, and both in vivo and in vitro nematicidal
activities against M. incognita were evaluated. Despite no direct inhibition in vitro,
ꢀ1
some of them exhibited good in vivo inhibitory activities at 10.0 mg L , which
implied that 1,2,3ꢀbenzotriazinꢀ4ꢀone is a potential active structure worth to study
further.
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ACKNOWLEGEMENT
This work was financial supported by National Natural Science Foundation of China
(21272071), National High Technology Research and Development Program of
China (863 Program, 2011AA10A207, 2013AA065202). This work was also partly
supported by Special Fund for Agroꢀscientific Research in the Public Interest
(201103007) and the Fundamental Research Funds for the Central Universities.
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agents. J. Agric. Food Chem. 2013, 61: 5696–5705.
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List of figure captions
Figure 1. Nematicidal chemicals developed in recent years.
Figure 2. Bioactive agrochemicals containing triazinone skeletons.
Figure 3. Design of title compounds (VIꢀ1–23).
Figure 4. Synthetic route of 1,2,3ꢀbenzotriazinꢀ4ꢀones (IVꢀ1–13).
Figure 5. Synthetic route of potassium salt of 2ꢀcyanoiminoꢀ4ꢀoxothiazolidine.
Figure 6. Synthetic route of title compounds (VIꢀ1–23).
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Journal of Agricultural and Food Chemistry
Figure 1. Nematicidal chemicals developed in recent years.
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Figure 2. Bioactive agrochemicals containing triazinone skeletons.
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Journal of Agricultural and Food Chemistry
Figure 3. Design of title compounds (VI-1–23).
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Figure 4. Synthetic route of 1,2,3ꢀbenzotriazinꢀ4ꢀones (IV-1–13).
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