Synthesis and nematicidal activities of 1,2,3-benzotriazin-4-one containing 4,5-dihydrothiazole-2-thiol derivatives against Meloidogyne incognita

Article abstract of DOI:10.1080/10426507.2019.1661413

A series of novel 1,2,3-benzotriazin-4-one derivatives containing 4,5-dihydrothiazole-2-thiol were synthesized and characterized by ¹H NMR, ¹³C NMR, ¹⁹F NMR and HRMS. The bioassay results showed that compounds 3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)-7-methoxybenzo[d][1–3]triazin-4(3H)-one, 3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)-6-nitrobenzo[d][1–3]triazin-4(3H)-one, 7-chloro-3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)benzo[d][1–3]triazin-4(3H)-one exhibited good control efficacy against the cucumber root-knot nematode disease caused by Meloidogyne incognita at the concentration of 10.0 mg L^?1 in vivo. Compound 7-chloro-3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)benzo[d][1–3]triazin-4(3H)-one showed excellent nematicidal activity with inhibition 68.3% at a concentration of 1.0 mg L^?1. It suggested that the structure of 1,2,3-benzotriazin-4-one containing 4,5-dihydro-thiazole-2-thiol could be optimized further.

Full text of DOI:10.1080/10426507.2019.1661413

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Synthesis and nematicidal activities of
1,2,3-benzotriazin-4-one containing 4,5-
dihydrothiazole-2-thiol derivatives against
Meloidogyne incognita
Xiulei Chen, Zhen Zhou, Zhong Li & Xiaoyong Xu
To cite this article: Xiulei Chen, Zhen Zhou, Zhong Li & Xiaoyong Xu (2019): Synthesis and
nematicidal activities of 1,2,3-benzotriazin-4-one containing 4,5-dihydrothiazole-2-thiol derivatives
against Meloidogyneꢀincognita, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2019.1661413
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2019.1661413
Synthesis and nematicidal activities of 1,2,3-benzotriazin-4-one containing
4,5-dihydrothiazole-2-thiol derivatives against Meloidogyne incognita
Xiulei Chena , Zhen Zhoua, Zhong Lia,b, and Xiaoyong Xua,b
aShanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, China;
bShanghai Collaborative Innovation Center for Biomanufacturing Technology, Shanghai, China
ABSTRACT
ARTICLE HISTORY
Received 13 June 2019
Accepted 26 August 2019
A series of novel 1,2,3-benzotriazin-4-one derivatives containing 4,5-dihydrothiazole-2-thiol were
synthesized and characterized by 1H NMR, 13C NMR, 19F NMR and HRMS. The bioassay results
showed that compounds 3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)-7-methoxybenzo[d][1–3]triazin-
4(3H)-one, 3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)-6-nitrobenzo[d][1–3]triazin-4(3H)-one, 7-chloro-
3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)benzo[d][1–3]triazin-4(3H)-one exhibited good control effi-
cacy against the cucumber root-knot nematode disease caused by Meloidogyne incognita at the
concentration of 10.0 mg Lꢀ1 in vivo. Compound 7-chloro-3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)-
benzo[d][1–3]triazin-4(3H)-one showed excellent nematicidal activity with inhibition 68.3% at a
concentration of 1.0 mg Lꢀ1. It suggested that the structure of 1,2,3-benzotriazin-4-one containing
4,5-dihydro-thiazole-2-thiol could be optimized further.
KEYWORDS
1,2,3-benzotriazin-4-one;
4,5-dihydrothiazole-2-thiol;
M. incognita;
nematicidal activity
GRAPHICAL ABSTRACT
Introduction
been brought into market.[5–7] In a broader context, achiev-
ing safe and effective nematicides is a key part of the move
toward environmentally sustainable agriculture.
Root-knot nematodes (Meloidogyne spp.) interact with more
than a thousand plant species in a remarkable manner.[1]
Most plant parasitic nematodes develop from juvenile stage
until reaching the adult stage (stage 1–4, J1–J4). J2 invade
and feed on living plants through a protrusible oral stylet.[2]
Root symptoms, root-gall, or root-necrosis indices, produced
at mid-season or at harvest, also can be correlated with yield
losses caused by Meloidogyne spp. and associated fungi.[2]
Nematode control is becoming more difficult for growers in
many regions of the world. Massive organophosphates and
carbamates compounds relying upon single mode of action
have been restricted.[3] For example, in Europe, most of the
chemical nematicides previously available have been banned
in recent years, due to their intrinsic toxicity, human health
and environmental concerns (European Community direct-
ive 2007/619/EC).[4] In recent years, the newly developed
To the end of 2017 a total of 23 unique sulfur-containing
structures were approved by the FDA.[8] More than 30% of
today’s agrochemicals contain at least one sulfur atom, mainly
in fungicides, herbicides and insecticides (Figure 2).[9]
Moreover, 75% of nematicides have at least one sulfur atom.[9]
Thiazole ring is an important pharmacologically active hetero-
cyclic ring and its reduced analogs such as thiazolines have
been widely studied in medicinal chemistry.[10,11] For example,
many compounds containing a thiazoline (4,5-dihydro-1,3-thia-
zole) fragment exhibited antibacterial, anticancer, antifungal,
etc.[12,13] 4,5-Dihydrothiazole structure was included in the
commercial carbapenems medicine tebipenem pivoxil and mar-
ine natural product with anti-cancer activity (Figure 3).[14,15] 4-
Methyl-2-((3,4,4-trifluorobut-3-en-1-yl) thio)-4,5-dihydrothiazole
containing 4,5-dihydrothiazole-2-thiol showed more than 90%
fluensulfone, fluopyram and fluazaindolizine (Figure 1) have inhibitory activity against M. incognita at a concentration of
CONTACT Xiaoyong Xu
xyxu@ecust.edu.cn
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and
Technology, Shanghai, 200237, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
Supplemental data for this article can be accessed on the publisher‘s website.
ß 2019 Taylor & Francis Group, LLC

2
X. CHEN ET AL.
Figure 1. Nematicidal chemicals developed in recent years.
Figure 2. Examples of agrochemicals containing sulfur atom.
Figure 3. The structure of Tebipenem pivoxil, Largazole and Structure from Bayer’s patent.
10.0 mg Lꢀ1 in Bayer’s patent (Figure 3).[16–18] 4,5- investigated the biological activities of the new molecules
Dihydrothiazole-2-thiol as a structure containing two S atoms
absorbs our attention (Scheme 1).
against M. incognita in vivo (Figure 6).
Recently, we have reported that 1,2,3-benzotriazin-4-one
derivatives 1–4 (Figure 4) had significant inhibitory activities
against M. incognita.[19–21] Sulfur-containing 1,2,3-benzotria-
zin-4-one derivative 5 and 6 were also reported to have anti-
parasitic activity against arthropod pest and nematicidal
activity against Anguillula nematodes, respectively
(Figure 5).[22,23]
Results and discussion
Synthesis
In our research, all of target compounds with various sub-
stituents can be obtained easily though the reported method.
During the synthetic process of intermediates substituted 3-
bromoalkyl-1,2,3-benzotriazin-4-ones (11), substituted 3-(3-
Based on the reports above, in this study, we introduced
4,5-dihydrothiazole-2-thiol into title compounds and hydroxypropyl) benzo[d][1–3] triazin-4(3H)-one (14) and

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Scheme 1. Synthetic procedure for title compounds. Reagents and conditions: (a) triphosgene (BTC), THF, ꢀ5 ꢁC, 5h. (b) (NH4)2CO3, 1,4-dioxane, 60 ꢁC, 8h. (c) i.
NaNO2, 1.0 M HCl, H2O, 0 ꢁC, 2 h; ii. 30% NaOH, pH ¼ 8, 15 min; (d) 1,2-dibromoethane, K2CO3, acetone, reflux 5–8 h, (e) K2CO3, acetone, reflux 5–8 h.
Figure 4. Compounds reported in our previous studies.
assigned as examples.). Compound A1 was obtained and con-
firmed by the X-ray diffraction (Figure 7) (Data was shown in
Table S2 and S3, Supplementary Materials).[25] Some substituted
3-(3-(2-thioxothiazolidin-3-yl)propyl)benzo[d]
[1–3]-triazin-4
(3H)-one (13) were obtained as by-products in yield of 0–40%.
But the other by-products were not obtained due to the effect
of different substituents. As the starting material 4,5-dihydro-
thiazole-2-thiol and the title compounds were hard to separate
with flash chromatography on silica gel and the reaction pro-
cess was difficult to be monitored by TLC, the content of the
4,5-dihydrothiazole-2-thiol should be less than substituted 3-
bromoalkyl-1,2,3-benzotriazin-4-ones in the reaction system.
Figure 5. Bioactive agrochemicals containing triazinone skeletons.
substituted 3,30-(propane-1,3-diyl) bis (benzo[d][1–3] tria-
zin-4 (3H)-one) (15) were also obtained as by-products.[24]
Water should be reduced as less as possible in the reaction
system in order to decrease the production of by-product
(14) due to the hydrolysis. The amount of 1,3-dibromopro-
pane was three times than substituted 1,2,3-benzotriazin-4-
one (10) to decrease the production of 15. Detailed data was
described in the Supplementary Material.
The other isomer of 4,5-dihydrothiazole-2-thiol is thiazoli-
dine-2-thione, it was reasonably foreseeable thing that keto
form of title compounds was also obtained. The structures were
well-characterized by 1H NMR, 13C NMR, and HRMS
(Original spectrum of the compounds were in Supplementary
Biological activity
As shown in Table S1 (Supplementary Materials), the in
vivo nematicidal activities of title compounds (A1–A18)
against M. incognita were initially evaluated at a concentra-
tion of 20.0 mg Lꢀ1. The preliminary bioassays indicated
that some of the target compounds had good inhibitory
activity against M. incognita at 20 mg Lꢀ1. The inhibitory
materials, and 1H NMR of A3 and 13C NMR of A1 were rate of compound A4, A7 and A12 reached 80%, 70% and

4
X. CHEN ET AL.
Figure 6. Design of target compounds.
Figure 7. X-ray crystal structure of A1 (Data was shown in Table S2 and S3).
100%, respectively. But compound A16 was toxic to the they feed before invading the root.[26] So it is hard for com-
plants and resulted in the death of plant at this concentra-
tion. All the by-products (B1–B5) had no inhibitory activity
against M. incognita at 20 mg Lꢀ1. When the concentration
decreased to 10 mg Lꢀ1, A12 and A16 kept more than 50%
inhibition, then when the concentration decreased to 1 mg
Lꢀ1 further, only compound A12 exhibited 68.3% inhibition.
Analyzing the influence of substituents, it was found that
when electron-donating group OCH3, electron-withdrawing
group NO2 or Cl, were introduced into the 1,2,3-benzotria-
zin-4-one, compound A4 (7-OCH3) and A12 (7-Cl) showed
higher inhibitory activity than others at 20 mg Lꢀ1, which
indicated that 7 position of 1,2,3-benzotriazin-4-one played
a positive role in promoting the nematicidal activity of the
target compounds. To evaluate the effect of substituents at 7
position of the 1,2,3-benzotriazin-4-one ring, different types
of substituted groups were introduced into 7 position of
1,2,3-benzotriazin-4-one. A12 (7-Cl) showed better inhibi-
tory activity than A14 (7-CH3), A15 (7-F), A17 (7-I) and
A18 (7-CF3). But A16 exhibited toxic to the plant at this
concentration.
In addition, the in vitro nematicidal evaluation of com-
pounds A1–A18 and B1–B5 against M. incognita was con-
ducted. As a positive control, avermectin had the LC50 of
1.0 0.1 mg Lꢀ1. Unexpectedly, all synthesized compounds
showed only <5% corrected mortalities at 50.0 mg Lꢀ1 (not
listed here), which indicated that these compounds had no
contact activity against M. incognita. The significant differ-
ence between in vivo and in vitro data attracted our atten-
tion. Root-knot nematodes are obligate biotrophic pathogens
pounds to get into the nematode before the feeding behav-
ior. Thus, these compounds could not kill the nematodes
directly like some nervous toxicants such as avermectin and
organophosphate nematicides. We supposed that the active
compounds may affect the movement of nematodes and
host finding or they could change the rhizosphere micro-
biology of the plant, strengthening antagonism against
nematodes.[27,28]
Experimental
Chemistry
Synthesis of substituted Anthranilamides (9). A suspension of
substituted isatoic anhydride (35 mmol), ammonium carbon-
ate (140 mmol), and 1,4-dioxane (150 mL) was heated at
60 ꢁC. After stirring for 8 h, the reaction mixture was cooled
to room temperature and evaporated under reduced pres-
sure, and then water (200 mL) was added to the residue,
which was extracted with CH2Cl2 (3 ꢂ 80 mL). The organic
layer was dried over anhydrous Na2SO4 and concentrated to
give compounds 9 in yields of 63–94%.
Synthesis of substituted 1,2,3-benzotriazin-4-ones (10)
(except 8-nitrobenzo[d][1–3]triazin-4(3H)-one).[29] A solution
of anthranilamide (30 mmol) in 1 N HCl (120 mL) was
stirred at 0 ꢁC for 20 min. Then, sodium nitrite (60 mmol)
dissolved in deionized water (100 mL) was added dropwise
to the above solution for 40 min. After another 2 h of stir-
ring at 0 ꢁC, 30% NaOH solution was added slowly to adjust
that can only feed on living cells. There is no evidence that pH value to 8.0. The reaction mixture was allowed to stir

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
vigorously for 15 min. The precipitated product was filtered, never exceeded 1% v/v. The one-week age cucumber seed-
washed with deionized water (200 mL), and dried to afford lings were replanted in sterilized sand in test tubes (one
compounds 10 in yields of 40–92%.
seedling per test tube, tube size: 20 ꢂ 250 mm), and the roots
Synthesis of substituted 3-bromoalkyl-1,2,3-benzotriazin-4- of each seedling were treated with 3 mL of test solution.
ones (11). A stirring suspension of substituted 1,2,3-benzo- Then approximately 2000 living J2 nematodes were inocu-
triazin-4-one (6 mmol), 1,3-dibromopropane (18 mmol), lated into the rhizosphere sand of each host plant.
potassium carbonate (12 mmol), and acetone (50 mL) was Fenamiphos and avermectin (B1) at concentrations of 20.0,
10.0, 5.0 and 1.0 mg Lꢀ1 served as positive control, and the
refluxed for 5–8 h and then cooled to room temperature.
The reaction solution was concentrated under reduced pres- negative control group was prepared in the same way but
sure, and water (100 mL) was added to the residue, which lacked the tested compound. Distilled water without nemat-
was extracted with CH2Cl2 (2 ꢂ 50 mL). The organic layer
odes served as blank control. Each treatment was replicated
was dried over anhydrous Na2SO4, concentrated, and puri- four times and the experiment was repeated three times. All
fied with flash chromatography on silica gel, eluting with the above test tubes were incubated at 20–25 ꢁC for 45 d,
petroleum ether (60–90 ꢁC)/EtOAc to afford compounds 11
with 10 h in the daylight and 14 h in the dark per day. The
in yields of 36–62%.
number of root knots in each test tube was counted and
recorded a score. The inhibition on J2 of M. incognita was
calculated by comparison with the negative control group
(Computing formula 1):
General synthetic procedure for target compounds (12). To
a mixture of compound 11 (2 mmol), potassium carbonate
(2 mmol), and acetone (20 mL), 4,5-dihydrothiazole-2-thiol
(1.9 mmol) was added, and then refluxed. The reaction pro-
cess was monitored by TLC. After the complete consump-
tion of 4,5-dihydrothiazole-2-thiol, the reaction was cooled
to room temperature. The reaction mixture was evaporated
under reduced pressure, and water (100 mL) was added to
the residue, which was extracted with CH2Cl2 (2 ꢂ 50 mL).
The organic layer was dried over anhydrous Na2SO4, con-
centrated, and purified with flash chromatography on silica
gel, eluting with petroleum ether (60–90 ꢁC)/EtOAc to afford
compounds 12 in yields of 56–70%. And some of the by-
products 13 were also obtained in yields of 0–40%. (Other
data of target compounds and by-products are presented in
the Supplemental Materials together with 1H and 13C
NMR spectra)
3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)benzo[d][1–3]-
triazin-4(3H)-one (A1): white solid, yield 50%; mp:
92.4–93.0 ꢁC; 1H NMR (400 MHz, CDCl3) d 8.35 (dd,
J ¼ 8.0, 1.2 Hz, 1H, Ph-H), 8.15 (d, J ¼ 8.0 Hz, 1H, Ph-H),
7.99–7.91 (m, 1H, Ph-H), 7.85–7.77 (m, 1H, Ph-H), 4.59 (t,
J ¼ 6.9 Hz, 2H, CH2), 4.13 (t, J ¼ 8.0 Hz, 2H, CH2), 3.36 (t,
J ¼ 8.0 Hz, 2H, CH2), 3.21 (t, J ¼ 7.2 Hz, 2H, CH2), 2.36 (p,
J ¼ 7.0 Hz, 2H, CH2) ppm; 13C NMR (100 MHz, CDCl3) d
164.94 (C ¼ N), 155.54 (C ¼ O), 144.26 (Ph-C), 134.78 (Ph-
C), 132.33 (Ph-C), 128.27 (Ph-C), 125.06 (Ph-C), 119.81
(Ph-C), 64.10 (CH2), 48.56 (CH2), 35.45 (CH2), 29.61 (CH2),
28.80 (CH2) ppm. HRMS m/z (ESþ) calcd. for
C13H14N4NaOS2 (M þ Na)þ, 329.0507; found, 329.0500.
1. Computing formula
Inhibition ð%Þ ¼ ½ðscore of negative control
– score of treatmentÞ=ðscore of negative controlÞꢃ
ꢂ 100:
Scoring criteria: 0: 0–5 knots; 5: 6–10 knots; 10: 11–20
knots; 20: more than 20 knots.
Nematicidal activity in vitro
Pure compounds (A1–A18 and B1–B5) were dissolved in
DMSO and diluted with distilled water to obtain stock solu-
tions of double the treatment concentration. Then, 2 mL of J2
aqueous suspension containing approximately 200 living nem-
atodes was added to a 6 cm diameter Petri dish and treated
with 2 mL of the above solution, meanwhile providing series
concentrations of 50.0, 25.0, 10.0, 5.0, and 1.0 mg Lꢀ1. The
final concentration of DMSO in each treatment never exceeded
1% (v/v). Avermectin (B1) at the above same treatment con-
centrations served as a positive control, and the negative con-
trol group was prepared in the same way but lacked the tested
compound. Distilled water served as a blank control. All of the
above test dishes were covered with the laboratory parafilm to
avoid the possible evaporation or pollution. Each treatment
was incubated at 25 ꢁC for 24 h and had three repetitions.
Nematodes in each test dish were collected after washing in
sterile water through a 500-mesh sieve, and finally, the activ-
ities of tested compounds were monitored under a microscope
Biological assay
The second-stage juveniles (J2) of M. incognita used in all tests by recording the death rates of tested nematodes. Nematodes
were cultured by Huzhou Modern Agricultural Biotechnology that did not move when prodded with a needle were consid-
Innovation Center, Chinese Academy of Sciences, China.
ered to be dead. The LC50 values of tested compounds were
calculated using the probit method.
Nematicidal activity in vivo
Conclusion
All compounds (A1–A18 and B1–B5) were dissolved with
DMSO, then diluted with distilled water to obtain series In conclusion, a series of novel 1,2,3-benzotriazin-4-one deriva-
concentrations of 20.0, 10.0, 5.0, and 1.0 mg Lꢀ1 for bioas- tives bearing 4,5-dihydrothiazole-2-thiol were synthesized, the
says. The final concentration of DMSO in each treatment nematicidal activities against M. incognita were evaluated in

6
X. CHEN ET AL.
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[11] Bandgar, B. P.; Adsul, L. K.; Chavan, H. V.; Shringare, S. N.;
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We are very thankful to Dr. Bingli Gao and his coworkers in Huzhou
Modern Agricultural Biotechnology Innovation Center, Chinese
Academy of Sciences, China, for the nematicidal evaluation. We are
very thankful to He Nan Metab BioPharma Co., Ltd. for providing the
test of X-ray.
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Funding
This work was financially supported by National Natural Science
Foundation of China (21672061), National Key Research Program of
China (2018YFD0200105, 2017YFD0200505). This work was also sup-
ported by the Fundamental Research Funds for the Central
Universities.
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ORCID
[15] Hong, J.; Luesch, H. Largazole: From Discovery to Broad-
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