Controllable Soil Degradation Rate of 5-Substituted Sulfonylurea Herbicides as Novel AHAS Inhibitors

Article abstract of DOI:10.1021/acs.jafc.9b06679

Chlorsulfuron has been applied in wheat fields as a recognized herbicide worldwide, yet it was officially banned in China since 2014 for its soil persistence problem. On the basis of our previous research that 5-dimethylamino distinctively accelerated degradation rate in soils, a modified amino moiety (Ia-c) and monosubstituted amino group (Id-e) were introduced onto the fifth position of the benzene ring in sulfonylurea structures, as well as heterocyclic amino substituents (If-g) to seek a suitable soil degradation rate during such an in situ crop rotation system. Referring to the biological data and ScAHAS inhibition and ScAHAS docking results, they turned out to be AHAS inhibitors with high potent herbicidal activities. The various influence on soil degradation rate along with crop safety indicated that different substituents on the fifth position have exerted an apparent impact. Their united study of structure-activity-safety-degradation relationship has great potential to provide valuable information for further development of eco-friendly agrochemicals.

Full text of DOI:10.1021/acs.jafc.9b06679

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Agricultural and Environmental Chemistry
Controllable Soil Degradation Rate of 5-Substituted
Sulfonylurea Herbicides as Novel AHAS Inhibitors
Shaa Zhou, Fan-Fei Meng, Xue-Wen Hua, Yong-Hong Li, Bin
Liu, Baolei Wang, Jie Chen, An-Liang Chen, and Zheng-Ming Li
J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.9b06679 • Publication Date (Web): 14 Feb 2020
Downloaded from pubs.acs.org on February 18, 2020
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Page 1 of 39
Journal of Agricultural and Food Chemistry
Controllable Soil Degradation Rate of 5-Substituted
Sulfonylurea Herbicides as Novel AHAS Inhibitors
†
,‡
‡
§
‡
Shaa Zhou, Fan-Fei Meng, Xue-Wen Hua, Yong-Hong Li,
‡
‡
†
†
,‡
Bin Liu, Bao-Lei Wang, Jie Chen, An-Liang Chen, Zheng-Ming Li*
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Controllable Soil Degradation Rate of 5-Substituted
Sulfonylurea Herbicides as Novel AHAS Inhibitors
Shaa Zhou,*,†,‡ Fan-Fei Meng, Xue-Wen Hua, Yong-Hong Li,
‡
§
‡
‡
‡
†
†
,‡
Bin Liu, Bao-Lei Wang, Jie Chen, An-Liang Chen, Zheng-Ming Li*
†
Collaborative Innovation Center of Green Pesticide, National Joint Engineering Laboratory
of Biopesticide Preparation, Zhejiang A&F University State Key Laboratory of Subtropical
Silviculture, School of Forestry and Biotechnology, Zhejiang A & F University, Hangzhou
311300, Zhejiang, China
‡State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of
Chemical Science and Engineering (Tianjin), College of Chemistry, Nankai University,
Tianjin 300071, China
§College of Agriculture, Liaocheng University, Liaocheng 252000, China
*Address correspondence to Zheng-Ming Li at State Key Laboratory of
Elemento-Organic Chemistry, Nankai University, No. 94, Weijin Road, Nankai
District, Tianjin 300071, China (telephone: +86 022-23503732; Fax: +86
0
22-23503732; e-mail: nkzml@vip.163.com)
*Address correspondence to Shaa Zhou at School of Forestry and Biotechnology,
Zhejiang A & F University, No. 666, Wusu st., Linan District, Hangzhou 311300,
China (telephone: +86 0571-61073177; e-mail: xiaomizhoulove@163.com)
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Abstract: Chlorsulfuron has been applied in wheat fields as a recognized herbicide
worldwide, yet it was officially banned in China since 2014 for its soil persistence
problem. On the basis of our previous research that 5-dimethylamino distinctively
accelerated degradation rate in soils, a modified amino moiety (Ia-c) and
th
mono-substituted amino group (Id-e) were introduced onto the 5 position of the
benzene ring in sulfonylurea structures, as well as heterocyclic amino substituents
(If-g) to seek a suitable soil degradation rate during such an in situ crop rotation
system. Referring to the biological data, ScAHAS inhibition and ScAHAS docking
results, they turned to be AHAS inhibitors with high potent herbicidal activities. The
various influence on soil degradation rate along with crop safety indicated that
1
1
1
1
1
th
different substituents on the 5 position have exerted apparent impact. Their united
study of Structure-Activity-Safety-Degradation Relationship has great prospect to
provide valuable information for further development of eco-friendly agrochemicals.
Keywords: Sulfonylurea herbicides, bioactivity, crop safety, soil degradation
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Introduction
ALS (acetolactate synthase), also named AHAS (acetohydroxyacid synthase) is a
crucial enzyme that catalyzes the biosynthesis of 3 essential amino acids (leucine,
1
isoleucine and valine) in plants. Once AHAS is inhibited, the synthesis of proteins
and the cell division will be blocked and finally results in the growth-inhibition and
2
death of harmful herbs. Sulfonylurea herbicides (SUs) as AHAS inhibitors have been
widely used due to their potent activity, low dosage, good selectivity, broad spectra of
herbs and safety for mammals.3,4 Nowadays, the weed resistance especially the
mutation of genes has challenged the use of commercial ALS-inhibiting herbicides
that traditional SUs should be renewed.5-9
Due to the in situ crop rotation system in China, the Ministry of Agriculture of
China banned the application of 3 sulfonylurea herbicides in 2014 on account of their
long persistence in soil.10-13 The long existence of these sulfonylureas in soil is
detrimental to the following sensitive seedlings, usually as paddy, wheat, corn, bean
and cotton.14 In recent years, a few sulfonylurea herbicides with a 5 substituent
group on the benzene ring such as Flupyrsulfuron-methyl and Iodosulfuron-methyl
sodium have been reported.15,16 The special 5th substituents have attracted our
attention that they might have significant influence on degradation rate.
th
th
Working on the assumption, our group firstly found that the 5 substituents on the
benzene ring in sulfonylureas distinctively affected their hydrolysis rate in phosphate
buffer. Furthermore, the smaller size of substituents attributed to the more accelerated
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hydrolysis rate.17-19 Afterwards, we systematically studied the soil degradation of our
structurally modified Chlorsulfuron and Metsulfuron-methyl whose soil degradation
th
20-23
rate were considerably influenced by various 5 substituent groups.
In particular,
the dimethylamino group accelerated their soil degradation rate by 25-30 times in
acidic (pH 5.41) and alkaline (pH 8.46) soils in comparing with Chlorsulfuron, with
their half-live as 0.43 and 3.36 days respectively. However, the degradation rate is too
fast to be used in practice that it should be optimized further. We designed
compounds Ia-c that an electron-withdrawing group (EWG) linked to the 5-N atom to
moderate the electronic effect comparing with 5-dimethyl amino group. After that, the
mono-substituted groups N-methyl amino (Id), N-trifluoroacetyl amino (Ie) as well as
heterocyclic amino substituents (If-g) were intended to be introduced onto the 5th
position of the benzene ring to study their different influence on bioactivities and crop
safety,
in
addition
with
soil
degradation
rate.
Their
Structure-Activity-Safety-Degradation Relationship should be taken as an integration
to be studied which is in favor to seeking novel ecological-benign weed regulators.
Materials and Methods
Instruments and materials. All reaction reagents were analytical grade, all
reagents for high performance liquid chromatograph (HPLC) were chromatographic
grade, and the water phase was double-distilled water. The melting points were
determined on an X-4 binocular microscope melting point apparatus (Beijing Tech
1
13
Instrument Co., Beijing, China), and the temperatures were uncorrected. H and C
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nuclear magnetic resonance (NMR) spectra were obtained on a Bruker AV-400
spectrometer (Bruker Co., Switzerland) in DMSO-d solution with tetramethylsilane
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(TMS) as the internal standard, and chemical-shift values (δ) were given in parts per
million (ppm). High-resolution mass spectrometry (HRMS) data were obtained on a
Varian QFT-ESI instrument. Elemental analyses were performed on a Vario EL
elemental analyzer. Ultraviolet (UV) spectra were performed on a TU-1810
ultraviolet-visible spectrophotometer (Persee general analysis Co., Beijing, China).
HPLC data were obtained on a SHIMADZU LC-20AT (SHIMADZU Co., Japan).
Column chromatography purification was carried out using silica gel (200~300
mesh).
General procedure for the synthesis of compounds 4 and 13.24 In a
round-bottom flask, 5-amino-2-chlorobenzenesulfonamide 3 (5 mmol) was added into
o
15 mL dichloromethane (DCM) solvent. The mixture was cooled to 0 C,
trifluoroacetic anhydride (TFAA, 6 mmol) was added dropwise and stirred for 0.5
hour. After completion of the reaction, the solution was evaporated in vacuum to
obtain compound N-(4-chloro-3-sulfamoylphenyl)-2,2,2-trifluoroacetamide 4.
Compound 13 was synthesized according to the same procedure.
General procedure for the synthesis of compounds 5 and 10.25 At room
temperature,
to
a
20
mL
dichloromethane
solution
of
N-(4-chloro-3-sulfamoylphenyl)-2,2,2-trifluoroacetamide 4 (10 mmol) was added
N,N-Dimethylformamide dimethyl acetal (DMF-DMA, 10 mmol) dropwise. The
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completed reaction mixture was evaporated in vacuum to get compound
N-(4-chloro-3-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-2,2,2-trifluoroaceta
mide 5. Compound 10 was obtained using the same procedure.
General procedure for the synthesis of compound 6.24 To a suspension of
N-(4-chloro-3-(N-((dimethylamino)methylene) sulfamoyl)phenyl)-2,2,2-trifluoro-
acetamide 5 (8 mmol) and potassium carbonate (K CO , 8.8 mmol) in dry DMF
2
3
solvent (25 mL) was added iodomethane (CH I, 16 mmol) under stirring. The mixture
3
o
was heated to 45 C for 2 hours until the reaction was completed. The cooled mixture
was added to ice water (300 mL) following filtration. The filter cake was dried under
vacuum
drying
oven
to
obtain
N-(4-chloro-3-(N-((dimethylamino)
methylene)sulfamoyl)phenyl)-2,2,2-trifluoro-N-methylacetamide 6.
General procedure for the synthesis of compound 7.26 To a solution of
N-(4-chloro-3-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-2,2,2-trifluoro-N-m
ethylacetamide 6 (1.5 mmol) in 10 mL ethanol was added 80 % hydrazine hydrate
(H NNH ·H O, 15 mmol), the mixture was stirred at room temperature for 2 hours
2
2
2
and evaporated in vacuum to afford 2-chloro-5-(methylamino)benzenesulfonamide 7.
2
7
General procedure for the synthesis of compounds 8, 12, 14, 16, 19 and 22. In
a round-bottom flask, potassium carbonate (10 mmol) was added into an acetone
solution dissolved with 2-chloro-5-(methylamino)benzenesulfonamide 7 (5 mmol)
and then stirred for several minutes before ethyl chloroformate (12 mmol) was added.
The reaction mixture was heated to reflux for 4 hours, evaporated in vacuum, and
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dissolved in 20 mL water to adjust pH to 1 by 2M hydrochloric acid (HCl). The
aqueous phase was extracted by ethyl acetate, and the organic phase was washed by
saturated salt solution, dried by anhydrous sodium sulfate, filtered and the filtrate was
evaporated to form ethyl (4-chloro-3-(((ethoxycarbonyl)amino)sulfinyl)phenyl)
(methyl)carbamate 8. Compounds 12, 14, 16, 19 and 22 were prepared by the similar
procedure except that the amount of ethyl chloroformate was 1.2 equivalent of the
relative reaction material.
General procedure for the synthesis of compound 9.28 The compounds
5-amino-2-chlorobenzenesulfonamide 3 (10 mmol) and Di-t-butyl dicarbonate
[(BOC) O, 12 mmol] were added to 20 mL tetrahydrofuran (THF) and refluxed for 6
2
hours.
The
mixture
was
concentrated
to
afford
t-butyl
(4-chloro-3-sulfamoylphenyl)carbamate 9.
2
4
General procedure for the synthesis of compound 11. Under ice bath, sodium
cyanide (NaH, 3.6 mmol) was added to a tetrahydrofuran (THF) solution of
t-butyl-(4-chloro-3-(N-((dimethylamino)methylene)sulfamoyl) phenyl)carbamate 10
(3 mmol) and stirred for 5 minutes. To the mixture was then added iodomethane (3.6
mmol), stirred for 1 hour, evaporated in vacuum, and extracted by ethyl acetate and
water. The organic phase was washed by saturated salt solution, dried with anhydrous
sodium sulfate, filtered and the filtrate was evaporated to obtain t-butyl
(4-chloro-3-sulfamoylphenyl)(methyl)carbamate 11.
2
4
General procedure for the synthesis of compound 15. To a solution of ethyl
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((2-chloro-5-(2,2,2-trifluoro-N-methylacetamido)phenyl) sulfonyl)carbamate 14 (4
mmol) in methanol/water (12 mL, 5:1, v:v) was added potassium carbonate (3.68
mmol) and stirred for 1 hour at room temperature. The mixture was concentrated and
extracted by ethyl acetate and water. The organic phase was washed by saturated salt
solution, dried with anhydrous sodium sulfate, filtered and the filtrate was purified
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with
silica
gel
column
to
afford
ethyl
((2-chloro-5-(methylamino)phenyl)sulfonyl)carbamate 15.
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General procedure for the synthesis of compound 18 and 21. To a 20 mL
glacial acetic acid solution with 0.5 g 5-amino-2-chlorobenzenesulfonamide 3 was
added 1.0 eq 2,5-dimethoxytetrahydrofuran 17. The mixture was heated to reflux for 3
h, and concentrated following adding appropriate water. The suspension was filtered
to acquire 5-pyrrole-2-chlorobenzenesulfonamide 18. Compound 21 was prepared
with 2,5-dimethoxytetrahydrofuran 17 was substituted by acetonylacetone 20.
General procedure for the synthesis of target compounds Ia-g.30 Ethyl
(4-chloro-3-(N-((4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamoyl)sulfamoyl)phenyl)
(methyl)carbamate Ia was prepared as followed. In
a
flask, ethyl
(4-chloro-3-(((ethoxycarbonyl)amino)sulfinyl)phenyl)(methyl)carbamate 8 (1.0 mmol)
and 2-amino-4-methoxy-6-methyl-1,3,5-triazine (1.2 mmol) were added into a toluene
solution. The mixture was stirred and heated to reflux for 7 hours with continuous
removal of ethanol. After completion of the reaction, the solvent was evaporated in
vacuum and the residue was purified on silica gel column eluting with
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petroleum/ethyl acetate (v/v, 1:1) to obtain Ia. Ib-g were synthesized by the same
procedure.
Herbicidal activity assay. Inhibition of the root-growth of rape (Brassica
campestris): the experiment was carried out with plating method for its high
2
7
efficiency. The chemicals were solved in DMF and diluted with distilled water into
-1
10, 1, 0.1 μg·mL to form inhibitor solutions. Rape seeds were soaked in distilled
water for 4 h that they were placed on a filter paper in a 6-cm Petri plate (15 seeds per
plate) followed the addition of 2 mL inhibitor solution, and each treatment was
triplicated. The plates were placed in dark incubator to germinate for 65 h at 25 (±2)
oC. The length of 10 rape roots selected from each plate were measured and the
inhibition rate was calculated.
Pot trials: the herbicidal activities against dicotyledons oil seed rape (Brassica
campestris), amaranth (Amaranthus retroflexus) and monocotyledons barnyard grass
(Echinochloa crusgalli), crab grass (Digitaria sanguinalis) were further examined by
soil and foliage treatment in greenhouse (25 ± 2 °C) following reported
procedures.27,31 The applied concentration was 15 and 150 g·ha , and each treatment
was triplicated. Soil treatment: sandy clay (100 g) was placed into a 6 cm-diameter
plastic flowerpot and 15 sprouting weed seeds were planted (about 0.6 cm depth) and
-1
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sprayed of tested chemicals with spray tower at 900L·ha volume. Foliage treatment:
the seeding was conducted following adjusting the moisture and temperature, and the
tested chemicals were sprayed until the weeds grew up to one leaf and one stem stage.
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For pot trials, the fresh weight of weeds was determined after 21 days, and the
inhibition rate was calculated. The variance analysis of the data was performed by the
Duncan multiple comparisons with the DPS16.5 software.
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Enzyme kinetic study of ScAHAS. In order to investigate whether the new
structures are AHAS inhibitors and foresee their herbicidal activities, the assay
against ScAHAS were conducted according to the reported procedures.32-34 The
expression and purification of ScAHAS catalytic subunit was operated as previously
described.35 There was a blank control without substrate pyruvate and a standard
control without inhibitor in each assay. The inhibitor was dissolved in DMSO and
diluted into 300, 150, 60, 24, 12, 6, 3, 1.2 μM to form inhibitor solution. To 3 mL
inhibitor solution was added 60 μL reaction buffer (a mixture of 75 mM pH 7.5
phosphate buffer, 15 mM MgCl , 1.5 mM ThDP and 15 μM FAD), 10 μL
2
double-distilled water, 7 μL pyruvate and 10 μL purified ScAHAS. The mixed system
o
was reacted for 1h at 37 C, terminated by adding 10 μL 3 M H SO and reacted for
2
4
o
15min at 60 C to promote the formation of acetoin from acetolactate. The reaction
system was then added 200 μL the mixture of 0.5% creatine and 5% α-naphthol,
o
incubated for 15min at 60 C to obtain a pink product and the A was measured. The
5
25
apparent inhibition constant Kapp i was obtained by fitting to the equation
v=v /(1+[I]/Kapp i) and the higher value of pKapp i (-lgKapp i) means the higher
0
inhibition capacity of corresponding compound. The assay was proceeded taking
Chlorsulfuron as active control.
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Molecular docking. To further verify the biological mechanism, Id was studied
about the binding mode to ScAHAS (Saccharomyces cerevisiae AHAS) with the
3
6
surflex-docking method by using the SYBYL 6.9 software package. The energy of
structures were minimized using the Tripos force field with the Gasteiger-Huckel
3
7
method before they were docked into the active site of ScAHAS based on the crystal
complex of Chlorsulfuron and ScAHAS which was retrieved from the RCSB Protein
Data Bank (1yhz.pdb).38
Crop safety assay. Wheat safety test: the wheat was dealt with selected compound
through soil and foliage treatment via pot trials in greenhouse (25 ± 2 °C). The
-1
applied concentration was 15 、 30 、 60 、 120 g·ha , and each treatment was
triplicated. In soil treatment, the compound was sprayed onto the soil in cups (d=7 cm)
following the seeding performance. After that, the moisture was maintained and
cultivated in greenhouse. The fresh weight of the cover crop was measured after 22
days, and the safety was represented by the inhibition rate. The variance analysis of
the data was performed by the Duncan multiple comparisons with the SPSS 22.0
software. In foliage treatment, the seeding was conducted following adjusting the
moisture and temperature until the wheat grew to four-leaf stage. The compound was
sprayed, and the result was measured after 28 days, the same procedure as soil
treatment.
Corn safety test: the corn safety was conducted by soil treatment as wheat. After
soil treatment of the relevant concentration of selected compound in cups (d=12 cm),
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the seeding was performed following the moisture and temperature adjustment. The
result was determined after 22 days, and variance analysis was proceeded as wheat
safety.
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Soil degradation assay. The study about soil degradation was conducted according
to the following steps.22,23 First, soil selection was the most key factor. The acidic and
alkaline soils were sampled from the fresh farmland (the upper layer, 0-25 cm) in
Jiangxi and Hebei Province respectively, air-dried in the shade, screened by 2 mm
o
sieve and stored under 4 C freezer according to the Chinese National Standard GB/T
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31270.1-2014. The physical data about the soil texture, organic matter, pH value,
cation exchange capacity (CEC) and mechanical composition which are listed in
Table S1 were tested by Tianjin Institute of Agriculture Resource and Environment.
Second, HPLC conditions of target compounds were explored and standard curves
were established according to the Chinese National Standard GB/T 16631-2008.40
The wavelength of each compound was determined by UV detector and the retention
time should remain between 10-20 minutes. Third, the various extraction solvents
were tried and recovery rate was measured according to the Chinese Agricultural
Industry Standard NY/T 788-2004.41 The recovery rate of each compound should
range from 70% to 130% with proper extraction solvent in 20 g soil at the
-1
concentration of 5, 2, 0.5 mg·kg respectively, and the soil humidity was kept at 60%
of the water holding capacity. Each concentration was replicated for 5 times and the
coefficient of variation should <4%. The analytical data for soil degradation was
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listed in Table S2-5. Last, it is the cultivation of target compounds in incubator at 25 ±
o
1 C and 80% humidity in the dark. The samples of each compound were carried out
-1
for 6 groups and triplicated in each group with initial concentration was 5 mg·kg .
The samples were extracted at 6 different intervals for establishment of the
degradation curves. The degradation curve was set up according to the first-order
kinetic equation and the half-life of degradation (DT ) were calculated by the
5
0
formula: DT = LN(2)/K.
5
0
33 Results and Discussion
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Chemistry. General synthetic route to target compounds Ia-g and intermediates
1-22 are listed in Figure 1. Compound 2 was obtained from the ammoniation by
ammonium hydroxide (H NNH ·H O) of benzene sulfonyl chloride which was
2
2
2
prepared by sodium bisulfite with diazonium in concentrated hydrochloric acid. After
then, the nitro group was successively reducted by iron in ehthanol with 2 drops of
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hydrochloric acid as initiator to give intermediate 3. In proceeding the methylation
of amino group from compound 3 to 7, the trifluoroacetic anhydride (TFAA) and
N,N-dimethylformamide dimethyl acetal (DMF-DMA) were selected to protect the
amino and sulfonamido groups respectively, and K CO was taken as the base instead
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of NaH to avoid unwanted deprotection and further methylation of sulfonamido group.
The deprotection of trifluoroacetyl and N,N-dimethylformimidamide group were
proceeded with H NNH ·H O in ehthanol to afford compound 7. Similarly, the
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trifluoroacetyl group was deprotected by K CO in methanol/water (v:v = 5:1) in the
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preparation of compound 15. Compound 8 was obtained by reaction of compound 7
with 2.0 eq K CO and 2.4 eq ClCO C H , while in preparation of 12、14、16、19、
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22 ， the equivalent of K CO and ClCO C H were 1.0 and 1.2 respectively. The
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pyrrole on the 5 of the benzene ring was obtained by reaction of 5-amino and
2,5-dimethoxytetrahydrofuran or 2,5-dimethoxytetrahydrofuran in glacial acetic acid
to afford intermediates 17 or 21. Finally, the target compound Ia-g were obtained by
reation of ethyl (phenylsulfonyl) carbamate with heterocyclic amine in toluene with
continuous removal of by-product ethanol.
1
Taking the H NMR spectra of target compound Ib for example, the chemical
shift of two active NH in sulfonylurea bridge was at δ 12.90 and δ 11.00 respectively.
The aromatic hydrogen were presented in δ 7.67 and δ 8.08 in singlet peak. The
chemical shift of CH on 5-amino was at δ 3.24, while (CH ) C-O were at δ 1.44. The
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4-CH and 6-CH O in heterocycle amine were displayed in δ 2.46 and δ 3.97
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individually. Comparing the chemical shift of 5-NH in Id and Ie, they appeared
respectively in δ 7.87 and δ 11.77 that the increased shift of Ie may be influenced by
the withdraw effect of trifluoroacetyl group.
Biological activity. The results of root inhibition of oilseed rape (B. campestris)
-1
was listed in Table S6. At 1 and 10 μg·mL , the inhibition rate of all target
compounds exhibited equivalent activity comparing with Chlorsulfuron. With the
decrease of dosage, the inhibition capacity decreased in some degree especially If
-1
whose inhibition rate was just 7.5% at 0.1 μg·mL . On the contrary, Id exhibited
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much more effective inhibition capacity that it’s inhibition rate is 70.8% which is
-1
higher than Chlorsulfuron with 65.4% at 0.1 μg·mL .
After the examination of the inhibition against oilseed rape (B. campestris) root
growth, the target compounds were further proceeded to study the herbicidal activities
against dicotyledons oil seed rape (B. campestris), amaranth (A. retroflexus) and
monocotyledons barnyard grass (E. crusgalli), crab grass (D. sanguinalis) by pre- and
post-emergence treatment with the results were listed in Table 1. Overall scanning of
the herbicidal activities, we observed the high retention of the herbicidal activities
-1
except Ib against monocotyledons while If and Ig are also unideal. At 15 g·ha for
compound Ia, the inhibition capacity against A. retroflexus and E. crusgalli all
surpassed Chlorsulfuron under pre- and post-emergence treatments. While in foliage
treatment, it also behaved better than the control against D. sanguinalis that its
inhibition rate is 41.6% comparing with 0% of Chlorsulfuron. For compound Ic, the
herbicidal activity against tested four grasses are better than Chlorsulfuron not only in
soil treatment but also in foliage treatment. In post-emergence, the inhibition rate
against B. campestris is 95.0-100% which is much higher than 65-70% of
-1
Chlorsulfuron at 15 and 150 g·ha . In the pre- and post-emergence treatment against
-1
D. sanguinalis, the inhibition rate are 100% and 78.2% under 150 g·ha while against
E. crusgalli, they are 96.9% and 81.1%. For compound Id, it displayed 98.7% and
90% inhibition activity against A. retroflexus in soil and foliage treatment which are
better than the control. In D. sanguinalis treatment after emergence, the inhibition rate
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of Id is 41.3% and 71.4% at 15 and 150 g·ha which are better than 0% and 23.6% of
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Chlorsulfuron. For compound Ie, the inhibition rate are 95.6% and 80% against B.
-1
campestris at 15 g·ha , while it encounters A. retroflexus, they are 100% and 80.3%
in soil and foliage treatment respectively.
Enzyme activity. In order to validate whether the new structures are AHAS
inhibitors, the enzyme inhibition assay against ScAHAS was carried out as showed in
Table 2. According to the data described, Id and Ie displayed better activity against
ScAHAS with their pKapp i are 4.41 and 4.15 respectively while Chlorsulfuron’s is
3.83. Taking Kapp ifor the 50% inhibition capacity, the concentration of Id and Ie
needed was 38.6 and 71.1 µM respectively, while Chlorsulfuron needs 149.4 µM. By
contrast, Ia showed lower inhibition activity than Chlorsulfuron with pKapp i as 3.73
while Ib and Ic exhibited similar inhibition activity as 3.80. The enzyme kinetic study
of ScAHAS illustrated that mono-substituted amino group increased the enzyme
inhibition activity while the inhibition of N-methyl-N- EWG amino was weaker.
Molecular docking results. The new structure Id who possess the highest AHAS
inhibition capacity was selected to be docked into the ScAHAS as Figure 2 listed.
From the results, we observed the apparent π−π stacking effect between the
heterocyclic part and the indole ring in tryptophan 574 (TRP 574). There are several
H-bonds within the ligand and arginine 377 (ARG 377) or serine 653 (SER 653) as
the yellow dashed line showed. The conformations of the ligand and interactions with
residues are similar to the complex of Chlorsulfuron and ScAHAS which
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demonstrated that they are consistent to the conventional AHAS inhibitors.
Crop safety results. After screening herbicidal activity of new structures, Ic was
chose to be evaluated about crop safety. The results of wheat (Jimai 22) safety by soil
and foliage treatment are listed in Table S7, and the photography under
post-emergence is showed in Figure 3. From left to right in the photography, the
-1
concentrations were 120、60、30、15 g·ha respectively which was much higher
than applied dosage, and the wheat growth was improved correspondingly. As can be
seen from the results, Ic has the similar safety with Chlorsulfuron in post-emergence
while it has severe damage in pre-emergence. Under foliage treatment, the inhibition
rate of Ic was 4.1%、5.8%、9.7%、9.8% respectively at four concentrations while
Chlorsulfuron’s was -2.2%、0.8%、7.7%、17.1%. In the particular concentration of
-1
120 g·ha , its inhibition rate was just 9.8% which exhibited lower damage than
Chlorsulfuron.
Furthermore, corn (Jinbei 288) safety was taken under pre-emergence as showed in
Figure 4 and Table S8. From left to right in each photography, the concentrations of
-1
Ic were 15、30、60 g·ha respectively while Chlorsulfuron’s were 30、60、120
-1
-1
g·ha . The corn was significantly inhibited by Chlorsulfuron since 30 g·ha as the
inhibition rate were higher than 90%. Comparatively, Ic was moderate that the
inhibition rate were 30.3%、37.1%、55.5% at corresponding concentrations.
After comprehensive consideration of bioactivity and degradation rate, the wheat
safety of Ib、Id and Ie were further evaluated by soil treatment as showed in Figure
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S1 and Table S9. From left to right in each photography, the concentrations were 60
-1
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and 120 g·ha respectively. As the data described, the inhibition rate of Chlorsulfuron
were 18.6% and 39.0% at two dosage treatment. Meanwhile, Ib、Id、Ie were 14.3%
and 28.8% 、 35.9% and 57.4% 、 12.9% and 12.1% which were consistent with
Chlorsulfuron.
Soil degradation results. The degradation of new compounds were firstly
examined in acidic soil (pH 5.59) as showed in Figure S2 and Table 3. Ia-b were
o
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cultivated at 25 C while Ic-e were at 30 C with Chlorsulfuron was taken as control.
o
At 25 C, the half-life (DT ) of Ia and Ib were 11.12 and 4.85 days respectively
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while Chlorsulfuron’s was 16.82 days. The degradation rate of Ib accelerated almost
o
4 times than the control while Ia degraded a bit faster. At 30 C, the degradation rate
of Id and Ie were significantly accelerated with DT as 2.85 and 2.01 days while
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0
Chlorsulfuron’s was 8.08 days. For compound Ic, there seems no acceleration
comparing with the control as its DT was 8.03 days. From the difference of DT of
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0
50
o
Chlorsulfuron at 25 and 30 C, we can find that the soil degradation rate was affected
by both structures and temperatures.
Considering the application geographical area in northern China and the
degradation difficulty in alkaline soils of Chlorsulfuron, the new compounds Ia-e
were finally tested for their alkaline soil degradation. The alkaline soil (pH 8.46)
degradation curves were displayed in Figure S3 and degradation results were listed in
Table 4, with Chlorsulfuron as control. As the table shows, the DT of Chlorsulfuron
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is 210.04 days while the half-live of Ia and Ic are 147.47 and 192.54 days, this
acceleration rate seems to be consistent with the regulation in acidic soil.
Simultaneously, the DT of Ib, Id and Ie are 22.07, 10.34 and 0.76 days that they all
5
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accelerated soil degradation rate dramatically comparing with Chlorsulfuron.
However, the 5-N-trifuoroacetyl amino substituted compound Ie degraded so fast
unpredictably. Comparing their degradation rate with dimethylamino substituted
Chlorsulfuron (DT =0.43 and 3.36 days in acidic and alkaline soils), we observed
5
0
that electron-withdrawing group connected to 5-N atom indeed decelerated soil
degradation than the dimethylamino group. Surprisingly, a single group linked to 5-N
atom accelerated soil degradation rate significantly that it may be instructive for
seeking a new structure that its degradation rate can be suitable in practice.
Unfortunately, the recovery rate of If and Ig in soil degradation assay cannot be
guaranteed between 70-130%. In acidic soil, the sample peaks were overlapped with
soil impurity resulted into the higher extraction rate than 130%. While in the alkaline
soil, the extraction rate was always lower than 70% despite various solvents were
tried and experimented.
In order to optimize the soil degradation rate of sulfonylurea herbicides, a series of
new 5-N substituted sulfonylurea structures with N-methyl-N-EWG (Ia-c),
N-monosubstituted amino (Id-e) and heterocyclic amino substituents (If-g) were
designed and synthesized. The enzyme activity against ScAHAS along with the
docking mode of new ligand to ScAHAS exhibited their AHAS inhibition, while the
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high herbicidal activities against dicotyledons B. campestris, A. retroflexus and
monocotyledons E. crusgalli, D. sanguinalis confirmed this mode of action. Crop
safety at high dosage indicated that this kind of new compounds have great prospect
in practice. The accelerated degradation rate of target compounds has confirmed our
original hypothesis that an electron-withdrawing group connected to 5-N atom (Ia-c)
increases half-life comparing with 5-dimethylamino substituted Chlorsulfuron.
Moreover, we also discovered that mono-substituent groups as N-methyl amino (Id)
and N-trifluoroacetyl amino (Ie) accelerated their soil degradation rate obviously in
comparison with Chlorsulfuron. A map of Structure-Activity-Degradation
Relationship (Figure S4) was established, and the integrated analysis demonstrates a
new approach of controllable degradation rate in SU chemistry.
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ACKNOWLEDGEMENT
This work was supported by the National Key Research and Development Program
of China (No. 2017YFD0200505 and 2017YFD0200507), the Key Research and
Development Program of Zhejiang Province (No. 2019C02024), the Natural Science
Foundation of Zhejiang Province LQ20C140001. We thank Professor Zhen Xi,
Congwei Niu and Jianguo Wang in Nankai University for providing enzyme and
instructions in the enzyme kinetic study of ScAHAS.
Supporting Information description
Figure S1-4, Table S1-9 and Physical properties of the target compounds. word
Herbicidal activities by pre- and post-emergence. excel
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Report of soil analysis. pdf
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FIGURE CAPTIONS
Figure 1 Synthetic procedures for target compounds Ia-g.
Figure 2 Binding mode of Id to ScAHAS.
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Figure 3 Wheat safety photography under post-emergence.
Figure 4 Corn safety photography under pre-emergence.
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