Discovery of ortho-Alkoxy Substituted Novel Sulfonylurea Compounds That Display Strong Herbicidal Activity against Monocotyledon Grasses

Article abstract of DOI:10.1021/acs.jafc.1c02081

In the present study, we have designed and synthesized a series of 42 novel sulfonylurea compounds with ortho-alkoxy substitutions at the phenyl ring and evaluated their herbicidal activities. Some target compounds showed excellent herbicidal activity against monocotyledon weed species. When applied at 7.5 g ha-1, 6-11 exhibited more potent herbicidal activity against barnyard grass (Echinochloa crus-galli) and crab grass (Digitaria sanguinalis) than commercial acetohydroxyacid synthase (AHAS; EC 2.2.1.6) inhibitors triasulfuron, penoxsulam, and nicosulfuron at both pre-emergence and postemergence conditions. 6-11 was safe for peanut for postemergence application at this ultralow dosage, suggesting that it could be considered a potential herbicide candidate for peanut fields. Although 6-11 and triasulfuron share similar chemical structures and have close Ki values for plant AHAS, a significant difference has been observed between their LUMO maps from DFT calculations, which might be a possible factor that leads to their different behaviors toward monocotyledon weed species.

Full text of DOI:10.1021/acs.jafc.1c02081

pubs.acs.org/JAFC
Article
Discovery of ortho-Alkoxy Substituted Novel Sulfonylurea
Compounds That Display Strong Herbicidal Activity against
Monocotyledon Grasses
Hai-Lian Wang, Hao-Ran Li, Yi-Chi Zhang, Wen-Tao Yang, Zheng Yao, Ren-Jun Wu, Cong-Wei Niu,
Yong-Hong Li, and Jian-Guo Wang*
Cite This: J. Agric. Food Chem. 2021, 69, 8415−8427
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ABSTRACT: In the present study, we have designed and synthesized a series of 42 novel sulfonylurea compounds with ortho-alkoxy
substitutions at the phenyl ring and evaluated their herbicidal activities. Some target compounds showed excellent herbicidal activity
against monocotyledon weed species. When applied at 7.5 g ha−1, 6−11 exhibited more potent herbicidal activity against barnyard
grass (Echinochloa crus-galli) and crab grass (Digitaria sanguinalis) than commercial acetohydroxyacid synthase (AHAS; EC 2.2.1.6)
inhibitors triasulfuron, penoxsulam, and nicosulfuron at both pre-emergence and postemergence conditions. 6−11 was safe for
peanut for postemergence application at this ultralow dosage, suggesting that it could be considered a potential herbicide candidate
for peanut fields. Although 6−11 and triasulfuron share similar chemical structures and have close Ki values for plant AHAS, a
significant difference has been observed between their LUMO maps from DFT calculations, which might be a possible factor that
leads to their different behaviors toward monocotyledon weed species.
KEYWORDS: sulfonylurea, monocotyledon, herbicide, AHAS, peanut, LUMO
many are ideal toward gramineous weeds from the
monocotyledon families. For example, barnyard grass (Echino-
chloa crus-galli) has been a pernicious weed in agricultural
fields worldwide for the past few decades, and losses of yield in
rice due to E. crus-galli competition are estimated to be about
35%.13,14 Another case is crab grass (Digitaria sanguinalis), a
troublesome annual weed that causes up to 90% losses of yield
in soybean fields in some parts of the world.15 There is an
urgent need to develop novel herbicides to control these
malignant grasses. It has been difficult to design and discover
AHAS inhibitors with a totally new chemical skeleton. We had
previously found that some isatin derivatives and nonsym-
metrical aryl disulfides are novel AHAS inhibitor families;
however, the in vivo herbicidal activities are much weaker than
those of the commercial AHAS-inhibiting herbicides.16,17 Yang
and Xi et al. developed a conformational flexible inhibitor
design strategy to combat plant AHAS Pro-197-Leu mutation
via rational modification of the pyrimidinylbenzoate family,
through which some excellent herbicidal compounds against
dicot weeds flixweed (Descurainia sophia) and amaranth
(Ammannia arenaria) were identified;18−23 nevertheless,
these studies did not especially aim at eliminating the
monocotyledon grass.
INTRODUCTION
■
Sulfonylurea herbicides have been invented for nearly 40 years,
and it is estimated that over 30 commercial products have been
used globally for crop protection.1,2 Although weed resistance
to these families of herbicides due to overuse by farmers has
become an inevitable concern,3 new sulfonylurea herbicides are
continuously produced by clever modification based on
structure−activity relationships. For example, monosulfuron,
recently developed in China, is a special herbicide used for
millet fields, where traditional sulfonylurea herbicides are
harmful to millet and no other effective herbicides are available
for this agricultural crop.4 The sulfonylureas control weeds by
inhibiting acetohydroxyacid synthase (AHAS, EC 2.2.1.6, also
referred to as acetolactate synthase, ALS), an essential enzyme
playing an important role in the biosynthesis pathway of
branched-chain amino acids (BCAAs), which is regarded to be
a biologically safe target because it does not exist in mammal
bodies.5,6 The mode of action and the binding site of
sulfonylurea herbicides have become clear at the molecular
level since crystal structures of plant AHAS in complex with
these inhibitors have been determined in the past containing
only the AHAS catalytic subunit bound with sulfonylur-
eas.4,7−10 Lately, AHAS full structures composed of both
catalytic and regulatory subunits, from plant and microbial
sources, have been successfully elucidated using either cryo-
EM or X-ray crystallography, and these advances have
provided a more detailed understanding of the functional
features and the inhibitory mechanism.11,12
Received: April 10, 2021
Revised: June 14, 2021
Accepted: July 9, 2021
Published: July 20, 2021
Most sulfonylurea herbicides are effective against broadleaf
weeds belonging to the dicotyledon species; however, not
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AHAS inhibition contributes enormously to herbicidal
activity; however, this is not the sole factor for the herbicidal
behavior of these agrochemicals. As is known, commercial
herbicidal imidazolinones and sulfonylureas are two typical
families of AHAS inhibitors, the application rates of which are
at very similar levels.24 Surprisingly, the Ki values of
imidazolinone herbicides are at the micromolar level, while
the inhibition constants of the sulfonylurea herbicides are at
nanomolar potency.7 In addition, as a totally new class of
AHAS inhibitors, nonsymmetrical disulfides have in vitro
inhibition constants equal to those of imidazolinones, but the
greenhouse herbicidal activity of the former is much weaker
than that of the latter.17 These are the cases for different types
of AHAS inhibitors. If we compare only the sulfonylurea
compounds themselves, such different herbicidal activities also
exist. For example, Ki values of monosulfuron and tribenuron
methyl against plant AHAS are 245 and 316 nM, respectively,
while for chlorsulfuron it is only 14nM,25 but their herbicidal
activities from the rape root growth inhibition method are at
the same level.26 Obviously, other factors involved in the
absorption, distribution, metabolism, and excretion (ADME)
process also have significant contributions to the in vivo
herbicidal activity. Therefore, it is hard to predict the in vivo
herbicidal activity of an AHAS inhibitor even if the in vitro
enzyme inhibition data is available.
ethoxysulfuron, triasulfuron, chlorimuron ethyl, penoxsulam,
and nicosulfuron are shown in Figure 2.
Figure 1. General structures of sulfonylureas (A), imidazolinones (B),
isatin derivatives (C), nonsymmetrical aryl disulfides (D), and
pyrimidinylbenzoates (E).
In many cases, sulfonylurea herbicides have an ester group
attached to the ortho-position for the phenyl ring or the five-
member aromatic ring.25,26 It is notable that some other
sulfonylurea herbicides have an alkoxy substituent at this
position, such as ethoxysulfuron and triasulfuron. Ethoxysulfur-
on is a selective herbicide used to control the dicot weed
species in paddy fields,27 while triasulfuron is a selective
herbicide for the control of the dicot weeds in wheat fields.28
Previously, ethoxysulfuron was also found to possess very
strong antifungal activity against Candida albicans, indicating
that the sulfonylurea compounds with an alkoxy substituent
instead of the ester group might possess better efficiency in the
ADME process,29 based on which a series of novel
ethoxysulfuron derivatives were synthesized and biologically
evaluated.30 For triasulfuron, the heterocycle ring connected to
the urea part is triazine; yet, many sulfonylurea herbicides such
as chlorimuron ethyl, monosulfuron, and ethoxysulfuron have a
pyrimidine ring at this position instead. Although triazine and
pyrimidine are bioisosteric groups, the replacement of one by
the other might result in unexpected biological activity.31−33 In
the present context, a series of ortho-alkoxy substituted novel
sulfonylurea compounds were designed and synthesized. The
in vitro inhibitory data against plant AHAS were measured,
and in vivo herbicidal activities were also determined by both
the rape root growth inhibition method and the greenhouse
pot assay. From the biological results, compounds 6-11 and 6-
21 exhibited fairly exciting herbicidal activity against the
monocotyledon weed species, much better than the
commercial triasulfuron and nicosulfuron. 6-11 also displayed
better herbicidal activity against crab grass than the
commercial AHAS inhibitor penoxsulam. This study has
hence provided meaningful guidance for the discovery of
herbicides to effectively tackle some monocotyledon grasses for
crop protection. The general structures of sulfonylureas,
imidazolinones, isatin derivatives, nonsymmetrical aryl disul-
fides, and pyrimidinylbenzoates are shown in Figure 1. The
structures of monosulfuron, tribenuron methyl, chlorsulfuron,
MATERIALS AND METHODS
■
Instruments and Chemicals. Chemical materials and reagents
were purchased from the following commercial suppliers: Ailai
Chemical (Shanghai), Sanbang Chemical (ChangChun), J&K
Chemical (Beijing), Aladdin Chemical (Shanghai), Fengyan Chemical
(Beijing), Shaoyuan Chemical (Shanghai), Energy Chemical (Shang-
hai), Xiezun Chemical (Nanjing), PharmaCore (Kunshan), Guangfu-
Chem (Tianjin), Heowns Chemical (Tianjin), Hedong Guangda
Chemical (Tianjin), and Tianjin Chemical & Reagents. All solvents
and liquid reagents were dried in advance using standard methods and
distilled before use. Melting points were determined using an RT-2
melting apparatus (Shanghai PuZhe photoelectric Co., Shanghai,
1
China) and were uncorrected. H NMR and 13C NMR spectra were
obtained using a Bruker Avance 400 MHz spectrometer (Bruker
Corporation, Switzerland). The chemical shift values (d) for the
NMR spectra were reported as parts per million (ppm) using
deuterated chloroform (CDCl3), dimethyl sulfoxide (DMSO-d6), or
acetone-d6 as the solvent and tetramethylsilane (TMS) as an internal
reference standard. High-resolution mass spectra were recorded on an
FT-ICR mass spectrometer (Ionspec, 7.0 T). Single-crystal X-ray
diffraction analyses were performed on a Bruker Smart 1000 CCD
diffractometer (Bruker Corporation, Switzerland). In vitro AHAS
inhibition was recorded on a BioTek ELx800 absorbance microplate
reader (BioTek Instruments, Inc., USA). The chemical preparation
procedures of the intermediates (2, 3, 4, and 5) and target
sulfonylurea compounds (6-1 to 6-42) are illustrated in Figure 3.
Synthesis of 2-1 and 2-2. The starting material 2-hydroxybenze-
nesulfonamide 1 was commercially available at PharmaCore.
Potassium carbonate (34.5 g, 250 mmol) was added to a solution
of 1 (8.65 g, 50 mmol) in 150 mL of dimethylformamide (DMF) and
the reactants were stirred at room temperature for 30 min. Then, 1-
fluoro-2-iodoethane or iodoethane (50 mmol) was added to the
reacting mixture. Next, the reaction was heated and continued
overnight under reflux. Subsequently, the mixture was cooled and
filtered. Water (300 mL) was added to the filtrate, and the product
was extracted with ethyl acetate (100 mL × 3). The organic phase was
dried, and the final product 2-1 or 2-2 was further purified in medium
yield using column chromatography.
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Figure 2. Structures of monosulfuron, tribenuron methyl, chlorsulfuron, ethxoysulfuron, triasulfuron, chlorimuron ethyl, penoxsulam, and
nicosulfuron.
Synthesis of 2-3. 2-Hydroxybenzenesulfonamide 1 (6.27 g, 36
mmol), 1,3-dioxolan-2-one (4.12 g, 47 mmol), and imidazole (83 mg,
1.2 mmol) were mixed together, and the reactants were then
protected using a nitrogen atmosphere. Then, the temperature was
increased to 90 °C until the mixture melted completely. The reaction
continued at 160 °C for 4 h and the temperature was decreased to 90
°C again. Ethanol (15 mL) was added to dissolve the mixture in the
next step. A suitable amount of silica gel was added and the solvent
was removed by evacuation. The resulting powder was purified using
column chromatography to give a white solid 2-(2-hydroxyethoxy)-
benzenesulfonamide 2-3 in 80% yield.
Synthesis of 2-4. This preparation was carried out according to a
method reported previously with slight modifications.34 Sulfoxide
chloride (0.95 g, 7.5 mmol) was added slowly to dimethylacetamide
(DMAc, 1.065 g, 12.25 mmol) under an ice bath before the mixture
was stirred at 15 °C for 30 min. 2-(2-Hydroxyethoxy) benzenesulfo-
namide 2-3 (1.10 g, 5 mmol) and dichloromethane (DCM, 2.5 mL)
were then added to the reactants and the reaction continued at room
temperature for 1 h. Then, the mixture was transferred into a mixed
liquid of iced water (25 mL) and DCM (25 mL). Liquid separation
was performed after the mixture was stirred to a homogeneous
condition. The organic phase was washed with iced water until no
DMAc could be detected. Following evacuation and column
chromatography, 2-(2-chloroethoxy)benzenesulfonamide 2-4 was
purified as a white powder in 61% yield.
purification, 2-(2-sulfamoylphenoxy)ethyl methanesulfonate 2-5 was
obtained as a white solid with a yield of 85%.
2-(2-Sulfamoylphenoxy)ethyl methanesulfonate 2-5 (1.714 g, 5.5
mmol), LiBr or NaI (23mmol), and acetone (16 mL) were mixed
together and the reactants were then stirred at 60 °C for 2 h. The
solvent was removed under vacuum and the resulting solid was
washed with water. After recrystallization, 2-(2-bromoethoxy)-
benzenesulfonamide 2-6 or 2-(2-iodoethoxy)benzenesulfonamide 2-
7 was purified in an excellent yield.
Synthesis of 4. The synthesis of these compounds is basically
according to a published method.35,36 After 3 (50 mmol) was
dissolved in tetrahydrofuran (THF, 80 mL), potassium carbonate
(11.7g, 84 mmol) was added to the mixture. Then, phenyl
carbonochloridate (9.4 mL, 50 mmol) was added to the reactants,
and the mixture was stirred for 18 h at room temperature. In the next
step, the reacting mixture was filtered, and THF was evacuated from
the filtrate. Compound 4 was then purified by column chromatog-
raphy in low-to-good yield.
Synthesis of 6-1 to 6-14. For the target sulfonylurea compounds
6-1 to 6-14, compound 4 (0.4 mmol) was dissolved in acetonitrile (5
mL) and compound 2 (0.44mmol) was added to the solution. Then,
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 65μL, 0.44mmol) was
added to the mixture under stirring and the reaction continued
overnight at room temperature. Subsequently, water (10 mL) was
added to the solution and 50% hydrochloric acid was added to adjust
the pH value to 2.0 when precipitants started to appear. The
precipitants were collected after filtration and washed with water to
give the pure final product 6 in desirable yields.
Synthesis of 2-6 and 2-7. 2-(2-Hydroxyethoxy)-
benzenesulfonamide 2-4 (1.6 g, 7.4 mmol), DCM (20 mL), and
anhydrous pyridine (1.7 mL) were mixed together. Subsequently,
methanesulfonic anhydride (Ms2O, 1.53 g, 8.8 mmol) was added to
the mixture under an ice bath. The reaction was stopped after 4 h, and
the solvent was removed under vacuum. After being washed with
water, filtered, and then dried by infrared light without further
Synthesis of 6-15 to 6-42. The target sulfonylurea compounds 6-
15 to 6-42 were synthesized using another conventional route.
Compound 2 (4 mmol) and 1,4-diazabicyclo[2.2.2]octane (DBACO,
4 mmol) were mixed in anhydrous toluene (20 mL). Oxalyl chloride
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Figure 3. Synthetic routes of the intermediates and the target sulfonylurea compounds.
(1.35 mL, 20 mmol) was then added dropwise to the mixture. The
reaction continued for 6 h at 60 °C, and then the temperature was
increased to 90 °C for 12 h. The solid was then separated from the
mixture by filtration, the solvent was removed by evacuation from the
remaining liquid, and phenyl sulfonyl isocyanate 5 was left as a sticky
oil without further purification. Subsequently, anhydrous acetonitrile
(10 mL) was added to the sticky oil, and compound 3 (4 mmol) was
added to the mixture at the ice temperature. Then, the reaction
continued for 12 h at room temperature and acetonitrile was removed
with evacuation. Next, a solution of sodium hydroxide (1 M, 20 mL)
was mixed with the remaining sticky substance and the mixture was
filtered, and the clear solution was kept. Further, 5% hydrochloric acid
was added slowly to the solution until there were no more
precipitants, and the mixture was kept still for 1 h. The final step
was filtration, and the filter residue was washed with water and dried
under infrared light to give the pure product 6 in medium-to-high
yields.
Analytical data and the unreported intermediates and new target
compounds 6-1 to 6-42 are detailed in the Supporting Information.
X-ray Diffraction. The crystal structure of compound 6-21 (0.20
×0.18 × 0.12 mm size) was determined, and X-ray intensity data were
recorded on a Rigaku Saturn 724 CCD diffractometer using graphite
monochromated Mo KR radiation (λ = 0.71073 Å). “Direct methods”
techniques of the Bruker software package SHELXTL were used to
solve the chemical structure.37 All calculations were refined
anisotropically.
Biological Assays. In Vitro Inhibition of Arabidopsis thaliana
AHAS (AtAHAS). The expression and purification of wild-type
AtAHAS have been detailed previously.38 The activity of this plant
AHAS enzyme was measured using the colorimetric assay in a buffer
(pH 7.0) that contained 50 mM potassium phosphate, 50 mM
pyruvate, 1 mM thiamine diphosphate, 10 mM magnesium chloride,
and 10 μM flavin adenine dinucleotide (FAD). The compounds to be
tested were dissolved in DMSO at a concentration of 5 mM and
diluted using MilliQ water to different concentrations. The reaction
mixture was incubated at 37 °C for 30 min before the reaction was
stopped by adding 25 μL of 10% sulfuric acid. Then, the mixture was
heated at 60 °C for 15 min to convert acetolactate into acetoin. The
acetoin formed was quantified by incubation with 0.5% creatine and a-
naphthol (5%, w/v) for 15 min at 60 °C, and A525 was measured.
For the measurement of inhibition constants, trial experiments with
a wide range of inhibitor concentrations were used to establish an
appropriate concentration scope. Subsequently, the AHAS activity
was measured in a series of inhibitor concentrations within this
window. Ki values were analyzed by fitting the data with nonlinear
regression using eqs 1 or 2, where v is the inhibited rate, v0 is the
uninhibited rate, v∞ is the small residual activity for some cases, and
[I] is the total inhibitor concentration.
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non-cross-validated method was used to produce the steric and
electrostatic model to depict the quantitative structure−activity
relationship (3D-QSAR).
v = v /(1 + [I]o/Ki)
(1)
(2)
o
v = (v − v∞)/(1 + [I]o/Ki) + v∞
o
Density Functional Theory (DFT) Calculation. Compounds 6-11,
6-21, and triasulfuron were chosen for DFT geometry optimization by
the SCF method using the B3LYP (Becke, three-parameter,
Lee_Yang_Parr) function with a basis set of 6-31G to describe
their molecular properties.42,43 Gaussian03 was used to perform the
calculations.44 Conformations of 6-11 and 6-12 were taken from the
molecular database from CoMFA analysis, and the 3D structure of
triasulfuron was built based on the 6-11 model.
In Vivo Inhibition of Rage (Brassica campestris L.) Root Growth.
Preliminary herbicidal activity of the sulfonylurea compounds was
evaluated using the rape root growth inhibition method.25 Briefly, a
0.1% water emulsion was prepared by mixing 1 g of emulsifier with
distilled water to a final volume of 1 L. The target compounds were
made into a DMSO stock solution of 30 mg mL−1 concentration and
diluted to different concentrations using the 0.1% water emulsion.
Rape seeds were soaked in distilled water for 4 h and then placed on a
filter paper in a 6 cm Petri plate, to which 2 mL of the inhibitor
solution had been added beforehand. Usually, 10 seeds were used on
each plate. The plate was placed in a dark room and allowed to
germinate for 72 h at 28 °C. The lengths of rape roots were measured,
and the means were calculated. Percentage inhibition was calculated
relative to controls using distilled water. Each trial was conducted in
duplicate to obtain a reliable result.
Greenhouse Herbicidal Activity against Monocotyledon and
Dicotyledon Weed Species. The pre-emergence and postemergence
greenhouse herbicidal activities of the target compounds were
evaluated against representative monocotyledon grasses (Echinochloa
crus-galli and Digitaria adscendens) and dicotyledon weeds (Brassica
campestris and Amaranthus retroflexus) using methods reported
previously.39,40 For compounds with promising activity, more weed
species (Eragrostis curvula (Schrad.) Nees, Bromus inermis Leyss.,
Eleusine indica (L.) Gaertn., Setaria viridis (L.) Beauv., Puccinellia
distans (L.) Parl., Elymus dahuricus Turcz., Flaveria bidentis (L.)
Kuntze., Ixeris polycephala Cass., Portulaca oleracea L., Pharbitis nil
(Linn.) Choisy, Abutilon theophrasti Medicus, Medicago sativa,
Capsella bursa-pastoris, Chenopodium album Linn, Taraxacum mongol-
icum Hand.-Mazz., and Polygonum L., among which the top six belong
to monocotyledon species and the last 10 belong to dicotyledon
species) were selected to assess the broad-spectrum herbicidal activity.
Soybean, peanut, and wheat were chosen for a preliminary crop safety
test using the same bioassay technique. Triasulfuron, nicosulfuron,
and penoxsulam were used as the control in different conditions.
In detail, the solution of compounds was prepared using the same
procedure for the above rape root growth inhibition assay. A 0.1%
water emulsion was prepared by mixing 1 g of emulsifier with distilled
water to a final volume of 1 L. The target compounds were made into
a DMSO stock solution of 30 mg mL−1 concentration and diluted to
different concentrations using the 0.1% water emulsion. A 3WPSH-
500E spray tower (from Nanjing Institute of Agricultural Mecha-
nization, Ministry of Agricultural and Rural Affairs) was utilized to
spray the aqueous samples.
RESULTS AND DISCUSSION
■
Chemistry. As shown in Figure 3, the target sulfonylurea
compounds were synthesized using two different routes.
Generally, when OR1 was an ethoxy or a fluoroethoxy group,
the substituted benzenesulfonamide (compound 2) reacted
with different phenyl (pyrimidin-2-yl)carbamates (compound
4) to give the corresponding title compounds (6-1 to 6-14) in
good yields. When OR1 was switched to the chloroethoxy,
bromoethoxy, iodoethoxy, or hydroxyethoxy substituent, after
compound 2 reacted with oxalyl chloride to produce sulfonyl
isocyanate (compound 5), the intermediate further reacted
with different pyrimidin-2-amines to obtain the desired
compounds (6-17 to 6-42). It should be noted that 6-15
and 6-16 had the fluoroethoxy substituent in the phenyl ring;
however, these two compounds could only be prepared using
the second method. For 1H NMR data, the −SO2NH− proton
signals were always in the range of δ 12−13 ppm, no matter
which solvent the sample was in. Meanwhile, for the
−CONH− proton, the signals were in the range of δ 7−8
ppm if the solvent was CDCl3 or acetone-d6, and such signals
moved to the δ 10−13 range in the case of DMSO-d6. For the
HRMS data, all of the compounds displayed a [M + H]+ result
within a reasonable error of the theoretical data. Moreover,
after attempts on several compounds, we successfully obtained
the crystal of compounds 6-21 and determined the chemical
structure using single-crystal X-ray diffraction. From Figure 4,
it is clear that the phenyl ring is attached with a chloroethoxy
group, which confirms the structure of this family. Notably, 6-
21 is highly similar to triasulfuron, with a very minor difference
in the heterocycyle. For this compound, it is a pyrimidine ring
while for triasulfuron it is a triazine ring instead. Another
For pre-emergence herbicidal activity, sandy clay (100 g) in a
plastic box (11 cm × 7.5 cm × 6 cm) was wetted with water.
Sprouting seeds of the weed under test were planted in fine earth (0.6
cm depth) in a greenhouse and sprayed with the test compound
solution at certain dosages. For postemergence herbicidal activity,
seedlings (one leaf and one stem) of the weed were sprayed with the
test compound solutions at different dosages. For both treatments, the
fresh weights of the aboveground portions were determined 3 weeks
later, and the percent inhibition relative to the controls was calculated.
Two replicates for each experiment were given.
Molecular Simulation. Comparative Field Analysis (CoMFA).
The three-dimensional (3D) structures of the target sulfonylurea
compounds were constructed using Sybyl 7.3 software (Tripos Inc., St
Louis, MO) based on the crystal structures of chlorsulfuron and
tribenuron methyl in complex with AtAHAS (pdb entry 1YHZ and
1YI1).7 The molecules were assigned Gasteiger-Hu
̈
ckel charges and
fully minimized by the Tripos force field with a convergence of 0.01
kcaL mol−1 Å−1. For CoMFA analysis,41 all of the 42 molecules were
put into a database and included in the training set. All of the
parameters used the default values within the CoMFA module and the
column filtering was set to 2.0 kcaL mol−1. The “leave-one-out”
(LOO) cross-validation method was applied to determine the
optimum number of partial least squares (PLS) components. The
Figure 4. Molecular structure of 6-21 from X-ray diffraction.
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Table 1. Chemical Structures, in Vitro AtAHAS Inhibition, and Rape Root Growth Inhibition of the Target Compounds
rape root growth inhibition (%)
no.
R1
R2
R3
AtAHAS inhibition Ki (nM)
10 μg μL−1
1 μg μL−1
0.1 μg μL−1
6-1
6-2
6-3
6-4
6-5
6-6
6-7
6-8
−CH2CH3
−CH2CH3
−CH2CH3
−CH2CH3
−CH2CH3
−CH2CH3
−CH3
−CH3
−CH3
−OCH3
−CH3
−OCH3
−OCH3
−CH3
−CH3
−CH3
−OCH3
−OCH3
−CH3
−OCH3
−CH3
−OCH3
−OCH3
−OCH3
−CH3
−OCH3
−OCH3
−CH3
−CH3
-OCH3
−CH3
−CH3
−OCH3
−OCH3
−CH3
−OCH3
−CH3
−OCH3
−CH3
-OCH3
−CH3
−H
950 110
1322 208
205 25
85 18
650 77
766 40
55 8.3
835 108
2354 155
228 18
36 6.4
145 36
358 20
444 40
725 64
88 13
68.4
60.6
61.9
71.0
62.9
69.2
70.2
59.0
64.0
61.1
82.5
65.2
64.6
65.3
66.5
69.2
70.4
68.2
71.5
67.6
79.3
61.0
64.2
67.6
62.8
62.6
75.7
64.0
53.6
62.0
60.6
58.6
46.1
57.3
63.7
64.2
59.8
66.5
63.1
64.8
85.5
70.4
78.7
59.0
65.8
60.3
62.9
58.7
61.4
64.5
59.8
59.5
60.3
75.8
52.2
53.3
58.2
65.3
65.7
67.9
59.2
63.7
66.5
74.3
58.6
55.0
63.1
53.9
52.8
72.6
62.8
36.0
59.0
53.8
53.6
36.0
51.4
40.8
62.8
55.9
62.6
57.5
60.9
57.8
39.1
76.5
54.8
44.9
62.7
56.1
45.4
59.8
65.5
53.5
50.1
55.2
72.3
44.8
50.4
54.6
34.7
64.6
67.0
58.6
48.0
59.8
68.1
50.8
43.0
55.0
18.4
0
−Br
−CH3
−Cl
−Cl
-OCH3
−CH3
−H
−Br
−CH3
−Br
−Cl
−Cl
−I
−CH2CH2F
−CH2CH2F
−CH2CH2F
−CH2CH2F
−CH2CH2F
−CH2CH2F
−CH2CH2F
−CH2CH2F
−CH2CH2F
−CH2CH2F
−CH2CH2Cl
−CH2CH2Cl
−CH2CH2Cl
−CH2CH2Cl
−CH2CH2Cl
−CH2CH2Br
−CH2CH2Br
−CH2CH2Br
−CH2CH2Br
−CH2CH2Br
−CH2CH2Br
−CH2CH2Br
−CH2CH2I
−CH2CH2I
−CH2CH2I
−CH2CH2I
−CH2CH2I
−CH2CH2I
−CH2CH2I
−CH2CH2I
−CH2CH2I
−CH2CH2OH
−CH2CH2OH
−CH2CH2OH
−CH2CH2OH
−CH2CH2OH
6-9
6-10
6-11
6-12
6-13
6-14
6-15
6-16
6-17
6-18
6-19
6-20
6-21
6-22
6-23
6-24
6-25
6-26
6-27
6-28
6-29
6-30
6-31
6-32
6-33
6-34
6-35
6-36
6-37
6-38
6-39
6-40
6-41
6-42
triasulfuron
−I
−Br
−Cl
−I
72 9.0
605 89
490 74
723 63
33 5.1
145 25
340 44
882 96
718 60
2215 310
90 4.6
182 36
105 19
600 210
469 152
895 103
1480 195
950 249
3590 445
320 83
135 45
613 158
420 67
326 86
431 60
5729 1190
31 5.4
−I
−CH3
−Br
−Cl
−Cl
−I
−H
−CH3
−OCH3
−Br
−Br
−Cl
−Cl
−I
62.9
57.1
0
32.7
29.9
50.0
0
−I
−H
38.0
0
−CH3
−OCH3
−OCH3
−OCH3
−CH3
−OCH3
−CH3
−CH3
-OCH3
-Br
−Cl
−Cl
−I
51.7
48.9
57.9
35.8
52.0
0
−CH3
−H
0
73.2
interesting observation is that the hydrogen atom connected
with the N1 atom is at a distance of a hydrogen bond with an
N3 atom, similar to our earlier result.45
Biological Activity. In Vitro Plant AHAS Inhibition. All of
the synthesized sulfonylureas were subjected to the AtAHAS
inhibition bioassay. From Table 1, it can be seen that the Ki
values are in a wide range of 33−5729 nM, although these
compounds share very close chemical structures. As a
comparison, triasulfuron was also included in this study, with
an inhibition constant of 31 nM. For the compounds with a
monosubstituent at the pyrimidine ring (6-2, 6-9, 6-26, 6-35,
and 6-42), the weakest Ki values have been observed (from
1322 to 5729 nM). Seven of the compounds (6-4, 6-7, 6-11, 6-
16, 6-17, 6-21, and 6-27) have Ki values below 100 nM, with a
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a
Table 2. Herbicidal Activity of Selected Compounds from the Greenhouse Pot Bioassay
pre-emergence activity (%)
postemergence activity (%)
no.
6-1
6-2
6-3
6-4
dosage g ha−1
Bc
Ar
Eg
Da
Bc
Ar
Eg
Da
30
30
30
30
15
7.5
30
30
30
30
15
7.5
30
30
15
7.5
30
30
30
30
15
7.5
30
15
7.5
30
30
30
15
7.5
15
7.5
30
15
7.5
89.1
33.2
61.2
95.4
87.1
79.4
11.2
86.4
91.0
94.6
83.9
78.8
38.1
96.4
93.2
83.4
60.1
89.1
75.2
91.3
84.6
80.7
69.8
62.5
60.3
93.3
7.4
81.9
41.1
69.1
97.2
90.6
85.0
21.1
93.1
93.1
81.9
70.0
58.8
40.8
93.7
92.9
91.3
75.0
91.7
61.5
90.4
75.6
70.0
73.1
50.5
45.1
51.0
38.5
96.1
90.8
81.5
85.0
81.3
64.1
48.7
28.2
65.4
22.5
0
12.9
0
0
24.0
52.0
0
95.7
94.8
90.0
0
18.0
79.6
19.7
NT
NT
79.9
89.9
19.8
40.3
96.4
87.1
46.0
5.6
28.8
77.7
61.2
NT
NT
34.9
100
98.7
87.3
0
100
16.0
94.5
97.3
80.7
25.4
21.4
0
15.2
0
6.9
75.0
67.1
46.8
0
36.3
27.4
28.0
17.7
0
0
74.8
56.0
49.0
0
88.7
63.6
58.2
13.4
53.5
64.1
81.4
65.5
58.2
7.5
95.9
94.7
93.1
16.3
39.5
38.0
90.8
90.3
85.5
75.5
62.3
20.4
33.7
13.5
45.0
43.6
30.1
65.9
56.4
12.3
6.7
78.3
67.4
54.2
0
13.7
24.7
63.8
61.6
55.3
0
84.5
78.0
71.7
17.3
18.8
8.5
50.4
49.3
46.9
25.6
0
6-5
6-6
6-7
6-8
20.9
23.8
38.8
NT
NT
21.9
84.6
80.8
65.2
1.5
33.2
18.1
65.2
59.3
45.6
29.3
15.1
0
14.9
26.9
25.3
19.7
12.3
55.9
36.8
1.7
NT
NT
0
6-9
6-11
100
100
100
92.9
90.9
88.8
4.2
51.2
7.8
6-13
6-14
6-17
6-21
1.5
80.5
33.0
95.7
93.9
93.7
30.6
20.1
0
26.1
28.5
100
100
93.2
82.0
75.1
73.8
86.7
61.2
35.0
42.7
33.5
45.2
41.3
15.2
85.8
79.4
94.9
69.5
44.1
6-27
0
6-36
6-40
TRSU
29.9
39.3
20.0
24.3
15.6
48.1
33.6
17.0
4.1
7.2
16.6
100
92.3
40.4
99.1
96.9
100
100
100
99.3
95.0
88.6
92.1
89.1
71.4
58.6
52.0
PNSL
NISU
98.3
92.0
100
100
92.0
0
0
0
2.1
a
Bc = Brassica campestris, Ar = Amaranthus retroflexus, Eg = Echinochloa crus-galli, Da = Digitaria adscendens, NT = no test, TRSU = triasulfuron,
PNSL = penoxsulam, and NISU = nicosulfuron.
methoxy group at the meta position of the pyrimidine ring and
a methyl, methoxy, bromo- or an iodo group at another meta
position. If we only compare the in vitro AtAHAS inhibition,
none of the target compounds in this study is more potent than
triasulfuron. Among all of the novel sulfonylureas in this study,
6-11 and 6-21 showed even potency to triasulfuron, and their
Ki values were 36 and 33 nM, respectively. The chemical
structures of 6-11 and 6-21 are close to that of triasulfuron,
with the same substituents (a methyl group and a methoxy
group) at the heterocycle ring. For these two compounds, 6-11
has a fluorine atom in the ortho-alkoxy group and 6-21 has a
chlorine atom instead, as detailed in the crystal structure.
Rape Root Growth Inhibition. It has been proven to be a
quick protocol to estimate the in vivo herbicidal activity
preliminarily for the sulfonylurea compounds using rape root
growth inhibition bioassay.25 This method takes only 3 days,
much shorter than the greenhouse pot assay method, which
needs several weeks. As can be seen from Table 1, all of the
target compounds exhibited promising activity at 10 μg μL−1
concentration. When the concentration dropped to 1.0 and
0.1μg μL−1, the inhibitions generally became be less potent.
Compounds 6-26, 6-29, 6-33, 6-35, 6-41, and 6-42 displayed
no herbicidal activity at 0.1 μg μL−1 treatment. This is not
surprising because these compounds are very weak AtAHAS
inhibitors, except 6-29, the Ki of which is 105 nM. In contrast,
for compounds 6-3, 6-7, 6-11, 6-16, 6-17, 6-21, and 6-27, the
herbicidal activities were all >60% even at 0.1μg μL−1. On the
whole, these seven compounds have the best AtAHAS
inhibitions (6-4 has a stronger Ki than 6-3, yet 6-3 has slightly
better rape root growth inhibition than 6-4, which is the only
exception). The herbicidal activities of 6-11 and 6-21 were
72.3 and 68.1% at 0.1 μg μL−1, respectively, and the biological
activity for triasulfuron is 73.2% at this condition. Taking
together the best and the worst herbicidal activities, there is a
basic but not absolute correlation of the in vivo rape root
growth and the in vitro plant AHAS inhibitions.
Greenhouse Herbicidal Activity from Pot Assay. Despite
the ideal herbicidal activities from rape root growth inhibition
of most target sulfonylureas, it is more meaningful to evaluate
the herbicidal activities in a greenhouse by both pre-emergence
and postemergence application, through which different weed
species can be tested and selectivity can be studied for a single
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compound. First, we chose all of the compounds bearing the
ethoxy group (6-1 to 6-6) and six compounds with the
fluoroethoxy group (6-7, 6-8, 6-9, 6-11, 6-13, and 6-14) for
the pot assay, regardless of their enzyme inhibition and rape
root growth inhibition potency. From Table 2, compounds 6-
2, 6-3, 6-5, 6-9, and 6-13 did not show good activities (<80%
inhibition) at 30 g ha−1 against all of the tested weeds.
Compounds 6-1, 6-6, 6-7, and 6-14 exhibited promising
activity upon Brassica campestris and Amaranthus retroflexus;
however, these compounds were not attractive because their
herbicidal activities against Echinochloa crus-galli and Digitaria
adscendens were poor. Compounds 6-4 and 6-11 not only
displayed desirable activities against the dicotyledon species
but also showed excellent activities against monocotyledon
grasses at both the pre-emergence and the postemergence
treatments. For 6-8, herbicidal activity against monocotyledon
species could be observed in the pre-emergence condition.
Therefore, these three compounds were further tested at
decreased dosages. Excitingly, even at 7.5 g ha−1, compound 6-
11 still showed remarkable activity against barnyard grass
(93.1% for pre-emergence and 88.8% for postemergence) and
crab grass (71.7% for pre-emergence and 65.2% for
postemergence), much stronger than the commercial AHAS-
inhibiting herbicides penoxsulam and nicosulfuron, which are
famous for the control of monocotyledon grasses. Since 6-4
and 6-11 both have a methyl group and a methoxy group at the
heterocycle ring, we thus chose 6-21, 6-27, and 6-36 from the
remaining compounds for the greenhouse assay. 6-17 was
selected for this assay since its AHAS inhibition and rape root
growth inhibition were both strong. 6-40 was also subjected to
the pot assay after consideration of the enzyme inhibition and
rape root inhibition to determine whether the hydroxyethoxy
group in the compound provides good greenhouse activity.
From the result, 6-21 displayed comparable activity to 6-11
against barnyard grass, but its activity against crab grass is less
potent than 6-11. Therefore, 6-21 was also tested at lower
dosages, and Figure 5 illustrates the pre-emergence herbicidal
activity of 6-21 against barnyard grass (90.3% at 15 g ha−1).
For 6-27, the herbicidal activity against barnyard grass was
around 80% at both conditions; however, when used at lower
dosages, there was a significant loss of the herbicidal activity.
For 6-17 and 6-40, no obvious weed control effect could be
seen at all of the conditions. For 6-36, it only exhibited 93.3%
herbicidal activity for rape at the pre-emergence condition,
which was not our emphasis in this study. Thus, from the
results of AtAHAS inhibition, rape root growth inhibition, and
the greenhouse pot assay, 6-11 and 6-21 were always the best
ones among all of the target compounds. To our surprise,
although triasulfuron was equal to 6-11 and 6-21, regarding
AHAS inhibition potency and rape root inhibition data, its
herbicidal activities against barnyard grass and crab grass were
much weaker at the same conditions in the greenhouse.
Due to the outstanding behaviors of 6-11 and 6-21 in the
pot assay, herbicidal activities of these two compounds were
further evaluated against 16 other weed species, among which
six were monocotyledon grasses (Eragrostis curvula (Schrad.)
Nees, Bromus inermis Leyss., Eleusine indica (L.) Gaertn.,
Setaria viridis (L.) Beauv., Puccinellia distans (L.) Parl., and
Elymus dahuricus Turcz) and the others belonged to
dicotyledon weeds. For comparison, triasulfuron and nic-
osulfuron were also included to determine the weeding effects.
Table 3 summarizes the broad-spectrum herbicidal activities of
these compounds at 15 g ha−1 dosage. From the results, 6-11
displayed better herbicidal activities than triasulfuron and
nicosulfuron for the monocotyledon weeds in most cases. The
only exception is the activity against Puccinellia distans (L.)
Parl., for which nicosulfuron had a better effect at the
postemergence condition. 6-21 also showed stronger activity
than nicosulfuron at pre-emergence conditions, except for the
effect against Eragrostis curvula (Schrad.) Nees. For the control
of the 10 dicotyledon weed species, 6-11 and 6-21 also had
promising activities, which were basically comparable to
triasulfuron and better than nicosulfuron for most weeds.
Generally, 6-11 had better performances than 6-21 at all of the
conditions, whether it was against monocotyledon or
dicotyledon weeds. It can also be seen that 6-11 and 6-21
had better herbicidal activities when applied at the pre-
emergence condition than at the postemergence condition.
The results herein strongly suggest that 6-11 and 6-21 should
be considered as possible herbicides to specifically defeat some
troublesome monocotyledon weeds.
Biological safety toward certain crops is an important
criterion for an agrochemical candidate to be used for crop
protection; otherwise, it can only be used as a nonselective
herbicide in lawns, forests, etc. An ideal herbicide usually
selectively eliminates unwanted weeds in the field; however, it
does no or little harm to the crops. For this purpose, we next
preformed a crop safety test at 15 g ha−1 dosage to determine
whether 6-11 or 6-21 could be used in wheat, peanut, and
soybean fields. In principle, if a compound shows <10%
inhibition of a certain crop, it is considered safe to the crop. As
is known, triasulfuron is a herbicide used in wheat fields,28,46
which shows 3.9% inhibition and 7.0% inhibition against wheat
in this experiment (Table 4). In contrast, triasulfuron was not
safe to soybean and peanut at the tested conditions.
Meanwhile, nicosulfuron was safe for all of the tested crops
at these conditions. It was encouraging that 6-11 exhibited no
inhibition for peanut at the postemergence condition. For
soybean, 6-11 displayed 9.3% inhibition and 6-21 displayed
7.0% inhibition at the pre-emergence condition. For wheat, 6-
21 displayed the same inhibition with triasulfuron against the
crop for the postemergence application. Hence, for primary
consideration, it is most likely that 6-11 will be considered as a
postemergence herbicide used in the peanut field based on the
Figure 5. Pre-emergence herbicidal activity of 6-21 against barnyard
grass at 15 g ha−1 dosage.
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a
Table 3. Broad-Spectrum Weed Control Effect of 6−11 and 6−21 at 15 g ha−1 Dosage
6-11
6-21
TRSU
NISU
weed species
A
B
A
B
A
B
A
B
Eragrostis curvula (Schrad.) Nees
Bromus inermis Leyss.
99.1
81.4
91.8
80.4
87.7
NT
45.1
77.0
63.3
41.3
65.0
82.7
97.7
80.3
64.0
NT
37.3
48.6
14.6
35.3
54.7
36.5
26.7
0
92.9
52.9
64.9
42.5
58.9
50.7
18.9
68.5
16.7
0
25.7
66.8
97.9
73.1
62.2
68.3
0
0
0
30.2
29.8
0
33.8
3.6
1.6
18.5
8.1
9.8
0
1.3
0
18.1
6.8
97.3
0
5.6
1.7
3.9
15.0
61.5
18.9
48.5
0
Eleusine indica (L.) Gaertn.
Setaria viridis (L.) Beauv.
Puccinellia distans (L.) Parl.
Elymus dahuricus Turcz.
Flaveria bidentis (L.) Kuntze.
Ixeris polycephala Cass.
Portulaca oleracea L.
Pharbitis nil (Linn.) Choisy
Abutilon theophrasti Medicus
Medicago sativa
14.0
31.7
28.8
NT
85.1
36.5
0
23.7
23.3
29.4
0
80.3
52.7
41.6
61.4
79.7
98.5
88.4
64.4
81.4
3.8
73.5
46.4
32.3
18.1
46.6
95.3
NT
NT
96.4
47.7
8.2
0
24.5
0
14.7
20.6
90.0
NT
NT
59.3
39.2
8.7
0
0
0
56.0
NT
NT
34.7
21.4
18.5
54.1
82.4
54.9
NT
0
Capsella bursa- pastoris
NT
NT
28.2
15.5
Chenopodium album Linn
Taraxacum mongo- licum Hand.-Mazz
Polygonum L.
a
A = pre-emergence activity (%), B = postemergence activity (%),TRSU = triasulfuron, NISU = nicosulfuron, and NT = no test. This occurred
when there were not enough grass seeds for some bioassay experiments.
the yellow region. For the electrostatic contour map (Figure
6B), a positively charged group provides an increase of activity
in the blue contour, whereas a negative charge is likely to
reinforce the inhibition in the red-contour region. Based on
this result, novel compounds bearing a difluoroethyl group
(−CH2CF2H) or a trifluoroethyl group (−CH2CF3) have been
designed and will be synthesized in the near future. The 3D-
QSAR model has provided valuable clues for further discovery
of novel inhibitors with improved binding affinity.
Table 4. Biosafety Test of 6−11 and 6−21 upon Selected
a
Crops at 15 g ha−1 Dosage
peanut
soybean
wheat
no
A
B
A
B
A
B
6-11
6-21
triasulfuron
nicosulfuron
26.7
30.9
57.8
8.7
0
9.3
7.0
18.9
2
34.6
25.3
45.5
0
80
66
3.9
2.3
39
11.1
46.5
0
7.0
7.0
5.3
a
A = pre-emergence activity (%) and B = postemergence activity (%).
Theoretical DFT (B3LYP) Calculation. 6-11 and 6-21
possess significant similarities with triasulfuron, whether from
their chemical structures or from Ki values of AHAS inhibition
and rape root inhibitory data. However, it is a bit strange that
6-11 and 6-21 displayed excellent herbicidal activity against
monocotyledon grasses such as barnyard grass, while
triasulfuron only showed medium-to-weak herbicidal activity
at the same conditions. The factors accounting for the
difference in the greenhouse activity against the monocotyle-
don species should be discovered for some plausible
explanation. As is known, for a plant that is not sensitive (in
other words, displaying nontarget site resistance) to an AHAS-
inhibiting herbicide, enhanced capacity of herbicide metabo-
lism (metabolic resistance) is considered to be a major reason,
in which cytochrome P450 is involved.2 Therefore, it is likely
that for the gramineous weeds, these compounds may have
different metabolism rates. Frontier molecular orbital is
regarded to play an important role in the related reactions of
a compound and hence has an impact on the biological
activity.16,48,49 We accordingly performed DFT calculations for
6-11, 6-21, and triasulfuron to see if useful information could
be observed. The bioactive conformation in the crystal
structure was assumed to be the dominant conformation in
the metabolic event. From Figure 7, HOMO maps for these
three compounds are quite similar, which cover the
heterocycyle ring and the sulfonyurea bridge. Interestingly,
LUMO maps for 6-11 and 6-21 locate on the heterocycle ring,
the sulfonyurea urea bridge, and the phenyl ring; yet, the
LUMO map for triasulfuron has very minor distribution at the
phenyl ring. The difference in LUMO maps is likely to be a
current biosafety data upon these crops. More species of crop
safety will be biologically screened for this compound in the
near future.
In Silico Computational Modeling. QSAR from CoMFA
Results. CoMFA is a tool to generate 3D contour models to
quantitatively analyze the structure−activity relationships of
bioactive compounds by steric and electrostatic contribu-
tions.41 As is known, the choice of the correct conformations is
most critical for the establishment of the CoMFA model. A
number of herbicidal sulfonylureas have been successfully co-
crystallized with fungal AHAS or plant AHAS, and they share
significant similarities in the conformations.4,7,47 Accordingly,
we built the chemical models of the inhibitors based on the
bioactive poses. From the PLS, the leave-one-out q2 value was
0.622 when the optimum number of components was 6, and
none of the compounds were excluded from the training set,
suggesting that the CoMFA model was successful. When
subjected to a non-cross-validation, the r2 value was 0.932 with
a standard error of estimate of 0.151 and F values of 56.667.
The steric and electrostatic contributions were 72.1 and 27.9%,
respectively. The predictive biological activity versus the
experimental biological activity has been listed in the
Supporting Information.
The 3D-CoMFA contour maps have been exhibited in
Figure 6. Compound 6-11 was used as the template to depict
the steric and electrostatic contour maps, which were fitted on
the AtAHAS binding site. For the steric contour map (Figure
6A), a bulky group is favorable for enhanced AHAS inhibition
in the green space while such a group decreases the potency in
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Figure 6. Steric contour map (A) and electrostatic contour map (B) for the CoMFA model mapped onto the binding site of AtAHAS. 6-11 was
chosen as a template to depict the structure−activity relationships.
possible reason leading to their different behaviors toward
monocotyledon grasses.
We must admit the fact that herbicide resistance is likely to
occur due to the overuse of all families of chemical herbicides,
especially for the sulfonylurea herbicides. Therefore, at the very
beginning stage of development of a new herbicide, some
practical strategies should be proposed to postpone weed
resistance toward this class of new sulfonylureas. One
preferable solution is to prepare a mixed product with other
commercial herbicides that have a distinct mode of action.
Field efficacy trials of these two sulfonylurea compounds are
currently in progress for some selected crop fields. Moreover,
we will try to evaluate the herbicidal activity of 6-11 and 6-21
against some resistant weed species to see whether these new
In 2006, Xi and Yang et al. reported a density functional
theory-based QSAR study of herbicidal sulfonylurea analogues,
in which a general quantum-chemical descriptor was used by
characterizing the volume of electron cloud for specific
substituent using the method of density functional theory.50
In our present study, we also found that frontier orbitals play
an important role in the structure−activity relationships of the
sulfonylurea herbicides. We therefore suggest that a quantum
chemistry study is necessary for the design and discovery of
novel AHAS-inhibiting sulfonylurea herbicides in the future.
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Figure 7. Frontier molecular orbital maps for triasulfuron, 6-11, and 6-21 from DFT calculations.
candidates are also potent inhibitors toward these troublesome
grasses in the near future.
(CIF)
Predicted biological data versus determined biological
data from CoMFA; H NMR, 13C NMR, HPLC (for 6-
1
In summary, we have designed and synthesized a series of
ortho-alkoxy substituted novel sulfonylurea compounds and
studied their herbicidal activities extensively. Compounds 6-11
and 6-21 showed strong inhibition of plant AHAS and
outstanding herbicidal activity against the monocotyledon
weed species. As a potential fluorine-containing herbicide
candidate, 6-11 was superior to triasulfuron, penoxsulam, and
nicosulfuron at all of the tested conditions regarding the
weeding efficiency upon the gramineous species. 6-11
displayed zero postemergence herbicidal activity against peanut
at 15 g ha−1, indicating that it could be considered for weed
control in such fields. Theoretical DFT calculation revealed
that LUMO is a probable cause for the sensitivity to
monocotyledon grasses for 6-11 and 6-21. This study has
provided valuable guidance for the discovery and development
of green herbicides to control some malignant weeds.
11 and 6-21) and HRMS data of intermediates and
target compounds; and 1H NMR, 13C NMR, HPLC (for
6-11 and 6-21) and HRMS spectra of target compounds
(from 6-1 to 6-42) (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Jian-Guo Wang − State-Key Laboratory and Research
Institute of Elemento-Organic Chemistry, National Pesticide
Engineering Research Center, College of Chemistry, Nankai
University, Tianjin 300071, China; orcid.org/0000-
0001-7577-1502; Phone: 0086-13820905092;
Email: nkwjg@nankai.edu.cn; Fax: 0086-22-23503627
Authors
Hai-Lian Wang − State-Key Laboratory and Research Institute
of Elemento-Organic Chemistry, National Pesticide
Engineering Research Center, College of Chemistry, Nankai
University, Tianjin 300071, China
Hao-Ran Li − State-Key Laboratory and Research Institute of
Elemento-Organic Chemistry, National Pesticide Engineering
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.jafc.1c02081.
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Research Center, College of Chemistry, Nankai University,
Tianjin 300071, China
Yi-Chi Zhang − State-Key Laboratory and Research Institute
of Elemento-Organic Chemistry, National Pesticide
Engineering Research Center, College of Chemistry, Nankai
University, Tianjin 300071, China
Wen-Tao Yang − State-Key Laboratory and Research Institute
of Elemento-Organic Chemistry, National Pesticide
Engineering Research Center, College of Chemistry, Nankai
University, Tianjin 300071, China
Zheng Yao − State-Key Laboratory and Research Institute of
Elemento-Organic Chemistry, National Pesticide Engineering
Research Center, College of Chemistry, Nankai University,
Tianjin 300071, China
Ren-Jun Wu − State-Key Laboratory and Research Institute of
Elemento-Organic Chemistry, National Pesticide Engineering
Research Center, College of Chemistry, Nankai University,
Tianjin 300071, China
Cong-Wei Niu − State-Key Laboratory and Research Institute
of Elemento-Organic Chemistry, National Pesticide
Engineering Research Center, College of Chemistry, Nankai
University, Tianjin 300071, China
Yong-Hong Li − State-Key Laboratory and Research Institute
of Elemento-Organic Chemistry, National Pesticide
Engineering Research Center, College of Chemistry, Nankai
University, Tianjin 300071, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jafc.1c02081
(15) Oreja, F. H.; Batlla, D.; de la Fuente, E. B. Digitaria sanguinalis
seed dormancy release and seedling emergence are affected by crop
canopy and stubble. Weed Res. 2020, 60, 111−120.
Notes
The authors declare no competing financial interest.
(16) Wang, J.; Tan, H.; Li, Y.; Ma, Y.; Li, Z.; Guddat, L. W.
Chemical synthesis, in vitro acetohydroxyacid synthase (AHAS)
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ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (no. 21977057) and the Natural
Science Foundation from Tianjin Municipal S&T Bureau (no.
19JCYBJC20800). This work is dedicated to the 100th
anniversary of Chemistry at Nankai University.
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