Discovery of N-Aroyl Diketone/Triketone Derivatives as Novel 4-Hydroxyphenylpyruvate Dioxygenase Inhibiting-Based Herbicides

Article abstract of DOI:10.1021/acs.jafc.9b01412

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is an important target site for discovering new bleaching herbicides. To explore novel HPPD inhibitors with excellent herbicidal activity, a series of novel N-aroyl diketone/triketone derivatives were rationally designed by splicing active groups and bioisosterism. Bioassays revealed that most of these derivatives displayed preferable herbicidal activity against Echinochloa crus-galli (EC) at 0.045 mmol/m² and Abutilon juncea (AJ) at 0.090 mmol/m². In particular, compound I-f was more potent compared to the commercialized compound mesotrione. Molecular docking indicated that the corresponding active molecules of target compounds and mesotrione shared similar interplay with surrounding residues, which led to a perfect interaction with the active site of Arabidopsis thaliana HPPD.

Full text of DOI:10.1021/acs.jafc.9b01412

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Agricultural and Environmental Chemistry
Discovery of N-Aroyl Diketone/Triketone Derivatives as Novel 4-
Hydroxyphenylpyruvatedioxygenase Inhibiting-based Herbicides
Ying Fu, Dong Zhang, Shuaiqi Zhang, Yongxuan Liu, Youyuan
Guo, Mengxia Wang, Shuang Gao, Li-Xia Zhao, and Fei Ye
J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.9b01412 • Publication Date (Web): 07 Oct 2019
Downloaded from pubs.acs.org on October 8, 2019
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Discovery
of
N-Aroyl
Diketone/Triketone
Derivatives
as
Novel
4-
Hydroxyphenylpyruvatedioxygenase Inhibiting-based Herbicides
Ying Fu†, Dong Zhang†, Shuai-Qi Zhang†, Yong-Xuan Liu†, You-Yuan Guo†, Meng-Xia
Wang†, Shuang Gao†, Li-Xia Zhao†, Fei Ye†*
†Department of Applied Chemistry, College of Science, Northeast Agricultural University,
Harbin 150030, China
*Corresponding Author
Fei
Ye,
Email
address:
yefei@neau.edu.cn,
Tel:
86-451-55191507
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ABSTRACT: 4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is an important
target site for discovering new bleaching herbicides. In order to explore novel HPPD inhibitors
with excellent herbicidal activity, a series of novel N-aroyl diketone/triketone derivatives were
rationally designed by splicing active groups and bioisosterism. Bioassays revealed that most
of these derivatives displayed preferable herbicidal activity against Echinochloa crus-galli
(EC) at 0.045 mmol/m2 and Abutilon juncea (AJ) at 0.090 mmol/m2. In particular, compound
I-f was more potent compared with the commercialized compound mesotrione. Molecular
docking indicated that the corresponding active molecules of target compounds and mesotrione
shared similar interplay with surrounding residues, which led to a perfect interaction with the
active site of Arabidopsis thaliana HPPD.
Keywords: 4-hydroxyphenylpyruvate dioxygenase, N-aroyl diketone/triketone, rationally
designed, herbicidal activity, molecular docking
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INTRODUCTION
4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) catalyzes the conversion
of 4-hydroxyphenylpyruvate acid (HPPA) to homogentisic acid (HGA) in the tyrosine
degradation pathway.1-3 The conversion is essential to all aerobic organisms such as plants,
animals and microorganisms.4 HGA is essential for the physiological activities of plants.5 In
plants, the inhibition of HPPD provokes unique bleaching (whitening) symptoms, which is
followed by necrosis and death.6-9 As a consequence, HPPD has become an important potential
target for the development of new herbicides, leading to a substantial number of commercial
herbicides.3 Most HPPD inhibitors possess a range of advantages, such as low application rate,
outstanding crop selectivity, low toxicity, broad-spectrum weed control, and environmental
safety.10-13 However, frequent use of existing HPPD inhibitors leads to increased resistance,12,14-17
and phytotoxicity to wheat, rape, cotton, soybean, and other crops.18,19 Some HPPD inhibitors
were used in combination with safeners to reduce damage to crops.20 Therefore, it is urgent to
develop new HPPD inhibitors to control resistant weeds.13
To date, HPPD inhibitors such as triketone derivatives, pyrazoles, isoxazole
(diketonitriles) and others, have also been commercialized as herbicides and widely used in
agriculture.7,19,21 Among them, isoxaflutole, benzobicyclon and mesotrione are three
representative commercialized HPPD herbicides with good crop selectivity and excellent weed
control. Isoxaflutole, which is used in corn fields, is a prodrug to diketonitrile and was
commercialized by Bayer Crop Science in 1996.22 The prodrug benzobicyclon (2001) is a
unique herbicide that generated the actual herbicidal triketone structure via its hydrolysis in
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paddy soil, water, and plants mainly for the control of some broadleaf and sedge weeds in
transplanted rice.23,24 The herbicide mesotrione (2001), an actual HPPD inhibitor (not prodrug)
that has been commercialized for the control of weeds in corn.10,25
Summarizing the structural features of the popular HPPD inhibitors, it can be concluded
that they always possess two common structural characteristic: (i) for the three carbonyl
groups, one of the carbonyl group attached to the alicyclic hydrocarbon and the external
carbonyl are requirement to form coordination with the active center metal-chelation; (ii) the
substituents attached to the external carbonyl group must be aromatic ring to form a more
favorable sandwich π-π interplay with the surrounding aromatic residues of Arabidopsis thaliana
HPPD (AtHPPD) in the active site.7 Therefore, the common chemical moiety of most of the
HPPD-inhibiting compounds is primarily based on 3-oxo-3-phenylpropanal or 2-
benzoylmalonaldehyde as the minimum substructure, which can bind to the metal-chelation of
HPPD (Scheme 1).
As one of the most important subunits for novel farm agrochemical discovery, nitrogen-
containing heterocycles, such as oxazolidine-2-one, thiazolidin-2-one, pyrrolidine-2,5-dione
and isoindole-1,3-dione derivatives, have received considerable attention.26-28
As an effective drug design methodology, the fragment splicing strategy, has been dedicated
in innovating potential agrochemicals.29-32 Inspired by the above viewpoints, herein, we intended
to develop novel highly potent herbicides by employing the active chemical substructure of
commercial HPPD inhibitors and splicing the nitrogen-containing heterocycle as the parent
skeleton forming the target molecules (Scheme 1). A series of novel N-aroyl diketone
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(I)/triketone (II) derivatives were rationally designed, synthesized, and characterized in this
context. The preliminary greenhouse tests established that most of them showed promising
herbicidal activity against the gramineous weed Echinochloa crus-galli (EC) and broadleaf
Abutilon juncea (AJ) at rates of 0.045 and 0.090 mmol/m2, respectively.
MATERIALS AND METHODS
Instruments and materials. All chemical reagents were commercially available without any
further purification. The melting points (mp) were recorded on a on a Shanghai INESA melting
point instrument (WRS-3) (INESA Company, China) and the thermometer was uncorrected.
The yields were not optimized. Infrared (IR) spectra were recorded on a KJ-IN-27G infrared
1
spectrophotometer (KBr, BRUKER Inc., USA). H and 13C nuclear magnetic resonance
(NMR) spectra were obtained on a Bruker AV400 spectrometer (BRUKER Inc., USA) with
CDCl3 or DMSO-d6 as the solvent and tetramethylsilane as the internal standard. HRMS data
was obtained by FTICR-MS (BRUKER Inc., USA).
General Synthetic Procedure for Compounds I-a~I-n.
The compounds I-a~I-n were synthesised according to the previously reported method
(Figure 1).28,33
Synthesis of compounds I-a~I-h. NaOH (0.6 g, 15 mmol) followed by acetone (45 mL)
and the corresponding aroyl chloride (15 mmol) were added to a solution of oxazolidin-2-one
(1.0 g, 12 mmol) in H2O (5 mL). The mixture was stirred for 1~3 h at room temperature (r.t.).
Acetone was removed under reduced pressure and the remaining aqueous was further diluted
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with H2O (20 mL) and then extracted with EtOAc (3×20 mL). The organic phase was
combined, dried over anhydrous MgSO4, and concentrated. The resulting residue was
chromatographed on 80-100 mesh silica gel using a mixture of petroleum ether and EtOAc
(1:1~1:3) as eluent to afford the target compounds I-a~I-h.
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Synthesis of compounds I-i~I-n. N,N-Dicyclohexylcarbodiimide (DCC) (2.3 g, 11 mmol)
and 4-dimethylaminopyridine (DMAP) (1.3 g, 11 mmol) were added to a solution of carboxylic
acid (10 mmol) in CH2Cl2 (100 mL). The mixture was stirred at r.t. for 20 min followed by the
addition of thiazolidin-2-one (1.0 g, 10 mmol) and stirred for an additional 3~4 h. The resulting
solution was concentrated, and the crude product was purified as compounds I-i~I-n.
General Synthetic Procedure for Compounds II-a~II-i.
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Synthesis of compounds II-a~II-e. Compounds II-a~II-e were prepared according to the
report of Meng et al.34 Pyrrolidine-2,5-dione (1.0 g, 10 mmol), acetone (50 mL), and anhydrous
KHCO3 (5.0 g, 50 mmol) were added successively to a 100-mL flask and stirred at r.t. Then,
aroyl chloride (10 mmol) was added to the mixture, and the solution was stirred under N2 for 3~4
h. After the reaction was completed (assessed by TLC monitoring), the mixture was filtered and
the filtrate was evaporated under vacuum. The residue was purified as compounds II-a~II-e.
Synthesis of compounds II-f~II-i. Compounds II-f~II-i were prepared according to the
method reported previously.35,36 Aroyl chloride (10 mmol) was added dropwise to a solution of
isoindoline-1,3-dione (1.5 g, 10 mmol), and anhydrous K2CO3 (5.0 g, 36 mmol) as the attaching
acid agent in acetone, and the mixture was stirred at r.t. for 3~4 h. The reaction progress was
monitored by TLC. The mixture was filtered, and the solvent was removed under reduced
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pressure. The crude product was purified as compounds II-f~II-i. The physical and spectra data
of compounds I and II were displayed in the Supporting Information.
X-ray Diffraction Analysis.
Compound II-h was obtained from a mixture of EtOAc/n-hexane for structure validation.
Both cell intensities and dimensions were measured at 293(2) K on a Rigaku RAXIS-RAPID
area detector diffractometer (Japan) with graphite monochromatic Mo Ka radiation (λ = 0.71073
Å). The structure was solved by direct methods using the SHELXS-97 refined by full-matrix
least-squares on F2.37,38 The hydrogen atoms were included in a calculated position and refined
in terms of riding model (Uiso (H) = 1.5 Ueq (C) for the atoms of the methyl and Uiso (H) = 1.2 Ueq
(C) for others). The crystallographic data for crystal II-h (0.160 × 0.130 × 0.110 mm) were
deposited with the Cambridge Crystallographic Data Centre (CCDC) under deposition number
1883943.
Herbicidal Activities.
All of the synthesized compounds were evaluated against gramineous weeds EC and
broadleaf AJ by postemergence application.39 The commercial triketone herbicide mesotrione
was used as a positive control. Using DMSO as the solvent, Tween 80 (0.1 g/mL) as the
emulsifier, all the test compounds were prepared. The solutions was diluted with water to the
desired concentration and sprayed onto the plants in a greenhouse. Clay soil was Mollisols-
cryolls clay loam type with a pH of 7.3. Approximately 15 seeds of the EC and AJ were planted
in pots and covered with soil to a thickness of 1.5 cm and grown at the temperature of 18-28 °C
in a greenhouse, and air humidity was 78%. Broadleaf weeds were treated at the two-leaf stage
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and monocotyledon weeds were treated at the one-leaf stage. When the weeds (EC and AJ) grew
approximately to the one-leaf stage and two-leaf stage, they were treated by the inhibitors at the
dosage of 0.045 and 0.090 mmol/m2 (approximately 150 and 300 g ai/ha), respectively. The
solvent control group weeds were treated by water. After 15 days of treatment by inhibitors, the
chlorophyll levels were surveyed and evaluated (Table 1), with three duplicates per experiment.
A bulk extract of chlorophyll from the grass leaves was made in semidarkness using the
formulations (acetone/ethanol/H2O, 16:19:5, v/v/v). The contents of chlorophyll a (Ca) and
chlorophyll b (Cb) were determined by eq 1 and eq 2, respectively.40,41
(
)
)
(1)
(2)
=
=
× ― ×
A663 12.72 A645 2.59
× /( )
×
Ca
Cb
V W 1000
(
×
―
×
× /( )
×
A645 22.88 A663 4.68
V W 1000
where Ca and Cb are the contents of chlorophyll a and chlorophyll b (mg/g), respectively; A645
and A663 are optical densities at 645 and 663 nm, respectively; V is the constant volume (mL),
and W is the weight of sample (g).
Visual injury experiments on two weeds were also performed, EC and AJ were respectively
planted in plots containing test soil and grown in a greenhouse at 15-30 °C. When the weeds (EC
and AJ) grew approximately to the one-leaf stage and two-leaf stage, they were treated by the
inhibitors at the dosage of 0.045 and 0.090 mmol/m2 (approximately 150 and 300 g ai/ha),
respectively. The visual injury and growth state of the individual plant were observed at regular
intervals. The solvent control group weeds were treated by water. After 28 days of treatment by
inhibitors, final evaluation for herbicidal activities was conducted by visual observation on the
0-100 scale (Table 1).
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Computational Methods.
The 3D structures of the corresponding active molecule of compound I-f(a) and
commercial herbicide mesotrione were generated with the sketch module of SYBYL-X 2.0
(Sybyl, Version 6.9, Tripos Inc., USA). Subsequently, the Gasteiger-Huckel charges were
applied to the calculation, and the test structures were optimized. The crystal structure of AtHPPD
was downloaded from the Protein Data Bank (PDB code 5YWG) as a reference.42 The docking
modeling used the CDOCKER algorithm to explore the probable interactions between ligand
and protein binding cavity in Accelrys Discovery Studio 3.0 (Catalyst, Version 4.10, BIOVIA
Inc., USA).43,44 CDOCKER adds and minimizes energy by adding polar hydrogen to the protein
while maintaining heavy atom fixation. The application of all-atom representations assigns
formal and partial charges to the ligand.45 Before docking, the CHARMM force field (general-
purpose all-atom force fields with a wide coverage for general organic molecules, nucleic acids
and proteins,) was performed on the protein structure, and other co-crystallized water and small
molecules were removed. After the protein preparation, the active site was defined, with a subset
region of 13.0 Å through the center of the known ligand. Energy minimization was obtained from
Smart Minimizer (Performs 1000 steps of Steepest Descent with an RMS gradient tolerance
being 3, followed by Conjugate Gradient minimization). CDOCKER generated random ligand
conformations, and a great number of rigid body translations/rotations were applicable for each
conformation to construct the initial ligand poses. The final postures of the ligands were then
contingent on simulated annealing to improve the postures of the compound. The docked
postures were ranked according to the -CDOCKER ENERGY. During the docking process, the
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top 10 conformations were deposited, and the remaining parameters were set to default values.
The rational posture of the ligand was assessed manually, and then the best conformation was
selected based on -CDOCKER ENERGY.
RESULTS AND DISCUSSION
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Synthesis. In this research, target compounds I and II were synthesized via N-acylation
with oxazolidine-2-one, thiazolidin-2-one, pyrrolidine-2,5-dione, and isoindole-1,3-dione as
the starting materials at r.t. without any expensive reagent or catalyst (Figures 1 and 2). As a
general trend, the yields of compounds I and II were obtained in 36.8-89.7% and 54.6-81.7%
yields, respectively, which were influenced greatly by the substituent pattern. The starting
materials of oxazolidine-2-one, thiazolidin-2-one, pyrrolidine-2,5-dione and isoindole-1,3-
dione affected the yields significantly. For the same substitutions of the aromatic ring (Ar), the
yields of the target compounds I were very similar when oxazolidine-2-one and thiazolidin-2-
one were used as the reactants; however, the yields of compounds II exhibited minimal
differences for the starting materials of pyrrolidine-2,5-dione and isoindole-1,3-dione. Thus,
compounds II-a~II-e provided a better yield than II-f~II-i with the same substitution to some
extent. The effects of aromatic substituent on yields were evaluated. Of note, different aromatic
substituents showed diverse yields comparing the target compounds for the same starting
materials as follows: isoxazole>furan>benzene>pyridine. The substituted position on the Ar
was studied. Interestingly, higher yields were obtained for the target compounds of isoxazole
with mono-substitution compared with none or di-substitution. For example, the yield of
compound I-a (87.3% yield) was better than that of compounds I-c and I-d. Moreover,
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compounds with a nitro group (I-g) or chloro (I-f) at the ortho position of benzene had similar
yields.
1
13
The structures of all the synthesized compounds were determined by IR, H NMR, C
193 NMR, and HRMS analyses. Furthermore, the structures of compound II-h were verified
194 by X-ray analysis (Figure 3).
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Biological Activity and Structure-Activity Relationships (SARs). The herbicidal
activity of compounds I and II were evaluated against the gramineous weed EC and broadleaf
AJ in the greenhouse environment. The chlorophyll levels were tested after spraying with the
synthesized compounds and mesotrione (Table 1). In addition, the treated grass displayed
unique bleaching symptoms followed by necrosis after 15 days. The herbicidal activity was
basically consistent with the levels of of Ca and Cb. Bioactivity evaluation showed that most of
the target compounds indicated good herbicidal activity (over 60% control) towards the test
weeds at 0.045 and 0.090 mmol/m2, respectively.
As noted in Table 1, most of the synthesized compounds decreased Ca and Cb levels to
different degrees and showed promising herbicidal activity. A summary of results against EC
and AJ is outlined in Figure 4. Among the series, compound I-f exhibited the best herbicidal
activity (>90% inhibition) against EC and AJ and was better than the commercial control
(80~89% inhibition). Specifically, nitrogen-containing heterocycle significantly affected
herbicidal activities. For the same substitutions of the aromatic ring (Ar), target compounds I
with oxazolidine-2-one (I-a~I-e, I-g) as the reactants displayed better herbicidal activity (>80%
inhibition) than those with thiazolidin-2-one as the starting materials (I-i~I-n), and compounds
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II with pyrrolidine-2,5-dione (II-f~II-i) showed worse herbicidal activity than those with
isoindole-1,3-dione (II-a~II-e) to some extent. Moreover, it can be further confirmed that the
number of carbonyls exerted significant influence on herbicidal activity. Compounds I (N-aroyl
diketone, with two carbonyl) demonstrated greater herbicidal potency compared with
compounds II (N-aroyl triketone, with three carbonyl) against two tested weeds. For example,
compounds I-a~I-e produced better herbicidal activity than II-a~II-e with the same nitrogen-
containing heterocycle to some extent. The SAR might be summarized as follows: oxazolidine-
2-one>thiazolidin-2-one>isoindole-1,3-dione>pyrrolidine-2,5-dione.
The aromatic ring (Ar) moiety played a key role in the herbicidal activity. For the target
compounds, different aromatic subunits exhibited diverse herbicidal activity. For example, the
compounds showed the best herbicidal activity when the Ar subunits were benzene ring (I-f,
I-g, and I-n as an example), while the compounds with an isoxazole ring (I-a~I-d, I-i~I-l, II-
a~II-d, and II-f~II-h) showed the worst herbicidal activity. The SAR at the Ar can be
summarized as follows: benzene>pyridine>furan>isoxazole. The SAR results suggested that
the substituents at the position of the Ar affected the herbicidal activities considerably.
Generally, compounds I with mono-substitution (I-a) displayed higher activities (>80%
inhibition) than those with non- (I-d) or di-substitution (I-c) (<70% inhibition); however, the
herbicidal activity of compounds II with mono-substitution (II-a) were the worst.
Molecular Structure Comparisons. The physicochemical properties of the compounds
significantly affected the pharmacological activity and its interaction with the herbicide target
enzyme. The compounds with same physicochemical properties had similar biological
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activities, which was also the theoretical basis for pharmacophore screening. Comparing the
physicochemical properties of the synthesized compound I-f and mesotrione, it was notable
that the logp, hydrogen bond donors (HBDs), aromatic rings (ARs) surface area (SA) and
electronegativity of compound I-f were all similar to those of mesotrione (Table 2). Moreover,
more hydrogen bond acceptors (HBAs) of mesotrione were noted compared with compound
I-f, but HBAs did not affect the interaction of ligand compound binding to the AtHPPD
receptor, which was due to that there was the lack of hydrogen-bonding interactions between
the compound and AtHPPD. However, the rotatable bonds (RBs) of compound I-f were
reduced compared with mesotrione, which could successfully lock the dominant conformation
of the compound and conducive to drug efficacy. In addition, the molecular weight (MW) of
I-f was lower, which was beneficial to the metabolism of the exogenous compounds of the
crop. Thus, compound I-f was safer for the crop. This finding indicated that on the basis of its
physicochemical properties, compound I-f has great potential as a lead structure for the future
development of novel HPPD inhibitors.
Molecular Docking Study. During more than 30 years of research, HPPD structures have
been stored, determined, and uploaded in protein data banks (PDBs).46,47 To further study the
interactions between inhibitors and the target enzyme of herbicides, AtHPPD (PDB code
5YWG) was selected as a reference for molecular docking experiments.42 The diketo form of
the target compound I-f may tend to undergo tautomerizations to form the exo-enol form in
vivo (Figure 5), which was same as the commercial herbicide mesotrione.42 Therefore, the exo-
252 enols of compound I-f and mesotrione with AtHPPD were conducted docking analysis. As
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253 depicted in Figure 6, both compound I-f(a) and mesotrione were well-matched to the active
254 site of HPPD. Compound I-f(a) and mesotrione shared similar binding postures at the active
255 site, and this finding indicated the excellent similarity between compound I-f(a) and
256 mesotrione activities (Figure 6). Moreover, compound I-f(a) with oxazolidine-2-one (a five-
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membered ring) instead of 1,3-cyclohexanedione (a six-membered ring) was a better match
258 with AtHPPD in the space. The simulated complexes of mesotrione and inhibitors I-f(a) with
259 the binding site of AtHPPD are shown in Figure 7. The inhibitor I-f(a) could form a stable
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bidentate interaction with the active center CoII-chelation, constituting a twisted square-
pyramidal complex with a mainly five-coordinate. The benzene ring was “sandwiched” by the
phenyl rings of Phe381 and Phe424, constituting the π-π interaction with the two amino acid
residues, which was same as mesotrione in complex with AtHPPD (Figure 7). The distances
from the CoII-chelation to the two carbonyl groups of mesotrione were 2.3 and 2.1 Å,
265 respectively, while the corresponding distances for compound I-f(a) were 1.9 and 1.8 Å,
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respectively. The short distances of the CoII-chelation from the two carbonyl groups may be
267 responsible for the better HPPD inhibitory activity of I-f(a). Therefore, compound I-f(a) might
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be developed as a postemergence herbicide for weed control.
In a word, a series of novel N-aroyl diketone/triketone derivatives were designed and
identified as potent HPPD inhibitors. Most of the synthesized compounds showed outstanding
herbicidal activities against two tested weeds (EC and AJ) via decreasing the levels of Ca and
Cb, and some of these compounds were even superior to the commercial herbicide mesotrione.
Molecular docking modeling revealed that promising herbicide potency was attributed
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274 compound I-f(a), and mesotrione shared similar structural skeleton and interactions with the
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surrounding residues. These findings indicate that both compounds achieved a perfect
interaction with AtHPPD in the active site. These results indicated that the novel N-aroyl
diketone/triketone scaffold might be a potential candidate for novel HPPD inhibitor discovery.
Further research on in vivo activity and the mechanism of action of these compounds is in
progress.
ACKNOWLEDGMENTS
The authors are grateful to Prof. Jia-Zhong Li (Lanzhou University) for assistance with
molecular docking analyses, and Prof. Chun-Hong Teng (Agronomy College, Northeast
Agricultural University) for assistance with bioactivity assay.
FUNDING
This work was supported by the National Nature Science Foundation of China (No. 31772208),
the Natural Science Foundation of Heilongjiang Province (ZD2017002), and the Research
Science Foundation in Technology Innovation of Harbin (2017RAQXJ017).
Notes
The authors have declared no conflicts of interest
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Figure Captions:
Scheme 1. Design of the target compounds I and II.
Figure 1. Synthetic route of the target compounds I-a~I-h and I-i~I-n.
Figure 2. Synthetic route of the target compounds II-a~II-e and II-f~II-i.
Figure 3. Molecular diagram of compound II-h.
Figure 4. Structure-activity relationships for N-aroyl diketone/triketone derivatives against EC and AJ.
Figure 5. Possible keto-enol tautomerization of compound I-f.
Figure 6. The docking modeling of mesotrione (A), and compound I-f(a) (B) with AtHPPD at the active
site. The carbon atoms are shown in gray, the hydrogen atoms are shown in cyan, the sulfur atoms are shown
in light yellow, the oxygen atoms are shown in red, and the nitrogen atoms are shown in light blue.
Figure 7. Binding modes of ligands mesotrione (A) and compound I-f(a) (B) with AtHPPD (PDB
code 5YWG). (Mesotrione is shown in purple sticks, and compound I-f(a) is shown in blue sticks).
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Tables
Table 1. The chlorophyll content of EC and AJ treated with target compounds and their
postemergent herbicidal activity (Inhibition Rating of 0-100) a
EC (0.045 mmol/m2)
AJ (0.090 mmol/m2)
b Rating
system
-
Structure
Compound
Ar
Rating
Ca (mg/g)
Cb (mg/g)
Ca (mg/g)
Cb (mg/g)
system
-
CK
1.838±0.027q
0.738±0.013e
0.994±0.015k
0.260±0.006ab
1.905±0.037o
0.683±0.013d
1.372±0.046o
mesotrione
++++
0.345±0.021bcd
+++
Cl
I-a
0.765±0.008fg
0.282±0.004bc
+++
0.754±0.013e
0.376±0.018de
+++
N
O
Cl
Cl
I-b
I-c
I-d
0.781±0.005fghi
0.836±0.005lm
0.877±0.006op
0.298±0.003cd
0.336±0.012efg
0.436±0.009ij
++
++
+
0.782±0.009fgh
0.847±0.009kl
0.871±0.010mn
0.394±0.023ef
0.456±0.019hi
0.493±0.021jk
+++
+
N
O
F
Cl
N
O
O
O
N
Ar
O
+
N
O
I-a~I-h
O
I-e
I-f
0.723±0.004de
0.651±0.010a
0.266±0.019ab
0.251±0.026a
++++
++++
0.663±0.015cd
0.561±0.018a
0.337±0.017bc
0.252±0.015a
+++
Cl
++++
SO2CH3
NO2
I-g
I-h
I-i
0.675±0.006b
0.708±0.003cd
0.785±0.006ghi
0.250±0.007a
0.260±0.010ab
0.323±0.012def
++++
+++
0.630±0.003b
0.673±0.013d
0.782±0.011fgh
0.325±0.012b
0.329±0.019b
0.430±0.020ghi
+++
+++
++
SO2CH3
O
N
Cl
O
N
O
Ar
Cl
S
+++
N
O
I-i~I-n
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Cl
Cl
I-j
I-k
I-l
0.817±0.013jkl
0.840±0.010mn
0.884±0.009p
0.341±0.027efgh
0.371±0.012h
0.438±0.017ij
++
+
0.801±0.021hi
0.859±0.013lm
0.883±0.014mn
0.467±0.012ij
0.511±0.018klm
0.523±0.016klmn
++
N
O
F
Cl
-
N
O
-
-
N
O
O
I-m
I-n
0.760±0.014f
0.701±0.014c
0.301±0.015cd
0.265±0.020ab
++
0.766±0.010ef
0.640±0.007bc
0.370±0.029cde
0.340±0.020bcd
+++
+++
NO2
+++
SO2CH3
Cl
II-a
II-b
II-c
0.790±0.011hi
0.813±0.012jk
0.852±0.016mn
0.342±0.017efgh
0.360±0.017gh
0.367±0.018gh
++
++
++
0.805±0.015hi
0.824±0.012ijk
0.885±0.013n
0.445±0.014hi
0.497±0.024jkl
0.531±0.015lmn
++
+
N
N
N
O
Cl
Cl
O
O
O
N
F
Ar
Cl
+
O
O
II-a~II-e
II-d
II-e
II-f
0.892±0.010p
0.770±0.012fgh
0.813±0.020jk
0.463±0.019j
0.317±0.015de
0.352±0.016fgh
-
0.893±0.011n
0.775±0.011efg
0.816±0.010ij
0.546±0.014mn
0.400±0.013efg
0.467±0.019ij
-
N
O
O
++
++
++
+
Cl
Cl
Cl
N
N
N
O
O
O
Cl
II-g
0.830±0.017klm
0.371±0.027h
++
0.834±0.011jk
0.523±0.023klmn
+
O
N
O
O
Ar
II-f~II-i
F
II-h
II-i
0.859±0.014no
0.803±0.017ij
0.428±0.019i
+
0.892±0.007n
0.799±0.011ghi
0.553±0.019n
0.421±0.015gfh
-
O
0.339±0.023efg
++
++
463
464
a Abbreviations: EC, Echinochloa crus-galli and AJ, Abutilon juncea. CK was treated by water. Data are presented as the mean
± standard deviation of triplicate experiments. Different letters in the same column show significant differences at the p < 0.05
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level through Duncan’s multiple range tests by using SPSS statistics 20.0. b Rating scale of herbicidal activity (percentage of
466
467
inhibition): ++++, ≥ 90%; +++, 80~89%; ++, 60-79%; +, 50~59%; -, <50%.
Table 2. Physical and chemical property comparisons of I-f and mesotrione
Name
Structure
Logpa
MWa
HBAsa
HBDsa
RBsa
ARsa
SAa
Electronegativityb
O
Cl
O
N
I-f
O
1.680
303.719
5
0
2
1
263.120
SO2CH3
O
O
O
NO2
Mesotrione
1.113
339.321
7
0
4
1
307.480
SO2CH3
468
469
a Discovery Studio 3.0 was used for logp, molecular weight (MW), hydrogen bond acceptors (HBAs) and donors (HBDs),
rotatable bonds (RBs), aromatic rings (ARs), and bsurface area (SA). Sybyl-X 2.0 for electronegativity.
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Scheme 1. Design of the target compounds I and II.
199x240mm (300 x 300 DPI)
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Figure 1. Synthetic route of the target compounds I-a~I-h and I-i~I-n.
88x56mm (300 x 300 DPI)
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Figure 2. Synthetic route of the target compounds II-a~II-e and II-f~II-i.
112x60mm (300 x 300 DPI)
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