Synthesis and herbicidal activities of aryloxyacetic acid derivatives as HPPD inhibitors

Article abstract of DOI:10.3762/bjoc.16.25

A series of aryloxyacetic acid derivatives were designed and synthesized as 4-hydoxyphenylpyruvate dioxygenase (HPPD) inhibitors. Preliminary bioassay results reveal that these derivatives are promising Arabidopsis thaliana HPPD (AtHPPD) inhibitors, in particular compounds I12 (K_i = 0.011 μM) and I23 (K_i = 0.012 μM), which exhibit similar activities to that of mesotrione, a commercial HPPD herbicide (K_i = 0.013 μM). Furthermore, the newly synthesized compounds show significant greenhouse herbicidal activities against tested weeds at dosages of 150 g ai/ha. In particular, II4 exhibited high herbicidal activity for pre-emergence treatment that was slightly better than that of mesotrione. In addition, compound II4 was safe for weed control in maize fields at a rate of 150 g ai/ha, and was identified as the most potent candidate for a novel HPPD inhibitor herbicide. The compounds described herein may provide useful guidance for the design of new HPPD inhibiting herbicides and their modification.

Full text of DOI:10.3762/bjoc.16.25

Synthesis and herbicidal activities of aryloxyacetic acid
derivatives as HPPD inhibitors
Man-Man Wang, Hao Huang, Lei Shu, Jian-Min Liu, Jian-Qiu Zhang, Yi-Le Yan
and Da-Yong Zhang*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 233–247.
School of Science, China Pharmaceutical University, Nanjing 211198,
P. R. China
doi:10.3762/bjoc.16.25
Received: 27 November 2019
Accepted: 07 February 2020
Published: 19 February 2020
Email:
Man-Man Wang - mmwang17@163.com; Da-Yong Zhang* -
cpuzdy@163.com
Associate Editor: J. S. Dickschat
* Corresponding author
© 2020 Wang et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
aryloxyacetic acid; herbicidal activity; 4-hydroxyphenylpyruvate
dioxygenase; modification; synthesis
Abstract
A series of aryloxyacetic acid derivatives were designed and synthesized as 4-hydoxyphenylpyruvate dioxygenase (HPPD) inhibi-
tors. Preliminary bioassay results reveal that these derivatives are promising Arabidopsis thaliana HPPD (AtHPPD) inhibitors, in
particular compounds I12 (Ki = 0.011 µM) and I23 (Ki = 0.012 µM), which exhibit similar activities to that of mesotrione, a com-
mercial HPPD herbicide (Ki = 0.013 µM). Furthermore, the newly synthesized compounds show significant greenhouse herbicidal
activities against tested weeds at dosages of 150 g ai/ha. In particular, II4 exhibited high herbicidal activity for pre-emergence treat-
ment that was slightly better than that of mesotrione. In addition, compound II4 was safe for weed control in maize fields at a rate
of 150 g ai/ha, and was identified as the most potent candidate for a novel HPPD inhibitor herbicide. The compounds described
herein may provide useful guidance for the design of new HPPD inhibiting herbicides and their modification.
Introduction
4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, Scheme 1 [2-6]. The HPPD amino acid sequence homologies in
HPPD), which belongs to the family of non-heme FeII-contain- plants and mammals are significantly different [7,8], and this
ing enzymes, is a vital enzyme for tyrosine catabolism. This en- difference affects the binding stability between an inhibitor and
zyme is found in microbes, mammals, and plants, and has dif- HPPD, leading to inhibitor activities that differ among various
ferent functions in different organisms [1]. In the catalytic species and genera and providing a theoretical basis for the
process of HPPD, 4-hydroxyphenylpyruvic acid (HPPA) and design of inhibitors that are highly selective and safe [2].
FeII form a chelate complex, from which the HPPA substrate is
converted into homogentisic acid (HGA). The generally In plants, HPPD inhibitors competitively restrain HPPA from
accepted catalytic mechanism for this process is shown in chelating to FeII. The production of plastoquinone is inhibited
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Scheme 1: The commonly recognized HPPD catalytic reaction mechanism.
and phytoene is accumulated when the transformation of HPPA hibiting herbicides mostly contain 1,3-dicarbonyl or analogous
to HGA is interfered with an HPPD inhibitor [9,10]; conse- structures [11,15]. Arabidopsis thaliana HPPD (AtHPPD) and
quently, plants become severely damage when exposed to its inhibitors have been reported to interact in two ways:
sunlight, ultimately resulting in bleaching symptoms followed 1) through 1,3-dicarbonyl bidentate chelation with the active
by necrosis and death [11,12]. Therefore, HPPD inhibitors play center metal, and 2) through favorable sandwich π–π stacking
important roles in the herbicide industry. In addition, HPPD in- interactions between aromatic rings and the Phe360, Phe403
hibiting herbicides are advantageous because of their low toxic- residues of the active site. Thus, 1,3-dicarbonyl and aromatic
ities, high efficiencies, broad-spectrum weed control, and safety moieties are indispensable pharmacophores for potent HPPD-
toward crops and the environment [13-15]. However, the abuse inhibiting compounds that interact with surrounding residues in
of HPPD inhibitors has led to increased weed resistance and AtHPPD [16-19].
crop damage. Furthermore, the long-term applications of a
single herbicide result in the resistance of the weed to the agent 2,4-Dichlorophenoxyacetic acid (2,4-D), which acts as a plant
[14]. Therefore, exploring effective HPPD-inhibiting com- growth hormone, was synthesized in 1941. It is a selective pre-
pounds for the control of resistant weeds is an emergent and im- and post-emergence herbicide that has applied to several crops
portant objective [2].
[17]. 2,4-D interferes with the hormone balance of the plant,
which interrupts nucleic-acid and protein metabolism, and is
A considerable number of HPPD inhibiting herbicides have especially effective in broadleaf weeds, such as Amaranthus
recently been commercialized and applied in the agrochemical retroflexus and Alfalfa. The application of 2,4-D causes exces-
industry. These herbicides are mainly divided into three cate- sive growth that ultimately results in plant death. Consequently,
gories: triketones, pyrazoles, and isoxazoles [9,15,16]. Figure 1 2,4-D has become one of the world’s major herbicides because
shows some HPPD-inhibiting herbicides, namely mesotrione, low dosage is used and less investment costs are required.
tefuryltrione, isoxaflutole, topramezone, and pyrasulfotole.
Among them, mesotrione is a highly successful representative Many researches in HPPD inhibitors have revealed that modi-
triketone HPPD herbicide. Figure 1 reveals that the HPPD in- fying of aromatic moieties is an effective way of producing new
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Figure 1: Chemical structures of the commercial HPPD inhibitors.
HPPD inhibiting herbicides [20-23]. However, little effort has binding modes. The result revealed the presence of two main
been directed toward modifying pyrazole derivatives and the interactions, the sandwich π−π interaction and the bidentate
carbon−carbon bond between 1,3-dicarbonyl and aroyl interaction, which are similar to those of commercial
moieties. Previously, a series of 2-(aryloxyacetyl)cyclohexane- mesotrione. Inspired by the above revelations, we synthesized a
1,3-diones was synthesized by Wang et al. [24]. We have been group of new HPPD inhibitors that contain pyrazole and trike-
interested in inserting a carbon−oxygen bond between the trike- tone moieties to study their bioactivities; the design strategy is
tone and aroyl moieties of HPPD inhibitors. Initially, molecular shown in Figure 2. By combining the two bioactive structures,
docking studies were performed on two representative com- namely the aromatic moieties of 2,4-D and the 1,3-dicarbonyl
pounds, namely I39 and I40 [25], in order to explore their unit, we designed and synthesized a series of novel aryloxy-
Figure 2: The design strategy of aryloxyacetic acid derivatives as HPPD inhibitors and simulate the binding modes of compound I39 and I40 in a
target enzyme (AtHPPD). The key residues in the active site are shown in blue sticks, the FeII is shown as a dark blue sphere, and compound I39 and
I40 is shown in gray sticks.
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Beilstein J. Org. Chem. 2020, 16, 233–247.
acetic acid derivatives. In this context, these derivatives were 2,3,5,6-tetrachloropyridine as the starting material. In the pres-
subjected to HPPD inhibition, herbicidal activity, crop safety ence of TBAB, the starting material was hydrolyzed using
and structure–activity relationship (SAR) studies. As expected, NaOH in water at 100 °C. The resulting solution was cooled
many of the title compounds displayed promising inhibitory ac- and hydrolyzed with HCl solution that yielded compound F.
tivity against Arabidopsis thaliana HPPD (AtHPPD) in vitro Subsequent preparations for compounds G, H, J and II were re-
and excellent herbicidal activities at a rate of 150 g ai/ha.
spectively the same as for compounds C, D, E and I.
Results and Discussion
Chemistry
All intermediates were synthesized and characterized as
detailed in Supporting Information File 1. The structures of all
Title compounds were classified into three series (I, II and III). prepared compounds were confirmed by 1H and 13C NMR
The preparation of the title compounds is shown in Scheme 2, spectroscopy, and HRMS. Furthermore, the structures of com-
Scheme 3 and Scheme 4. The synthesis of compounds I and III pounds I18 and III4 were verified by X-ray diffractometry
was depicted in Scheme 2 and Scheme 3. The commercially (Figure 3). Crystallographic data for crystalline I18 and III4
available starting materials reacted with methyl chloroacetate in have been deposited with the Cambridge Crystallographic Data
CH3CN and anhydrous potassium carbonate (K2CO3) as the Centre (CCDC 1959130, CCDC 1959152).
base, and the corresponding products C and K were prepared.
The products were hydrolyzed using K2CO3 as a base to yield HPPD inhibition
the product D and L [26-30]. In the presence of 3-(ethylimi- The title compounds displayed promising AtHPPD inhibitory
nomethylideneamino)-N,N-dimethylpropane-1-amine, hydro- activities, with Table 1 and Table 2 revealing that compounds
chloride (EDCI), the aromatic oxyacetic acid reacted with I12 (Ki = 0.011 µM) and I23 (Ki = 0.012 µM) exhibit similar
substituted 1,3-cyclohexanediones or substituted 1,3-dimethyl- inhibitor potencies to that of mesotrione (Ki = 0.013 µM).
1H-pyrazole-5-ol, using DMAP as the catalyst. Subsequently, Docking studies using the CDOCKER module within
the key enol ester E and M were respectively obtained. Finally, Discovery Studio 4.0 revealed the bioactive binding site posi-
Fries-type rearrangements were performed in anhydrous DCM tions of potential inhibitors within the targets active site. We
at room temperature to afford the title compounds I and III modeled the interactions of I12 and II4 (C) with AtHPPD (PDB
[31].
ID: 1TFZ). The structure of AtHPPD was taken from the PDB
data bank. All molecular modeling studies were carried out as
As shown in Scheme 4, the title compounds II were obtained by previously reported [10,19,32-34]. The results show that two
a five-step synthetic route using the commercially available main interactions exist between I12 and the AtHPPD
Scheme 2: Synthetic route of the title compounds I. Reagents and conditions: (a) methyl chloroacetate, K2CO3, CH3CN, 65 °C; (b) K2CO3, H2O,
65 °C; (c) aqueous HCl solution (10%), rt; (d) substituted 1,3-cyclohexanediones, EDCI, DMAP, DCM, rt; (e) substituted 1,3-dimethyl-1H-pyrazol-5-ol,
EDCI, DMAP, DCM, rt; (f) Et3N, acetone cyanohydrin, DCM, rt.
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Scheme 3: Synthetic route of the title compound III. Reagents and conditions: (a) methyl chloroacetate, K2CO3, CH3CN, 65 °C; (b) K2CO3, H2O,
65 °C; (c) aqueous HCl solution (10%), rt; (d) substituted 1,3-cyclohexanediones, EDCI, DMAP, DCM, rt; (e) substituted 1,3-dimethyl-1H-pyrazol-5-ol,
EDCI, DMAP, DCM, rt; (f) Et3N, acetone cyanohydrin, DCM, rt.
Scheme 4: Synthetic route of the title compounds II. Reagents and conditions: (a) NaOH, TBAB, H2O, 100 °C; (b) concentrated HCl solution, rt;
(c) methyl chloroacetate, K2CO3, CH3CN, 65 °C; (d) K2CO3, H2O, 65 °C; (e) aqueous HCl solution (10%), rt; (f) substituted 1,3-cyclohexanediones,
EDCI, DMAP, DCM, rt; (g) substituted 1,3-dimethyl-1H-pyrazol-5-ol, EDCI, DMAP, DCM, rt; (h) Et3N, acetone cyanohydrin, DCM, rt.
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Figure 3: Crystal structures of I18 and III4.
Table 1: Chemical structures of title compound I and their biological activity against AtHPPD.
I1–40
compound
R1
R
AtHPPD inhibition
Ki (μM)
I1
I2
I3
H
H
1.5 0.031
1.3 0.017
0.36 0.012
2-chloro
I4
I5
I6
2-chloro
4-chloro
4-chloro
0.59 0.043
1.0 0.036
0.93 0.032
I7
2,4-dichloro
0.36 0.012
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Table 1: Chemical structures of title compound I and their biological activity against AtHPPD. (continued)
I8
2,4-dichloro
0.22 0.023
I9
2,4,6-trichloro
2,4,6-trichloro
0.31 0.048
0.24 0.003
I10
I11
I12
2,4,6-trichloro
2,4,6-trichloro
0.081 0.001
0.011 0.012
I13
I14
2-nitro
2-nitro
0.45 0.033
0.21 0.042
I15
2-nitro
0.27 0.004
I16
I17
2-nitro
4-nitro
0.44 0.013
0.23 0.004
I18
I19
4-nitro
4-nitro
0.93 0.006
0.63 0.002
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Table 1: Chemical structures of title compound I and their biological activity against AtHPPD. (continued)
I20
I21
4-nitro
4-nitro
0.50 0.003
1.5 0.041
I22
I23
2-chloro-4-nitro
2-chloro-4-nitro
1.02 0.009
0.012 0.009
I24
2-chloro-4-nitro
0.26 0.012
I25
I26
2-chloro-4-nitro
0.21 0.043
1.9 0.001
2-(2,4-dichlorophenoxy)-4-chloro
I27
I28
2-(2,4-dichlorophenoxy)-4-chloro
2-(2,4-dichlorophenoxy)-4-chloro
2.2 0.041
0.032 0.002
I29
2-(2,4-dichlorophenoxy)-4-chloro
1.3 0.022
I30
I31
2,4-dimethyl
2,4-dimethyl
2.2 0.034
3.1 0.34
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Table 1: Chemical structures of title compound I and their biological activity against AtHPPD. (continued)
I32
I33
2,4-dmethyl
2,4-dimethyl
2.0 0.009
2.8 0.045
I34
I35
2,4-dimethyl
2.8 0.67
3.3 0.14
4-methyl-5-methoxy
I36
I37
4-methyl-5-methoxy
4-methyl-5-methoxy
3.4 0.21
2.7 0.53
I38
I39
4-methyl-5-methoxy
2.9 0.038
1.3 0.056
H
H
I40
1.2 0.031
mesotrione
0.013 0.001
Table 2: Chemical structures of title compound II, III and their biological activity against AtHPPD.
II1–5, III1–6
compound
R5
R
AtHPPD inhibition
Ki (μM)
II1
2,3,5-trichloro-6-pyridyl
0.093 0.007
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Table 2: Chemical structures of title compound II, III and their biological activity against AtHPPD. (continued)
II2
II3
2,3,5-trichloro-6-pyridyl
2,3,5-trichloro-6-pyridyl
0.097 0.010
0.021 0.004
II4
II5
2,3,5-trichloro-6-pyridyl
2,3,5-trichloro-6-pyridyl
0.023 0.006
0.12 0.003
III1
III2
2-bromo-2-naphthyl
2-bromo-2-naphthyl
2.50 0.011
2.2 0.090
III3
2-bromo-2-naphthyl
2.2 0.13
III4
III5
2-bromo-2-naphthyl
2-nitro-3-pyridyl
2.0 0.012
0.23 0.011
III6
2-nitro-3-pyridyl
0.21 0.042
0.013 0.001
mesotrione
active site (Figure 4), as was observed for mesotrione; influenced the HPPD inhibition activity. We found that elec-
the 1,3-dicarbonyl unit is chelated to the iron ion, and the aro- tron-withdrawing groups improve the activity; for example, I3
matic ring moiety formed π–π interactions with Phe403 and (Ki = 0.36 µM) and I4 (Ki = 0.59 µM) were more potent than I1
Phe360.
(Ki = 1.5 µM) and I2 (Ki = 1.3 µM). In addition, the position of
the electron-withdrawing group played an essential role in de-
Electron-withdrawing and electron-donating groups were intro- termining the HPPD inhibitory activity. In most cases,
duced onto the benzene ring of I1, which significantly compounds with a chlorine atom at the 2-position (I4) were
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Figure 4: Simulated binding mode of mesotrione (A), compound I12 (B) and compound II4 (C) with AtHPPD. The key residues in the active site are
shown in blue sticks, and FeII is shown as a dark blue sphere. mesotrione, compound I12, and II4 are shown in gray sticks.
more active than those with the chlorine at the 4-position (I6), were unfavorable to activity (I17 > I18, I26 > I27, II1 > II2),
clearly an electron-withdrawing group at the 2-position and that the introduction a nitro group led to more potent
provides enhanced activity compared to the 4-position. In addi- activity compared to that generated by a chlorine atom (except
tion, electron-donating groups were found to be detrimental to for I6 and I21), such that I15 > I3, I18 > I5, and I24 > I7 in
HPPD inhibition activity (I1 > I33, I38). We observed that terms of activity. Generally speaking, compounds with a
methyl groups at the 5-position of the 1,3-cyclohexane ring pyrazole ring exhibited better HPPD inhibitory activities than
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those with cyclohexanedione rings (I28, I29 > I26, I27; tive control drug, we observed that it perfectly fits into the
II3, II4 > II1, II2).
active pocket, as shown in Figure 6.
Herbicidal activity
In this work, two categories of HPPD inhibitors were synthe-
The post-emergence herbicidal activities of the title compounds sized, including triketone and pyrazole derivatives. Compared
are summarized in Figure 5. In our work, these weeds, E. crus- with the triketone derivatives, the pyrazole-containing deriva-
galli (EC), S. faberii (SF), D. sanguinalis (DS), A. retroflexus tives were generally more herbicidally potent. For instance,
(AR), E. prostrata (EP), and A. juncea (AJ), were selected for pyrazole-containing compounds I11 and I12 displayed en-
evaluating the post-emergence herbicidal activities of the title hanced activities relative to compound I9, which contains a
compounds.
cyclohexanedione ring. We also observed that the introduction
of methyl groups at the 5-position of the 1,3-cyclohexane ring
Some of the synthesized compounds exhibited better control was detrimental to herbicidal activity (I17 > I18, I26 > I27,
efficiencies for the test weed; among them, compounds I28, II1 > II2). Compounds with electron-withdrawing groups on
I29, II3 and II4 showed broad-spectrum herbicidal activities, the aromatic ring were found to displayed higher herbicidal ac-
with II4 even showing a slightly higher herbicidal activity than tivities than those with electron-donating groups (i.e., I7 > I33,
mesotrione at a rate of 150 g ai/ha. When the structure of com- I8 > I34), which is consistent with the observed AtHPPD
pound II4 was superimposed onto that of mesotrione, the posi- inhibitory activity, and I28 and I29 had significantly superior
Figure 5: Sum of inhibition rate of title compounds at 150 g ai/ha. (Abbreviations: AJ, Abutilon juncea; AR, Amaranthus retroflexus; EP, Eclipta pros-
trata; DS, Digitaria sanguinalis; EC, Echinochloa crus-galli; SF, Setaria faberii.)
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Crop safety
Crop safety is one of the main considerations during herbicide
discovery. Compound II3, II4, and II5, which exhibited excel-
lent herbicidal activities, were chosen for further crop safety
studies and to evaluate whether or not they have the potential to
be developed as herbicides (Table 3). Commercial mesotrione
was selected as the positive control HPPD herbicide. We found
that wheat and maize showed high tolerance to compound II3 at
a dosage of 150 g ai/ha, however, its herbicidal activity could
not compete with that of mesotrione. In addition, maize
displayed tolerance to compound II4, indicating that II4 had the
potential to be developed as a postemergence herbicide for
weed control in maize fields.
Conclusion
A series of aryloxyacetic acid derivates was synthesized as
novel HPPD inhibitors. The bioassay studies revealed that some
of the title compounds, such as compound I12 (Ki = 0.011 µM),
I23 (Ki = 0.012 µM), showed similar AtHPPD inhibitor poten-
cies to that of mesotrione (Ki = 0.013 µM). Moreover, several
newly synthesized compounds displayed strong, broad
spectrum weed control when dosed at 150 g ai/ha. Most impor-
tantly, compound II4, with good HPPD inhibition activity
(Ki = 0.023 µM), exhibited a slightly higher herbicidal activity
Figure 6: Simulated folding mode of mesotrione (yellow sticks) and
compound II4 (gray sticks) with AtHPPD. The key residues in the
active site are shown in blue sticks, and FeII is shown as a dark blue
sphere.
herbicidal activities. Thus, the introduction of large groups on than mesotrione. In addition, II4 was found to be safe for use
the benzene ring appears to be beneficial to the activity and on maize. These results suggest that compound II4 is a promis-
deserves further structural optimization.
ing HPPD inhibiting herbicide candidate deserving of further
optimization studies.
The herbicidal activities of compounds containing other aromat-
ic rings, compound II and III bearing a pyridine ring and a Experimental
naphthalene ring, were examined. The results show that the The experimental details and analytical data for intermediates C
chloro-substituted pyridine exhibited superior herbicidal activi- to M and title compounds were given in Supporting Informa-
ty, which provides a theoretical basis for the further develop- tion File 1. The chemical structures of all title compounds were
ment of highly effective HPPD herbicides. Some compounds confirmed by 1H and 13C NMR spectroscopic analyses and
with significant AtHPPD inhibitory activities were found not to HRMS spectrometric analyses.
exhibit promising herbicidal activities. For example, compound
I12, with the best AtHPPD inhibition activity (Ki = 0.011 µM) X-ray diffraction
exhibited poorer than expected herbicidal activity, which is Single crystals of compounds I18 and III4 were cultivated for
possibly related to its stability and metabolism in the plant [2]. structure validation. Compound I18 was recrystallized from a
Table 3: Postemergence crop safety of compounds II3, II4 and II5 (150 g ai/ha).
compound
dosage(g ai/ha)
% injury
rice
wheat
maize
cotton
soybean
canola
II3
II4
II5
150
150
150
150
40
30
50
50
10
50
50
40
10
10
30
10
60
60
90
80
50
30
70
50
90
100
100
100
mesotrione
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mixture of DCM/methanol to afford a colorless transparent the pots and covered with soil to a thickness of 0.2 cm and
crystal. It crystallized in the monoclinic space group: P–1 (2), grown in the greenhouse. When the weeds grew to about the
cell: a = 6.425(4) Å, b = 9.854(6) Å, c = 13.205(8) Å, three-leaf stage, they were treated by the title compounds at the
α = 93.974(7)°, β = 102.211(7)°, γ = 107.567(7)°, temperature: rate of 150 g ai/ha. After 18 days of treatment with inhibitors,
298 K. Compound III4 was recrystallized from a mixture of the herbicidal activities were surveyed and evaluated with two
DCM/methanol to afford a colorless transparent crystal. It crys- duplicates per experiment [19]. (Figure 5)
tallized in the monoclinic space group: P–1 (2), cell:
a = 5.191(5) Å, b = 12.133(12) Å, c = 13.576(14) Å, Crop selectivity
α = 80.141(13)°, β = 81.978(12)°, γ = 79.496(12)°, temperature: The representative crops, rice, wheat, maize, cotton, soybean,
296 K. X-ray crystal structure of compound I18 and III4 are and canola were selected to test the crop safety of compound
shown in Figure 3.
II3, II4, and II5. The six crops were separately planted in
flowerpots (12 cm diameter) containing the composite nutrient
Crystallographic data for crystal compounds I18 and III4 were soil and grown at room temperature. When the crops had
deposited with the Cambridge Crystallographic Data Centre as reached the four-leaf stage, the safety experiments were con-
supplementary publications with the deposition numbers CCDC ducted at the rate of 150 g ai/ha. After 15 days, the final results
1959130 and CCDC 1959152, respectively. The data can be ob- of crop safety were evaluated with two duplicates per experi-
tained free of charge from http://www.ccdc.cam.ac.uk/.
ment (Table 3).
Docking study
Supporting Information
The docking study was conducted with the method reported
previously [10,19,32-34]. Crystal structures of Arabidopsis
thaliana HPPD (PDB ID: 1TFZ) with the native ligand, named
DAS869 were downloaded from the Protein Data Bank. The
docking was carried out using Discovery Studio 4.0. During the
docking process, all water molecules were removed. The ligand
and protein were prepared with the Dock Ligands tool before
docking. By using Define and Edit Binding Site tool to identify
the active site. Then the center of the native ligand was deleted.
Utilizing the CDOCKER, the prepared ligand was docked into
the protein receptor binding site. After the docking calculations
were performed, the best binding modes were determined by
docking scores and also compared with the simulated binding
mode of mesotrione with AtHPPD.
Supporting Information File 1
Additional experimental and analytical data, and NMR
spectra of synthesized compounds.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-25-S1.pdf]
Acknowledgments
The author thanks Prof. Da-Yong Zhang and Hao Huang for ex-
perimental guidance, Zhejiang University Chemical Industry
Research Institute for biological activity assay, and National
Natural science Foundation of China (30973607, 81172934),
"Double First-Class" New Drug Development Project of China
Pharmaceutical University (CPU2018PZQ15) for financial
supports
Enzyme inhibition study
AtHPPD was prepared and purified according to the reported
methods in the literature [19,20,35-37]. The inhibition constant
(Ki) was obtained and shown in Table 1 and Table 2.
ORCID® iDs
Man-Man Wang - https://orcid.org/0000-0003-1038-1559
Preprint
Herbicidal activities
A non-peer-reviewed version of this article has been previously published
as a preprint doi:10.3762/bxiv.2019.150.v1
The post-emergence herbicidal activities of the title compounds
were evaluated against monocotyledon weeds (E. crus-galli,
S. faberii, and D. sanguinalis) and broadleaf weeds
(A. retroflexus, E. prostrata, and A. juncea) in the greenhouse
experiments. The commercial HPPD herbicide mesotrione was
regarded as a control. All tested compounds were dissolved in
DMF as 100 g/L emulsified concentrates, containing 1%
Tween-80 as emulsifier. Then the solvent was diluted with
distilled water. Flowerpots with an inner diameter of 7.5 cm
were filled with complex nutrient soil to three-fourths of their
height. The above six weed targets were respectively grown in
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