Fragment splicing-based design, synthesis and safener activity of novel substituted phenyl oxazole derivatives

Article abstract of DOI:10.1016/j.bmcl.2018.12.061

Fragment splicing is a primary strategy in the design and optimization of leading compound toward new skeleton with target bioactivity. Herein a series of novel substituted phenyl oxazole derivatives were designed via fragment analysis and coupling strategy that led to highly potent and bio-selective herbicide safener. The biological tests showed that most of the compounds could enhance the maize growth index, glutathione content and anti-reverse enzyme glutathione S-transferase activity in vivo. The molecular docking model exhibited that the novel compound could compete with chlorsulfuron binding to the herbicide target enzyme, which consequently attained the herbicide detoxification. Especially compound I-f displayed the best activities than commercial safener isoxadifen-ethyl and other compounds. The present work demonstrates that the synthesized compounds could be developed as potential candidates for the discovery of novel herbicide safeners in the future.

Full text of DOI:10.1016/j.bmcl.2018.12.061

Bioorganic & Medicinal Chemistry Letters xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Fragment splicing-based design, synthesis and safener activity of novel
substituted phenyl oxazole derivatives
⁎
Ying Fu, Dong Zhang, Tao Kang, You-Yuan Guo, Wen-Geng Chen, Shuang Gao, Fei Ye
Department of Applied Chemistry, College of Science, Northeast Agricultural University, Harbin 150030, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Fragment splicing is a primary strategy in the design and optimization of leading compound toward new ske-
leton with target bioactivity. Herein a series of novel substituted phenyl oxazole derivatives were designed via
fragment analysis and coupling strategy that led to highly potent and bio-selective herbicide safener. The bio-
logical tests showed that most of the compounds could enhance the maize growth index, glutathione content and
anti-reverse enzyme glutathione S-transferase activity in vivo. The molecular docking model exhibited that the
novel compound could compete with chlorsulfuron binding to the herbicide target enzyme, which consequently
attained the herbicide detoxification. Especially compound I-f displayed the best activities than commercial
safener isoxadifen-ethyl and other compounds. The present work demonstrates that the synthesized compounds
could be developed as potential candidates for the discovery of novel herbicide safeners in the future.
Fragment splicing
Substituted phenyl oxazole
Biological tests
Molecular docking
Herbicide safener
The phytotoxicity and resistance problems occur continuously with the
extensive use of herbicides. People come up with some solutions to the
serious problems of herbicides. It is no doubt that herbicide safener is an
effective route to reduce the injury caused by herbicides, and may even
bring more unexpected benefits. Herbicide safeners have played a sig-
crop by enhancing the activity of the mediating enzymes such as gly-
cosyltransferases (UGTs), glutathione S-transferases (GSTs) and a co-
factor endogenous glutathione (GSH) as well as ATP-binding casette
3
–6
(ABC) transporter proteins involved in detoxification of herbicides.
Therefore, conclusive elucidation of the exact mechanisms underlying
safener action will remain a challenge that requires further research.
In recent years, a number of structurally diverse herbicide safeners
1
nificant role in agricultural development. However, the commercial
safeners are limited for “minor” crops such as strawberry, chrysanthemum,
mulberry, bamboo, etc., novel safeners aimed at the problems of various
herbicides in more crop plants and weeds should be obtained.
7
have been commercialized, such as isoxadifen-ethyl, fenchlorazole-
8
3
ethyl, and mefenpyr-diethyl, which aim at different types of herbi-
cides. Oxazole is one of the common substructures of the effective
The detoxifying mechanism by safener is not completely clear, and
there are various hypotheses proposed explaining the mechanisms of
action. Safeners act by reducing the ability of herbicides to reach or
inhibit their target sites. This may be achieved through safener inter-
9
,10
herbicide safeners.
Safener AD-67 (N-dichloroacetyl-1-oxa-4-azas-
piro-4,5-decane), a spirooxazolidine compound, is used to protect
1
,8,11
maize seed treatments against herbicide acetochlor.
Furilazole
actions with herbicide target sites, particularly acetolactate synthase
(MON-13900), apart from protection against acetochlor, possess a good
safening effect on the sulfonylureas herbicides particularly halo-
2
(
ALS), acetyl CoA carboxylase (ACCase), or other receptor proteins.
1
2
Alternatively, safeners may reduce the amount of active herbicide
reaching target in its active form, either by safener-induced reductions
in herbicide absorption or translocation, by the direct chemical reaction
of the safener with the herbicide molecule, or by safener-enhanced
sulfuron-methyl. Flurazole, 2,4-disubstituted 5-thiazolecarboxylate,
can also be used a seed treatment safener against alachlor in grain
1
3–16
sorghum
Heterocycle is another important skeleton unit of safe-
ners. It can be seen that 2-dichloromethyl-2-methyl-1,3-dioxolane (MG-
191), the most active member of ketal or dichloroacetal derivatives,
protects maize against chloroacetanilide, in particular, thiocarbamate
3
metabolism of herbicides to less active or immobile metabolites. Some
safeners were found to elevate the metabolism and detoxification in the
Abbreviations: ALS, acetolactate synthase; ACCase, acetyl CoA carboxylase; UGT, glycosyltransferase; GST, glutathione S-transferase; GSH, glutathione; ABC, ATP-
binding cassette; AR, aromatic ring; RB, rotatable bond; HBA, hydrogen bond acceptor; HBD, hydrogen bond donor; SA, surface area; MW, molecular weight; DMF,
N,N-dimethylformamide; NBS, N-bromosuccinimide; DMAP, 4-dimethylaminopyridin; mp, melting point; NMR, nuclear magnetic resonance; TLC, thin-layer chro-
matography; UV, ultraviolet; HRMS, high-resolution mass spectrometry; FTICR-MS, Fourier transformion cyclotron resonance mass spectrometry; EtOAc, ethyl
acetate; DTNB, 5,5′-dithiobis(2-nitrobenzoic) acid; PDB, Protein Data Bank
⁎
Corresponding author.
E-mail addresses: fuying@neau.edu.cn (Y. Fu), gaoshuang@neau.edu.cn (S. Gao), yefei@neau.edu.cn (F. Ye).
https://doi.org/10.1016/j.bmcl.2018.12.061
Received 29 October 2018; Received in revised form 28 December 2018; Accepted 28 December 2018
0960-894X/ © 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: Fu, Y., Bioorganic & Medicinal Chemistry Letters, https://doi.org/10.1016/j.bmcl.2018.12.061

Y. Fu et al.
Bioorganic & Medicinal Chemistry Letters xxx (xxxx) xxx–xxx
Table 1
Physical and chemical properties of commercial safeners.
Name
Structure
Log pa
MWa
HBAsa
5
HBDsa
0
RBsa
4
ARsa
1
SAa
Electronegativityb
Oxabetrinil
1.457
232.24
228.51
Fluxofenim
Flurazole
3.185
4.262
2.531
1.462
1.952
0.561
3.418
3.598
4.946
0.985
4.077
3.338
309.67
321.70
260.12
278.13
252.14
212.07
225.07
268.35
403.48
171.02
373.23
295.33
4
3
2
2
2
2
2
1
4
2
6
4
0
0
0
0
0
0
0
2
0
0
0
0
5
5
1
2
1
1
1
3
5
1
7
5
1
2
1
1
0
0
2
2
2
0
1
2
262.18
268.72
231.79
255.36
226.44
199.74
201.3
Benoxacor
Furilazole
AD-67
R28725
Fenclorim
Daimuron
279.2
Fenchlorazole-ethyl
MG-191
344.49
152.46
351.69
280.33
Cl
Cl
O
O
Mefenpyr-diethyl
Isoxadifen-ethyl
a
b
23
The parameters were calculated by Accelrys Discovery Studio 3.0 (Catalyst, Version 4.10. Accelrys Inc., San Diego, CA, USA, 2005).
24
The electronegativity was predicted by SYBYL-X 2.0 (SYBYL, Version 6.9. Tripos Inc., St. Louis, MO, USA).
injuries.8 Oxabetrinil and fluxofenim are developed as seed treatment
,11
oxabetrinil, fluxofenim, flurazole, benoxacor, furilazole, fenclorim,
daimuron, fenchlorazole-ethyl, mefenpyr-diethyl and isoxadifen-ethyl
(Table 1).
1
7
safeners to protect grain sorghum from chloroacetanilides injury.
Aromatic rings are an important substructure of many safeners such as
2

Y. Fu et al.
Bioorganic & Medicinal Chemistry Letters xxx (xxxx) xxx–xxx
Thinking about the aforementioned results of structural analysis,
herein we design the new safener skeleton structure containing the
above-mentioned fragment structure to obtain a series of novel, broad-
spectrum herbicide safeners.
To date, over twenty kinds of structurally diverse safeners have been
successfully developed. A survey of the safener structures, it can be
found that all of these herbicide safeners share common chemical
structures and physical properties, such as consist of heterocyclic ring,
aromatic ring (AR), similar electronegativity, rotatable bonds (RBs), a
few of hydrogen bond acceptors and donors (HBAs and HBDs) (range
from 0 to 6), surface area (SA), lower log p (range from 0.561 to 4.946)
and molecular weight (MW) is from 171.02 to 403.48 (Table 1). Het-
erocyclic ring, as a substructure, is one of the most important moieties
for novel farm chemical discovery including safeners development.
Approximately 70% of agrochemicals and pharmaceuticals include at
1
8
least one heterocyclic ring. Aromatic ring feature generates strong
π–π interactions with amino acids to increase the binding affinity. The
number of rotatable bonds, a simple topological parameter, is a mea-
sure of molecular flexibility and the increased rotatable bond has a
1
9
negative effect on the permeation rate. The lower log p and MW lead
8
to a better leaf uptake at usage. The number of rotatable bonds, log p,
and surface area showed negative correlation with respect to the bio-
logical activity. HBAs and HBDs are other important parameters related
to compounds polarity, permeability and the capacity of ligand binding
2
0,21
to receptors.
Usually the number of HBAs, HBDs, and aromatic
22
rings exhibited a positive correlation with the biological activity.
Summarized the structure information of the existing herbicide
safeners, it can be concluded that they always possess some common
structural features: (i) at least one aromatic ring; (ii) penta- or hexa-
heterocycle including N, O atoms; (iii) polar functional groups; (iv) MW
being less than 400; (v) the number of rotatable bonds being between 1
and 4; and (vi) hydrogen bond acceptor atoms and only daimuron with
hydrogen bond donor atoms.
Scheme 1. Design of the target compounds I and II.
Inspired by these findings, herein, it would be of great interest in the
pursuit of highly potent safeners to take advantage of the rich structural
information of commercial safeners and the active fragment combina-
tion strategy. In this context, the fragment splicing strategy is an ef-
fective drug design methodology that has been widely applied to the
2
5–27
Scheme 2. Synthetic route of the target compounds I-a–I-h.
discovery of potential agrochemicals.
In the present study, a series
of novel substituted 4-(2,4-disubstituted phenyl)-5-substitued-2-((2-
methyl-1,3-dioxolan-2-yl)methyl) oxazole (I) and propyl 2-phenylox-
azolidine-3-carboxylate derivatives (II) were designed based on the
fragment splicing of six commercial safeners subunits (Scheme 1). The
target compounds were also evaluated for the growth index, GSH, GST
and ALS activity in vivo. Furthermore, molecular docking analysis was
extensively performed to identify the possible detoxification me-
chanism for their safener potency.
As shown in Scheme 2, the key intermediates 1-a and 1-b under-
went a ring-forming reaction to give the target compounds I in DMF
Scheme 3. Synthetic route of the target compounds II-a–II-h.
under N at room temperature. It was found that the yields of com-
2
pounds I were increased with the electron-donating group on the ben-
zene ring, however, it was inverse effect on the yields with the sub-
stitutions on the oxazole ring. The compound I-b gave better yield than
others.
diffraction. The molecular structure and the packing diagram of com-
pound I-f are shown in Figs. 1 and 2, respectively, and the crystal-
lographic parameters were listed in Table 2. It was noteworthy that
compound I-f was consisted of three rings benzene, oxazole and diox-
olame. Among them, the oxazole ring and benzene ring near the same
plane, and the dioxolame occupied another plane, just as shown in
Fig. 1. The π–p–π conjugation of O(1), C(8)]C(7), benzene ring, N
The target compounds II were synthesized in the yields of 28–65%
via acylation in the presence of anhydrous DMAP at room temperature
(
Scheme 3). It was observed that the yields of compounds II were also
increased with the introduction of electron-donating groups on the
benzene ring. Compound II-c gave the best yield. It was worth mention
that key intermediate 2-a could not be prepared when the position of
the benzene ring was introduced with strong electron-withdrawing
groups.
(
1)]C(9) results in shorter bond length of N(1)eC(9) [1.288(2) Å],
C(7)eC(8) [1.347(2) Å], than the typical NeC, CeC bond length
28,29
[
1.47 Å] and [1.53 Å].
Compound I-f contained an original benzene
ring [C1, C2, C3, C4, C5, and C6], dioxolame ring [C7, C8, O1, C9 and
N1] and a new oxazole ring [C11, O2, C12, C13 and O3]. The dihedral
angle between benzene ring and dioxolame ring is 17.698(71)°, and the
oxazole ring makes a dihedral angle of 54.03(7)°, with benzene ring.
The presence of the intermolecular π–π led to the stability of the
The chemical structures of the target compounds were confirmed by
1
13
IR, H NMR, C NMR and HRMS (see supporting data). Furthermore,
the structure of compound I-f was verified by X-ray diffraction analysis.
The structure of I-f was further studied by single crystal X-ray
3

Y. Fu et al.
Bioorganic & Medicinal Chemistry Letters xxx (xxxx) xxx–xxx
Table 3
i,ii,iii
Safener effects of compounds I and II to growth index of maize.
Compound
Recovery of
plant height
Recovery of
plant fresh
weight (%)
Recovery of
root length
(%)
Recovery of
root fresh
(
%)
weight (%)
Isoxadifen-
ethyl
I-a
86.98 ± 0.59
89.05 ± 0.79
84.17 ± 0.44
80.90 ± 1.12
77.51 ± 0.65
91.56 ± 0.85
79.90 ± 0.98
83.53 ± 1.38
88.26 ± 0.79
93.58 ± 1.13
53.60 ± 0.87
79.87 ± 0.87
29.78 ± 0.93
81.86 ± 1.14
27.75 ± 0.68
79.92 ± 0.39
37.90 ± 1.00
20.06 ± 0.70
83.37 ± 0.57
85.10 ± 1.39
55.86 ± 3.53
84.71 ± 0.93
60.08 ± 2.87
93.41 ± 0.49
95.45 ± 1.59
100.40 ± 1.12
38.03 ± 1.71
48.47 ± 2.05
43.82 ± 1.66
85.71 ± 0.84
27.88 ± 1.12
89.36 ± 0.77
53.66 ± 1.13
37.25 ± 2.56
79.82 ± 0.52
83.02 ± 1.70
57.17 ± 0.21
82.07 ± 0.60
50.05 ± 1.26
28.98 ± 0.97
80.03 ± 0.78
88.12 ± 0.50
63.18 ± 1.64
90.54 ± 0.87
80.53 ± 1.03
94.73 ± 0.83
25.42 ± 1.05
84.06 ± 0.29
40.14 ± 3.00
37.37 ± 1.26
85.65 ± 0.58
81.18 ± 1.51
41.77 ± 1.78
91.87 ± 1.77
62.98 ± 1.49
22.86 ± 0.29
88.60 ± 0.96
81.69 ± 1.43
51.37 ± 0.73
67.20 ± 1.85
75.65 ± 1.09
90.88 ± 0.58
44.29 ± 3.13
77.69 ± 0.31
51.56 ± 2.41
16.97 ± 1.11
83.74 ± 1.37
80.98 ± 1.28
I-b
I-c
I-d
Fig. 1. Crystal structure of compound I-f at 30% probability level.
Crystallographic data for I-f has been deposited in the Cambridge
Crystallographic Data Center (CCDC 1843486).
I-e
I-f
I-g
I-h
II-a
II-b
II-c
II-d
II-e
II-f
II-g
II-h
i
Data are presented as the mean ± standard deviation of triplicate experi-
ments.
CK was treated by water.
ii
concentration of the target compounds, and compound II-a was se-
lected for the preliminary screening and commercial safener isoxadifen-
ethyl was selected as the positive control. It could be seen that the
excellent growth index was got at the concentration of 25 μmol/L with
seed treated. All the target compounds revealed differing recovery rates
for plant height, plant fresh weight, root length, and root fresh weight,
which indicated the rational design of the target compounds. Among
the series, compounds I-b, I-e, I-f, II-b, II-d, II-g and II-h exerted ex-
cellent safener activity against chlorsulfuron injury, similar or better
than the commercial control to some extent. The recovery rates of the
growth indexes of compound I-f were the best among the synthesized
compounds. It is noteworthy that compounds I demonstrated potent
activities higher than compounds II against chlorsulfuron.
Fig. 2. Packing diagram of compound I-f in a unit cell.
Table 2
Crystal and structure refinement for compound I-f.
Item
Value
CCDC
1843486
Empirical formula t
Formula weigh
Temperature
14 3
C H14ClNO
The detoxification ability of safener was also determined by the
level of GSH conjugation in the plant. The increase of GSH content
279.71
293(2) K
0.71073 Å
5
,8,30
Radiation λ
induced by safener has also been reported previously.
In this
Crystal system, space group
Unit cell dimensions
1
Monoclinic, P2 /c
evaluation, the GSH content of treated maize exhibited significantly
improved (Table 4). The GSH level treated by compounds I-f, II-a and
II-e, were better than that of isoxadifen-ethyl. In particular, the GSH
content of compound I-f was superior to that of the other compounds.
GSTs are present at each stage of plant development from early
embryogenesis to senescence and in every tissue style examined. GSTs
possibly function to protect the plant cell from oxidative damage by
a = 5.6676(11) Å, α = 99.69(3)°
b = 10.566(2) Å, β = 100.07(3)°
c = 11.647(2) Å, γ = 102.27(3)°
3
Volume
655.5(2) Å
Z
2
3
Calculated density
1.417 mg/m
−
1
Absorption coefficient
F(0 0 0)
0.294 mm
292
3
1
extinguishing reactive molecules with the addition of GSH. The role
Crystal size
0.41 × 0.32 × 0.25 mm
2.99–27.48°
3
2–36
Theta range for data collection
Range/indices (h, k, l)
Reflections collected/unique
Completeness to theta = 27.48
Absorption correction Tmax and Tmin
Data/restraints/parameters
of GST is essential for the detoxification of safener.
There were
−6, 7; −13, 13; −15, 15
6491/2978 (Rint = 0.0152)
99.0%
increases in the GST activity in vivo of treated maize (Table 4).
Chlorsulfuron caused a little bit increase of GST activity as compared
with the control. The GST activity of maize treated by compounds I-a, I-
h, I-f, II-h were significantly higher than that of isoxadifen-ethyl. To be
specific, compounds with weak electron-withdrawing groups (I-e–I-h)
or without any substituent (I-a) at the para position of the benzene ring
had good GST activities.
0.9290 and 0.8883
2978/0/173
2
Goodness-of-fit on F
1.129
R
1
1
, wR
2
2
[I > 2σ(I)]
0.0487, 0.1407
0.0573, 0.1572
0.252 and −0.446
R
, wR
(all data)
Largest diff. peak and hole (e Å−3)
These studies demonstrated that isoxadifen-ethyl and the target
compounds decreased herbicide injury to maize by enhancing GSH
content as well as GST activity, which was similar to the results re-
compound.
3
2
ported by Cummins et al.
All the novel substituted phenyl oxazole derivatives I and II were
Sulfonylurea herbicides are a kind of ALS inhibitors. ALS activity in
vivo were assayed to verify the protective effect of synthesized com-
pounds on herbicide target enzymes (Table 4). Chlorsulfuron presented
a significant decrease in the ALS activity compared with the control.
visually tested for their protection of maize against herbicide chlor-
−
1
sulfuron injury at the dosage of 20 mg kg
(Table 3). Before the ex-
periments, a preliminary screening was performed to obtain the best
4

Y. Fu et al.
Bioorganic & Medicinal Chemistry Letters xxx (xxxx) xxx–xxx
Table 4
i,ii,iii
Effect of compounds I and II on the enzyme activity of maize.
−
1
GST activity (μmol min−1 mg−1 protein)
ALS activity (nmol h−1 mg−1 protein)
Compound
GSH content (μg g
)
ab
ab
ab
ab
ab
abc
bc
c
abc
abc
ab
abc
bc
bc
bc
ab
abc
bc
abc
abc
d
a
d
a
ab
a
a
a
c
a
c
a
ab
ab
bc
ab
CK
9.552 ± 0.408
0.999 ± 0.315
0.204 ± 0.024
Chlorsulfuron
9.561 ± 0.430
1.093 ± 0.327
0.081 ± 0.014
Isoxadifen-ethyl
9.667 ± 0.773
1.295 ± 0.289
0.215 ± 0.028
I-a
9.685 ± 0.681
1.632 ± 0.645
0.086 ± 0.014
bcd
ab
I-b
I-c
10.387 ± 0.162
1.052 ± 0.388
0.101 ± 0.015
9.454 ± 0.371
9.723 ± 0.692
1.048 ± 0.281
0.090 ± 0.016
ab
cde
I-d
I-e
0.993 ± 0.371
0.091 ± 0.021
10.873 ± 0.626
13.595 ± 0.843
11.233 ± 0.567
1.101 ± 0.347
0.091 ± 0.021
e
de
ab
I-f
1.486 ± 0.377
0.165 ± 0.025
I-g
1.225 ± 0.269
0.083 ± 0.022
I-h
II-a
II-b
II-c
II-d
II-e
II-f
II-g
II-h
9.471 ± 0.527
11.877 ± 0.773
10.213 ± 0.492
1.597 ± 0.489
0.159 ± 0.025
d
abcd
ab
0.996 ± 0.047
0.088 ± 0.018
1.066 ± 0.042
0.103 ± 0.022
9.259 ± 0.152
11.125 ± 0.940
11.216 ± 0.839
1.156 ± 0.072
0.097 ± 0.019
cde
de
ab
1.128 ± 0.054
0.134 ± 0.018
1.049 ± 0.113
0.103 ± 0.023
a
abc
bc
ab
ab
ab
9.553 ± 0.228
10.047 ± 0.705
9.137 ± 0.119a
0.546 ± 0.034
0.115 ± 0.023
abc
1.035 ± 0.057
0.118 ± 0.020
1.480 ± 0.337
0.102 ± 0.030
i
ii
iii
Data are presented as the mean ± standard deviation of triplicate experiments.
CK was treated by water.
Different letters in the same column showed significant difference at the p < 0.05 level through Duncan’s multiple range test in SPSS statistics 20.
The tested target compounds have a remarkable positive impact on ALS
effectively binding within and obstructing the entrance channel and
keeping the substrate molecules from binding with the target active site
residues, leading to herbicidal activity. In contrast, the whole molecules
of compound I-f and isoxadifen-ethyl rotated to the left side in the
active site compared with that of chlorsulfuron, only partially blocking
the entrance. As shown in Fig. 4, chlorsulfuron occupied the ALS
binding site through three H-bond interactions with ARG-377 and ASP-
376, and a π–π interaction with TRP-574. Similarly, compound I-f and
isoxadifen-ethyl could form interactions with two active site residues
(ARG-377 and TRP-574) in the binding site of ALS, and the calculated
binding energy scores for compound I-f (14.0638 kcal/mol) and iso-
xadifen-ethyl (10.4891 kcal/mol) were relatively less than that of
chlorsulfuron (28.3038 kcal/mol). The small substrate had more
chances to propel itself into the channel leading to the active site and
catalyze the active site while the binding of chlorsulfuron with ALS was
−
1
−1
activity ranging from 0.083 to 0.165 nmol h mg
protein. Never-
theless, there are only a few compounds that could increase the ALS
activity. Moreover, the ALS activity of maize treated by compounds II
were a little bit better than that of I to some extent. For example, the
ALS activity of the compounds II-a–II-b, and II-d were higher than that
of I-a–I-b with the same substitutions at the benzene moiety. Among the
compounds tested, compound I-f showed the best effects that the value
−
1
−1
of ALS activity is 0.165 nmol h mg
isoxadifen-ethyl.
protein, but still lower than
On the basis of the aforementioned results, most compounds could
enhance the growth level, GSH content, GST activity and ALS activity in
vivo. Especially compound I-f gave the best safener activity.
Comparing the physicochemical properties of the compound I-f and
isoxadifen-ethyl, it was observed that the log p, MW, HBAs, HBDs, ro-
tatable bonds, aromatic rings, surface area and electronegativity of
compound I-f were all consistent with that of isoxadifen-ethyl (Table 5).
To further investigate the effect of the herbicide safeners on the
target enzyme of herbicides, the three-dimensional structures of com-
pound I-f, isoxadifen-ethyl and chlorsulfuron with ALS (PDB code
3
7,38
prevented.
When compound I-f was applied simultaneously or be-
fore with chlorsulfuron, it could compete with chlorsulfuron at the ALS
active site by keeping the herbicide from acting or reaching on the
target active site. This result is similar to the results of previous
3
9,40
study,
and may be the detoxification mechanism of the novel target
1
YHY) were constructed. The molecular docking models indicated that
compounds.
both compound I-f and isoxadifen-ethyl could compete with chlorsul-
furon at the target active site of ALS (Figs. 3 and 4). In the docking
modeling, the phenyl moiety of chlorsulfuron turned right at the target
active site with the rest of the molecule inserting into the channel,
In summary, a series of novel substituted phenyl oxazole derivatives
were rationally designed and synthesized via fragment analysis and
coupling strategy. The results of bioassay illustrated that all of the
compounds had moderate to remarkable safener activities to
Table 5
Physical and chemical properties comparisons of I-f and isoxadifen-ethyl.
Name
Structure
Logpa
MWa
HBAsa
3
HBDsa
0
RBsa
3
ARsa
2
SAa
Electronegativityb
I-f
2.410
279.72
259.56
Isoxadifen-ethyl
3.338
295.33
4
0
5
2
280.33
a
b
23
The parameters were calculated by Accelrys Discovery Studio 3.0 (Catalyst, Version 4.10. Accelrys Inc., San Diego, CA, USA, 2005).
24
The electronegativity was predicted by SYBYL-X 2.0 (SYBYL, Version 6.9. Tripos Inc., St. Louis, MO, USA).
5

Y. Fu et al.
Bioorganic & Medicinal Chemistry Letters xxx (xxxx) xxx–xxx
Fig. 3. The docking modeling of I-f (A), isoxadifen-ethyl (B) and chlorsulfuron (C) with ALS at the active site. The carbon atoms are shown in blue, the sulfur atoms
are shown in yellow, the oxygen atoms are shown in red, the nitrogen atoms are shown in light blue and the chlorine atoms are shown in green.
Fig. 4. The receptor–ligand interactions of I-f (A), isoxadifen-ethyl (B) and chlorsulfuron (C) with the active site of ALS, and they are all shown in cyan sticks.
chlorsulfuron. Most intriguingly, compound I-f was even superior to the
commercial safener isoxadifen-ethyl. The molecular docking experi-
ment exhibited that the promising safener potency might be ascribed to
the competition between compound I-f and chlorsulfuron. The pro-
mising finding will provide a powerful complement to the commercial
safeners and lay a solid foundation for novel safeners candidate dis-
covery.
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This work was supported by the National Nature Science
Foundation of China (Nos. 31772208 and 31572042), and Natural
Science Foundation of Heilongjiang Province (ZD2017002), and the
Research Science Foundation in Technology Innovation of Harbin
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Disclosure statement
2 1
9. Hopkins CD, Schmitz JC, Chu E, Wipf P. Total synthesis of (−)-CP -disorazole C . Org
Lett. 2011;13:4088–4091. https://doi.org/10.1021/ol2015994.
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conflicts of interest.
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