Bioactivity and structure–activity relationship of cinnamic acid derivatives and its heteroaromatic ring analogues as potential high-efficient acaricides against Psoroptes cuniculi

Article abstract of DOI:10.1016/j.bmcl.2017.08.051

A series of cinnamic acid derivatives and its heteroaromatic ring analogues were synthesized and evaluated for acaricidal activity in vitro against Psoroptes cuniculi, a mange mite. Among them, eight compounds showed the higher activity with median lethal concentrations (LC₅₀) of 0.36–1.07 mM (60.4–192.1 μg/mL) and great potential for the development of novel acaricidal agent. Compound 40 showed both the lowest LC₅₀ value of 0.36 mM (60.4 μg/mL) and the smallest median lethal time (LT₅₀) of 2.6 h at 4.5 mM, comparable with ivermectin [LC₅₀ = 0.28 mM (247.4 μg/mL), LT₅₀ = 8.9 h], an acaricidal drug standard. SAR analysis showed that the carbonyl group is crucial for the activity. The type and chain length of the alkoxy in the ester moiety and the steric hindrance near the ester group significantly influence the activity. The esters were more active than the corresponding thiol esters, amides, ketones or acids. Replacement of the phenyl group of cinnamic esters with α-pyridyl or α-furanyl significantly increase the activity. Thus, a series of cinnamic esters and its heteroaromatic ring analogues with excellent acaricidal activity emerged.

Full text of DOI:10.1016/j.bmcl.2017.08.051

Accepted Manuscript
Bioactivity and structure–activity relationship of cinnamic acid derivatives and
its heteroaromatic ring analogues as potential high-efficient acaricides against
Psoroptes cuniculi
Dong-Dong Chen, Bing-Yu Zhang, Xiu-Xiu Liu, Xing-Qiang Li, Xin-Juan
Yang, Le Zhou
PII:
S0960-894X(17)30844-2
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.08.051
BMCL 25245
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 March 2017
14 August 2017
19 August 2017
Please cite this article as: Chen, D-D., Zhang, B-Y., Liu, X-X., Li, X-Q., Yang, X-J., Zhou, L., Bioactivity and
structure–activity relationship of cinnamic acid derivatives and its heteroaromatic ring analogues as potential high-
efficient acaricides against Psoroptes cuniculi, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://
dx.doi.org/10.1016/j.bmcl.2017.08.051
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Graphical Abstract
Bioactivity and structure–activity
relationship of cinnamic acid derivatives and
its heteroaromatic ring analogues as
potential high-efficient acaricides against
Psoroptes cuniculi
∗
Dong-Dong Chen§, Bing-Yu Zhang§, Xiu-Xiu Liu, Xing-Qiang Li, Xin-Juan Yang and Le Zhou*
College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
Bioactivity and structure–activity relationship of cinnamic acid derivatives and its heteroaromatic
ring analogues as potential high-efficient acaricides against Psoroptes cuniculi
∗
∗
Dong-Dong Chen§, Bing-Yu Zhang§, Xiu-Xiu Liu, Xing-Qiang Li, Xin-Juan Yang and Le Zhou
College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
A series of cinnamic acid derivatives and its heteroaromatic ring analogues were synthesized
and evaluated for acaricidal activity in vitro against Psoroptes cuniculi, a mange mite. Among
them, eight compounds showed the higher activity with median lethal concentrations (LC50) of
−
Accepted
0.36−1.07 mM (60.4 192.1 µg/mL) and great potential for the development of novel acaricidal
Available online
agent. Compound 40 showed both the lowest LC50 value of 0.36 mM (60.4 µg/mL) and the
smallest median lethal time (LT50) of 2.6 h at 4.5 mM, comparable with ivermectin [LC50 = 0.28
mM (247.4 µg/mL), LT50 = 8.9 h], an acaricidal drug standard. SAR analysis showed that the
carbonyl group is crucial for the activity. The type and chain length of the alkoxy in the ester
moiety and the steric hindrance near the ester group significantly influence the activity. The
esters were more active than the corresponding thiol esters, amides, ketones or acids.
Replacement of the phenyl group of cinnamic esters with α-pyridyl or α-furanyl significantly
increase the activity. Thus, a series of cinnamic esters and its heteroaromatic ring analogues with
excellent acaricidal activity emerged.
Keywords:
Cinnamic acid ester
Acaricidal activity
Psoroptes cuniculi
Psoroptic disease
Structure–activity relationship
2009 Elsevier Ltd. All rights reserved.
Animal acariasis is a skin disease caused by mites, which are
widely parasitic on the body surfaces or epidermises of animals
or human. Psoroptes cuniculi is an animal ear mite living in the
ear canal of animals and can infect rabbits, goats, horses, buffalo,
sheep and so on1. Additionally, Psoroptic acariasis is a highly
contagious disease. The infestation can cause intense pruritus,
inflammation, serous exudations, the formation of crusts and
scabs, reduction of weight gain, and even death2. At present,
psoroptic acariasis has been a global disease, which causes
serious economic losses for the animal industry3.
effective and safe acaricidal agents for treatment and control of
animal acariasis.
Over the past decades, cinnamic acid and its esters widely
distributed in plants10 have attracted much attention of many
pharmacologists due to a variety of important pharmacological
activities11 such as anticancer12, antimicrobial13, antioxidative14,
anti-inflammatory15,
anti-Mycobacterium
tuberculosis16,
antiviral17, anti-human immunodeficiency virus (HIV)18,
antidiabetic19,
anticholesterolemic20,
inducing neural
hepatoprotective21,
progenitor cell
immunoprotective22,
proliferation23 and anti-parasitic activities24. Additionally,
cinnamic acid and its esters also have low toxicity to mammals25.
Thus, cinnamic acid derivatives are already a class of very
promising lead compounds for the development of new, highly
effective drugs.
Our previous research found that ethyl cinnamate derivatives
with substituents on the benzene ring are a class of promising
lead compounds for the development of new acaricidal agents
against P. cuniculi26. The structure-activity relationship showed
that the substitution pattern on the benzene dramatically impact
the activity. Strong electron-withdrawing groups like o-NO2 or
m-NO2 can significantly improve the activity whereas hydroxy,
methoxy, acetoxy, methylenedioxy, bromo or chloro groups led
to decrease of the activity. As our continuing research, in order to
more fully know the SAR of cinnamic acid esters and discover
more potent acaricidal compounds, in the present study, a series
of cinnamic acid derivatives including esters, amides, thiol esters,
ketones, ethers and its heteroaromatic ring analogues were
Figure 1. Structure of ivermectin (the mixture B1a and B1b)
Therapy and control of both human scabies and animal
mange mainly depend on the use of drugs and chemicals4.
Among them, organochlorine, organophosphates, pyrethrins5,
especially, ivermectin (Fig. 1) and abamectin6 have been more
commonly used drugs for treatment and control of animal
acariasis. However, continuous use of these drugs has presented
some serious problems such as drug-resistance7, 8, toxicity and
environmental damage9. Therefore, it is urgent to develop new
———
∗ Corresponding author. Tel./Fax: +86-29-87092226; E-mail: zhoulechem@nwsuaf.edu.cn (L. Zhou); yxjsn2@163.com (X. -J. Yang.)
§ These authors contributed equally to this work.

prepared and evaluated for acaricidal activity against P. cuniculi.
Meanwhile, the structure-activity relationship was discussed also.
O
O
O
R
Cl
b or c
OH
a
1 28
31
(ester, thioester, amide)
O
CHO
O
d
+
H3C
29
OCH2CH3
e, f
OH
30
O
g
R
CHO
( R = heteroaryl )
R
O
32 45
Scheme 1. Synthetic Route of Compounds 1−45. Reagents and conditions: (a) SOCl2, 75 °C, 2 h; (b) R-OH or EtSH, DCM, 0 °C, 1 h, for 1−26; (c)
NH3, R-NH2 or R2NH, H2O, 0 °C, 1 h, for 26−29; (d) 10% NaOH, EtOH, r.t., 6 h; (e) SOCl2, 0 °C, 1 h; (f) EtONa, EtOH, r.t., 1 h. (g) Ph3P=CHCO2Et,
EtOH, 80 °C, 5 h.
In order to have an insight into the effect of the chain length,
branching degree and type of the alkyl group in the ester moiety
on the activity, a series of cinnamic acid esters (1–23) formed
from cinnamic acid and various alcohols or phenols were
designed (Table 1). The alkyl groups include C1-C8 linear alkyl,
C3-C5 branched-chain alkyl, cyclohexyl, benzyl and substituted
benzyl, phenyl and substituted phenyl. Additionally, we also
designed some amide, thioester, ketone or ether derivatives (24–
30) (Table 1) of ethyl cinnamate to inspect the relationship
between the ester group itself or its two oxygen atoms and the
activity. On the other hand, a series of heteroacromatic ring
analogues (32–45) (Table 1) were also designed to know the
influence of various heteroaromatic rings on the activity. It was
expected that the structural similarity and diversity could lead to
the discovery of more potent acaricidal compounds.
The synthetic rout is outlined in Scheme 1. Commercially
available cinnamic acid was used as a starting material to
synthesize compounds 1–28. Cinnamic acid was treated with
SOCl2 to provide cinnamoyl chloride. The esters (1–23), thioester
(24) or amides (25–28) were obtained by reaction of cinnamoyl
chloride with the appropriate alcohols, phenols, ethyl mercaptan,
ammonia or amines in 85–94% yield. Ketone 29 was synthesized
by aldol condensation reaction of benzaldehyde with 2-pentanone
in 61% yield. Commercially available cinnamyl alcohol was
treated with SOCl2 to yield cinnamyl chloride, and followed by
treatment with sodium ethoxide to yield ether 30. Compounds
32–45 were obtained by Wittig reaction of ethyl
triphenylphosphanylideneacetate [(C6H5)3P=CHCO2Et] and the
corresponding heterocyclic formaldehydes in ethanol in 55‒92%
yield.
moiety, and signals of one additional methylene at δH 4.20 (dd, J
= 6.0, 1.4 Hz, 2H) and δC 71.3 compared with 2. The coupling
constant values of Hα and Hβ (J = ca. 16 Hz) confirmed trans
configuration of the compounds.
Compounds 1–45 were screened for acaricidal activity in
vitro against P. cuniculi according to our previously reported
method27. Ivermectin, a clinical acaricidal drug standard, was
used as a reference control. The results are listed in Table 1. All
the compounds showed the activity at various degrees at 0.5
mg/mL, and of which 15 compounds (1–5, 15, 16, 24, 29, 32–34,
38, 40, 41) showed the mortality rates of 70‒100%, equal to or
higher than that of ivermectin (75.0%) (p ＜ 0.05). At 0.25
mg/mL, nine compounds (1−3, 16, 32, 34, 38, 40, 41) showed the
mortality rates of 66‒100%, equal to or higher than that of
ivermectin (68.0%) (p＜0.05). Compounds 2, 32 and 40 gave the
highest mortality rates of 98‒100% (p＞0.05) at 0.25 mg/mL.
In order to get insight into acaricidal potency in more detail,
the compounds (1−3, 16, 32, 34, 38, 40) with the higher initial
activity were further determined for median lethal concentrations
(LC50) and median lethal times (LT50) according to the same
method as described above. Ivermectin was used as a reference
drug. The mortality rates caused by various test concentrations of
the compounds for the same time (24 h) or various treatment
times at the same concentration (4.5 mM) are shown in Fig. 2 and
3, respectively. LC50 and LT50 values of the compounds are listed
in Tables 2 and 3, respectively.
It was seen from Fig. 2 and 3 that the activity of all the
compounds including ivermectin increased with increase of both
test concentration and treatment time. However, the various
compounds showed the different change trend (or steepness) of
the curves, showing that the effects of the treatment
concentration or time on the activity of the various compounds
are different. In most cases, the test compounds showed the
higher activity at the same test mass concentration than
ivermectin (Fig. 2A), but the opposite was observed at the same
molar concentration (Fig. 2B). The results above were further
confirmed by LC50 values of the various compounds (Table 2).
When LC50 values are expressed in millimolar concentration, all
the compounds (LC50 = 0.36 to 1.07 mM) were less active than
ivermectin (LC50 = 0.28 mM). On the contrary, when mass
concentration is applied, all the compounds (LC50 = 60 to192
µg/mL) were more active than ivermectin (247.4 µg/mL). The
results above are due to the molecular weight of ivermectin
The synthesized known compounds were confirmed by
comparison of its 1H, 13C-NMR and MS data with those reported
1
in literature. New compound 21 was characterized by H NMR,
1
13C NMR and HRMS analysis. In H-NMR spectra, the esters
(1−23, 32−45), amides (25−28) and thioester (24) showed two
doublet signals in the ranges of δH 7.5−8.0 (1H, d, J = 16.0 Hz)
and 6.2−7.3 (1H, d, J = 16.0 Hz) due to Hβ and Hα of the acryloyl
moiety, respectively. In 13C-NMR spectra, the esters and amides
−167.9. The carbonyl
showed signal of one carbonyl at δC 164.4
signals of thioester 24 and ketone 29 were observed at δC 190.0
and 200.6, respectively. Ether 30 showed one doublet signal at δH
6.67 (d, J = 15.9 Hz, 1H) and one double triplet signal at δH 6.37
(2×t, J = 15.9, 6.0 Hz, 1H) due to two protons of the ethylene

Table 1.
Structures and preliminary acaricidal activity of the tested compounds against P. cuniculi a
Compound
Mortality % (mean S.D.)
Compound
Mortality % (mean S.D.)
0.5 mg/mL 0.25 mg/mL
No.
Substituent (R)
0.5 mg/mL
0.25 mg/mL
No. and structure
20.0 6.3 rs
1
2
3
4
5
6
7
8
9
CH3
100.0 0.0 a
100.0 0.0 a
90.0 8.9 bc
74.0 5.5 d
78.3 7.5 bc
98.3 4.1 a
76.0 5.5 c
54.0 5.5 e
30.0 8.9 i
16.7 5.2 k
16.0 5.5 s
C2H5
n-C3H7
n-C4H9
n-C5H11
n-C6H13
n-C7H15
n-C8H17
i-C3H7
98.0 4.5 ab
46.0 5.5 f
70.0 10.0 def
65.0 5.5 efg
23.3 10.3 qrs
38.3 7.5 lmn
52.0 8.4 ijk
26.0 5.5 pqr
16.7 8.2 s
22.0 4.5 jk
58.3 7.5 e
100.0 0.0 a
100.0 0.0 a
44.0 5.5 fg
80.0 7.1 bc
28.0 4.5 ij
10
11
12
i-C4H9
t-C4H9
t-C5H11
63.3 10.3 fgh
40.0 6.3 lmn
16.7 10.3 s
76.0 5.5 d
100.0 0.0 a
56.0 5.5 hi
24.0 5.5 qrs
O
32.0 4.5 nopq
46.0 5.5 jkl
72.0 4.5 de
84.0 5.5 c
OCH2CH3
13
14
15
34
N
44.0 5.5 fg
68.0 4.5 d
16
17
18
19
20
36.0 5.5 mno
100.0 0.0 a
64.0.0 5.5 efgh
100.0 0.0 a
98.0 4.5 ab
28.0 4.5 opqr
32.0 4.5 nopq
36.0 5.5 mno
40.0 7.1 lnm
84.0 5.5 b
46.0 5.5 f
100.0 0.0 a
66.0 5.5 d
NO2
34.0 5.5 nop
40.0 7.1 lmn
21
36.0 5.5 mno
24.0 5.5 qrs
22
23
58.0 4.5 ghi
94.0 5.5 ab
34.0 5.5 hi
44.0 5.5 fg
54.0 5.5 ij
38.0 4.5 gh
44.0 5.5 klm
20.0 6.3 rs
46.0 8.9 jkl
Ivermectin
Control
75.0 5.5 d
0.0 0.0 t
68.3 7.5 d
0.0 0.0 l
a The difference between data with the different lowercases within a column is significant (P < 0.05).
(MW = 875) being much higher than that of the compounds
(MWs = 166–258). Although the acaricidal mechanism of
cinnamic acid esters is still unknown at present, the great
structural difference between ivermectin and cinnamic acid esters
strongly suggests that the two class of compounds may well
possess different acaricidal mechanism. In this case, the mass
number of LC50 values should be more suitable than its molar
number for comparison of the activity strength and application
potential of ivermectin and the compounds. Among the
compounds, 40 displayed the highest activity (LC50 = 0.36 mM or
60.4 µg/mL) followed by 32 (LC50 = 0.45 mM or 81.6µg/mL),
and their relative molar activity reach 0.78 and 0.62 that of
ivermectin, respectively (Table 2).
From the change trend of the curves in Fig. 3, it was found
that the sensitivity of the mites to the treatment-time change of
all the compounds was much higher than ivermectin. Among
them, both 38 and 40 showed the higher activity with LT50 values
of 6.8 and 2.6 h than ivermectin (LT50 = 8.9 h). From the point of
view of LT50, the relative activity of 40 reached up to 3.4-fold
that of ivermectin. It was worth mentioning that all the LT50
values in Table 3 were measured at the same test molar
concentration (4.5 mM). Considering the fact that the molecular
weight of ivermectin is much higher than the test compounds, it
was speculated that most or all the compounds should have
smaller or much smaller LT50 values than ivermectin if the same
mass concentration is used for test. This inference was confirmed
to some extent by the compounds in Table 3 having the higher

Table 3
Median lethal times (LT50) of the compounds (4.5 mM) a
Compound
LT50 (h)
13.3
12.0
13.9
15.2
9.8
95% CI
RA
0.67
0.74
0.64
0.59
0.9
1
13.2–13.1
11.7–12.2
13.8–14.0
15.0–15.3
9.6–10.0
15.4–15.8
6.8–6.9
2
3
16
32
34
38
40
15.6
6.8
0.6
1.3
2.6
2.4–2.8
3.4
Ivermectin
8.9
8.8–9.0
1.00
a
95% CI: 95% confidence interval. RA: relative activity = LT50 value of
ivermectin / LT50 value of the tested compound.
initial activity at the same mass concentration than ivermectin
(Table 1).
Compared with ivermectin, as potential acaricidal agents, the
compounds in Table 2 have some attractive advantages, such as
the high activity, lower molecular weight and simple structure,
easy synthesis, low-cost as well as low toxicity to mammals25.
Comparison of the activities and structures of the compounds
in Tables 1, 2 showed that the type and substitution site of the
heteroaryl groups (32−45), the alkoxy group (1−23) in the ester
group and the ester group itself significantly influence the
activity. For cinnamic acid esters (1−23), the chain length,
branching degree and type of the alkyl group (R) can
significantly affect the activity (Table 1). For the linear alkyl
esters (1-8), the ethyl ester (2) showed the highest activity (LC50
= 0.56 mM), followed by the n-propyl ester (3) (LC50 = 0.87
mM) and methyl ester (1) (LC50 = 1.07 mM). The linear alkyl
groups with ≥ 4 carbon atoms cause decrease of the activity (6-
8). Compared with linear alkyl groups, branched alkyl groups
including cycloalkyl groups (13) lead to decrease of the activity
(3 vs 9; 4 vs both 10 and 11; 5 vs 12; 6 vs 13), showing that the
steric hindrance near the ester group is disadvantageous to
improvement of the activity.
Compared with most of the linear alkyl esters (1−6),
replacement of the linear alkyl groups with phenyl (14) or benzyl
(20) causes decrease of the activity. However, it is worth noting
that for the phenyl or benzyl esters, the introduction of
substituents to the benzene ring significantly influence the
activity. Compared with phenyl ester 14, the presence of 4′-
chloro (16, LC50 = 0.74 mM) or 4′-methyl (15) significantly
enhances the activity. A similar case also exists in the 3′-
nitrobenzyl (22) or 4′-nitrobenzyl ester (23).
Transformation of the carbonyl group or the saturated oxygen
atom in the ester group into a methylene leads to a sharp fall of
the activity (2 vs 30 or 29), but ketone 29 was much more active
than ether 30. The results above show that the carbonyl group in
the ester group is crucial for the activity. Moreover,
transformation of the ester (2) into the corresponding thiol ester
(24), amide (25−28) or acid (31) also causes significant decrease
of the activity, but the thiol ester (24) was obviously more active
that the amides (25−28). These results suggest that the strong fat-
solubility of the compounds and low electron density of the
carbonyl group are helpful to improvement of the activity. Since
the acaricidal action of cinnamic acid esters was not a Michael
addition mechanism26, we conjectured that the acaricidal activity
of the compounds very likely involves an acyl transfer
mechanism, in which the ester group probably acts as a hydrogen
bond receptor when the compounds interact with their biological
receptor. At present, the study on the acaricidal bio-target and
mechanism of cinnamic acid esters has been in our plan.
Figure 2. Effects of the tested concentration on the activity against P.
cuniculi.
Table 2
Median lethal concentrations (LC50) of the compounds (24 h) a
Compound
LC50 [mM (µg/mL)]
1.07 (174.0)
0.56 (98.0)
95% CI
RA
0.26
0.50
0.32
0.38
0.62
0.34
0.44
0.78
1.00
1
0.83–1.33
0.52–0.60
0.72–0.99
0.72–0.76
0.60–0.64
0.78–0.88
0.61–0.70
0.31–0.35
0.23–0.35
2
3
0.87 (165.6)
0.74 (192.1)
0.45 (81.6)
16
32
34
38
40
0.82 (146.6)
0.64 (116.0)
0.36 (60.4)
Ivermectin
0.28 (247.4)
a
95% CI: 95% confidence interval of LC50 (mM). RA: relative activity = LC50
value (mM) of ivermectin / LC50 value (mM) of the tested compound.
Figure 3. Effects of treatment time of the compounds on the activity
against P. cuniculi.
For the heteroaromatic analogues (32−45) of cinnamic acid
esters, the type and substitution site of the heterocyclic groups

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significantly influence the activity. Replacement of the phenyl
group (2) with 2-pyridinyl (32) or 2-furanyl (40) obviously
increase the activity, whereas 3- or 4-pyridinyl (33, 34) or 3-
furanyl (39) decreases the activity. Unlike pyridinyl or furanyl,
both 2- and 3-thiophenyl groups decreases the activity (2 vs 38,
39). A similar case also exists in both 2- and 3-pyrrolyl (2 vs 42,
43). Since pyridine ring and furan ring are an electron-deficient
and electron-rich moiety, respectively, it is concluded that the
effect factor of the heterocyclic rings on the activity should not
be electronic effect. Considering the fact that pyrrole ring is a
hydrogen bond donor while the other heteroaromatic rings are
hydrogen bond receptors, we assume that the high activity of
compounds 32 and 40 is probably related with both pyridinyl and
furanyl groups being good hydrogen bond receptors. The
speculation above was further supported by the fact that N-
methylation of the pyridine ring leads to dramatic decrease of the
activity (32−34 vs 35−37).
In summary, a series of cinnamic acid derivatives and its
heteroaromatic analogues were synthesized and evaluated for
acaricidal activity in vitro against Psoroptes cuniculi. Eight
compounds were found to possess the strong acaricidal activity.
Among them, compound 40 showed the highest activity
comparable with ivermectin, an acaricidal drug standard and
great potential for the development of novel acaricidal agent.
SAR analysis found that the carbonyl group of the compounds is
crucial for the activity and both the type, chain length and
branching degree of the alkyl group in the ester moiety
significantly influence the activity. The esters were more active
than the corresponding thiol esters, amides, ketones or acids. For
the heteroaromatic analogues of cinnamic acid esters, the type
and substitution site of the heteroaryl groups significantly
influence the activity. Replacement of the phenyl group with α-
pyridinyl or α-furanyl significantly increase the activity. Thus,
cinnamic acid esters and its heteroaryl analogues are a class of
promising candidates or lead compounds for the development of
novel acaricides.
25. Lafay S, Gil-Izquierdo A. Phytochem Rev. 2008;7:301.
26. Zhang B, Lv C, Li W, Cui Z, Chen D, Cao F, Miao F, Zhou L.
Chem Pharm Bull. 2015;63:255.
Supplementary Material
Electronic supplementary information (ESI) available:
Experimental procedure, 1H and 13C NMR, MS spectra and
acaricidal toxicity regression equations of the compounds. See
DOI: xxxxx.
Acknowledgments
The authors are grateful for financial support from the National
Natural Science Foundation of China (No. 31172365) and the
Agricultural Science and Technology Innovation Project of
Shaanxi Province (2016NY-171). This work was also supported
by Chinese University Scientific Fund (2452015085).
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