Design, synthesis, and antifungal activity of novel cinnamon–pyrazole carboxamide derivatives

Article abstract of DOI:10.1002/ddr.21469

(Table presented.). To discover succinate dehydrogenase inhibitors with a novel structure, we introduced cinnamic acid structure to optimize the lead structure 1 and synthesized four series of cinnamon–pyrazole carboxamide derivatives. The bioassay data showed that compounds (E)-N-(1-[4-chlorophenyl]-4-cyano-1H-pyrazol-5-yl)-3-(2-fluorophenyl) acrylamide (5III-d) and (E)-3-(2-chlorophenyl)-N-(1-[4-chlorophenyl]-4-cyano-1H-pyrazol-5-yl) acrylamide (5III-f) showed the significant antifungal activity against three fungi. In addition, 5III-d and 5III-f exhibited the excellent inhibitory effect against succinate dehydrogenase (SDH) enzymes with IC₅₀ values ranging from 19.4 to 28.7 μM. The study demonstrates that the chlorine substituent group is present on both the phenyl and pyrazole rings that have a very good effect on the antifungal effect, and the compounds 5III-d and 5III-f can act as potential SDH inhibitors (SDHI) and throw a sprat for a new generation of SDHI.

Full text of DOI:10.1002/ddr.21469

Received: 17 July 2018
DOI: 10.1002/ddr.21469
Revised: 17 August 2018
Accepted: 18 August 2018
R E S E A R C H A R T I C L E
Design, synthesis, and antifungal activity of novel
cinnamon–pyrazole carboxamide derivatives
1
†
1†
1
1
1
1
Zi-Li Ren | Hao Liu | Di Jiao | Hao-Tian Hu | Wei Wang | Jie-Xiu Gong |
1
2
1,3
Ai-Li Wang | Hai-Qun Cao | Xian-Hai Lv
Enabling Technologies
Strategy, Management & Health Policy
Hit, Lead &
Candidate Discovery
Preclinical Research
& Development
Clinical
Research
Post-Market
Research
1
School of Science, Anhui Agricultural
Abstract
University, Hefei, People's Republic of China
2
To discover succinate dehydrogenase inhibitors with a novel structure, we introduced cin-
namic acid structure to optimize the lead structure 1 and synthesized four series of
cinnamon–pyrazole carboxamide derivatives. The bioassay data showed that compounds
School of Plant Protection, Anhui Agricultural
University, Hefei, People's Republic of China
3
Division of Chemistry and Biological
Chemistry, School of Physical and
Mathematical Sciences, Nanyang
Technological University, Singapore
(
E)-N-(1-[4-chlorophenyl]-4-cyano-1H-pyrazol-5-yl)-3-(2-fluorophenyl) acrylamide (5III-d)
and (E)-3-(2-chlorophenyl)-N-(1-[4-chlorophenyl]-4-cyano-1H-pyrazol-5-yl) acrylamide
5III-f) showed the significant antifungal activity against three fungi. In addition, 5III-d and
(
Correspondence
Xian-Hai Lv, School of Science, Anhui
Agricultural University, Hefei 230036, People's
Republic of China.
5III-f exhibited the excellent inhibitory effect against succinate dehydrogenase (SDH)
enzymes with IC50 values ranging from 19.4 to 28.7 μM. The study demonstrates that the
chlorine substituent group is present on both the phenyl and pyrazole rings that have a very
good effect on the antifungal effect, and the compounds 5III-d and 5III-f can act as potential
SDH inhibitors (SDHI) and throw a sprat for a new generation of SDHI.
Email: lvxianhai@ahau.edu.cn
Funding information
National Key R&D Program of China, Grant/
Award Number: 2017YFD0600805; Natural
Science Foundation of Education Committee
of Anhui Province, Grant/Award Number:
KJ2018A0162; National Natural Science
Foundation of China, Grant/Award Number:
KEYWORDS
3D-QSAR, cinnamamide, fungicidal activity, molecular docking, pyrazole, succinate
dehydrogenase inhibitors
2
1302002
1
| INTRODUCTION
productive respiratory chains. SDHIs exhibit biological activity in
blocking mitochondrial energy supply, resulting in death of fungi
Fungicide plays an extremely important role in protecting crops, which
is due to its ability to control the growth and reproduction of plant
pathogens. Among the 55 classes of fungicides listed by the Fungicide
Resistance Action Committee, succinate dehydrogenase inhibitors
(
Lv et al., 2017; Selby, Hughes, Rauh, & Hanna, 2010). To date,
9 commercial SDHI fungicides have been approved for plant protec-
1
tion since the first launch of carboxin in 1966. However, the unlimited
use of such fungicides results in resistance to fungi (De et al., 2014;
Lalève et al., 2014). Therefore, novel structures of SDHIs need to be
developed and widely used in agricultural production.
(
SDHIs) have been extensively used to combat destructive plant fungi,
such as Sclerotinia sclerotiorum, Rhizoctonia solani, and Botrytis cinerea
Chen, Zhang, Wang, Zhang, & Gao, 2012; Veloukas & Karaoglanidis,
012; Yao et al., 2017). SDH is one of the hubs linking oxidative phos-
(
Two large distinct classes of phenolic acids are known in plants—
derivatives of benzoic acid and of cinnamic acid (Lafay & Gilizquierdo,
2008; Sova, 2012). Schultz and Wiese (1959) had found that cinnamic
acid has better fungicidal activity than benzoic acid. Cinnamic acid is
widely distributed in plants and is present in fruits, vegetables, and
beverages (Clifford, 1999; Edreva, 2005; Lafay & Gilizquierdo, 2008).
2
phorylation and electron transport and can provide electrons for
eukaryotic mitochondria and various prokaryotic aerobic and
†Zi-Li Ren and Hao Liu contributed equally to this work.
Drug Dev Res. 2018;1–6.
wileyonlinelibrary.com/journal/ddr
© 2018 Wiley Periodicals, Inc.
1

2
REN ET AL.
However, cinnamic acid and its derivatives are widely used in food
(
Naczk
Lapczynski, Lalko, & Api, 2005), cosmetics, and drugs (Khan & Rathod,
015). It is also the main scaffold of some clinical drugs such as cine-
& Shahidi, 2004), fragrance material (Letizia, Cocchiara,
2
pazide (Zhao et al., 2014), tranilast (Darakhshan & Pour, 2015), and
ilepcimide (Xiao, Yan, Chen, & Zhou, 2015; Neogi et al., 2003; Qian
et al., 2010). It is also applied to be a lead molecule or starting material
in some medicinal chemistry studies (Carvalho, Da, de Souza,
Lourenço, & Vicente, 2008; Gao et al., 2018; Li et al., 2011). Based on
these studies, selecting cinnamic acid as a lead molecule to develop
potential new SDHIs and clarifying the structure–activity relationship
SCHEME 1 Design strategy of target compounds. [Color figure can
be viewed at wileyonlinelibrary.com]
performed with Discovery Studio3.5. Crystal structure determination of
compounds was carried out on a Bruker D8 VENTURE PHOTON.
(
SAR) study is a reasonable choice.
In the previous research work (Lv et al., 2017), we discovered a
2.2 | General procedure for the synthesis of
novel SDHI lead compound 1 (Figure 1), which exhibited potent activities
against H. maydis (EC50 = 33.5 μM) and R. cerealis (EC50 = 21.4 μM). At
the same time, it also shows an eye-catching activity against H. maydis
SDH (IC50 = 25.4 μM) and R. cerealis SDH (IC50 = 20.2 μM). In the
search for a class of new SDHI, we introduced cinnamic acid structure to
optimize the lead structure 1 and got a new scaffold (Scheme 1). After
that, a total of 28 compounds were synthesized based on molecular
docking and synthetic feasibility analysis. Valsa mali Miyabe et Yamada,
Colletotrichum gloeosporioides Penz, and Rhizoctonia solani were used to
determine their antifungal activity. From the results of antifungal experi-
ments, there are some improvements in the biological activity of the new
batch of compounds relative to the lead compound 1, but it has not
achieved significant improvement, which is also a place we regret. In
addition, molecular docking stimulation was carried out on all the synthe-
sized derivatives and the SAR has been fully discussed.
5-amino-1-aryl-1H-pyrazole-4-carbonitriles (3)
Intermediates 3 were synthesized according to the literature by
Harden, Quinn, and Scammells (1992). A stirred mixture of p-
substituted phenylhydrazine hydrochloride was dissolved in EtOH,
then the pH was adjusted to alkaline by the addition of 10% NaOH
solution to remove the hydrochloride, which were then refluxed for
3
hrs with 2-(ethoxymethyl)malononitrile in ethanol. Finally, the mix-
ture was cooled at room temperature, and the intermediates 3 were
filtered under vacuum and recrystallized from ethanol to give the pure
products (Figure 2).
2
.3 | General procedure for the synthesis of N-
(
4-cyano-1-phenyl-1H-pyrazol-5-yl) cinnamamide (5I-IV)
Cinnamic acid and intermediate 3 were dissolved in pyridine; phos-
phorus oxychloride was slowly added dropwise under ice bath condi-
ꢀ
tions, then at 40–60 C reacted for 5–8 hrs Figure 3. Finally, the
2
2
| MATERIALS AND METHODS
.1 | General methods
mixture was poured into 30 mL saturated Na CO solution and stirred
2
3
4
well. After the mixture was acidified, the saturated CuSO solution
was used to remove pyridine, which greatly improved the purity and
yield of the product. The data for compounds 5I-IV are provided in
the Supporting Information.
All chemicals were purchased from Energy, Meryer, and Aladdin Chemi-
1
13
cals and were used as received. H NMR and C NMR spectra were car-
ried out using Agilent DD2 600 Hz spectrometer with CDCl or DMSO-
3
2
.4 | Biological testing
d6 as the solvent and tetramethylsilane as the internal standard. Electro-
spray Ionization- Mass Spectrometer (ESI-MS) spectra were carried out
on a Mariner System 5304 mass spectrometer. Elemental analyses were
performed on a CHN-O-Rapid instrument. Quantitative structure–
activity relationship (QSAR) analyses and molecular docking were
2.4.1
| In vitro fungicidal assay
Valsa mali Miyabe et Yamada, Colletotrichum gloeosporioides Penz, and
Rhizoctonia solani were provided by the Plant Disease Control Labora-
tory of Anhui Agricultural University. The antifungal activities of the
FIGURE 1 Lead structure 1 and its binding mode with succinate dehydrogenase. [Color figure can be viewed at wileyonlinelibrary.com]

REN ET AL.
3
13
NMR, C NMR, and MS. The crystal data and checkcif files for com-
pound 5II-c are listed in Supporting Information, and the crystal struc-
ture is shown in Figure 4. Crystallographic data (excluding structure
factors) for the structure were deposited with the Cambridge Crystal-
lographic Data Center as supplementary publication No. CCDC-
1820926.
FIGURE 2 Synthetic routes for intermediates 3. Reagents and
ꢀ
conditions: H
2
O, NaOH, ethanol, 3 hrs, reflux, 80 C
3
.2 | Biological activity
3
.2.1 | Fungicidal activities and SAR discussion
compounds are measured by the mycelial growth inhibition method
Abdelgaleil, Hashinaga, & Nakatani, 2010; Ye et al., 2014).
All newly synthesized compounds were evaluated for in vitro antifun-
gal activity against three destructive fungi (Valsa mali Miyabe et
Yamada, Colletotrichum gloeosporioides Penz, and Rhizoctonia solani.).
Boscalid was used as a reference standard. The results of the in vitro
antifungal activity screening of the test compounds are summarized in
Table 1.
(
2.4.2 | In vitro enzyme assay
The mitochondria of Valsa mali Miyabe et Yamada and Rhizoctonia
solani were isolated according to previously reported methods
(
Lv et al., 2017; Zeun, Scalliet, & Oostendorp, 2013).
Among them, the 5III series exhibits unparalleled suppression
compared to the first two series. Six newly synthesized derivatives
2
.5 | Three-dimensional QSAR analysis
(
i.e., 5III-b, 5III-e, 5III-d, 5III-f, 5III-g, and 5IV-f) displayed improved
The three-dimensional QSAR analysis was performed with Discovery
Studio 3.5, by using genetic function algorithm (Dai et al., 2010).
fungicidal activities against Valsa mali Miyabe et Yamada with inhibitor
rate (%) values ranging from 45.32 to 100. The entire 5III series and
5
IV-f exhibit potent antifungal activities against Colletotrichum gloeos-
porioides Penz with inhibitor rate (%) values ranging from 40.16 to
00. For the Rhizoctonia solani, 5III series is still the leader with inhibi-
2
.6 | Molecular docking
1
The crystal structure of SDH (PDB entry: 2fbw) was downloaded from
the RCSB Protein Data Bank. The molecular docking procedures were
carried out by Discovery Studio 3.5 (Liu et al., 2017; Wu, Robertson,
Iii, & Vieth, 2003).
tor rate (%) values ranging from 43.48 to 100. The above results indi-
cate the rationality of our molecular design.
As shown in Table 1, antifungal activities are enhanced when
1
1
there is a substituent at the R position. When R is fluorine group,
the introduction of 4-methoxy has increased the antifungal effects,
whereas the introduction of 4-chloro reduces the antifungal effects.
3
3
| RESULTS AND DISCUSSION
.1 | Chemical synthesis
1
When R is chlorine group, the antifungal activity of almost all com-
pounds has increased dramatically. Especially, 5III-d, 5III-f, and 5III-g
showed significant inhibitory effect on the three fungi (among them,
A series of novel cinnamon–pyrazole carboxamide derivatives were
synthesized, and the general pathways are outlined in Figure 2. The
intermediates structure 3 were obtained by refluxing the mixture of
parasubstituted phenylhydrazine hydrochlorides and 2-(ethoxymethyl)
malononitrile in the ethanol for 3 hrs. The target compounds were
obtained by a convenient, efficient method for one pot under mild
1
the inhibition rates can be compared with the boscalid). When R is
methyl group, the inhibitory effect is better than the 5I and 5II series
2
but far from the 5III series. When R is 2-chloro group, the activity is
conditions by converting amines and acids to amides using POCl
pyridine. We optimized the posttreatment conditions of the products
by using saturated Na CO to liberate pyridine. After the system was
acidified, the saturated CuSO was used to remove pyridine, which
3
in
2
3
4
greatly improved the purity and yield of the product. The chemical
1
structures of all synthesized compounds were determined by
H
FIGURE 4 The molecular structure of 5II-c showing 30% probability
displacement ellipsoids. [Color figure can be viewed at
wileyonlinelibrary.com]
FIGURE 3 Synthetic routes for target compounds 5I-IV. Reagents
ꢀ
and conditions: POCl
3
, pyridine, 40–60 C

4
REN ET AL.
TABLE 1 Chemical structures of compounds 5I-IV and inhibition rate
values against Valsa mali Miyabe et Yamada, Colletotrichum
gloeosporioides Penz, and Rhizoctonia solani at 50 mg/L
TABLE 3 IC50 values of fungal succinate dehydrogenase inhibition
activity
IC50 (μM)
V. y
Compounds
R. s
5III-d
5III-f
5III-g
20.5 Æ 0.4
19.4 Æ 0.3
33.6 Æ 0.2
28.7 Æ 0.3
21.3 Æ 0.1
41.2 Æ 0.3
2
obviously better than that of other groups in R . The introduction of
2-methoxy is also superior to 4-methoxy, as is 2-fluoro and 4-fluoro
2
group. When R is methyl group, the introduction of other groups will
adversely affect the antifungal activity of the compound. From the
results of the activities, the 2-methoxy and 4-methoxy activities are
almost the same, but the fluorine group and the chlorine group are
Inhibition rate (%)
1
2
Compounds
R
R
V. y
C. p
R. s
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
I-a
H
H
2.56
7.17
5.16
1
introduced as if R is chlorine group. To further discuss the SAR, we
I-b
H
2-OCH
4-OCH
2-F
3
5.63
30.81
29.91
18.99
6.78
26.13
13.75
20.31
10.43
2.65
selected some compounds for EC50 experiment (Table 2). From the
results, 5III-d and 5III-f exhibited good results for all three fungi, the
antifungal effect of 5III-g is relatively poor, which was also consistent
with the previous inhibition rate. SAR results indicate that the fungi-
cidal efficiency of the synthesized compounds may be attributed to
these factors, such as the chlorine substitution at the benzene ring
attached to the pyrazole ring, pyridine was replaced by benzene, and
variation of the substituent groups.
I-c
H
3
3.75
I-d
H
10.15
7.85
I-e
H
4-F
I-f
H
2-Cl
4-Cl
H
3.52
7.36
I-g
H
11.35
1.50
20.88
18.80
27.33
16.28
22.48
18.02
7.35
24.38
8.75
II-a
II-b
II-c
II-d
II-e
II-f
F
F
2-OCH
4-OCH
2-F
3
3.75
16.25
11.88
24.88
23.25
10.58
11.88
43.56
49.07
43.48
100
F
3
10.78
11.44
3.84
F
3
.2.2 | In vivo fungicidal activities
F
4-F
F
2-Cl
4-Cl
H
4.30
To determine the relationships by which substituent is beneficial to
2
1
II-g
III-a
III-b
III-c
III-d
III-e
III-f
III-g
IV-a
IV-b
IV-c
IV-d
IV-e
IV-f
IV-g
F
8.10
9.69
inhibit fungi at the R position when R is chlorine group, the inhibi-
tory activities of selected compounds (5III-d, 5III-f, and 5III-g) were
examined. As shown in Table 3, 5III-d and 5III-f showed the best
inhibitory ability. We suspect that the reasons for this difference are
that 5III-d and 5III-f contain two electron-donating groups, one of
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CH
CH
CH
CH
CH
CH
CH
38.75
45.32
39.74
100
40.16
43.74
40.60
100
2-OCH
4-OCH
2-F
3
3
1
2
4-F
54.38
100
56.35
100
50.63
100
which is fixed, that is R , and the other is in position R . Based on this,
we can speculate that in the structure of these compounds, when the
electron-donating group is located at the 2-position of cinnamic acid,
the activity is better than at the 4-position. The results of SDH inhibi-
tory activity test further confirmed that compounds 5III-d and 5III-f
have great potential as SDH inhibitors and the rationality of molecular
design strategies.
2-Cl
4-Cl
H
87.52
30.15
33.35
24.76
34.42
26.53
46.87
35.65
100
82.67
32.35
25.37
18.94
40.39
28.77
47.79
35.58
100
93.81
35.07
23.78
20.65
39.39
29.54
35.75
25.25
100
3
3
3
3
3
3
3
2-OCH
4-OCH
2-F
3
3
4-F
2-Cl
4-Cl
3
.3 | Docking analysis
After the previous bioactivity test, to further obtain the relation-
ship between the structure of the compounds and the inhibition of
antifungal activity, all synthesized compounds were molecularly
docked using Discover Studio 3.5. The detailed interactions of rep-
resentative derivative compounds 5III-d and 5III-f with SDH are
shown in Figure 5. In the binding model of two compounds, their
structures are deeply embedded in active pocket, indicating its
good complementarity with active site and the rationality and
integrity of molecular design strategies. As shown in Figure 5a,
three H-bonds are formed among amide bond, fluorine group, and
Ser 39, Tyr 59, and Arg 43. Arg 43 established π-π interaction with
benzene ring which is attached to pyrazole ring. As shown in
Figure 5b, His216 established π-π interaction with benzene ring in
Boscalid
Note. V. y = Valsa mali Miyabe et Yamada; C. p = Colletotrichum gloeospor-
ioides Penz; R.s = Rhizoctonia solani.
TABLE 2 EC50 values against the selected compounds
EC50 (μM)
Compounds
V. y
C. p
R. s
5
5
5
III-d
III-f
III-g
22.5 Æ 0.3
20.5 Æ 1.3
35.3 Æ 0.6
7.3 Æ 0.5
26.4 Æ 1.5
24.8 Æ 0.4
36.1 Æ 0.6
5.1 Æ 0.6
31.5 Æ 1.5
29.4 Æ 0.8
30.4 Æ 1.2
4.5 Æ 0.3
Boscalid

REN ET AL.
5
FIGURE 5 (a) Binding model of 5III-d (3D and 2D diagram). (b) Binding model of 5III-f (3D and 2D diagram). [Color figure can be viewed at
wileyonlinelibrary.com]
cinnamic acid, Arg43 established cation-π interactions between
phenyl moiety and pyrazole ring, and Ile40 formed σ-π interaction
with pyrazole ring. In addition, a stable H-bond was also detected
are grateful to Prof. Hai-Liang Zhu (State Key Laboratory of Pharma-
ceutical Biotechnology, Nanjing University, Nanjing) for computational
molecular docking assistance.
in the binding model between
9(angle = 180 degrees, distance = 2.1 Å). It may provide valuable
information for the further design of new class SDH inhibitors.
O in the amide and Ser
3
ORCID
Xian-Hai Lv
http://orcid.org/0000-0001-8535-0015
4
| CONCLUSIONS
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SUPPORTING INFORMATION
Additional supporting information may be found online in the Sup-
porting Information section at the end of the article.
How to cite this article: Ren Z-L, Liu H, Jiao D, et al. Design,
synthesis, and antifungal activity of novel cinnamon–pyrazole
carboxamide derivatives. Drug Dev Res. 2018;1–6. https://doi.
org/10.1002/ddr.21469