Discovery of a new fungicide by screening triazole sulfonylhydrazone derivatives and its downy mildew inhibition in cucumber

Article abstract of DOI:10.1002/jhet.3932

Downy mildew is a very important detrimental disease that lead reduced to fruits and vegetables. Due to the continuous growth of drug resistance, finding novel fungicides with dissimilar modes of function from present fungicides for controlling downy mildew are imminent. This work is an extension of our preceding research on the original triazole sulfonamide derivatives lead compound. Triazole sulfonamide as a remarkable nitrogen-containing heterocyclic compound opposed cucumber downy mildew (CDM) develops a quite vital part in the sphere of the study of new farm chemicals. The existing report designs a certain amount of 1,2,4-triazole-1,3-disulfonamide derivatives. Hydrazones have obtained extensive attention in the field of pharmaceutical due to its unique chemical structure and remarkable activity (insecticidal, antibacterial, antifungal and herbicidal). By means of coupling numerous hydrazone with triazole sulfonyl chloride groups, 24 novel derivatives were synthesized. Spectrum analysis of LC-MS, ¹H NMR and ¹³C NMR were used for characterizing these new compounds. Compared with commercial Cyazofamid using bioassays, most of these compounds displayed preferable fungicidal activities. Moreover, compounds 8q illustrated the greatest CDM resistance (EC₅₀ = 7.776 mg/L). Field efficacy trials revealed that compound 8q fungicidal activity was higher than the purchased agrochemical Cyazofamid and Amisulbrom. Thus, the research declared that 8q displayed a great potential for the application of fungicide against CDM.

Full text of DOI:10.1002/jhet.3932

Received: 3 December 2019
DOI: 10.1002/jhet.3932
Revised: 16 January 2020
Accepted: 2 February 2020
A R T I C L E
Discovery of a new fungicide by screening triazole
sulfonylhydrazone derivatives and its downy mildew
inhibition in cucumber
Yitao Li | Jian Lin
Yang Wu
| Wenqiang Yao | Guoliang Gao | Dewang Jing
|
Dongguan HEC Pesticides R&D Co., Ltd.,
Dongguan 523871, Guangdong, People's
Republic of China
Abstract
Downy mildew is a very important detrimental disease that lead reduced to
fruits and vegetables. Due to the continuous growth of drug resistance, finding
novel fungicides with dissimilar modes of function from present fungicides for
controlling downy mildew are imminent. This work is an extension of our pre-
ceding research on the original triazole sulfonamide derivatives lead com-
pound. Triazole sulfonamide as a remarkable nitrogen-containing heterocyclic
compound opposed cucumber downy mildew (CDM) develops a quite vital
part in the sphere of the study of new farm chemicals. The existing report
designs a certain amount of 1,2,4-triazole-1,3-disulfonamide derivatives.
Hydrazones have obtained extensive attention in the field of pharmaceutical
due to its unique chemical structure and remarkable activity (insecticidal,
antibacterial, antifungal and herbicidal). By means of coupling numerous
hydrazone with triazole sulfonyl chloride groups, 24 novel derivatives were
Correspondence
Jian Lin, Dongguan HEC Pesticides R&D
Co., Ltd., Dongguan 523871, Guangdong,
People's Republic of China.
Tel +86-076985315888-5575
Email: linjian@hec.cn
1
13
synthesized. Spectrum analysis of LC-MS, H NMR and C NMR were used
for characterizing these new compounds. Compared with commercial
Cyazofamid using bioassays, most of these compounds displayed preferable
fungicidal activities. Moreover, compounds 8q illustrated the greatest CDM
resistance (EC50 = 7.776 mg/L). Field efficacy trials revealed that compound
8q fungicidal activity was higher than the purchased agrochemical Cyazofamid
and Amisulbrom. Thus, the research declared that 8q displayed a great poten-
tial for the application of fungicide against CDM.
1
| INTRODUCTION
mildew (CDM), caused by Pseudoperonospora cubensis, is
a devastating disease found in cucumber. Due to the
Plant diseases caused by pathogenic fungi seriously affect
production and quality of crops in agriculture
rapid onset and seriousness of the disease, over 50%
cucumber yield can be seriously decreased if the CDM is
not prevented in time. Chemical fungicide applications
[1–3]
[6]
worldwide.
As for example, downy mildew is one of
the most highly destructive diseases that cause serious
damage to fruits, vegetables and other economic crops
such as muskmelon, grape, cucumber, spinach, radish
are, and will remain, the most effective tools for CDM
management. However, the frequent use and misuse of
fungicides inevitably lead to developing serious
[4,5]
[7–9]
and scallion etcetera.
Among them, cucumber downy
resistance.
It has been reported that the pathogen has
J Heterocyclic Chem. 2020;1–11.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
LI ET AL.
[
10]
evolved resistance within 2 y of a new fungicide usage.
activities were evaluated in vivo against CDM. Fortu-
nately, compound 8q (Figure 1) was finally identified and
showed excellent fungicidal activity toward CDM.
Futhermore, compound 8q was tested as a potent candi-
date with activity against P. cubensis in the cucumber
field. This novel structure may represent a new efficient
antifungal alternative that can be used to control CDM.
Thus, there is an urgent need for discovering and devel-
oping new fungicides with innovative structures and
improved activities for the crop protection.
Triazole sulfonamide is a new anti-mitochondrial
complex III (MET III) electron transport inhibitor,
exhibiting a variety of important pharmacological and
agricultural activities for promising lead derivation and
[11–18]
novel agrochemical development.
Their derivatives
Amisulbrom have also been developed as commercial
2 | RESULTS AND DISCUSSION
2.1 | Chemistries
fungicides against downy mildew and Phytophthora
[19–23]
infestans.
It is worth mentioning that Amisulbrom
is comparatively secure for non-target creatures. More-
over, it is not worry about the cross-resistance of most
commercial fungicides. Therefore, the above characteris-
tics revealed that triazole sulfonamide could be a potent
Design of the derivatives of target compound was rev-
ealed in Scheme 1. The target compound embodys two
portions: one is the triazole-disulfonamide and another is
the hydrazone part. First, the 1 was regarded as a raw
material to obtain 4 by means of three steps. Then the
intermediate 2 consist of 1 and benzenesulfonyl chloride.
And with that, another part thiol reacts with it and pro-
duces symmetrical disulfides 2 when pyridine existed.
After that, N,N-dimethylsulfamoyl chloride reacted with
2 to acquire 3 using K CO as the base. Then, oxidation
of the disulfide is carried out by blowing chlorine to the
aqueous solution containing DCM, and the intermediate
4 was achieved. Through condensation reaction of appro-
priately substituted aromatic aldehyde or ketone and
hydrazine, so the important intermediate 7 was acquired.
The triazole sulfonyl chloride and various hydrazone pro-
vide the designed product 8 in excellent yield.
[24–30]
antifungal lead scaffold for fungicides discovery.
On
the other hand, hydrazones (iNHN=C-1) are known as
biologically active fragements, which are widely used as a
[31–33]
scaffold in agricultural chemistry.
It has been
reported that derivatives of hydrazones are shown to pos-
sess a wide range of biological activities, such as antifun-
gal, antibacterial, insecticidal, herbicidal, antiviral and
2
3
[34–39]
anticancer activities.
Heretofore, some pharmaceu-
tical companies have developed dozens of fungicides,
insecticides, plant growth regulators such as benquinox,
[40–42]
hydramethylnon and diflufenzopyr.
All of the find-
ings inspired us to design the bioactive structures with
these functional motifs as potential agrochemical leads
for plant disease control.
In a previous work, we reported an array of triazole
sulfonamide derivatives using the intermediate derivati-
zation method (IDM). Bioactivity assay showed that com-
pound 9 (Figure 1) exhibited promising antifungal
activities against CDM in greenhouse with an ideal EC50
value of 6.91 mg/L. However, compound 9 did not per-
2.2 | Antifungal activity
The indoor pot tests displayed that practically more than
50% of the composed ramifications have cracking
inhibitory activity counter cucumber downy mildew. Var-
ious triazole sulfonamide ramifications comprised
benzylamine moiety conveyed obviously activity differ-
ence. Several target compounds showed high domination
against CDM based on Table 1. Among 8a-8x have a
repression activity of 100% when the concentration is
[43]
form well in field efficacy trials.
In this study, to con-
tinue our previous work, a series of novel structures that
combine triazole sulfonamide and hydrazone moieties
together were designed and synthesized to produce the
corresponding compounds with the anticipation of creat-
ing several promising antifungal agents. Antifungal
FIGURE 1 A conspectus of the majorization devise of new triazolesulfonamide derivatives and the optimized potential fungicide
candidate 8q

LI ET AL.
3
SCHEME 1 Methods for
synthesizing target compound.
Conditions and reagents:
(
A) Pyridine, benzenesulfonyl
ꢀ
Chloride, CH
2
Cl
2
, 12 h, 20 C;
(
B) Dimethylsulfamoyl chloride,
ꢀ
3
0 min to 15 h, 0 to 20 C; (C) Cl ,
2
(
v:v:v)CH
2
Cl
2
/CH
3
ꢀ
COOH/
H
2
O = 1:2:1, 2 h, 0 C; (D) MgSO
4
,
ꢀ
CH
2
Cl
2
, 20 C,12 h;
(
E) Tetrahydrofuran, pyridine,
ꢀ
1
2 h, 20 C
2
00 mg/L. But also, 8a, 8b, 8p, 8q, 8t, 8u kept the same
activity. Compound 8p (2-Cl-3,4-F) exhibited high activity,
which was better than that of compound 8h (2-Br-4-F)
and 8j (3-F-5-F), suggesting that halogen type and quan-
entire control at the concentration of 100 mg/L. Particu-
larly it should be noted that 8q maintained positive domi-
nate even if the concentration is 50 mg/L, at this
horizontal, Cyazofamid and Amisulbrom merely existed
tity on the benzene ring of R group could contribute to
1
the antifungal activity against CDM. It can be observed
5
0% and 95% dominate. Compound 8q revealed the same
that changing -CH substituent to methyl ester substituent
3
fungicidal activity for CDM than Cyazofamid and Ami-
sulbrom separately if the concentration is 12.5 and
on R group could lead to significant changes in the activ-
3
ity. Among them, 3-bromobenzene-containing compound
8q exhibited the strongest antifungal activity against CDM
with EC50 value of 7.776 mg/L, which was even stronger
than that of Cyazofamid (EC50 = 48.522 mg/L) and Ami-
sulbrom (EC50 = 11.309 mg/L). It may become a new lead
compound for antifungal research. All results exhibited
that the antifungal effect of traget compounds against
CDM can be affected by multifarious factors, such as the
type of the substituent, the position of substituents, the
type of halogen on the benzene ring.
6
.25 mg/L.
Initial antibacterial examine against cucumber downy
mildew at the various concentration showed that active
compounds 8q had unexceptionable effectiveness. There-
fore we opted all these positive ramifications for further
appraision. But also, we chose Cyazofamid and Ami-
sulbrom as frontage contrast, and they are the most effi-
cacious commonly used fungicide and they had excellent
dominate activity aimed at cucumber downy mildew.
To further analyze the structure-activity relationships,
we transformed the activity results to EC50 values. As
shown in Table 2, we tested some aromatic heterocycle
derivatives 8a-8d, and we found N-methylpyrrole 8b
2.3 | Analysis of field efficacy trials
exhibited the good activity. Inserting a -CH group (for
Many cucumber leaves were covered with yellow mould
layer in the blank space, following their DI values
raised from 4.17 to 19.53. Cucumber leaves treated with
synthetic active compounds can be well controlled. DI
values are in the range of 2.25 and 6.36. These effica-
cies of compound 8q on cucumber downy mildew in
cucumber fields are shown in Table 3. Compared with
3
compound 8e) to R dramatically reduced the antifungal
2
ability, revealing that substituent of this position was not
recommended in improving biological activity. The fusion
of a substituent with greater steric hindrance (for com-
pound 8f, 8n, 8o) decreased bioactivity, suggesting that
relatively rigid and hydrophobic aromatic rings are not
conducive to the improvement of activity. A similar
decreased activity can be observed after replacing the
2
2
high (6.67 g ai/667 m ) and low (3.33 g ai/667 m ) posi-
tive control Amisulbrom, the effect of applying 8q
showed better control effect. In order to control cucum-
ber downy mildew in the field, the recommended dos-
-
CH on R group into a relatively rigid aromatic ring (for
3 3
compound 8u, 8v, 8w, 8x). The introduction of pyridine
2
rings to R group (for compound 8k, 8l, 8m) showed rela-
age applications of compound 8q is 6.67 g ai/667 m
1
tively lower biological activity, which is also demostrated
three times a week.
with methyl ester-bearing compounds (for compound 8s,
The field efficacy trials further indicated that 8q may
has better therapeutic and protective activity than Ami-
sulbrom (Figure 2). The structural optimization field and
devise test of 8q were yet under exploration, and synthe-
sis of analogs. The outcomes showed that active com-
pound 8q, displayed the fungicide activity against CDM
8
t). Comparison of the electronic property revealed that
the introduction of a strong electron-donating group
4-OCH , for compound 8g) and electron-withdrawing
(
3
group (3-CF , for compound 8i) on the benzene ring of R1
3
group had no significant effect in promoting antifungal

4
LI ET AL.
TABLE 1 In vivo fungicidal activity of target compounds against cucumber downy at differett concentrations
Cucumber downy mildew
%
inhibition (mg/L)
Examples
200
100
75
50
25
30
12.5
0
6.25
0
8
a
b
80
60
8
100
100
80
70
30
0
8
8
c
100
100
90
90
80
50
60
20
10
0
0
0
d
8
e
f
80
10
20
0
0
0
0
0
0
0
0
8
100
8
8
g
100
100
70
40
60
0
0
0
0
h
100
30
20
8
i
j
90
90
60
80
20
60
0
0
0
0
0
8
20
8
k
l
100
100
20
60
0
0
0
0
0
0
0
8
20
8
8
m
n
100
100
30
20
0
0
0
0
0
0
0
0
(
Continues)

LI ET AL.
5
TABLE 1 (Continued)
Cucumber downy mildew
inhibition (mg/L)
%
8
o
100
50
30
0
0
0
8
8
p
q
100
100
100
100
80
70
80
50
60
30
50
100
8
8
r
s
100
80
80
70
70
50
50
20
20
0
0
0
8
8
t
80
95
75
90
60
60
30
20
0
0
0
0
u
8
8
v
100
100
80
60
0
0
0
0
0
0
0
w
20
8
x
100
90
80
0
0
0
Amisulbrom
Cyazofamid
100
100
100
80
95
50
85
20
45
5
30
0
was better than commercial fungicides Cyazofamid and
Amisulbrom. The expandment of repellency may be post-
poned through the exploration of novel triazole dis-
ulfonamide fungcides, which will also help resist
administration. Present outcomes supply sustains the
exploration of triazole disulfonamide as a new agricul-
tural chemical.
3 | EXPERIMENTALS
3.1 | Materials and means
All of the commercially available reagents can be used
1
13
immediately without purification. H and C NMR char-
acterization data were collected at 300 K on a VARIAN

6
LI ET AL.
TABLE 2 Determination of activity of different agents on cucumber downy mildew
Examples
Toxic regression equation
Y = −6.510 + 3.773X
Y = −7.289 + 5.590X
Y = −7.764 + 5.443X
Y = −11.457 + 6.863X
Y = −17.064 + 7.837X
Y = −16.978 + 8.186X
Y = −13.873 + 7.623X
Y = −8.100 + 5.336X
Y = −13.195 + 6.789X
Y = −8.388 + 4.927X
Y = −16.978 + 8.186X
Y = −16.186 + 8.474X
Y = −16.955 + 8.289X
Y = −16.978 + 8.186X
Y = −13.598 + 7.111X
Y = −3.658 + 3.318X
Y = −3.341 + 3.751X
Y = −6.062 + 4.081X
Y = −7.129 + 3.950X
Y = −6.510 + 3.773X
Y = −10.089 + 6.097X
Y = −25.021 + 13.113X
Y = −16.186 + 8.474X
Y = −17.452 + 10.636X
Y = −4.861 + 4.614X
Y = −9.132 + 5.417X
EC50 (mg/L)
53.159
20.134
26.688
46.708
150.476
118.556
66.059
32.954
87.845
50.413
118.556
81.313
111.062
118.556
81.698
12.660
7.776
95% confidence interval (mg/L)
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
a
b
c
d
e
f
28.519-110.651
12.773-30.666
17.627-39.879
38.086-57.354
118.990-203.737
74.002-221.857
47.631-92.718
18.999-56.829
79.744-97.014
35.560-72.674
74.002-221.857
65.370-101.288
77.502-169.885
74.002-221.857
51.857-134.008
7.113-18.818
g
h
i
j
k
l
m
n
o
p
q
r
2.824-12.209
30.571
63.797
53.159
45.149
80.926
81.313
43.747
11.309
48.522
18.789-48.917
41.860-104.535
28.519-110.651
35.534-57.519
68.594-93.275
65.370-101.288
7.478-127.024
8.242-14.566
s
t
u
v
w
x
Amisulbrom
Cyazofamid
39.494-59.850
Mercury-Plus 400 spectrometer (varian Inc., Palo Alto,
CA) operating at 400.0 and 100.0 MHz (respectively) with
chemical shifts reported in parts per million relative to
aminethiourea (8.90 g 70.0 mmol) and K CO (16.50 g,
2 3
150.0 mmol) were mixed in a 150 mL double-mouth bot-
ꢀ
tle. Then the temperature was raised to 110 C at 3.0 h,
CHCl . Several abridgations put to used show that multi-
plicity as follow, s: singlet, t: triplet, d: doublet, br: broad,
m: multiplet.
and subsequently lowered to room tempurature, and
then the mixture was mixed at −15 C to tardily
decrystallize. Then filtering and dring to get white solid
3
ꢀ
3.42 g, yield 65%.
3
.2 | The synthesis of intermediate
compound (1)
3.3 | The synthesis of intermediate
compound (2)
At the 250 mL double-mouth bottle, 14.32 g (320.0 mmol)
of the formic acid was added to 35.0 mL of deionized
2.95 g of (40.0 mmol) pyridine was added to 100 mL
DCM with 4.12 g (40.0 mmol) of (1). And the solution
lower the temperature to zero, and so that by tardily
putting 3.42 g (20.0 mmol) in benzenesulfonyl chloride
at 2 h. And the mixture was reacted at room
tempurature for 12.0 h. DCM was concentrated under
decreased pressure and the dregs was washed with
water, after that pour in 14.32 g (160.0 mmol) of
ꢀ
1
-aminothiourea. The temperature was raised to 100 C
ꢀ
for 1 h, after that andantely cooled to 25 C. Then further
downing to −5 C, and crystal was tardily decrystallized,
ꢀ
lastly, then aldehyde was getted through filtrating and
drying. After that water (85.0 mL), aldehyde

LI ET AL.
7
TABLE 3 Efficacy of Compound 8q against cucumber downy mildew in field
c
DD
2
a
b
Compd
Rate (g ai/667 m )
BaseDi
4.08
afterDI
4.98
Field efficacy (%)
5%
bcd
aA
1%
cde
aA
8
q
3.33
74.61
84.10
70.91
79.35
ND
6
.67
3.33
.67
2.98
2.25
Amisulbrom
4.58
6.36
cde
AB
ND
def
AB
ND
6
3.82
3.81
d
CK
ND
4.17
19.53
a
Base disease index.
b
Disease index after used compound.
c
Significant difference a, b, c, d, and e, distinct difference at 95% of confidence limits. A, B, distinct difference at 99% of confidence limits.
d
ND = not detected.
FIGURE 2 Comparison of field efficacy trials
water (40 mL) and EA (20 mL) for 2 h, after the precip-
itate filtering, and washing by water (35 mL) and EA
3.5 | The synthesis of intermediate
compound (4)
(
30 mL) according to priority. Then the accumulation
ꢀ
was dried at 60 C to acquire 3.50 g (88%) of the aim
50 mL of DCM solution embodying 8.05 g (19.0 mmol) of
[44]
product.
the product 3, after adding 60 mL of water to the system
ꢀ
and then cooled to 0 C. Then, the chlorine was bubbling,
and the temperature and the solution was dominated
ꢀ
3
.4 | The synthesis of intermediate
from 15 to 25 C over 2.0 h, after that adding 15 mL of
compound (3)
EA. Washing with 25 mL of H O to organic layer when
the reaction was accomplished. After that 7.25 g of target
product was acquired in 88% yield.
2
[
46]
4
.52 g (34.0 mmol) of K CO and 3.00 g (15.0 mmol)
2
3
of (2) were mixed in 100 mL of DMF, then the tem-
ꢀ
perature cooling to 6 C. Added 2.16 g (12.0 mmol) of
N,N-dimethylsulfamoyl chloride to the reaction mix-
3.6 | The synthesis of intermediate
compound (7)
ture slowly and temperature was dominated between
ꢀ
2
0 and 25 C over 3 h. Then, 20 mL of DCM add to
the reaction system, next in importance adding
Adding aromatic ketone or aromatic aldehyde (14.2 mmol),
6
0.0 mL of 15% HCl to the system at the temperature
DCM (25 mL) and MgSO (3.40 g, 26.0 mmol) to a 150 mL
4
ꢀ
from 15 to 30 C. After that 6.44 g of target product
was getted from the cumulative organic phase get
3
three-neck bottle, and the reaction system was reacted at
room temperature over 10.0 h, after that adding 25 mL of
EA. Separating the organic layer and washing with 25 mL
[
45]
.20 g (78%).

8
LI ET AL.
of H O after the reaction was accomplished. The residue
J = 7.1, 2.1 Hz, 2H), 3.32 (m, 3H), 3.53 (s, 3H), 2.95 (s, 6H).
C NMR: δ 177.39, 159.33, 148.60, 139.46, 133.38, 131.66,
2
13
with purification by silica gel column chromatography as
[47]
eluent the product 7 was obtained.
130.05, 128.24, 120.06, 38.88, 38.73, 21.02. HRMS (EI):
+
C H BrN O S (M) calcd. 464.9936; found 464.9937.
13
17
6 4 2
3-((2-(diphenylmethylene)-1-methylhydrazinyl)sulfonyl)-
3
.7 | The synthesis of active
N,N-dimethyl-1H-1,2,4-triazole-1-sulfonamide (8f). White
ꢀ
1
compound (8)
solid (55%). Melting points: 123-125 C. H NMR (CDCl ) δ
3
8.76 (s, 1H), 8.61 (s, 1H), 8.10 (s, 1H), 7.47 (ddd, J = 12.3,
7
(3.0 mmol), pyridine (0.34 g, 3.5 mmol) and THF (15 mL)
8.7, 5.0 Hz, 6H), 7.32 (d, J = 7.5 Hz, 2H), 3.03 (s, 6H), 2.92
(s, 3H). C NMR: δ 171.61, 159.63, 154.04, 148.71, 130.32,
13
were blended to a 100 mL double-mouth bottle, stirred at
ꢀ
0
3
C. The THF (15.0 mL) and compound of 4 (0.65 g,
129.23, 128.78, 38.87, 38.66. HRMS (EI): C H N O S
18
20 6 4 2
+
.5 mmol) were added tardily over 15 min, and the reaction
(M) calcd. 449.0987; found 449.0984.
system is stirred at room temperature over 3.0 h. The resi-
due with purification by silica gel column chromatography
(E)-3-((2-(2,5-dimethoxybenzylidene)-1-methylhydrazinyl)
sulfonyl)-N,N-dimethyl-1H-1,2,4-triazole-1-sulfonamide (8g).
[48,49]
ꢀ
1
as eluent the product 8 was acquired.
E)-N,N-dimethyl-3-((1-methyl-2-((5-methylisoxazol-3-yl)-
White solid (62%). Melting points: 103-106 C. H NMR
(
(CDCl ) δ 8.60 (s, 1H), 8.12 (s, 1H), 7.34 (d, J = 3.1 Hz, 1H),
3
methylene)hydrazinyl)sulfonyl)-1H-1,2,4-triazole-1-sulfon-
6.91 (dd, J = 9.0, 3.2 Hz, 1H), 6.83 (d, J = 9.0 Hz, 1H), 3.82
(s, 3H), 3.76 (s, 3H), 3.55 (s, 3H), 2.99 (s, 6H). C NMR: δ
ꢀ
13
amide (8a). White solid (58%). Melting points: 84-88 C.
1
H NMR (CDCl ) δ 8.61 (s, 1H), 7.76 (s, 1H), 6.35
163.83, 162.19, 160.72, 148.88, 143.12, 137.96, 110.20, 106.10,
3
1
3
+
(
s, 1H), 3.56 (s, 3H), 3.04 (s, 6H), 2.39 (s, 3H). C NMR:
105.75, 38.70, 34.84. HRMS (EI): C H N O S (M) calcd.
1
4 20 6 6 2
δ 171.02, 160.72, 160.27, 148.87, 135.70, 99.24, 38.76,
433.0886; found 433.0884.
(E)-3-((2-(2-bromo-4-fluorobenzylidene)-1-methylhydra-
zinyl)sulfonyl)-N,N-dimethyl-1H-1,2,4-triazole-1-sulfonamide
+
3
3
4.78, 12.11. HRMS (EI): C H N O S (M) calcd.
1
0
15
7 5 2
78.0576; found 378.0572.
E)-N,N-dimethyl-3-((1-methyl-2-((1-methyl-1H-pyrrol-
-yl)methylene)hydrazinyl)sulfonyl)-1H-1,2,4-triazole-1-sul
ꢀ
1
(
(8h). White solid (53%). Melting points: 115-119 C. H
2
NMR (CDCl ) δ 8.62 (s, 1H), 8.00 (s, 1H), 7.94 (dd, J = 8.8,
3
fonamide (8b). White solid (45%). Melting points:
6.2 Hz, 1H), 7.34-7.29 (m, 1H), 7.09-7.00 (m, 1H), 3.59 (s,
3H), 3.04 (s, 6H). C NMR: δ 164.38, 161.87, 160.75,
ꢀ
1
13
9
6-98 C. H NMR (CDCl ) δ 8.63 (s, 1H), 7.82 (s, 1H),
3
6
1
.72 (s, 1H), 6.47 (dd, J = 3.6, 1.4 Hz, 1H), 6.15-6.10 (m,
H), 3.78 (s, 3H), 3.43 (s, 3H), 3.03 (s, 6H). C NMR: δ
148.84, 142.46, 129.69 (d, J = 9.7 Hz), 124.23 (d,
13
J = 10.2 Hz), 120.52, 116.35, 38.74, 34.79. HRMS (EI):
+
1
62.47, 155.78, 148.45, 130.47, 127.65, 117.45, 62.58,
C H BrFN O S (M) calcd. 468.9686; found 468.9684.
12
14
6 4 2
+
5
3.18, 38.72, 14.56. HRMS (EI): C H N O S (M)
(E)-3-((2-(4-fluoro-3-(trifluoromethyl)benzylidene)-1-methyl-
11
17 7 4 2
calcd. 376.0856; found 376.0859.
hydrazinyl)sulfonyl)-N,N-dimethyl-1H-1,2,4-triazole-1-sulfo
(
E)-N,N-dimethyl-3-((1-methyl-2-(thiophen-2-ylmethylene)-
namide (8i). White solid (43%). Melting points:
ꢀ
1
hydrazinyl)sulfonyl)-1H-1,2,4-triazole-1-sulfonamide
White solid (36%). Melting points: 93-96 C. H NMR
CDCl ) δ 8.62 (s, 1H), 8.03 (s, 1H), 7.36 (d, J = 5.0 Hz, 1H),
.31-7.26 (m, 1H), 7.04 (dd, J = 4.9, 3.8 Hz, 1H), 3.52 (s, 3H),
.00 (s, 6H). C NMR: δ 160.85, 148.75, 141.99, 138.73,
31.94, 129.66, 128.32, 38.74, 35.33. HRMS (EI):
C H N O S (M) calcd. 379.0239; found 379.0236.
0 14 6 4 3
(8c).
109-112 C. H NMR (CDCl ) δ 8.61 (s, 1H), 7.87
3
ꢀ
1
(t, J = 7.4 Hz, 2H), 7.73 (s, 1H), 7.23 (t, J = 9.1 Hz, 1H),
13
(
7
3
1
3.56 (s, 3H), 3.04 (s, 6H). C NMR: δ 160.77, 148.85,
143.38, 133.74 (d, J = 9.1 Hz), 131.48 (d, J = 3.4 Hz),
126.22 (d, J = 4.8 Hz), 123.69, 118.64, 60.20, 38.69, 34.33.
3
13
+
HRMS (EI): C H F N O S (M) calcd. 459.0454; found
13
14 4 6 4 2
+
459.0452.
1
(
Z)-3-((2-((1H-imidazol-1-yl)methylene)-1-methylhydra-
(E)-3-((2-(3,5-difluorobenzylidene)-1-methylhydrazinyl)
sulfonyl)-N,N-dimethyl-1H-1,2,4-triazole-1-sulfonamide
(8j). White solid (36%). Melting points: 101-105 C. H
zinyl)sulfonyl)-N,N-dimethyl-1H-1,2,4-triazole-1-sulfonamide
8d). White solid (41%). Melting points: 103-107 C. H
ꢀ
1
ꢀ
1
(
NMR (CDCl ) δ 8.58 (s, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 7.64
NMR (CDCl ) δ 8.62 (s, 1H), 7.62 (s, 1H), 7.17 (d,
3
3
13
(s, 1H), 7.44 (s, 1H), 3.32 (m, 3H), 2.95 (s, 6H). C NMR: δ
J = 5.9 Hz, 2H), 6.82 (t, J = 7.6 Hz, 1H), 3.56 (s, 3H), 3.05
13
1
62.47, 155.78, 148.45, 130.47, 127.65, 62.58, 38.72, 14.56.
(s, 6H). C NMR: δ 163.83 (d, J = 13.3 Hz), 162.19 (d,
J = 13.3 Hz), 160.72, 143.12, 137.96 (t, J = 9.9 Hz), 106.10,
+
HRMS (EI): C H N O S (M) calcd. 363.0579; found
9
14 8 4 2
+
3
63.0577.
Z)-3-((2-(1-(2-bromophenyl)ethylidene)-1-methylhydra-
zinyl)sulfonyl)-N,N-dimethyl-1H-1,2,4-triazole-1-sulfonamide
105.75, 38.70, 34.84. HRMS (EI): C H F N O S (M)
12
14 2 6 4 2
(
calcd. 409.0486; found 409.0488.
(E)-N,N-dimethyl-3-((1-methyl-2-(pyridin-
3-ylmethylene)hydrazinyl)sulfonyl)-1H-1,2,4-triazole-1-sul-
ꢀ
1
(8e). White solid (52%). Melting points: 113-117 C. H NMR
(
CDCl ) δ 8.58 (s, 1H), 7.74 (s, 1H), 7.64 (s, 1H), 7.62 (dd,
fonamide (8k). White solid (48%). Melting points:
3

LI ET AL.
9
ꢀ
1
1
8
15-119 C. H NMR (CDCl ) δ 8.75 (d, J = 1.3 Hz, 1H),
J = 19.9 Hz), 38.72, 20.69. HRMS (EI): C H ClF N O S
13 15 2 6 4 2
(M) calcd. 457.0253; found 457.0256.
3
+
.62 (s, 1H), 8.58 (dd, J = 4.7, 1.3 Hz, 1H), 8.03 (d,
J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.34-7.27 (m, 1H), 3.57 (s,
Methyl(E)-2-((6-chloropyridin-2-yl)methylene)-1-((1-(N,
N-dimethylsulfamoyl)-1H-1,2,4-triazol-3-yl)sulfonyl)hydra-
zine-1-carboxylate (8q). White solid (64%). Melting points:
13
3
H), 3.01 (s, 6H). C NMR: δ 160.82, 154.07, 150.36,
1
48.86, 146.72, 142.84, 135.08, 124.93, 38.75, 34.91.
+
ꢀ
1
HRMS (EI): C H N O S (M) calcd. 374.0627; found
132-136 C. H NMR (CDCl ) δ 13.79 (s, 1H), 8.75 (d,
11
15
7
4 2
3
3
74.0625.
E)-3-((2-((2-chloropyridin-3-yl)methylene)-1-methy-
J = 8.5 Hz, 1H), 8.58 (dd, J = 4.7, 1.4 Hz, 1H), 7.85 (dd,
(
J = 8.2, 1.5 Hz, 1H), 7.32 (dd, J = 8.2, 4.7 Hz, 1H), 3.91 (s,
13
lhydrazinyl)sulfonyl)-N,N-dimethyl-1H-1,2,4-triazole-1-sul-
3H), 2.99 (s, 6H). C NMR: δ160.76, 151.74, 149.46,
fonamide (8l). White solid (42%). Melting points:
148.82, 141.84, 137.04, 129.73, 125.22, 108.34, 38.73,
ꢀ
1
+
1
20-125 C. H NMR (CDCl ) δ 8.62 (s, 1H), 8.40 (dd,
34.77. HRMS (EI): C H ClN O S (M) calcd. 452.0136;
3
12 14
7 6 2
J = 4.6, 1.8 Hz, 1H), 8.27 (dd, J = 7.8, 1.7 Hz, 1H), 7.98 (s,
found 452.0132.
13
1
H), 7.28 (t, J = 6.2 Hz, 1H), 3.62 (s, 3H), 3.05 (s, 6H).
C
Methyl(E)-1-((1-(N,N-dimethylsulfamoyl)-1H-
NMR: δ 160.69, 151.52, 149.78, 148.89, 139.79, 136.59,
1,2,4-triazol-3-yl)sulfonyl)-2-(naphthalen-1-ylmethylene)
hydrazine-1-carboxylate (8r). White solid (57%). Melting
+
1
28.49, 38.76, 34.78. HRMS (EI): C H ClN O S (M)
11 14 7 4 2
ꢀ
1
calcd. 408.0237; found 408.0235.
points: 138-142 C. H NMR (CDCl ) δ 9.97 (s, 1H), 8.75
3
(
E)-3-((2-((6-chloropyridin-3-yl)methylene)-
-methylhydrazinyl)sulfonyl)-N,N-dimethyl-1H-1,2,4-tri-
azole-1-sulfonamide (8m). White solid (57%). Melting
(d, J = 8.5 Hz, 1H), 8.47 (s, 1H), 7.93 (d, J = 8.1 Hz, 2H),
1
7.89 (d, J = 7.1 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.56 (dt,
13
J = 20.7, 7.7 Hz, 2H), 2.99 (s, 6H), 2.41 (s, 3H). C NMR:
δ162.13, 154.51, 144.20, 133.99, 130.51, 130.11, 129.21,
127.56, 126.65, 125.98, 124.47, 116.98, 112.47, 52.49,
ꢀ
1
points: 124-128 C. H NMR (CDCl ) δ 8.61 (s, 1H), 8.52
d, J = 2.0 Hz, 1H), 8.05 (dd, J = 8.4, 2.3 Hz, 1H), 7.71 (s,
3
(
+
1
H), 7.35 (d, J = 8.4 Hz, 1H), 3.58 (s, 3H), 3.05 (s, 6H).
C NMR: δ 160.76, 151.74, 149.46, 148.82, 141.84, 137.04,
29.73, 125.22, 38.73, 34.77. HRMS (EI): C H ClN O S
38.72, 14.56. HRMS (EI): C H N O S (M) calcd.
17
18 6 6 2
13
467.0729; found 467.0725.
1
Methyl(E)-2-((6-chloropyridin-2-yl)methylene)-1-((1-(N,
N-dimethylsulfamoyl)-1H-1,2,4-triazol-3-yl)sulfonyl)hydra-
zine-1-carboxylate (8s). White solid (47%). Melting points:
11
14
7
4 2
+
(
M) calcd. 408.0237; found 408.0235.
Z)-3-((2-((1H-indol-4-yl)methylene)-1-methylhydra-
zinyl)sulfonyl)-N,N-dimethyl-1H-1,2,4-triazole-1-sulfon-
(
ꢀ
1
128-133 C. H NMR (CDCl ) δ 13.79 (s, 1H), 8.75
3
ꢀ
amide (8n). White solid (42%). Melting points: 114-118 C.
H NMR (CDCl ) δ 11.21 (s, 1H), 9.37 (s, 1H), 8.36 (d,
J = 7.3 Hz, 1H), 8.24 (s, 2H), 7.91 (d, J = 8.3 Hz, 1H), 7.42
(d, J = 8.5 Hz, 1H), 8.58 (dd, J = 4.7, 1.4 Hz, 1H), 7.85
1
(dd, J = 8.2, 1.5 Hz, 1H), 7.32 (dd, J = 8.2, 4.7 Hz, 1H),
3
13
3.91 (s, 3H), 2.99 (s, 6H). C NMR: δ160.76, 151.74,
(
2
t, J = 7.5 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H),3.72 (s, 3H),
.81 (s, 6H). C NMR: δ 163.97, 162.33, 160.89, 148.78,
149.46, 148.82, 141.84, 137.04, 129.73, 125.22, 108.34,
13
+
38.73, 34.77. HRMS (EI): C H ClN O S (M) calcd.
12
14
7 6 2
1
44.27, 140.72, 129.99, 128.87, 117.97, 113.67, 34.82.
452.0136; found 452.0138.
+
HRMS (EI): C H N O S (M) calcd. 412.0783; found
Methyl(E)-2-((2,5-dichloropyridin-3-yl)methylene)-1-
((1-(N,N-dimethylsulfamoyl)-1H-1,2,4-triazol-3-yl)sulfonyl)
hydrazine-1-carboxylate (8t). White solid (35%). Melting
14
17 7 4 2
4
12.0784.
Z)-N,N-dimethyl-3-((1-methyl-2-(6-nitro-4H-chromen-
(
ꢀ
1
4
-ylidene)hydrazinyl)sulfonyl)-1H-1,2,4-triazole-1-sulfon-
points: 136-139 C. H NMR (CDCl ) δ 13.79 (s, 1H), 8.75
3
ꢀ
amide (8o). White solid (46%). Melting points: 132-137 C.
(d, J = 8.5 Hz, 1H), 8.58 (dd, J = 4.7, 1.4 Hz, 1H), 7.32
(dd, J = 8.2, 4.7 Hz, 1H), 3.91 (s, 3H), 2.99 (s, 6H).
1
13
H NMR (CDCl ) δ 8.58 (s, 1H), 7.74 (s, 1H), 7.69 (s, 1H),
C
3
7
2
1
.64 (s, 1H), 7.62 (dd, J = 7.1, 2.1 Hz, 2H), 3.32 (m, 3H),
.95 (s, 6H). C NMR: δ 169.92, 161.43, 148.35, 141.11,
NMR: δ163.76, 152.74, 145.46, 141.82, 137.04, 129.73,
13
123.22, 105.34, 39.73, 35.77. HRMS (EI): C H C N O S
12
13 l2 7 6 2
+
32.66, 130.47, 127.65, 127.17, 61.30, 39.06, 38.52, 36.87.
(M) calcd. 485.9746; found 485.9748.
+
HRMS (EI): C H N O S (M) calcd. 458.0474; found
(E)-3-((2-(2-bromobenzylidene)-1-(6-chloropyridin-2-yl)
hydrazinyl)sulfonyl)-N,N-dimethyl-1H-1,2,4-triazole-1-sul-
fonamide (8u). White solid (41%). Melting points:
14
15 7 7 2
4
58.0477.
E)-3-((2-(1-(2-chloro-4,5-difluorophenyl)ethylidene)-
-methylhydrazinyl)sulfonyl)-N,N-dimethyl-1H-1,2,4-tri-
(
ꢀ
1
1
141-143 C. H NMR (CDCl ) δ 8.69 (s, 1H), 8.04 (d,
3
azole-1-sulfonamide (8p). White solid (53%). Melting
J = 9.2 Hz, 1H), 8.00 (s, 1H), 7.94 (t, J = 7.8 Hz, 1H), 7.65
(d, J = 7.7 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.46 (d,
J = 7.9 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.30-7.23 (m,
1H), 2.98 (s, 6H). C NMR: δ162.13, 154.51, 144.20,
133.99, 130.51, 130.11, 129.21, 127.56, 126.65, 125.98,
ꢀ
1
points: 115-118 C. H NMR (CDCl ) δ 8.69 (s, 1H), 7.34
3
(
3
1
dd, J = 9.9, 8.4 Hz, 1H), 7.26 (dd, J = 10.3, 7.7 Hz, 1H),
.23 (s, 3H), 3.07 (s, 6H), 2.59 (s, 3H). C NMR: δ 174.45,
64.26159.26, 151.07 (d, J = 13.4 Hz), 149.44 (t,
13
13
J = 13.3 Hz), 148.62, 147.84 (d, J = 12.5 Hz), 126.90 (dd,
J = 8.9, 3.2 Hz), 120.02 (d, J = 20.8 Hz), 119.08 (d,
124.47, 116.98, 112.47, 52.49, 38.72. HRMS (EI):
+
C H BrClN O S (M) calcd. 547.9499; found 547.9497.
16
15
7 4 2

10
LI ET AL.
ꢀ
(
E)-3-((1-(4-chlorobenzoyl)-2-(3,5-difluorobenzylidene)
house (24 ± 1 C, RH = 100%, dark) for 24 h later,
cucumber seedlings were migrated to a greenhouse
hydrazinyl)sulfonyl)-N,N-dimethyl-1H-1,2,4-triazole-1-sul-
fonamide (8v). White solid (52%). Melting points:
34-137 C. H NMR (CDCl ) δ 8.95 (s, 1H), 8.75 (s, 1H),
.85 (t, J = 8.2 Hz, 3H), 7.43 (d, J = 8.5 Hz, 2H), 7.13 (dd,
J = 8.3, 2.3 Hz, 1H), 7.06-6.98 (m, 1H), 3.08 (s, 6H).
NMR: δ 164.04 (d, J = 13.5 Hz), 163.61, 162.40 (d,
J = 13.0 Hz), 156.20, 149.84, 145.45, 133.95, 130.30,
29.17, 120.41, 114.31, 106.46, 34.78. HRMS (EI):
C H ClF N O S (M) calcd. 533.0202; found 533.0204.
ꢀ
(18-30 C, RH = 95%) after infection. Three duplicated
ꢀ
1
1
7
experiments were advanced and every composite was
assessed the activity via visual inspection after 5 days.
The consequents were expressed e range from 0%
(no control) to 100% (complete control). The inhibitory
rate (%) = [(viability of the no control-viability of the
total control)/viability of the no control] × 100. DPS
3
13
C
1
+
18
15
2 6 5 2
version 15.0 was made use of calculating the EC50
(E)-3-((2-benzylidene-1-tosylhydrazinyl)sulfonyl)-N,N-
values.
dimethyl-1H-1,2,4-triazole-1-sulfonamide (8w). White
ꢀ
1
solid (45%). Melting points: 123-127 C. H NMR (CDCl )
3
δ 8.80 (s, 1H), 8.60 (s, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.81
3.9 | Field efficacy trials of activity
compound (8q)
(d, J = 7.2 Hz, 2H), 7.56 (t, J = 6.9 Hz, 1H), 7.48 (t,
J = 7.6 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 3.05 (s, 6H), 2.48
13
(
s, 3H). C NMR: δ 173.28, 160.76, 148.65, 146.84,
According to the in vivo cucumber downy mildew
inhibitory activity, the field test of cucumber further
verified the efficacy of compound 8q to valid its fungi-
cidal activity. The activity compound 8q was prepared
as 10% emulsifiable concentrate and diluted with water
1
3
5
42.54, 133.95, 132.14, 130.32, 129.70, 129.32, 38.72,
+
4.77, 21.70. HRMS (EI): C H N O S (M) calcd.
18
20 6 6 3
13.0606; found 513.0604.
E)-3-((2-(2-chloro-4-fluorobenzylidene)-1-((4-fluoro-
phenyl)sulfonyl)hydrazinyl)sulfonyl)-N,N-dimethyl-1H-1,
,4-triazole-1-sulfonamide (8x). White solid (49%). Melt-
(
2
2
to 3.33 g ai/667 m and 6.67 g ai/667 m for application.
In the early onset of cucumber downy mildew, the
activity compound 8q was uniformly sprayed on the
cucumbers. Amisulbrom (10%, emulsifiable concentrate)
was used as the positive control, and an equal amount
of water was used as the blank. Depending on the dis-
ease level of the investigated leaves, the disease indexes
(DI) and control efficacies were calculated. The control
efficacy (CE) was calculated by the formula CE
(%) = [1 − CK × pt /(CK × pt )] × 100, and DI was
2
ꢀ
1
ing points: 129-132 C. H NMR (CDCl ) δ 9.19 (s, 1H),
3
8
.64 (s, 1H), 8.06 (ddd, J = 15.0, 8.8, 5.6 Hz, 3H), 7.25
(
6
1
ddd, J = 10.8, 8.3, 3.4 Hz, 4H), 7.13-7.05 (m, 1H), 3.08 (s,
H). C NMR: δ 173.28, δ 164.04 (d, J = 13.5 Hz), 163.61,
62.40 (d, J = 13.0 Hz), 153.24, 151.66, 146.84, 133.95(d,
13
J = 11.5 Hz), 132.14, 130.32, 129.70, 129.32, 38.72, 34.77.
+
HRMS (EI): C H ClF N O S (M) calcd. 568.9872;
17
15
2 6 6 3
found 568.9874.
0
1
1
0
evaluated by the formula DI = Σ(A × B) × 100/(C × 9),
where CK (control check) shows that the disease index
0
3
.8 | Biological evaluation
of the blank before the pesticide application, and CK1
shows the DI after the application of pesticide, A is the
number of diseased leaves, B is the corresponding disease
level, C is the total number of leaves investigated, pt1
show that the disease index of the pesticide-treatment
Antifungal activity of cucumber downy mildew (CDM)
was tested by in vivo experiment. The test compounds
with a valid density resulting in a 50% Control effect
(
EC ) was firmed afterwards. The positive control
group after compound application, and pt is the disease
5
0
0
Cyazofamid and Amisulbromand were purchased from
Shanghai Sinopharm Chemical reagent Co. Ltd. Mean-
while, the pure water was preserved as no control of fun-
gus. Breeding the seeds (Cucumber Cucumissativus L.) to
the one-heart and one-leaf section, the seedlings were
spouted with the experiment mixture (test chemicals dis-
solved in DMF to 1% emulsifiable concentrate [EC])
through a home-made sprayeron. The seedlings leaves
were 24 h later cultivated and embeded by Sporangium
suspension in China by Shenyang Sinochem Agrochemi-
cals R&D Co. Ltd. from Pseudoperonosporacubensis
index of the pesticide treatment group before compound
application. The statistical analysis of control effects was
established via variance analysis and reverse arcsine
transformation. In addition, the significant difference was
[50]
compared by LRS method between each treatment.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the technical support
of the research institute of Shenzhen Dongyangguang
Industry Co., Ltd.
5
fungus at 2-3 × 10 spores per milliliter applying double
ORCID
action 0.3 mm spray gun (0.1 Mpa) called PS289 Procon
Boy WA (GSI, Tokyo, Japan). Remaining in a humidity
Jian Lin https://orcid.org/0000-0003-0789-5567
Dewang Jing https://orcid.org/0000-0001-5359-0049

LI ET AL.
11
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