Synthesis, Antimicrobial Activity, and Molecular Docking of Benzoic Hydrazide or Amide Derivatives Containing a 1,2,3-Triazole Group as Potential SDH Inhibitors

Article abstract of DOI:10.1002/cjoc.202100007

The present study was carried out in an attempt to synthesize a new class of antimicrobial agents containing a 1,2,3-triazole motif formed by classical copper catalyzed click chemistry. Antifungal bioassay results showed that five compounds 5a, 5e, 5h, 5j

Full text of DOI:10.1002/cjoc.202100007

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中
国 化 学
Cite this paper: Chin. J. Chem. 2021, 39, 1319—1330. DOI: 10.1002/cjoc.202100007
Synthesis, Antimicrobial Activity, and Molecular Docking of
Benzoic Hydrazide or Amide Derivatives Containing
a 1,2,3-Triazole Group as Potential SDH Inhibitors
a
a
a,b
b
,a
Yue Ding, Ling Zhang, Song Yang, Zhong Li, and Pei-Yi Wang*
a
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricul-
tural Bioengineering, Ministry of Education, Center for R&D of Fine Chemicals of Guizhou University, Guiyang, Guizhou 550025, China
b
College of Pharmacy, East China University of Science & Technology, Shanghai 200237, China
Keywords
Hydrazide| Amide | 1,2,3-Triazole | Molecular docking | SDH inhibitory activity
Main observation and conclusion
The present study was carried out in an attempt to synthesize a new class of antimicrobial agents containing a 1,2,3-triazole motif
formed by classical copper catalyzed click chemistry. Antifungal bioassay results showed that five compounds 5a, 5e, 5h, 5j, and 5k
possessed a remarkable growth inhibitory activity against Botryosphaeria dothidea, Rhizoctonia solani and Gibberella zeae with EC50
values within 10.0—0.306 µg/mL. The in vitro efficacy was better than those of the commercial agrochemicals Azoxystrobin, Boscalid,
and Fluxapyroxad. In vivo trials showed that compound 5l was effective for the control of rice sheath blight and wheat scab with the
effects of 75% and 95%, respectively. Antifungal mechanism studies suggested that target compounds were potential succinate dehy-
drogenase inhibitors (SDHIs), which were proposed by the agreeable molecular docking study and restrained SDH activity (IC50 = 3.95
µg/mL, 5l). Interestingly, compounds 5r and 5s displayed good antibacterial activity against phytopathogens. In vivo screening of 5r
and 5s against rice bacterial blight afforded a superior control effect (up to 51%) than those of commercial agents Bismerthiazol and
Thiodiazole copper. The current studies could support some title compounds to be the lead compounds for exploring highly bioactive
antimicrobial substrates, particularly the potential SDHIs.
Comprehensive Graphic Content
*E-mail: pywang888@126.com
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Supporting Information
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Comprehensive Report
Ding et al.
alternatives based on these commercial SDHIs (especially the
pyrazole amides) were performed and afforded certain similar
Background and Originality Content
[
28-41]
structures with admirable bioactivity.
On the other hand,
As the population continues to grow, food security has once
[1-4]
fabrication of fresh molecular frameworks to break the original
molecular skeleton of current SDHIs is highly approved.
again become a rigid demand.
Among the many factors con-
tributing to food shortages, plant microbial diseases cause a dra-
matic decline in crop quality and yield, as a result of which farm-
Investigation reveals that triazole fungicides with their deriva-
tives have been persistently studied in view of the versatile tria-
[
5-6]
ers suffer huge economic losses.
Pathogenic fungi, such as
[42-47]
Botryosphaeria dothidea (B. d.), Rhizoctonia solani (R. s.), Colleto-
trichum gloeosporioides (C. g.) and Gibberella zeae (G. z.) are the
most damaging plant parasitic organisms, which can cause serious
degrees of diseases on the various types of crops; followed by
pathogenic bacteria, including the disreputable strains Xantho-
monas oryzae pv. oryzae (Xoo), Pseudomonas syringae pv. acti-
nidiae (Psa), and Xanthomonas axonopodis pv. citri (Xac). Current-
ly, chemical pesticide is still the main helper for controlling plant
microbial diseases, however, the progressively reduced effective-
ness as well as resistance generated by pathogenic microorgan-
isms have always plagued people and resulted in an increasing
zole moiety acting as a crucial bioactive nucleus.
Among
these flexible and multifarious triazoles, 1,2,3-triazole which can
be easily fabricated by Cu(I)-catalyzed click chemistry reaction
[
48-49]
with Huisgen 1,3-dipolecycloaddition
has aroused great in-
terests due to its derivatives bearing diverse pharmacological
[
50-51]
[52-53]
activities including antibacterial,
antifungal,
anti-
activities. Especially,
some 1,2,3-triazole compounds (Figure 1) have been commercial-
[
54]
[55]
[56]
cancer,
antitubercular,
and anti-HIV
[
57]
ized as the β-lactamase inhibitor (Tazobactam acid), antibacte-
rial drug (Cefatrizine), anticancer drug (Carboxyamidotriazole),
and anticonvulsant drug (Rufinamide). Notably, the incorpora-
tion of 1,2,3-triazole as the promising pharmacophore to the tar-
get compound might promote the discovery of new fungicides
[58]
[59]
[60]
[
7-8]
number of infections.
Furthermore, the emergence and pullu-
lation of multidrug-resistant microbial strains have complicated
[
9-13]
the situation.
Therefore, novel and efficient pesticides with
[61]
differentiating from the current structures of SDHIs. Additional-
unique modes of action are urgently developed to manage plant
microbial diseases.
ly, our previous work has discovered 1,3,4-oxadiazole-2-carbohy-
[62]
drazides as potential SDHIs with significant antifungal activities.
Exploring new pesticides based on identified targets can pro-
mote and accelerate the discovery of alternatives to traditional
agrochemicals. Succinate dehydrogenase (SDH), which involves in
the respiration chain and Krebs cycle and catalyzes the oxidation
of succinate to fumarate in the mitochondrial matrix, has been
definitely recognized as one of the most important molecular
In this work, we reserved the carbohydrazide motif and incorpo-
rated the 1,2,3-triazole scaffold to the target compounds (Figure 1)
to explore new SDHIs with prospective antifungal effects both in
vitro and In vivo. Meanwhile, the broadened bioactive potentials
against plant pathogenic bacteria were also screened.
[
14-18]
targets in the development of new fungicides.
Since the first
[
19]
commercial SDHI carboxin was launched in 1966, a total of Results and Discussion
twenty-three SDHI fungicides have been created with broad fun-
gicidal spectrum and promising market prospects.
[
20-23]
Careful
Chemistry. The synthesis of 1,2,3-triazole-tailored benzoic hy-
drazide derivatives 5a—5n was executed by four steps and illus-
trated in Figure 2. Initially, intermediate 4 was prepared by step-
wise substitution reaction, click cyclization reaction, and hydroly-
sis reaction, which was then reacted with substituted phenylhy-
drazines under the classical condensating agent to afford the tar-
get compounds, which were confirmed by NMR, HRMS, and the
crystal structure of compound 5m (Figure 3 and Table 1). As a
comparison for the bioactivity, compounds 5o—5s bearing the
amide bond were also constructed.
observation found that these structures include a conserved am-
ide moiety (−CO-NH−) as the linker to combine substituted benzo-
ic/pyrazol/pyridyl/pyrazinyl/furyl acids and most substituted ani-
line/thiophenine/pyridinamine, and naturally leading to a rela-
[
24-25]
tively monotonous molecular skeleton.
Thereby, resistance is
rapidly emerged and developed, and more than ten kinds of
pathogens were reported to have high resistance to SDHIs.
solve this problem, novel SDHIs bearing multifarious frameworks
must be explored. Consequently, extensive works for the design of
[
26-27]
To
Figure 1 Commercial drugs and bioactive compounds containing the 1,2,3-triazole moiety and design strategy for title compounds.
1320
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© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2021, 39, 1319—1330

Benzoic Hydrazide or Amide Derivatives as Potential SDH Inhibitors
Chin. J. Chem.
Figure 2 Synthetic route for title compounds 5a—5s.
In vitro antifungal activity. Antifungal screening against B. d.,
R. s., C. g. and G. z. was carried out by the classical mycelium
growth rate method, and Azoxystrobin (AS), Boscalid (BS) and
Fluopyram (FP) were used as the positive agrochemicals. The pre-
liminary screening result at 50 µg/mL (Table 2) demonstrated that
compounds 5a (-H), 5e (4-F), 5h (4-Cl), 5j (4-Br), and 5k (4-OCF
were bioactive against B. d. with the inhibitory rates within
7.5%—77.9%, which were comparative to AS (77.3%) and FP
67.9%), and superior to BS (55.8%); compounds 5h (4-Cl), 5j
3
)
6
(
Figure 3 X-ray crystal structure of target compound 5m.
Table 1 Crystal data and structural refinement parameters of 5m
(4-Br), 5k (4-OCF ), and 5l (4-CN) presented good anti-R. s. activity
3
with the values of 62.2%—70.2%, which were better than AS
(37.5%) and FP (18.2%), but lower than BS (83.6%); compounds 5a
(
3
-H), 5b (3-OCH ), 5g (3-Cl), and 5i (3,4-diCl) displayed a moderate
Compound
Formula
CCDC number
Crystal system
Space group
a/Å
b/Å
c/Å
α/(°)
β/(°)
5m
anti-C. g. activity with inhibitory values within 50.8%—58.3%,
which were similar with that of AS (59.8%), but quite lower than
BS (94.2%) and FP (94.8%); compound 5e afforded an excellent
anti-G. z. activity with the rate of 92.6%, which was quite better
than AS (65.7%), BS (26.4%), and FP (74.2%). The EC50 values of
bioactive compounds were determined and filled in Table 3.
23 3 5
C H17ClF N O
2055076
Monoclinic
P2(1)/n
11.0683(9)
17.3757(13)
11.3045(9)
90.00
97.739(10)
90.00
2154.3(3)
4
1.455
3
Clearly, compounds 5h (4-Cl), 5j (4-Br), 5k (4-OCF ), and 5l (4-CN)
provided the EC50 values of 2.95, 3.55, 1.55, and 3.87 µg/mL
against R. s., respectively, which were lower than that of BS (1.01
µg/mL). The EC50 of compound 5e (4-F) against G. z. could reach
0.306 µg/mL, which was quite better than FP (3.47 µg/mL). Mean-
γ/(°)
3
V/Å
3
while, compounds 5e (4-F), 5h (4-Cl), 5j (4-Br) and 5k (4-OCF )
Z
displayed excellent activities against B. d. with EC50 of 0.404, 0.526,
1.09, and 1.03 µg/mL, respectively, which exceeded those of com-
mercial agents AS (2.30 µg/mL) and FP (24.1 µg/mL). To visualize
the inhibitory effect, the mycelium growth maps of B. d. on agar
medium triggered by compound 5e (0.404 μg/mL) was presented
in Figure 4. Distinctly, the hypha growth and extension of B. d. was
dramatically restricted with enhancing the concentration of com-
pound 5e, indicating that the designed compounds were en-
dowed with perceptible antifungal competency. By contrast,
compounds 5o—5p bearing an amide bond yielded insignificant
−
3
Calculated density/(g·cm )
F (000)
Reflections
collected/unique
Goodness-of-fit on F
968
10672/3798
[R(int) = 0.0457]
1.020
2
Final R indices
R
1
= 0.0508
wR = 0.1136
2
= 0.1131, wR = 0.1362
[
I >2σ(I)]
2
R indices (all data)
R
1
Chin. J. Chem. 2021, 39, 1319—1330
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Ding et al.
Table 2 Antifungal activities of compounds 5a—5s against pathogens B. d., R. s., C. g., and G. z. in vitro at 50.0 µg/mL
Inhibition rate/%
No.
B. d.
R. s.
31.0 ± 1.2
27.0 ± 1.2
44.3 ± 2.0
49.6 ± 1.2
0
C. g.
43.1 ± 2.5
39.4 ± 0.0
58.3 ± 1.2
53.5 ± 5.7
12.5 ± 1.0
27.3 ± 0.1
0
12.5 ± 1.8
50.8 ± 2.0
49.2 ± 1.5
57.6 ± 0.1
48.2 ± 1.2
48.2 ± 2.3
21.2 ± 0.1
0
G. z.
0
0
67.6 ± 0.3
35.2 ± 1.2
0
3
4
56.8 ± 1.5
48.8 ± 0.7
70.5 ± 1.9
43.4 ± 1.0
14.8 ± 0.1
56.0 ± 0.7
77.9 ± 1.0
22.1 ± 1.7
35.0 ± 1.0
70.5 ± 1.8
0
67.5 ± 0.6
73.8 ± 0.1
36.9 ± 6.0
21.9 ± 1.6
12.6 ± 0.4
0
5a
5b
5c
5
5
d
e
28.4 ± 0.1
0
0
92.6 ± 0.2
36.1 ± 1.6
53.4 ± 0.5
39.8 ± 0.2
39.8 ± 0.2
57.4 ± 0.8
29.6 ± 0.6
43.7 ± 1.4
9.26 ± 0.17
0
5f
10.5 ± 0.1
28.2 ± 0.1
70.2 ± 0.1
47.6 ± 4.3
68.2 ± 0.1
69.2 ± 1.1
62.2 ± 0.1
0
5g
5h
5i
5j
5k
5l
5m
5
5
5
5
n
o
p
q
16.4 ± 0.0
0
0
0
0
0
0
0
0
29.0 ± 1.2
0
56.9 ± 1.2
0
37.0 ± 2.2
0
56.2 ± 5.3
0
5r
5
s
58.5 ± 1.9
77.3 ± 0.8
55.8 ± 0.4
67.9 ± 0.4
11.7 ± 1.2
37.5 ± 0.9
83.6 ± 1.0
18.2 ± 0.5
42.1 ± 3.2
59.8 ± 0.8
94.2 ± 0.8
94.8 ± 0.5
26.2 ± 0.9
65.7 ± 3.0
26.4 ± 2.5
74.2 ± 3.8
AS
BS
FP
Table 3 EC50 values of target compounds 5a, 5e, 5h, 5j and 5k against
tested fungi in vitro
‒1
No.
Pathogens
Toxic regression equation
EC50/(µg·mL )
5
5
5
a
e
h
B. d.
G. z.
B. d.
G. z.
B. d.
R. s.
B. d.
R. s.
B. d.
R. s.
R. s.
B. d.
R. s.
B. d.
G. z.
y = 0.523x + 4.626
y = 1.597x + 3.402
y = 1.944x + 5.766
y = 0.836x + 5.430
y = 0.827x + 5.231
y = 0.511x + 4.760
y = 1.356x + 4.952
y = 0.523x + 4.713
y = 1.501x + 4.984
y = 1.410x + 4.732
y = 0.345x + 4.797
y = 0.367x + 4.867
y = 1.760x + 4.920
y = 0.439x + 4.394
y = 0.345x + 4.813
5.19 ± 0.07
10.0 ± 0.78
0.404 ± 0.005
0.306 ± 0.174
0.526 ± 0.037
2.95 ± 0.13
1.09 ± 0.02
3.55 ± 0.41
1.03 ± 0.01
1.55 ± 0.04
3.87 ± 0.22
2.30 ± 0.06
1.01 ± 0.03
24.1 ± 0.9
5
j
5
k
5
l
AS
BS
FP
Figure 4 The mycelium growth and extension of B. d. after treatment
with different concentrations of compound 5e on the agar medium: CK) 0
μg/mL; a) 4.0 μg/mL; b) 2.0 μg/mL; c) 1.0 μg/mL; d) 0.5 μg/mL; e) 0.25
μg/mL.
3.47 ± 0.65
bioactivity after replacing the hydrazide moiety; while compounds
q and 5s possessing the alkylamine substituents showed moder-
ate inhibition effect against R. s. (56.9%), G. z. (56.2%), and B. d.
minimum EC50 values of 0.404 and 0.306 µg/mL against the cor-
responding fungi B. d. and G. z.; (5) the amide bond significantly
reduces the bioactivity, for instance, 5h (CONHNH, 70.5%, 70.2%,
49.2%, 39.8%) and 5o (CONH, 0), 5j (CONHNH, 67.5%, 68.2%,
48.2%, 57.4%) and 5p (CONH, 0). In general, the fabricated com-
pounds bearing 1,2,3-triazole group could be considered as anti-
fungal leads.
5
(
58.5%), respectively.
The structure-activity relationship (SAR) was proposed based
on the above screening results: (1) the substituent at the 4-posi-
tion is beneficial to antifungal activity, such as 5a (3-Cl, 35.0%) and
5
h (4-Cl, 70.5%) against B. d.; (2) multi-substituents on the ben-
In vivo antifungal activity toward R. s. and G. z. In vivo trial
against rice sheath blight (caused by R. s.) was evaluated by
zene ring can block the inhibitory effect, illustrated by 5i (3,4-diCl,
0
and 47.6%) and 5h (4-Cl, 70.5% and 70.2%) against B. d. and R. s., Shenyang Sinochem Agrochemicals R&D Co., Ltd. (Shenyang, Chi-
respectively, 5f (2,6-diF, 22.1% and 36.1%) and 5e (4-F, 77.9% and
2.6%) against B. d. and G. z., respectively; (3) the type of halogen
showed the order of 4-F (EC50 = 0.404 µg/mL, 5e) > 4-Cl (EC50
.526 µg/mL, 5h) > 4-Br (EC50 = 1.03 µg/mL, 5j) against B. d.; (4)
na), and compounds 5k and 5l with good anti-R. s. effects (69.2%
and 62.2% at 50 µg/mL in vitro, respectively) along with BS and FP
served as the positive drugs were used (Table 4). The result
showed available control effects were afforded for compound 5l
with 75% and 65% at 200 and 100 µg/mL, respectively, which
were comparable to that of FP (85% and 70%). By contrast, com-
9
=
0
introducing the weak electron-withdrawing group promotes the
bioactivity, for example, 4-F (5e) on the benzene ring affords the
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Benzoic Hydrazide or Amide Derivatives as Potential SDH Inhibitors
Chin. J. Chem.
pound 5k gave the lower efficacy (30% and 10%). Moreover, the
bioassay against wheat scab (caused by G. z.) of 5k and 5l was also
evaluated, which displayed good control effects of 65% and 95%
at 200 µg/mL (FP gave the effect of 85%), respectively. As the
dosage decreased to 100 µg/mL, the effectiveness reduced to the
corresponding 40% and 45%. These outcomes suggested the de-
signed compounds could be regarded as antifungal leads for fur-
ther investigations.
Table 5 SDH inhibitory effects of 5l and Boscalid in R. s. strain
‒1
No.
Regression equation
r
IC50/(µg·mL )
5
l
y = 2.743x + 3.363
y = 4.776x + 2.622
0.99
0.99
3.95 ± 0.23
3.15 ± 0.02
Boscalid
to exploit other potential applications, and Bismerthiazol (BT) and
Thiodiazole copper (TC) were used as positive agrochemicals.
Preliminary screening results showed that target compounds af-
forded poor, moderate to good inhibitory effects (Table 6). At the
doses of 100 and 50 µg/mL, compounds 5r and 5s bearing the
corresponding 4-propylmorpholine and N,N-dimethylethanamine
patterns owned the best antibacterial capacity, providing the inhi-
bition rates of 99.4% and 68.1%, 98.6% and 30.0% against Xoo,
8.7% and 80.0%, 97.0% and 89.3% against Xac, and 50.6% and
3.7%, 55.7% and 42.3% against Psa, respectively. This finding
indicated that the flexible alkylamine substituents might benefit
the antibacterial potency. Meanwhile, compounds 5c, 5i, 5j, 5m,
and 5q gave moderate anti-Xac activity with the inhibitory values
within 52.5%—64.0% at 100 µg/mL, while compound 5h bearing a
Molecular docking analysis and inhibitory activity of SDH. To
expound the designed compounds as potential SDHIs, molecular
docking study between SDH (PDB entry: 2FBW) and compounds
5k, 5l, and Boscalid was performed. As displayed in Figure 5,
compounds 5k and 5l, and commercial SDHI Boscalid located in
the same binding pocket of SDH and displayed interactions with
amino acid residues of SDH, indicating that the designed com-
pounds might be potential SDHIs. For compound 5k, the nitrogen
atoms from the hydrazide group formed two hydrogen bonds with
the key residue Ser39 with the bond lengths of 2.8 and 3.2 Å,
respectively (Figure 5A). In comparison, two nitrogen atoms from
8
4
1
,2,3,-triazole motif of compound 5l yielded strong hydrogen
bonds with the residues Trp173 (bond lengths 3.1 and 3.3 Å) and
Tyr58 (bond lengths 3.1 and 3.0 Å) of SDH (Figure 5B), suggesting
that 1,2,3,-triazole group could be considered as a functional tool
to promote the interactions targeting SDH. Additionally, the
4
-methylsulfonyl group showed certain anti-Psa activity with the
rate of 54.1% at 100 µg/mL. Subsequently, the EC50 values of
highly bioactive molecules 5r and 5s were further screened and
presented values of 28.2 and 60.7 µg/mL against Xoo and 34.4
and 17.9 µg/mL against Xac, respectively, which were comparable
to the commercial agents BT and TC (Table 7).
In vivo antibacterial activity toward rice bacterial blight. In
vivo antibacterial activity of compounds 5r and 5s against rice
bacterial blight (caused by Xoo) was performed (Table 8 and
Figure 6). Interestingly, although the in vitro activity of 5s was
weaker than that of 5r, compound 5s showed excellent in vivo
bactericidal activity in potted rice with curative and protective
activities of 51.05% and 49.25%, respectively. This effect was bet-
ter than those of compound 5r (42.48% and 46.99%), BT (37.40%
and 40.79%), and TC (32.33% and 39.09%), demonstrating that
the amide series compounds could be regarded as antibacterial
leads.
4
-cyanophenyl moiety of compound 5l formed an extra π−π
stacking interaction with the residue Trp-32, deeply promoting the
interactions with SDH. For the commercial SDHI Boscalid, two
hydrogen bonds between the carbonyl group and Trp173 (bond
length 3.0 Å) and Tyr58 (bond length 3.1 Å) and one hydrogen
bond between the nitrogen atom of pyridinyl group and Ser39
(bond length 2.9 Å) were observed (Figure 5C). This outcome in-
dicated that compound 5l afforded more similarity with that of
Boscalid in the binding mode with SDH, which was in agreement
with the in vivo bioassay result that compound 5l was more bioac-
tive than that of compound 5k. Furthermore, the SDH enzymatic
activity in R. s. strain was obviously suppressed by compound 5l
with the IC50 value of 3.95 µg/mL (For the Boscalid, IC50 = 3.15
µg/mL, Table 5), confirming that title compounds could act as the
potential SDHIs.
Conclusions
In vitro antibacterial activity. The antibacterial activities of
compounds 5a—5s towards Xoo, Xac, and Psa were also evaluated
In conclusion, a type of benzoic hydrazide or amide deriva-
tives containing a valuable 1,2,3-triazole motif was developed and
biologically screened against plant pathogens. Antifungal bioas-
says indicated that target compounds were extremely bioactive
against the notorious strains B. d., G. z., and R. s. with the minimal
EC50 values of 0.404, 0.306, and 1.55 μg/mL, respectively. In vivo
assays confirmed that compound 5l was effective for the control
of rice sheath blight and wheat scab with the corresponding effi-
ciencies of 75% and 95%. The subsequent molecular docking
studies showed that the five-membered 1,2,3,-triazole ring of 5l
could form strong hydrogen bonds with the amino acid residues
Table 4 Control effects of 5k and 5l against rice sheath blight and wheat
scab in vivo
Control effect/%
No.
Rice sheath blight
Wheat scab
100 µg/mL
200 µg/mL
100 µg/mL
200 µg/mL
5
5
BS
FP
k
l
10
65
100
70
30
75
100
85
40
45
10
80
65
95
15
85
Figure 5 Molecular docking and binding sites of compounds 5k (A), 5l (B), and Boscalid (C) with SDH (PDB entry: 2FBW).
Chin. J. Chem. 2021, 39, 1319—1330
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Comprehensive Report
Ding et al.
Figure 6 Control effects of 5r, 5s, BT, and TC against rice bacterial blight under greenhouse conditions at 200 μg/mL.
Table 6 Preliminary inhibitory effects of target compounds 5a—5s against Xoo, Xac, and Psa
Xoo, Inhibition/% Xac, Inhibition/% Psa, Inhibition/%
100 µg/mL 50 µg/mL
No.
100 µg/mL
50 µg/mL
100 µg/mL
50 µg/mL
3
4
28.3 ± 5.0
26.6 ± 5.0
34.8 ± 2.7
39.6 ± 4.8
27.6 ± 1.7
38.3 ± 8.1
19.4 ± 6.1
12.5 ± 1.8
19.3 ± 1.5
17.0 ± 4.6
14.4 ± 5.6
30.9 ± 3.6
18.4 ± 2.2
16.9 ± 5.2
9.66 ± 1.2
0
52.8 ± 4.1
35.9 ± 2.5
39.6 ± 5.2
44.1 ± 5.8
53.6 ± 0.9
39.0 ± 4.8
34.9 ± 3.8
45.8 ± 5.6
24.6 ± 1.1
26.2 ± 1.1
26.8 ± 3.9
33.8 ± 3.3
34.2 ± 4.0
24.8 ±3.4
22.0 ± 3.4
36.6 ± 6.6
23.0 ± 0.7
16.0 ± 1.0
34.6 ± 4.4
45.4 ± 3.0
47.5 ± 3.7
43.9 ± 3.9
41.0 ± 3.7
30.5 ± 9.7
17.2 ± 1.4
0
5a
13.4 ± 4.3
32.6 ± 1.5
31.8 ± 7.1
17.6 ± 5.5
29.4 ± 6.8
22.2 ± 2.7
5b
5c
5
5
d
e
5f
38.7 ± 6.6
5g
28.4 ± 3.7
47.0 ± 5.7
30.6 ± 6.5
31.5 ± 0.4
25.4 ± 6.4
5
5
5
5
h
i
j
k
29.0 ± 4.1
22.6 ± 4.1
40.6 ± 4.4
47.8 ± 2.1
17.4 ± 4.4
37.8 ± 1.7
17.5 ± 1.3
39.8 ± 1.1
24.5 ± 4.5
44.9 ± 1.8
99.4 ± 0.4
98.6 ± 0.5
51.0 ± 2.1
100 ± 1.2
20.1 ± 2.5
15.7 ± 7.8
27.3 ± 1.5
30.2 ± 3.3
12.1 ± 2.9
20.6 ± 7.4
0
25.2 ± 0.2
10.9 ± 2.6
22.7 ± 6.8
68.1 ± 9.5
30.0 ± 4.1
38.8 ± 2.3
100 ± 0.4
48.1 ± 2.8
53.7 ± 2.1
55.2 ± 2.6
13.8 ± 1.0
42.4 ± 7.1
52.5 ± 5.2
38.4 ± 4.2
34.7 ± 1.4
27.7 ± 1.9
64.0 ± 6.4
88.7 ± 3.5
97.0 ± 1.7
57.9 ± 2.7
99.8 ± 0.3
39.3 ± 1.1
44.1 ± 5.9
40.6 ± 7.6
0
54.1 ± 0.4
34.2 ± 1.3
42.9 ± 3.0
0
46.0 ± 4.1
20.5 ± 3.5
21.9 ± 2.0
0
5
l
31.3 ± 1.5
41.4 ± 3.4
27.2 ± 4.4
27.6 ± 5.7
13.8 ± 6.2
57.7 ± 2.8
80.0 ± 3.7
89.3 ± 0.8
36.2 ± 0.3
49.5 ± 2.2
25.1 ± 6.5
45.4 ± 3.5
32.2 ± 2.0
26.6 ± 4.3
16.6 ± 3.3
49.5 ± 2.2
50.6 ± 6.8
55.7 ± 4.3
57.3 ± 0.8
24.7 ± 0.2
14.0 ± 4.5
36.0 ± 1.1
12.9 ± 3.4
21.1 ± 7.4
9.56 ± 1.76
39.1 ± 4.5
43.7 ± 3.4
42.3 ± 6.3
46.6 ± 2.0
0
5m
5
5
5
5
n
o
p
q
5
5
TC
BT
r
s
1324
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© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2021, 39, 1319—1330

Benzoic Hydrazide or Amide Derivatives as Potential SDH Inhibitors
Chin. J. Chem.
Table 7 EC50 values of target compounds 5r and 5s against Xoo and Xac in vitro
Xoo
Xac
No.
‒1
‒1
Toxic regression equation
r
EC50/(µg·mL )
28.2 ± 0.1
Toxic regression equation
r
EC50/(µg·mL )
5r
y = 5.930x‒3.602
0.99
y = 1.485x + 2.718
0.99
34.4 ± 1.3
17.9 ± 0.2
67.0 ± 0.5
50.5 ± 2.1
5
s
y = 6.331x‒6.289
y = 4.105x‒2.740
y = 5.069x‒2.625
0.99
1
60.7 ± 0.8
76.8 ± 2.2
31.9 ± 3.6
y = 2.235x + 2.200
y = 1.706x + 1.885
y = 1.893x + 1.776
1
TC
BT
0.97
0.98
0.93
Table 8 In vivo control effects of 5r and 5s against rice bacterial blight at 200 μg/mL
Curative activity (14 days after spraying) Protective activity (14 days after spraying)
No.
b
b
Morbidity/%
100
Disease index/%
Control efficiency /%
Morbidity/%
Disease index/%
Control efficiency /%
5r
48.57
41.33
52.86
57.14
84.44
42.48B
51.05A
37.40B
32.33B
—
100
100
100
100
100
44.76
42.86
50.00
51.43
84.44
46.99A
49.25A
40.79B
39.09B
—
5s
100
100
100
100
BT
TC
a
CK
a
b
Negative control. Statistical analysis was conducted via the ANOVA method under a condition of equal variances assumed (P > 0.05) and equal vari-
ances not assumed (P < 0.05). Different uppercase letters indicate the values of control efficiency with significant difference among different treatment
groups at P < 0.05.
Trp173 and Tyr58 of SDH, which yielded the similar binding sites
with the commercial SDHI Boscalid, suggesting the designed
compounds were potential SDHIs, consequently validated by the
highly restrained SDH activity (IC50 = 3.95 µg/mL, 5l). Antibacterial
results manifested that the amide series compounds 5r and 5s
could not only significantly suppress the growth of Xoo and Xac in
vitro, but also display appreciable in vivo efficacy against rice bac-
terial blight disease. This study could support some of the hydra-
zide series compounds as the potential SDHIs and the amide se-
ries compounds as the antibacterial leads.
cated that the combination of 5l with SDH was superior to that of
5k, and the hydrogen bonds formed were nearly consistent with
that of Boscalid.
SDH inhibitory assay
The SDH enzyme activity affected by 5l was determined by
spectrophotometer using the SDH Activity Detection Kit (Solabio,
BC0955). R. s. was treated by compound 5l with different concen-
trations and grew in potato dextrose medium on a constant
temperature shaker (180 r/min, 28 °C) for two weeks, while
Boscalid and DMSO were used as the controls at the same
conditions. The fungal hyphae was collected by vacuum filtration,
then washed with water and PBS (10 mmol/L, pH 7.2) 2—3 times,
respectively, and stored in an refrigerator under ‒80 °C after
freeze-drying. After that, the samples were ground in a tissue
grinder and then subjected to SDH enzyme activity test by using
the Assay Kit.
Experimental
Instruments
Using the DMSO-d or CDCl as the solvent, and TMS as the
6 3
1
13
internal standard, H NMR and C NMR spectra were generated
from the Varian Mercury 500 MHz or a Bruker Biospin AG-400
spectrometer. The mass spectra were analyzed by Agilent mass
spectrometer. The melting points were measured by the SGW®
X-4B, Shanghai Yidian Physical Optical Instrument Co., Ltd.
Antibacterial activity assay
The experimental procedures of in vitro and in vivo antibacte-
rial bioassays were performed by our previously reported meth-
[
65-67]
Antifungal activity assay
ods.
Compared with the commercially available SDHIs Azoxystrobin,
Boscalid and Fluxapyroxad, the synthesized compounds were
screened for their antifungal activities in vitro against B. d., R. s., C.
g., G. z. following our previously reported method. The in vivo
fungicidal activities of the synthesized compounds against R. s.
and G. z. were carried out by Shenyang Sinochem Agrochemicals
R&D Co. Ltd.
Synthetic procedure and characterization data
Synthesis of intermediate 2 (methyl 4-(azidomethyl)ben-
zoate). Sodium azide (7.10 g, 0.11 mol), methyl 4-(bromomethyl)-
benzoate (5.00 g, 21.83 mmol) and N,N-dimethylformamide (DMF,
[
62]
1
4 mL) were added into a 25 mL round-bottom flask. Then the
o
mixture system was reacted at 60 C for 4 h. After that, the mix-
ture was added with 60 mL ethyl acetate. The organic layer was
Molecular docking study towards SDH
washed with saturated NH Cl, water, dried with anhydrous sodium
4
All reported SDHs are highly reserved in their spatial structure,
subunit and electron transport pathway, as well as the ubiquinone
binding site in the prokaryotes and eukaryotes. For these reasons,
avian (Gallus gallus) respiratory complex II with carboxin bound
sulfate, filtered, followed by the removal of the solvent under
vacuum. The residue was further purified by column chro-
matography on a silica gel using petroleum ether and ethyl ace-
tate (12 : 1, V/V) as the eluent to afford the intermediate 2, a
white solid, yield 98.8%.
Synthesis of intermediate 3 (methyl 4-((4-(2-chlorophenyl)-
1H-1,2,3-triazol-1-yl)methyl)benzoate). Intermediate 2 (4.00 g,
20.92 mmol) and 1-chloro-2-ethynylbenzene (2.60 g, 19.02 mmol)
were dissolved in 10 mL dry THF, then 10 mL water was added.
(
PDB code: 2FBW) was chosen for the molecular docking
[33,63]
study.
The 3D structures of the title compounds (5k and 5l)
with good antifungal activity and positive control Boscalid were
constructed by Sybyl X 2.0. Molecular docking studies were also
performed using the Sybyl X 2.0. All the water molecules and lig-
and were eliminated from this crystal complex protein and the
4 2
Then CuSO ·5H O (0.48 g, 1.90 mmol) and sodium ascorbate (0.75
[
28,64]
polar hydrogens were added to the protein.
The results indi-
g, 3.80 mmol) were firstly dissolved in water (8.0 mL) and added
Chin. J. Chem. 2021, 39, 1319—1330
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de
1325

Comprehensive Report
Ding et al.
1
into the above reaction system. The mixture was stirred for 14 h
at room temperature. After that, the mixture was added with 60
mL ethyl acetate. The organic layer was washed with water, brine,
dried with sodium sulfate, filtered, followed by removal of the
solvent under vacuum. The residue was further purified by
column chromatography on a silica gel using petroleum ether and
ethyl acetate (20 : 1, V/V) as the eluent to afford the intermediate
m.p. 134.0—134.6 °C . H NMR (400 MHz, DMSO-d
6
) δ: 10.37 (d,
J = 2.9 Hz, 1H, CONH), 8.84 (s, 1H, triazole-H), 8.09 (dd, J = 7.8,
1.8 Hz, 1H, 2-Cl-phenyl-H), 7.98–7.92 (m, 2H, CO-benzene-H), 7.91
(s, 1H, CONHNH), 7.58 (dd, J = 7.9, 1.3 Hz, 1H, 2-Cl-phenyl-H),
7.51—7.47 (m, 2H, CO-benzene-H), 7.45 (dd, J = 7.7, 1.4 Hz, 1H,
2-Cl-phenyl-H),7.42—7.33 (m, 1H, 2-Cl-phenyl-H), 7.04 (t, J = 8.0
Hz, 1H, 3-OCH
3
-phenyl-H), 6.37 (dd, J = 7.7, 1.6 Hz, 1H, 3-OCH
-phenyl-H), 5.79 (s, 2H, CH
). C NMR (101 MHz, DMSO-d ) δ: 166.0, 160.1,
3
-
2
),
3
.
phenyl-H), 6.34—6.26 (m, 2H, 3-OCH
3
1
3
Methyl 4-((4-(2-chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-
benxzoate (3). A white solid, yield 99.4%; m. p. 209.1—209.5 °C.
3.66 (s, 3H, OCH
3
6
151.0, 142.9, 139.6, 132.8, 130.4, 130.3, 129.7, 129.6, 129.5,
129.1, 128.0, 127.8, 127.6, 124.7, 105.1, 104.1, 98.2, 54.8, 52.5.
HRMS (ESI) [M‒H] calcd for C23
1
H NMR (500 MHz, CDCl
phenyl-H), 8.15 (s, 1H, triazole-H), 8.03–8.00 (m, 2H, benzene-H),
.40 (dd, J = 8.0, 1.3 Hz, 1H, 2-Cl-phenyl-H), 7.36—7.33 (m, 2H,
benzene-H), 7.33—7.31 (m, 1H, 2-Cl-phenyl-H), 7.24 (ddd, J = 9.1,
3
) δ: 8.23 (dd, J = 7.9, 1.7 Hz, 1H, 2-Cl-
‒
H
19
O
2
N
5
Cl: 432.1222, found:
7
432.1230.
4-((4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-N'-(m-
6
2
), 3.89 (s, 3H, CH
3
);
1
3
1
1
30.4, 130.3, 129.8, 129.2, 129.1, 127.8, 127.3, 123.4, 53.8, 52.4.
Synthesis of intermediate 4 (4-((4-(2-chlorophenyl)-1H-1,2,3-
CONH), 8.84 (s, 1H, triazole-H), 8.10 (dd, J = 7.8, 1.8 Hz, 1H,
2-Cl-phenyl-H), 7.93 (d, J = 8.3 Hz, 2H, CO-benzene-H), 7.85 (s, 1H,
CONHNH), 7.58 (dd, J = 7.9, 1.3 Hz, 1H, 2-Cl-phenyl-H), 7.49 (d, J =
8.3 Hz, 2H, CO-benzene-H), 7.45 (dd, J = 7.7, 1.4 Hz, 1H, 2-Cl-
phenyl-H), 7.42—7.35 (m, 1H, 2-Cl-phenyl-H), 7.02 (t, J = 7.8 Hz,
triazol-1-yl)methyl)benzoic acid). Intermediate 3 (4.30 g, 13.12
mmol) dissolved in 20 mL dry THF and KOH (1.10 g, 19.68 mmol)
dissolved in water (20.0 mL) were separately added into the reac-
tion bottle. The mixture was heated to 60 °C for 10 h. After that,
the solvent was removed under vacuum, followed by adding a
small amount of water. The pH of the solution was adjusted to
1H, 3-CH
3
-phenyl-H), 6.58 (d, J = 7.6 Hz, 2H, 3-CH
-phenyl-H), 5.79 (s, 2H, CH
). C NMR (101 MHz, DMSO-d ) δ: 165.9, 149.59, 142.9,
3
-phenyl-H), 6.53
(d, J = 7.6 Hz, 1H, 3-CH
3
2
), 2.19 (s, 3H,
1
3
CH
3
6
3
—4 with dilute hydrochloric acid. Then the system was cooled in
139.59, 137.9, 132.9, 130.4, 130.3, 129.6, 129.5, 129.1, 128.7,
an ice bath for 30 min and subsequently resulted in the formation
of abundant white precipitates. Finally, the precipitates were
filtered and dried to afford the desired product 4.
128.0, 127.9, 127.6, 124.7, 119.6, 112.9, 109.7, 52.6, 21.3. HRMS
‒
(ESI) [M‒H] calcd for C23
H19ON
5
Cl: 416.1273, found: 416.1284.
N'-(4-(tert-Butyl)phenyl)-4-((4-(2-chlorophenyl)-1H-1,2,3-tri-
4
-((4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)benzoic
azol-1-yl)methyl)benzohydrazide (5d). A white solid, yield: 46.7%,
1
1
acid (4). A white solid, yield: 93.4%, m.p. 208.5—209.1 °C. H
NMR (400 MHz, DMSO-d ) δ: 13.04 (s, 1H, COOH), 8.82 (s, 1H,
triazole-H), 8.09 (dd, J = 7.8, 1.8 Hz, 1H, 2-Cl-phenyl-H), 7.96 (d, J =
.3 Hz, 2H, benzene-H), 7.56 (dd, J = 7.9, 1.3 Hz, 1H, 2-Cl-phenyl-
H), 7.48—7.44 (m, 2H, benzene-H), 7.44 (d, J = 2.5 Hz, 1H, 2-Cl-
phenyl-H), 7.41—7.35 (m, 1H, 2-Cl-phenyl-H), 5.80 (s, 2H, CH
NMR (101 MHz, DMSO-d ) δ: 167.4, 143.3, 141.3, 131.0, 130.8,
30.7, 130.3, 130.0, 129.5, 128.4, 128.0, 125.2, 53.0.
Synthesis of title compound 5a (4-((4-(2-chlorophenyl)-1H-
,2,3-triazol-1-yl)methyl)-N'-phenylbenzohydrazide). Intermedi-
ate 4 (0.20 g, 0.64 mmol), EDCI (0.24 g, 1.27 mmol) and HOBT
0.09 g, 0.64 mmol) were dissolved in 8 mL CH Cl and
triethylamine (0.13 g, 1.27 mmol). Then the reaction was stirred
at room temperature for 10 min, followed by adding phenylhydra-
zine hydrochloride (0.11 g, 0.76 mmol). The mixture was stirred
for another 12—24 h at room temperature. After that, the solvent
was removed under vacuum followed by adding 40 mL ethyl ace-
tate. The organic layer was washed with water, brine, dried with
sodium sulfate, filtered, followed by removal of the solvent under
vacuum. The pure product 5a could be obtained by column
chromatography using petroleum ether and ethyl acetate (1 : 1) as
eluent. The synthesis of 5b—5s was carried out by the same
method for 5a.
m.p. 191.3—191.7 °C . H NMR (400 MHz, DMSO-d
6
) δ: 10.38 (d,
6
J = 2.9 Hz, 1H, CONH), 8.84 (s, 1H, triazole-H), 8.10 (dd, J = 7.8,
1.8 Hz, 1H, 2-Cl-phenyl-H), 7.92 (d, J = 8.3 Hz, 2H, CO-benzene-H),
7.78 (d, J = 2.9 Hz, 1H, CONHNH), 7.58 (dd, J = 7.9, 1.3 Hz, 1H,
2-Cl-phenyl-H), 7.51—7.47 (m, 2H, CO-benzene-H), 7.46 (dd, J =
7.7, 1.4 Hz, 1H, 2-Cl-phenyl-H), 7.43—7.37 (m, 1H, 2-Cl-phenyl-H),
8
1
3
2
); C
6
7.16 (d, J = 8.7 Hz, 2H, 4-C(CH
4-C(CH -phenyl-H), 5.79 (s, 2H, CH
NMR (101 MHz, DMSO-d ) δ: 166.0, 147.2, 142.9, 141.0, 139.5,
3 3
) -phenyl-H), 6.72 (d, J = 8.7 Hz, 2H,
13
1
3
)
3
2 3 3
), 1.21 (s, 9H, 4-C(CH ) ). C
6
1
132.9, 130.4, 130.4, 129.6, 129.5, 129.1, 128.0, 127.8, 127.6,
‒
125.4, 124.7, 112.2, 52.6, 33.7, 31.4. HRMS (ESI) [M‒H] calcd for
(
2
2
C
26
H
25ON
5
Cl: 458.1742, found: 458.1752.
4-((4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-N'-(4-
fluorophenyl)benzohydrazide (5e). A yellow solid, yield: 51.9%,
1
6
m.p. 175.1—175.3 °C . H NMR (400 MHz, DMSO-d ) δ: 10.41 (d,
J = 3.2 Hz, 1H, CONH), 8.83 (s, 1H, triazole-H), 8.09 (dd, J = 7.8,
1.8 Hz, 1H, 2-Cl-phenyl-H), 7.94 (s, 1H, CONHNH), 7.92 (d, J = 2.1
Hz, 2H, CO-benzene-H), 7.58 (dd, J = 7.9, 1.3 Hz, 1H, 2-Cl-phenyl-
H), 7.48 (dd, J = 4.9, 3.5 Hz, 2H, CO-benzene-H), 7.45 (dd, J = 7.7,
1.4 Hz, 1H, 2-Cl-phenyl-H), 7.42—7.36 (m, 1H, 2-Cl-phenyl-H),
7.03—6.94 (m, 2H, 4-F-phenyl-H), 6.82—6.75 (m, 2H, 4-F-phenyl-
1
3
H), 5.79 (s, 2H, CH ). C NMR (101 MHz, DMSO-d ) δ: 166.4, 156.4
2 6
(d, JC-F = 233.4 Hz), 146.5 (d, JC-F = 1.7 Hz), 143.3, 140.0, 133.2,
1
4
4
-((4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-N'-phe-
130.8, 130.7, 130.0, 129.6, 129.3, 128.4, 128.3, 128.1, 125.2,
2
3
19
nylbenzohydrazide (5a). A yellow solid, yield: 86.4%, m.p. 200.2—
00.6 °C. H NMR (400 MHz, DMSO-d
.82 (s, 1H, triazole-H), 8.09 (d, J = 7.7 Hz, 1H, 2-Cl-phenyl-H),
.98—7.89 (m, 3H, CO-benzene-H & CONHNH), 7.58 (d, J = 7.9 Hz,
H, 2-Cl-phenyl-H), 7.49 (d, J = 6.6 Hz, 2H, CO-benzene-H), 7.45 (d,
J = 7.7 Hz, 1H, 2-Cl-phenyl-H), 7.39 (t, J = 7.6 Hz, 1H, 2-Cl-phenyl-
H), 7.14 (t, J = 7.7 Hz, 2H, benzene-H), 6.78 (d, J = 7.2 Hz, 2H,
115.7 (d, JC-F = 22.3 Hz), 114.0 (d, JC-F = 7.6 Hz), 53.0. F NMR
1
‒
2
8
7
1
6
) δ: 10.37 (s, 1H, CONH),
(377 MHz, DMSO-d
ClF: 420.1022, found: 420.1031.
4-((4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-N'-(2-
fluoro-6-methylphenyl)benzohydrazide (5f). A white solid, yield:
6
) δ: ‒126.35. HRMS (ESI) [M‒H] calcd for
22 5
C H16ON
1
6
87.4%, m.p. 194.5—195.2 °C . H NMR (400 MHz, DMSO-d ) δ:
10.48 (d, J = 1.7 Hz, 1H, CONH), 8.84 (s, 1H, triazole-H), 8.20 (s, 1H,
CONHNH), 8.10 (dd, J = 7.8, 1.8 Hz, 1H, 2-Cl-phenyl-H), 7.95 (d, J =
2
benzene-H), 6.71 (t, J = 7.3 Hz, 1H, benzene-H), 5.79 (s, 2H, CH ).
C NMR (101 MHz, DMSO-d
1
3
6
) δ: 166.4, 149.9, 143.4, 140.0, 133.3, 8.3 Hz, 2H, CO-benzene-H), 7.58 (dd, J = 7.9, 1.3 Hz, 1H, 2-Cl-phe-
1
1
4
30.8, 130.7, 130.0, 129.6, 129.2, 128.4, 128.3, 128.0, 125.2,
19.1, 112.8, 53.0. HRMS (ESI) [M‒H] calcd for C22H17ON Cl:
5
02.1116, found: 402.1125.
nyl-H), 7.53—7.48 (m, 2H, CO-benzene-H), 7.48—7.43 (m, 1H,
2-Cl-phenyl-H), 7.42—7.35 (m, 1H, 2-Cl-phenyl-H), 7.13 (ddd, J =
11.3, 8.8, 5.0 Hz, 1H, 2,6-2F-phenyl-H), 6.61—6.44 (m, 2H, 2,6-2F-
‒
1
3
4
-((4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-N'-(3-
phenyl-H), 5.80 (s, 2H, CH
2
). C NMR (101 MHz, DMSO-d
6
) δ:
1
1
methoxyphenyl)benzohydrazide (5b). A white solid, yield: 42.1%,
166.5, 159.5 (dd, JC-F = 237.5, 1.2 Hz), 146.7 (dd, JC-F = 235.1, 2.0
1326
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© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2021, 39, 1319—1330

Benzoic Hydrazide or Amide Derivatives as Potential SDH Inhibitors
Chin. J. Chem.
3
Hz), 143.3, 140.2, 139.1 (dd, JC-F =13.0, 10.8 Hz), 132.9, 130.8,
1
30.7, 130.0, 130.0, 129.6, 128.5, 128.4, 128.1, 125.2, 116.3 (dd,
C-F = 20.3, 10.3 Hz), 104.3 (dd, JC-F = 24.4, 7.2 Hz ), 100.6 (dd,
C-F = 28.9, 3.8 Hz), 53.0. F NMR (376 MHz, DMSO-d
138.4. HRMS (ESI) [M‒H] calcd for C22
found: 438.0938.
N'-(3-Chlorophenyl)-4-((4-(2-chlorophenyl)-1H-1,2,3-triazol-
-yl)methyl)benzohydrazide (5g). A yellow solid, yield: 67.0%, m.p. calcd for C23
2
2
J
J
2
19
6
) δ: ‒117.9,
: 438.0928,
‒
‒
H15ON
5
ClF
2
1
1
1
95.2—195.7 °C . H NMR (400 MHz, DMSO-d
6
) δ: 10.44 (d, J = 2.5
Hz, 1H, CONH), 8.83 (s, 1H, triazole-H), 8.25 (d, J = 2.5 Hz, 1H,
CONHNH), 8.09 (dd, J = 7.8, 1.8 Hz, 1H, 2-Cl-phenyl-H), 7.94 (d, J =
cyanophenyl)benzohydrazide (5l). A white solid, yield: 93.2%, m.p.
1
114.3—114.6 °C . H NMR (400 MHz, DMSO-d
6
) δ: 10.55 (s, 1H,
8
.3 Hz, 2H, CO-benzene-H), 7.58 (dd, J = 7.9, 1.3 Hz, 1H, 2-Cl-phe-
CONH), 8.84 (s, 2H, triazole-H & CONHNH), 8.09 (dd, J = 7.8, 1.8
Hz, 1H, 2-Cl-phenyl-H), 7.94 (d, J = 8.3 Hz, 2H, CO-benzene-H),
7.59—7.57 (m, 1H, 2-Cl-phenyl-H), 7.55 (dd, J = 5.7, 3.9 Hz, 2H,
4-CN-phenyl-H), 7.50 (d, J = 8.4 Hz, 2H, CO-benzene-H), 7.46 (td,
J = 7.6, 1.4 Hz, 1H, 2-Cl-phenyl-H), 7.43—7.36 (m, 1H, 2-Cl-phe-
nyl-H), 7.49 (d, J = 8.4 Hz, 2H, CO-benzene-H), 7.45 (dd, J = 7.6, 1.4
Hz, 1H, 2-Cl-phenyl-H), 7.42—7.36 (m, 1H, 2-Cl-phenyl-H), 7.16 (t,
J = 8.0 Hz, 1H, 3-Cl-phenyl-H), 6.77—6.73 (m, 2H, 3-Cl-phenyl-H),
1
3
6
.72 (t, J = 1.9 Hz, 1H, 3-Cl-phenyl-H), 5.80 (s, 2H, CH
2
). C NMR
1
3
(
101 MHz, DMSO-d ) δ: 166.4, 151.5, 143.3, 140.2, 134.0, 133.0,
6
nyl-H), 6.88—6.73 (m, 2H, 4-CN-phenyl-H), 5.80 (s, 2H, CH
2
).
C
1
1
C
30.9, 130.8, 130.7, 130.0, 129.6, 128.5, 128.4, 128.1, 125.2,
18.6, 112.0, 111.4, 53.0. HRMS (ESI) [M‒H] calcd for
NMR (101 MHz, DMSO-d ) δ: 166.0, 153.0, 142.9, 139.9, 133.5,
6
‒
132.3, 130.4, 130.3, 129.6, 129.5, 129.1, 128.1, 128.0, 127.6,
‒
22
H
4
16ON
5
Cl
-((4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-N'-(4-
cyanophenyl)benzohydrazide (5h). A white solid, yield: 80.1%,
2
: 436.0726, found: 436.0739.
124.7, 120.1, 111.9, 99.1, 52.5. HRMS (ESI) [M‒H] calcd for
C
23
H
16ON
6
Cl: 427.1069, found: 427.1079.
4-((4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-N'-(2-
(trifluoromethyl)phenyl)benzohydrazide (5m). A white solid,
1
m.p. 167.6—168.1 °C . H NMR (500 MHz, DMSO-d
J = 2.8 Hz, 1H, CONH), 8.84 (s, 1H, triazole-H), 8.15 (d, J = 2.8 Hz,
6
) δ: 10.44 (d,
1
6
yield: 51.1%, m.p. 156.1—156.7 °C . H NMR (400 MHz, DMSO-d )
H, CONHNH), 8.09 (dd, J = 7.8, 1.7 Hz, 1H, 2-Cl-phenyl-H),
.97—7.88 (m, 2H, CO-benzene-H), 7.58 (dd, J = 8.0, 1.3 Hz, 1H,
-Cl-phenyl-H), 7.48 (dd, J = 6.1, 4.2 Hz, 2H, CO-benzene-H), 7.45
δ: 10.57 (s, 1H, CONH), 8.83 (s, 1H, triazole-H), 8.10 (dd, J = 7.8,
1.8 Hz, 1H, 2-Cl-phenyl-H), 7.96 (d, J = 8.3 Hz, 2H, CO-benzene-H),
7.71 (s, 1H, CONHNH), 7.58 (dd, J = 7.9, 1.3 Hz, 1H, 2-Cl-phenyl-H),
7.7, 1.4 Hz, 1H, 2-CF
H), 7.39 (dd, J = 7.5, 1.8 Hz, 1H, 2-CF
1H, 2-CF -phenyl-H), 6.88 (t, J = 7.5 Hz, 1H, 2-CF
(s, 2H, CH
140.2, 134.0, 132.9, 130.8, 130.7, 130.0 130.0, 129.6, 128.5, 128.4,
3
-phenyl-H), 7.44—7.41 (m, 1H, 2-Cl-phenyl-
-phenyl-H), 6.97 (d, J = 8.4 Hz,
-phenyl-H), 5.80
2
). C NMR (101 MHz, DMSO) δ: 166.4, 146.8, 143.3,
1
3
)
3
3
3
1
3
3
1
128.1, 126.6 ( JC-F = 5.4 Hz), 125.2, 125.1 ( JC-F = 273.7 Hz), 118.8,
2 19
113.5, 112.4 ( JC-F = 31.0 Hz), 53.0. F NMR (376 MHz, DMSO-d
6
) δ:
‒
‒60.7. HRMS (ESI) [M‒H] calcd for C23H16ON ClF : 470.0990,
5 3
found: 470.0999.
4-((4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-N'-(4-
(methylsulfonyl)phenyl)benzohydrazide (5n). A white solid, yield:
1
90.2%, m.p. 125.1—125.8 °C . H NMR (400 MHz, DMSO-d
6
) δ:
10.57 (d, J = 1.5 Hz, 1H, CONH), 8.84 (s, 1H, triazole-H), 8.81 (d, J =
1.3 Hz, 1H, CONHNH), 8.09 (dd, J = 7.8, 1.8 Hz, 1H, 2-Cl-phenyl-H),
7.95 (d, J = 8.3 Hz, 2H, CO-benzene-H), 7.66 (d, J = 8.8 Hz, 2H,
NH-phenyl-H), 7.58 (dd, J = 7.9, 1.3 Hz, 1H, 2-Cl-phenyl-H), 7.51 (d,
J = 8.4 Hz, 2H, CO-benzene-H), 7.46 (td, J = 7.6, 1.4 Hz, 1H, 2-Cl-
phenyl-H), 7.42—7.37 (m, 1H, 2-Cl-phenyl-H), 6.93—6.83 (m, 2H,
13
NH-phenyl-H), 5.80 (s, 2H, CH
MHz, DMSO-d
129.6, 129.6, 129.3, 129.1, 128.8, 128.1, 128.0, 127.6, 124.8,
2
), 3.08 (s, 3H, CH
3
). C NMR (101
6
) δ: 166.0, 153.6, 142.9, 139.9, 132.4, 130.4, 130.3,
‒
480.0892, found: 480.0904.
CONH), 8.83 (s, 1H, triazole-H), 8.15 (s, 1H, CONHNH), 8.09 (dd, J =
.8, 1.8 Hz, 1H, 2-Cl-phenyl-H), 7.92 (d, J = 8.3 Hz, 2H, CO-ben-
zene-H), 7.58 (dd, J = 7.9, 1.3 Hz, 1H, 2-Cl-phenyl-H), 7.51—7.47
m, 2H, CO-benzene-H), 7.45 (dd, J = 7.6, 1.4 Hz, 1H, 2-Cl-phenyl-
N-(4-Chlorophenyl)-4-((4-(2-chlorophenyl)-1H-1,2,3-triazol-1-
7
yl)methyl)benzamide (5o). A white solid, yield: 32.2%, m.p.
1
216.6—217.1 °C . H NMR (400 MHz, DMSO-d
6
) δ: 10.38 (s, 1H,
(
CONH), 8.83 (s, 1H, triazole-H), 8.09 (dd, J = 7.8, 1.8 Hz, 1H,
2-Cl-phenyl-H), 7.95 (d, J = 8.3 Hz, 2H, CO-benzene-H), 7.83—7.76
(m, 2H, 4-Cl-phenyl-H), 7.57 (dd, J = 7.9, 1.3 Hz, 1H, 2-Cl-phenyl-H),
7.51 (d, J = 8.3 Hz, 2H, CO-benzene-H), 7.46 (td, J = 7.6, 1.4 Hz, 1H,
H), 7.42—7.36 (m, 1H, 2-Cl-phenyl-H), 7.33—7.24 (m, 2H, 4-Br-
phenyl-H), 6.78—6.68 (m, 2H, 4-Br-phenyl-H), 5.77 (d, J = 12.8 Hz,
1
3
2
1
1
2 6
H, CH ). C NMR (101 MHz, DMSO-d ) δ: 166.4, 149.3, 143.3,
40.1, 133.1, 131.8, 130.8, 130.7, 130.0, 130.0, 129.6, 128.5,
28.3, 128.1, 125.2, 114.8, 109.9, 53.0. HRMS (ESI) [M+H] calcd
2-Cl-phenyl-H), 7.43—7.37 (m, 3H, 2-Cl-phenyl-H & 4-Cl-phenyl-H),
+
13
5.81 (s, 2H, CH
2
). C NMR (101 MHz, DMSO-d
6
) δ: 165.7, 143.3,
for C22
H
18ON
5
BrCl: 482.0378, found: 482.0374.
-((4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-N'-(4-
trifluoromethoxy)phenyl)benzohydrazide (5k). A white solid,
140.0, 138.5, 135.0, 130.8, 130.7, 130.0, 130.0, 129.6, 129.0,
128.7, 128.4, 128.1, 127.8, 125.2, 122.3, 53.0. HRMS (ESI) [M‒H]
calcd for C22H15ON Cl : 421.0617, found: 421.0629.
4 2
‒
4
(
1
yield: 96.5%, m.p. 161.9—162.6 °C . H NMR (500 MHz, DMSO-d
6
)
N-(4-Bromophenyl)-4-((4-(2-chlorophenyl)-1H-1,2,3-triazol-1-
δ: 10.46 (d, J = 2.7 Hz, 1H, CONH), 8.84 (s, 1H, triazole-H), 8.22 (d,
J = 2.7 Hz, 1H, CONHNH), 8.10 (dd, J = 7.8, 1.7 Hz, 1H, 2-Cl-phenyl-
yl)methyl)benzamide (5p). A light yellow solid, yield: 54.9%, m.p.
1
220.0—220.3 °C . H NMR (400 MHz, DMSO-d
6
) δ: 10.37 (s, 1H,
H), 7.95—7.90 (m, 2H, CO-benzene-H), 7.58 (dd, J = 8.0, 1.3 Hz, 1H, CONH), 8.83 (s, 1H, triazole-H), 8.09 (dd, J = 7.8, 1.8 Hz, 1H, 2-Cl-
Chin. J. Chem. 2021, 39, 1319—1330
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de
1327

Comprehensive Report
Ding et al.
phenyl-H), 7.95 (d, J = 8.4 Hz, 2H, CO-benzene-H), 7.77—7.71 (m,
References
2
7
7
5
1
1
H, 4-Br-phenyl-H), 7.57 (dd, J = 7.9, 1.3 Hz, 1H, 2-Cl-phenyl-H),
.55—7.48 (m, 4H, CO-benzene-H & 4-Br-phenyl-H), 7.46 (td, J =
.6, 1.4 Hz, 1H, 2-Cl-phenyl-H), 7.43—7.36 (m, 1H, 2-Cl-phenyl-H),
.78 (d, J = 18.8 Hz, 2H, CH ). C NMR (101 MHz, DMSO-d ) δ:
2 6
65.7, 143.3, 140.1, 139.0, 135.0, 131.9, 130.8, 130.7, 130.0,
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[
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H17ON
4
BrCl: 467.0269, found: 467.0266.
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1
8
7
5
5
.0, 1.3 Hz, 1H, 2-Cl-phenyl-H), 7.37—7.31 (m, 2H, CO-benzene-H),
.30 (s, 1H, 2-Cl-phenyl-H), 7.27—7.21 (m, 1H, 2-Cl-phenyl-H),
.77 (d, J = 60.9 Hz, 2H, , CH
.11 (m, 4H, CH -CH=CH ), 3.95 (d, J = 124.7 Hz, 4H, CH
C NMR (101 MHz, CDCl ) δ: 171.0, 144.5, 136.6, 136.4, 133.0,
2
-CH=CH
2
), 5.61 (s, 2H, CH
2
2
2
2
-CH=CH
1
3
3
1
1
C
32.5, 131.2, 130.2, 129.7, 129.1, 129.1, 127.8, 127.4, 127.2,
23.4, 117.8, 117.7, 53.7, 50.7, 47.1. HRMS (ESI) [M+H] calcd for
+
[
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suppressing bacterial resistance and eradicating biofilms. New J.
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22
H22ON
4
Cl: 393.1477, found: 393.1466.
-((4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-N-(3-
morpholinopropyl)benzamide (5r). A light yellow solid, yield:
4
1
9
(
7
(
1.0%, m.p. 121.1—121.9 °C . H NMR (400 MHz, CDCl
dd, J = 7.9, 1.7 Hz, 1H, 2-Cl-phenyl-H), 8.15 (s, 1H, triazole-H),
.98 (s, 1H, CONH), 7.82 (d, J = 8.2 Hz, 2H, CO-benzene-H), 7.42
dd, J = 8.0, 1.2 Hz, 1H, 2-Cl-phenyl-H), 7.36 (dd, J = 10.5, 4.6 Hz,
H, 2-Cl-phenyl-H & CO-benzene-H), 7.29—7.23 (m, 1H, 2-Cl-phe-
nyl-H), 5.65 (s, 2H, CH ), 3.72—3.64 (m, 4H, morpholine-H), 3.55
dd, J = 11.5, 5.9 Hz, 2H, CONH-CH ), 2.52 (dd, J = 16.5, 10.4 Hz,
), 1.83—1.74 (m, 2H, CONH-CH CH ).
) δ: 166.6, 144.6, 135.2, 131.2, 130.2,
29.8, 129.2, 129.0, 127.9, 127.8, 127.2, 123.3, 66.9, 58.4, 53.8,
3
) δ: 8.23
[
[
3
2
(
2
6
H, morpholine-H & N-CH
2
2
2
1
3
C NMR (101 MHz, CDCl
3
1
5
4
‒
[10] Li, P.; Tian, P. Y.; Chen, Y. Z.; Song, X. P.; Xue, W.; Jin, L. H.; Hu, D. Y.;
Yang, S.; Song, B. A. Novel bisthioether derivatives containing a
25 2 5
3.7, 40.4, 24.2. HRMS (ESI) [M‒H] calcd for C23H O N Cl:
38.1691, found: 438.1701.
1,3,4-oxadiazole moiety: design, synthesis, antibacterial and nemato-
4
-((4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-N-(2-(di-
cidal activities. Pest Manag. Sci. 2018, 74, 844‒852.
methylamino)ethyl)benzamide (5s). A white solid, yield: 77.9%,
[
[
11] Zhou, J.; Tao, Q. Q.; Wang, P. Y.; Shao, W. B.; Wu, Z. B.; Li, Z.; Yang, S.
Antimicrobial evaluation and action mechanism of pyridinium-dec-
orated 1,4-pentadien-3-one derivatives. Bioorg. Med. Chem. Lett.
1
m.p. 131.2—131.7 °C . H NMR (400 MHz, DMSO-d
triazole-H), 8.41 (t, J = 5.6 Hz, 1H, CONH), 8.08 (dd, J = 7.8, 1.8 Hz,
H, 2-Cl-phenyl-H), 7.84 (d, J = 8.3 Hz, 2H, CO-benzene-H), 7.57
dd, J = 7.9, 1.3 Hz, 1H, 2-Cl-phenyl-H), 7.46 (dd, J = 7.5, 1.4 Hz, 1H,
6
) δ: 8.79 (s, 1H,
1
(
2018, 28, 1742‒1746.
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1879‒1888.
2
7
3
-Cl-phenyl-H), 7.43 (dd, J = 4.9, 3.4 Hz, 2H, CO-benzene-H),
.41—7.36 (m, 1H, 2-Cl-phenyl-H), 5.76 (d, J = 2.0 Hz, 2H, CH ),
.34 (d, J = 6.0 Hz, 2H, CONHCH ), 2.40 (t, J = 6.8 Hz, 2H
). C NMR (101 MHz, DMSO-d ) δ:
2
2
1
3
CONHCH
2
CH
2
), 2.18 (s, 6H, CH
3
6
1
1
66.1, 143.3, 139.4, 134.8, 130.8, 130.7, 123.0, 129.6, 128.2+,
28.1, 128.0, 125.1, 58.6, 53.0, 45.6, 37.8. HRMS (ESI) [M+H]
Cl: 384.1586, found: 384.1576.
[13] Wang, M. W.; Zhu, H. H.; Wang, P. Y.; Zeng, D.; Wu, Y. Y.; Liu, L. W.;
Wu, Z. B.; Li, Z.; Yang, S. Synthesis of Thiazolium-Labeled 1,3,4-Oxadi-
azole Thioethers as Prospective Antimicrobials: In vitro and In vivo
Bioactivity and Mechanism of Action. J. Agric. Food Chem. 2019, 67,
calcd for C20H23ON
5
1
2696‒12708.
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1
13
19
Supplementary materials include H NMR, C NMR, F NMR,
and HRMS spectra of intermediates 2—4, title compounds 5a—5s
(Figures S1 to S65).
[
[
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Acknowledgement
We acknowledge the financial supports of the National Natu-
ral Science Foundation of China (21662009, 21702037, 31860516,
2
1877021), Guizhou Provincial S&T Program ([2017]5788), Fron-
tiers Science Center for Asymmetric Synthesis and Medicinal
Molecules, Department of Education, Guizhou Province [Qi-
anjiaohe KY number (2020)004], Key Technologies R&D Program
(2014BAD23B01), and Program of Introducing Talents of Discipline
to Universities of China (111 Program, D20023).
[18] Xiong, L.; Shen, Y. Q.; Jiang, L. N.; Zhu, X. L.; Yang, W. C.; Huang, W.;
1328
www.cjc.wiley-vch.de
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2021, 39, 1319—1330

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Manuscript received: January 4, 2021
Manuscript revised: January 19, 2021
Manuscript accepted: January 20, 2021
Accepted manuscript online: January 22, 2021
1330
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© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2021, 39, 1319—1330