Antibacterial activities against rice bacterial leaf blight and tomato bacterial wilt of 2-mercapto-5-substituted-1,3,4-oxadiazole/thiadiazole derivatives

Article abstract of DOI:10.1016/j.bmcl.2014.12.038

In this study, a series of 2-mercapto-5-substituted-1,3,4-oxadiazole/thiadiazole derivatives were synthesized and evaluated for their antibacterial activities against rice bacterial leaf blight and tomato bacterial wilt caused by Xanthomonas oryzae pv. oryzae (Xoo) and Ralstonia solanacearum (R. solanacearum) via the turbidimeter test in vitro. Antibacterial bioassays indicated that most compounds demonstrated appreciable antibacterial bioactivities against Xoo and R. solanacearum. Among the title compounds, compound 4i demonstrated the best inhibitory effect against Xoo and R. solanacearum with half-maximal effective concentration (EC₅₀) values of 14.69 and 15.14 μg/mL, respectively, which were even better than those of commercial agents Bismerthiazol and Thiodiazole Copper. In vivo antibacterial activities tests under greenhouse conditions revealed that the control efficiency of compound 4i against rice bacterial leaf blight and tobacco bacterial wilt were better than those of Bismerthiazol and Thiodiazole Copper. Meanwhile, field trials also indicated that compound 4i demonstrated appreciable control efficiency against rice bacterial leaf blight and tomato bacterial wilt.

Full text of DOI:10.1016/j.bmcl.2014.12.038

Bioorganic & Medicinal Chemistry Letters 25 (2015) 481–484
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Antibacterial activities against rice bacterial leaf blight and tomato
bacterial wilt of 2-mercapto-5-substituted-1,3,4-oxadiazole/
thiadiazole derivatives
⇑
Pei Li, Li Shi, Man-Ni Gao, Xia Yang, Wei Xue, Lin-Hong Jin, De-Yu Hu, Bao-An Song
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of
Education, Center for Research and Development of Fine Chemicals, Guizhou University, Guiyang 550025, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, a series of 2-mercapto-5-substituted-1,3,4-oxadiazole/thiadiazole derivatives were synthe-
sized and evaluated for their antibacterial activities against rice bacterial leaf blight and tomato bacterial
wilt caused by Xanthomonas oryzae pv. oryzae (Xoo) and Ralstonia solanacearum (R. solanacearum) via the
turbidimeter test in vitro. Antibacterial bioassays indicated that most compounds demonstrated appre-
ciable antibacterial bioactivities against Xoo and R. solanacearum. Among the title compounds, compound
4i demonstrated the best inhibitory effect against Xoo and R. solanacearum with half-maximal effective
Received 16 September 2014
Revised 28 November 2014
Accepted 12 December 2014
Available online 19 December 2014
Keywords:
Synthesis
Antibacterial activity
Rice bacterial leaf blight
Tomato bacterial wilt
1,3,4-Oxadiazole/thiadiazole
concentration (EC50) values of 14.69 and 15.14 lg/mL, respectively, which were even better than those
of commercial agents Bismerthiazol and Thiodiazole Copper. In vivo antibacterial activities tests under
greenhouse conditions revealed that the control efficiency of compound 4i against rice bacterial leaf
blight and tobacco bacterial wilt were better than those of Bismerthiazol and Thiodiazole Copper. Mean-
while, field trials also indicated that compound 4i demonstrated appreciable control efficiency against
rice bacterial leaf blight and tomato bacterial wilt.
Ó 2014 Elsevier Ltd. All rights reserved.
Bacteria diseases, such as rice bacterial leaf blight and tomato
bacterial wilt caused by pathogen Xanthomonas oryzae pv. oryzae
(Xoo) and Ralstonia solanacearum (R. solanacearum), are extremely
difficult to manage in agricultural production. The high incidence
of plant mortality and the lack of effective control methods make
Xoo and R. solanacearum become two of the world’s most
destructive plant pathogens. Rice bacterial leaf blight is the most
important bacterial disease of rice in the rice growing countries.1
The disease can affect rice plants at any plant growth stages.2
The infection at the maximum tillering stage results in blighting
of leaves. Yield losses of up to 80% due to rice bacterial leaf blight
have been reported.1 Meanwhile, tomato bacterial wilt is devastat-
ing and soil-borne plant disease. The pathogen R. solanacearum,
with a global distribution and an unusually wide host range, is b-
proteobacteria and considered as complex species. It was
discovered to cause fatal wilt diseases first by Smith in 1896 in
many important crops such as potato, tomato, eggplant and
subsequently in 1908 in tobacco.3,4 Currently, available traditional
bactericides are not very effective and can even enhance resistance
in host plants. Pathogenic bacteria are responsible for billions of
dollars of economic losses worldwide each year. Therefore, the
search for new antibacterial agents remains a daunting task in
pesticide science.5
1,3,4-Oxadiazole/thiadiazole, a privileged structure, represent a
key motif in heterocyclic chemistry and attract a lot of interest in
the fields of medicinal chemistry and synthetic study due to their
competence to exhibit a wide range of pharmacological activities,
such as antibacterial,6–8 antifungal,9–13 inflammatory,14 antianxi-
ety15 and antitubercular activities.16 Literature survey revealed
that minor modification in the structure of 1,3,4-oxadiazole/thiadi-
azole can lead to quantitative as well as qualitative changes in the
biological activity.17 In addition, in our previous study, we have
Abbreviations: R. solanacearum, Ralstonia solanacearum; Xoo, Xanthomonas
oryzae pv. oryzae; Xoc, Xanthomonas oryzae pv. oryzicolaby; EC50, half-maximal
effective concentration; 1H NMR, 1H nuclear magnetic resonance; 13C NMR, 13C
nuclear magnetic resonance; MS, mass spectroscopy; ai, active ingredient.
reported
a series of 1,3,4-oxadiazole/thiadiazole derivatives
(Fig. 1), which showed potent antibacterial activities against Xoo,
Xanthomonas oryzae pv. oryzicolaby (Xoc) and R. solanacearum.6–8
Moreover, in the past research, 2-mercapto-5-substituted-1,3,
⇑
Corresponding author. Tel.: +86 (851) 362 0521; fax: +86 (851) 362 2211.
E-mail address: songbaoan22@yahoo.com (B.-A. Song).
http://dx.doi.org/10.1016/j.bmcl.2014.12.038
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

482
P. Li et al. / Bioorg. Med. Chem. Lett. 25 (2015) 481–484
bactericide Bismerthiazol and Thiodiazole Copper. Field trials also
R1
indicated that compound 4i demonstrated appreciable control effi-
ciency against rice bacterial leaf blight and tomato bacterial wilt.
To the best of our knowledge, this is the first report of 2-mer-
capto-5-substituted-1,3,4-oxadiazole/thiadiazole derivatives with
potent effect against rice bacterial leaf blight and tomato bacterial
wilt.
O
O
X
N
O
N
S
S
R1
R2
R2
N
O
N
1a
X=O/S
O
1b
Figure 1. Compounds that were reported against Xoo, Xoc and R. solanacearum.
Compounds 4a to 4p were synthesized, as shown in Scheme 1,
based on previously described methods.4–7 Using benzoic acid and
phenylacetic acid as the starting materials, compounds 4a to 4p
were synthesized in three steps including esterification, hydrazida-
tion and cyclization. The physical characteristics, 1H NMR, 13C
NMR, MS and elemental analysis data for all synthesized com-
pounds are reported in the Supplementary data, and the represen-
tative data for 4i are shown below.
2-Mercapto-5-phenyl-1,3,4-thiadiazole (4i): Light yellow solid;
mp 215–216 °C; yield 82.3%; 1H NMR (500 MHz, DMSO-d6, ppm)
d: 8.12–7.56 (m, 5H, Ar-H), 13.02 (s, 1H, SH); 13C NMR (125 MHz,
DMSO-d6, ppm) d: 184.02, 174.09, 133.53, 130.92, 129.21,
128.73; MS (ESI) m/z: 195.3 ([M+H]+); Anal. Calcd for C8H6N2S2:
C, 49.46; H, 3.11; N, 14.42; Found: C, 49.51; H, 3.15; N, 14.48.
The results of the preliminary bioassays, as indicated in Table 1,
showed that compounds 4f, 4i, 4l, 4m and 4p exhibited significant
inhibition effects against Xoo, and a control efficacy of 100% was
4-oxadiazole/thiadiazole derivatives, due to their simple structure
and good biological activities, had been gotten more attention in
medical field.18–20 However, their agricultural activities were still
not reported so far. With this in view, it prompted us to synthesize
a series of 2-mercapto-5-substituted-1,3,4-oxadiazole/thiadiazole
derivatives derived from benzoic acid and phenylacetic acid and
evaluated for their agricultural activities against rice bacterial leaf
blight and tomato bacterial wilt, respectively.
In our present study, we reported the synthesis of a series of 2-
mercapto-5-substituted-1,3,4-oxadiazole/thiadiazole derivatives
and evaluated for their antibacterial activities in vitro against Xoo
and R. solanacearum by the turbidimeter test.6–8,21 For comparison,
the activities of Bismerthiazol and Thiodiazole Copper were evalu-
ated at the same conditions. Antibacterial bioassays indicated that
most compounds demonstrated appreciable antibacterial bioactiv-
ities against Xoo and R. solanacearum. Among the title compounds,
compound 4i demonstrated the best inhibitory effect against Xoo
observed at 200 and 100 lg/mL, which were even better than those
of Bismerthiazol (72% and 54%, respectively) and Thiodiazole Cop-
per (64% and 43%, respectively). Meanwhile, Table 2 demonstrated
that 4b, 4d, 4f, 4h, 4i, 4m and 4n exhibited significant inhibition
effects of 100% against R. solanacearum at 200 and 100 lg/mL,
which were superior to those of Thiodiazole Copper (92% and
and R. solanacearum with EC50 values of 14.69 and 15.14 lg/mL,
respectively, which were even better than those of commercial
agents Bismerthiazol and Thiodiazole Copper. In vivo antibacterial
activities tests under greenhouse conditions demonstrated that the
control efficiency of compound 4i against rice bacterial leaf blight
and tomato bacterial wilt were better than those of the commercial
52%, respectively).
R
R
O
SH
SH
5% HCl
N
N
4a-4h
98% H2SO4
CH3OH
NH2NH2 H2O
CH3OH
KOH, CS2
C2H5OH
R
COOH
R
COOCH3
R
CONHNH2
3
1
2
S
98% H2SO4
N
N
4g-4p
Scheme 1. Synthetic route of the title compounds.
Table 1
Inhibition effect of the title compounds against Xoo
No.
Compounds
R
Inhibition (%)
g/mL) 100 (lg/mL)
Toxic regression equation
r
EC50 (lg/mL)
X
200 (l
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
O
O
O
O
O
O
O
O
S
S
S
S
S
Phenyl
88 1.37
73 4.92
70 2.55
75 0.51
45 2.56
100 0.44
100 0.76
21 4.32
100 0.17
100 0.07
81 1.17
100 0.75
100 0.56
73 4.92
100 0.50
100 0.38
72 0.65
64 2.76
65 5.64
38 4.34
31 4.21
56 2.09
34 1.35
100 0.33
72 1.27
12 0.38
100 0.10
64 0.65
55 2.05
100 0.66
100 0.48
58 4.34
84 0.87
100 0.59
54 1.23
43 3.15
y = 2.232x + 0.957
/
/
y = 1.886x + 1.321
/
y = 1.372x + 3.305
y = 1.687x + 2.198
/
y = 3.087x + 1.397
y = 1.503x + 2.352
y = 1.941x + 1.242
y = 2.508x + 1.960
y = 1.545x + 3.174
y = 1.862x + 1.360
y = 2.185x + 1.548
y = 1.577x + 3.006
y = 1.499x + 2.052
y = 1.540x + 1.788
0.99
/
/
0.99
/
0.99
0.99
/
0.98
0.98
0.97
0.91
0.99
0.98
0.99
0.98
0.98
0.98
64.77 3.79
/
/
89.25 2.54
/
17.20 1.76
45.81 5.11
/
14.69 1.21
57.78 4.17
86.32 5.74
16.30 0.13
15.20 1.22
90.16 3.87
38.01 2.94
18.38 1.11
92.61 2.15
121.82 3.59
4-Fluorophenyl
4-Chlorophenyl
2,4-Dichlorophenyl
Benzyl
4-Fluorobenzyl
4-Chlorobenzyl
2,4-Dichlorobenzyl
Phenyl
4-Fluorophenyl
4-Chlorophenyl
2,4-Dichlorophenyl
Benzyl
4-Fluorobenzyl
4-Chlorobenzyl
2,4-Dichlorobenzyl
S
S
S
Bismerthiazol
Thiodiazole Copper

P. Li et al. / Bioorg. Med. Chem. Lett. 25 (2015) 481–484
483
Table 2
Inhibition effect of the title compounds against R. solanacearum
No.
Compounds
R
Inhibition (%)
g/mL) 100 (lg/mL)
Toxic regression equation
r
EC50 (lg/mL)
X
200 (l
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
O
O
O
O
O
O
O
O
S
S
S
S
S
Phenyl
73 9.97
100 1.58
75 1.24
100 0.98
42 2.21
100 1.37
92 1.76
100 0.83
100 2.45
91 7.74
100 6.48
75 3.46
100 0.52
100 3.37
36 5.52
28 2.67
100 3.95
92 2.65
49 3.48
100 1.19
54 2.55
100 0.66
30 1.34
100 0.35
60 2.39
100 0.24
100 1.87
41 2.23
56 3.08
42 1.07
100 0.98
100 0.35
24 0.91
24 2.28
100 6.54
52 4.91
y = 1.738x + 1.454
y = 1.758x + 2.211
y = 1.821x + 1.445
y = 2.256x + 1.743
/
y = 1.894x + 1.938
y = 2.357x + 0.728
y = 1.891x + 2.471
y = 2.900x + 1.533
y = 2.155x + 0.952
y = 1.284x + 2.501
y = 1.720x + 1.532
y = 2.051x + 1.766
y = 1.631x + 2.262
/
0.96
0.99
0.99
0.96
/
0.96
0.98
0.97
0.92
0.95
0.98
0.98
0.98
0.99
/
109.61 8.14
38.59 2.11
89.57 4.45
27.78 1.75
/
41.37 4.51
64.94 5.71
21.75 1.38
15.14 0.64
75.67 3.73
88.21 6.54
103.75 6.21
34.74 3.45
47.72 2.22
/
4-Fluorophenyl
4-Chlorophenyl
2, 4-Dichlorophenyl
Benzyl
4-Fluorobenzyl
4-Chlorobenzyl
2,4-Dichlorobenzyl
Phenyl
4-Fluorophenyl
4-Chlorophenyl
2,4-Dichlorophenyl
Benzyl
4-Fluorobenzyl
4-Chlorobenzyl
2,4-Dichlorobenzyl
S
S
S
/
/
/
Bismerthiazol
Thiodiazole Copper
y = 1.214x + 2.844
y = 1.028x + 2.945
0.98
0.99
59.69 2.53
99.80 4.72
mL). Moreover, among the title compounds, 4i demonstrated the
best inhibitory effects against Xoo and R. solanacearum with EC50
values of 14.69 and 15.14 lg/mL, respectively.
Table 3
Control efficiency of compound 4i against rice bacterial leaf blight under greenhouse
conditions at the concentration of 200
l
g/mL
To determine the control efficiency of antibacterial potency
in vivo, the antibacterial bioassays of compound 4i against rice
bacterial leaf blight and tomato bacterial wilt were carried out
under greenhouse conditions via the leaf-cutting method and
injuring root method,7,22 respectively. Bismerthiazol and Thiodiaz-
ole Copper, the most successful registered bactericides for plants,
were used as the positive control samples. The results, as listed
in Table 3, indicated that, at 15 days after spraying, compound 4i
had potent control efficiency of 47.15% against rice bacterial leaf
Compounds
15 Days after spraying
Disease index (%)
Control efficiency (%)c
4i
48.62 3.51
68.55 2.26
57.51 2.73
0.00
47.15 3.21a
25.49 1.68a
37.49 3.32a
100.00 0.00a
/
Bismerthiazol
Thiodiazole Copper
CK1a
CK2b
92.00 2.79
a
b
c
CK1: untreated blank control.
CK2: negative control sample.
Statistical analysis was conducted via the ANOVA method at a condition of
blight at 200 lg/mL, which was better than those of Bismerthiazol
equal variances assumed (p >0.05) and equal variances not assumed (p <0.05). Same
lowercase letters indicate the values of control efficiency with no significant dif-
ference among different treatment groups at p >0.05.
(25.49%) and Thiodiazole Copper (37.49%). Meanwhile, Table 4
showed that, at 7 days after the first, the second and the third
spraying, respectively, the control efficiency of compound 4i
against tomato bacterial wilt at 500 lg/mL were 61.14%, 31.03%
and 16.02%, respectively, which were superior to those of
Bismerthiazol (34.53%, 27.02% and 8.04%, respectively) and
Thiodiazole Copper (43.51%, 25.24% and 5.12%, respectively).
Field trials of compound 4i against rice bacterial leaf blight and
tomato bacterial wilt were performed, and the results were sum-
marized in Tables 5 and 6. Table 5 indicated that, at 14 days after
the third spraying, the control efficiency of compound 4i at 150 g
ai/ha against rice bacterial leaf blight was 62.54%, which was
slightly below those of Bismerthiazol (65.29%) and Zhongsheng-
mycin (64.39%). Meanwhile, Table 6 showed that, at 13 days after
the second spraying, compound 4i had potent control efficiency of
79.07% against tomato bacterial wilt at 150 g ai/ha, which was
The EC50 values of some of the synthesized compounds as well
as for Bismerthiazol and Thiodiazole Copper were also presented in
Tables 1 and 2. Table 1 showed that compounds 4a, 4d, 4f, 4g, 4i,
4j, 4k, 4l, 4m, 4n, 4o and 4p inhibited Xoo in vitro with the EC50
values of 64.77, 89.25, 17.20, 45.81, 14.69, 57.78, 86.32, 16.30,
15.20, 90.16, 38.01 and 18.38
superior to those of Bismerthiazol (92.61
Copper (121.82 g/mL). Meanwhile, Table 2 indicated that com-
l
g/mL, respectively, which were
l
g/mL) and Thiodiazole
l
pounds 4b, 4d, 4f, 4h, 4i, 4m and 4n inhibited R. solanacearum with
the EC50 values of 38.59, 27.78, 41.37, 21.75, 15.14, 34.74 and
47.72 lg/mL, respectively, which were even better than those of
Bismerthiazol (59.69 lg/mL) and Thiodiazole Copper (99.80 lg/
Table 4
Control efficiency of compound 4i against tomato bacterial wilt under greenhouse conditions at the concentration of 500 lg/mL
Compounds
7 Days after the first spraying
Disease index (%)
Control efficiency (%)c
7 Days after the second spraying
Disease index (%)
Control efficiency (%)c
7 Days after the third spraying
Disease index (%)
Control efficiency (%)c
79.78 5.91
87.36 6.82
90.14 8.16
0.00
4i
20.98 3.76
35.35 5.52
30.50 7.12
0.00
61.14 4.21a
34.53 3.63a
43.51 4.27a
100.00 0.00a
/
54.14 2.50
57.29 1.93
58.69 3.66
0.00
31.03 2.36a
27.02 2.40a
25.24 3.16a
100.00 0.00a
/
16.02 4.13a
8.04 2.14a
5.12 3.50a
100.00 0.00a
Bismerthiazol
Thiodiazole Copper
CK1a
CK2b
54.00 5.58
78.50 2.50
95.00 4.50
a
b
c
CK1: untreated blank control.
CK2: negative control sample.
Statistical analysis was conducted via the ANOVA method at a condition of equal variances assumed (p >0.05) and equal variances not assumed (p <0.05). Same lowercase
letters indicate the values of control efficiency with no significant difference among different treatment groups at p >0.05.

484
P. Li et al. / Bioorg. Med. Chem. Lett. 25 (2015) 481–484
Table 5
bacterial leaf blight and tomato bacterial wilt compared with the
Field trials of compound 4i against rice bacterial leaf blight
commercial agents. This work demonstrated that 2-mercapto-5-
substituted-1,3,4-oxadiazole/thiadiazole derivatives, due to their
simple structure, lower production cost, lower dosage use and
better antibacterial activities, can be used to develop potential
bactericides for plants.
Compounds
Dosage
14 Days after the third spraying
(g ai/ha)a
Disease index (%)
Control efficiency (%)c
4i
75
4.22 0.93
2.89 0.37
2.68 0.39
2.75 0.44
7.71 0.17
45.49 4.77a
62.54 3.97a
65.29 4.40a
64.39 5.05a
/
150
337.5
67.5
Bismerthiazol
Zhongshengmycin
CKb
Acknowledgment
a
b
c
Active ingredient.
The authors gratefully acknowledge the financial support of the
Key Technologies R&D Program (No. 2011BAE06B05-6).
Untreated blank control.
Statistical analysis was conducted via the ANOVA method at a condition of
equal variances assumed (p >0.05) and equal variances not assumed (p <0.05). Same
lowercase letters indicate the values of control efficiency with no significant dif-
ference among different treatment groups at p >0.05.
Supplementary data
Supplementary data (which contain information on the
synthesis, characterization, and bioactivity test methods of the title
compounds) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.bmcl.2014.12.038. These
data include MOL files and InChiKeys of the most important
compounds described in this article.
Table 6
Field trials of compound 4i against tomato bacterial wilt
Compounds
Dosage
13 Days after the second spraying
(g ai/ha)a
Disease index (%) Control efficiency (%)c
4i
75
17.33 2.31
12.00 2.41
16.00 4.00
18.67 2.12
14.67 2.41
57.33 2.22
69.77 6.04a
79.07 6.98a
72.09 5.33a
67.43 3.96a
74.41 6.98a
/
150
360
21.6
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Zhongshengmycin
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better than those of Bismerthiazol (72.09%), Zhongshengmycin
(67.43%) and Thiodiazole Copper (74.41%).
The data of the antibacterial bioassay of compound 4i against
rice bacterial leaf blight and tomato bacterial wilt under green-
house conditions and field trials were statistically analyzed via
ANOVA (least significant difference), and the results showed that
no significant differences (p >0.05) exist between compound 4i
and each of the commercial agents.
In summary, a series of 2-mercapto-5-substituted-1,3,4-oxadi-
azole/thiadiazole derivatives were synthesized and evaluated for
their in vitro antibacterial activities against rice bacterial leaf
blight and tomato bacterial wilt caused by Xoo and R. solanacearum,
respectively, and assayed their control efficiency against rice bac-
terial leaf blight and tomato bacterial wilt at greenhouse condi-
tions and field trials, respectively. In vitro antibacterial bioassay
results indicated that most compounds demonstrated excellent
inhibitory effect against Xoo and R. solanacearum. In vivo antibacte-
rial activities tests at greenhouse conditions demonstrated that the
control efficiency of compound 4i against rice bacterial leaf blight
and tomato bacterial wilt were better than those of Bismerthiazol
and Thiodiazole Copper. Field trials also indicated that compound
4i demonstrated appreciable control efficiency against rice
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