Synthesis of novel indole derivatives containing double 1,3,4-oxadiazole moiety as efficient bactericides against phytopathogenic bacterium Xanthomonas oryzae

Article abstract of DOI:10.1007/s11696-018-0555-y

Abstract: A series of novel indole derivatives containing double 1,3,4-oxadiazole moiety was designed, synthesized and evaluated for their antibacterial activities in vitro. These compounds were fully characterized by ¹H NMR, ¹³C NMR, and HRMS. Bioassay results indicated that most of title compounds exhibited excellent antibacterial activities against rice bacterial pathogen Xanthomonas oryzae (Xoo). For example, compounds 7d, 7h, 7i, 7j, 7k, 7l and 7m had the half-maximal effective concentration (EC₅₀) values of 52.31, 54.12, 40.65, 38.80, 51.13, 52.75 and 50.66?μg/mL, respectively, which was better than that of commercial product bismerthiazol (BMT) (85.18?μg/mL). The experimental results proved that indole derivatives bearing double 1,3,4-oxadiazole unit are promising candidates for the development of new agricultural bactericides against pathogenic bacterium Xoo. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11696-018-0555-y

Chemical Papers
https://doi.org/10.1007/s11696-018-0555-y
ORIGINAL PAPER
Synthesis of novel indole derivatives containing double
1
,3,4‑oxadiazole moiety as eꢀcient bactericides
against phytopathogenic bacterium Xanthomonas oryzae
1
1
1
2
2
1
1
2
Kun Tian · Xiao‑Qin Li · Li Zhang · Yi‑Yuan Gan · Jiao Meng · Shou‑Qun Wu · Jin‑Lin Wan · Yang Xu ·
2
1,2,3
2,3
Chao‑Ting Cai · Gui‑Ping Ouyang
· Zhen‑Chao Wang
Received: 26 September 2017 / Accepted: 11 July 2018
Institute of Chemistry, Slovak Academy of Sciences 2018
©
Abstract
A series of novel indole derivatives containing double 1,3,4-oxadiazole moiety was designed, synthesized and evaluated
1
13
for their antibacterial activities in vitro. These compounds were fully characterized by H NMR, C NMR, and HRMS.
Bioassay results indicated that most of title compounds exhibited excellent antibacterial activities against rice bacterial
pathogen Xanthomonas oryzae (Xoo). For example, compounds 7d, 7h, 7i, 7j, 7k, 7l and 7m had the half-maximal eꢀective
concentration (EC ) values of 52.31, 54.12, 40.65, 38.80, 51.13, 52.75 and 50.66 µg/mL, respectively, which was better
5
0
than that of commercial product bismerthiazol (BMT) (85.18 µg/mL). The experimental results proved that indole deriva-
tives bearing double 1,3,4-oxadiazole unit are promising candidates for the development of new agricultural bactericides
against pathogenic bacterium Xoo.
Graphical abstract
Keywords Indole · 1,3,4-Oxadiazole · Antibacterial activity
Introduction
Xanthomonas oryzae (Xoo) and Ralstonia solanacearum
(
Rs) are pathogenic bacteria for rice bacterial leaf blight and
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-018-0555-y) contains
supplementary material, which is available to authorized users.
tobacco bacterial wilt, respectively, which do serious harm
to global agricultural products and give rise to huge eco-
nomic losses to farmers all over the world (Carvalho 2006).
Rice is a staple crop for much of the world population, as
well as a model for cereal biology (Ronald and Leung 2002).
Kun Tian and Xiao-Qin Li contributed equally to the ꢁrst
authorship
Extended author information available on the last page of the article
Vol.:(0
1
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3

Chemical Papers
Taking the phytobacterium Xoo, a member of the gamma
subdivision of the proteobacteria, as an example, it is one
of the most destructive bacterial diseases for the rice crop,
which occurs throughout all the growth stages of rice and
triggers bacterial blight by invading vascular tissues (Niño-
Liu et al. 2006), entering rice leaves through water pores
or wounds and moves systemically by invading the xylem,
causing a disease known as bacterial blight (Salzberg et al.
many researchers. Therefore, there is an urgent need to
develop new and more eꢂcient antibacterial agents in the
agrochemical ꢁeld.
It is well known that the indole moiety which is prob-
ably the most widely spread nitrogen heterocycle in nature
is very important for its medicinal and biological aspects,
thus attracting a lot of scientiꢁc attention. It has been found
to possess pharmacological and chemotherapeutic proper-
ties such as antibacterial (Mahboobi et al. 2006), antifungal
(Williams et al. 2005), antidiabetic (Dropinski et al. 2005),
antiinꢃammatory (Karg et al. 2009), antimalarial (Agarwal
et al. 2005), antiviral (Chen et al. 2005), and anticancer
(Akué-Gédu et al. 2009). Some indole derivatives have been
conꢁrmed to have antibacterial activity, such as compounds
1 (Williams et al. 2013), 2 (Li et al. 2016), 3 (Franz et al.
2017), and 4 (Hong et al. 2017) (Fig. 1).
2
008). The most important bacterial disease of rice in the
rice growing countries (Mew 1987) carrying the potential
to reduce yields by as much as 50% (Huang et al. 1997).
Additionally, the pathogen Rs, with a global distribution and
an unusually wide host range, is β-proteobacteria and con-
sidered as complex species. It was ꢁrst discovered to cause
fatal wilt diseases threatening many important crops such as
eggplant, tomato, potato by Smith in 1896 and subsequently
tobacco in 1908 (Li et al. 2011). Meanwhile, it is also one
kind of highly devastating and widespread soil-borne plant
pathogen (Li et al. 2015). When it infects at the growth
stage, the tobacco plants are rapid yellowing and wilting of
tobacco leaves (Ronald and Leung 2002). At present, sev-
eral commercial antibacterial agents (i.e., bismerthiazol and
thiodiazole copper) are currently available on the market for
Furthermore, in the exploration of novel bactericide, het-
erocyclic systems containing 1,3,4-oxadiazole have attracted
great attentions due to their potent biological activities
against bacteria and fungi (Joshi and Parikh 2014; Desai
and Kotadiya 2014; Wang et al. 2016), such as compounds
5 (Bhat et al. 2013), 6 (Desai et al. 2014), 7 (Palekar et al.
2009), and 8 (Xu et al. 2012) (Fig. 1). Meanwhile, Patel and
co-workers (Patel et al. 2012) have evaluated the antibac-
terial activity of a series of 3-(5-sulfanyl-1,3,4-oxadiazol-
2-yl)-2H-chromen-2-ones bearing various substituted pip-
erazines and piperidines against two types of Gram-positive
bacteria and six types of Gram-negative bacteria.
ꢁ
ghting against the two bacterial diseases. However, poor
eꢂciency, high phytotoxicities and residue levels, adverse
eꢀects on the natural environment and growing problems of
antibacterial resistance related with the utilization of these
bactericides are continuously attracting attention from so
Fig. 1 Chemical structures of cited molecules with antibacterial and antifungal activities
1
3

Chemical Papers
Until now, the method of “active substructure combina-
tion” is still quite useful for the development of new bioac-
tive molecules (Guan et al. 2014; Zhu et al. 2016), which
means that combining separate pharmacophoric groups into
one compound to achieve more potent molecule with bio-
logical activity (Saundane et al. 2017). The ꢁndings made
by Shi et al. (2015) (compound 9), just one good example of
ingenious combination of indole and 1,3,4-oxadiazole het-
erocycles, exhibits excellent activity against Staphylococcus
aureus and Escherichia coli using the disc diꢀusion assay.
On the basis of previous work, a series of 1,3,4-oxadiazole
hybrid derivatives can serve as potential alternative bacteri-
cides (Li et al. 2014, 2015; Wang et al. 2016; Xu et al. 2013).
The attachment of new indole derivatives containing double
bearing double 1,3,4-oxadiazole unit are promising candi-
dates for the development of new agricultural bactericides
against pathogenic bacterium Xoo.
Experimental
All the chemicals were obtained from commercial suppli-
ers and used without further puriꢁcation (unless otherwise
stated). Melting points (M.P.) were determined on a XT-4
binocular microscope (Beijing Tech Instrument Co., China).
1
13
H and C NMR (solvent DMSO-d ) spectra were meas-
6
ured on a JEOL-ECX 500 NMR spectrometer and Ascend
400 NMR at room temperature using TMS as an internal
standard, and chemical shift (δ) was expressed in parts per
million (ppm). HRMS-ESI spectra were recorded on Thermo
Scientiꢁc Q Exactive series.
1,3,4-oxadiazole moiety might provide structures with inter-
esting biological activity against Xoo and Rs. In continuation
of our interest, a series of 2-((2-((5-(1H-indol-3-yl)-1,3,4-
oxadiazol-2-yl)thio)ethyl)thio)-5-phenyl-1,3,4-oxadiazole
were designed and synthesized (Scheme 1) so as to get bio-
logically more potent molecules. The bioassays reveal that
most of target compounds exhibited better inhibition activi-
ties against Xoo than positive controls bismerthiazol (BMT).
Among them, 7d, 7h, 7i, 7j, 7k, 7l and 7m exert excellent
inhibition activities against Xoo with half-maximal eꢀective
concentration (EC ) values ranging from 38.80 to 54.12 µg/
General synthetic procedure
for intermediate 2‑((2‑bromoethyl)
thio)‑5‑(1H‑indol‑3‑yl)‑1,3,4‑oxadiazole (3)
Briefly, methyl 1H-indole-3-carboxylate as starting
material was reacted with N H ·H O to give 1H-indole-
2
4
2
3-carbohydrazide 1 which was then subjected to sub-
50
mL. The experimental results proved that indole derivatives
stitution reaction with KOH and CS to generate
2
Scheme 1 Synthetic route of
the title compounds 7a–7m
7
7
7
7
a R = Phenyl
7f R = 2-chlorophenyl
7g R= 3-chlorophenyl
7h R = 4-chlorophenyl
7i R = 2,4-dichlorophenyl
7j R = 3,5-dichlorophenyl
7k R = 2-pyridyl
7l R = 3-pyridyl
7m R = 4-pyridyl
b R = 2-methylphenyl
c R = 4-aminophenyl
d R = 3,4,5-trimethoxyphenyl
7
e R = 3-fluorophenyl
1
3

Chemical Papers
5
-(1H-indol-3-yl)-1,3,4-oxadiazole-2-thiol 2. Subsequently,
it was converted into the corresponding key intermediate
through reaction with BrCH CH Br under CH COCH /
data of intermediate 3 and compounds 7a–7m were listed in
Table 1, and the spectral data of those were listed in Table 2.
3
2
2
3
3
K CO system. Additionally, analysis of variance (ANOVA)
2
3
was used for improving the yield of the intermediate 3. Dif-
ferent solvents, reaction times, base and temperature were
investigated to obtain the best conditions. The results of nine
orthogonal tests with four factors and three conditions are
shown in Table S1 (Supporting Information). For a complete
experiment, 27 tests were carried out for intermediate 3.
The results of orthogonal experimental ANOVA are listed
in Table S2 (Supporting Information). The data obtained in
all experiments demonstrated that the type of solvent was
the most important factor in achieving the highest response
value corresponding to A1 (solvent: acetone) B2 (time: 6 h)
C2 (temperature: 40 °C) D2 (alkali: K CO ) (Table S1),
Results and discussion
Chemistry
The synthetic route of target compounds 7a–7m was
depicted in Scheme 1. Results of physical properties of inter-
mediate 3 and compounds 7a–7m were listed in Tables 1
1
and 2. Taking 7a as an example, the H NMR spectrum of it
in DMSO-d displayed a multiplet at δ 3.77–3.73 ppm that
6
corresponds to –SCH CH S– functionality, the singlet at δ
2
2
8.12 ppm integrating for only one proton was assigned to the
1
3
–CH in the position 2 of indole. In the C NMR spectrum,
2
3
which was consistent with the optimum results for interme-
diate 3. As F ratio >F critical value (Table S2), the response
value was inꢃuenced by the type of solvent.
the –SCH CH S– carbon signal was found at δ 32.53 and δ
2
2
32.50 ppm. The high-resolution mass spectrum (HRMS) of
7a demonstrated an intense peak at m/z=422.0739 attrib-
+
uted to the species of [M+H] .
General synthetic procedure for intermediates
6
a–6m
Antibacterial activity screening of the title
compounds against Rs and Xoo in vitro
Taking 6a as an example, a mixture of benzoic acid (2.5 g,
2
0.0 mmol), 4 mL sulfuric acid, and 50 mL ethanol was
Using Ralstonia solanacearum (Rs, Nanjing Agricultural
University, China) and Xanthomonas oryzae (Xoo, strain
PXO99A, Nanjing Agricultural University, China) as the
tested bacterial strains, the turbidimetric assay (Yang and
Bao 2017; Wang et al. 2017; Xu et al. 2012) was conducted
to evaluate antibacterial activities of target compounds
7a–7m and intermediate 3 the same as two commercial
agricultural bactericides (namely bismerthiazol (BMT) and
thiodiazole copper (TDC)) which were utilized as the control
agents against two phytopathogenic bacteria Xoo and Rs.
heated under reꢃux for 7 h (hour, h). After ꢁnishing the
reaction, it was poured into water and extracted by ethyl
acetate, dried with anhydrous Na SO , and then the solvent
2
4
of the organic phase was evaporated under vacuum to give
colorless liquid 4a. Then excess 80% N H ·H O and 15 mL
2
4
2
of ethanol were added into the ꢃask containing 4a, which
was heated under reꢃux about 5 h. After the reaction was
completed, it should be cooled into room temperature over-
night and the white solid 5a was given after being ꢁltered,
washed with ethanol and dried in open air. Finally, 5a (1.4 g,
8
.0 mmol) was then subjected to substitution reaction with
Table 1 Physical properties of intermediate 3 and compounds 7a–7m
KOH (0.9 g, 15.6 mmol) and CS (1.2 g, 15.0 mmol) to
2
generate intermediate 6a. At the same time, 6b–6m was syn-
Compound Formula
Yield (%) Appearance M.P. (°C)
thesized by the methods described in the literature (Shi et al.
3
7
7
7
7
7
7
7
7
7
7
7
7
7
C H BrN OS
67
60
49
50
53
52
58
60
65
Yellow solid 157–158
White solid 140–141
White solid 164–165
White solid 179–180
White solid 190–191
White solid 182–183
White solid 157–158
White solid 150–151
White solid 148–149
White solid 237–238
1
2
10
3
2
015; Du et al. 2013).
a
b
c
d
e
f
C H N O S
20 15 5 2
2
2
2
2
C H N O S
2
1
17
5
2
General synthetic procedure for title compounds
a–7m
C H N O S
2
0
16
6
2
7
C H N O S
2
3
21
5
5
C H FN O S
2 2
2
0
14
5
The key intermediate 3 (1.0 g, 3.1 mmol) and various
derivatives 6a–6m (0.7 g, 3.4 mmol) were reacted under
MeCN/K CO system (20 mL; 0.8 g, 6.1 mmol) at room
C H ClN O S
2
0
14
5
2
2
2
2
g
h
i
C H ClN O S
20 14 5 2
2
3
C H ClN O S
2
0
14
5
2
temperature and monitored by TLC (petroleum ether/ethyl
acetate, V/V = 1:1.5). After the reaction was ꢁnished, the
mixture was poured into water and the residue was ꢁltered,
recrystallized from ethanol with little N,N-dimethylforma-
C H Cl N O S 70
2
0
13
2
5
2 2
j
C H Cl N O S 76
Gray solid
235–236
2
0
13
2
5
2 2
k
l
C H N O S
62
63
65
White solid 142–143
White solid 143–144
White solid 144–145
1
9
14
6
2
2
2
2
C H N O S
1
9
14
6
2
mide (the value of V
/V
is about 8)
ethanol N,N-dimethylformamide
m
C H N O S
19 14 6 2
to obtain title compounds 7a–7m. The physical properties
1
3

Chemical Papers
Table 2 Physical property data of compounds 7a–7m
Compounds Spectral data
1
3
7
7
H NMR (500 MHz, DMSO-d ) δ 12.05 (s, 1H, indole-NH), 8.19 (s, 1H, indole-CH), 8.05 (d, J=6.4 Hz, 1H, Ph-H), 7.54 (d,
6
13
J=7.4 Hz, 1H, Ph-H), 7.32–7.19 (m, 2H, Ph-H), 3.89 (t, J=7.5 Hz, 2H, –CH –), 3.75 (t, J=7.5 Hz, 2H, –CH –); C NMR
2
2
(
125 MHz, DMSO-d ) δ 163.72, 160.43, 136.96, 128.95, 124.43, 123.44, 121.81, 120.64, 113.01, 99.57, 34.49, 31.67; HRMS,
6
+ +
ESI (m/z): 323.9802 [M+H] ; 323.9801 calcd [M+H] for C H ON BrS
1
2
11
3
1
1
a
H NMR (500 MHz, DMSO-d ) δ 8.12 (s, 1H, indole-CH), 7.98 (d, J=5.0 Hz, 1H, Ph-H), 7.93 (d, J=5.0 Hz, 2H, Ph-H),
6
1
3
7
1
3
.55–7.50 (m, 4H, Ph-H), 7.15–7.18 (m, 2H, Ph-H), 3.77–3.73 (m, 4H, –CH CH –); C NMR (125 MHz, DMSO-d ) δ 165.82,
2 2 6
63.72, 163.58, 160.50, 136.95, 132.45, 129.85, 128.93, 126.95, 124.43, 123.53, 123.41, 121.78, 120.66, 112.97, 99.61, 32.53,
+
+
2.50; HRMS, ESI (m/z): 422.0739 [M+H] ; 422.0740 calcd [M+H] for C H O N S
5 2
2
0
16
2
b
H NMR (500 MHz, DMSO-d ) δ 12.02 (s, 1H, indole-NH), 8.16 (s, 1H, indole-CH), 8.03 (d, J=10.0 Hz, 1H, Ph-H), 7.85 (d,
6
J=10.0 Hz, 1H, Ph-H), 7.52 (s, 1H, Ph-H), 7.44 (t, J=7.5 Hz, 1H, Ph-H), 7.39 (s, 1H, Ph-H), 7.33 (s, 1H, Ph-H), 7.26 (d,
1
3
J=5.0 Hz, 2H, Ph-H), 3.80–3.76 (m, 4H, –CH CH –), 2.57 (s, 3H, CH ); C NMR (100 MHz, DMSO-d ) δ 165.89, 163.65,
2
2
3
6
1
3
63.09, 160.39, 137.91, 136.89, 132.10, 131.85, 129.14, 128.86, 126.88, 124.37, 123.33, 122.61, 121.69, 120.60, 112.90, 99.54,
+
+
2.44, 31.59, 21.93; HRMS, ESI (m/z): 436.0891 [M+H] ; 436.0896 calcd [M+H] for C H O N S
5 2
2
1
18
2
1
1
1
1
1
1
1
1
1
7
7
7
7
7
7
7
7
7
c
d
e
f
H NMR (500 MHz, DMSO-d ) δ 12.10 (s, 1H, indole-NH), 8.17 (s, 1H, indole-CH), 8.06 (d, J=5.0 Hz, 2H, Ph-H), 7.64 (d,
6
J=10.0 Hz, 1H, Ph-H), 7.54 (d, J=5.0 Hz, 2H, Ph-H), 7.26 (d, J=5.0 Hz, 2H, Ph-H), 6.67 (d, J=8.6 Hz, 1H, Ph-H), 5.97 (s,
1
3
1
1
3
H, Ph-H), 3.80–3.63 (m, 4H, –CH CH –), 2.89 (s, 1H, –NH –H), 2.74 (s, 1H, –NH –H); C NMR (100 MHz, DMSO-d ) δ
2 2 2 2 6
66.62, 162.78, 161.18, 160.44, 152.85, 136.90, 128.89, 128.47, 124.37, 123.33, 121.72, 120.62, 113.98, 112.92, 109.78, 99.54,
+
+
2.43, 32.07; HRMS, ESI (m/z): 437.0846 [M+H] ; 437.0849 calcd [M+H] for C H O N S
6 2
2
0
17
2
H NMR (400 MHz, DMSO-d ) δ 12.01 (s, 1H, indole-NH), 8.13 (s, 1H, indole-CH), 8.01 (d, J=5.0 Hz, 1H, Ph-H), 7.50 (d,
6
J=10.0 Hz, 1H, Ph-H), 7.25–7.22 (m, 2H, Ph-H), 7.17 (s, 2H, Ph-H), 3.84 (s, 6H, –OCH ), 3.82–3.74 (m, 4H, –CH CH ), 3.70
3
2
2
1
3
(
s, 3H, –OCH ); C NMR (100 MHz, DMSO-d ) δ 165.65, 163.59, 163.29, 160.39, 153.81, 140.88, 136.86, 128.79, 124.31,
3
6
+
1
23.31, 121.66, 120.53, 118.55, 112.85, 104.13, 99.46, 60.60, 56.55, 32.52, 32.42; HRMS, ESI (m/z): 512.1054 [M+H] ;
+
5
12.1057 calcd [M+H] for C H O N S
2
3
22
5
5
2
H NMR (500 MHz, DMSO-d ) δ 12.04 (s, 1H, indole-NH), 8.20–8.16 (m, 1H, indole-CH), 8.04 (d, J=5.0 Hz, 2H, Ph-H), 7.77
6
(
d, J=10.0 Hz, 1H, Ph-H), 7.59–7.52 (m, 2H, Ph-H), 7.43 (d, J=5.0 Hz, 1H, Ph-H), 7.25 (t, J=7.5, Hz, 2H, Ph-H), 3.82–3.75
13
(
m, 4H, –CH CH –); C NMR (101 MHz, DMSO-d ) δ 164.00, 163.62, 162.63 (d, J=245.5 Hz), 160.40, 136.87, 132.15,
2
2
6
1
28.85, 125.42 (d, J=8.8 Hz), 124.36 (d, J=2.6 Hz), 123.32, 123.11, 121.67, 120.59, 119.32 (d, J=21.1 Hz), 113.79, 113.55,
+ +
1
12.88, 99.52, 32.47, 32.38; HRMS, ESI (m/z): 440.0641 [M+H] ; 440.0646 calcd [M+H] for C H O N FS
2
2
0
15
2
5
H NMR (500 MHz, DMSO-d ) δ 11.98 (s, 1H, indole-NH), 8.13 (s, 1H, indole-CH), 7.99 (d, J=10.0 Hz, 1H, Ph-H), 7.92 (t,
6
J=7.5 Hz, 1H, Ph-H), 7.63 (d, J=5.0 Hz, 1H, Ph-H), 7.55 (t, J=5.0 Hz, 1H, Ph-H), 7.47 (d, J=5.0 Hz, 2H, Ph-H), 7.23–7.19
1
3
(
m, 2H, Ph-H), 3.78–3.74 (m, 4H, –CH –CH –); C NMR (100 MHz, DMSO-d ) δ 164.16, 163.79, 163.67, 160.34, 136.90,
2
2
6
1
32.59, 132.10, 131.63, 131.52, 128.34, 128.23, 124.38, 123.36, 121.73, 120.69, 118.72, 112.90, 99.56, 32.52, 32.41; HRMS,
+
+
ESI (m/z): 456.0347 [M+H] ; 456.0350 calcd [M+H] for C H O N ClS
2
0
15
2
5
2
g
h
i
H NMR (500 MHz, DMSO-d ) δ 12.00 (s, 1H, indole-NH), 8.15 (s, 1H, indole-CH), 8.06–7.99 (m, 1H, Ph-H), 7.96–7.86 (m,
6
13
2
H, Ph-H), 7.62–7.65 (m, 1H, Ph-H), 7.57–7.45 (m, 2H, Ph-H), 7.22–7.25(m, 2H, Ph-H), 3.80–3.73 (m, 4H, –CH –CH –); C
2 2
NMR (100 MHz, DMSO-d ) δ 164.15, 163.58, 163.14, 159.92, 136.40, 133.99, 131.71, 131.29, 128.37, 125.87, 125.09, 124.88,
6
+
+
1
23.87, 122.84, 121.20, 120.11, 112.40, 99.04, 32.04, 31.92; HRMS, ESI (m/z): 456.0346 [M+H] ; 456.0350 calcd [M+H]
for C H O N ClS
2
20
15
2
5
H NMR (500 MHz, DMSO-d ) δ 12.01 (s, 1H, indole-NH), 8.15 (d, J=5.0 Hz, 1H, indole-CH), 8.02–7.91 (m, 2H, Ph-H), 7.68–
6
7
–
1
.62 (m, 1H, Ph-H), 7.51–7.43 (m, 2H, Ph-H), 7.20–7.23 (m, 3H, Ph-H), 3.85 (t, J=7.5 Hz, 2H, –CH –), 3.71 (t, J=7.5 Hz, 2H,
2
13
CH –); C NMR (100 MHz, DMSO-d ) δ 164.07, 163.71, 160.37, 151.78, 141.66, 136.92, 128.85, 125.05, 124.76, 124.39,
2
6
+
+
23.36, 121.73, 120.61, 118.72, 110.66, 99.60, 32.48, 32.42; HRMS, ESI (m/z): 456.0364 [M+H] ; 456.0350 calcd [M+H]
for C H O N ClS
2
0
15
2
5
2
H NMR (500 MHz, DMSO-d ) δ 12.04 (s, 1H, indole-NH), 8.17 (s, 1H, indole-CH), 8.05 (d, J=7.5 Hz, 1H, Ph-H), 7.99 (d,
6
J=10.0 Hz, 1H, Ph-H), 7.84 (s, 1H, Ph-H), 7.58 (d, J=10.0 Hz, 1H, Ph-H), 7.53 (t, J=7.5 Hz, 1H, Ph-H), 7.27–7.24 (m, 2H,
1
3
Ph-H), 3.84–3.80 (m, 4H, –CH –CH –); C-NMR (125 MHz, DMSO-d ) δ 164.35, 163.70, 163.17, 160.39, 137.56, 136.94,
2
2
6
1
33.16, 132.74, 131.18, 128.89, 128.60, 124.38, 123.39, 121.76, 121.55, 120.62, 112.95, 99.56, 32.59, 32.48; HRMS, ESI (m/z):
+
+
4
89.9978 [M+H] ; 489.9961 calcd [M+H] for C H O N Cl S
2 2
2
0
14
2
5
j
H NMR (500 MHz, DMSO-d ) δ 12.00 (s, 1H, indole-NH), 8.10 (s, 1H, indole-CH), 7.96 (d, J=5.0 Hz, 1H, Ph-H), 7.88–7.86
6
(
m, 2H, Ph-H), 7.77 (s, 1H, Ph-H), 7.48 (d, J=10.0 Hz, 1H, Ph-H), 7.19–7.21 (m, 2H, Ph-H), 3.94–3.64 (m, 4H, –CH –CH –);
2 2
3
1
C NMR (100 MHz, DMSO-d ) δ 164.15, 163.58, 163.14, 159.92, 136.40, 133.99, 131.71, 131.29, 128.37, 125.87, 125.09,
6
+
+
1
22.84, 121.20, 120.11, 112.40, 99.04, 32.04, 31.92; HRMS, ESI (m/z): 489.9964 [M+H] ; 489.9961 calcd [M+H] for
C H O N Cl S
20
14
2
5
2 2
k
H NMR (500 MHz, DMSO-d ) δ 11.99 (s, 1H, indole-NH), 8.67 (d, J=5.0 Hz, 1H, indole-CH), 8.13 (d, J=5.0 Hz, 1H, pyridine-
6
H), 8.07 (d, J=10.0 Hz, 1H, pyridine-H), 7.97–7.94 (m, 2H, Ph-H), 7.55–7.52 (m, 1H, pyridine-H), 7.48 (d, J=5.0 Hz, 1H,
1
3
Ph-H), 7.21 (t, J=7.5 Hz, 2H, Ph-H), 3.79–3.73 (m, 4H, –CH CH –); C NMR (125 MHz, DMSO-d ) δ 165.25, 164.67,
2
2
6
1
3
63.69, 160.39, 150.74, 142.92, 138.31, 136.93, 128.94, 126.83, 124.41, 123.38, 123.30, 121.76, 120.66, 112.95, 99.60, 32.61,
+
+
2.38; HRMS, ESI (m/z): 423.0700 [M+H] ; 423.0692 calcd [M+H] for C H O N S
6 2
1
9
15
2
1
3

Chemical Papers
Table 2 (continued)
Compounds Spectral data
1
7
l
H NMR (500 MHz, DMSO-d ) δ 12.02 (s, 1H, indole-NH), 9.15 (d, J=5.0 Hz, 1H, indole-CH), 8.74–8.77 (m, 1H, pyridine-
6
H), 8.38–8.28 (m, 1H, pyridine-H), 8.17 (d, J=5.0 Hz, 1H, Ph-H), 8.03 (m, 1H, Ph-H), 7.67–7.47 (m, 2H, Ph-H), 7.23–7.27
1
3
(
m, 2H, Ph-H), 3.85–3.77 (m, 4H, –CH –CH –); C NMR (100 MHz, DMSO-d ) δ 163.90, 163.74, 163.35, 160.13, 152.57,
2
2
6
1
47.28, 136.60, 134.20, 128.60, 124.39, 124.07, 123.05, 121.43, 120.31, 119.83, 112.61, 99.24, 32.29, 32.09; HRMS, ESI (m/z):
+ +
4
23.0693 [M+H] ; 423.0692 calcd [M+H] for C H O N S
6 2
1
9
15
2
1
1
7
m
H NMR (400 MHz, DMSO-d ) δ 12.03 (s, 1H, indole-NH), 8.76 (d, J=5.0 Hz, 2H, pyridine-H), 8.17 (d, J=5.0 Hz, 1H, indole-
6
CH), 8.00–8.04 (m, 1.7 Hz, 1H, pyridine-H), 7.86–7.89 (m, 1.6 Hz, 2H, Ph-H), 7.62–7.38 (m, 1H, Ph-H), 7.24–7.26 (m, 1.4 Hz,
2
H, Ph-H), 4.15–3.59 (m, 4H, –CH CH –);
2 2
3
C NMR (DMSO-d , 100 MHz) δ 164.95, 164.21, 163.65, 160.42, 151.27, 136.87, 130.48, 128.88, 124.33, 123.35, 121.71,
6
+
+
1
20.54, 120.44, 112.90, 99.50, 32.55, 32.35; HRMS, ESI (m/z): 423.0689 [M+H] ; 423.0692 calcd [M+H] for C H O N S
19 15 2 6 2
Table 3 Inhibition eꢀect of the target compounds 7a–7m against two
phytopathogenic bacteria Xoo and Rs
and 54.2% at the above two concentrations, respectively),
which adequately proved the necessity for introduction
of indole moiety and 1,3,4-oxadiazole group into target
compounds. Further introduction of substituted benzene
ring with 1,3,4-oxadiazole moiety (6a–6m) linked with
the intermediate 3 largely improved the activity of these
compounds against Xoo compared with intermediate 3,
which demonstrated that 6a–6m segment provide a struc-
tural advantage. Diꢀerent from the bacterium Xoo, a large
majority of the target compounds did not have noticeable
antibacterial activity against the Rs, except compound 7j
a
Compounds Inhibition rate (%)
Xoo
Rs
2
00 µg/mL 100 µg/mL 200 µg/mL 100 µg/mL
3
7
7
7
7
7
7
7
7
7
7
7
7
7
90.0± 4.1
74.2± 6.7
46.4± 3.7
68.2± 7.8
98.1± 0.3
72.1± 4.3
75.6± 5.8
74.8± 0.9
93.2± 0.8
99.6± 4.1
100± 2.8
98.2± 2.0
97.9± 1.9
98.7± 2.1
77.4± 1.5
NT
54.2± 3.5
44.8± 4.9
29.3± 4.5
38.0± 3.2
65.4± 2.8
41.0± 3.1
30.2± 4.9
29.5± 7.2
81.4± 5.7
86.4± 3.2
80.0± 4.3
70.1± 3.3
68.8± 5.2
69.3± 3.4
53.4± 2.3
NT
61.5± 4.1
51.5± 6.2
37.3± 5.9
69.5± 5.2
69.6± 2.8
37.3± 5.9
56.1± 8.2
67.0± 1.4
71.8± 1.7
74.9± 4.1
95.9± 4.2
66.4± 6.2
69.7± 0.8
67.6± 1.3
80.2± 3.1
75.2± 3.1
34.2± 2.1
29.2± 2.4
19.7± 2.2
43.9± 2.7
38.5± 4.9
19.7± 2.0
48.1± 1.9
41.8± 3.2
43.7± 2.5
52.8± 2.5
79.8± 2.4
33.7± 7.5
37.4± 8.3
36.5± 5.3
45.9± 1.3
52.9± 0.7
a
b
c
d
e
f
g
h
i
(
better than standard drug BMT and more active than con-
trol drug than TDC) at 200 µg/mL and compounds 7f, 7i,
7
j (better than BMT), 7i (comparable activity with TDC)
at 100 µg/mL. Among them, compounds 7j and 7i show
better activity than the others. Notably, 3,5-dichloro sub-
stituted compound 7j was found to possess a potent inhi-
bition activity against the bacterium Rs (79.8%) even at
j
k
l
1
00 µg/mL, which was far better than two control agents
BMT and TDC (45.9 and 52.9%, respectively). On the
basis of previous bioassays, all test compounds showed
moderate to excellent activity against Xoo.
m
BMT
b
TDCb
In terms of the experimental results, the EC (half-
5
0
NT not tested
maximal eꢀective concentration) values of the above-
mentioned nine compounds with remarkable antibacterial
activity and intermediate 3 against the pathogen Xoo were
further determined. As shown in Table 4, almost all of the
target compounds did exhibit much lower EC values rela-
a
The average of three trials
Commercial agricultural bactericides bismerthiazol (BMT) and thio-
b
diazole copper (TDC) were used as control agent
5
0
As shown in Table 3, most of the target compounds
exhibited comparable or even better antibacterial activ-
ity against the pathogen Xoo. For example, compounds
tive to control drug BMT. Speciꢁcally, compounds 7d, 7h,
7i, 7j, 7k, 7l and 7m had an EC value of 52.31, 54.12,
5
0
40.65, 38.80, 51.13, 52.75 and 50.66 µg/mL, respectively,
which was obviously better than control BMT (85.18 µg/
mL). In addition, the experimental results showed that the
inhibition rate value was linear with the corresponding
concentration in the range of 12.5–200 µg/mL depicted by
“Toxic regression equation” in Table 4 and good linearity
was obtained (Correlation coeꢂcient (a number between
−1 and +1 calculated so as to represent the linear depend-
ence of two variables or sets of data) > 0.9128).
7
d, 7h, 7i, 7j, 7k, 7l, and 7m had the inhibition rate of
9
8.1, 93.2, 99.6, 100, 98.2, 97.9 and 98.7% against this
bacterium at 200 µg/mL, respectively, which was more
active than the control agent BMT (77.4%). Additionally,
intermediate 3 and the above nine compounds were also
found to possess higher inhibition capability against the
pathogen Xoo (relative to BMT), at 100 µg/mL. Moreover,
intermediate 3 only exhibited better antibacterial activity
towards this bacterium (with the inhibition rate of 90.0
1
3

Chemical Papers
Table 4 EC50 values of target compounds 7d, 7h, 7i, 7j, 7k, 7l, 7m
and intermediate 3 against the pathogen Xoo
values. Although the compounds 7a–7m showed moderate
antibacterial activities against Rs, 7j was found to possess
a potent inhibition activity against the bacterium Rs, which
was far better than two control agents BMT and TDC. Fur-
ther introduction of substituted benzene ring with 1,3,4-oxa-
diazole moiety (6a–6m) linked with the intermediate 3
largely improved the activity of these compounds against
Xoo compared with intermediate 3. Given the above results
that novel indole derivatives exhibited excellent antibacte-
rial activities, we found out that double 1,3,4-oxadiazole
moiety will enhance the bioactivities of the ꢁnal products.
Meanwhile, the structure–activity relationships reveal that
the bioactivities of the target compounds are enhanced with
the electron-withdrawing substituent.
a
Compounds EC (µg/mL) Toxic regression equa-
Correlation
coeꢂcient
5
0
tion
(
r)
3
7
7
7
7
7
7
7
69.52± 0.3
52.31± 2.2
54.12± 1.5
40.65± 1.3
38.80± 2.1
51.13± 1.4
52.75± 1.5
50.66± 1.3
85.18± 3.4
y=2.1227x+1.0897
y=2.8168x+0.1590
y=2.5479x+0.5836
y=3.6529x−0.8779
y=4.0354x−1.4117
y=2.8627x+0.1086
y=2.7516x+0.2611
y=2.9096x+0.0402
y=1.7838x+1.5567
0.9758
0.9541
0.9823
0.9580
0.9128
0.9616
0.9662
0.9568
0.9958
d
h
i
j
k
l
m
b
BMT
a
The average of three trials
The commercial bactericide bismerthiazol (BMT) was used as con-
Acknowledgements This research was ꢁnancially supported by the
Project Enterprises and Business (H 110029), the Scientiꢁc Research
Foundation of Guizhou University (no. 201542), and Guizhou Sci-
ence Technology Program (no. 20161055), the Young Talents Scientiꢁc
Research Foundation of Guizhou Education Department (no. 2017).
b
trol agent
Structure–activity relationship analysis
of antibacterial activities
A preliminary structure–activity relationship analysis was
conducted, which showed that the ꢁnal compounds with
electron-donating substituents (e.g., 2-CH and 4-NH )
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Chemical Papers
Aꢀliations
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Kun Tian · Xiao‑Qin Li · Li Zhang · Yi‑Yuan Gan · Jiao Meng · Shou‑Qun Wu · Jin‑Lin Wan · Yang Xu ·
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Chao‑Ting Cai · Gui‑Ping Ouyang
· Zhen‑Chao Wang
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Gui-Ping Ouyang
of Fine Chemicals, Guizhou University, Guiyang 550025,
People’s Republic of China
oygp710@163.com
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Zhen-Chao Wang
College of Pharmacy, Guizhou University, Guiyang 550025,
People’s Republic of China
wzc.4884@163.com
Drug Synthetic Engineering Laboratory of Guizhou
Province, Guiyang 550025, People’s Republic of China
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State Key Laboratory Breeding Base of Green Pesticide
and Agricultural Bioengineering, Key Laboratory of Green
Pesticide and Agricultural Bioengineering, Ministry
of Education, Centre for Research and Development
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