Synthesis and biological activities of novel quinazolinone derivatives containing a 1,2,4-triazolylthioether moiety

Article abstract of DOI:10.1515/chempap-2016-0034

A series of novel quinazolinone derivatives containing a 1,2,4-triazolylthioether moiety were synthesised and their antimicrobial activities were evaluated. All the target compounds were characterised by ¹H NMR, ¹³C NMR, ESI-MS, IR and elemental analyses. The single crystal structure of 3-((5-((2-fluorobenzyl)thio)-4-phenyl-4H-1,2,4-triazol-3-yl)methyl)quinazolin-4(3H)-one (VIIi) was also determined. The preliminary bioassays indicated that some of the target compounds possessed good antimicrobial activities. For example, 3-((4-phenyl-5-((4-(trifluoromethyl)benzyl)thio)-4H- 1,2,4-triazol-3-yl)methyl)quinazolin-4(3H)-one (VIIs) exhibited the best inhibitory effect against Xanthomonas oryzae pv. oryzae and Xanthomonas axonopodis pv. citri with the half-effective concentration (EC₅₀) values of 47.6 μg mL^-1 and 22.1 μg mL^-1, respectively, which were superior to the commercial bactericide, bismerthiazol. Meanwhile, 3-((5-((4-chlorobenzyl)thio)-4-phenyl-4H- 1,2,4-triazol-3-yl)methyl)quinazolin-4(3H)-one (VIIh) exhibited better fungicidal activities against Pellicularia sasakii and Colletotrichum capsici at the concentration of 50 μg mL^-1, in comparison with the commercial fungicide, hymexazol.

Full text of DOI:10.1515/chempap-2016-0034

Chemical Papers
DOI: 10.1515/chempap-2016-0034
5
16-15
ORIGINAL PAPER
Synthesis and biological activities of novel quinazolinone derivatives
containing a 1,2,4-triazolylthioether moiety
Bo-Ren Yan, Xin-Yang Lv, Huan Du, Man-Ni Gao, Jian Huang, Xiao-Ping Bao*
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 of Fine Chemicals,
Guizhou University, Guiyang 550025, China
Received 7 July 2015; Revised 10 December 2015; Accepted 8 January 2016
A series of novel quinazolinone derivatives containing a 1,2,4-triazolylthioether moiety were syn-
thesised and their antimicrobial activities were evaluated. All the target compounds were charac-
1
13
terised by H NMR, C NMR, ESI-MS, IR and elemental analyses. The single crystal structure of
-((5-((2-fluorobenzyl)thio)-4-phenyl-4H-1,2,4-triazol-3-yl)methyl)quinazolin-4(3H)-one (VIIi) was
3
also determined. The preliminary bioassays indicated that some of the target compounds possessed
good antimicrobial activities. For example, 3-((4-phenyl-5-((4-(trifluoromethyl)benzyl)thio)-4H-
1,2,4-triazol-3-yl)methyl)quinazolin-4(3H)-one (VIIs) exhibited the best inhibitory effect against
Xanthomonas oryzae pv. oryzae and Xanthomonas axonopodis pv. citri with the half-effective con-
−
1
−1
centration (EC50) values of 47.6 µg mL
to the commercial bactericide, bismerthiazol. Meanwhile, 3-((5-((4-chlorobenzyl)thio)-4-phenyl-4H-
,2,4-triazol-3-yl)methyl)quinazolin-4(3H)-one (VIIh) exhibited better fungicidal activities against
and 22.1 µg mL , respectively, which were superior
1
−
1
Pellicularia sasakii and Colletotrichum capsici at the concentration of 50 µg mL , in comparison
with the commercial fungicide, hymexazol.
ꢀ
c 2016 Institute of Chemistry, Slovak Academy of Sciences
Keywords: quinazolinone, 1,2,4-triazolylthioether, antimicrobial activity, synthesis
Introduction
a major challenge in the field of pesticide chem-
istry.
Many quinazolin-4(3H)-one derivatives have at-
Many plant pathogenic bacteria, such as Xan-
thomonas oryzae pv. oryzae (XOO) and Xanthomonas
axonopodis pv. citri (XAC), are difficult to con-
trol in the agricultural production process. The high
loss-rate in bacteria-infected plants and the lack of
effective control methods cause an enormous eco-
nomic loss to farmers worldwide every year. The
traditional bactericides currently available are not
very effective, and frequent use of these bacteri-
cides has resulted in the development of bacterial
resistance to them. Like pathogenic bacteria, phy-
topathogenic fungi also cause severe yield losses
and a reduction in the quality of agricultural prod-
ucts every year. Accordingly, the development of
new antibacterial and antifungal agents represents
tracted growing attention in recent years due to
their various biological activities, such as antibacterial
(Panneerselvam et al., 2009; Shi et al., 2013; Dixit et
al., 2015), antifungal (Bartroli et al., 1998; Wang et al.,
2013; El-Hashash et al., 2015), antimalarial (Zhu et
al., 2010), antiviral (Ma et al., 2014), antitumour (Cao
et al., 2005) and anticonvulsant activities (Jatav et al.,
2008). Recently, Asker’s study indicated that an N-
substituted-2-methyl quinazolin-4(3H)-one derivative
bearing 1,3,4-thiadiazole and 2-azetidinone moieties
(compound A, Fig. 1) exhibited a broad spectrum of
antimicrobial activity (Asker et al., 2014). In addition,
1,2,4-triazole derivatives (as another important hete-
rocyclic compounds) have attracted attention in the
*Corresponding author, e-mail: baoxp 1980@aliyun.com
Unauthenticated
Download Date | 3/30/16 10:12 AM

ii
B. R. Yan et al./Chemical Papers
Fig. 1. Chemical structures of compounds A, B, C and VIIa–VIIt.
Fig. 2. Synthesis of target compounds VIIa–VIIt.
development of new antibacterial or antifungal agents
one backbone with 1,2,4-triazolylthioether into a sin-
gle molecule for the development of new agrochem-
icals has been reported to date. In a previous work
(Liu et al., 2013), a series of quinazoline derivatives
containing 1,2,4-triazole Schiff-base unit (compounds
C, Fig. 1) were synthesised and some compounds were
found to exhibit a certain fungicidal activity against
the tested fungi. On the basis of the above consid-
erations and in a continuing search for highly active
antimicrobial agents, in the present study a series
of novel quinazolinone derivatives containing 1,2,4-
triazolylthioether moiety were designed and synthe-
sised in accordance with the principle of the combina-
(Holla et al., 2000; Turan-Zitouni et al., 2005; Cao et
al., 2008; Hasan et al., 2011; Plech et al., 2013; Zhang
et al., 2014). Fluquinconazole (compound B, Fig. 1),
as the best-known example of a combination of quina-
zolinone backbone with 1,2,4-triazole heterocycle, has
been used extensively as an agricultural fungicide for
crop protection. Moreover, previous studies indicated
that the introduction of a thioether unit into pesti-
cide molecules was helpful in improving their bioac-
tivities (G u¨ lerman et al., 2001; Shin et al., 2001; Patil
et al., 2010). However, to the best of our knowledge,
no example of the integration of a quinazolin-4(3H)-
Unauthenticated
Download Date | 3/30/16 10:12 AM

B. R. Yan et al./Chemical Papers
iii
Table 1. Physical properties and analytical data for target compounds VIIa–VIIt
wi(calc.)/%
wi(found)/%
Yield
M.p.
Compound
Formula
Appearance
Mr
◦
C
H
N
%
C
VIIa
VIIb
VIIc
VIId
VIIe
VIIf
VIIg
VIIh
VIIi
VIIj
VIIk
VIIl
C24H19N5OS
Colourless solid
White solid
Yellow solid
Colourless solid
White solid
Colourless solid
Yellow solid
White solid
Colourless solid
White solid
White solid
Yellow solid
Yellow solid
White solid
White solid
Colourless solid
White solid
White solid
White solid
Brown solid
425.13
481.19
470.12
493.05
515.08
459.05
459.05
459.05
443.12
443.12
443.12
439.15
439.15
439.15
455.14
455.14
493.12
493.12
493.12
460.09
67.74
4.50
4.93
5.65
6.01
3.86
4.14
3.47
3.68
2.74
3.00
3.94
4.20
3.94
4.20
3.94
4.35
4.09
4.34
4.09
4.07
4.09
4.36
4.82
5.09
4.82
5.19
4.82
5.23
4.65
4.67
4.65
5.04
3.68
4.05
3.68
4.06
3.68
4.02
3.72
3.85
16.46
16.86
14.54
14.87
17.86
18.06
14.17
14.55
13.59
13.94
15.23
15.58
15.23
15.57
15.23
15.46
15.79
16.14
15.79
16.14
15.79
16.20
15.93
16.26
15.93
16.32
15.93
16.30
15.37
15.75
15.37
15.76
14.19
14.21
14.19
14.58
14.19
14.52
18.23
18.41
71.6
188–190
175–178
188–199
> 250
6
7.79
69.83
9.57
61.27
0.88
58.30
8.12
55.92
5.90
62.67
2.87
62.67
2.79
62.67
2.74
65.00
5.38
65.00
5.13
65.00
5.40
68.32
8.69
68.32
8.66
68.32
8.60
65.92
6.30
65.92
6.17
60.84
0.47
60.84
1.13
60.84
0.58
59.93
9.57
C28H27N5OS
58.0
50.0
90.4
60.1
72.9
72.9
75.8
75.6
90.7
58.4
89.0
69.8
83.7
92.0
70.1
92.7
86.7
67.9
70.0
6
C24H18N6O3S
C24H17Cl2N5OS
C24H14F5N5OS
C24H18ClN5OS
C24H18ClN5OS
C24H18ClN5OS
C24H18FN5OS
C24H18FN5OS
C24H18FN5OS
C25H21N5OS
6
5
127–128
211–213
150−151
145–146
200–202
168–169
134–136
210–213
146–148
153–154
162–164
151–153
180–181
116–119
98–101
5
6
6
6
6
6
6
6
VIIm
VIIn
VIIo
VIIp
VIIq
VIIr
VIIs
VIIt
C25H21N5OS
6
C25H21N5OS
6
C25H21N5O2S
C25H21N5O2S
C25H18F3N5OS
C25H18F3N5OS
C25H18F3N5OS
C23H17ClN6OS
6
6
6
6
6
132–134
5
tion of bioactive substructures (Fig. 2). The biological
test indicated that some of the target compounds pos-
sessed good antibacterial activities against XOO and
XAC.
pressed in parts per million (ppm). Mass spectra were
recorded on an Agilent LC/MSD Trap VL spectrome-
ter (Agilent, USA). Elemental analysis was performed
on an Elementar Vario-III CHN analyser (Elementar,
Germany). The X-ray data for compound VIIi were
collected using a Bruker Smart Apex CCD area de-
tector diffractometer (Bruker, Germany) with Mo-Kα
radiation. The progress of the reactions was monitored
by TLC performed on silica gel GF254. Intermediates
II, III and IV were prepared as previously described
in the literature (Sun et al., 2013; Mali et al., 2009).
Experimental
All the solvents and materials were of analytical
grade and used without further purification. Melt-
ing points were uncorrected and determined on an
XT-4 binocular microscope (Beijing Tech Instrument,
China); the IR spectra were recorded on an IR
Prestige-21 spectrometer (Shimadzu, Japan) using the
Synthesis of 2-(2-(4-oxoquinazolin-3(4H)-yl)
acetyl)-N-phenylhydrazinecarbothioamide (V)
1
13
KBr disk technique. The H and C NMR spectra
were measured on a JEOL-ECX 500 NMR spectrome-
ter (JEOL, Japan) at ambient temperature using TMS
as an internal standard and chemical shifts δ are ex-
Compound IV (2.29 mmol) and phenylisothio-
cyanate (2.52 mmol) were dissolved in ethanol (20 mL)
Unauthenticated
Download Date | 3/30/16 10:12 AM

iv
B. R. Yan et al./Chemical Papers
and heated to reflux for 3 h. Subsequently, the reaction
mixture was cooled to ambient temperature and the
precipitate thus formed was separated by filtration,
washed with ethanol and dried to afford intermediate
V . White solid; yield, 83.9 %; m.p.: 218–220 C; H
NMR (DMSO-d6, 500 MHz), δ: 4.74 (s, 2H, QuCH2),
tural University, China) were evaluated using the tur-
bidimeter test (Xu et al., 2012).
The antifungal activities of compounds VIIa–VIIt
against six phytopathogenic fungi: Gibberella zeae
(G. zeae), Cytospora mandshurica (C. mandshurica),
Phytophthora infestans (P. infestans), Pellicularia
sasakii (P. sasakii), Colletotrichum capsici (C. cap-
sici) and Gloeosporium fructigenum (G. fructigenum),
stored in Guizhou University, were evaluated using the
mycelium growth-rate method (Liu et al., 2008).
◦
1
7
2
7
7
1
.15 (d, J = 7.5 Hz, 1H, ArH), 7.32 (t, J = 7.5 Hz,
H, ArH), 7.46 (d, J = 7.5 Hz, 2H, ArH), 7.54 (t, J =
.2 Hz, 1H, QuH), 7.68 (d, J = 8.0 Hz, 1H, QuH),
.83 (t, J = 7.7 Hz, 1H, QuH), 8.10 (d, J = 8.0 Hz,
H, QuH), 8.30 (s, 1H, QuH), 9.42 (s, 1H, NH), 9.78
(s, 1H, NH), 10.53 (s, 1H, NH).
Results and discussion
Synthesis of 3-((5-mercapto-4-phenyl-4H-
,2,4-triazol-3-yl)methyl)quinazolin-4(3H)-one
VI)
Synthesis
1
(
The synthesis of target compounds VIIa–VIIt is
shown in Fig. 2. First, quinazolin-4-one (II ) was syn-
thesised by the condensation of methyl o-aminobenzo-
ate with formamide in refluxing formic acid (Sun et
al., 2013). The treatment of II with ethyl bromoac-
etate in the presence of K2CO3 in refluxing acetone
afforded ethyl 2-(4-oxoquinazolin-3(4H)-yl) acetate
(III ) (Mali et al., 2009). The further reaction of III
with hydrazine hydrate in refluxing ethanol afforded 2-
(4-oxoquinazolin-3(4H)-yl)acetohydrazide (IV ) (Mali
et al., 2009), which was subsequently allowed to re-
act with phenylisothiocyanate to generate 2-(2-(4-
oxoquinazolin-3(4H)-yl)acetyl)-N-phenylhydrazine-
carbothioamide (V ). The 5 mass % aqueous potas-
sium carbonate solution of V was heated to reflux for
6 h and then neutralised with 10 mass % HCl; the
resulting 3-((5-mercapto-4-phenyl-4H-1,2,4-triazol-3-
yl)methyl)quinazolin-4(3H)-one (VI ) was obtained
with a 50 % yield. Finally, target compounds VIIa–
VIIt were readily obtained by the reaction of VI with
substituted benzyl halide or 2-chloro-5-chloromethyl-
pyridine in DMF with K2CO3 as catalyst at ambient
temperature.
Compound V (1.87 mmol) was slowly added to
5
mass % aqueous potassium carbonate solution
(
20 mL) and heated to reflux for 6 h. After cooling to
ambient temperature, the resulting solid was removed
by filtration and the filtrate was neutralised with di-
lute HCl to pH 7. The precipitate was separated by
filtration, washed with water, dried and recrystallized
with DMF/H2O (1 : 1, vol.) to give VI. White solid;
◦
1
yield, 50.0 %; m.p.: 260–261 C; H NMR (DMSO-d6,
00 MHz) δ: 5.05 (s, 2H, QuCH2), 7.49 (d, J = 6.9
Hz, 2H, ArH), 7.54–7.59 (m, 4H, ArH & QuH), 7.69
d, J = 8.0 Hz, 1H, QuH), 7.86 (t, J = 7.4 Hz, 1H,
5
(
QuH), 8.10 (d, J = 6.9 Hz, 1H, QuH), 8.27 (s, 1H,
QuH), 13.91 (s, 1H, NH).
General synthetic procedure for target com-
pounds VIIa–VIIt
Substituted benzyl halide or 2-chloro-5-chlorome-
thylpyridine (0.6 mmol) was added to a solution of
compound VI (0.5 mmol) in DMF (10 mL) at ambi-
ent temperature, then potassium carbonate (1 mmol)
was added. The resulting mixture was stirred at ambi-
ent temperature for several hours. Upon completion of
the reaction as indicated by TLC (CH2Cl2/CH3OH,
The structures of target compounds (VIIa–VIIt)
were characterised using 1H NMR, C NMR, MS,
13
1
IR and elemental analyses. In the H NMR spectra of
VIIa–VIIt, one singlet at δ 5.22–5.15 was attributed to
the signal of the CH2 protons linked to the quinazoli-
none ring, and the other CH2 protons of the —SCH2—
fragment appeared at δ 4.69–4.36 as a singlet. The
chemical shift at around δ 160.0 in the 13C NMR spec-
tra of target compounds showed the existence of C—O
5
: 1, vol.), the reaction mixture was poured into cold
water and the resulting precipitate was separated by
filtration, washed with water and recrystallized from
CH2Cl2/CH3CH2OH (1 : 15, vol.) to afford the ti-
tle compounds. The physical properties and analytical
data of these compounds are listed in Table 1, and the
corresponding spectral data are shown in Table 2.
group of the quinazolinone ring. The IR spectra of
VIIa–VIIt also displayed characteristic bands at 1689–
−
1
1
672 cm , attributed to the stretching vibration of
Antibacterial and antifungal activity
the quinazolinone C—O group. All the target com-
pounds were confirmed using ESI-MS, which displayed
+
+
The antibacterial activities of compounds VIIa–
VIIt against tobacco bacterial wilt (Ralstonia solana-
cearum strain MR111, Guizhou University, China),
Xanthomonas axonopodis pv. citri (strain 29-1, Shang-
hai Jiao Tong University, China) and Xanthomonas
oryzae pv. oryzae (strain PXO99A, Nanjing Agricul-
the existence of [M + H] and [M + Na] peaks. The
structure of VIIi was also confirmed using the X-ray
single-crystal diffraction method (Fig. 3 and Table 3).
The crystallographic data for this compound were de-
posited in the Cambridge Crystallographic Data Cen-
tre, no. CCDC-1036531.
Unauthenticated
Download Date | 3/30/16 10:12 AM

B. R. Yan et al./Chemical Papers
Table 2. Spectral data of target compounds VIIa–VIIt
v
Compound
Spectral data
IR, ν˜ /cm 1: 1172 (C—S), 1610 (C—N),1683 (C—O), 3053 (ArH)
−
VIIa
1
H NMR (CDCl3), δ: 4.41 (s, 2H, SCH2), 5.17 (s, 2H, CH2), 7.09 (d, J = 7.4 Hz, 2H, ArH), 7.23–7.28 (m, 5H,
ArH), 7.40 (t, J = 7.4 Hz, 2H, ArH), 7.44–7.48 (m, 2H, ArH), 7.71 (d, J = 7.5 Hz, 1H, ArH), 7.76 (t, J = 7.0 Hz,
1
H, ArH), 8.14 (d, J = 8.6 Hz, 1H, ArH), 8.15 (s, 1H, ArH)
13
C NMR (CDCl3), δ: 37.4, 39.6, 121.8, 126.7, 127.1, 127.6, 127.7, 127.9, 128.8, 129.2, 130.1, 130.6, 132.2, 134.6,
36.3, 145.8, 147.9, 151.0, 153.0, 160.3
MS (ESI) m/z: 426.3 ([M + H]+), 448.3 ([M + Na]+
1
)
−
1
VIIb
VIIc
VIId
VIIe
VIIf
VIIg
VIIh
VIIi
IR, ν˜ /cm : 1172 (C—S), 1610 (C—N), 1685 (C—O), 2962 (CH2)
1
H NMR (CDCl3), δ: 1.27 (s, 9H, CH3), 4.38 (s, 2H, SCH2), 5.18 (s, 2H, CH2), 7.04 (d, J = 8.0 Hz, 2H, ArH), 7.19
(
d, J = 8.0 Hz, 2H, ArH), 7.28 (d, J = 8.6 Hz, 2H, ArH), 7.38 (t, J = 7.7 Hz, 2H, ArH), 7.42–7.47 (m, 2H, ArH),
.71 (d, J = 8.0 Hz, 1H, ArH), 7.75 (t, J = 7.0 Hz, 1H, ArH), 8.14 (d, J = 8.0 Hz, 1H, ArH), 8.16 (s, 1H, ArH)
7
1
3
C NMR (CDCl3), δ: 31.4, 34.6, 37.3, 39.5, 121.8, 125.7, 126.8, 127.1, 127.6, 127.8, 128.9, 130.0, 130.5, 132.2, 133.3,
34.6, 145.7, 147.9, 150.9, 151.0, 153.2, 160.2
1
MS (ESI) m/z: 482.4 ([M + H] ), 504.4 ([M + Na]+
+
)
−
1
IR, ν˜ /cm : 1165 (C—S), 1610 (C—N), 1672 (C—O), 3076 (ArH)
1
H NMR (CDCl3), δ: 4.47 (s, 2H, SCH2), 5.15 (s, 2H, CH2), 7.20 (d, J = 7.4 Hz, 2H, ArH), 7.46–7.52 (m, 4H,
ArH), 7.55 (d, J = 8.6 Hz, 2H, ArH), 7.71 (d, J = 8.0 Hz, 1H, ArH), 7.76 (t, J = 6.9 Hz, 1H, ArH), 8.12–8.15 (m,
4
H, ArH)
1
3
C NMR (CDCl3), δ: 35.8, 39.8, 121.8, 123.9, 126.7, 127.0, 127.7, 127.8, 130.2, 130.3, 130.8, 132.0, 134.7, 144.4,
45.8, 147.4, 148.0, 151.4, 152.0, 160.4
MS (ESI) m/z: 471.3 ([M + H]+), 493.3 ([M + Na]+
1
)
−
1
IR, ν˜ /cm : 1238 (C—S), 1608 (C—N), 1683 (C—O), 2937 (CH2)
1
H NMR (CDCl3), δ: 4.69 (s, 2H, SCH2), 5.22 (s, 2H, CH2), 7.13 (t, J = 8.0 Hz, 1H, ArH), 7.22 (d, J = 7.4 Hz,
2
1
H, ArH), 7.24−7.26 (m, 2H, ArH), 7.40–7.49 (m, 4H, ArH), 7.72 (d, J = 7.4 Hz, 1H, ArH), 7.76 (t, J = 7.5 Hz,
H, ArH), 8.15 (d, J = 8.0 Hz, 1H, ArH), 8.19 (s, 1H, ArH)
1
3
C NMR (CDCl3), δ: 33.6, 39.7, 121.8, 126.8, 127.1, 127.6, 127.8, 128.5, 129.6, 130.1, 130.6, 132.1, 132.2, 134.6,
36.2, 145.8, 147.9, 151.4, 152.4, 160.3
MS (ESI) m/z: 494.2 ([M + H]+), 516.2 ([M + Na]+
1
)
−
1
IR, ν˜ /cm : 1170 (C—S), 1612 (C—N), 1676 (C—O), 3066 (ArH)
1
H NMR (CDCl3), δ: 4.41 (s, 2H, SCH2), 5.19 (s, 2H, CH2), 7.29 (d, J = 6.8 Hz, 2H, ArH), 7.47–7.53 (m, 4H,
ArH), 7.72 (d, J = 8.0 Hz, 1H, ArH), 7.76 (t, J = 7.4 Hz, 1H, ArH), 8.16 (d, J = 8.0 Hz, 1H, ArH), 8.18 (s, 1H,
ArH)
1
3C NMR (CDCl3), δ: 24.0, 39.8, 121.8, 126.7, 127.0, 127.6, 127.8, 130.3, 130.8, 132.0, 134.7, 145.8, 148.0, 151.2,
51.7, 160.4
1
MS (ESI) m/z: 516.3 ([M + H]+), 538.3 ([M + Na]+
)
−
1
IR, ν˜ /cm : 1172 (C—S), 1610 (C—N), 1674 (C—O), 3051 (ArH)
1
H NMR (CDCl3), δ: 4.53 (s, 2H, SCH2), 5.17 (s, 2H, CH2), 7.12 (d, J = 8.0 Hz, 2H, ArH), 7.15–7.21 (m, 2H,
ArH), 7.33 (d, J = 7.5 Hz, 1H, ArH), 7.42 (t, J = 7.5 Hz, 2H, ArH), 7.44–7.48 (m, 3H, ArH), 7.70 (d, J = 8.0 Hz,
1
H, ArH), 7.69–7.77 (m, 1H, ArH), 8.14–8.15 (m, 2H, ArH)
1
3
C NMR (CDCl3), δ: 35.0, 39.7, 121.8, 126.8, 127.0, 127.1, 127.6, 127.8, 129.4, 129.7, 130.2, 130.6, 131.6, 132.1,
34.4, 134.5, 134.7, 145.8, 147.9, 151.2, 153.0, 160.3
1
MS (ESI) m/z: 460.3 ([M + H] ), 482.3 ([M + Na]+
+
)
−
1
IR, ν˜ /cm : 1168 (C—S), 1610 (C—N), 1682 (C—O), 3051 (ArH)
1
H NMR (CDCl3), δ: 4.37 (s, 2H, SCH2), 5.17 (s, 2H, CH2), 7.14 (d, J = 7.0 Hz, 2H, ArH), 7.19–7.22 (m, 3H,
ArH), 7.29 (s, 1H, ArH), 7.43–7.49 (m, 4H, ArH), 7.71 (d, J = 7.5 Hz, 1H, ArH), 7.76 (t, J = 7.0 Hz, 1H, ArH),
8
.15 (d, J = 8.0 Hz, 1H, ArH), 8.16 (s, 1H, ArH)
1
3
C NMR (CDCl3), δ: 36.6, 39.7, 121.8, 126.8, 127.0, 127.5, 127.6, 127.8, 128.1, 129.3, 130.0, 130.2, 130.7, 132.1,
34.5, 134.7, 138.5, 145.8, 147.9, 151.2, 152.6, 160.3
1
MS (ESI) m/z: 460.3 ([M + H] ), 482.3 ([M + Na]+
+
)
−
1
IR, ν˜ /cm : 1172 (C—S), 1610 (C—N), 1676 (C—O), 3061 (ArH)
1
H NMR (CDCl3), δ: 4.37 (s, 2H, SCH2), 5.17 (s, 2H, CH2), 7.13 (d, J = 8.0 Hz, 2H, ArH), 7.22–7.24 (m, 4H,
ArH), 7.42–7.49 (m, 4H, ArH), 7.71 (d, J = 8.0 Hz, 1H, ArH), 7.76 (t, J = 7.5 Hz, 1H, ArH), 8.14–8.15 (m, 2H,
ArH)
1
3C NMR (CDCl3), δ: 36.4, 39.7, 121.8, 126.7, 127.0, 127.6, 127.8, 128.9, 130.2, 130.6, 130.6, 132.1, 133.7, 134.5,
35.1, 145.8, 147.9, 151.2, 152.7, 160.3
1
MS (ESI) m/z: 460.3 ([M + H]+), 482.3 ([M + Na]+
)
−
1
IR, ν˜ /cm : 1172 (C—S), 1610 (C—N), 1676 (C—O), 3055 (ArH)
1
H NMR (CDCl3), δ: 4.44 (s, 2H, SCH2), 5.17 (s, 2H, CH2), 6.99 (t, J = 9.2 Hz, 1H, ArH), 7.04 (d, J = 7.7 Hz,
1
1
H, ArH), 7.14 (d, J = 8.0 Hz, 2H, ArH), 7.21–7.24 (m, 1H, ArH), 7.39–7.49 (m, 5H, ArH), 7.70 (d, J = 7.4 Hz,
H, ArH), 7.76 (t, J = 7.5 Hz, 1H, ArH), 8.15 (d, J = 8.0 Hz, 1H, ArH), 8.16 (s, 1H, ArH)
1
3
C NMR (CDCl3), δ: 30.4, 39.7, 115.5, 115.6, 121.8, 123.8, 123.9, 124.3, 124.4, 126.7, 127.0, 127.6, 127.8, 129.8,
29.9, 130.2, 130.6, 131.5, 131.6, 132.1, 134.6, 145.8, 147.9, 151.2, 152.8, 160.0, 160.3, 162.0
1
MS (ESI) m/z: 444.3 ([M + H] ), 466.3 ([M + Na]+
+
)
Unauthenticated
Download Date | 3/30/16 10:12 AM

vi
B. R. Yan et al./Chemical Papers
Table 2. (continued)
Compound
Spectral data
IR, ν˜ /cm 1: 1172 (C—S), 1610 (C—N), 1685 (C—O), 3062 (ArH)
−
VIIj
VIIk
VIIl
1
H NMR (CDCl3), δ: 4.40 (s, 2H, SCH2), 5.17 (s, 2H, CH2), 6.94 (t, J = 8.3 Hz, 1H, ArH), 7.04 (d, J = 9.7 Hz,
H, ArH), 7.09 (d, J = 7.4 Hz, 1H, ArH), 7.15 (d, J = 6.3 Hz, 2H, ArH), 7.20–7.23 (m, 1H, ArH), 7.44–7.49 (m,
H, ArH), 7.71 (d, J = 8.0 Hz, 1H, ArH), 7.75 (t, J = 7.7 Hz, 1H, ArH), 8.13–8.15 (m, 2H, ArH)
1
4
13
C NMR (CDCl3), δ: 36.5, 39.6, 114.7, 114.9, 116.0, 116.2, 121.7, 124.8, 124.9, 126.6, 126.9, 127.5, 127.7, 130.2,
30.3, 130.6, 132.0, 134.6, 138.7, 138.8, 145.7, 147.8, 151.1, 152.6, 160.2, 161.7, 163.7
1
MS (ESI) m/z: 444.3 ([M + H] ), 466.3 ([M + Na]+
+
)
−
1
IR, ν˜ /cm : 1172 (C—S), 1610 (C—N), 1674 (C—O), 3062 (ArH)
1
H NMR (CDCl3), δ: 4.39 (s, 2H, SCH2), 5.17 (s, 2H, CH2), 6.95 (t, J = 8.6 Hz, 2H, ArH), 7.16 (d, J = 7.4 Hz,
H, ArH), 7.27–7.30 (m, 2H, ArH), 7.42–7.50 (m, 4H, ArH), 7.71 (d, J = 7.4 Hz, 1H, ArH), 7.76 (t, J = 8.0 Hz,
H, ArH), 8.15 (d, J = 8.0 Hz, 1H, ArH), 8.16 (s, 1H, ArH)
2
1
13
C NMR (CDCl3), δ: 36.4, 39.7, 115.6, 115.7, 121.8, 126.7, 127.0, 127.6, 127.8, 130.2, 130.6, 130.9, 131.0, 132.1,
32.2, 134.7, 145.8, 147.9, 151.1, 152.8, 160.3, 161.4, 163.4
1
MS (ESI) m/z: 444.3 ([M + H] ), 466.3 ([M + Na]+
+
)
−
1
IR, ν˜ /cm : 1172 (C—S), 1608 (C—N), 1676 (C—O), 3045 (ArH)
1
H NMR (CDCl3), δ: 2.27 (s, 3H, CH3), 4.42 (s, 2H, SCH2), 5.18 (s, 2H, CH2), 7.06 (d, J = 8.0 Hz, 2H, ArH), 7.10
(
t, J = 8.3 Hz, 2H, ArH), 7.15 (t, J = 7.4 Hz, 1H, ArH), 7.20 (d, J = 7.4 Hz, 1H, ArH), 7.39 (t, J = 7.7 Hz, 2H,
ArH), 7.43−7.49 (m, 2H, ArH), 7.72 (d, J = 8.0 Hz, 1H, ArH), 7.76 (t, J = 8.0 Hz, 1H, ArH), 8.14 (d, J = 8.0 Hz,
H, ArH), 8.15 (s, 1H, ArH)
1
1
3
C NMR (CDCl3), δ: 19.1, 35.9, 39.6, 121.8, 126.4, 126.8, 127.1, 127.6, 127.8, 128.3, 130.0, 130.2, 130.5, 130.7,
32.2, 133.8, 134.6, 137.2, 145.8, 147.9, 151.0, 153.1, 160.3
1
MS (ESI) m/z: 440.3 ([M + H] ), 462.3 ([M + Na]+
+
)
−
1
VIIm
VIIn
VIIo
IR, ν˜ /cm : 1178 (C—S), 1610 (C—N), 1683 (C—O), 3035 (ArH)
1
H NMR (CDCl3), δ: 2.29 (s, 3H, CH3), 4.38 (s, 2H, SCH2), 5.18 (s, 2H, CH2), 7.04–7.10 (m, 5H, ArH), 7.15 (t,
J = 7.7 Hz, 1H, ArH), 7.41 (t, J = 7.4 Hz, 2H, ArH), 7.45–7.49 (m, 2H, ArH), 7.71 (d, J = 8.0 Hz, 1H, ArH), 7.76
(
t, J = 6.9 Hz, 1H, ArH), 8.15 (d, J = 7.5 Hz, 1H, ArH), 8.16 (s, 1H, ArH)
13
C NMR (CDCl3), δ: 21.4, 37.4, 39.6, 121.8, 126.3, 126.8, 127.1, 127.6, 127.8, 128.7, 129.9, 130.1, 130.6, 132.2,
33.1, 134.6, 136.1, 138.5, 145.8, 147.9, 151.0, 153.2, 160.3
1
MS (ESI) m/z: 440.3 ([M + H] ), 462.3 ([M + Na]+
+
)
−
1
IR, ν˜ /cm : 1172 (C—S), 1610 (C—N), 1687 (C—O), 3059 (ArH)
1
H NMR (CDCl3), δ: 2.29 (s, 3H, CH3), 4.38 (s, 2H, SCH2), 5.18 (s, 2H, CH2), 7.05–7.08 (m, 4H, ArH), 7.18 (d,
J = 8.0 Hz, 2H, ArH), 7.40 (t, J = 7.7 Hz, 2H, ArH), 7.44–7.49 (m, 2H, ArH), 7.71 (d, J = 7.4 Hz, 1H, ArH), 7.76
(
t, J = 6.9 Hz, 1H, ArH), 8.14 (d, J = 7.0 Hz, 1H, ArH), 8.15 (s, 1H, ArH)
13
C NMR (CDCl3), δ: 21.2, 37.2, 39.5, 121.8, 126.8, 127.1, 127.6, 127.8, 129.1, 129.4, 130.1, 130.5, 132.2, 133.2,
36.6, 137.7, 145.8, 147.9, 151.0, 153.2, 160.3
1
MS (ESI) m/z: 440.3 ([M + H] ), 462.3 ([M + Na]+
+
)
−
1
IR, ν˜ /cm : 1153 (C—S), 1610 (C—N), 1683 (C—O), 3001 (ArH)
1
H NMR (CDCl3), δ: 3.74 (s, 3H, OCH3), 4.37 (s, 2H, SCH2), 5.17 (s, 2H, CH2), 6.78 (d, J = 8.0 Hz, 1H, ArH),
6
7
.81 (s, 1H, ArH), 6.86 (d, J = 8.0 Hz, 1H, ArH), 7.10 (d, J = 8.0 Hz, 2H, ArH), 7.17 (t, J = 7.7 Hz, 1H, ArH),
.40 (t, J = 8.0 Hz, 2H, ArH), 7.44–7.48 (m, 2H, ArH), 7.70 (d, J = 7.4 Hz, 1H, ArH), 7.75 (t, J = 7.0 Hz, 1H,
ArH), 8.12–8.14 (m, 2H, ArH)
1
3C NMR (CDCl3), δ: 37.4, 39.6, 55.3, 113.7, 114.5, 121.5, 121.8, 126.7, 127.1, 127.6, 127.8, 129.8, 130.1, 130.5,
1
32.2, 134.6, 137.7, 145.8, 147.9, 151.0, 153.0, 159.8, 160.3
MS (ESI) m/z: 456.3 ([M + H] ), 478.3 ([M + Na]+
+
)
−
1
VIIp
IR, ν˜ /cm : 1172 (C—S), 1608 (C—N), 1683 (C—O), 3051 (ArH)
1
H NMR (CDCl3), δ: 3.75 (s, 3H, OCH3), 4.36 (s, 2H, SCH2), 5.17 (s, 2H, CH2), 6.79 (d, J = 8.6 Hz, 2H, ArH),
7.11 (d, J = 8.0 Hz, 2H, ArH), 7.21 (d, J = 9.2 Hz, 2H, ArH), 7.40 (t, J = 8.0 Hz, 2H, ArH), 7.43–7.38 (m, 2H,
ArH), 7.70 (d, J = 7.4 Hz, 1H, ArH), 7.74 (t, J = 7.0 Hz, 1H, ArH), 8.13 (d, J = 8.0 Hz, 1H, ArH), 8.14 (s, 1H,
ArH)
1
3C NMR (CDCl3), δ: 36.9, 39.6, 55.4, 114.1, 121.8, 126.7, 127.1, 127.6, 127.8, 128.2, 130.1, 130.4, 130.5, 132.2,
1
34.6, 145.8, 147.9, 151.0, 153.2, 159.3, 160.3
MS (ESI) m/z: 456.3 ([M + H] ),478.3 ([M + Na]+
+
)
−
1
VIIq
IR, ν˜ /cm : 1170 (C—S), 1614 (C—N), 1689 (C—O), 3062 (ArH)
1
H NMR (CDCl3), δ: 4.63 (s, 2H, SCH2), 5.18 (s, 2H, CH2), 7.16 (d, J = 8.0 Hz, 2H, ArH), 7.36 (t, J = 7.7 Hz,
1
8
H, ArH), 7.42–7.50 (m, 5H, ArH), 7.61 (d, J = 7.4 Hz, 1H, ArH), 7.67–7.72 (m, 2H, ArH, 7.75–7.78 (m, 1H, ArH),
.16 (d, J = 8.0 Hz, 1H, ArH), 8.17 (s, 1H, ArH)
1
3
C NMR (CDCl3, 125 MHz) δ: 33.3, 39.6, 121.8, 123.1, 125.2, 126.2, 126.3, 126.7, 127.0, 127.6, 127.8, 130.2, 130.7,
32.0, 132.3, 132.4, 134.7, 135.3, 145.8, 148.0, 151.3, 153.0, 160.4
1
MS (ESI) m/z: 494.3 ([M + H] ), 516.3 ([M + Na]+
+
)
Unauthenticated
Download Date | 3/30/16 10:12 AM

B. R. Yan et al./Chemical Papers
vii
Table 2. (continued)
Compound
Spectral data
IR, ν˜ /cm 1: 1166 (C—S), 1612 (C—N), 1683 (C—O), 3062 (ArH)
−
VIIr
VIIs
VIIt
1
H NMR (CDCl3), δ: 4.45 (s, 2H, SCH2), 5.16 (s, 2H, CH2), 7.13 (d, J = 7.0 Hz, 2H, ArH), 7.39 (t, J = 7.7 Hz,
H, ArH), 7.42–7.55 (m, 7H, ArH), 7.71 (d, J = 8.0 Hz, 1H, ArH), 7.76 (t, J = 7.0 Hz, 1H, ArH), 8.12–8.14 (m,
H, ArH)
1
2
13
C NMR (CDCl3), δ: 36.6, 39.7, 121.8, 122.9, 124.6, 124.7, 125.9, 126.7, 127.0, 127.6, 127.8, 129.2, 130.2, 130.7,
32.0, 132.7, 134.7, 137.6, 145.8, 147.9, 151.2, 152.4, 160.3
1
MS (ESI) m/z: 494.3 ([M + H] ), 516.3 ([M + Na]+
+
)
−
1
IR, ν˜ /cm : 1165 (C—S), 1612 (C—N), 1683 (C—O), 3051 (ArH)
1
H NMR (CDCl3), δ: 4.44 (s, 2H, SCH2), 5.16 (s, 2H, CH2), 7.14 (d, J = 7.5 Hz, 2H, ArH), 7.42–7.45 (m, 4H,
ArH), 7.46–7.49 (m, 2H, ArH), 7.53 (d, J = 8.0 Hz, 2H, ArH), 7.71 (d, J = 6.9 Hz, 1H, ArH), 7.76 (t, J = 7.5 Hz,
1
H, ArH), 8.13−8.16 (m, 2H, ArH)
13
C NMR (CDCl3), δ: 36.4, 39.7, 121.8, 125.6, 125.7, 126.7, 127.0, 127.6, 127.8, 129.6, 130.2, 130.7, 131.1, 132.0,
34.7, 140.8, 145.8, 147.9, 151.3, 152.4, 160.4
1
MS (ESI) m/z: 494.3 ([M + H] ),516.3 ([M + Na]+
+
)
−
1
IR, ν˜ /cm : 1165 (C—S), 1608 (C—N), 1683 (C—O), 3064 (ArH)
1
H NMR (CDCl3), δ: 4.38 (s, 2H, SCH2), 5.16 (s, 2H, CH2), 7.21 (d, J = 7.0 Hz, 2H, ArH), 7.25 (d, J = 8.0 Hz,
1
H, ArH), 7.47–7.53 (m, 4H, ArH), 7.70–7.78 (m, 3H, ArH), 8.14–8.16 (m, 2H, ArH), 8.35 (d, J = 2.3 Hz, 1H, ArH)
13
C NMR (CDCl3), δ: 32.9, 39.8, 121.8, 124.2, 126.7, 126.9, 127.6, 127.8, 130.3, 130.8, 131.9, 131.9, 134.7, 139.8,
45.8, 148.0, 150.1, 150.8, 151.4, 152.0, 160.4
1
MS (ESI) m/z: 461.3 ([M + H] ), 483.3 ([M + Na]+
+
)
VIIh and VIIs against XOO at 200 µg mL 1 were
−
9
9.2 %, 99.8 % and 99.9 %, respectively, which
were even better than those of the positive con-
trols, thiodiazole-copper and bismerthiazol. In addi-
tion, compounds VIIb and VIIs exhibited 53.0 %
−
1
and 99.9 % inhibition rates against at 100 µg mL
,
better than that of thiodiazole-copper (17.0 %). Ta-
ble 5 shows that compounds VIIh and VIIs exhib-
ited potent activities against with EC50 values of
−
1
−1
8
8.5 µg mL
and 47.6 µg mL , respectively, im-
plying that these two compounds had higher in-
hibition activities against XOO than bismerthiazol
−
1
(
92.6 µg mL ). Table 6 shows that compounds VIIb
and VIIs exhibited significant activities against XAC,
with EC50 values of 82.1 µg mL and 22.1 µg mL ,
Fig. 3. Crystal structure of compound VIIi.
−
1
−1
respectively, suggesting that VIIs had a higher inhibi-
tion activity against XAC than bismerthiazol (EC50 =
−
1
Antibacterial activity and structure-activity
relationship
58.2 µg mL ).
A preliminary analysis of structure-activity rela-
tionship was conducted based on the results given in
Table 4. Out of the target compounds, compound VIIs
(having 4-CF3 on the phenyl ring) was the best an-
tibacterial agent against XOO and XAC. The presence
of a strong electron-donating substitution (—OCH3)
on the phenyl ring (viz. VIIo and VIIp) was found to
exhibit no activity against tobacco bacterial wilt. As
far as XOO was concerned, the presence of —F or —Cl
substitution on the 4-position of phenyl ring was ben-
eficial to the activity, in comparison with that of the
halogen at the 2- or 3-position of phenyl ring. In ad-
dition, the existence of a weak electron-donating sub-
stitution (t-Bu) or a strong electron-withdrawing sub-
stitution (—CF3) at the 4-position of phenyl ring was
favourable for an inhibition effect against XAC. The
results indicated that quinazolinone derivatives con-
The commercial agricultural bactericides, thiodi-
azole-copper and bismerthiazol, were used as posi-
tive controls (Table 4). Some of the compounds with
good antibacterial activities were tested at five double-
−
1
−1
declining concentrations (80 µg mL , 40 µg mL ,
− −1 −1
1
2
0 µg mL , 10 µg mL and 5.0 µg mL ) in order
to obtain their corresponding EC50 values. The aver-
age EC50 was calculated from at least three separate
analyses of growth inhibition using the software pack-
age SPSS 17.0. The screening results are summarised
in Tables 5 and 6.
As shown in Table 4, the biological tests in vitro in-
dicated that some compounds possessed good antibac-
−
1
terial activities at a concentration of 200 µg mL
.
For example, the inhibition rates of compounds VIIg,
Unauthenticated
Download Date | 3/30/16 10:12 AM

viii
B. R. Yan et al./Chemical Papers
Table 3. Crystallographic data and structural refinements for compound VIIi
−
Empirical formula
Formula mass
Crystal system
Space group
a/˚A
C24H18FN5OS
443.49
Triclinic, colourless crystal
P –1
Dcalc/(g cm 3)
1.416
1.55–25.00
0.193
◦
2θ/
−
1
M /mm
µ
Unique reflections
Observed reflections
Parameters
Rint
3557
2331
284
0.0430
0.0704
0.2671
0.1123
0.2136
1.126
8.884(9)
9.123(10)
b/˚A
c/˚A
13.739(14)
87.870(15)
73.215(13)
77.362(14)
1039.9(19)
2
◦
α/
β/
γ/
R[I > 2σ(I)]
wR[I > 2σ(I)]
R(all data)
wR(all data)
GOF on F2
F (000)
◦
◦
V /˚A
Z/˚A
3
3
Crystal size/mm3
0.31 × 0.26 × 0.22
460
Table 4. Antibacterial activities of compounds VIIa–VIIt against XOO, XAC and tobacco bacterial wilt
a
Inhibition rate /%
Compound
XOO
XAC
Tobacco bacterial wilt
−
1
−1
−1
−1
−1
−1
100 µg mL
200 µg mL
100 µg mL
200 µg mL
100 µg mL
200 µg mL
VIIa
VIIb
VIIc
VIId
VIIe
VIIf
VIIg
VIIh
VIIi
VIIj
VIIk
VIIl
VIIm
VIIn
VIIo
VIIp
VIIq
30.1 ± 2.5
52.7 ± 1.3
48.5 ± 1.2
41.9 ± 3.6
20.2 ± 3.8
37.2 ± 6.9
99.2 ± 2.3
99.8 ± 2.0
35.4 ± 2.6
44.0 ± 2.3
60.5 ± 4.6
30.1 ± 4.6
62.5 ± 3.5
53.4 ± 2.2
42.5 ± 3.1
45.5 ± 1.2
84.1 ± 3.6
52.1 ± 3.8
99.9 ± 1.2
25.4 ± 3.3
35.3 ± 1.8
71.9 ± 0.6
24.0 ± 0.9
38.0 ± 2.6
26.3 ± 3.7
24.4 ± 2.8
18.3 ± 4.1
33.3 ± 1.8
45.5 ± 7.4
59.4 ± 7.2
10.1 ± 3.7
26.8 ± 1.6
24.3 ± 2.2
29.6 ± 3.3
32.1 ± 2.1
25.7 ± 6.5
32.2 ± 2.0
32.3 ± 5.1
32.4 ± 3.0
48.6 ± 1.0
87.4 ± 6.8
17.7 ± 3.5
29.1 ± 2.0
54.1 ± 1.2
44.5 ± 2.3
85.3 ± 1.7
7.2 ± 3.4
23.4 ± 1.3
53.0 ± 2.9
3.0 ± 2.1
7.2 ± 4.9
11.8 ± 2.7
6.1 ± 1.6
0
5.1 ± 3.6
12.0 ± 2.8
4.2 ± 4.3
10.0 ± 3.0
5.0 ± 3.7
30.3 ± 1.0
20.0 ± 2.2
11.3 ± 5.9
16.1 ± 1.7
9.9 ± 1.2
18.1 ± 2.3
99.9 ± 1.1
29.3 ± 1.1
17.0 ± 2.3
67.1 ± 6.8
37.3 ± 1.0
42.5 ± 1.3
45.4 ± 2.5
27.1 ± 3.0
36.5 ± 1.5
50.8 ± 1.6
41.3 ± 2.8
37.2 ± 1.4
31.4 ± 2.9
39.2 ± 3.8
56.0 ± 1.1
29.4 ± 1.4
26.1 ± 2.2
14.0 ± 2.7
0
10.0 ± 3.8
32.3 ± 1.8
27.1 ± 1.9
35.0 ± 2.6
38.0 ± 1.8
50.0 ± 1.2
–
19.1 ± 1.0
29.0 ± 2.7
25.2 ± 2.9
24.5 ± 1.6
36.0 ± 3.2
34.5 ± 2.8
33.0 ± 1.3
22.0 ± 2.6
29.0 ± 2.9
18.3 ± 1.2
40.0 ± 3.9
28.2 ± 2.9
25.8 ± 1.1
4.8 ± 6.6
0
6.1 ± 2.7
24.2 ± 0.4
16.0 ± 3.8
15.0 ± 1.1
29.9 ± 2.4
30.2 ± 2.1
–
36.1 ± 1.5
22.1 ± 2.6
30.0 ± 3.0
3.2 ± 7.1
13.0 ± 2.9
25.3 ± 3.8
10.9 ± 1.2
23.2 ± 2.8
14.3 ± 1.0
42.4 ± 2.0
27.2 ± 1.8
38.5 ± 1.4
42.2 ± 2.6
32.0 ± 2.8
45.3 ± 2.8
99.9 ± 2.8
50.1 ± 2.9
45.1 ± 3.0
99.9 ± 0.6
VIIr
VIIs
VIIt
b
Thiodiazole-copper
Bismerthiazolb
a) Average of three replicates; b) the commercial agricultural bactericides, thiodiazole-copper and bismerthiazol, were used in a
comparison of antibacterial activity.
Table 5. Inhibitory effect of VIIg, VIIh and VIIs against XOOa
Inhibition/%
Compound
R
Toxic regression equation
r
EC50/(µg mL 1)
−
−
1
−1
100 µg mL
2
00 µg mL
VIIg
VIIh
VIIs
Bismerthiazolb
3-Cl-Ph
4-Cl-Ph
4-CF3-Ph
99.2 ± 2.3
99.8 ± 2.0
99.9 ± 1.2
71.9 ± 0.6
45.5 ± 7.4
59.4 ± 7.2
87.4 ± 6.8
54.1 ± 1.2
y = 0.9155x + 3.0944
y = 1.2915x + 2.4855
y = 1.3156x + 2.7924
y = 1.4990x + 2.0520
0.9908
0.9916
0.9933
0.9800
120.6 ± 1.7
88.5 ± 2.5
47.6 ± 0.1
92.6 ± 2.1
a) Average of three replicates; b) the commercial agricultural bactericide bismerthiazol was used for comparison of antibacterial
activity.
Unauthenticated
Download Date | 3/30/16 10:12 AM

B. R. Yan et al./Chemical Papers
Table 6. Inhibitory effect of VIIb and VIIs against XACa
Inhibition/%
ix
EC50/(µg mL 1)
−
Compound
R
Toxic regression equation
r
−
1
−1
100 µg mL
200 µg mL
VIIb
VIIs
Bismerthiazolb
4-t-Bu-Ph
4-CF3-Ph
85.3 ± 1.7
99.9 ± 2.8
99.9 ± 0.6
53.0 ± 2.9
99.9 ± 1.1
67.1 ± 6.8
y = 0.7844x + 3.4908
y = 1.5547x + 2.9105
y = 1.6100x + 2.1500
0.9944
0.9924
0.9856
82.1 ± 2.4
22.1 ± 0.3
58.2 ± 2.7
a) Average of three replicates; b) commercial agricultural bactericide bismerthiazol was used for comparison of antibacterial activity.
−
1
Table 7. Fungicidal activities of VIIa–VIIt at a concentration of 50 µg mL
Inhibition rate/%a
Compound
G. zeae
C. mandshurica
P . infestans
P . sasakii
C. capsici
G. fructigenum
VIIa
VIIb
VIIc
VIId
VIIe
VIIf
VIIg
VIIh
VIIi
VIIj
VIIk
VIIl
VIIm
VIIn
VIIo
VIIp
VIIq
VIIr
VIIs
21.5 ± 2.7
4.2 ± 1.2
17.6 ± 1.9
2.9 ± 0.7
21.8 ± 2.4
10.9 ± 1.2
17.9 ± 1.8
29.2 ± 1.6
3.8 ± 2.0
13.5 ± 2.7
8.0 ± 0.4
2.9 ± 0.7
10.9 ± 0.9
47.1 ± 2.8
14.4 ± 2.0
16.7 ± 3.5
10.3 ± 1.9
50.3 ± 1.6
26.3 ± 3.9
12.2 ± 0.9
55.5 ± 3.9
11.5 ± 2.4
7.9 ± 1.2
10.4 ± 0.4
16.3 ± 6.5
15.3 ± 2.3
8.1 ± 1.3
28.8 ± 1.2
23.7 ± 0.4
33.1 ± 1.5
4.5 ± 0.4
46.7 ± 0.4
24.3 ± 1.3
28.3 ± 0.8
24.6 ± 1.4
43.6 ± 0.8
23.7 ± 0.1
14.4 ± 1.0
65.1 ± 1.3
29.7 ± 1.0
50.4 ± 1.0
40.5 ± 0.4
54.9 ± 0.1
18.4 ± 0.6
39.6 ± 1.3
25.6 ± 1.1
36.1 ± 3.0
21.3 ± 4.0
43.8 ± 2.6
56.2 ± 2.0
21.9 ± 0.8
45.0 ± 7.8
27.3 ± 2.0
15.9 ± 1.7
29.4 ± 1.3
32.3 ± 0.5
37.2 ± 0.8
41.4 ± 0.5
28.0 ± 1.0
47.9 ± 0.8
25.2 ± 1.0
31.6 ± 2.1
45.7 ± 1.7
21.3 ± 0.8
42.2 ± 0.5
27.3 ± 1.0
20.7 ± 1.6
16.7 ± 1.0
16.2 ± 2.5
43.5 ± 1.5
35.5 ± 1.0
7.3 ± 1.0
8.2 ± 1.6
6.9 ± 0.9
7.9 ± 0.4
23.1 ± 3.3
9.1 ± 0.8
51.3 ± 0.1
5.7 ± 0.1
15.5 ± 1.6
27.5 ± 0.4
46.4 ± 0.9
11.9 ± 1.6
10.2 ± 2.1
26.3 ± 3.2
30.7 ± 1.6
15.1 ± 1.6
18.7 ± 1.2
27.3 ± 2.4
13.2 ± 2.9
26.6 ± 0.9
39.1 ± 3.2
23.7 ± 2.0
27.9 ± 0.9
49.6 ± 7.8
10.7 ± 1.6
29.7 ± 2.2
11.1 ± 0.8
25.4 ± 3.6
17.3 ± 2.0
29.1 ± 0.4
10.7 ± 0.4
33.2 ± 1.6
14.9 ± 1.6
15.6 ± 2.0
7.2 ± 0.8
3.9 ± 0.1
65.9 ± 1.8
18.8 ± 1.9
18.8 ± 1.2
75.4 ± 1.4
15.4 ± 1.1
29.7 ± 0.6
19.1 ± 0.4
30.4 ± 3.7
36.9 ± 1.8
26.2 ± 0.1
43.4 ± 2.2
47.6 ± 2.3
39.9 ± 1.5
51.2 ± 3.9
30.9 ± 2.5
32.9 ± 2.5
11.1 ± 0.8
68.2 ± 2.4
VIIt
Hymexazolb
58.2 ± 2.4
a) Average of three replicates; b) commercial agricultural fungicide hymexazol was used for comparison of antifungal activity.
taining 1,2,4-triazolylthioether unit exhibited a cer-
tain antibacterial activity. One possible explanation
is that flexible methylene spacers among quinazoli-
none, 1,2,4-triazolylthioether moiety and substituted
aromatic ring allowed target compounds to bind to the
protein cavity of the pathogenic bacteria with lower
binding energy.
%, 49.6 %, 68.2 %, 51.2 %, 45.0 % and 58.2 %, respec-
tively. Notably, compound VIIr exhibited an activity
comparable with hymexazol against G. zeae (50.3 % vs
55.5 % inhibition). In addition, compounds VIIe, VIIh
and VIIk exhibited better antifungal activities against
P. sasakii, with inhibition rates of 51.3 %, 65.9 % and
75.4 %, than that of hymexazol (51.2 % inhibition).
Compounds VIIh, VIIl and VIIs possessed stronger
antifungal activities against C. capsici, with inhibition
rates of 65.1 %, 54.9 % and 56.2 %, than hymexazol
Antifungal activity and structure-activity rela-
tionship
(45.0 % inhibition). Out of all the target compounds,
The antifungal results thus obtained were com-
pared with those obtained from hymexazol (Table 7),
a commercial fungicide with a broad-spectrum activ-
ity. The target compounds VIIa–VIIt against G. zeae,
C. mandshurica, P. infestans, P. sasakii, C. capsici
and G. fructigenum displayed inhibition rates ranging
from 2.9 % to 50.3 %, 6.9 % to 46.4 %, 7.2 % to 33.2 %,
compound VIIh (R = 4-Cl-Ph) had the broadest fungi-
cidal spectrum, with an inhibition rate of more than
45 % against four kinds of fungi. Additionally, out of
the six kinds of fungi tested, the compounds evaluated
displayed the best inhibitory activity against C. cap-
sici, and seven of target compounds demonstrated an
activity similar to or better than that of hymexazol.
The structure-activity relationship analysis indi-
cated that the compound with 4-Cl-Ph substitution
(VIIh) had a clear advantage over those substituted
3
.9 % to 75.4 %, 14.4 % to 65.1 %, 7.3 % to 47.9 %,
−
1
respectively, at 50 µg mL . The inhibition rates of
−
1
5
0 µg mL of hymexazol on the above fungi were 55.5
Unauthenticated
Download Date | 3/30/16 10:12 AM

x
B. R. Yan et al./Chemical Papers
at the 2- (VIIf ) or 3-position (VIIg) against all the
fungi tested. Similar phenomena were also observed
for those having —F substitution on the phenyl ring,
but only effective against C. mandshurica, P. sasakii
and G. fructigenum. As far as the strong electron-
withdrawing substitution (—CF3) was concerned, the
substitution at the 3-position (VIIr) displayed more
favourable activities towards most of the fungi tested,
relative to its 2- and 4-isomers (VIIq and VIIs). The
position of the substitution (especially for —Cl, —F
and —CF3) on the phenyl ring had a significant effect
on their antifungal activities.
quinazolin-4(3H)-one derivatives. Synthetic Communica-
tions, 45, 2240–2250. DOI: 10.1080/00397911.2015.1074697.
G u¨ lerman, N. N., Do ˘g an, H. N., Rollas, S., Johansson, C.,
&
C¸ elik, C. (2001). Synthesis and structure elucidation of
some new thioether derivatives of 1,2,4-triazoline-3-thiones
and their antimicrobial activities. II Farmaco, 56, 953–958.
DOI: 10.1016/s0014-827x(01)01167-3.
Hasan, A., Francis, N., Thomas, N. F., & Gapil, S. (2011).
Synthesis, characterization and antifungal evaluation of
5-substituted-4-amino-1,2,4-triazole-3-thioesters. Molecules,
16, 1297–1309. DOI: 10.3390/molecules16021297.
Holla, B. S., Gonsalves, R., & Shenoy, S. (2000). Synthesis and
antibacterial studies of a new series of 1,2-bis(1,3,4-oxadiazol-
2-yl)ethanes and 1,2-bis(4-amino-1,2,4-triazol-3-yl)ethanes.
European Journal of Medicinal Chemistry, 35, 267–271.
DOI: 10.1016/s0223-5234(00)00154-9.
Jatav, V., Mishra, P., Kashaw, S., & Stables, J. P. (2008). CNS
depressant and anticonvulsant activities of some novel 3-[5-
substituted-1,3,4-thiadiazole-2-yl]-2-styryl-quinazoline-
Conclusions
A series of novel quinazolinone derivatives con-
taining a 1,2,4-triazolylthioether unit were synthesised
and their antimicrobial activities were preliminarily
evaluated in vitro. Out of this series of compounds,
compound VIIs exhibited the highest antibacterial
activities against Xanthomonas axonopodis pv. citri
and Xanthomonas oryzae pv. oryzae with EC50 val-
4(3H)-ones. European Journal of Medicinal Chemistry, 43,
1945–1954. DOI: 10.1016/j.ejmech.2007.12.003.
Liu, F., Luo, X. Q., Song, B. A., Bhadury, P. S., Yang, S.,
Jin, L. H., Xue, W., & Hu, D. Y. (2008). Synthesis and
antifungal activity of novel sulfoxide derivatives contain-
ing trimethoxyphenyl substituted 1,3,4-thiadiazole and 1,3,4-
oxadiazole moiety. Bioorganic & Medicinal Chemistry, 16,
−
1
−1
ues of 47.6 µg mL and 22.1 µg mL , respectively,
which was superior to that of commercial bactericide,
bismerthiazol. To the best of our knowledge, this is
the first example of the use of quinazolinone deriva-
tives bearing 1,2,4-triazolylthioether moiety as poten-
tial antimicrobial agents in agricultural applications.
3632–3640. DOI: 10.1016/j.bmc.2008.02.006.
Liu, J. H., Liu, Y., Jian, J. Y., & Bao, X. P. (2013). Synthesis
and fungicidal activities of novel quinazoline derivatives con-
taining 1,2,4-triazole Schiff-base unit. Chinese Journal of Or-
ganic Chemistry, 33, 370–374. DOI: 10.6023/cjoc201209023.
Ma, J., Li, P., Li, X. Y., Shi, Q. C., Wan, Z. H., Hu, D. Y., Jin,
L. H., & Song, B. A. (2014). Synthesis and antiviral bioac-
tivity of novel 3-((2-((1E,4E)-3-oxo-5-arylpenta-1,4-dien-1-
yl)phenoxy)methyl)-4(3H)-quinazolinone derivatives. Jour-
nal of Agricultural and Food Chemistry, 62, 8928–8934. DOI:
Acknowledgements. This work was financially supported
by the National Natural Science Foundation of China (no.
21362003).
10.1021/jf502162y.
References
Mali, J. R., Pratap, U. R., Netankar, P. D., & Mane, R.
A. (2009). An efficient synthetic route for quinazolinyl 4-
thiazolidinones. Tetrahedron Letters, 50, 5025–5027. DOI:
Asker, F. W., Abbas, S. A. R., Al-Bayati, R. I., & Al-Tamemi, H.
A. (2014). Synthesis and biological evaluation of new quina-
zolinone derivatives. European Journal of Chemistry, 5, 628–
10.1016/j.tetlet.2009.06.086.
Panneerselvam, P., Rather, B. A., Reddy, D. R. S., & Kumar,
N. R. (2009). Synthesis and anti-microbial screening of some
Schiff bases of 3-amino-6,8-dibromo-2-phenylquinazolin-4
6
34. DOI: 10.5155/eurjchem.5.4.628-634.1120.
Bartroli, J., Tumo, E., Algueró, M., Boncompte, E., Ver-
icat, M. L., Conte, L., Ramis, J., Merlos, M., García-
Rafanell, J., & Forn, J. (1998). New azole antifungals. 3.
Synthesis and antifungal activity of 3-substituted-4(3H)-
quinazolinones. Journal of Medicinal Chemistry, 41, 1869–
882. DOI: 10.1021/jm9707277.
Cao, S. L., Feng, Y. P., Jiang, Y. Y., Liu, S. Y., Ding, G. Y., &
Li, R. T. (2005). Synthesis and in vitro antitumor activity of
(3H)-quinazolinone derivatives with dithiocarbamate side
chains. Bioorganic & Medicinal Chemistry Letters, 15, 1915–
917. DOI: 10.1016/j.bmcl.2005.01.083.
Cao, X. F., Li, F., Hu, M., Lu, W. C., Yu, G. A., & Liu, S. H.
2008). Chiral γ-Aryl-1H-1,2,4-triazole derivatives as highly
potential antifungal agents: Design, synthesis, structure and
in vitro fungicidal activities. Journal of Agricultural and
Food Chemistry, 56, 11367–11375. DOI: 10.1021/jf8026843.
Dixit, R., Mehta, H., & Dixit, B. (2015). Synthesis, characteri-
zation and antimicrobial studies of new 2-(2-chloroquinolin-
(3H)-ones. European Journal of Medicinal Chemistry, 44,
2328–2333. DOI: 10.1016/j.ejmech.2008.04.010.
Patil, B. S., Krishnamurthy, G., Naik, H. S. B., Latthe, P.
R., & Ghate, M. (2010). Synthesis, characterization and
antimicrobial studies of 2-(4-methoxy-phenyl)-5-methyl-4-(2-
arylsulfanyl-ethyl)-2,4-dihydro-[1,2,4]triazolo-3-ones and
their corresponding sulfones. European Journal of Medicinal
Chemistry, 45, 3329–3334. DOI: 10.1016/j.ejmech.2010.04.
016.
Plech, T., Wujec, M., Kosikowska, U., & Malm, A. (2013). Syn-
thesis and antibacterial activity of 4,5-disubstituted-1,2,4-
triazole-3-thiones. Letters in Drug Design & Discovery, 10,
917–922. DOI: 10.2174/15701808113109990082.
Shi, L. P., Jiang, K. M., Jiang, J. J., Jin, Y., Tao, Y. H., Li,
K., Wang, X. H., & Lin, J. (2013). Synthesis and antimi-
crobial activity of polyhalobenzonitrile quinazolin-4(3H)-one
derivatives. Bioorganic & Medicinal Chemistry Letters, 23,
5958–5963. DOI: 10.1016/j.bmcl.2013.08.068.
1
4
1
(
3
-yl)-3-(substituted phenyl/pyridinyl) quinazolin-4(3H)-one
derivatives using L-proline as a catalyst. Medicinal Chem-
istry Research, 24, 773–786. DOI: 10.1007/s00044-014-1116-
Shin, K. J., Koo, K. D., Yoo, K. H., Kang, Y. K., Park, S. W., &
Kim, D. J. (2001). Synthesis and biological properties of new
1-β-methylcarbapenems containing heteroaromatic thioether
moiety. Bioorganic & Medicinal Chemistry Letters, 11, 2397–
2399. DOI: 10.1016/s0960-894x(01)00451-6.
8.
El-Hashash, M. A., Elshahawi, M. M., Ragab, E. A., &
Nagdy, S. (2015). Synthesis and antifungal activity of novel
Unauthenticated
Download Date | 3/30/16 10:12 AM

B. R. Yan et al./Chemical Papers
xi
Sun, J., Li, D. D., Li, J. R., Fang, F., Du, Q. R., Qian, Y.,
Zhu, H. L. (2013). Design, synthesis, biological evalua-
tion and molecular modeling study of 4-alkoxyquinazoline
Xu, W. M., Han, F. F., He, M., Hu, D. Y., He, J., Yang, S.,
& Song, B. A. (2012). Inhibition of tobacco bacterial wilt
with sulfone derivatives containing an 1,3,4-oxadiazole moi-
ety. Journal of Agricultural and Food Chemistry, 60, 1036–
1041. DOI: 10.1021/jf203772d.
&
derivatives as potential VEGFR2 kinase inhibitors. Or-
ganic
& Biomolecular Chemistry, 11, 7676–7686. DOI:
1
0.1039/c3ob41136b.
Zhang, F., Wen, Q., Wang, S. F., Karim, B. S., Yang, Y. S., Liu,
J. J., Zhang, W. M., & Zhu, H. L. (2014). Design, synthe-
sis and antibacterial activities of 5-(pyrazin-2-yl)-4H-1,2,4-
triazole-3-thiol derivatives containing Schiff base formation
as FabH inhibitory. Bioorganic & Medicinal Chemistry Let-
ters, 24, 90–95. DOI: 10.1016/j.bmcl.2013.11.079.
Turan-Zitouni, G., Kaplancikli, Z. A., Yildiz, M. T., Cheval-
let, P., & Kaya, D. (2005). Synthesis and antimicrobial
activity of 4-phenyl/cyclohexyl-5-(1-phenoxyethyl)-3-[N-(2-
thiazolyl)acetamido]thio-4H-1,2,4-triazole derivatives. Euro-
pean Journal of Medicinal Chemistry, 40, 607–613. DOI:
1
0.1016/j.ejmech.2005.01.007.
Zhu, S. R., Wang, J., Chandrashekar, G., Smith, E., Liu, X.
J., & Zhang, Y. S. (2010). Synthesis and evaluation of 4-
quinazolinone compounds as potential antimalarial agents.
European Journal of Medicinal Chemistry, 45, 3864–3869.
DOI: 10.1016/j.ejmech.2010.05.040.
Wang, X., Li, P., Li, Z. N., Yin, J. A., He, M., Xue, W., Chen,
Z. W., & Song, B. A. (2013). Synthesis and bioactivity eval-
uation of novel arylimines containing a 3-aminoethyl-2-[(p-
trifluoromethoxy)anilino]-4(3H)-quinazolinone moiety. Jour-
nal of Agricultural and Food Chemistry, 61, 9575–9582. DOI:
10.1021/jf403193q.
Unauthenticated
Download Date | 3/30/16 10:12 AM