Synthesis and bioactivity evaluation of novel arylimines containing a 3-aminoethyl-2-[(p-trifluoromethoxy)anilino]-4(3H)-quinazolinone moiety

Article abstract of DOI:10.1021/jf403193q

Twenty-seven novel (E)-3-[2-arylideneaminoethyl]-2-[4-(trifluoromethoxy) anilino]-4(3H)-quinazolinone derivatives were synthesized by reacting various aromatic aldehydes with intermediate 6. The target compounds were characterized by ¹H NMR,

Full text of DOI:10.1021/jf403193q

Article
pubs.acs.org/JAFC
Synthesis and Bioactivity Evaluation of Novel Arylimines Containing
a 3‑Aminoethyl-2-[(p‑trifluoromethoxy)anilino]-4(3H)‑quinazolinone
Moiety
†
,§
†
†
†
†
†
†
,†
Xiang Wang, Pei Li, Zhining Li, Juan Yin, Ming He, Wei Xue, Zhiwei Chen, and Baoan Song*
†State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and
Agricultural Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, People’s Republic of China
§College of Chemistry and Materials Engineering, Kaili University, Kaili 556011, People’s Republic of China
*
S Supporting Information
ABSTRACT: Twenty-seven novel (E)-3-[2-arylideneaminoethyl]-2-[4-(trifluoromethoxy)anilino]-4(3H)-quinazolinone deriv-
atives were synthesized by reacting various aromatic aldehydes with intermediate 6. The target compounds were characterized by
1
3
H NMR, C NMR, IR, and elemental analysis. Bioassay results revealed that some of the compounds have strong antifungal
activities against six fungi (Gibberella zeae, Fusarium oxysporum, Clematis mandshurica, Paralepetopsis sasakii, Phytophthora
infestans, and Sclerotinia sclerotiorum) and three bacteria (Xanthomonas oryzae, tomato bacterial wilt, and tobacco bacterial wilt).
Notably, these compounds exhibited the highest activity against tomato bacterial wilt and X. oryzae, with 50% effective
concentration (EC ) values ranging from 45.96 to 93.31 μg/mL and from 20.09 to 21.33 μg/mL, respectively, which are
5
0
superior to those of the commercial antibacterial agents thiodiazole-copper (99.80 μg/mL) and bismerthiazol (92.61 μg/mL).
These results indicate that novel arylimine derivatives containing the 4(3H)-quinazolinone moiety can effectively control tobacco
bacterial wilt, tomato bacterial wilt, and X. oryzae. Evaluation of their bactericidal properties in field studies as well as the
mechanisms underlying their enhanced antibacterial activity should be interesting topics for future investigations.
KEYWORDS: 4(3H)-quinazolinone moiety, arylimine derivatives, antibacterial activities, antifungal activities
23
INTRODUCTION
sized by Mohamed et al. In particular, 2-[4-(2-phenyl-6,8-
dibromo-4-oxo-(4H)quinazolin-3-yl]-N-ethylamidobenzoic
acid hydrazide exhibited the highest in vitro antimicrobial
activity against E. coli, Salmonella typhimurium, Listeria
monocytogenes, S. aureus, P. aeruginosa, and Bacillus cereus,
with 1.56, 3.12, 1.56, 25, 25, and 25 μg/mL MICs, respectively.
Meanwhile, 2-[4-(2-phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-
3-yl]-N-methylthioamidobenzoic acid hydrazide exhibited the
highest in vitro antifungal activity against C. albicans and
Aspergillus flavus, with 0.78 and 0.097 μg/mL MICs,
■
The 4(3H)-quinazolinone family is a group of high-potential,
biologically active pharmacophoric nitrogen-containing hetero-
1
,2
cyclic molecules. A large number of 4(3H)-quinazolinone
derivatives have been reported to date, and they have received
considerable attention in recent years because of their broad
spectrum of biological properties, including antibacterial,
antifungal, antimalarial, antiviral, anticancer, and anticon-
3
−5
6
7
8
9
1
0−12
vulsant
activities. Imines (also known as Schiff bases or
azomethines), which are usually synthesized from the
condensation of amines with active carbonyl groups, also
exhibit a broad range of biological activities, including
24,25
respectively. In our previous work,
we showed that I [2-
methyl-3-(2,3-dichlorobenzalamino)-4(3H)-quinazolinone]
and II {(1E,4E)-1-aryl-5-[2-(quinazolin-4-yloxy)phenyl]-1,4-
pentadien-3-one} exhibited high ex vivo antiviral activity
against tobacco mosaic virus (TMV). Structure−activity
relationship (SAR) analyses further suggested that the 4(3H)-
quinazolinone moiety is crucial for its potent activity.
Plant bacteria, such as Ralstonia solanacearum, Pseudomonas
solanacearum, and Xanthomonas oryzae, are extremely difficult
to manage in agricultural production. The high incidence of
mortality among infected plants and the lack of effective control
methods make R. solanacearum, P. solanacearum, and X. oryzae
three of the world’s most destructive plant pathogens.
Currently available traditional bactericides such as inorganic
1
3,14
15
16
17
antifungal,
herbicidal, insecticidal, antibacterial, and
1
8
19
antiviral, activities and inhibition of nitrification. Various
natural products with critical pharmacophores contain imine
2
0
groups. Efficient bioactivity of these compounds is mainly
attributed to the alkyl/aryl/heteroaryl group at the second or
third position in the quinazolin-4(3H)-one core or attached to
the CN moiety. For example, 2-methyl-3-[5-(4-chlorophen-
yl)-1,3,4-oxadiazole-2-yl]-quinazoline-4(3H)-ones exhibit mod-
erate to high antibacterial activity against Staphylococcus aureus,
Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli, as
well as antifungal activity against Aspergillus niger and Fusarium
oxysporum, with minimal inhibitory concentrations (MICs) of
21
7
9, 75, 86, 70, 130, and 141 μg/mL, respectively. Ilangovan et
2
2
al. reported a series of 2-aryl-3-aminoquinazoline-4(3H)-one
semicarbazones with high inhibitory activity against E. coli and
Candida albicans. Moreover, 6,8-dibromo-3-substituted phenyl-
quinazoline-4(3H)-one derivatives were successfully synthe-
Received: July 21, 2013
Revised: September 12, 2013
Accepted: September 12, 2013
Published: September 13, 2013
©
2013 American Chemical Society
9575
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Journal of Agricultural and Food Chemistry
Article
Figure 1. Schematic diagram showing the synthesis of intermediate 6.
Figure 2. Schematic diagram showing the synthesis of final compounds 8a−8aa.
bactericides (e.g., copper formulations) are not very effective
and can even enhance resistance in host tobacco, tomato, and
rice plants. Each year, pathogenic bacteria are responsible for
billions of dollars in economic loss worldwide. Therefore, the
search for alternative antibacterial agents remains a daunting
abbreviations were used to designate chemical shift multiplicities: s =
singlet, d = doublet, t = triplet, m = multiplet, and bs = broad singlet.
All first-order splitting patterns were assigned on the basis of multiplet
appearance. Splitting patterns that could not be easily interpreted were
designated multiplet (m) or broad (br). Elemental analysis was
performed on an Elementar Vario-III CHN analyzer. Mass spectral
studies were conducted on an Agilent 5973 organic mass spectrometer.
Analytical TLC was performed on silica gel GF254. Column
chromatographic purification was performed using silica gel. All
reagents were of analytical reagent grade or chemically pure. All
solvents were dried, deoxygenated, and redistilled prior to use.
General Procedures for the Preparation of Intermediate 6.
Intermediate 6 was synthesized by a five-step process following
26
task in pesticide science.
On the basis of these considerations, a series of (E)-3-[2-
substituted-arylideneamino)ethyl]-2-[4-(trifluoromethoxy)-
(
anilino]quinazolin-4(3H)-one derivatives were designed and
synthesized (Figure 2). Biological assay revealed that some of
the title compounds displayed good antibacterial and antifungal
activities. For example, title compound 8f, 8w, and 8x showed
superior activities compared with the commercially available
agricultural antibacterial agent thiodiazole-copper and bismer-
thiazol against tomato bacterial wilt and X. oryzae in vitro. The
structure−activity relationship (SAR) analyses of antifungal and
antibacterial and activities were also studied. To the best of our
knowledge, this paper is the first to discuss the antibacterial
activities of (E)-3-[2-arylideneaminoethyl]-2-[4-
2
7,28
previously reported procedures (Figure 1).
White, solid o-
azidobenzoic acid 2 was synthesized from 13.7 g (0.1 mol) anthranilic
acid via a diazotization azide reaction under a salt ice bath. A yellow,
oily liquid of o-azidobenzoic acid ethyl ester 3 was obtained by
esterification of 16.3 g (0.1 mol) o-azidobenzoic acid 2 with ethanol. o-
Azidobenzoic acid ethyl ester 3 (10 mmol) dissolved in anhydrous
CH Cl (10 mL) was added to a solution of triphenylphosphine (2.62
2
2
g, 10 mmol) in anhydrous CH Cl (20 mL). After stirring overnight
2
2
(
trifluoromethoxy)anilino]quinazolin-4(3H)-one derivatives.
and desolventizing under reduced pressure, the obtained residue was
recrystallized with petroleum ether and then filtered to obtain a white,
solid iminophosphorane 4. Aromatic isocyanate (3 mmol) was added
to a solution of iminophosphorane 4 (1.28 g, 3.0 mmol) in anhydrous
THF (10 mL) at room temperature. The resulting mixture was stirred
at 0−5 °C for 12 h to generate carbodiimide 5, which was used directly
without further purification. Afterward, 5 was added dropwise into a
solution of primary diamines (3.0 mmol) in THF (10 mL). The
reaction mixture was then stirred for 12 h at room temperature. Upon
completion, the solvent was removed under reduced pressure, and the
residue was recrystallized from CH Cl /CH OH (1:1, v/v) to obtain
MATERIALS AND METHODS
■
Instruments. The melting points of the products were determined
on an XT-4 binocular microscope (Beijing Tech Instrument Co.,
China) and were not corrected. The IR spectra were recorded on a
Bruker VECTOR 22 spectrometer using KBr disks. NMR was
performed in a CDCl or DMSO-d solvent on a JEOL-ECX 500
3
6
NMR spectrometer operating at 500 and 125 MHz at room
temperature and using TMS as an internal standard. The following
2
2
3
9
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Journal of Agricultural and Food Chemistry
Article
a
Table 1. Physical and Analytical Data of Synthesized Compounds 8a−8aa
elemental analysis (found/calcd)/%
b
compd
R
molecular formula (MW)
C H F N O (470.1)
time/h
mp/°C
yield /%
C
H
N
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
a
b
c
d
e
f
2-F phenyl
1/2
1
170−171
160−161
190−191
153−154
168−169
130−131
143−144
201−202
134−135
150−151
136−137
139−140
198−199
175−176
207−208
175−176
157−158
186−187
149−150
213-214
98
95
95
92
85
89
69
89
88
95
88
97
98
88
97
87
52
90
55
97
64
67
50
40
97
53
88
61.26/61.28
55.60/55.29
59.31/59.21
63.89/63.71
57.16/57.64
59.89/59.73
64.22/64.37
67.03/66.93
57.82/57.93
57.66/57.95
57.59/57.95
53.93/54.20
54.37/54.25
61.07/60.93
60.48/60.93
55.21/55.29
55.23/55.29
55.44/55.29
58.90/59.21
57.26/57.32
61.30/61.28
59.95/60.24
59.87/60.24
61.70/61.54
62.47/62.24
63.45/63.02
56.18/56.14
3.99/3.86
3.23/3.29
3.98/3.73
4.07/4.23
3.65/3.74
3.68/3.87
4.20/4.54
4.25/4.21
3.38/3.65
3.67/3.65
3.62/3.65
3.15/3.22
3.33/3.41
4.13/4.52
4.05/4.52
3.03/3.29
3.04/3.29
2.93/3.29
3.50/3.73
3.28/3.61
3.47/3.86
3.87/4.25
3.77/4.25
3.63/4.09
4.03/4.39
4.89/4.88
3.52/3.53
12.08/11.91
10.52/10.75
11.53/11.51
12.94/12.38
12.62/12.22
12.86/12.66
12.20/12.01
11.33/11.15
14.26/14.08
14.54/14.08
14.52/14.08
13.52/13.17
10.44/10.54
11.04/10.93
10.92/10.93
11.05/10.75
11.04/10.75
10.98/10.75
11.92/11.51
11.27/11.14
12.31/11.91
11.51/11.24
11.20/11.24
12.11/11.96
12.10/11.61
14.53/14.13
13.92/13.64
2
4
18
4
4
2
3,4-di-Cl phenyl
2-Cl phenyl
phenyl
C H Cl F N O (520.1)
24 17 2 3 4 2
C H ClF N O (486.1)
2/3
1
2
4
18
3
4
2
C H F N O (452.2)
2
4
19
3
4
2
2-thienyl
C H F N O S (458.1)
4.5
1/6
1.5
1.5
3
2
2
17
3
4
2
2-furyl
C H F N O (442.1)
22 17 3 4 3
g
h
i
4-CH phenyl
C H F N O (466.2)
25 21 3 4 2
3
1-naphthyl
C H F N O (502.2)
28 21 3 4 2
4-NO phenyl
C H F N O (497.1)
24 18 3 5 4
2
j
3-NO phenyl
C H F N O (497.1)
2
2
24 18
3
5
4
k
l
2-NO phenyl
C H F N O (497.1)
10
1.5
1/6
4.5
3
2
24 18
3
5
4
4-Cl-3-NO phenyl
C H ClF N O (531.1)
24 17 3 5 4
2
m
n
o
p
q
r
2-Br phenyl
C H BrF N O (530.1)
24 18 3 4 2
2,5-dimethoxyl phenyl
2,3-dimethoxyl phenyl
2,3-di-Cl phenyl
2,6-di-Cl phenyl
3,5-di-Cl phenyl
4-Cl phenyl
C H F N O (512.2)
26 23 3 4 4
C H F N O (512.2)
2
6
23
3
4
4
C H Cl F N O (520.1)
1
2
4
17
2
3
4
2
C H Cl F N O (520.1)
1.5
2
2
4
17
2
3
4
2
C H Cl F N O (520.1)
2
4
17
2
3
4
2
s
C H ClF N O (486.1)
2
2
4
18
3
4
2
t
2-OH-5-Cl phenyl
4-F phenyl
C H ClF N O (502.1)
1/6
1/4
3
2
4
18
3
4
3
u
v
w
x
y
z
C H F N O (470.1)
152−153
176−177
156−157
186−187
211−212
138−139
2
4
18
4
4
2
3-OH-4-OCH phenyl
C H F N O (498.2)
25 21 3 4 4
3
4-OH-3-OCH phenyl
C H F N O (498.2)
3
3
25 21
3
4
4
4-OH phenyl
C H F N O (468.1)
1
2
4
19
3
4
3
2-OH-5-CH phenyl
C H F N O (482.2)
1/6
1
3
25 21
3
4
3
2-OH-5-NO phenyl
C H F N O (513.1)
24 18 3 5 5
2
aa
N,N-dimethyl phenyl
C H F N O (495.2)
1/4
244−246
b
2
6
24
3
5
2
a
The reaction was performed according to the general experimental program. Isolated yields based on 3-(2-aminoethyl)-2-(4-(trifluoromethoxy)-
phenylamino)quinazolin-4(3H)-one 6.
white, crystalline 3-aminoethyl-2-[(p-trifluoromethoxy)anilino]-
quinazolin-4(3H)-one 6: mp 159−160 °C; yield, 82%; IR (KBr,
experimental protocols. The data for 8x is shown below, and data for
others can be found in the Supporting Information.
−1
cm ) ν 3383 (N−H, NH ), 3307 (N−H, Qu-ring-NHAr), 1670
(E)-3-[2-(4-Hydroxybenzylideneamino)ethyl]-2-[4-
2
(
CO), 1612 (CN), 1562−1491 (CC, benzene and Qu-ring);
(trifluoromethoxy)anilino]quinazolin-4(3H)-one (8x): white solid; IR
1
−1
H NMR (500 MHz, CDCl ) δ 11.21 (s, 1H, Qu-ring-NHAr), 8.10
(KBr, cm ) ν 3184 (NH, QuringNHAr), 3041 (OH,
3
ArOH), 1678 (CO), 1610 (CN), 1442−1583 (CC and
(
t, J = J = 8.0 Hz, 1H, QuH), 7.40−7.58 (m, 3H, QuH, 1H,
1
2
NH, benzene and Quring and NH bend), 1276 (CN), 1222
ArH), 7.19−7.28 (m, 3H, ArH), 4.23 (s, 2H, −CH −), 3.23 (s,
2
13
1
2
H, −CH NH ), 1.86 (bs, 2H, −NH ); C NMR (125 MHz, CDCl )
(CF), 1161 (ArCO); H NMR (500 MHz, DMSO-d
) δ 9.04
6
2
2
2
3
δ 163.42, 148.95, 148.42, 144.04, 138.79, 134.43, 126.84,
25.54,123.66, 121.77, 120.94, 119.66, 118.22, 47.27, 41.47. Anal.
Calcd for C H F N O : C, 56.04; H, 4.15; N, 15.38. Found: C,
(s, 1H, ArOH), 8.23 (s, 1H, QuringNHAr), 8.01 (s, 1H,
−NCH−), 7.17−7.26 (m, 10H, QuH and ArH), 6.75 (s, 2H,
C
1
1
3
ArH), 4.56 (s, 2H, NCH −), 3.88 (s, 2H, NCH
NMR (125 MHz, DMSO-d ) δ 163.52, 162.38, 160.71, 148.71, 148.31,
6
−);
1
7
15
3
4
2
2
2
+
5
5.94; H, 4.39; N, 15.61. MS (ESI) m/z 365.1 ([M + H] ), 387 ([M +
+
Na] ).
General Synthetic Procedures for Title Compounds 8a−8aa.
Target compounds 8a−8aa were synthesized as schematized in Figure
. Aromatic aldehyde (1.2 mmol) was added to a solution of 3-
aminoethyl-2-[(p-trifluoromethoxy)anilino]quinazolin-4(3H)-one 6
364 mg, 1 mmol) in anhydrous CH CH OH (15 mL) at 0−50 °C.
143.93, 139.09, 130.39, 127.52, 126.92, 125.55, 123.87, 123.38, 121.78,
+
119.71, 118.08, 115.92, 58.71, 43.61. MS (ESI) m/z 499.1 ([M + H] ),
+
521.1 ([M + Na] ).
2
In Vitro Antifungal Bioassay. The antifungal activities were
screened and evaluated against six pathogenic fungi, namely, G. zeae, F.
oxysporum, C. mandshurica, P. sasakii, P. infestans, and S. sclerotiorum,
(
3
2
2
9,30
The resulting mixture was refluxed to 75 °C with stirring for a specific
reaction time (ranging from 10 min to 10 h). Upon completion of
reaction (as indicated by TLC), the solvent was removed under
depressurization, and the residue was recrystallized from CH Cl /
by the poison plate technique.
All final compounds were dissolved
in DMSO (1 mL) before mixing with potato dextrose agar (PDA; 90
mL). The compounds were tested at a concentration of 50 μg/mL. All
fungi were cultivated in PDA at 27 ± 1 °C for 4 days to make new
mycelium for the identification of antifungal activity. Then, mycelia
dishes of approximately 4 mm diameter were cut from the culture
medium. A mycelium was obtained using a germ-free inoculation
needle and inoculated in the middle of the PDA plate aseptically. The
inoculated plates were incubated at 27 ± 1 °C for 5 days. DMSO in
2
2
CH CH OH (1:15, v/v). The product was then filtered, washed, and
3
2
dried to obtain (E)-3-[2-(substituted-arylideneamino)ethyl]-2-[4-
trifluoromethoxy)anilino]quinazolin-4(3H)-one derivatives. The
(
1
13
physical characteristics, IR, H NMR, C NMR, and elemental
analysis data for all of the synthesized compounds are reported in the
9
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Journal of Agricultural and Food Chemistry
Article
Table 2. Fungicidal Activity of the Title Compounds 8a−8aa at a Concentration of 50 μg/mL
a
inhibition rate (%)
compd
G. zeae
F. oxysporum
C. mandshurica
P. sasakii
P. infestans
S. sclerotiorum
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
a
31.25 ± 0.97
37.19 ± 0.86
21.88 ± 0.90
46.56 ± 0.95
19.06 ± 0.98
37.19 ± 0.86
47.50 ± 1.02
18.75 ± 1.01
40.63 ± 1.06
30.63 ± 1.39
40.00 ± 1.52
38.75 ± 1.33
2.50 ± 0.84
40.00 ± 0.93
32.19 ± 1.65
35.00 ± 1.28
35.00 ± 1.72
30.94 ± 1.54
25.63 ± 0.92
11.25 ± 0.69
53.88 ± 0.92
33.75 ± 0.99
36.88 ± 1.43
40.94 ± 0.89
17.50 ± 0.92
10.00 ± 1.00
36.25 ± 1.07
55.54 ± 3.90
12.73 ± 0.94
13.60 ± 0.97
0
24.77 ± 1.97
19.88 ± 0.59
13.76 ± 1.23
13.76 ± 0.79
22.32 ± 1.17
15.90 ± 0.52
10.70 ± 0.86
24.16 ± 1.19
7.03 ± 1.67
3.36 ± 0.53
20.18 ± 0.63
13.15 ± 1.60
21.41 ± 0.54
3.36 ± 1.52
10.70 ± 0.56
16.21 ± 0.57
34.25 ± 0.60
10.09 ± 1.21
13.76 ± 0.79
11.93 ± 0.78
10.70 ± 0.56
1.22 ± 0.48
1.25 ± 0.49
13.45 ± 1.45
2.75 ± 1.16
21.41 ± 0.54
10.70 ± 1.71
49.61 ± 7.84
16.94 ± 0.75
16.28 ± 0.81
6.98 ± 0.87
12.96 ± 1.03
12.29 ± 0.79
22.59 ± 0.91
23.59 ± 1.11
7.31 ± 0.73
19.60 ± 0.77
20.93 ± 1.32
18.94 ± 0.76
23.26 ± 1.24
9.63 ± 0.72
20.27 ± 0.99
17.28 ± 0.77
8.64 ± 0.84
9.63 ± 0.72
15.28 ± 0.92
29.24 ± 0.84
6.31 ± 0.76
23.06 ± 1.50
19.27 ± 0.78
16.94 ± 0.75
8.97 ± 0.72
7.97 ± 1.09
6.64 ± 1.29
7.31 ± 1.01
51.21 ± 5.96
0.96 ± 0.93
5.85 ± 1.48
0
36.57 ± 2.61
47.57 ± 1.84
21.04 ± 0.76
29.45 ± 0.98
14.24 ± 2.06
39.16 ± 0.88
32.69 ± 2.08
29.45 ± 2.75
29.45 ± 0.88
20.06 ± 0.71
28.48 ± 0.93
20.71 ± 0.71
25.57 ± 0.78
8.74 ± 0.90
6.47 ± 1.43
51.78 ± 1.20
29.13 ± 0.99
66.67 ± 1.55
20.06 ± 0.71
27.51 ± 0.97
37.86 ± 1.46
25.89 ± 1.42
7.77 ± 0.71
9.06 ± 0.95
8.41 ± 0.82
10.36 ± 1.28
10.03 ± 1.10
77.51 ± 3.96
b
c
d
e
f
26.71 ± 1.98
3.11 ± 0.84
8.39 ± 0.63
35.40 ± 1.28
3.42 ± 1.87
17.08 ± 1.00
0
3.83 ± 0.79
0
5.75 ± 0.64
9.58 ± 0.65
19.17 ± 0.69
2.88 ± 0.67
13.10 ± 0.86
2.88 ± 0.67
19.81 ± 0.70
0
g
h
i
j
k
l
7.76 ± 0.95
16.46 ± 0.82
0
m
n
o
p
q
r
9.94 ± 0.83
9.63 ± 0.96
0
16.61 ± 0.90
8.31 ± 1.25
11.18 ± 0.70
8.31 ± 0.81
12.14 ± 0.60
27.80 ± 1.10
6.39 ± 0.64
34.82 ± 0.98
16.93 ± 1.14
12.46 ± 0.71
18.21 ± 1.03
17.89 ± 0.71
18.85 ± 1.36
16.93 ± 1.24
68.22 ± 2.41
18.01 ± 0.91
0
s
42.55 ± 0.83
0
t
u
v
w
x
y
z
60.87 ± 0.97
12.11 ± 0.93
17.39 ± 0.87
7.14 ± 0.78
10.25 ± 1.14
0
aa
10.87 ± 0.80
56.12 ± 4.10
b
hymexazol
DMSO
a
b
Average of five replicates. The commercial agricultural fungicide hymexazol was used for comparison of antifungal activity.
sterile distilled water served as the negative control, whereas
hymexazol served as the positive control. Each treatment condition
consisted of three replicates. Radial growth of the fungal colonies was
measured, and the data were statistically analyzed. Inhibitory effects of
the test compounds in vitro on these fungi were calculated by the
formula I (%) = [(C − T)/(C − 0.4)] × 100, where C represents the
diameter of fungal growth on untreated PDA, T represents the
diameter of fungi on treated PDA, and I represents the inhibition rate.
In Vitro Antibacterial Bioassay. The antibacterial activities of
some title compounds against R. solanacearum and X. oryzae were
distilled water, pH 7.0−7.2), and thiodiazole-copper served as the
positive control.
The solvent for X. oryzae was M210 (9.6 g of casein acid
hydrolysate, 6.0 g of saccharose, 4.8 g of yeast powder, 3.6 g of
K HPO , 0.36 g of MgSO ·7H O, 1200 mL of distilled water, pH 7.0−
2 4 4 2
7.2), and thiodiazole-copper served as the positive control. The
inoculated test tubes were incubated at 30 ± 1 °C with continuous
shaking at 180 rpm for 24 h.
Some of the title compounds were tested against tobacco bacterial
wilt and tomato bacterial wilt at five double-declining concentrations
(e.g., 200, 100, 50, 25, and 12.5 μg/mL), and their corresponding EC50
values were obtained. Average EC50 was computed from at least three
separate analyses of growth inhibition using the software package SPSS
2
6,31
evaluated by the turbidimeter test.
The final compounds were
dissolved in 150 μL of dimethylformamide (DMF) and diluted with
water containing Tween-20 (0.1%) to obtain final concentrations of
1
7.0.
200 and 100 μg/mL. DMF in sterile distilled water served as a blank
control, whereas thiodiazole-copper served as a positive control.
Approximately 1 mL of sample liquid was added to the nontoxic
nutrient broth (NB, 1.5 g of beef extract, 2.5 g of peptone, 0.5 g of
yeast powder, 5.0 g of glucose, and 500 mL of distilled water, pH 7.0
to 7.2) liquid medium in 4 mL tubes. Then, approximately 40 μL of
NB containing tobacco bacterial wilt was added to 5 mL of solvent NB
containing the test compounds or thiodiazole-copper. The inoculated
test tubes were incubated at 30 ± 1 °C with continuous shaking at 180
rpm for 48 h. Culture growth was monitored with a spectropho-
tometer by measuring the optical density at 600 nm (OD600) given by
corrected turbidity values. The relative inhibitory rate (I%) of the
circle mycelium compared with a blank assay was calculated as follows:
RESULTS AND DISCUSSION
■
A series of new quinazolinone analogues was synthesized with
good yields within a short condensation reaction time. Their
1
13
structures were characterized by IR, H NMR, C NMR, MS,
and elemental analysis techniques, as shown in Table 1. The IR
spectral data of compounds 8a−8aa showed characteristic
−1
absorption bands at 3209−3517 cm , which were assigned to
NH of Qu ringNHAr. The absorption bands of the
CO and CN groups of the skeleton stretching frequency
−1
appeared at 1690−1650 and 1600−1640 cm , respectively. A
I (%) = (Ctur − T )/C × 100. Ctur is the corrected turbidity value of
tur
tur
1
singlet varying from 8.00 to 9.50 ppm in H NMR belonged to
bacterial growth on untreated NB (blank control), and Ttur is the
corrected turbidity value of bacterial growth on treated NB.
Qu ringNHAr and −NCH− proton, and the singlet
Similarly, the solvent for tomato bacterial wilt was SM (10.0 g of
that appeared at δ 4.00 ppm to 4.99 ppm revealed the
H
peptone, 5.0 g of glucose, 1.0 g of casein acid hydrolysate, 1000 mL of
presence of N−CH − and NCH −. The chemical shifts at
2
2
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Journal of Agricultural and Food Chemistry
Article
Table 3. Antibacterial Activity of Compounds 8a−8aa against Tobacco Bacterial Wilt, Tomato Bacterial Wilt, and Xanthomomu
oryzae
a
inhibition rate (%)
tobacco bacterial wilt
tomato bacterial wilt
X. oryzae pv. oryzae
compd
200 μg/mL
100 μg/mL
200 μg/mL
100 μg/mL
200 μg/mL
100 μg/mL
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
a
b
c
d
e
f
61
52
33
72
53
94
100
65
32
100
91
100
56
74
28
34
38
42
28
42
40
50
76
85
42
65
100
50
29
39
23
55
24
55
62
58
12
61
54
43
43
29
24
33
24
30
25
16
31
30
30
29
35
42
60
30
38
22
39
80
12
100
54
34
71
60
59
45
21
43
42
15
15
16
55
15
67
78
100
100
0
27
16
23
64
7
40
52
27
33
28
100
79
41
35
48
36
29
25
51
11
14
50
9
14
33
11
26
11
94
50
24
26
27
16
8
78
48
8
g
h
i
55
54
39
38
0
j
k
l
m
n
o
p
q
r
15
31
9
40
41
0
0
7
11
8
2
s
44
14
63
75
77
75
0
30
16
27
100
100
100
22
36
70
35
72
0
17
11
12
94
93
91
10
13
27
29
54
0
t
u
v
w
x
y
z
45
88
100
36
83
67
aa
b
thiodiazole-copper
b
bismerthiazol
control
0
0
0
0
a
b
Average of three replicates. The commercial agricultural antibacterial agents thiodiazole-copper and bismerthiazol were used for comparison of
antibacterial activity.
nearly 168.00, 40.00, and 55.00 ppm in 13C NMR confirmed
the existence of CO, NCH −, and QuNCH −
Antibacterial Biological Assay of Final Products 8a−
8aa. A series of (E)-3-[2-(substituted-arylideneamino)ethyl]-2-
[4-(trifluoromethoxy)anilino]quinazolin-4(3H)-ones 8a−8aa
was tested for in vitro antibacterial activity against three
phytopathogenic bacteria (X. oryzae, tomato bacterial wilt, and
tobacco bacterial wilt) by the turbidimeter test. Commercial
agricultural antibacterial thiodiazole-copper was used as
reference, as shown in Table 3. Most of the compounds
exhibited excellent antibacterial activity against tomato bacterial
wilt and tobacco bacterial wilt at 100 or 200 μg/mL. Some of
the compounds showed prominent activity against X. oryzae
compared with thiodiazole-copper. In particular, compounds
2
2
groups, respectively. Furthermore, all final products were
confirmed by MS, which were in accordance with their
molecular formulas.
26
Antifungal Activity Screening of Title Compounds
a−8aa. The inhibitory effects of the synthesized (E)-3-[2-
substituted-arylideneamino)ethyl]-2-[4-(trifluoromethoxy)-
8
(
anilino]quinazolin-4(3H)-one derivatives on the six phytopa-
thogenic fungi were studied, and the mycelial growth rate
32
method was selected for screening fungicides. The results
were compared with those obtained from hymexazol, a
commercial fungicide with a broad spectrum of bioactivity, as
indicated in Table 2. The final products 8a−8aa against G. zeae,
F. oxysporum, C. mandshurica, P. sasakii, P. infestans, and S.
sclerotiorum displayed inhibition rates ranging from 2.50 to
8g, 8j, 8l, and 8aa and compounds 8f, 8w, and 8x showed
comparable antibacterial activity against tobacco bacterial wilt
and tomato bacterial wilt at 200 μg/mL, respectively, compared
with the standard drug thiodiazole-copper. However, the
antibacterial activities of compounds 8f, 8v, 8w, 8x, and 8aa
against tomato bacterial wilt at 100 μg/mL were 78, 75, 77, 75,
and 83%, respectively, exceeding that of thiodiazole-copper
(67%). Most importantly, the antibacterial activities of
compounds 8f, 8v, 8w, and 8x against X. oryzae at 200 and
100 μg/mL were 100 and 94%, 100 and 94%, 100 and 93%, and
100 and 91%, respectively, which were much higher than those
5
2
3.88%, from 0 to 60.87%, from 1.22 to 34.25%, from 6.31 to
9.24%, from 0 to 34.82%, and from 7.77 to 66.67% at 50 μg/
mL, respectively. The inhibition rates of 50 μg/mL of
hymexazol on the corresponding fungi were 55.54, 56.12,
49.61, 51.21, 68.22, and 77.51%, respectively. Notably, 8u
showed potent antifungal activity compared with hymexazol
against G. zeae (53.88 vs 55.54% inhibition) and F. oxysporum
(
60.87 vs 56.12% inhibition).
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Journal of Agricultural and Food Chemistry
Article
of thiodiazole-copper (35 and 29%) or bismerthiazol (72 and
Table 6. Inhibitory Effect of Compounds 8f, 8v, 8w, and 8x
against X. oryzae
a
5
4%).
On the basis of previous bioassays, all test compounds
EC50
(μg/mL)
pEC50
(μM)
showed moderate to excellent activity against plant pathogens
tobacco bacterial wilt and tomato bacterial wilt). The EC50
compd
toxic regression eq
R
(
8
8
8
8
f
20.09
20.83
21.33
20.23
92.61
4.3429
4.3787
4.3786
4.3643
y = 2.2590x + 2.0561
y = 2.0497x + 2.2967
y = 2.1413x + 2.1541
y = 2.1343x + 2.2126
y = 1.4990x + 2.0520
0.9895
0.9957
0.9903
0.9969
0.9800
values of some of the synthesized compounds are listed in
v
w
x
Table 4. Notably, compounds 8f, 8j, and 8aa exhibited excellent
Table 4. Inhibitory Effect of Compounds 8f, 8g, 8j, 8l, and
b
bismerthiazol
a
8aa against Tobacco Bacterial Wilt
a
b
Average of three replicates. The commercial agricultural antibacterial
EC50
(μg/mL)
pEC50
(μM)
agent bismerthiazol was used for comparison of antibacterial activity.
compd
toxic regression eq
R
8
f
78.90
121.36
65.09
3.7484
3.5845
3.8892
3.7260
3.7468
y = 2.3702x + 0.5035
y = 1.4607x + 1.9558
y = 2.4076x + 0.6338
y = 1.4178x + 2.1656
y = 1.6589x + 1.7685
y = 1.0312x + 2.9418
0.9761
0.9729
0.9797
0.9666
0.9981
0.9903
activities of compounds 8b, 8p, 8r, and 8q. The final
compounds with electron-withdrawing groups (4-F phenyl, 4-
Cl phenyl, 2,6-di-Cl phenyl, 2,3-di-Cl phenyl, 3,5-di-Cl phenyl,
and 3,4-di-Cl phenyl) were observed to show strong inhibition
against the aforementioned fungi. Thus, our results show that
electron-withdrawing substitutions are more preferable for
improving the antifungal activities of these compounds.
8
8
8
8
g
j
l
99.81
aa
88.71
thiodiazole-
216.70
b
copper
a
b
Average of three replicates. The commercial agricultural antibacterial
agent thiodiazole-copper was used for comparison of antibacterial
activity.
SAR Analysis of Antibacterial Activities. Table 3 shows
the results of our antibacterial bioassays. Thiodiazole-copper, a
commercial agent for controlling R. solanacearum and X. oryzae,
was used as a reference for comparison. Some of the
compounds showed good potency against tobacco bacterial
wilt. Different substituent groups were introduced into the
quinazolin-4(3H)-one ring system to examine its SAR. Most of
the final compounds showed low to high antibacterial activities
against R. solanacearum and X. oryzae at 200 μg/mL. When R
was substituted with phenyl, 2-furyl, 4-methylphenyl, 3-
nitrophenyl, 2-nitrophenyl, 4-chloro-3-nitrophenyl, 4-hydrox-
yl-3-methoxyphenyl, 4-hydroxylphenyl, or 2-hydroxyl-5-nitro-
phenyl groups, the corresponding target compounds exhibited
significant activity against tobacco bacterial wilt. Some of the
compounds showed antibacterial activities comparable to that
of thiodiazole-copper. The strongest activity against tomato
bacterial wilt was observed when R was changed to phenyl, 2-
furyl, 2-, 3- or 4-nitro substituted phenyl, 4-chlorophenyl, 4-
fluorophenyl, 3-hydroxyl-4-methoxy phenyl, 4-hydroxyl-3-me-
thoxyphenyl, 4-hydroxylphenyl, or 2-hydroxyl-5-nitrophenyl
groups. Some title compounds were found to be as potent as
thiodiazole-copper. When R was substituted with 2-furyl, 4-
methylphenyl, 3-hydroxyl-4-methoxyphenyl, 4-hydroxyl-3-me-
thoxyphenyl, 4-hydroxylphenyl, or 2-hydroxyl-5-nitrylphenyl
groups, the target compounds exhibited remarkable activities
against X. oryzae that surpassed those of thiodiazole-copper or
bismerthiazol. When R was changed to 2-furyl, 4-hydrox-
ylphenyl, 4-hydroxyl-3-methoxyphenyl, or N,N-dimethyl
groups, the resulting target compounds showed efficient
broad-spectrum activities against all three bacteria.
activities against tobacco bacterial wilt with EC50 values of
7
8
8.90, 65.09, and 88.71 μg/mL, respectively. Compounds 8d,
f, 8j, 8x, and 8aa showed strong activity against tomato
bacterial wilt in vitro, with EC50 values of 80.75, 50.21, 96.08,
5.96, and 93.31 μg/mL, respectively. As indicated in Table 5,
4
Table 5. Inhibitory Effect of Compounds 8f, 8w, 8x, and 8aa
a
against Tomato Bacterial Wilt
EC50
(μg/mL)
pEC50
(μM)
compd
toxic regression eq
R
8
8
8
8
f
50.21
51.46
45.96
93.31
99.80
3.9447
3.9859
4.0079
3.7249
y = 2.6567x + 1.1466
y = 1.7045x + 2.0828
y = 2.2004x + 1.3420
y = 1.6832x + 1.6842
y = 1.0301x + 2.9414
0.9759
0.9959
0.9713
0.9897
0.9913
w
x
aa
thiodiazole-
b
copper
a
b
Average of three replicates. The commercial agricultural antibacterial
agent thiodiazole-copper was used for comparison of antibacterial
activity.
these values reflect stronger antibacterial activity of these
compounds than that of the commercial bactericide thiodia-
zole-copper (99.80 μg/mL). Finally, compounds 8f, 8v, 8w,
and 8x showed excellent antibacterial activity against X. oryzae
in vitro, with EC values of 20.09, 20.83, 21.33, and 20.23 μg/
50
mL, respectively. As shown in Table 6, these compounds are
markedly more potent against X. oryzae than the commercial
bactericide bismerthiazol (EC50 = 92.61 μg/mL).
SAR Analysis of Antifungal Activities. Results of our
assessment of the antifungal activities of the synthesized
compounds are shown in Table 2. Among the synthesized
final compounds (8a−8aa), SAR based on activity against G.
zeae, F. oxysporum, P. sasakii, and P. infestans showed that the
On the basis of the values indicated in Tables 3−6, we could
infer relationships between antibacterial activities and different
aryl groups (style, position, and substituent group). Oxygen
heterocyclic group of R was superior to sulfur heterocyclic and
phenyl groups in terms of antibacterial activity. For example,
inhibition rates of 8f (R = 2-furyl) against tobacco bacterial wilt,
tomato bacterial wilt, and X. oryzae were 94 and 55%, 100 and
78%, and 100 and 94%, at 200 and 100 μg/mL, respectively. By
contrast, 8e (R = 2-thienyl) displayed only 53 and 24%, 12 and
7%, and 28 and 11% inhibition rates at the same conditions.
The presence of the −NO , −CH , or −OH groups in a
substituent group at the 4-position of R (= CH phenyl, F
3
phenyl, Cl phenyl) had a critical effect on the antifungal activity
of compounds 8g, 8u, and 8s. Moreover, experiments on C.
mandshurica and S. sclerotiorum indicated that the disubstituent
group of R (= 2,6-di-Cl phenyl, 2,3-di-Cl phenyl, 3,5-di-Cl
phenyl, and 3,4-di-Cl phenyl) was crucial for antifungal
2
3
compound was found to be more effective than that of other
groups in improving its antibacterial activity. For instance,
9
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Journal of Agricultural and Food Chemistry
Article
inhibition rates of 8g (R = 4-methylphenyl), 8j (R = 3-
nitrophenyl), 8l (R = 4-chloro-3-nitrylphenyl), and 8aa (R = 4-
N,N-dimethylphenyl) against tobacco bacterial wilt were all
AUTHOR INFORMATION
Corresponding Author
(B.S.) Phone: +86 (851) 362-0521. Fax: +86 (851) 362-2211.
■
*
100% at 200 μg/mL. Moreover, 8w (R = 4-hydroxyl-3-
E-mail: songbaoan22@yahoo.com.
methoxyphenyl), 8x (R = 4-hydroxyphenyl), and 8aa (R = 4-
N,N-dimethylphenyl) consistently showed 100% inhibition
rates against tomato bacterial wilt with EC50 values of 51.46,
Present Address
State Key Laboratory Breeding Base of Green Pesticide and
Agricultural Bioengineering, Key Laboratory of Green Pesticide
and Agricultural Bioengineering, Ministry of Education,
Research and Development Center for Fine Chemicals,
Guizhou University, Guiyang 550025, People’s Republic of
China.
#
4
5.96, and 93.31 μg/mL, whereas 8v (R = 3-hydroxyl-4-
methoxyphenyl), 8w (R = 4-hydroxyl-3-methoxyphenyl), and
x (R = 4-hydroxylphenyl) all exhibited 100 (94), 100 (93),
8
and 100% (91%) inhibition rates against X. oryzae at 200 (100)
μg/mL, respectively, with EC50 values ranging from 20.09 to
Funding
21.33 μg/mL.
We gratefully acknowledge the National Key Program for Basic
Research (No. 2010CB 126105), the Key Technologies R&D
Program (Grant 2011BAE06B05-6), and the Natural Science
Foundation of Guizhou Science and Technology Department
Our antibacterial bioactivity assays and preliminary SAR data
revealed that arylimine derivatives containing quinazolinone
moieties had good antibacterial activity. A possible explanation
for the increase in antibacterial activity of the compounds we
tested is as follows: we introduced an N-aryl group in position 2
of the quinazolinone fragment of the target compound,
resulting in retainment of the hydrogen-bonding donor
group. Then, an aminoethyl group was inserted on the
quinazolinone fragment at position 3, which may have
enhanced the flexibility of the molecular backbone, allowing it
to combine with the lowest energy and receptor protein
molecular pathogenic bacteria. The nitrogen atom in the CN
(
Grant J20122303).
Notes
The authors declare no competing financial interest.
ABRREVIATIONS USED
■
TLC, thin layer chromatography; EC , 50% effective
5
0
1
1
13
concentration; H NMR, H nuclear magnetic resonance;
C
13
NMR, C nuclear magnetic resonance; MS, mass spectroscopy
2
bond has a lone pair of electrons due to SP hybridization and
can been regarded as a hydrogen bond acceptor. This perhaps
is the key to improve the antibacterial activity of the target
compounds.
REFERENCES
■
(
1) Maggio, B.; Daidone, G.; Raffa, D.; Plescia, S.; Mantione, L.;
Cutuli, V. M. C.; Mangano, N. G.; Caruso, A. Synthesis and
pharmacological study of ethyl 1-methyl-5-(substituted 3,4-dihydro-
-oxoquinazolin-3-yl)-1H-pyrazole-4-acetates. Eur. J. Med. Chem. 2001,
6, 737−742.
(2) Kung, P. P.; Casper, M. D.; Cook, K. L.; Wilson-Lingard, L.;
In summary, a series of novel arylimine derivatives containing
a quinazolinone nucleus was synthesized with moderate to
good yields and screened for biological activity. All of the final
4
3
1
compounds were confirmed on the basis of spectral data ( H
13
NMR, C NMR, MS, and IR), elemental analysis, and melting
points and were further subjected to various assays of biological
activity including in vitro antifungal and antibacterial activities.
Preliminary SAR analysis indicated that −CH , −NO , −OH or
Risen, L. M.; Vickers, T. A.; Ranken, R.; Blyn, L. B.; Wyatt, R.; Cook,
P. D.; Ecker, D. J. Structure-activity relationships of novel 2-substituted
quinazoline antibacterial agents. J. Med. Chem. 1999, 42, 4705−4713.
(
3) Li, F.; Feng, Y. Q.; Meng, Q. Q.; Li, W. H.; Li, Z. M.; Wang, Q.
3
2
R.; Tao, F. G. An efficient construction of 4(3H)-quinazolinones
under microwave irradiation. Arkivoc (Gainesville, FL, U.S.) 2007, I,
N,N-dimethyl groups on the benzene ring (substituted for R)
enhanced the antifungal and antibacterial activities of the
4
0−50.
synthesized compounds. Moreover, introduction of −F, −CH ,
3
(4) Carpintero, M.; Cifuentes, M.; Ferritto, R.; Haro, R.; Toledo, M.
−
NO , or −OH aromatic compounds resulted in moderate to
2
A. Automated liquid-liquid extraction workstation for library synthesis
and its use in the parallel and chromategraphy-free synthesis of 2-alkyl-
3-alkyl-4-(3H)-quinazolinones. J. Comb. Chem. 2007, 9, 818−822.
(5) Panneerselvam, P.; Rather, B. A.; Reddy, D. R. S; Ramesh Kumar,
N. Synthesis and anti-microbial screening of some schiff bases of 3-
amino-6,8-dibromo-2-phenylquinazolin-4(3H)-ones. Eur. J. Med.
Chem. 2009, 44, 2328−2333.
6) Bartroli, J.; Turmo, E.; Alguero, M.; Boncompte, E.; Vericat, M.
́
L.; Conte, L.; Ramis, J.; Merlos, M.; Gracía-Rafanell, J.; Forn, J. New
azole antifungals. 3. synthesis and antifungal activity of 3-substituted-
(3H)-quinazolinones. J. Med. Chem. 1998, 41, 1869−1882.
(7) Zhu, S.; Wang, J.; Chandrashekar, G.; Smith, E.; Liu, X.; Zhang,
Y. Synthesis and evaluation of 4-quinazolinone compounds as
potential antimalarial agents. Eur. J. Med. Chem. 2010, 45, 3864−3869.
8) Kumar, K. S.; Ganguly, S.; Veerasamy, R. Synthesis, antiviral
activity and cytotoxicity evaluation of schiff bases of some 2-phenyl
quinazoline-4(3)H-ones. Eur. J. Med. Chem. 2010, 45, 5474−5479.
9) Cao, S. L.; Feng, Y. P.; Jiang, Y. Y.; Liu, S. Y.; Ding, G. Y.; Li, R.
T. Synthesis and in vitro antitumor activity of 4(3H)-quinazolinone
derivatives with dithiocarbamate side chains. Bioorg. Med. Chem. Lett.
005, 15, 1915−1917.
10) Alagarsamy, V.; Thangathirupathy, A.; Mandal, S. C.;
Rajasekaran, S.; Vijayakumar, S.; Revathi, R.; Anburaj, J.; Arunkumar,
S.; Rajesh, S. Pharmacological evaluation of 2-substituted (1,3,4)
thiadiazolo quinazolines. Indian J. Pharm. Sci. 2006, 68, 108−111.
good antifungal activities against G. zeae, F. oxysporum, and S.
sclerotiorum. Antibacterial tests showed that all of the
synthesized final products containing 2-furyl, −OH, or −NO2
groups exhibited significant antibacterial activity against R.
solanacearum and X. oryzae. In addition, our antibacterial assays
demonstrated that the inhibition rates of compounds 8f, 8w,
and 8x were better than those of the commercial bactericides
thiodiazole-copper and bismerthiazol. To our knowledge, this is
the first report on the use of arylimine derivatives containing
quinazolinone moieties as potential disease control agents
against R. solanacearum and X. oryzae. Further evaluation of
their bactericidal properties, particularly in field studies
examining their biological efficacy, crop safety, and toxicity, is
necessary before they can be adopted for widespread use.
(
4
(
(
ASSOCIATED CONTENT
■
*
S
Supporting Information
2
(
Results of our physical and analytical assays as well as data on
the synthesis and characterization of intermediate 6 and target
compounds 8a−8aa. This material is available free of charge via
the Internet at http://pubs.acs.org.
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Journal of Agricultural and Food Chemistry
Article
(
11) Paneersalvam, P.; Raj, T.; Ishar, M. P. S.; Singh, B.; Sharma, V.;
sulfone derivatives containing 1,3,4-oxadiazole moieties. Molecules
2011, 16, 9129−9141.
Rather, B. A. Anticonvulsant activity of Schiff bases of 3-amino-6,8-
dibromo-2-phenyl-quinazolin-4(3H)-ones. Indian J. Pharm. Sci. 2010,
(31) Lee, J. Y.; Moon, S. S.; Hwang, B. K. Isolation and in vitro and
in vivo activity against phytophthora capsici and colletotrichum
orbiculare of phenazine-1-carboxylic acid from pseudomonas aerugi-
nosa strain GC-B26. Pest Manag. Sci. 2003, 59, 872−882.
(32) Govindaraj, S.; Perumal, P.; Chinnasamy, R. P. Synthesis and
antimicrobial screening of novel Schiff bases of 3-amino-2-methyl-
4(3H)-quinazolinone. J. Adv. Pharm. Technol. Res. 2010, 1, 320−325.
7
(
2, 375−378.
12) Saravanan, G.; Pannerselvam, P.; Prakash, C. R. Synthesis and
anti-convulsant screening of novel Schiff bases of 3-amino-2-methyl
quinazolin-4-(3H)-one. Int. J. Res. Pharm. Sci. 2010, 1, 277−281.
(
Schiff bases as potential fungicides and nitrification inhibitors. J. Agric.
Food Chem. 2009, 57, 8520−8525.
(
13) Aggarwal, N.; Kumar, R.; Dureja, P.; Diwan, S.; Rawat, D. S.
14) Wang, B. L.; Shi, Y. X.; Ma, Y.; Liu, X. H.; Li, Y. H.; Song, H. B.;
Li, B. J.; Li, Z. M. Synthesis and biological activity of some novel
trifluoromethyl-substituted 1,2,4-triazole and bis(1,2,4-triazole) man-
nich bases containing piperazine rings. J. Agric. Food Chem. 2010, 58,
5
(
515−5522.
15) Ward, C. E.; Berthold, R. V.; Koerwer, J. F.; Tomlin, J. B.;
Manning, D. T. Synthesis and herbicidal activity of 1,2,3,4-tetrahydro-
1
1
(
,3,5-triazino[1,2-a]benzimidazoles. J. Agric. Food Chem. 1986, 34,
005−1010.
16) DeMilo, A. B.; Redfern, R. E. New insect juvenile hormone
mimics: aromatic schiff bases and related compounds against the large
milkweed bug and yellow mealworm. J. Agric. Food Chem. 1979, 27,
7
(
60−762.
17) Shi, L.; Ge, H. M.; Tan, S. H.; Li, H. Q.; Song, Y. C.; Zhu, H. L.;
Tan, R. X. Synthesis and antimicrobial activities of Schiff bases derived
from 5-chloro-salicylaldehyde. Eur. J. Med. Chem. 2007, 42, 558−564.
(
18) Sriram, D.; Yogeeswari, P.; Myneedu, N. S.; Saraswat, V.
Abacavir prodrugs: microwave-assisted synthesis and their evaluation
of anti-HIV activities. Bioorg. Med. Chem. Lett. 2006, 16, 2127−2129.
(
19) Datta, A.; Walia, S.; Parmar, B. S. Some furfural derivatives as
nitrification inhibitors. J. Agric. Food Chem. 2001, 49, 4726−4731.
(
20) Przybylski, P.; Huczynski, A.; Pyta, K.; Brzezinski, B.; Bartl, F.
Biological properties of Schiff bases and azo derivatives of phenols.
Curr. Org. Chem. 2009, 13, 124−148.
(
21) Gupta, V.; Kashaw, S. K.; Jatav, V.; Mishra, P. Synthesis and
antimicrobial activity of some new 3-[5-(4-substituted)phenyl-1,3,4-
oxadiazole-2-yl]-2-styrylquinazoline-4(3H)-ones. Med. Chem. Res.
2
(
008, 17, 205−211.
22) Ilangovan, P.; Ganguly, S.; Pandi, V. Design and synthesis of
novel quinazolinone derivatives as broad spectrum anticonvulsant and
antimicrobial agent. J. Pharm. Res. 2010, 3, 703−706.
(
23) Mohamed, M. S.; Kamel, M. M.; Kassem, E. M. M.; Abotaleb,
N.; Abd El-moez, S. I.; Ahmed, M. F. Novel 6,8-dibromo-4(3H)-
quinazolinone derivatives of anti-bacterial and anti-fungal activities.
Eur. J. Med. Chem. 2010, 45, 3311−3319.
(
24) Gao, X. W.; Cai, X. J.; Yan, K.; Song, B. A.; Gao, L. L.; Chen, Z.
Synthesis and antiviral bioactivities of 2-aryl- or 2-methyl-3-
substituted-benzalamino)-4(3H)-quinazolinone derivatives. Molecules
007, 12, 2621−2642.
25) Luo, H.; Liu, J. J.; Jin, L. H.; Hu, D. Y.; Chen, Z.; Yang, S.; Wu,
(
2
(
J.; Song, B. A. Synthesis and antiviral bioactivity of novel (1E,4E)-1-
aryl-5-(2-(quinazolin-4-yloxy) phenyl)-1,4-pentadien-3-one deriva-
tives. Eur. J. Med. Chem. 2013, 63, 662−669.
(
26) Xu, W. M.; Han, F. F.; He, M.; Hu, D. Y.; He, J.; Yang, S.; Song,
B. A. Inhibition of tobacco bacterial wilt with sulfone derivatives
containing an 1,3,4-oxadiazole moiety. J. Agric. Food Chem. 2012, 60,
1
(
036−1041.
27) Gopalsamy, A.; Yang, H. Combinatorial synthesis of hetero-
cycles: solid-phase synthesis of 2-amino-4(1H)-quinazolinone deriva-
tives. J. Comb. Chem. 2000, 2, 378−381.
(
28) Yang, X. H.; Wu, M. H.; Sun, S. F.; Ding, M. W.; Xie, J. L.; Xia,
Q. H. Synthesis of 3-aminoalkyl-2-arylaminoquinazolin-4(3H)-ones
and 3,3′-disubstituted bis-2-arylaminoquinazolin-4(3H)-ones via re-
actions of 1-aryl-3-(2-ethoxycarbonylphenyl) carbodiimides with
diamines. J. Heterocycl. Chem. 2008, 45, 1365−1369.
(
29) Chattapadhyay, T. K.; Dureja, P. Antifungal activity of 4-methyl-
-alkyl-2H-pyran-2-ones. J. Agric. Food Chem. 2006, 54, 2129−2133.
30) Xu, W. M.; He, J.; He, M.; Han, F. F.; Chen, X. H.; Pan, Z. X.;
Wang, J.; Tong, M. G. Synthesis and antifungal activity of novel
6
(
9
582
dx.doi.org/10.1021/jf403193q | J. Agric. Food Chem. 2013, 61, 9575−9582