Synthesis, antibacterial, and antiviral activities of novel penta-1,4-dien-3-one derivatives containing a benzotriazin-4(3H)-one moiety

Article abstract of DOI:10.1007/s11696-018-0422-x

A series of penta-1,4-dien-3-one containing a benzotriazin-4(3H)-one moiety were prepared and evaluated for their antibacterial and antiviral activities. Bioassays indicated that some compounds exhibited good antibacterial and antiviral activities. Among them, the EC₅₀ values of compound 6d against Xanthomonas axonopodis pv. citri and compound 6l against Ralstonia solanacearum were, respectively, 22.45 and 34.77?μg/mL, which were better than that of thiodiazole copper (51.35 and 87.26?μg/mL, respectively). Meanwhile, some title compounds were found to show remarkable antiviral activities against tobacco mosaic virus (TMV). These results indicated that penta-1,4-dien-3-one derivatives containing benzotriazin-4(3H)-one moiety could play significant roles in searching for novel agrochemicals.

Full text of DOI:10.1007/s11696-018-0422-x

Chemical Papers
https://doi.org/10.1007/s11696-018-0422-x
ORIGINAL PAPER
Synthesis, antibacterial, and antiviral activities of novel
penta‑1,4‑dien‑3‑one derivatives containing a benzotriazin‑4(3H)‑one
moiety
Ju‑Ping Zhang1 · Qin Li1 · Cheng Zhang1 · Pu Li1 · Li‑Juan Chen1 · Yi‑Hui Wang1 · Xiang‑Hui Ruan1 · Wei Xiao1 ·
Wei Xue1
Received: 19 September 2017 / Accepted: 14 February 2018
© Institute of Chemistry, Slovak Academy of Sciences 2018
Abstract
A series of penta-1,4-dien-3-one containing a benzotriazin-4(3H)-one moiety were prepared and evaluated for their antibac-
terial and antiviral activities. Bioassays indicated that some compounds exhibited good antibacterial and antiviral activities.
Among them, the EC50 values of compound 6d against Xanthomonas axonopodis pv. citri and compound 6l against Ralsto-
nia solanacearum were, respectively, 22.45 and 34.77 μg/mL, which were better than that of thiodiazole copper (51.35 and
87.26 μg/mL, respectively). Meanwhile, some title compounds were found to show remarkable antiviral activities against
tobacco mosaic virus (TMV). These results indicated that penta-1,4-dien-3-one derivatives containing benzotriazin-4(3H)-
one moiety could play signifcant roles in searching for novel agrochemicals.
Keywords Penta-1,4-dien-3-one · Antiviral · Antibacterial · Benzotriazin-4(3H)-one
Introduction
roles in the treatment of agricultural diseases. Among them,
penta-1,4-dien-3-ones, analogues of curcumin that were
isolated from the plant Curcuma longa L, have attracted
great interests of biologists for several reasons. First, the
structure of penta-1,4-dien-3-one is more stable than that of
curcumin under neutral or alkaline condition (Guo 2013).
Second, penta-1,4-dien-3-one, to some extent, possesses
a simple chemical structure and is easy to be synthesized.
Third, penta-1,4-dien-3-one was found to exhibit desirable
bioactivities including anti-oxidative (Al-Omara et al. 2005),
anti-infammatory (Liu et al. 2014), bactericidal (Baldwin
et al. 2015), anticancer (Yuan et al. 2011), antiviral (Chen
et al. 2015), and insecticidal (Xia et al. 2017) properties.
In addition, the last decade studies reported that penta-1,4-
dien-3-one can serve as potential alternative templates in
the search for novel, highly efcient virucides (Wang et al.
2017). Studies on agricultural bioactivities of penta-1,4-
dien-3-ones only focused on their antiviral activity against
some plant viruses. However, penta-1,4-dien-3-one deriva-
tives with agricultural antibacterial activities were rarely
reported.
Featuring unique modes of action, environmental friendli-
ness, and desirable bioactivities, natural products are cur-
rently regarded as promising alternative lead compounds in
searching for novel agrochemicals (Qian et al. 2010). Based
on structures of natural products, series of osthole (Zhang
et al. 2016), tetramic acid (Jeong and Moloney 2013), cur-
cumin (Changtam et al. 2010), chalcone (Gan et al. 2017),
myricetin (Xiao et al. 2017), ferulic acid (Wu et al. 2017),
and vanillin (Zhang et al. 2017) derivatives were synthe-
sized, and found that these compounds could play important
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-018-0422-x) contains
supplementary material, which is available to authorized users.
Ju-Ping Zhang and Qin Li have contributed equally to this work.
* Wei Xue
wxue@gzu.edu.cn
1
State Key Laboratory Breeding Base of Green Pesticide
Possessing of extensive bioactivities including anti-
infammatory (Ibrahim et al. 2012), insecticidal (Zuo et al.
2013), herbicidal (Niu et al. 2008), and anticancer (Sirisoma
et al. 2010) properties, benzotriazin-4(3H)-one was regarded
and Agricultural Bioengineering, Key Laboratory
of Green Pesticide and Agricultural Bioengineering,
Ministry of Education, Guizhou University, Huaxi District,
Guiyang 550025, China
Vol.:(0123456789)
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as an important nitrogenous motif that was commonly used
in developing for agrochemicals. As important benzotriazin-
4(3H)-one derivatives, azinphos-methyl and azinphos-ethyl
were widely used to manage crop diseases and pest damages
in China. Recently, series of benzotriazin-4(3H)-one deriv-
atives, respectively, containing 2-cyanoiminothiazolidin-
4-one and spirocyclic indoline-2-one fragments were synthe-
sized and exhibited remarkable nematicidal activity against
Meloidogyne incognita (Wang et al. 2015a, b). However,
studies on benzotriazin-4(3H)-one derivatives with potent
antiviral and bactericidal were rarely reported.
electro-static feld orbitrap mass spectrometer. Thin-layer
chromatography purifcations [V (Ethyl Acetate): V (Petro-
leum ether) = 1:3] were carried out on 200–300 mesh sil-
ica gel. All solvents and reagents were freshly distilled or
purifed according to standard procedures. As depicted in
Scheme 2, intermediates 1 and 2 were, respectively, syn-
thesized by the procedures described in the literature (Chen
et al. 2015; Wu et al. 2016; Ma et al. 2014).
Chemicals
Here, aiming to searching for novel, efcient, and eco-
friendly lead compounds with better agricultural activities
and simpler structures, a series of penta-1,4-dien-3-one
containing a benzotriazin-4(3H)-one moiety were designed,
prepared, and evaluated for their biological activities against
plant bacteria and virus. Bioassay results indicated that some
title compounds enhanced activities against Xanthomonas
axonopodis pv. citri (Xac) and Ralstonia solanacearum
(Rs) in vitro. Importantly, the EC50 values of compound
6d against Xac and compound 6l against Rs were, respec-
tively, 22.45 and 34.77 μg/mL, which were better than that
of thiodiazole copper (51.35 and 87.26 μg/mL, respectively).
Meanwhile, some title compounds were found to show
remarkable antiviral activities against tobacco mosaic virus
(TMV) (Scheme 1).
Synthesis of intermediate benzotriazin‑4(3H)‑one (3)
2-Aminobenzamide (0.5 g, 3.67 mmol) was dissolved in
4 mL 8N hydrochloric acid and 7 mL 3N NaNO2 was added
dropwise and stirred under ice-cooling. The reaction was
continued for 1 h. The liquid was neutralized with NaOH
to a pH of 7–8 and fltered. The solid was recrystallized
from methanol to obtain intermediate 3, yield 85.2%, m.p.
207–209 °C.
Synthesis of intermediate 3‑(hydroxymethyl)
benzotriazin‑4(3H)‑one (4)
The solution, which contained intermediate 3 (1.0 g,
6.8 mmol), 37.0% formaldehyde solution (7 mL), and
1,4-dioxane (10 mL), was heated under refux for 5 h. After
cooling the reaction mixture to room temperature, 10 mL
water was added and the mixture was extracted with dichlo-
romethane three times. The organic phase was separated and
dried with sodium sulphate, and solvent was evaporated to
obtain intermediate 4, yield 76.7%, m.p. 216–218 °C.
Experimental
Materials
Unless noted, the melting points (m.p.) were recorded auto-
matically and they were not corrected on an XT-4-MP appa-
ratus from Beijing Tech. Instrument Co. (Beijing, China).
The 1H NMR and 13C NMR spectra (solvent CDCl3) were
measured with a Bruker ASCEND 400 NMR spectrometer
operating at 400 and 100 MHz and a JEOL-ECX 500 NMR
spectrometer operating at 500 and 125 MHz at room tem-
perature with tetramethylsilane (TMS) as an internal stand-
ard. Mass spectral studies were performed on a quadrupole/
Synthesis of intermediate 3‑(chloromethyl)
benzotriazin‑4(3H)‑one (5)
Intermediate 4 (0.5 g, 2.82 mmol), 1,4-dioxane (7 mL), and
thionyl chloride (5 mL) were heated under refux for 2 h.
After the reaction was fnished, the solvent was removed
under reduced pressure. The solid residue was then dis-
solved in dichloromethane (10 mL), washed with distilled
Scheme 1 Design of the title compounds
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Scheme 2 Synthetic route to the title compounds 6a–6s
water, and dried with sodium sulphate, and the solvent
was evaporated to obtain intermediate 5, yield 81.8%, m.p.
125–127 °C.
Results and discussion
Chemistry
The structures of all the target compounds (6a–6s) were
1
verifed by H NMR, 13C NMR, and HRMS (Tables 1,
Synthesis of 3‑((4‑((1E,4E)‑3‑oxo‑5‑substituted
penta‑1,4‑dien‑1‑yl)phenoxy)methyl)
benzotriazin‑4(3H)‑ones (6a–6s)
1
2). H NMR data showed that all the aryl protons were
presented in multiplets at δ 6.87–7.89 ppm. Meanwhile,
1
singlets at δ 6.35–6.40 ppm in the H NMR spectra were
A mixture of intermediates 2a (2.10 mmol), 5 (1.91 mmol),
acetonitrile (30 mL), and K2CO3 (3.82 mmol) were stirred at
80 °C for 4 h. Then, the mixture was fltered and the solvent
was evaporated under reduced pressure. The solid residue
was purifed by column chromatography; the obtained solu-
tion was evaporated under vacuum. The solid was chromato-
graphed on silica gel (200–300 mesh) to obtain 6a. Using a
similar procedure, the title compounds 6b–6s were prepared.
The physical properties and HRMS data of compounds
6a–6s are listed in Table 1, and the 1H NMR and 13C NMR
data of compounds 6a–6s are listed in Table 2.
attributed to the –CH2– protons. The typical carbon reso-
nance frequencies at δ 75.40–75.50 ppm in 13C NMR also
confrmed the existence of –CH2– group.
Antiviral activity screening of the title compounds
against TMV
Using growing N. tobacum L. leaves at the same age as the
test subjects, the curative and protective activities against
TMV were evaluated based on the half-leaf blight spot
method (Long et al. 2015; Gan et al. 2016; Yu et al. 2017),
and the commercial agent ribavirin was tested as the con-
trol under the same conditions. The preliminary bioas-
say results are listed in Table 3 and indicated that most
of the target compounds exhibited good antiviral activi-
ties against TMV in vivo at 500 μg/mL. For example, the
inhibitory rates of compounds 6d, 6e, 6k, and 6p were,
respectively, 49.0, 37.3, 35.7, and 36.9%, in terms of their
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Table 1 Physical properties
and HRMS data of compounds
6a–6s
Compd R1
Appearance
Yield (%) M.p./°C
HRMS (Calcd.) [M + H]+
6a
6b
6c
6d
6e
6f
6g
6h
6i
Thiophen-2-yl
4-Methylphenyl
Pyridin-3-yl
Yellow solid 82
Yellow solid 57
Yellow solid 40
Yellow solid 29
Yellow solid 76
Yellow solid 79
Yellow solid 58
Yellow solid 46
Yellow solid 69
Yellow solid 54
Yellow solid 55
Yellow solid 43
164–166
191–193
153–155
155–156
211–213
161–162
169–171
172–173
166–167
147–149
129–130
188–189
209–211
158–159
159–160
141–142
148–150
144–145
181–182
416.1043 (416.1063)
424.1641 (424.1656)
411.1447 (411.1452)
411.1449 (411.1452)
440.1586 (440.1605)
440.1591 (440.1605)
444.1100 (444.1110)
470.1709 (470.1711)
428.1408 (428.1405)
470.1712 (470.1711)
410.1498 (410.1499)
455.1339 (455.1350)
489.0954 (489.0960)
436.1648 (436.1656)
431.1166 (431.1172)
400.1285 (400.1292)
444.1102 (444.1110)
430.1213 (430.1220)
494.0161 (494.0169)
Pyridin-2-yl
4-Methoxyphenyl
2-Methoxyphenyl
4-Chlorophenyl
2,4-Dimethoxyphenyl
4-Fluorophenyl
3,4-Dimethoxyphenyl
Phenyl
6j
6k
6l
3-Nitrophenyl
6m
6n
6o
6p
6q
6r
6s
2-Chloro-5-nitrophenyl Yellow solid 23
Ethenylphenyl
5-Methylthiazole-2-yl
Furan-2-yl
2-Chlorophenyl
3-Methylthiophen-2-yl
4-Bromothiophen-2-yl
Yellow solid 63
Yellow solid 31
Yellow solid 71
Yellow solid 65
Yellow solid 82
Yellow solid 79
curative activities, which were better than that of ribavirin
(35.0%). Compounds 6d, 6e, and 6h were found to exhibit
slightly higher protective activity (52.9, 59.2, and 57.7%,
respectively) than ribavirin (50.8%).
44.51, 48.47, 39.89, 27.29, and 26.27%, respectively, which
were superior to that of thiodiazole copper (21.04%).
Based on the preliminary bioassays, the EC50 values of
selected compounds that exhibited good activities against
Xac and Rs are calculated and summarized in Tables 5 and
6. Table 5 indicates that compounds 6a, 6c, 6d, and 6p
efectively inhibited Xac in vitro, with the EC50 values of
31.41, 35.86, 22.45, and 34.16 µg/mL, respectively, which
were better than that of thiodiazole copper (51.35 µg/mL).
Meanwhile, Table 6 indicates that compounds 6a, 6f, 6g,
6l, 6m, and 6n efectively inhibited Rs, with the EC50 val-
ues of 62.67, 52.51, 61.42, 34.77, 62.29, and 64.42 µg/mL,
respectively, which were better than that of thiodiazole cop-
per (87.26 µg/mL). Strickingly, the EC50 values of the title
compound 6a against Xac and Rs were, respectively, 31.41
and 62.67 µg/mL, which were better than that of thiodiazole
copper (51.35 and 87.26 μg/mL, respectively).
Antibacterial activities’ screening of the title
compounds against Xac and Rs in vitro
The preliminary bioassays results in Table 4, which obtained
by turbidity method (Xu et al. 2012; Li et al. 2013), indi-
cated that some title compounds exhibited good antibacterial
activities against Xac and Rs in vitro at 100 and 50 μg/mL
(Table 4). For instance, the inhibitory rates of compounds
6a and 6p against Xac were 68.14 and 68.05%, respectively,
which were similar to that of thiodiazole copper (67.67%)
at 100 μg/mL. Meanwhile, the inhibition rates of com-
pounds 6c, 6d, 6g, 6h, 6i, 6m, 6p, 6q, and 6s against Xac
at 50 μg/mL were 49.76, 51.14, 46.19, 45.10, 44.52, 46.32,
62.23, 45.48, and 47.04%, respectively, which were slightly
exceeded than that of thiodiazole copper (44.26%). The bio-
assay results in Table 4 also indicated that the antibacterial
activities of compounds 6a, 6e, 6f, 6g, 6i, 6j, 6k, 6l, 6m,
6n, 6p, and 6r against Rs at 100 μg/mL were 59.94, 41.64,
53.22, 50.79, 42.15, 44.69, 52.93, 88.14, 49.55, 50.45,
45.52, and 44.68%, respectively, which were superior to
thiodiazole copper (37.01%). Compounds 6a, 6c, 6e, 6f,
6g, 6h, 6i, 6j, 6k, 6l, 6m, 6n, and 6p had fne antibacterial
activity against Rs at 50 μg/mL, with the inhibition rates
of 22.77, 22.36, 35.82, 44.35, 43.19, 24.35, 32.88, 22.66,
Structure–activity relationship analysis
of the antiviral activities against TMV
Antiviral activities of penta-1,4-dien-3-one derivatives
containing a benzotriazin-4(3H)-one moiety were afected
by variation of diferent substitutes on R1 position. Based
on these data (Table 3), we can conclude that the intro-
duction of pyridin-2-yl and 4-methoxyphenyl groups, the
corresponding target compounds, exhibited good curative
activity against TMV. For instance, compounds 6d and 6e
showed curative rates of 49.0 and 37.3%. Likewise, good
protection activity against TMV was also observed when
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Table 3 Antiviral activities of the title compounds against TMV
by variation of diferent substitutes on R1 position. The
inhibitory rates in Table 4 indicate that most title compounds
bearing the same substituted fragment were found to exhibit
better antibacterial activity against Xac than Rs. For exam-
ple, the inhibitory rates of compounds 6b, 6c, 6d, 6h, 6o,
6p 6q, and 6s against Xac were, respectively, 44.57, 58.10,
52.29, 46.57, 41.62, 68.05, 50.75, and 56.13% at 100 μg/mL,
which were superior to that against Rs (29.49, 26.44, 25.99,
29.10, 18.61, 45.52, 18.21, and 24.98%, respectively). The
antibacterial results in Table 5 also indicated that the difer-
ent groups on R1 had signifcant efects on the antibacterial
activity of the target compounds against Xac. Obviously,
the presence of unsubstituted heterocycles can efectively
enhance the antibacterial activity against Xac. As exam-
ples of this phenomenon, compounds 6a, 6c, 6d, and 6p,
which contained, respectively, thiophen-2-yl, pyridin-3-yl,
pyridin-2-yl, and furan-2-yl groups, exhibited fne antibac-
terial activity against Xac, with the EC50 values of 31.41,
35.86, 22.45, and 34.16 μg/mL, respectively, which were
better than thiodiazole copper (51.35 μg/mL). Meanwhile,
when R1 was substituted with 4-chlorophenyl, 4-fuorophe-
nyl, 2-chloro-5-nitrophenyl, and 2-chlorophenyl groups,
the corresponding compounds 6g, 6i, 6m, and 6q exhib-
ited remarkable antibacterial activity against Xac, with the
inhibitory rates of 46.19, 44.52, 46.32, and 45.48% at 50 μg/
mL, respectively, which were better than thiadiazole-copper
(44.26%).
in vivo at 500 μg/mL
Compd.
R1
Curative activity
(%)a
Protection
activity (%)a
6a
6b
6c
6d
6e
6f
Thiophen-2-yl
4-Methylphenyl
Pyridin-3-yl
24.2 5.0
33.3 2.8
23.1 3.6
49.0 1.3
37.3 7.2
28.6 2.9
13.3 8.5
40.0 5.5
36.6 7.5
37.3 2.5
52.9 2.5
59.2 2.1
34.3 7.1
24.8 4.8
57.7 0.6
Pyridin-2-yl
4-Methoxyphenyl
2-Methoxyphenyl
4-Chlorophenyl
6g
6h
2,4-Dimethoxyphe- 29.1 1.3
nyl
6i
6j
4-Fluorophenyl
30.8 4.2
35.2 5.5
34.5 8.6
3,4-Dimethoxyphe- 22.0 5.7
nyl
6k
6l
6m
Phenyl
3-Nitrophenyl
35.7 8.6
19.2 4.5
22.6 4.1
43.2 4.7
25.4 6.8
37.8 5.2
2-Chloro-5-nitro-
phenyl
6n
6o
Ethenylphenyl
31.1 1.6
24.6 2.3
45.5 2.2
35.3 2.2
5-Methylthiazole-
2-yl
6p
6q
6r
Furan-2-yl
2-Chlorophenyl
36.9 1.9
20.8 6.8
15.4 2.6
41.4 7.3
27.0 6.7
16.8 3.3
3-Methylthiophen-
2-yl
6s
4-Bromothiophen-
2-yl
–
22.8 3.0
35.0 4.7
24.4 1.1
50.8 3.1
ribavirinb
Conclusions
aAverage of three replicates
bThe commercial agricultural ribavirin was used for comparison of
In summary, aiming to searching for novel, efcient, and
eco-friendly lead compounds with better agricultural activi-
ties and simpler structures, a series of penta-1,4-dien-3-one
containing a benzotriazin-4(3H)-one moiety were designed,
prepared, and evaluated for their biological activities against
plant bacteria and virus. Among them, the EC50 values of
compound 6d against Xac and compound 6l against Rs
were, respectively, 22.45 and 34.77 μg/mL, which were
better than that of thiodiazole copper (51.35 and 87.26 μg/
activity
substituent groups were changed to 4-methoxyphenyl and
2,4-dimethoxyphenyl. The inhibitory rate of compounds 6e
and 6h was up to 59.2 and 57.7%, respectively. These com-
pounds showed better antiviral activities than the reference
compound.
Structure–activity relationship analysis
of the antibacterial activities against Xac and Rs
Antibacterial activities of penta-1,4-dien-3-one derivatives
containing a benzotriazin-4(3H)-one moiety were afected
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Table 4 Antibacterial activities
(inhibition rate/%) of target
compounds 6a–6s
Compd
Xac/%
Rs/%
100 μg/mL
50 μg/mL
100 μg/mL
50 μg/mL
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
68.14 8.66
44.57 1.61
58.10 1.40
52.29 1.74
39.86 6.53
39.71 4.90
49.76 4.51
46.57 3.00
50.10 4.40
36.38 1.07
35.62 4.85
38.05 4.10
53.57 2.13
20.14 2.38
41.62 2.16
68.05 2.59
50.75 4.61
40.04 3.37
56.13 1.04
67.67 3.67
29.76 6.56
30.33 4.08
49.76 3.81
51.14 2.65
35.43 3.48
31.10 2.54
46.19 5.27
45.10 1.02
44.52 6.34
29.67 8.39
23.28 7.14
30.36 6.27
46.32 0.98
17.71 3.36
12.29 7.54
62.23 4.91
45.48 6.43
26.46 4.20
47.04 3.30
44.26 4.06
59.94 4.99
29.49 5.37
26.44 6.68
25.99 2.78
41.64 1.89
53.22 3.44
50.79 3.70
29.10 6.16
42.15 8.39
44.69 4.41
52.93 3.59
88.14 2.91
49.55 0.72
50.45 2.47
18.61 3.44
45.52 2.76
18.21 3.27
44.68 3.37
24.98 3.17
37.01 3.76
22.77 5.68
18.87 6.41
22.36 1.38
2.88 1.68
35.82 1.15
44.35 3.78
43.19 4.12
24.35 8.68
32.88 0.51
22.66 2.92
44.51 5.85
48.47 7.46
39.89 6.87
27.29 2.00
13.93 2.67
26.27 2.67
14.58 2.70
18.26 5.12
16.67 2.86
21.04 4.42
Thiodiazole
coppera
Average of three replicates
aThe commercial bactericide (thiodiazole copper) were used for comparison of antibacterial activity
mL, respectively). Meanwhile, some title compounds were
found to show remarkable antiviral activity against TMV.
Furthermore, study on the antibacterial mechanism is cur-
rently underway.
Table 5 EC50 values of the title compounds against Xac in vitro
Compd
Toxic regression equa-
tion
R
EC50/(µg/mL)
6a
6c
6d
6p
6s
y = 0.9318x + 3.5276 0.9509 31.41
y = 0.7661x + 3.6247 0.9538 35.86
y = 1.1277x + 2.9799 0.9588 22.45
y = 1.5553x + 2.4769 0.9882 34.16
y = 2.3560x + 0.7190 0.9933 62.71
Acknowledgements This research was supported by the National Key
Research and Development Program of China (No. 2017YFD0200506),
the National Nature Science Foundation of China (No. 21462012), the
Special Fund for Outstanding Scientifc and Technological Candidates
of Guizhou Province (No. 201535), and the Innovation Fund for Gradu-
ate Student of Guizhou University (No. 2017059).
Thiodiazole copper y = 2.3250x + 1.4553 0.9930 51.35
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