Synthesis and antibacterial activity of novel myricetin derivatives containing sulfonylpiperazine

Article abstract of DOI:10.1007/s11696-020-01363-3

Myricetin derivatives containing sulfonylpiperazine were synthesized and their structures were confirmed by NMR and HRMS. The antibacterial activity results indicated that some compounds showed good antibacterial activity against Xanthomonas oryzaepv. ory

Full text of DOI:10.1007/s11696-020-01363-3

Chemical Papers
https://doi.org/10.1007/s11696-020-01363-3
ORIGINAL PAPER
Synthesis and antibacterial activity of novel myricetin derivatives
containing sulfonylpiperazine
Jun He1 · Xue‑Mei Tang1 · Ting‑Ting Liu1 · Feng Peng1 · Qing Zhou1 · Li‑Wei Liu1 · Ming He1 · Wei Xue1
Received: 10 June 2020 / Accepted: 15 September 2020
© The Author(s) 2020
Abstract
Myricetin derivatives containing sulfonylpiperazine were synthesized and their structures were confrmed by NMR and
HRMS. The antibacterial activity results indicated that some compounds showed good antibacterial activity against Xan-
thomonas oryzaepv. oryzae (Xoo), Xanthomonas axonopodispv. citri (Xac) and Ralstonia solanacearum (Rs). Among them,
compounds 4m and 4p revealed excellent antibacterial activities against Rs with a concentration for 50% of maximal efect
(EC50) value of 4 and 4 μg/mL, which were better than the control drugs bismerthiazol (13 μg/mL) and thiodiazole-copper
(185 μg/mL). As observed using scanning electron microscope (SEM), these compounds act by causing folding and defor-
mation of the bacterial surface, resulting in incomplete bacterial structure, so as to achieve the goal of bacteriostasis. The
myricetin derivatives synthesized are expected to guide the research direction of new antibacterial agents.
Keywords Myricetin derivative · Sulfonylpiperazine · Antibacterial activity · Concentration for 50% of maximal efect ·
Scanning electron microscope
Introduction
use of traditional fungicides, the resistance of plant bacteria
to them has gradually increases (Yan et al. 2016; Jiang et al.
2020a, b). Therefore, the development of new antibacterial
agents is of great signifcance.
Plant diseases have always been a headache in agricultural
production. The plant bacterial diseases are extremely dif-
fcult to control in agricultural production, such as rice
bacterial blight, tobacco bacterial wilt, citrus canker and
so on (Zou et al. 2011; Li et al. 2017). Since the earliest
fungicide bordeaux liquid, a lot of agricultural fungicides
have been developed successively. With the development of
chemistry, new types of nano-antibacterial agents have also
come into the sight of chemists (Khatoon et al. 2017, 2018).
Until today, there have been many commercial antibacte-
rial agents with good activity, such as bismerthiazol and
thiodiazole-copper etc. However, with the increase in the
Flavonoids are widely existed in plants in nature, and
belong to the secondary metabolites of plants (Manthey and
Guthrie 2002). It plays an important role in plant growth,
development, flowering, fruiting, antibacterial and dis-
ease prevention. Moreover, many studies in recent years
have shown that favonoid-based scafolds as multi-target-
directed ligands (MTDLs) have shown an important role
in the treatment of Alzheimer’s disease (Jalili-Baleh et al.
2018). Therefore favonoids have become a research hot-
spot in the pharmaceutical and pesticide industries due to
their extensive biological activities. Myricetin is a common
plant-derived favonol derived from fruits, vegetables, ber-
ries, nuts, tea, etc. (Zhang et al. 2020). Research over the
years has shown that myricetin has a wide range of bio-
logical activities. Such as antibacterial (Mo et al. 2020),
anticancer (Sun et al. 2012), anti-infammatory (Wang et al.
2010), antiviral (Yu et al. 2012) and antioxidant activities
(Guitard et al. 2016). Studies have found that myricetin has
the least cytotoxicity to TZM-bl, HeLa, PBMC and H9 cells
at a concentration of 100 μM, with cell viability above 85%,
which is better than quercetin and pinocembrin (Pasetto et al.
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-020-01363-3) contains
supplementary material, which is available to authorized users.
* Wei Xue
wxue@gzu.edu.cn
1
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, China
Vol.:(0123456789)
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Chemical Papers
2014). Piperazine is an important intermediate in medicine,
pesticide and dye. Due to the special chemical structure
of piperazine. Piperazine and its series of compounds are
important products connecting the chemical industry and the
pharmaceutical industry (Suleman et al. 2020), widely used
in medicine (Alina et al. 2020), pesticides (Peng and Wang
2018) and other felds. As a kind of pharmacophore group
with extensive biological activities in antibacterial (Nadia
and Mona 2020), weeding (Chen et al. 2018), anticancer
(Štěpánková et al. 2020), antioxidant (Soliman et al. 2020)
etc., sulfonamide group has shown excellent activity and
great value in the feld of medicine and pesticides. There-
fore, the structure of sulfonylpiperazine is often used in new
drug design and development (Xu et al. 2015).
by SEM. Compared with the previous work of research
group, the inhibitory activity of this series of compounds
4 on Rs has been greatly improved. This article attempts
to optimize the superposition of these active fragments to
fnd drugs with high antibacterial activity, and provide a
reliable research direction for the screening of new antibac-
terial drugs.
Experimental
Materials
piperazine and arylsulfonyl chloride were obtained from
Shanghai Titanchem Co., Ltd., and all other reagents were
analytical grade. A Bruker Ascend 400 NMR spectrom-
eter (Bruker Optics, Switzerland) was used to record the
1H, 13C and 19F nuclear magnetic resonance (NMR), with
tetramethylsilane (TMS) as the internal standard, and CDCl3
as solvent. The melting point tests were conducted in an
XT-4 binocular microscope (Beijing Tech Instrument Co.,
Ltd.). A WFH-203B with three UV analyzer (Shanghai Jin-
gke Industrial Co., Ltd.) was used for thin-layer chromatog-
raphy (TLC). Deionizing water purifer (Hokee). Vertical
High-Pressure Steam Sterilization Pot (Shanghai ShenAn
Medical instrument Factory). Multiskan FC (Thermo Fisher
Scientifc (Shanghai) Co., Ltd.).
As a favonoid with good biological activity, the applica-
tion of myricetin derivatives have become more and more
extensively. For example, some of the myricetin derivatives
containing acylhydrazone showed excellent anticancer activ-
ity (Xue et al. 2015). Meanwile, some myricetin derivatives
containing piperazine amide also showed good anticancer
activity (Ruan et al. 2018a, b). And there were also reported
some agricultural antibacterial activities of myricetin deriva-
tives (Li et al. 2019; Chen et al. 2019; Jiang et al. 2020a, b).
At the cellular level, chalcone containing myricetin can be
infuenced by inhibiting the diferentiation of Gaoyou duck
embryonic osteoclasts in vitro (Fu et al. 2019). Tobacco
mosaic virus has a great harm to plant growth and develop-
ment. Some of the myricetin derivatives containing oxadia-
zole (Zhang et al. 2019) or ferulic acid (Tang et al. 2020)
showed good anti-TMV activity.
Chemicals
In summary, we hope to develop a fast and efficient
method for constructing the partial skeleton of piperazine
and sulfonamides structure with the lead of myricetin by
consulting a large number of literatures and combining our
previous work of research group, so as to synthesize the
new myricetin derivatives containing both piperazine and
sulfonyl structure (Fig. 1), and investigated their antibacte-
rial efcacy against Xoo, Xac and Rs in vitro. The antibacte-
rial mechanism of compounds 4 were preliminarily studied
General procedure for preparing the intermediates 1, 2
and 3
As shown in Scheme 1, intermediate 1 and 2 were pre-
pared via the reported methods (Chen et al. 2019). Myri-
cetrin (1 mmol) and methyl iodide (15 mmol) were stirred
43 °C for 48 h, and then suction fltration and the flter was
extracted with CH2Cl2, most of the solvent in the fltrate
was removed by spin evaporation and hydrochloric acid
OMe
OMe
OMe
MeO
O
OH
OMe
O
S
O
OMe
OMe
O
S
R
OH
OH
HN
N
R
O
nN
Me
N
O
MeO
O
HO
O
O
OMe O
piperazine-sulfonamide
O
N
n
O
OH
OMe
OMe O
N
combinatorial optimizatiom
S
OH
OMe
OMe
R
O
O
myricetin
Target compounds
our present work
MeO
O
N
R
N
O
OMe O
our previous work
Fig. 1 Design route of the target compounds 4a–4y
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Chemical Papers
Scheme 1 Synthetic route of the target compounds 4a–4y
(10 mL) was added under refux in the ethanol to obtain
the intermediate 1. Finally, the intermediate 1 (10 mmol)
was stirred in DMF at room temperature for 1 h and
dibromoalkane (30 mmol) was added; this reaction was
allowed to continue for 12 h and pour into water to obtain
the intermediate 2. And the intermediate 3 was prepared
by known methods (Henderson et al. 2011). Arylsulfonyl
chloride (10 mmol) was added in one portion to a solution
of piperazine (60 mmol) in CH2Cl2 at 0 °C. The reac-
tion mixture was stirred at 0 °C for 30 min, diluted with
CH2Cl2, quenched by the addition of saturated NaHCO3
(aq), washed with brine, and concentrated in vacuo to
obtain the intermediate 3.
Results and discussion
Chemistry
Twenty-fve myricetin derivative containing sulfonylpiper-
azine were obtained in this study, all their structures were
1
identifed via H NMR, 13C NMR, 19F NMR and HRMS.
The data of 4a was shown and discussed below. In the
1H NMR spectrum, multiplet signals at δ 7.68–6.28 ppm
revealed the presence of aromatic nuclei, and a tri-
plet peak at δ 3.91–3.94 ppm indicated the presence of
O–CH2–C group. In addition, the high-frequency single
peaks at δ 3.89–3.83 ppm revealed the presence of fve
–OCH3. The nuclear magnetic signal at δ 2.93–2.38 ppm
revealed the presence of nuclear magnetic signal peak of
piperazine’s hydrogen proton. Finally, and three absorp-
tion signals at δ 2.28–1.40 ppm indicated the presence
of C–CH2CH2CH2–N group. The absorption signals at
δ 174.02 and 72.12 ppm in 13C NMR spectra confrmed
the presence of –C=O and –OCH2– groups, respectively.
When fuorine is substituted on the benzene ring, carbon
atoms attached to fuorine will migrate to the low feld and
the fuorine atom will split the two adjacent carbon atoms
in 13C NMR spectra. For example, compound 4b had an
absorption peak at δ 163.99 ppm, which represented the
nuclear magnetic peak of C–F. The absorption peak of
the carbon atom at the same position in 4a was shown at
δ 132.83 ppm. In addition, two adjacent carbon atoms of
a carbon atom substituted by fuorine split into two adja-
cent absorption peaks at δ 116.42 and 116.19 ppm. The
Synthesis of the target compounds 4a–4y
The synthetic route to the title compounds, the myrice-
tin derivatives containing sulfonylpiperazine (4a–4y) are
shown in Scheme 1. The intermediate 3 (2.4 mmol) and
potassium carbonate (3.0 mmol) were stirred in 30 mL
acetonitrile for 30 min, then the intermediate 2 (2.0 mmol)
was added, the temperature was increased to 90 °C for 5 h,
the potassium carbonate was removed by fltration, and the
acetonitrile was removed by spin evaporation. The target
compounds 4a–4y were obtained by column chromatog-
raphy (ethyl acetate:petroleum ether = 1:2–2:1), with dif-
ferent yields. Their physical properties and spectral data
are listed in the Supporting Information, and the 1H NMR,
13C NMR, 19F NMR and HRMS spectra attached in the
Supporting Information.
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Chemical Papers
two carbons at the same position in 4a showed a single
absorption peak at δ 132.83 ppm. The high resolution mass
spectrometry (HRMS) spectra of title compounds show
characteristic absorption signals of [M + H]+ ions, which
are consistent with their molecular weight.
has no obvious antibacterial activity, but most of the tar-
get compounds showed better antimicrobial activity than
the lead compound myricetin. Compounds 4a, 4c and 4d
were exhibited favorable antibacterial activity against Xoo
at 100 μg/mL, with the inhibition rates of 72, 77 and 75%,
which gained an advantage over that of bismerthiazol (55%)
and thiodiazole-copper (62%). The inhibition rates of com-
pounds 4a, 4c and 4d against Xoo at 50 μg/mL were 52, 53
and 43%, which were better than that of bismerthiazol (39%)
and thiadiazole-copper (36%). Similarly, compounds 4h
and 4p showed higher antibacterial activity against Xac at
100 μg/mL, the calculated inhibition of 74 and 87%, which
exceeded that of bismerthiazol (63%) and thiodiazole-copper
(51%). Compounds 4h and 4p revealed superior antibacte-
rial activities against Xac at 50 μg/mL with the inhibition
rates of 42 and 41%, respectively, which were also higher
compared to bismerthiazol (19%) and thiadiazole-copper
Antibacterial activity examination of the title
compounds against Xoo, Xac and Rs in vitro
The bacteriostatic activity of the compounds were measured
by turbidimetric method (Zhong et al. 2017; Li et al. 2013),
using Xac, Xoo and Rs as test strains, while using the com-
mercial antibacterial agents bismerthiazol and thiodiazole-
copper as control drugs. Some of the target compounds
exhibited better antibacterial activities against Xac, Xoo and
Rs in vitro at 100 and 50 μg/mL, and the observed results
would be shown in Table 1. For example, the myricetin
Table 1 Antibacterial activities
Compounds
Xoo
Xac
Rs
of compounds 4a–4y
100 μg/mL
50 μg/mL
100 μg/mL
50 μg/mL
100 μg/mL
50 μg/mL
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
74
25
77
75
41
26
46
41
38
40
57
24
28
22
22
57
12
42
28
60
29
35
19
14
33
11
55
62
4
4
7
6
1
3
5
1
5
2
3
2
5
2
4
1
5
1
9
1
6
5
6
2
2
4
2
5
52
24
53
43
26
20
33
33
33
36
25
21
25
21
13
29
7
19
3
7
17
5
8
9
15
9
39
36
4
1
2
5
1
2
3
5
5
2
6
3
3
5
2
6
1
7
3
0
5
2
6
4
2
5
2
4
55
55
47
53
57
42
40
74
33
54
46
55
26
48
38
87
33
36
36
37
32
25
22
32
37
–
3
6
2
1
2
2
3
2
3
2
6
3
3
1
4
2
4
2
3
7
3
1
0
6
6
31
27
33
36
31
33
39
42
11
40
23
29
25
37
23
41
28
33
26
16
26
26
11
17
26
–
2
1
0
2
3
2
2
1
5
3
4
3
1
3
2
1
1
3
2
4
3
3
4
2
7
27
93
34
63
38
–
3
4
4
2
5
25
66
10
51
28
–
2
3
4
5
2
80
–
5
39
–
3
69
73
100
68
100
48
98
100
51
57
16
36
86
69
75
41
82
21
60
38
4
6
51
39
96
37
86
17
90
90
19
55
10
29
80
30
73
22
77
8
3
1
5
5
5
2
3
2
2
1
1
3
3
5
3
6
3
2
3
1
2
1
4
4
3
2
3
0
3
1
1
3
2
6
4
4w
4x
4y
Myricetin
BTb
TCb
5
63
51
1
2
19
19
6
2
52
21
0
2
Average of three replicates
BT bismerthiazol, TC thidiazole-copper
bThe commercial antibacterial agents bismerthiazol and thiodiazole-copper was used as positive control
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Chemical Papers
(19%). In addition, compounds 4b, 4k, 4m, 4o, 4p, 4u and
4y exhibited better antibacterial activities against Rs at 100
and 50 μg/mL, with the inhibition rates of 93 and 66%, 100
and 96%, 100 and 86, 98 and 90%, 100 and 90%, 86 and
80%, 82 and 77%, respectively, which were over the control
agents bismerthiazol (60 and 52%) and thiodiazole-copper
(38 and 20%).
According to the preliminary screening results of anti-
bacterial activity, EC50 values of some of the compounds
showed excellent antibacterial activities against Xoo, Xac
and Rs, as shown in Table 2. We can know from Table 2, the
compounds 4a, 4c and 4d exerted distinct activity against
Xoo with the EC50 values were 36, 38 and 40 μg/mL, respec-
tively, which preceded that of bismerthiazol (89 μg/mL) and
thiodiazole-copper (68 μg/mL). Compound 4p revealed pref-
erable antibacterial activity against Xac with EC50 values of
41 μg/mL, which was superior to bismerthiazol (93 μg/mL)
and thiodiazole-copper (70 μg/mL). Compounds 4k, 4m, 4o,
4p, 4u and 4y against Rs with EC50 values of 6, 4, 10, 4, 5
and 5 μg/mL, respectively, which prevailed over that of bis-
merthiazol (13 μg/mL) and thiodiazole-copper (185 μg/mL)
signally. We can clearly observe the diference in activity
against Rs between compound 4p, myricetin, control drugs
bismerthiazol and thiodiazole-copper in Fig. 2.
Table 2 EC50 values of some compounds against Xoo, Xac and Rs
Tested Compounds Regression equation
r
EC50 (µg/mL)
Xoo
4a
y=1.0037x+3.4383 0.9627 36
y=1.3975x+2.7873 0.9754 38
y=1.2546x+2.9887 0.9715 40
y=1.8570x+1.5964 0.9910 68
y=1.2079x+2.6426 0.9844 89
y=1.2056x+2.7741 0.9589 70
y=2.0575x+1.6741 0.9550 41
y=1.2141x+2.7624 0.9752 70
y=1.1147x+2.8064 0.9878 93
y=2.3189x+1.6664 0.9921 27
y=0.8746x+3.9683 0.9632 15
y=0.6887x+3.9954 0.9585 29
y=1.5022x+2.8776 0.9636 26
4c
4d
TCa
BTa
4h
Xac
Rs
4p
TCa
BTa
4b
4d
Structure–activity relationship analysis
of antibacterial activities
4i
4j
4k
y=1.8641x+3.5488 0.9507
y=1.3204x+4.2077 0.9633
6
4
Table 1 revealed that the antibacterial activities of the title
compounds were considerably afected by the length of the
carbon chain and diferent substituents on sulfonyl groups.
For instance, When n=3 and R were substituted with phe-
nyl, 4–CH3–Ph, 4–NO2–Ph, thienyl or 2–NO2–Ph, these
compounds exhibited signifcant Rs inhibitory activity with
the inhibition rates of 100, 98, 100 and 82% at 100 µg/mL,
respectively, which were better than the compounds with
n=4 on the same substituent group with the inhibition rates
of 27, 34, 63 and 68%. When n=4 and R were substituted
with 4–F–Ph or pyridyl, these compounds performed better
Rs inhibitory activity with the inhibition rates of 93 and
100% at 100 µg/mL, which were exceeded than the com-
pounds with n = 3 on the same substituent group with the
4m
4o
y=1.9801x+3.0192 0.9934 10
y=1.3149x+4.2120 0.9617
y=0.6145x+4.1342 0.9938 26
y=0.8169x+4.2210 0.9904
y=1.3517x+3.1764 0.9582 22
y=1.0833+4.2902 0.9604
4p
4
4r
4u
5
4w
4y
5
TCa
BTa
y=0.6931x+3.4289 0.9773 185
y=0.8701x+4.0372 0.9747 13
Average of three replicates
BT bismerthiazol, TC thidiazole-copper
aThe commercial antibacterial agents bismerthiazol and thidiazole-
copper was used as positive control
Fig. 2 Antibacterial activities of compound 4p (a), myricetin (b), thiodiazole-copper (c) and bismerthiazol (d) against Rs test in vitro at 100, 50,
25, 12.5 and 6.25 μg/mL
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Chemical Papers
Fig. 3 SEM images for Rs after incubated in diferent concentration of compound 4p. a 0 mg/mL, b 50 μg/mL and c100 μg/mL. Scale bar for
a–c are 2 μm
inhibition rates of 48 and 41%. When R was substituted with
4–NO2–Ph, compounds 4d and 4p showed certain inhibi-
tory activity against Xoo, Xac and Rs at 100 µg/mL. The
inhibitory activity of compound 4d against Xoo is better
when n=4. Similarly, the inhibitory activity of compound
4p against Xac and Rs is best when n=3. Compared with
the previous work of research group, this article introduced
sulfonylpiperazine to the structure of myricetin, and some
compounds show better inhibitory activity against Rs with
EC50 values between 4 and 10 μg/mL, which is superior to
the myricetin derivatives containing thiadiazole sulfde with
EC50 values between 28 and 39 μg/mL (Ruan et al. 2018a,
b). And the antibacterial activity of these compounds were
verifed by SEM.
compound 4p against Xac and Rs with EC50 value of 41
and 4 μg/mL, which far exceeded that of bismerthiazol (93
and 13 μg/mL, respectively) and thiodiazole-copper (67 and
185 μg/mL), respectively. Meanwhile, the inhibitory rate
of compound 4p on Xoo is 57% at 100 μg/mL, which was
slightly better than the control drug bismerthiazol (55 μg/
mL). Meanwhile, compound 4m against Rs with EC50 value
of 4 μg/mL, which better than the control drug bismerthiazol
(13 μg/mL) and thiodiazole-copper (185 μg/mL). Scanning
electron microscopy analysis further confrmed that the title
compounds caused the bacteria to shrink by acting on the
surface of the bacteria, so as to achieve antibacterial efect.
Therefore, the designed compounds can be used as potential
antibacterial drugs for further research to fnd new antibacte-
rial drugs.
Scanning electron microscopy (SEM) studies
Acknowledgements The authors gratefully acknowledge the fnancial
support of the National Key Research and Development Program of
China (No. 2017YFD0200506), the National Nature Science Founda-
tion of China (No. 21867003) and Science Fundof Guizhou, China
(Nos. 20191105, 20192452).
To further explore the mechanism of antibacterial action
against Rs, scanning electron microscopy (SEM) studies
were carried out using the designated compound 4p and
the observed SEM micrographs are shown in Fig. 3. Obvi-
ously, when there is no drug action, the form of the strain
is plump and short and thick. However, the surface of the
bacteria began to appear wrinkle at 50 µg/mL, which became
more pronounced as the concentration of the drug increased
to 100 µg/mL. It was obtained by SEM, the bacteriostatic
mechanism of compound 4p is to act on the surface of bac-
teria by drugs, thus causing the bacteria to fold and shrink,
resulting in incomplete bacterial structure, so as to achieve
the goal of bacteriostasis.
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Conclusion
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