Synthesis and antiviral activity of novel myricetin derivatives containing ferulic acid amide scaffolds

Article abstract of DOI:10.1039/c9nj05867b

A variety of myricetin derivatives bearing ferulic acid amide scaffolds were designed and synthesized. The structures of all title compounds were determined by ¹H NMR, ¹³C NMR, ¹⁹F NMR and HRMS. Preliminary bioassays suggested that some of the target compounds exhibited remarkable antiviral activities. In particular, compound 4l possessed significant protective activity against tobacco mosaic virus (TMV), with a half maximal effective concentration (EC₅₀) value of 196.11 μg mL^-1, which was better than that of commercial agent ningnanmycin (447.92 μg mL^-1). Meanwhile, microscale thermophoresis (MST) indicated that compound 4l has strong binding capability to the tobacco mosaic virus coat protein (TMV-CP) with a dissociation constant (K_d) value of 0.34 μmol L^-1, which was better than that of ningnanmycin (0.52 μmol L^-1). These results suggested that novel myricetin derivatives bearing ferulic acid amide scaffolds may be considered as an activator for antiviral agents.

Full text of DOI:10.1039/c9nj05867b

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Chechia Hu, Tzu-Jen Lin et al.
Yellowish and blue luminescent graphene oxide quantum dots
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Synthesis and Antiviral Activity of Novel Myricetin Derivatives
Containing a Ferulic Acid Amide Scaffolds
Xu Tanga,†, Cheng Zhanga,†, Mei Chena, Yining Xueb, Tingting Liua, Wei Xuea,*
Abstract: A variety of myricetin derivatives bearing ferulic acid amide scaffolds were designed and synthesized. The
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structures of all title compounds were determined by H NMR, C NMR, F NMR and HRMS. Preliminary bioassays
suggested that some of the target compounds exhibited remarkable antiviral activities. In particular, compound 4l
possessed significant protective activity against tobacco mosaic virus (TMV), with an half maximal effective concentration
(EC50) value of 196.11 μg/mL, which was better than commercial agent ningnamycin (447.92 μg/mL). Meanwhile,
microscale thermophoresis (MST) indicated that compound 4l have strong binding capability to tobacco mosaic virus coat
protein (TMV-CP) with dissociation constant (Kd) values of 0.34 μmol/L, which was better than ningnamycin (0.52 μmol/L).
These results suggested that novel myricetin derivatives bearing ferulic acid amide scaffolds may be considered as an
activator for antiviralagents.
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
9
Abelmoschus manihot and onions.10 It has been reported that
1.Introduction
12
myricetin has various biological activities, such as antiviral,11,
Plant diseases cause economic loss and decreases in the
quality and quantity of agricultural products around the world. For
example, tobacco mosaic virus (TMV) can easily infect economic
crops and causes economic losses. It takes millions of dollars to
prevent and cure these deseases.1 Unfortunately, traditional
pesticide, such as ningnanmycin and ribavirin, have been eliminated
and banned gradually due to their poor efficiencies, high
phytotoxicities, environment damages, pesticide residues and
resistant from pesticide.2. 3 It is an urgent need to develop greener
and more efficient pesticides to control and prevent plant diseases.
Due to their low toxicities, easy decompositions, novel
structures and environmental friendlinesses, natural products have
been used to synthesize new pesticides.4-6 Myricetin is a kind of
natural product which can be extracted from several medicinal
plant organs, vegetables and fruits,7 such as myrica rubra Sieb,8
16, 17
antibacterial,13, 14 antioxidant,15 anticancer
and so on. In our
previous study, we have reported a series of myricetin derivatives
with appreciable bioactivities against TMV.11
Ferulic acid is a phenolic acid present in many plants, such as
Angelica sinensis, Cimicifuga heracleifolia and Lignsticum
chuangxiong.18 According to previous studies, ferulic acid exhibits a
wide range of bioactivities, such as antiviral,19 antibacterial,20
anticancer.21, 22 Therefore, it has attracted great attention in the
field of medicinal chemistry. In the further development of antiviral
agents, a series of novel myricetin derivatives containing a 1,3,4-
thiadiazole moiety was found to have excellent anti-TMV activity.12
In this study, we aimed to use a ferulic acid amide to replace the
1,3,4-thiadiazole system to build novel myricetin derivatives
containing a ferulic acid amide moiety for the development of
antiviral agents. The preliminary bioassay results indicated that
some of target compounds showed excellent antiviral activities.
Among them, compound 4l possessed significant protective activity
against TMV. Meanwhile, MST and molecular docking indicated that
compound 4l have strong binding capability to TMV-CP. To the best
a. State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering,
Key Laboratory of Green Pesticide and Agriculture Bioengineering, Ministry of
Education, Guizhou University, Huaxi District, Guiyang 550025, P.R. China.
E-mail: wxue@gzu.edu.cn (Wei Xue); Tel: 0086-851-88292090; Fax: 0086-851-88292090
b. College of Chemistry, Chemical Engineering and Environment, Minnan Normal
University, Zhangzhou 363000, P.R. China.
Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx00000x
† These authors contributed to this work equally
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of our knowledge, this is the first report on the synthesis and
antiviral activity evaluation of myricetin
derivatives containing a ferulic acid amide moiety (Figure 1).
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DOI: 10.1039/C9NJ05867B
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Figure 1. Design of novel myricetin derivatives containing ferulic acid amide scaffolds
2.3. General synthesis procedure for intermediate 2
2. Experimental
Intermediate 1 (0.55 g, 2.33 mmol), 1-Hydroxybenzotriazole
(0.38 g, 2.79 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide hydrochloride (0.54 g, 2.79 mmol) were added
dropwise into acetonitrile (20 mL), the mixture was stirred at room
temperature for 3 h. Then substituted aniline (0.27 g, 2.56 mmol) in
acetonitrile (20 mL) was slowly added into the mixture, stirred and
refluxed at 90 oC for 5 h until the reaction was completed
(monitored by TLC: Vethyl acetate : Vmethanol = 10:1). Then the reaction
mixture was extracted by ethyl acetate and evaporated under
reduced pressure. The product was dissolved in acetonitrile again,
added hydrazine hydrate (0.24 g, 4.66 mmol), and stirred at room
temperature for 2 h to obtained the intermediate 2.19, 23
2.1. Methods and materials
The melting points were determined by X-4B microscopic
melting point meter (Shanghai Yi Dian Physical Optics Instrument
Co., Ltd. China); proton nuclear magnetic resonance (NMR) spectra
were obtained on JEOL-ECX500 NMR spectrometer (JEOL, Tokyo,
Japan) and Bruker Ascend-400 spectrometer (Bruker, Germany)
with DMSO or CDCl3 as the solvent and TMS as the internal
standard. High-resolution mass spectral (HRMS) data were
performed with Thermo Scientific Q Exactive (Thermo Scientific,
USA ). The micro thermophoresis of the compound and TMV CP was
determined by a micro thermophoresis instrument (NanoTemper
Tchnologies GmbH, Germany); the fluorescence spectroscopy of the
compound interacting with TMV CP was determined by FluoroMax-
4 fluorescence spectrometer (HORIBA Scientific, France). All
reagents (analytical grade) were purchased from commercial
suppliers.
2.4. General synthesis procedure for intermediate 3
Preparation of the intermediate 3 has been previously
described.24 The mixture of myricitrin (0.55 g, 5.01 mmol), CH3I
(2.02 g, 60.02 mmol), and K2CO3 (0.19 g, 6.13 mmol) was dissolved
in N,N-dimethyl formamide (DMF, 30 mL), and stirred at 40 oC for 2
d until the reaction was complete (as indicated by TLC analysis). The
reaction mixtures were then filtered, and the filtrate was dissolved
in 50 mL water and finally extracted three times with
dichloromethane (30 mL×3), combined the dichloromethane and
concentrated under reduced pressure. The concentrated solution
was diluted with 20 mL of absolute ethanol, stirred, and refluxed for
1 h. The concentrated hydrochloric acid (3 mL) was slowly added to
the above obtained, for 2 h in reflux. The solid was precipitated
2.2. General synthesis procedure for intermediate 1
Ferulic acid (3.01 g, 15.45 mmol) was added into round bottom
flask and dissolved by 10 % NaOH (30 mL), then acetic anhydride
(1.97 g, 19.31 mmol) was added. The mixture was stirred at room
temperature for 1 h. Then 200 mL H2O was added into the reaction
mixture. 10 % Aqueous HCl was added into the above mixture till
pH = 4-5. Then the mixture was filtered and the precipitate was
washed by H2O to obtained the intermediate 1.16
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from the clear solution. After cooling to room temperature, the h, then DMF (20 mL) containing intermediate 3 (0.50Vgie,w0.A9rt8iclme Omnloinle)
DOI: 10.1039/C9NJ05867B
o
reaction mixture was filtered, and the obtained solid product was was dropped slowly to the mixture and reacted at 105 C for 6 h.
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dried at 40 oC for 2 h. Finally, dibromoalkanes and DMF were added After cooling to the room temperature, the reaction mixture was
reflux 6h to obtained intermediate 3.
added about 200 mL H2O and adjusted pH to 4-5 by 10 % HCl,
filtered and washed by H2O. Finally, compounds 4a–4v were gained
by recrystallization from methanol.
2.5. General synthesis procedure for target compounds
9
4a–4v.
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A mixture of intermediate 2 (0.31 g, 1.08 mmol ), anhydrous
K2CO3 (0.41 g, 2.94 mmol) in DMF (30 mL) was stirred at 85 oC for 1
O
O
O
O
O
O
O
O
O
O
c
R
OH
NH
OH
NH
R
a
b
HO
HO
2
1
O
O
O
O
O
O
O
O
O
d
e
HO
O
O
O
O
O
O
O
O
Br
O
OH
O
n
OH O
OH
OH
O
O
O
O
3
OH
O
O
O
O
O
O
O
O
O
O
O
f
NH
R
O
Br
O
n
n = 3,4,5
HO
O
O
O
O
n
O
O
2
3
NH
R
O
O
4a-4v
a
b
c
reation condition: : acetic anhydride, 5 % NaOH; : R-PhNH2, HOBt, EDCl; :NH2NH2H2O, CH3CN;
d
e
f
: DMF, K2CO3, CH3I, conc HCl; :DMF, Br(CH2CH2)nBr; : DMF, K2CO3
4a
4e
4i
4b
4f
4j
4c
4g
4k
4o
4d
4h
4l
4p
4t
: R = 4-CH3, n = 3;
: R = 3-Cl, n = 3;
: R = H, n = 3;
: R = 4- OCH3, n = 3;
: R = 3-Cl, n = 4;
: R = 3,4-di-CH3, n = 3;
: R = 4-CH3, n = 4;
: R = 4-Cl, n = 4;
: R = 3,4-di-CH3, n = 4;
: R = 4-Br, n = 4;
: R = 4-OCH3, n = 4;
: R = H, n = 4;
: R = 3,4-di-OCH3, n = 3;
: R = 3,4-di-Cl, n = 3;
: R = 4-OCH3, n = 5;
4m
4q
4u
4n
: R = 3,4-di-OCH3, n = 4
: R = 4-Br, n = 3;
4r
: R = 3,4-di-Cl, n = 4; : R = 4-Cl, n = 5;
4s
: R = 3-Cl, n = 5;
4v
: R = 2-F, n = 3;
: R = 2-F, n = 4
Scheme 1. Synthesis of the title compounds 4a–4v
addition, the four high-frequency single peaks and doublets peaks
at 3.94 –3.77 ppm revealed the presence of five –OCH3, and double
peak at δ 2.31 ppm indicate the presence of –CH3 group. Absorption
3. Results and discussion
3.1. Spectral properties
The structures of all title compounds were determined by 1
H
13
signals at δ 174.07, 164.12 and 20.91 ppm in C NMR spectra
19
NMR, 13 C NMR , F NMR and HRMS, and the spectra data were
confirm the presences of –C=O– , –C=O–NH– and –CH3 groups,
respectively. The high-resolution mass spectrometry (HRMS)
spectra of title compounds show characteristic absorption signals of
[M + H]+ ions, which is consistent with their molecular weight.
shown in the Supplementary Materials. The data of 4a was shown
1
and discussed below. In the H NMR, multiplet signals at δ 8.01–
6.36 ppm revealed the presence of nitrogen hydrogen bond,
protons in olefinic bonds and aromatic nuclei, and triplet singlets at
δ 4.23 and 4.18 ppm indicate the presence of –CH2– group. In
3.2. Antiviral activity of title compounds against TMV in
vivo
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Using N. tabacun L. leaves under the same age as that of test activities ranged from 5.3 to 62.1 %. Especially, compound 4n
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subjects, the curative and protective activities against TMV (in vivo) showed 55.5 % curative effects at 500 μgD/mOIL:,10w.1h0i3c9h/Cw9aNsJ0b5e8t6t7eBr
at a concentration of 500 μg/mL were evaluated by the half-leaf than that of myricetin (35.7 %) and ningnanmycin (53.2 %). In
blight spot methods.25, 26 The obtained results were shown in Table addition, compound 4l exhibited significant protective activities
1. The preliminary bioassay results indicated that the inhibitory against TMV at 500 μg/mL, the inhibition rate was 62.1 %, which
rates of target compounds (4a–4v) against TMV ranged from 15.8 was even better than that of myricetin (41.5 %) and ningnanmycin
to 55.5 % in terms of their curative activities, while their protective (55.7 %).
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Table 1 Inhibition effect (%) of the compounds 4a–4v against TMV a
Compd.
4a
R
n
Curative Activity (%)
Protection Activity (%)
4-CH3
4-OCH3
4-CH3
4-OCH3
3-Cl
3
3
4
4
3
4
4
4
3
3
4
3
4
3
4
3
4
5
5
5
3
4
-
33.0 ± 2.1
42.1 ± 1.2
39.6 ± 3.3
15.8 ± 0.6
37.5 ± 1.1
32.1 ± 4.2
38.1 ± 0.8
41.3 ± 4.3
43.5 ± 0.8
39.4 ± 0.3
21.1 ± 0.9
37.4 ± 1.1
31.2 ± 4.2
55.5 ± 7.3
28.4 ± 6.1
37.2 ± 0.9
34.2 ± 0.7
40.4 ± 5.2
43.2 ± 4.1
39.9 ± 3.8
37.0 ± 8.2
21.8 ± 2.7
35.7 ± 5.2
53.2 ± 0.6
11.6 ± 0.9
35.6 ± 3.7
21.2 ± 2.1
5.3 ± 0.8
4b
4c
4d
4e
51.6 ± 3.3
52.3 ± 4.1
40.3 ± 5.2
48.5 ± 7.2
31.2 ± 3.6
46.4 ± 0.8
25.9 ± 2.1
62.1 ± 7.2
13.5 ± 0.6
53.3 ± 4.5
19.5 ± 5.5
58.1 ± 4.1
43.9 ± 7.2
44.1 ± 4.1
37.8 ± 0.8
24.1 ± 2.2
41.1 ± 3.1
32.5 ± 4.2
41.5 ± 3.3
55.7 ± 4.5
4f
3-Cl
4g
4-Cl
4h
H
4i
H
4j
3,4-di-CH3
3,4-di-CH3
3,4-di-OCH3
3,4-di-OCH3
4-Br
4k
4l
4m
4n
4o
4-Br
4p
3,4-di-Cl
3,4-di-Cl
4-Cl
4q
4r
4s
3-Cl
4t
4-OCH3
2-F
4u
4v
2-F
MY b
NNM c
-
-
-
a Average of three replicates; b The lead compound of (MY, myricetin);
c The commercial agent (NNM, ningnamycin) was used for comparison of antiviral activity
To confirm the potential inhibitory capacity of these 425.3 and 386.7 μg/mL respectively, which were superior to
compounds against TMV, we further evaluated the EC50 of some ningnamycin (447.9 μg/mL). Compound 4n shows good curative
title compounds against TMV based on our preliminary bioassay. activity against TMV with an EC50 value of 472.4 μg/mL, which was
As shown in Table 2, compounds 4l, 4n and 4p exhibit excellent closed to ningnamycin (428.8 μg/mL).
protective activities against TMV with the EC50 values of 196.1,
As indicated in Tables 1 and 2, the antiviral effects of target
3.3. Structure activity relationship (SAR) of the title
compounds were greatly affected by structural variations. Some
compounds against TMV
structure–activity relationships (SAR) analyses were discussed as
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below. The presence of 4-Br, 3-Cl, 4-OCH3 and H groups at the R 42.1, 43.5, 55.5 and 43.2 %, respectively. Furthermore, when R
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position greatly increased the curative activities of the target were 3-Cl, 3,4-di-OCH3 and 3,4-di-Cl groups,DthOeI:p10ro.1t0e3c9t/iCve9NaJc0ti5v8it6i7eBs
compounds against TMV. For instance, the target compounds 4b (4- of the relevant compounds 4f, 4l and 4p at 500 µg/mL were 52.3,
OCH3, n=3), 4i (H, n=3 ), 4n (4-Br, n=3) and 4s (3-Cl, n=5) showed 62.1, and 58.1 %, respectively, which were superior to other
important antiviral activities against TMV, with inhibition rates of substituent groups.
Table 2 The EC50 values of 4l, 4n and 4p against TMV a
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Compd.
R
n
3
-
Toxic regression equation
y=1.4582x+1.1002
y=0.7650x+2.9863
y=2.0488x-0.3031
y=1.7099x+1.7002
y=1.4133x+2.3311
y=1.5482x+0.8954
r
EC50 µg/mL
472.4
Curative Activity
4n
4-Br
0.9902
0.9830
0.9891
0.9888
0.9970
0.9819
NNM b
4l
-
3,4-di-OCH3
4-Br
428.8
3
3
3
-
196.1
4n
425.3
Protection Activity
4p
3,4-di-Cl
-
386.7
NNM b
447.9
a Average of three replicates; b The commercial agent (NNM, ningnamycin) was used for comparison of antiviral activity
As showed in MST, compound 4l (Kd=0.34 ± 0.09 μmol/L) shared
strong affinity, which was better than that of ningnanmycin
(Kd=0.52 ± 0.25 μmol/L) and lead compound myricetin (Kd=92.23 ±
47.54 μmol/L). Based on anti-TMV activities and MST results, we
can predict that the structural modification of the lead compound
myricetin, such as the introduction of the active groups ferulic acid
amide, could greatly improved the antiviral activities.
3.4. Binding sites of 4l, 4m, myricetin and ningnanmycin
to TMV-CP
To further analyze the interactions between the compounds 4l,
4m, myricetin, ningnanmycin and TMV-CP, MST analysis was carried
out.27-29 The MST results were summarized in Figure 2 and Table 3.
The binding of compounds 4l, 4m, myricetin and ningnanmycin to
TMV-CP protein gave Kd values of 0.34 ± 0.09 μmol/L, 2.30 ± 0.77
μmol/L, 92.23 ± 47.54 μmol/L and 0.52 ± 0.25 μmol/L, respectively.
Figure 2. Microscale thermophoresis results of compounds 4l (A), 4m (B),myricetin (C) and ningnamycin (D)
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Table 3. The dissociation constant of 4l, 4m, myricetin and ningnanmycin with TMV-CP
Compd.
Kd (μmol/L)
4l
0.34 ± 0.09
4m
2.30 ± 0.77
92.23 ± 47.54
0.52 ± 0.25
myricetin
ningnanmycin
residue, including ARG-90, CLN-38 and THR-37. These interactions
between small molecules and the TMV-CP may impair the
interaction of twoTMV-CP subunits, hence preventing self-assembly
of the TMV particle. As shown in the Figure 3, The hydrogen bond
strength of compound 4l was stronger than that of myricetin (C and
D). Based on molecular docking results of compound 4l and
myricetin, we can predict that the structural modification of the
lead compound myricetin could greatly improve the antiviral
activities.
3.5. Molecular docking of 4l and myricetin with TMV-CP
To identify the 4l and myricetin recognition sites in TMV-CP
(Protein Data Bank (PDB) code: 1EI7),we performed molecular
docking using the gold method with 200 cycles.27, 29, 30 As shown in
the Figure 3, the compound 4l was well-embedded between the
two subunits of TMV-CP. Previous reports have shown that these
residues play key roles in the self-assembly of TMV particles.31 The
binding orientation of compound 4l was clearly shown in Figure 3 (A
and B), it forms one hydrogen bond with ARG-46, with the highest
docking score (1.909 Å) among the designed molecules. Besides,
compound 4l deep into the active pocket formed by amino-acid
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Figure 3 Molecular docking studies of compounds 4l (A–B) and myricetin (C–D)
μg/mL). Further the microscale thermophoresis studies revealed
4. Conclusions
that compound 4l have strong binding capability with TMV-CP, and
the molecular docking studies were consistent with the
experimental results. All these results support that the myricetin
derivatives bearing ferulic acid amide scaffolds possess antiviral
activities, and thus could be further studied as potential alternative
templates in the search for novel antiviral agents.
A series of myricetin derivatives bearing ferulic acid amide
scaffolds were designed and synthesized. Preliminary bioassays
suggested that these compounds exhibit favorable curative and
protective activities against TMV. Among them, compound 4l
showed remarkable protective activity against TMV, with the EC50
values of 196.11 μg/mL, which was superior to ningnamycin (447.92
7.
8.
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Competing interests
The authors declare that they have no competing interests.
Acknowledgements
9.
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222–227.
The authors gratefully acknowledge grants from the National
Nature Science Foundation of China (No. 21867003), Science Fund
of Guizhou, China (Nos. 20192452,20191105),Graduate Education
Innovation Program of Guizhou Province (No.YJSCXJH2019018).
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