Structural Simplification of Marine Natural Products: Discovery of Hamacanthin Derivatives Containing Indole and Piperazinone as Novel Antiviral and Anti-phytopathogenic-fungus Agents

Article abstract of DOI:10.1021/acs.jafc.1c04098

With the increasing severity of plant diseases and the emergence of pathogen resistance, there is an urgent need for the development of new efficient and environment-friendly pesticides. Marine natural product (MNP) resources are rich and diverse. Structural simplification based on MNPs is an important strategy to find novel pesticide candidates. In this work, the marine natural product 6″-debromohamacanthin A (1a) was efficiently prepared and selected as the parent structure. A series of hamacanthin derivatives were designed, synthesized, and studied on the antiviral and antifungal activities. Most of these compounds displayed higher antiviral activities than ribavirin. The antiviral activities of compounds1aand13e-13hare similar to or higher than that of ningnanmycin (perhaps the most efficient anti-plant-virus agent). Compound13hwas selected for further antiviral mechanism research via transmission electron microscopy, molecular docking, and fluorescence titration. The results showed that compound13hcould bind to TMV CP and interfere with the assembly process of TMV CP and RNA. In addition, these hamacanthin derivatives also exhibited broad-spectrum inhibitory effects against eight common agricultural pathogens. Compounds1a12b, and12fwith excellent fungicidal activities can be considered as new fungicidal candidates for further research. These results provide a basis for the application of hamacanthin alkaloids in crop protection.

Full text of DOI:10.1021/acs.jafc.1c04098

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Article
Structural Simplification of Marine Natural Products: Discovery of
Hamacanthin Derivatives Containing Indole and Piperazinone as
Novel Antiviral and Anti-phytopathogenic-fungus Agents
Tienan Wang, Lin Li, Yanan Zhou, Aidang Lu,* Hongyan Li, Jianxin Chen, Zhongyu Duan,*
and Qingmin Wang*
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ABSTRACT: With the increasing severity of plant diseases and the emergence of pathogen resistance, there is an urgent need for
the development of new efficient and environment-friendly pesticides. Marine natural product (MNP) resources are rich and diverse.
Structural simplification based on MNPs is an important strategy to find novel pesticide candidates. In this work, the marine natural
product 6″-debromohamacanthin A (1a) was efficiently prepared and selected as the parent structure. A series of hamacanthin
derivatives were designed, synthesized, and studied on the antiviral and antifungal activities. Most of these compounds displayed
higher antiviral activities than ribavirin. The antiviral activities of compounds 1a and 13e−13h are similar to or higher than that of
ningnanmycin (perhaps the most efficient anti-plant-virus agent). Compound 13h was selected for further antiviral mechanism
research via transmission electron microscopy, molecular docking, and fluorescence titration. The results showed that compound
13h could bind to TMV CP and interfere with the assembly process of TMV CP and RNA. In addition, these hamacanthin
derivatives also exhibited broad-spectrum inhibitory effects against eight common agricultural pathogens. Compounds 1a, 12b, and
12f with excellent fungicidal activities can be considered as new fungicidal candidates for further research. These results provide a
basis for the application of hamacanthin alkaloids in crop protection.
KEYWORDS: marine natural product, hamacanthin alkaloids, anti-TMV activity, fungicidal activity, mode of action
advantages for being developed into new drugs. The diversity
of structure and prevalidated biological activity has made
natural products valuable lead compounds for drug
discovery.7,8 However, unmodified natural products often
have some shortcomings, such as limited compound
availability, poor solubility, and the structural complexity of
MNPs, which results in synthetic difficulties and so on.9,10
Simplifying the complex structures of NPs without interfering
with the desired biological activity provides an alternative
approach for both NP lead optimization and the development
of a new generation of NP-based drugs. Many successful
examples have validated the effectiveness of structural
simplification in the development of NP-based drugs, such
as fingolimod, bicyclol, eribulin, and vorinostat.7
The biindole alkaloid hamacanthin was first isolated from
the deep-water sponge Hamacantha sp. in 1994.11 Then,
Jung’s group isolated hamacanthin alkaloids (Figure 1) from
the sponge Spongosorites sp.12,13 6″-Debromohamacanthin A
(1a), hamacanthin A (1b), hamacanthin B (1e), and their
analogues (Figure 1) have various kinds of biological
INTRODUCTION
■
Sustainable nutrition and food security are key themes in the
United Nations Sustainable Development Goals. By 2050, the
world will need to feed about 9 billion people. The need to
increase food production has never been so urgent.1 Plant
diseases caused by viral pathogens are seriously threatening
the safety and stability of crop production. As reflected in the
field of crop protection, modern chemical fungicides and
antiviral drugs can be used to reduce plant diseases and
increase crop yields. According to the analysis of major crops
such as rice, wheat, barley, corn, etc., without crop protection,
the yield will be reduced by 50%.2 However, the emergence
of pathogen resistance has made some pesticides inefficient,
and after the process of long-term use, some pesticides have
caused adverse effects such as environmental pollution and
harm to human health. Therefore, the modern agrochemical
industry needs innovative solutions to respond to current and
future challenges.3,4
Seventy percent of the Earth’s surface area is the ocean,
which is rich in biological resources. The unique extreme
environment of the ocean, such as high salt, high pressure,
low temperature, etc., has forced marine organisms to form
many marine natural products (MNPs) with unique
structures and significant biological activities.5,6 These natural
products have special frameworks that can interact with
biological macromolecules and have good effects in biological
regulation or treatment, which provides them with great
Received: July 8, 2021
Revised: August 13, 2021
Accepted: August 16, 2021
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© XXXX American Chemical Society
A

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(Tecnai G2 F20). The single-crystal data were obtained via an X-ray
single-crystal diffractometer (Supernova; Agilent Technologies Inc.).
The photoluminescence spectra data were measured on a Hitachi F-
2700 photoluminescence spectrophotometer. Compounds 4a−
4e23,24 and 5a−5k25 were prepared by using reported methods,
and the data are accordance with that of the literature. The detailed
synthetic procedures of compounds 9−14 can be seen in the
Supporting Information.
Preparation of (Z)-N-Benzyl-2-((tert-butoxycarbonyl)-
amino)ethan-1-imine Oxide (2).23 N-Benzylhydroxylamine (1.0
g, 8.1 mmol, 1.0 equiv) and tert-butyl (2-oxoethyl)carbamate (1.9 g,
12.2 mmol, 1.5 equiv) were dissolved in CH2Cl2 (15 mL), and then
anhydrous magnesium sulfate (5.0 g) was added. The mixture was
stirred at room temperature for 3 h, filtered, and concentrated in
vacuum. The residue was purified by flash chromatography on a
Figure 1. Hamacanthins A and B and their Congeners.
activities, including cytotoxicity,12−14 bactericidal activ-
ity,12,13,15 antimicrobial activity,14 etc. The complex chemical
structures of hamacanthin alkaloids complicated their total
synthesis,15−20 which limits the systematic biological activity
research of these molecules. At present, the biological activity
research of hamacanthin alkaloids mainly focuses on the
treatment of human diseases, while there are few reports on
the agricultural application of these molecules.
We have long been committed to the discovery of new
pesticide candidates based on MNPs.21,22 In this work, the
marine natural product 6″-debromohamacanthin A (1a) was
efficiently prepared and selected as the parent structure. A
series of chiral hamacanthin derivatives were designed (Figure
2) and synthesized based on previous research foundation
and our research experience. The antiviral and antifungal
effects of these alkaloids were systematically evaluated. The
antiviral mechanism of optimized compounds was further
studied through transmission electron microscopy (TEM),
molecular docking, or fluorescence titration.
1
silica gel to give compound 2 as a brown oil. Yield: 37%; H NMR
(400 MHz, CDCl3): δ 7.39 (s, 5H), 6.87 (s, 1H), 5.39 (s, 1H), 4.87
(s, 2H), 4.04 (t, J = 5.7 Hz, 2H), 1.42 (s, 9H); 13C NMR (100
MHz, CDCl3): δ 167.7, 129.3, 129.0, 128.8, 128.6, 128.5, 71.2, 65.6,
37.1, 28.2.
Preparation of tert-Butyl (2-(Benzyl(hydroxy)amino)-2-(1H-
indol-3-yl)ethyl)carbamate (3).23 Freshly distilled acetyl chloride
(0.9 g, 11.0 mmol, 2.0 equiv) was added to the dry methanol (15
mL) solution at 0 °C under a N2 atmosphere. The mixture was
stirred for 10 min, and a mixture of indole (0.6 g, 5.5 mmol, 1.0
equiv) and compound 2 (0.7 g, 5.5 mmol, 1.0 equiv) in methanol
(15 mL) was added. The mixture was stirred for further 6 h, then
quenched with sodium bicarbonate solution (100 mL), and
extracted with CH2Cl2 (50 mL × 2). The organic phases were
combined and dried with anhydrous magnesium sulfate, filtrated,
and concentrated in vacuo. The residue was purified by flash
chromatography on a silica gel to give compound 3 as a white solid.
1
Yield: 38%; mp: 136−140 °C; H NMR (400 MHz, DMSO-d6): δ
11.01 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.40−7.15
(m, 7H), 7.06 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 7.4 Hz, 1H), 6.46 (s,
1H), 4.17 (t, J = 6.8 Hz, 1H), 3.63−3.49 (m, 2H), 3.33 (s, 2H),
1.38 (d, J = 16.4 Hz, 9H); 13C NMR (100 MHz, DMSO-d6): δ
153.3, 137.0, 133.5, 126.4, 126.2, 125.2, 124.9, 123.8, 121.8, 118.3,
116.9, 115.8, 108.8, 75.1, 60.0, 57.8, 40.6, 25.7.
MATERIALS AND METHODS
■
Materials and Equipment. Chemicals. The reagents were
purchased from commercial sources and were used as received. All
anhydrous solvents were dried and purified by standard techniques
prior to use.
Preparation of tert-Butyl (2-(2-(6-Bromo-1H-indol-3-yl)-2-
oxoacetamido)-2-(1H-indol-3-yl)ethyl)carbamate (6). To a
stirred solution of compound 4a (0.3 g, 1.1 mmol, 1.0 equiv) in
CH2Cl2 (20 mL) were added Et3N (1.3 g, 1.3 mmol, 1.2 equiv) and
compound 5a (0.2 g, 1.2 mmol, 1.1 equiv) at 0 °C. The mixture was
stirred at 0 °C for 2 h and at 25 °C for 12 h, and then H2O (50
mL) was added. The mixture was extracted with CH2Cl2 (30 mL ×
2). The combined organic phase was dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo to obtain
Instruments. The melting points of the compounds were tested
on an X-4 binocular microscope (Beijing Tech Instruments
Company). NMR spectra were obtained with a Bruker AV 400
MHz (100 MHz for 13C) spectrometer with either CDCl3 or
DMSO-d6 as the solvent. High-resolution mass spectra were
obtained with an FT-ICR mass spectrometer (Ionspec, 7.0 T).
The in vitro TMV rod assembly inhibition and 20S CP disk
assembly inhibition were tested via transmission electron microscopy
Figure 2. Design of hamacanthin analogues.
B
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Figure 3. Synthesis of the natural product 6″-debromohamacanthin A (1a).
compound 6 as a brown solid, which was directly used for the next
step without further purification.
°C for 2 h and then extracted with ethyl acetate (30 mL × 2). The
combined organic phase was washed with brine, dried with
anhydrous sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography to give compound 1a.
Brown solid, yield: 92%; mp: 198−201 °C; [α]2D9 = +0.8° (c 1.0,
Preparation of tert-Butyl (2-(2-(6-Bromo-1-tosyl-1H-indol-
3-yl)-2-oxoacetamido)-2-(1-tosyl-1H-indol-3-yl)ethyl)-
carbamate (7).26 To a stirred solution of compound 6 (1.2 g, 2.29
mmol, 1.0 equiv) in CH2Cl2 (30 mL) were added 4-tosyl chloride
(TsCl) (1.09 g, 5.73 mmol, 2.5 equiv), NaOH (0.14 g, 3.44 mmol,
1.5 equiv), and Et3N (0.58 g, 5.73 mmol, 2.5 equiv). The mixture
was stirred at 25 °C for 24 h, and then H2O (50 mL) was added.
The mixture was extracted with CH2Cl2 (50 mL × 2). The
combined organic phase was dried with anhydrous sodium sulfate,
filtered, and concentrated. The residue was purified by column
1
THF); H NMR (400 MHz, DMSO-d6): δ 11.63 (d, J = 9.4 Hz,
1H), 11.05 (d, J = 9.5 Hz, 1H), 8.80 (d, J = 11.3 Hz, 1H), 8.53−
8.38 (m, 1H), 8.32 (q, J = 11.4, 8.2 Hz, 1H), 7.79−7.57 (m, 2H),
7.39 (q, J = 11.2, 7.8 Hz, 1H), 7.33−7.18 (m, 2H), 7.18−6.98 (m,
2H), 5.01 (s, 1H), 4.12 (d, J = 9.3 Hz, 2H); 13C NMR (100 MHz,
DMSO-d6): δ 157.6, 157.4, 137.0, 136.4, 132.7, 125.5, 125.0,
124.13, 123.4, 123.2, 121.2, 118.9, 118.7, 114.7, 114.2, 112.7, 111.7,
111.0, 53.6, 46.4; HR-MS (ESI): calcd. for C20H16BrN4O [M + H]+:
407.0502, found (ESI+): 407.0489.
Biological Assay. The anti-TMV activities and fungicidal
activities of the target compounds were evaluated with three
replicates at 25 1 °C. Activity results were estimated according to
a percentage scale of 0−100 (0: no activity; 100: totally inhibited).
The detailed procedures of anti-TMV activity and fungicidal
activity were carried out applying reported methods,28,29 which also
can be found in the Supporting Information.
Mode of Action Studies. The mode of action studies of in vitro
TMV and 20S CP disk assembly inhibition were carried out using
the literature method,28,29 and the detailed procedures also can be
seen in the Supporting Information.
Fluorescence Spectroscopy. The binding constant was
calculated by using fluorescence titration between TMV CP and
compound 13h by the literature method.30 The detailed procedures
can be found in the Supporting Information.
chromatography to obtain compound 7. Brown solid, yield: 50%;
1
mp: 123−126 °C; H NMR (400 MHz, CDCl3): δ 9.34 (s, 1H),
8.22−8.13 (m, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.0 Hz,
2H), 7.77 (d, J = 8.0 Hz, 2H), 7.66−7.54 (m, 2H), 7.47 (d, J = 8.8
Hz, 1H), 7.39−7.20 (m, 7H), 5.49−5.22 (m, 1H), 4.85 (s, 1H),
3.71 (d, J = 6.3 Hz, 2H), 2.37 (d, J = 15.5 Hz, 6H), 1.43 (s, 9H);
13C NMR (100 MHz, CDCl3): δ 180.9, 160.9, 156.7, 146.4, 145.3,
138.5, 135.3, 134.9, 134.8, 134.2, 130.5, 130.0, 128.7, 128.5, 127.3,
127.0, 126.9, 125.2, 124.0, 123.6, 123.5, 119.8, 119.7, 116.3, 115.8,
113.9, 80.3, 47.7, 43.6, 28.3, 21.7.
Preparation of 3-(6-Bromo-1-tosyl-1H-indol-3-yl)-6-(1-
tosyl-1H-indol-3-yl)-5,6-dihydro-pyrazin-2(1H)-one (8).19,26
To a solution of compound 7 (0.2 g, 0.24 mmol, 1.0 equiv) in
CH2Cl2 (20 mL) was added anhydrous formic acid (20 mL). The
mixture was stirred for 12 h at 25 °C. After completion, the solvent
was removed in vacuum. The residue was taken into 60 mL of 1,2-
dichloroethane. The mixture was treated with formic acid until pH =
4 and heated to reflux for 1 h and then concentrated. The residue
was purified by column chromatography to obtain compound 8.
RESULTS AND DISCUSSION
■
1
White solid, yield: 66%; mp: 154−158 °C; H NMR (400 MHz,
Chemistry. Since the first report of alkaloid hamacan-
thin,11 scientists have completed the synthesis of racemic and
optical isomers of alkaloids hamacanthin A, hamacanthin B,
and their derivatives.16−20,31 In these synthetic methods, it is
found that 1-(1H-indol-3-yl)ethane-1,2-diamine and its
derivatives were the key intermediates. The amino alkylation
of indoles at the 3-position using the nitrone 2 was selected
to synthesize compound 3.23 The key intermediate 4a was
obtained by simultaneous reduction and debenzylation of
compound 3 under mild conditions with a quantitative
yield.19 Although deprotection of 6 by formic acid to the
primary amine was achieved,19 many attempts to provide the
expected 6″-debromohamacanthin A (1a) by ring closing
DMSO-d6): δ 9.25 (s, 1H), 8.84 (s, 1H), 8.21 (d, J = 8.7 Hz, 1H),
8.13 (s, 1H), 7.99 (d, J = 7.8 Hz, 2H), 7.87 (d, J = 8.2 Hz, 1H),
7.78 (d, J = 7.7 Hz, 1H), 7.58 (s, 1H), 7.45 (t, J = 9.7 Hz, 3H),
7.41−7.25 (m, 4H), 6.61 (d, J = 7.9 Hz, 2H), 5.12 (s, 1H), 4.21 (s,
2H), 2.19 (s, 3H), 2.05 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
δ 156.6, 156.4, 146.3, 144.9, 134.7, 134.5, 133.5, 133.3, 131.9, 130.6,
129.6, 128.3, 127.4, 126.9, 126.2, 125.4, 125.2, 124.4, 123.5, 121.5,
120.5, 118.2, 115.8, 115.6, 113.3, 52.2, 45.4, 20.9, 20.7.
Preparation of 3-(6-Bromo-1H-indol-3-yl)-6-(1H-indol-3-yl)-
5,6-dihydropyrazin-2(1H)-one (1a).27 A solution of sodium (33
mg, 1.42 mmol, 9.0 equiv) and naphthalene (0.152 g, 1.18 mmol,
7.5 equiv) in dry THF (3 mL) was stirred for 2 h at 25 °C, then
cooled to −78 °C, and added with a THF solution of compound 8
(0.113 g, 0.158 mmol, 1.0 equiv). The mixture was stirred at −78
C
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Figure 4. Synthesis of compounds 11a, 11b, and 12a−12k.
failed. Fortunately, when N−H on the indole of intermediate
7 was protected by the tosyl (Ts) group, the cyclization
proceeded smoothly, and compound 8 was obtained with a
98% yield. The Ts protective group of the nitrogen atom in
the indole structure could be removed with sodium and
naphthalene at low temperatures successfully (Figure 3).
Compounds 11a,11b, and 12a−12k with different substitu-
ents of indole structures and 5,6-dihydro-1(2H) pyrazinone
structural units were prepared by changing 1,2-diamines 4
and 5 (Figure 4).
structures of other chiral compounds 11b and 12−14 were
also clear demonstrations.
Compound (5S,6S)-12l was obtained by refluxing (5S,6S)-
12k in the presence of hydrazine hydrate (Figure 6). Then,
two series of hamacanthin derivatives were obtained as shown
in Figures 6 and 7. Compound (5S,6S)-12l reacted with
isothiocyanates or aldehydes in THF under refluxing
conditions to give compounds 13a−13k and 14a−14h in
good to moderate yields, respectively.
Phytotoxic Activity. The phytotoxic activity tests
demonstrated that the hamacanthin analogues 1a, 11a−11b,
12a−12l, 13a−13k, and 14a−14h were safe for testing on
plants at 500 μg/mL. The detailed test procedures can be
seen in the Supporting Information.
Antiviral Activity In Vivo. The activities of 6″-
debromohamacanthin A (1a) and its analogues 11a, 11b,
12a−12l, 13a−13k, and 14a−14h against TMV are listed in
Table 1 with the commercial plant virucides ningnanmycin
and ribavirin as the controls. Most of these compounds
exhibited higher antiviral activities than ribavirin. The
antiviral activities of compounds 1a and 13e−13h are similar
to or higher than that of ningnanmycin, which may be the
most effective plant viral inhibitor at present.
As shown in Table 1, the substitutes of the piperazinone
ring have a great influence on antiviral activities. Removal of
the indole group at the 6-position of 1a sharply decreased the
anti-TMV activity (inhibitory effect: 1a > 11a). Compound
11b with a 5,6-ring structure showed the same level of
biological activity as compound 11a. The introduction of a
phenyl group at the 5,6-position of 5,6-dihydro-1(2H)
According to the reported cyclization method,26 the
transamidation−cyclization was observed in the regioisomer
to result in the production of both hamacanthin A and
hamacanthin B derivatives. Optically pure (1R,2R)-N-Boc-1,2-
cyclohexane diamine (4c), (1R,2R)-N-Boc-1,2-diphenylethy-
lene diamine (4d), and (1S,2S)-N-Boc-1,2-diphenylethylene
diamine (4e) were selected for structural simplification of the
natural product hamacanthins. It was not known whether the
stereochemical structure can be maintained. A flaky crystal of
12k, which was prepared from (1S,2S)-N-Boc-1,2-diphenyl-
ethylene diamine (4e), was obtained by recrystallization from
THF:CH3OH (v/v = 1: 1). Single-crystal X-ray diffraction
analysis with Cu Kα [Flack parameter = −0.018(14), CCDC
2089734] suggested the absolute configuration of 12k to be
5S,6S (Figure 5). Accordingly, the structure of (5S,6S)-12k
was corroborated. By analyzing the single-crystal X-ray
diffraction of compound (5S,6S)-12k and comparing the
optical rotation values of compounds (5R,6R)-12a, (5S,6S)-
12a, (5R,6R)-12k, and (5S,6S)-12 k, it can be determined
that the stereochemical structure can be maintained. The
D
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Figure 5. X-ray crystal structure of (5S,6S)-12k.
Figure 6. Synthesis of compounds 12l and 13a−13k.
pyrazinone can improve the anti-TMV activity, and the
chirality at the 5,6-position has little effect on the activity
(inhibitory effect: (5R,6R)-12a ≈ (5S,6S)-12a > 11a).
Compounds 12a−12d exhibited about a similar level of
anti-TMV activities, which indicated that the introduction of
halogen at the 5-position of the indole ring had little effect
on the activity. However, the introduction of a methoxy
group at the 5-position, a halogen group at the 6-position,
and an alkyl or benzyl group at the 1-position of the indole
ring was not conducive to the improvement of antiviral
activity (inhibitory effect: 12a > 12e−12 k). (5S,6S)-12k
with relatively high antiviral activity was further modified. To
our delight, the introduction of a hydrazide group at the 1-
position of the indole ring significantly improved the
biological activity (inhibitory effect: 12l > (5S,6S)-12k).
Thiourea is a kind of pharmacophore widely existing in
drug molecules. The introduction of thiourea can increase the
Figure 7. Synthesis of compounds 14a−14h.
E
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Table 1. In Vivo Antiviral Activities of 1a, 11a, 11b, 12a−12l, 13a−13k, 14a−14h, Ribavirin, and Ningnanmycin against
TMV
concn
inactive effect curative effect
protective
concn
inactive effect curative effect
protective
a
a
a
a
a
a
compd
(μg/mL)
(%)
(%)
effect (%)
compd
13c
(μg/mL)
(%)
49
23
(%)
46
23
effect (%)
48
23
1a
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
53
1
1
2
51
1
1
2
1
3
1
2
3
2
1
4
3
1
1
2
1
3
56
29
32
11
40
15
50
17
51
20
49
23
45
17
53
24
23
0
1
1
2
1
3
2
3
2
3
1
1
3
1
1
2
2
1
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
2
3
2
1
4
2
30
44
9
25
39
15
32
12
44
16
45
19
45
17
42
15
46
19
21
0
11a
13d
45
28
58
25
57
25
55
27
60
34
45
17
46
21
52
25
30
11
38
26
32
10
36
29
23
9
1
1
2
2
4
3
3
1
1
2
3
1
3
2
3
1
3
3
2
4
1
2
2
1
3
2
4
1
1
3
1
2
1
2
1
2
45
23
58
23
55
26
53
25
59
31
43
18
47
21
50
21
28
12
35
21
32
9
3
4
2
4
4
2
2
3
1
2
2
3
4
3
4
3
2
1
3
3
2
3
4
1
3
3
4
1
2
1
2
3
3
1
3
2
47
26
61
28
59
29
57
27
63
37
47
21
48
21
55
29
30
11
38
26
35
13
39
25
23
11
43
19
47
24
53
28
41
15
59
27
3
2
2
4
3
2
3
3
1
2
3
1
4
4
2
4
4
3
3
2
4
2
3
3
2
2
3
2
4
4
3
3
1
1
2
3
1
11b
36
18
48
19
47
16
47
22
43
22
48
26
25
0
2
3
3
2
4
1
3
2
1
1
2
3
2
13e
(5R,6R)-12a
(5S,6S)-12a
12b
13f
13g
13h
12c
13i
12d
13j
12e
13k
12f
34
17
27
0
3
1
2
36
13
22
0
4
2
3
39
23
25
0
2
3
3
14a
12g
14b
12h
39
19
15
0
2
2
2
38
17
11
0
2
2
3
40
21
12
0
2
2
2
14c
12i
14d
37
23
19
9
12j
35
12
39
17
40
20
51
22
48
17
44
25
1
2
1
2
1
2
4
2
1
3
3
3
33
10
37
16
38
18
49
20
45
19
45
21
3
3
2
1
4
1
1
1
2
1
2
4
36
14
42
19
44
20
53
26
49
23
47
23
1
2
3
2
3
2
1
1
3
1
2
1
14e
(5R,6R)-12k
(5S,6S)-12k
12l
14f
41
16
44
24
50
26
39
13
54
27
39
17
45
21
48
25
37
13
53
25
14g
14h
13a
ribavirin
ningnanmycin
13b
a
Average of three replicates; all results are expressed as mean SD.
hydrogen bond interaction between drug molecules and
biomacromolecules. Based on this, a series of thiourea
derivatives 13a−13k were designed and synthesized, and
their antiviral activity was evaluated. As shown in Table 1, all
the thiourea-containing compounds 13a−13 k demonstrated
higher antiviral activities than ribavirin. The difference
between compounds 13a−13h is the substituted group on
the benzene ring. Compounds 13b−13d with an electron-
drawing group on the 4-position of the benzene ring showed
similar antiviral activities with 13a, which is slightly lower
than that of 12l. Compounds 13e−13h exhibited significantly
higher antiviral activities than 13a, which indicated that the
electron-donating group in the para position and the halogen-
substituting group in ortho and meta positions of the
benzene ring are beneficial to improve the activity.
Compound 13h, with better activity than ningnanmycin
and 1a, emerged as a new antiviral agent. Compared with
phenyl, naphthalene and benzyl have little effect on biological
activity, while alkanes are more beneficial to virus activity
(inhibitory effect: 13k > 13a ≈ 13j ≈ 13i).
Acylhydrazone is also a good pharmacophore. We also
prepared a series of acylhydrazone derivatives 14a−14e. The
anti-TMV activities of 14a−14e are similar to or higher than
that of ribavirin. Compound 14h showed the same level of
antiviral activity with 12l and 1a.
Through systematic structure−activity relationship studies,
we found a highly effective antiviral candidate and a variety of
effective structural skeletons.
Preliminary Mode of Action. The optimized compound
13h was further investigated for its antiviral mechanism
according to the reported method.28 As shown in Figure 8,
the 20S CP disk can be assembled with the RNA, forming a
rod-like length of approximately 300 nm TMV virus particles
(Figure 8A). A small amount of dimethylsulfoxide (DMSO)
does not inhibit the assembly of viral particles (Figure 8B).
Compound 13h can significantly inhibit the assembly process
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Figure 8. TMV rod assembly inhibition of compound 13h (200 nm scale bar): (A) 20S CP disk + RNA, (B) 20S CP disk + RNA + 1/100
DMSO, and (C) 20S CP disk + RNA +10 μM 13h.
Figure 9. 20S CP disk assembly inhibition of compound 13h (100 nm scale bar): (A) CP, (B) CP + 1/100 DMSO (100 nm scale bar), and
(C) CP + 10 μM 13h.
Figure 10. Molecule docking results of compounds 13h and 14h with TMV CP.
of TMV virus particles and result in no intact virus particles
(Figure 8C). The 20S CP disk assembly experiment was
further designed to study the interaction between 13h and
the 20S CP disk. 20S CP disks have a disk-like structure
(Figure 9A), and a small amount of DMSO does not affect
the formation of the 20S CP disk (Figure 9B). Compound
13h can interact with the 20S CP disk and cause
depolymerization of the 20S CP disk (Figure 9C), which
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Figure 11. Fluorescence titration. Fluorescence emission spectra of TMV CP in the presence of (A) 13h and (B) 14h with different
concentrations (λex = 278 nm). Inset: the linear relationship for quenching TMV CP by 13h and 14h, respectively.
indicates that inhibition of virus assembly by interaction with
CP was the main reason for the antiviral activity of these
compounds. How these compounds affect the assembly
process of virus particles needs to be further studied.
Molecular Docking. To further disclose the binding
modes between hamacanthin analogues and TMV CP (PDB
code: 1EI7), a molecular docking study was carried out using
AutoDock-vina 1.1.2.32 Combined with anti-TMV activity
and molecular structure characteristics, compounds 13h and
14h were chosen for molecular docking research (Figure 10).
As shown in Figure 10A, compound 13h interacted with
TMV CP through one conventional hydrogen bond. In this
interaction, N−H of 13h interacted with the oxygen atoms of
the SER-138 residue by hydrogen bonding: N−H···OC =
2.7 Å. Compound 14h forms two hydrogen bonds with the
amino acid residue ALA-74 (2.7 Å) and GLN-257 (2.3 Å)
(Figure 10B). The results of molecular docking showed that
hamacanthin analogues had a strong interaction with TMV
CP, and the interaction sites and strength were greatly
affected by the molecular structure.
Binding Constant of Compounds 13h and 14h to
TMV CP. TMV CP is an important functional protein for
TMV to infect the host and an essential protein for virus
assembly initiation and elongation.33 To further verify the
interaction of 6″-debromohamacanthin A (1a) and its
derivatives with TMV CP, the interaction of compounds
13h and 14h with TMV CP was measured with FT
according to the reported literature.34 The results of
fluorescence spectroscopy analysis are exhibited in Figure
11 Compound 13h has a good affinity to TMV CP, with a Ka
value of 5.32 × 105 L/mol (Figure 11A), which is better than
compound 14h (Ka = 1.05 × 105 L/mol, Figure 11B). This
result confirms that compounds 13h and 14h can combine
with TMV CP and the binding ability is consistent with the
antiviral activity.
have broad-spectrum inhibitory activities against all eight
common agricultural pathogens. 6″-Debromohamacanthin A
(1a), 12b, and 12f exhibited moderate to good antifungal
activities against all the tested fungi. Compounds 12b, 12f,
12k, 13h, and 14a not only gave higher inhibitory effects
against Alternaria solani than chlorothalonil and carbendazim
but also displayed more than 80% inhibitory effects on three
pathogens including Sclerotinia sclerotiorum, Physalospora
piricola, and Rhizoctonia cerealis. For P. piricola, some
compounds of each series showed more than 80% inhibitory
activities, such as 1a, 12b, 12c, 13h, and 14a. The structure−
activity relationship was different from that of antiviral
activity. Compounds 12b and 12c with poor antiviral
activities showed good fungicidal effects. Therefore, hama-
canthin alkaloids also can be considered as novel fungicide
candidates for further research.
In summary, using the natural product 6″-debromohama-
canthin (1a) as the parent structure, three series of
hamacanthin derivatives were designed, synthesized, and
investigated for the antiviral and antifungal activities. Starting
from (1R,2R)-N-Boc-1,2-diphenylethylene diamines or
(1S,2S)-N-Boc-1,2-diphenylethylene diamines can efficiently
achieve the structure-simplified hamacanthin derivatives. Most
of these compounds exhibited higher antiviral activities than
ribavirin. Compounds 1a and 13e−13 h displayed similar or
higher anti-TMV activities than ningnanmycin at 500 μg/mL.
Compound 13h was selected for further anti-TMV
mechanism research by TEM, molecular docking, and
fluorescence titration. The results revealed that compound
13h could bind to TMV CP with an excellent affinity (Ka =
5.32 × 105 L/mol), leading to inhibition of viral assembly.
Furthermore, these hamacanthin derivatives also exhibited
broad-spectrum fungicidal activities. Compounds 12b, 12f,
12k, 13h, and 14a exhibited moderate to good antifungal
activities, with an activity of more than 80% against some
fungi, such as S. sclerotiorum, P. piricola, and R. cerealis. This
work involves leader selection, design and synthesis,
structure−activity relationship, and mechanism of action,
which lays a foundation for the application of these
compounds as plant disease protective agents.
Fungicidal Activity. The fungicidal activities of 6″-
debromohamacanthin A (1a) and its derivatives 11a, 11b,
12a−12l, 13a−13k, and 14a−14 h were also evaluated, and
the commercial fungicides chlorothalonil and carbendazim
were used as controls (Table 2). At a concentration of 50
μg/mL, 6″-debromohamacanthin A (1a) and its derivatives
H
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Table 2. Fungicidal Activities of 1a, 11a, 11b, 12a−12l, 13a−13k, 14a−14h against Eight Kinds of Fungi
a
fungicidal activities (%) at 50 μg/mL
b
b
b
b
b
b
b
compd
S.S
C.H
F.C
48
14
4
P.C
85
3
A.S
P.Pb
80
32
6
R.C
P.G
1a
11a
11b
83
12
28
1
2
1
61
22
15
2
3
2
1
1
1
2
1
1
81
35
13
1
2
3
2
1
1
94
22
7
1
1
1
64
0
18
2
1
9
(5R,6R)-12a
(5S,6S)-12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
(5R,6R)-12k
(5S,6S)-12k
12l
13a
13b
13c
13d
13e
13f
13g
13h
13i
13j
13k
14a
14b
14c
14d
14e
14f
14g
14h
50
2
37
1
26
1
27
20
1
42
1
55
3
53
1
0
0
91
64
0
0
33
80
56
9
1
2
1
1
2
1
1
1
1
1
1
1
1
1
1
3
1
1
1
1
2
1
1
1
2
2
3
1
1
3
2
1
26
58
55
21
37
70
26
5
0
0
18
18
9
15
3
15
9
12
10
9
3
3
12
18
9
1
1
2
2
3
2
2
1
36
42
37
18
36
58
11
14
25
14
21
21
8
19
19
17
15
12
12
14
12
17
21
21
31
15
12
10
23
15
17
12
100
100
2
1
1
1
2
1
1
1
3
1
1
1
1
1
2
1
1
1
1
1
1
1
1
3
1
1
1
1
1
1
1
1
1
1
2
1
3
1
1
1
1
1
1
1
2
2
1
1
1
1
1
1
1
1
1
2
1
1
1
1
1
1
1
1
1
2
24
56
38
29
6
50
30
0
18
24
13
13
31
6
2
2
1
3
1
1
1
58
91
80
46
54
80
39
31
31
46
80
80
0
30
9
0
12
6
1
1
2
2
1
2
2
1
2
2
1
1
49
80
61
25
44
88
37
16
37
30
12
12
30
24
8
17
11
27
17
11
16
18
17
15
12
12
17
17
24
27
35
16
100
100
1
1
1
3
1
1
2
3
1
2
1
1
1
1
1
1
1
2
1
1
1
2
1
1
1
2
1
3
1
1
1
1
41
24
28
40
41
16
12
12
12
12
12
24
6
9
6
6
9
3
6
15
6
6
1
2
44
81
30
23
15
14
40
40
36
42
36
42
22
39
64
28
28
36
50
50
51
4
82
2
0
0
0
0
2
1
1
1
1
1
1
1
3
1
1
1
2
1
1
1
1
1
2
3
2
1
1
1
1
18
1
1
1
1
1
1
1
1
2
1
2
1
1
1
1
1
1
2
3
1
1
1
18
77
9
9
9
9
5
55
9
10
5
1
2
1
1
1
1
1
1
1
1
2
1
1
1
1
1
3
1
1
1
2
1
2
1
6
6
13
10
50
10
10
9
31
13
9
38
31
31
38
31
44
31
<50
<50
1
1
1
1
2
1
1
2
1
1
2
1
1
1
1
1
1
6
21
80
6
21
36
80
50
51
51
35
35
21
6
9
9
5
9
7
9
9
9
3
6
3
6
6
6
6
18
15
21
15
74
52
33
11
83
19
42
11
100
92
5
18
27
9
9
6
91
90
10
100
100
c
chlorothalonil
89
100
c
carbendazim
1
a
b
Average of three replicates; all results are expressed as mean SD. F.C, Fusarium oxysporum f. sp. cucumeris; C.H, Cercospora arachidicola Hori;
P.P, Physalospora piricola; R.C, Rhizoctonia cerealis; A.S, Alternaria solani; P.G, Pyricularia grisea; P.C, Phytophthora capsici; S.S, Sclerotinia
c
sclerotiorum. The commercial agricultural fungicides were used for comparison of antifungal activity.
Zhongyu Duan − School of Chemical Engineering and
Technology, Hebei University of Technology, Tianjin
300130, China; Phone: 0086-22-60204305;
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.jafc.1c04098.
■
sı
Email: zyduan@hebut.edu.cn; Fax: 0086-22-60204305
Qingmin Wang − State Key Laboratory of Elemento-Organic
Chemistry, Research Institute of Elemento-Organic
Chemistry, College of Chemistry, Collaborative Innovation
Center of Chemical Science and Engineering (Tianjin),
Nankai University, Tianjin 300071, China; orcid.org/
0000-0002-6062-3766; Phone: 0086-22-23503952;
Email: wangqm@nankai.edu.cn; Fax: 0086-22-23503952
Detailed bio-assay procedures, detailed procedures for
fluorescence titration, detailed synthesis of compounds
9−14, and spectra data of compounds 1−14 (PDF)
Crystallographic data of (5S,6S)-12k (CIF)
AUTHOR INFORMATION
Corresponding Authors
Aidang Lu − School of Chemical Engineering and
Technology, Hebei University of Technology, Tianjin
300130, China; orcid.org/0000-0002-2255-8828;
Phone: 0086-22-60302812; Email: luaidang@
hebut.edu.cn; Fax: 0086-22-60204274
■
Authors
Tienan Wang − School of Chemical Engineering and
Technology, Hebei University of Technology, Tianjin
300130, China
I
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Article
(14) Oh, K. B.; Mar, W.; Kim, S.; Kim, J. Y.; Lee, T. H.; Kim, J.
G.; Shin, D.; Sim, C. J.; Shin, J. Antimicrobial activity and
cytotoxicity of bis(indole) alkaloids from the sponge Spongosorites
sp. Biol. Pharm. Bull. 2006, 29, 570−573.
(15) Kim, A.; Kim, M. J.; Noh, T. H.; Hong, J.; Liu, Y.; Wei, X.;
Jung, J. H. Synthesis and antibacterial evaluation of hamacanthin B
analogues. Bioorg. Med. Chem. Lett. 2016, 26, 5013−5017.
(16) Jiang, B.; Yang, C. G.; Wang, J. Enantioselective synthesis for
the (−)-antipode of the pyrazinone marine alkaloid, hamacanthin A.
J. Org. Chem. 2001, 66, 4865−4869.
(17) Jiang, B.; Yang, C.-G.; Wang, J. Enantioselective synthesis of
marine indole alkaloid hamacanthin B. J. Org. Chem. 2002, 66,
1396−1398.
(18) Kouko, T.; Matsumura, K.; Kawasaki, T. Total synthesis of
marine bisindole alkaloids, (+)-hamacanthins A, B and (−)-antipode
of cis-dihydrohamacanthin B. Tetrahedron 2005, 61, 2309−2318.
(19) Guinchard, X.; Vallée, Y.; Denis, J.-N. Total syntheses of
brominated marine sponge alkaloids. Org. Lett. 2007, 9, 3761−3764.
(20) Golantsov, N. E.; Festa, A. A.; Golubenkova, A. S.; Nguyen,
K. M.; Yakovenko, E. A.; Varlamov, A. V.; Voskressensky, L. G.
Total synthesis of hamacanthin B class marine bisindole alkaloids.
Chem. Heterocycl. Compd. 2020, 56, 331−338.
Lin Li − School of Chemical Engineering and Technology,
Hebei University of Technology, Tianjin 300130, China
Yanan Zhou − School of Chemical Engineering and
Technology, Hebei University of Technology, Tianjin
300130, China
Hongyan Li − School of Chemical Engineering and
Technology, Hebei University of Technology, Tianjin
300130, China
Jianxin Chen − School of Chemical Engineering and
Technology, Hebei University of Technology, Tianjin
300130, China; orcid.org/0000-0002-1436-8127
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jafc.1c04098
Funding
This study was supported by the Key R&D Program of
Hebei Province (21326504D), the Natural Science Founda-
tion of Hebei Province (B2020202028), and the National
Natural Science Foundation of China (21772145 and
U20A20140).
(21) Li, G.; Guo, J.; Wang, Z.; Liu, Y.; Song, H.; Wang, Q. Marine
natural products for drug discovery: first discovery of kealiinines A−
C and their derivatives as novel antiviral and antiphytopathogenic
fungus agents. J. Agric. Food Chem. 2018, 66, 7310−7318.
(22) Zhang, M.; Ding, X.; Kang, J.; Gao, Y.; Wang, Z.; Wang, Q.
Marine natural product for pesticide candidate: pulmonarin alkaloids
as novel antiviral and anti-phytopathogenic-fungus agents. J. Agric.
Food Chem. 2020, 68, 11350−11357.
(23) Hequet, A.; Burchak, O. N.; Jeanty, M.; Guinchard, X.; Le
Pihive, E.; Maigre, L.; Bouhours, P.; Schneider, D.; Maurin, M.;
Paris, J.-M.; Denis, J.-N.; Jolivalt, C. 1-(1H-indol-3-yl)ethanamine
derivatives as potent Staphylococcus aureus NorA efflux pump
inhibitors. ChemMedChem 2014, 9, 1534−1545.
(24) Takeda, T.; Terada, M. Development of a chiral bis-
(guanidino)iminophosphorane as an uncharged organosuperbase
for the enantioselective amination of ketones. J. Am. Chem. Soc.
2013, 135, 15306−15309.
(25) Ji, X.; Wang, Z.; Dong, J.; Liu, Y.; Lu, A.; Wang, Q. Discovery
of topsentin alkaloids and their derivatives as novel antiviral and
anti-phytopathogenic fungus agents. J. Agric. Food Chem. 2016, 64,
9143−9151.
(26) Kawasaki, T.; Kouko, T.; Totsuka, H.; Hiramatsu, K.
Synthesis of marine bisindole alkaloids, hamacanthins A and B
through intramolecular transamidation−cyclization. Tetrahedron Lett.
2003, 44, 8849−8852.
(27) Ji, X.; Guo, J.; Liu, Y.; Lu, A.; Wang, Z.; Li, Y.; Yang, S.;
Wang, Q. Marine-natural-product development: First discovery of
nortopsentin alkaloids as novel antiviral, anti-phytopathogenic-
fungus, and insecticidal agents. J. Agric. Food Chem. 2018, 66,
4062−4072.
(28) Lu, A.; Wang, T.; Hui, H.; Wei, X.; Cui, W.; Zhou, C.; Li, H.;
Wang, Z.; Guo, J.; Ma, D.; Wang, Q. Natural products for drug
discovery: Discovery of gramines as novel agents against a plant
virus. J. Agric. Food Chem. 2019, 67, 2148−2156.
(29) Wang, T.; Yang, S.; Li, H.; Lu, A.; Wang, Z.; Yao, Y.; Wang,
Q. Discovery, structural optimization, and mode of action of
essramycin alkaloid and its derivatives as anti-tobacco mosaic virus
and anti-phytopathogenic fungus agents. J. Agric. Food Chem. 2020,
68, 471−484.
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) King, T.; Cole, M.; Farber, J. M.; Eisenbrand, G.; Zabaras, D.;
Fox, E. M.; Hill, J. P. Food safety for food security: Relationship
between global megatrends and developments in food safety. Trends
Food Sci. Technol. 2017, 68, 160−175.
(2) Jeschke, P. Progress of modern agricultural chemistry and
future prospects. Pest Manage. Sci. 2016, 72, 433−455.
(3) Da Silva, R. R.; do Couto Santos, R. Pest control: Can
chitinases help to reduce pesticide use? J. Agric. Food Chem. 2019,
67, 8071−8073.
(4) Yu, X.; Zhu, X.; Zhou, Y.; Li, Q.; Hu, Z.; Li, T.; Tao, J.; Dou,
M.; Zhang, M.; Shao, Y.; Sun, R. Discovery of N-aryl-pyridine-4-
ones as novel potential agrochemical fungicides and bactericides. J.
Agric. Food Chem. 2019, 67, 13904−13913.
(5) Urban, S.; Hickford, S. J. H.; Blunt, J. W.; Munro, M. H. G.
Bioactive marine alkaloids. Curr. Org. Chem. 2000, 4, 765−807.
(6) Meng, Z. H.; Sun, T. T.; Zhao, G. Z.; Yue, Y. F.; Chang, Q.
H.; Zhu, H. J.; Cao, F. Marine-derived fungi as a source of bioactive
indole alkaloids with diversified structures. Mar. Life Sci. Technol.
2021, 3, 44−61.
(7) Wang, S.; Dong, G.; Sheng, C. Structural simplification of
natural products. Chem. Rev. 2019, 119, 4180−4220.
(8) Koehn, F. E.; Carter, G. T. The evolving role of natural
products in drug discovery. Nat. Rev. Drug Discovery 2005, 4, 206−
220.
(9) Rodrigues, T.; Reker, D.; Schneider, P.; Schneider, G.
Counting on natural products for drug design. Nat. Chem. 2016,
8, 531−541.
(10) Yao, H.; Liu, J.; Xu, S.; Zhu, Z.; Xu, J. The structural
modification of natural products for novel drug discovery. Expert
Opin. Drug Discovery 2017, 12, 121−140.
(11) Gunasekera, S. P.; McCarthy, P. J.; Kelly-Borges, M.
Hamacanthins A and B, New Antifungal Bis Indole Alkaloids from
the Deep-Water Marine Sponge, Hamacantha Sp. J. Nat. Prod. 1994,
57, 1437−1441.
(12) Bao, B.; Sun, Q.; Yao, X.; Hong, J.; Lee, C.-O.; Sim, C. J.; Im,
K. S.; Jung, J. H. Cytotoxic bisindole alkaloids froma marine sponge
Spongosorites sp. J. Nat. Prod. 2005, 68, 711−715.
(30) Wang, Z.; Xie, D.; Gan, X.; Zeng, S.; Zhang, A.; Yin, L.; Song,
B.; Jin, L.; Hu, D. Synthesis, antiviral activity, and molecular docking
study of trans-ferulic acid derivatives containing acylhydrazone
moiety. Bioorg. Med. Chem. Lett. 2017, 27, 4096−4100.
(31) Golantsov, N. E.; Festa, A. A.; Varlamov, A. V.;
Voskressensky, L. G. Revision of the structure and total synthesis
of topsentin C. Synthesis 2017, 49, 2562−2574.
(13) Bao, B.; Sun, Q.; Yao, X.; Hong, J.; Lee, C.-O.; Cho, H. Y.;
Jung, J. H. Bisindole alkaloids of the topsentin and hamacanthin
classes from a marine sponge Spongosorites sp. J. Nat. Prod. 2007, 70,
2−8.
J
https://doi.org/10.1021/acs.jafc.1c04098
J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry
pubs.acs.org/JAFC
Article
(32) Trott, O.; Olson, A. J. Autodock vina: Improving the speed
and accuracy of docking with a new scoring function, efficient
optimization, and multithreading. J. Comput. Chem. 2010, 31, 455−
461.
(33) Chen, M.; Hu, D.; Li, X.; Yang, S.; Zhang, W.; Li, P.; Song,
B. Antiviral activity and interaction mechanisms study of novel
glucopyranoside derivatives. Bioorg. Med. Chem. Lett. 2015, 25,
3840−3844.
(34) Gan, X.; Wang, Y.; Hu, D.; Song, B. Design, synthesis, and
antiviral activity of novel chalcone derivatives containing a purine
moiety. Chin. J. Chem. 2017, 35, 665−672.
K
https://doi.org/10.1021/acs.jafc.1c04098
J. Agric. Food Chem. XXXX, XXX, XXX−XXX