Streptindole and Its Derivatives as Novel Antiviral and Anti-Phytopathogenic Fungus Agents

Article abstract of DOI:10.1021/acs.jafc.0c03994

Plant diseases caused by plant viruses and pathogens seriously affect the production and storage of food crops. With the emergence of drug resistance, it is very difficult to control. Natural products are the source of new drug discovery. Here, the natural product streptindole was found to have good antiviral activity against tobacco mosaic virus (TMV) and fungicidal activities against 14 kinds of phytopathogenic fungi. A series of derivatives of streptindole were designed, synthesized, and evaluated for their antiviral and fungicidal activities. Compounds 4, 5, 11, 12c, 12d, 13d, and 13i-13l showed higher anti-TMV activities than ribavirin (inhibitory rate: 38, 37, and 40% at 500 μg/mL for inactivation, curative, and protection activity in vivo, respectively), among which compound 12d (inhibitory rate: 57, 55, and 53% at 500 μg/mL for inactivation, curative, and protection activity in vivo, respectively) with excellent antiviral activity was further evaluated for the mode of action. The mechanism research revealed that 12d can break the three-dimensional structure of TMV coat protein (CP) through hydrogen bonds, thus inhibiting the assembly of virus particles. The molecular docking result showed that compound 12d did exhibit strong interaction with TMV CP. The derivatives of streptindole also displayed broad-spectrum fungicidal activities. The current study provided valuable insights into the antiviral and fungicidal activities of streptindole derivatives.

Full text of DOI:10.1021/acs.jafc.0c03994

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Agricultural and Environmental Chemistry
Streptindole and Its Derivatives as Novel Antiviral
and Anti-phytopathogenic-fungus Agents
Jin Kang, Yongyue Gao, Mingjun Zhang, Xin Ding, Ziwen Wang, Dejun Ma, and Qingmin Wang
J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.0c03994 • Publication Date (Web): 10 Jul 2020
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Journal of Agricultural and Food Chemistry
Streptindole and Its Derivatives as Novel Antiviral and
Anti-phytopathogenic-fungus Agents
†
†
†
†
†
,
‡
Jin Kang , Yongyue Gao , Mingjun Zhang , Xin Ding , Ziwen Wang *, Dejun Ma ,
Qingmin Wang‡,*
†Tianjin Key Laboratory of Structure and Performance for Functional Molecules, College of
Chemistry, Tianjin Normal University, Tianjin 300387, China
‡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
* To whom correspondence should be addressed. For Ziwen Wang, E-mail: hxxywzw@tjnu.edu.cn;
Phone: 0086-22-23766531; Fax: 0086-22-23766531; For Qingmin Wang, E-mail:
wangqm@nankai.edu.cn; Phone: 0086-22-23503952; Fax: 0086-22-23503952.
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ABSTRACT: Plant diseases caused by plant viruses and pathogens seriously affect the
production and storage of food crops. With the emergence of drug resistance, it is very
difficult to control. Natural products are the source of new drug discovery. Here, natural
product streptindole was found to have good antiviral activity against tobacco mosaic
virus (TMV) and fungicidal activities against 14 kinds of phytopathogenic fungi. A series
of derivatives of streptindole were designed, synthesized and evaluated for their antiviral
and fungicidal activities. Compounds 4, 5, 11, 12c, 12d, 13d and 13i–13l showed higher
anti-TMV activities than ribavirin (inhibitory rate: 38%, 37%, 40% at 500 μg/mL for
inactivation, curative, and protection activity in vivo, respectively), among which,
compound 12d (inhibitory rate: 57%, 55%, 53% at 500 μg/mL for inactivation, curative,
and protection activity in vivo, respectively) with excellent antiviral activity was further
evaluated mode of action. The mechanism research revealed that 12d can break the
three-dimensional structure of TMV coat protein (CP) through hydrogen bond, thus
inhibiting the assembly of virus particles. Molecular docking result showed that
compound 12d did exhibit strong interaction with TMV CP. The derivatives of
streptindole also displayed broad-spectrum fungicidal activities. Current study provided
valuable insights into the antiviral and fungicidal activities of streptindole derivatives.
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KEYWORDS: natural product, structure optimization, streptindole alkaloid, antiviral
activity, fungicidal activity, mode of action
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INTRODUCTION
Facing the continuous growth of global population, high efficiency, environmental
protection and health will be the development trend of modern agriculture in the
future.1,2 Plant diseases caused by plant viruses and pathogens, known as plant cancer,
are the main factors restricting the efficient production of agriculture.3 Tobacco mosaic
virus (TMV) is one of the earliest and most well-known viruses. It contains a single
stranded RNA encapsulated in 2130 CP monomers. The particle of TMV is rod-shaped,
with a total length of about 300 nm.4 TMV is named for its first discovery on tobacco. Its
host is very wide, and it can infect many plants including capsicum, cucumber, tomato,
eggplant, solanum nigrum and so on, which brings great harm to agricultural production.4
Although there are some commercial antiviral agents, efficient and practical varieties are
few, the field control effect is mostly less than 60%. As a common antiviral agent,
ribavirin can only give a inhibition rate of no more than 50% at 500 μg/mL. It is urgent to
develop environment-friendly antiviral agents with simple structure and outstanding
activity.5,6
Natural products play an important role in the process of new drug development
because of their unique structures and wide range of biological activities, which alway
offer a range of uncharted chemotypes for chemists to discover new drugs.7-10 Through
the unremitting efforts of scientists in recent years, some breakthroughs have been made
in the development of new antiviral agents based on natural products. A series of natural
products have been found to have antiviral activities, which may be developed into new
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type of antiviral agents.11-22 However, the new pesticide has the characteristics of long
cycle, large investment and low success rate. It is necessary to continuously discover new
drug candidates, so as to improve the success rate of creation. Streptindole, a genotoxic
metabolite of human intestinal bacteria Streptococcus faecium IB 37, was isolated and
determined structure by Osawa and Namiki in 1983.23 Studies revealed that streptindole
exhibited DNA-damaging and genotoxic properties.24
We have been committed to the development of new antiviral candidates based on
indole natural products for a long time. Streptindole with simple structure has aroused
our great interest. Considering the above findings and our work experiences, a series of
streptindole derivatives were designed (Figure 1) and synthesized based on electronic
effect, steric hindrance effect and pharmacophore splicing strategy. The activities,
structure-activity relationship and mode of action of these compounds were
systematically evaluated.
MATERIALS AND METHODS
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.
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 spectrometer with either CDCl3 or DMSO-d6 as the solvent.
High-resolution mass spectra were obtained with an FT-ICR mass spectrometer (Ionspec,
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7.0 T). The in vitro TMV rod assembly inhibition and 20S CP disk assembly inhibition
were tested via transmission electron microscopy (Tecnai G2 F20).
General Procedures for the Preparation of Compounds 3a–3c. To the stirred solution
of corresponding indoles 1a–1c (5 mmol) and ethyl glyoxylate 2 (0.26 g, 2.5 mmol) in
acetonitrile (25 mL) was added I2 (0.13 g, 0.5 mmol) at 0 °C. The reaction mixture was
stirred for 0.5 h, quenched with 5％Na2S2O3 solution (20 mL) and extracted with ethyl
acetate (50 mL × 3). The organic phase was washed with brine (100 mL), dried over
anhydrous MgSO4 and evaporated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (5:1 PE/EA) to give 3a–3c.
1
Ethyl 2,2-di(1H-indol-3-yl)acetate (3a). Brown oil, yield 91%; H NMR (400 MHz,
CDCl3) δ 8.03 (s, 2H, NH), 7.67 (d, J = 7.9 Hz, 2H, Ar-H), 7.30 (t, J = 8.1 Hz, 2H, Ar-H),
7.23−7.21 (m, 2H, Ar-H), 7.14−7.10 (m, 2H, Ar-H), 7.00 (d, J = 2.0 Hz, 2H, Ar-H), 5.53
13
(s, 1H, Ar2-CH), 4.25 (q, J = 7.1 Hz, 2H, CH2), 1.29 (t, J = 7.1 Hz, 3H, CH3); C NMR
(100 MHz, CDCl3) δ 173.7, 136.3, 126.7, 123.5, 122.1, 119.5, 119.3, 113.5, 111.3, 61.2,
40.7, 14.3.
1
Ethyl 2,2-bis(5-bromo-1H-indol-3-yl)acetate (3b). Brown oil, yield 85%; H NMR
(400 MHz, CDCl3) δ 8.28 (s, 2H, NH), 7.75 (d, J = 1.7 Hz, 2H, Ar-H), 7.27 (d, J = 1.8
Hz, 1H, Ar-H), 7.25 (d, J = 1.8 Hz, 1H, Ar-H), 7.17 (s, 1H, Ar-H), 7.15 (s, 1H, Ar-H),
7.00 (d, J = 2.3 Hz, 2H, Ar-H), 5.37 (s, 1H, Ar2-CH), 4.26 (q, J = 7.1 Hz, 2H, CH2), 1.31
13
(t, J = 7.1 Hz, 3H, CH3); C NMR (100 MHz, CDCl3) δ 173.5, 135.1, 128.1, 125.1,
124.7, 121.8, 113.0, 112.9, 112.6, 61.7, 40.6, 14.2.
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Ethyl 2,2-bis(6-bromo-1H-indol-3-yl)acetate (3c). Brown oil, yield 85%; H NMR
(400 MHz, CDCl3) δ 8.27 (s, 2H, NH), 7.46 (s, 2H, Ar-H), 7.44 (s, 1H, Ar-H), 7.20 (d, J
= 1.4 Hz, 1H, Ar-H), 7.17 (d, J = 1.3 Hz, 1H, Ar-H), 6.98−7.07 (m, 3H, Ar-H), 5.42 (s,
1H, Ar2-CH), 4.24 (q, J = 7.1 Hz, 2H, CH2), 1.28 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (100
MHz, CDCl3) δ 173.4, 137.1, 125.4, 124.0, 122.9, 120.5, 115.7, 114.3, 113.4, 61.5, 40.5,
14.3.
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Preparation of 2,2-di(1H-indol-3-yl)ethan-1-ol (4). At 0 °C, to the tetrahydrofuran
(THF, 50 mL) was slowly added LiAlH4 (0.57 g, 15 mmol) in the stirring state. After
stirring for 10 min, ester 3a (1.59 g, 5 mmol) was slowly added, then the reaction
mixture was naturally rose to room temperature and stirred for further 3 h, quenched with
water (10 mL). Diatomite was added into the reaction mixture to assist filtration, the
filter cake was washed with ethyl acetate. The organic phase was dried over anhydrous
Na2SO4 and evaporated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (1:1 PE/EA) to give compound 4: Yellow oil, yield
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74%; H NMR (400 MHz, CDCl3) δ 7.95 (s, 2H, NH), 7.60 (d, J = 7.9 Hz, 2H, Ar-H),
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7.17−7.20 (m, 4H, Ar-H), 7.09 (t, J = 6.2 Hz, 2H, Ar-H), 6.72 (s, 2H, Ar-H), 4.72 (t, J =
13
5.9 Hz, 1H, Ar2-CH), 4.20 (d, J = 5.8 Hz, 2H, CH2), 2.32 (s, 1H, OH); C NMR (100
MHz, CDCl3) δ 136.5, 126.9, 122.9, 122.0, 119.4, 119.3, 115.9, 111.5, 85.7, 36.9.
C18H17N2O [M+H]+ 277.1335, found (ESI+) 277.1331.
Preparation of streptindole (5). To a solution of 4 (1.38 g, 5 mmol) and Et3N (0.76 g,
7.5 mmol) in CH2Cl2 (30 mL) was slowly added CH3COCl (0.43 g, 5.5 mmol), then the
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reaction mixture was naturally rose to room temperature and stirred for further 3 h,
quenched with water (40 mL) and extracted with CH2Cl2 (30 mL × 2). The organic phase
was washed with brine (100 mL), dried over anhydrous MgSO4 and evaporated under
reduced pressure. The residue was purified by flash column chromatography on silica gel
(2:1 PE/EA) to give streptindole (5): Brown oil, yield 58%; 1H NMR (400 MHz, CDCl3)
δ 7.92 (s, 2H, NH), 7.60 (d, J = 7.9 Hz, 2H, Ar-H), 7.28 (d, J = 8.1 Hz, 2H, Ar-H), 7.15 (t,
J = 7.5 Hz, 2H, Ar-H), 7.05 (t, J = 7.6 Hz, 2H, Ar-H), 6.86 (d, J = 2.1 Hz, 2H, Ar-H),
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4.92 (t, J = 7.1 Hz, 1H, Ar2-CH), 4.71 (d, J = 7.1 Hz, 2H, CH2), 1.95 (s, 3H, CH3); C
NMR (100 MHz, CDCl3) δ 171.5, 136.5, 127.0, 122.2, 122.1, 119.5, 119.4, 116.2, 111.2,
67.5, 33.6, 21.2. C20H19N2O2 [M+H]+ 319.1441, found (ESI+) 319.1447.
Preparation of (E)-3-(2-nitrovinyl)-1H-indole (7). The mixture of indole formaldehyde
(1.0 g, 6.9 mmol), ammonium acetate (0.53 g, 6.9 mmol), acetic acid (5.3 mL) and
nitromethane (1.3 g, 21.3 mmol) was stirred at 120 °C for 4 h. After completion, most of
the acetic acid was removed in vacuo, the residue was taken into H2O (100 mL) and
extracted with ethyl acetate (50 mL × 3). The organic phase was dried over anhydrous
Na2SO4 and evaporated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (6:1 PE/EA) to give compound 7: Red solid, yield
84%; mp 170−172 °C; 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H, NH), 8.29 (d, J = 13.5
Hz, 1H, NO2CH), 7.80 (d, J = 13.5 Hz, 1H, Ar-CH), 7.76–7.80 (m, 1H, Ar-H), 7.67 (d, J
= 2.9 Hz, 1H, Ar-H), 7.47–7.49 (m, 1H, Ar-H), 7.32–7.37 (m, 2H, Ar-H).
Preparation of 3,3'-(2-Nitroethane-1,1-diyl)bis(1H-indole) (8). To the stirred solution
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of compound 7 (1.0 g, 5.32 mmol) in CH2Cl2 (100 mL) was slowly added indole (0.62 g,
5.32 mmol) and NBS (0.95 g, 5.32 mmol). The mixture was refluxed for 16 h, then
cooled to room temperature and taken into H2O (100 mL), extracted with CH2Cl2 (50 mL
× 3). The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced
pressure. The residue was purified by flash column chromatography on silica gel (2:1
PE/EA) to give compound 8: Red solid, yield 45%; mp 63−65 °C; 1H NMR (400 MHz,
CDCl3) δ 8.06 (s, 2H, NH), 7.62 (d, J = 7.9 Hz, 2H, Ar-H), 7.38 (d, J = 8.1 Hz, 2H, Ar-H),
7.23 (t, J = 7.8 Hz, 2H, Ar-H), 7.13 (t, J = 7.8 Hz, 2H, Ar-H), 7.05 (t, J = 2.3 Hz, 2H,
Ar-H), 5.53 (t, J = 7.8 Hz, 1H, Ar-CH), 5.11 (d, J = 7.8 Hz, 2H, NO2-CH2).
Preparation of 2-(2,2-Di(1H-indol-3-yl)ethyl)isoindoline-1,3-dione (10). To the stirred
solution of indole (0.59 g, 5 mmol) and aldehyde 9 (0.48 g, 2.5 mmol) in acetonitrile (25
mL) was added I2 (0.13 g, 0.5 mmol) at 0 °C. The reaction mixture was stirred for 0.5 h,
quenched with 5％Na2S2O3 solution (20 mL) and extracted with ethyl acetate (50 mL ×
3). The organic phase was washed with brine (100 mL), dried over anhydrous MgSO4
and evaporated under reduced pressure. The residue was purified by flash column
chromatography on silica gel (3:1 PE/EA) to give compound 10: Pink solid, yield 96%;
mp 210−211 °C; 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 2H, NH), 7.75 (d, J = 8.0 Hz, 2H,
Ar-H), 7.72 (dd, J = 3.2, 5.5 Hz, 2H, Ar-H), 7.61 (dd, J = 3.0, 5.4 Hz, 2H, Ar-H), 7.29 (d,
J = 8.0 Hz, 2H, Ar-H), 7.13 (t, J = 7.2 Hz, 2H, Ar-H), 7.09 (d, J = 2.0 Hz, 2H, Ar-H),
7.03 (t, J = 7.5 Hz, 2H, Ar-H), 5.31 (t, J = 7.7 Hz, 1H, Ar2-CH), 4.37 (d, J = 7.8 Hz, 2H,
CH2). C26H20N3O2 [M+H]+ 406.1550, found (ESI+) 406.1556.
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Preparation of 2,2-Di(1H-indol-3-yl)ethan-1-amine (11). To the stirred solution of
compound 10 (1 g, 2.5 mmol) in toluene (50 mL) was added 80% NH2NH2·H2O (0.78 g,
12.5 mmol). The mixture was refluxed for 20 h, then cooled to room temperature and
evaporated under reduced pressure. The residue was taken into 2 mol/L NaOH solution
(100 mL), extracted with CH2Cl2 (100 mL × 2). The organic phase was dried over
anhydrous Na2SO4 and evaporated under reduced pressure to give compound 11: White
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solid, yield 91%; mp 164−165 °C; H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 2H, NH),
7.50 (d, J = 7.9 Hz, 2H, Ar-H), 7.30 (d, J = 8.1 Hz, 2H, Ar-H), 7.21 (s, 2H, Ar-H), 7.00 (t,
J = 7.6 Hz, 2H, Ar-H), 6.87 (t, J = 7.6 Hz, 2H, Ar-H), 4.38 (t, J = 7.1 Hz, 1H, Ar2-CH),
3.26 (d, J = 7.0 Hz, 2H, CH2), 1.33 (s, 2H, NH2). C18H18N3 [M+H]+ 276.1495, found
(ESI+) 276.1491.
General Procedures for the Preparation of Compounds 12a–12d. To a stirred
solution of 11 (1 g, 3.64 mmol) and Et3N (0.76 g, 7.5 mmol) in CH2Cl2 (80 mL) was
o
added corresponding acyl chlorides (4 mmol) at 0 C, then the reaction mixture was
naturally rose to room temperature and stirred for further 3 h, quenched with water (40
mL) and extracted with CH2Cl2 (30 mL × 2). The organic phase was washed with brine
(100 mL), dried over anhydrous MgSO4 and evaporated under reduced pressure. The
residue was purified by flash column chromatography on silica gel (1:1 PE/EA) to give
compounds 12a–12d.
N-(2,2-Di(1H-indol-3-yl)ethyl)benzamide (12a). Brown solid, yield 80%; mp 74−75 °C;
1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H, NH), 8.30 (d, J = 7.8 Hz, 1H, NH), 7.84 (d, J
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= 7.9 Hz, 1H, Ar-H), 7.78 (d, J = 8.0 Hz, 2H, Ar-H), 7.69–7.63 (m, 2H, Ar-H), 7.57–7.51
(m, 4H, Ar-H), 7.47 (s, 1H, Ar-H), 7.39 (t, J = 7.3 Hz, 2H, Ar-H), 7.27–7.24 (m, 3H,
Ar-H), 6.54 (t, J = 4.5 Hz, 1H, CH2-NH), 5.07 (t, J = 6.9 Hz, 1H, Ar2-CH), 4.45 (t, J =
6.3 Hz, 2H, CH2); 13C NMR (100 MHz, CDCl3) δ 167.8, 136.7, 133.7, 131.4, 130.2,
128.5, 126.9, 126.8, 122.3, 122.2, 119.6, 119.5, 116.7, 111.3, 44.2, 34.3. C25H22N3O
[M+H]+ 380.1757, found (ESI+) 380.1751.
N-(2,2-Di(1H-indol-3-yl)ethyl)-4-methylbenzenesulfonamide (12b). Brown solid,
yield 90%; mp 108−109 °C; 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 2H, NH), 7.61 (d, J =
8.3 Hz, 2H, Ar-H), 7.41–7.34 (m, 4H, Ar-H), 7.23–7.18 (m, 5H, Ar-H, CH2-NH),
7.05–7.01 (m, 2H, Ar-H), 6.92 (d, J = 2.1 Hz, 2H, Ar-H), 4.66 (t, J = 6.7 Hz, 1H,
Ar2-CH), 3.69 (d, J = 6.7 Hz, 2H, CH2), 2.43 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3)
δ 143.4, 136.53, 136.45, 129.7, 127.1, 126.4, 122.8, 122.2, 119.5, 119.2, 115.6, 111.4,
46.6, 34.2, 21.6. C25H24N3O2S [M+H]+ 430.1584, found (ESI+) 430.1588.
N-(2,2-Di(1H-indol-3-yl)ethyl)acetamide (12c). Brown solid, yield 82%; mp 69−70 °C;
1H NMR (400 MHz, CDCl3) δ 8.21–8.15 (m, 2H, NH), 7.58 (d, J = 8.0 Hz, 2H, Ar-H),
7.33 (d, J = 8.1 Hz, 2H, Ar-H), 7.16 (t, J = 7.1 Hz, 2H, Ar-H), 7.04–6.95 (m, 4H, Ar-H),
5.59 (s, 1H, CH2-NH), 4.71 (t, J = 6.8 Hz, 1H, Ar2-CH), 4.01 (t, J = 6.4 Hz, 2H, CH2),
1.85 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 170.3, 136.6, 126.9, 122.1, 119.5,
119.4, 116.9, 111.3, 45.4, 34.3, 23.4. C20H20N3O [M+H]+ 318.1601, found (ESI+)
318.1607.
N-(2,2-Di(1H-indol-3-yl)ethyl)pivalamide (12d). Brown solid, yield 87%; mp
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125−126 °C; 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 2H, NH), 7.52 (d, J = 7.9 Hz, 2H,
Ar-H), 7.25 (d, J = 8.1 Hz, 2H, Ar-H), 7.08 (t, J = 14.9 Hz, 2H, Ar-H), 6.95 (t, J = 14.8
Hz, 2H, Ar-H), 6.80 (s, 2H, Ar-H), 5.74 (t, J = 5.0 Hz, 1H, CH2-NH), 4.65 (t, J = 7.1 Hz,
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1H, Ar2-CH), 3.92 (t, J = 6.5 Hz, 2H, CH2), 0.97 (s, 9H, CH3); C NMR (100 MHz,
CDCl3) δ 178.8, 136.6, 126.9, 122.2, 122.0, 119.5, 119.3, 116.7, 111.4, 44.0, 34.1, 27.5.
C23H26N3O [M+H]+ 360.2070, found (ESI+) 360.2075.
General Procedures for the Preparation of Compounds 13a–13l. To a stirred solution
of 11 (1 g, 3.64 mmol) in CH2Cl2 (50 mL) was added corresponding isothiocyanates
o
(3.64 mmol) at 0 C, then the reaction mixture was naturally rose to room temperature
and stirred for further 3 h, quenched with water (40 mL) and extracted with CH2Cl2 (30
mL × 2). The organic phase was washed with brine (100 mL), dried over anhydrous
MgSO4 and evaporated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (1:2 PE/EA) to give compounds 13a–13l.
1-(2,2-Di(1H-indol-3-yl)ethyl)-3-phenylthiourea (13a). Brown solid, yield 70%; mp
214−215 °C; 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 2H, indole-NH), 7.64 (d, J = 8.0 Hz,
2H, Ar-H), 7.36 (t, J = 8.4 Hz, 4H, Ar-H), 7.29 (d, J = 7.0 Hz, 1H, Ar-H), 7.18–7.24 (m,
3H, Ar-H), 6.99–7.08 (m, 5H, Ar-H), 6.63 (d, J = 7.8 Hz, 1H, CH2-NH), 6.17 (s, 1H,
13
CH2NHCS-NH), 4.97 (t, J = 7.1 Hz, 1H, Ar2-CH), 4.43 (t, J = 5.4 Hz, 2H, CH2); C
NMR (100 MHz, DMSO-d6) δ 180.4, 139.6, 137.0, 130.4, 129.0, 127.2, 124.4, 123.2,
123.0, 121.4, 119.5, 118.7, 116.5, 111.9, 48.9, 33.5. C25H23N4S [M+H]+ 411.1638, found
(ESI+) 411.1633.
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1-(2,2-Di(1H-indol-3-yl)ethyl)-3-(p-tolyl)thiourea (13b). Yellow solid, yield 77%; mp
227−229 °C; 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 2H, indole-NH), 7.65 (d, J = 8.0 Hz,
2H, Ar-H), 7.38 (d, J = 8.1 Hz, 4H, Ar-H), 7.16 (d, J = 3.4 Hz, 2H, Ar-H), 6.99 (d, J = 2.2
Hz, 2H, Ar-H), 6.84 (d, J = 8.2 Hz, 2H, Ar-H), 6.54 (d, J = 8.1 Hz, 2H, Ar-H), 6.20–6.25
(m, 1H, CH2-NH), 6.12 (s, 1H, CH2NHCS-NH), 4.97 (t, J = 7.2 Hz, 1H, Ar2-CH),
13
4.41–4.44 (m, 2H, CH2), 2.37 (s, 3H, CH3); C NMR (100 MHz, DMSO-d6) δ 180.4,
137.0, 136.8, 133.7, 129.5, 127.2, 123.4, 123.1, 121.4, 119.5, 118.6, 116.6, 111.9, 48.9,
33.5, 20.9. C26H25N4S [M+H]+ 425.1794, found (ESI+) 425.1798.
1-(3-Chlorophenyl)-3-(2,2-di(1H-indol-3-yl)ethyl)thiourea (13c). Brown solid, yield
1
53%; mp 103−104 °C; H NMR (400 MHz, CDCl3) δ 8.05 (s, 2H, indole-NH), 7.91 (s,
1H, Ar-H), 7.64 (d, J = 8.0 Hz, 2H, Ar-H), 7.37 (d, J = 8.1 Hz, 2H, Ar-H), 7.21 (t, J = 7.4
Hz, 2H, Ar-H), 7.07 (t, J = 7.3 Hz, 3H, Ar-H), 6.98 (d, J = 2.1 Hz, 2H, Ar-H), 6.94 (t, J =
8.0 Hz, 1H, Ar-H), 6.79 (s, 1H, Ar-H), 6.53 (d, J = 7.5 Hz, 1H, CH2-NH), 6.20 (s, 1H,
13
CH2NHCS-NH), 4.96 (t, J = 7.0 Hz, 1H, Ar2-CH), 4.43 (s, 2H, CH2); C NMR (100
MHz, CDCl3) δ 179.9, 136.6, 130.7, 129.1, 128.3, 126.6, 124.4, 122.4, 122.33, 122.27,
119.65, 119.56, 116.3, 111.4, 49.5, 31.9. C25H22ClN4S [M+H]+ 445.1248, found (ESI+)
445.1257.
1-(2-Chlorophenyl)-3-(2,2-di(1H-indol-3-yl)ethyl)thiourea (13d). Brown solid, yield
25%; mp 62−63 °C; 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 2H, indole-NH), 7.62 (d, J =
8.0 Hz, 2H, Ar-H), 7.34 (d, J = 8.3 Hz, 2H, Ar-H), 7.28 (dd, J = 1.7, 7.9 Hz, 2H, Ar-H),
7.06–7.12 (m, 4H, Ar-H), 6.95 (d, J = 1.7 Hz, 2H, Ar-H), 6.71–6.80 (m, 4H, Ar-H,
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CH2-NH, CH2NHCS-NH), 4.56 (t, J = 7.1 Hz, 1H, Ar2-CH), 3.45 (d, J = 7.1 Hz, 2H,
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234
235
236
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CH2); C NMR (100 MHz, CDCl3) δ 180.1, 142.9, 136.60, 136.55, 129.4, 127.8, 127.7,
122.2, 122.1, 119.6, 119.5, 119.2, 119.0, 115.9, 111.3, 37.1, 32.0. C25H22ClN4S [M+H]+
445.1248, found (ESI+) 445.1253.
1-(2,2-Di(1H-indol-3-yl)ethyl)-3-(4-fluorophenyl)thiourea (13e). Brown solid, yield
58%; mp 228−229 °C; 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 2H, indole-NH), 7.62 (d, J
= 7.9 Hz, 2H, Ar-H), 7.37 (d, J = 8.2 Hz, 2H, Ar-H), 7.20 (t, J = 5.9 Hz, 2H, Ar-H), 7.06
(d, J = 7.7 Hz, 2H, Ar-H), 6.98 (s, 2H, Ar-H), 6.70 (t, J = 8.9 Hz, 2H, Ar-H), 6.58–6.61
(m, 2H, Ar-H), 6.28 (s, 1H, CH2NHCS-NH), 5.93 (s, 1H, CH2-NH), 4.95 (t, J = 7.5 Hz,
1H, Ar2-CH), 4.39–4.42 (m, 2H, CH2); 13C NMR (100 MHz, CDCl3) δ 180.5, 136.5,
127.3, 127.24, 127.16, 126.7, 124.5, 123.0, 122.4, 122.1, 119.7, 119.5, 116.5, 111.2, 37.1,
31.9. C25H22FN4S [M+H]+ 429.1544, found (ESI+) 429.1549.
1-(3,5-Bis(trifluoromethyl)phenyl)-3-(2,2-di(1H-indol-3-yl)ethyl)thiourea
(13f).
1
Brown solid, yield 90%; mp 128−129 °C; H NMR (400 MHz, CDCl3) δ 7.94 (s, 2H,
indole-NH), 7.54 (d, J = 8.0 Hz, 2H, Ar-H), 7.52 (s, 1H, Ar-H), 7.39 (s, 1H, Ar-H), 7.26
(t, J = 8.3 Hz, 2H, Ar-H), 7.12–7.18 (m, 4H, Ar-H), 6.99 (t, J = 7.3 Hz, 2H, Ar-H), 6.85
(s, 2H, Ar-H, CH2NHCS-NH), 6.18 (s, 1H, CH2-NH), 4.86 (s, 1H, Ar2-CH), 4.33 (s, 2H,
13
CH2); C NMR (100 MHz, CDCl3) δ 180.4, 136.5, 129.1, 128.3, 126.5, 124.2, 123.6,
122.5, 122.4, 121.4, 119.7, 119.3, 111.5, 49.4, 29.7. C27H21F6N4S [M+H]+ 547.1386,
found (ESI+) 547.1382.
1-(2,2-Di(1H-indol-3-yl)ethyl)-3-(4-methoxyphenyl)thiourea (13g). Brown solid, yield
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66%; mp 265−266 °C; 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 2H, indole-NH), 7.65 (d, J
= 8.0 Hz, 2H, Ar-H), 7.39 (d, J = 8.2 Hz, 2H, Ar-H), 7.20–7.23 (m, 3H, Ar-H), 7.06–7.10
(m, 2H, Ar-H), 7.01 (d, J = 2.1 Hz, 2H, Ar-H), 6.86 (t, J = 8.8 Hz, 1H, CH2-NH), 6.58
(dd, J = 8.9 Hz, 4H, Ar-H), 5.95 (s, 1H, CH2NHCS-NH), 4.97 (t, J = 7.3 Hz, 1H,
Ar2-CH), 4.42 (q, J = 5.8 Hz, 2H, CH2), 3.75 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6) δ 179.5, 136.4, 126.7, 125.2, 122.6, 120.9, 118.9, 118.1, 116.01, 115.97,
113.8, 111.4, 55.1. C26H25N4OS [M+H]+ 441.1744, found (ESI+) 441.1741.
1-(2,2-Di(1H-indol-3-yl)ethyl)-3-(3,4-dimethoxyphenyl)thiourea (13h). Brown solid,
yield 94%; mp 231−232 °C; 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 2H, indole-NH), 7.58
(d, J = 7.8 Hz, 2H, Ar-H), 7.43 (s, 1H, Ar-H), 7.34 (d, J = 8.1 Hz, 2H, Ar-H), 7.17 (t, J =
7.1 Hz, 2H, Ar-H), 7.03 (t, J = 7.4 Hz, 2H, Ar-H), 6.91 (d, J = 2.0 Hz, 2H, Ar-H),
6.75–6.82 (m, 1H, Ar-H), 6.48 (d, J = 8.2 Hz, 1H, Ar-H), 6.29 (s, 1H, CH2NHCS-NH),
6.03–6.05 (m, 1H, CH2-NH), 4.90 (t, J = 7.1 Hz, 1H, Ar2-CH), 4.39 (t, J = 6.5 Hz, 2H,
CH2), 3.87 (s, 3H, CH3), 3.81 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 180.6, 149.6,
148.2, 136.5, 126.7, 122.3, 122.1, 119.60, 119.56, 118.2, 116.6, 111.4, 111.1, 109.4, 56.0,
55.8, 49.3, 33.4. C27H27N4O2S [M+H]+ 471.1849, found (ESI+) 471.1853.
1-Benzhydryl-3-(2,2-di(1H-indol-3-yl)ethyl)thiourea (13i). Brown solid, yield 39%;
1
mp 89−90 °C; H NMR (400 MHz, CDCl3) δ 7.91 (s, 2H, indole-NH), 7.54 (d, J = 7.9
Hz, 2H, Ar-H), 7.30–7.39 (m, 7H, Ar-H), 7.10–7.20 (m, 4H, Ar-H), 7.04 (t, J = 7.6 Hz,
2H, Ar-H), 6.94–7.02 (m, 3H, Ar-H), 6.70 (s, 2H, Ar-H), 6.34 (s, 1H, CH2NHCS-NH),
5.98 (s, 1H, CH2-NH), 5.63 (s, 1H, Ph2-CH), 4.73 (t, J = 6.9 Hz, 1H, Ar2-CH), 4.28 (s,
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2H, CH2); C NMR (100 MHz, CDCl3) δ 183.1, 139.2, 136.5, 129.0, 128.94, 128.86,
128.3, 128.0, 127.1, 126.6, 122.2, 119.5, 111.3, 64.6, 33.6, 32.0. C32H29N4S [M+H]+
501.2107, found (ESI+) 501.2111.
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1-Benzyl-3-(2,2-di(1H-indol-3-yl)ethyl)thiourea (13j). Brown solid, yield 69%; mp
1
93−94 °C; H NMR (400 MHz, CDCl3) δ 8.00 (s, 2H, indole-NH), 7.56 (d, J = 7.8 Hz,
2H, Ar-H), 7.29–7.43 (m, 5H, Ar-H), 7.16–7.21 (m, 4H, Ar-H), 7.02–7.06 (m, 2H, Ar-H),
6.75 (d, J = 2.0 Hz, 2H, Ar-H), 6.02 (s, 1H, CH2NHCS-NH), 5.75 (s, 1H, CH2NH), 4.76
13
(t, J = 6.7 Hz, 1H, Ar2-CH), 4.73 (s, 2H, Ph-CH2), 4.13–4.18 (m, 2H, Ar2CH-CH2); C
NMR (100 MHz, CDCl3) δ 180.6, 135.5, 133.2, 127.9, 127.7, 127.6, 127.4, 126.7, 126.4,
125.8, 121.3, 121.2, 118.5, 110.3, 47.6, 32.7, 28.7. C26H25N4S [M+H]+ 425.1794, found
(ESI+) 425.1799.
1-Cyclohexyl-3-(2,2-di(1H-indol-3-yl)ethyl)thiourea (13k). Brown solid, yield 83%;
1
mp 86−87 °C; H NMR (400 MHz, CDCl3) δ 8.14 (s, 2H, indole-NH), 7.60 (d, J = 7.8
Hz, 2H, Ar-H), 7.36 (d, J = 8.1 Hz, 2H, Ar-H), 7.20 (t, J = 7.0 Hz, 4H, Ar-H), 7.08 (d, J =
7.7 Hz, 2H, Ar-H), 6.93 (s, 1H, CH2NHCS-NH), 5.72 (s, 1H, CH2-NH), 4.84 (s, 1H,
Ar2-CH), 4.14–4.23 (m, 2H, Ar2CH-CH2), 3.71 (t, J = 3.5 Hz, 1H, CSNH-CH), 1.40–1.92
13
(m, 10H, (CH2)5); C NMR (100 MHz, DMSO-d6) δ 181.8, 137.0, 127.3, 123.0, 121.3,
119.6, 118.6, 116.8, 111.8, 52.1, 48.7, 34.1, 32.8, 25.7, 24.9. C25H29N4S [M+H]+
417.2107, found (ESI+) 417.2101.
1-Butyl-3-(2,2-di(1H-indol-3-yl)ethyl)thiourea (13l). Brown solid, yield 72%; mp
1
85−86 °C; H NMR (400 MHz, CDCl3) δ 8.08 (s, 2H, indole-NH), 7.58 (d, J = 7.8 Hz,
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2H, Ar-H), 7.33 (d, J = 8.1 Hz, 2H, Ar-H), 7.17 (t, J = 7.4 Hz, 2H, Ar-H), 7.04 (d, J = 7.3
Hz, 2H, Ar-H), 6.89 (s, 2H, Ar-H), 5.70 (s, 1H, CH2NHCS-NH), 4.82 (s, 1H, CH2-NH),
4.19 (s, 1H, Ar2CH-CH2), 3.51 (t, J = 6.6 Hz, 1H, Ar2-CH), 3.00 (s, 2H, CSNH-CH2),
0.78–1.71 (m, 8H, Ar2CH-CH2, NHCH2-(CH2)2CH3); 13C NMR (100 MHz, CDCl3) δ
181.1, 136.5, 126.7, 122.4, 122.2, 119.5, 119.4, 116.3, 111.4, 33.7, 29.7, 22.7, 19.9, 14.2,
13.7. C23H27N4S [M+H]+ 391.1951, found (ESI+) 391.1956.
Preparation of 2,2-Di(1H-indol-3-yl)acetohydrazide (14). To the stirred solution of
compound 3a (1.59 g, 5 mmol) in ethanol (25 mL) was added 80% NH2NH2·H2O (25
mL). The mixture was refluxed for 3 h, then cooled to room temperature and evaporated
under reduced pressure to remove ethanol. The resulting precipitate was collected by
filtration in vacuo and was washed with H2O to provide compound 14: White solid, yield
83%; mp 234−235 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 2H, NH), 9.42 (s, 1H,
NH2-NH), 7.57 (d, J = 7.9 Hz, 2H, Ar-H), 7.34 (d, J = 8.1 Hz, 2H, Ar-H), 7.17 (d, J = 2.2
Hz, 2H, Ar-H), 7.07−7.03 (m, 2H, Ar-H), 6.96−6.92 (m, 2H, Ar-H), 5.26 (s, 1H, Ar2-CH),
13
4.26 (s, 2H, NH-NH2); C NMR (100 MHz, DMSO-d6) δ 172.3, 136.6, 127.1, 124.1,
121.3, 119.4, 118.6, 114.3, 111.8, 39.5.
General Procedures for the Preparation of Compounds 15a–15h. To a solution of 14
(1.52 g, 5 mmol) in ethanol (125 mL) was added corresponding aldehydes (5.5 mmol).
The mixture was reluxed for 7 h, then cooled to room temperature and evaporated under
reduced pressure to remove part of ethanol. The resulting precipitate was collected by
filtration in vacuo and was washed with H2O to provide compounds 15a–15h.
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N'-Benzylidene-2,2-di(1H-indol-3-yl)acetohydrazide (15a). Yellow solid, yield 87%;
1
317
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323
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329
330
331
332
333
334
335
336
mp 295−296 °C; E: Z = 5: 4, H NMR (DMSO-d6, 400 MHz): 11.86 (for E isomer, s,
0.53H, CO-NH), 11.40 (for Z isomer, s, 0.41H, CO-NH), 10.96 (s, 1.06H, NH), 10.92 (s,
0.84H, NH), 8.28 (for E isomer, s, 0.52H, CONHN-CH), 8.03 (for Z isomer, s, 0.41H,
CONHN-CH), 7.74 (d, J = 7.2 Hz, 0.90H, Ar-H), 7.63−7.69 (m, 3H, Ar-H), 7.36−7.45
(m, 5H, Ar-H), 7.26 (d, J = 1.8 Hz, 0.89H, Ar-H), 7.23 (d, J = 1.8 Hz, 1.11H, Ar-H),
7.05−7.10 (m, 2H, Ar-H), 6.94−7.00 (m, 2H, Ar-H), 6.57 (for Z isomer, s, 0.45H,
Ar2-CH), 5.46 (for E isomer, s, 0.55H, Ar2-CH); 13C NMR (100 MHz, DMSO-d6) δ 173.9,
168.8, 146.5, 142.5, 136.23, 136.17, 134.4, 134.3, 129.8, 129.6, 128.8, 128.6, 126.9,
126.7, 126.5, 124.0, 123.8, 120.9, 120.8, 118.85, 118.79, 118.3, 113.3, 113.2, 111.43,
111.40, 35.1. C25H21N4O [M+H]+ 393.1710, found (ESI+) 393.1706.
N'-(4-Fluorobenzylidene)-2,2-di(1H-indol-3-yl)acetohydrazide (15b). Brown solid,
1
yield 74%; mp 176−177 °C; E: Z = 3: 2, H NMR (400 MHz, DMSO-d6): 11.87 (for E
isomer, s, 0.61H, CO-NH), 11.38 (for Z isomer, s, 0.4H, CO-NH), 10.94 (s, 1H, NH),
10.91 (s, 1H, NH), 8.28 (s, 0.6H, CONHN-CH), 8.00 (s, 0.41H, CONHN-CH),
7.97−7.94 (m, 1H, Ar-H), 7.82−7.71 (m, 2H, Ar-H), 7.61 (s, 1H, Ar-H), 7.59 (s, 1H,
Ar-H), 7.38−7.20 (m, 5H, Ar-H), 7.08−6.92 (m, 4H, Ar-H), 6.52 (for Z isomer, s, 0.4H,
Ar2-CH), 5.43 (for E isomer, s, 0.59H, Ar2-CH); 13C NMR (100 MHz, DMSO-d6) δ 168.7,
160.3, 145.3, 141.3, 136.2, 136.1, 130.65, 130.56, 129.1, 129.0, 126.5, 124.0, 123.8,
120.9, 120.8, 118.82, 118.77, 118.3, 118.2, 115.84, 115.79, 113.2, 111.4, 35.1.
C25H20FN4O [M+H]+ 411.1616, found (ESI+) 411.1622.
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2,2-Di(1H-indol-3-yl)-N'-(4-(trifluoromethyl)benzylidene)acetohydrazide
(15c).
1
White solid, yield 59%; mp 269−270 °C; E: Z = 5: 4, H NMR (DMSO-d6, 400 MHz):
12.02 (for E isomer, s, 0.53H, CO-NH), 11.57 (for Z isomer, s, 0.42H, CO-NH), 10.96 (s,
1.07H, NH), 10.92 (s, 0.85H, NH), 8.35 (s, 0.53H, CONHN-CH), 8.08 (s, 0.42H,
CONHN-CH), 7.96 (d, J = 8.1 Hz, 0.87H, Ar-H), 7.90 (d, J = 8.2 Hz, 1.08H, Ar-H),
7.78−7.80 (m, 2H, Ar-H), 7.59−7.62 (m, 2H, Ar-H), 7.36 (t, J = 7.7 Hz, 2H, Ar-H), 7.26
(s, 0.85H, Ar-H), 7.22 (s, 1.06H, Ar-H), 7.04−7.09 (m, 2H, Ar-H), 6.93−6.99 (m, 2H,
Ar-H), 6.54 (s, 0.42H, Ar2-CH), 5.46 (s, 0.53H, Ar2-CH); 13C NMR (100 MHz, DMSO-d6)
δ 174.1, 169.0, 144.7, 140.7, 138.3, 136.22, 136.16, 127.5, 127.2, 126.6, 126.5, 125.6,
125.5, 124.0, 123.8, 120.9, 120.8, 118.8, 118.32, 118.27, 113.2, 113.0, 111.4, 35.2.
C26H20F3N4O [M+H]+ 461.1584, found (ESI+) 461.1588.
2,2-Di(1H-indol-3-yl)-N'-(3,4,5-trimethoxybenzylidene)acetohydrazide (15d). Pink
1
solid, yield 88%; mp 265−266 °C; E: Z = 1: 1, H NMR (DMSO-d6, 400 MHz): 11.81
(for E isomer, s, 0.52H, CO-NH), 11.42 (for Z isomer, s, 0.48H, CO-NH), 10.92 (d, J =
12.7 Hz, 2H, NH), 8.20 (s, 0.50H, CONHN-CH), 7.91 (s, 0.47H, CONHN-CH),
7.37−7.34 (m, 2H, Ar-H), 7.23−7.20 (m, 2H, Ar-H), 7.08−7.03 (m, 2H, Ar-H), 6.99−6.91
(m, 4H, Ar-H), 6.51 (for Z isomer, s, 0.48H, Ar2-CH), 5.42 (for E isomer, s, 0.51H,
13
Ar2-CH), 3.80 (s, 6H, OCH3), 3.68 (s, 3H, OCH3); C NMR (100 MHz, DMSO-d6) δ
174.0, 168.7, 153.1, 146.6, 142.0, 136.2, 136.1, 129.9, 129.8, 126.7, 126.5, 123.9, 123.8,
120.94, 120.86, 118.9, 118.6, 118.3, 113.5, 113.2, 111.4, 105.6, 104.3, 103.8, 60.1, 55.9,
35.2. C28H27N4O4 [M+H]+ 483.2027, found (ESI+) 483.2021.
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N'-(Furan-2-ylmethylene)-2,2-di(1H-indol-3-yl)acetohydrazide (15e). Yellow solid,
1
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
yield 49%; mp 285−286 °C; E: Z = 5: 3, H NMR (DMSO-d6, 400 MHz): 11.81 (for E
isomer, s, 0.57H, CO-NH), 11.37 (for Z isomer, s, 0.35H, CO-NH), 10.97 (d, J = 1.9 Hz,
1.24H, NH), 10.94 (d, J = 1.7 Hz, 0.68H, NH), 8.20 (s, 0.58H, CONHN-CH), 7.96 (s,
0.36H, CONHN-CH), 7.87 (d, J = 1.2 Hz, 0.34H, Ar-H), 7.81 (d, J = 1.2 Hz, 0.59H,
Ar-H), 7.61 (d, J = 7.9 Hz, 0.98H, Ar-H), 7.60 (d, J = 7.9 Hz, 0.93H, Ar-H), 7.34−7.44
(m, 3H, Ar-H), 7.26 (d, J = 2.1 Hz, 0.79H, Ar-H), 7.22 (d, J = 2.1 Hz, 1.22H, Ar-H),
7.05−7.11 (m, 2H, Ar-H), 6.96−7.01 (m, 2H, Ar-H), 6.92 (d, J = 3.3 Hz, 0.37H, Ar-H),
6.88(d, J = 3.3 Hz, 0.58H, Ar-H), 6.64 (q, J = 1.8 Hz, 0.36H, Ar-H), 6.61 (q, J = 1.8 Hz,
13
0.64H, Ar-H), 6.52 (s, 0.34H, Ar2-CH), 5.43 (s, 0.54H, Ar2-CH); C NMR (100 MHz,
DMSO-d6) δ 173.9, 168.8, 149.4, 149.3, 145.0, 144.8, 136.4, 136.2, 136.1, 132.7, 126.7,
126.5, 124.0, 123.8, 121.0, 120.9, 118.8, 118.4, 118.3, 113.3, 113.2, 113.1, 112.1, 111.5,
111.4, 34.8. C23H19N4O2 [M+H]+ 383.1503, found (ESI+) 383.1509.
2,2-Di(1H-indol-3-yl)-N'-(thiophen-2-ylmethylene)acetohydrazide (15f). Yellow solid,
1
yield 53%; mp 297−298 °C; E: Z = 1: 1, H NMR (DMSO-d6, 400 MHz): 11.80 (for E
isomer, s, 0.59H, CO-NH), 11.39 (for Z isomer, s, 0.41H, CO-NH), 10.96 (s, 2H, NH),
8.51 (s, 0.6H, CONHN-CH), 8.22 (s, 0.4H, CONHN-CH), 7.66−7.60 (m, 3H, Ar-H),
7.43−7.36 (m, 3H, Ar-H), 7.26−7.21 (m, 2H, Ar-H), 7.14−7.05 (m, 3H, Ar-H), 7.00−6.94
(m, 2H, Ar-H), 6.50 (for Z isomer, s, 0.41H, Ar2-CH), 5.41 (for E isomer, s, 0.59H,
13
Ar2-CH); C NMR (100 MHz, DMSO-d6) δ 173.7, 168.6, 141.7, 139.4, 139.1, 137.4,
136.2, 136.1, 130.4, 129.7, 128.5, 128.0, 127.8, 127.6, 126.7, 126.5, 124.0, 123.8, 120.9,
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397
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399
120.8, 118.8, 118.7, 118.3, 113.2, 113.1, 111.4, 34.6. C23H19N4OS [M+H]+ 399.1274,
found (ESI+) 399.1277.
2,2-Di(1H-indol-3-yl)-N'-octylideneacetohydrazide (15g). White solid, yield 41%; mp
187−188 °C; E: Z = 3: 2, 1H NMR (DMSO-d6, 400 MHz): 11.36 (for E isomer, s, 0.58H,
CO-NH), 10.88 (for Z isomer, s, 0.38H, CO-NH), 10.91 (d, J = 7.1 Hz, 2H, NH),
7.56−7.50 (m, 3H, Ar-H), 7.34 (d, J = 7.4 Hz, 2H, Ar-H), 7.16−7.15 (m, 2H, Ar-H),
7.07−7.02 (m, 2H, Ar-H), 6.96−6.90 (m, 2H, Ar-H), 6.40 (for Z isomer, s, 0.38H,
Ar2-CH), 5.29 (for E isomer, s, 0.59H, Ar2-CH), 2.27−2.15 (m, 2H, CONHNCH-CH2),
1.52−1.41 (m, 2H, CONHNCHCH2-CH2), 1.35−1.20 (m, 8H, CONHNCH(CH2)2-(CH2)4),
13
0.84 (d, J = 6.4 Hz, 3H, CH3); C NMR (100 MHz, DMSO-d6) δ 173.4, 168.2, 150.7,
146.5, 136.2, 136.1, 126.7, 126.5, 123.8, 123.7, 120.8, 120.7, 118.8, 118.7, 118.2, 118.1,
113.5, 113.4, 111.4, 111.3, 34.5, 31.9, 31.2, 31.1, 28.6, 28.5, 28.4, 26.0, 25.7, 22.0, 13.9.
C26H31N4O [M+H]+ 415.2492, found (ESI+) 415.2487.
N'-Butylidene-2,2-di(1H-indol-3-yl)acetohydrazide (15h). Yellow solid, yield 33%;
1
mp 198−199 °C; E: Z = 7: 4, H NMR (DMSO-d6, 400 MHz): 11.37 (for E isomer, s,
0.63H, CO-NH), 10.92 (for Z isomer, s, 0.39H, CO-NH), 10.90 (for E isomer, s, 1.21H,
NH), 10.87 (for Z isomer, s, 0.80H, NH), 7.50−7.56 (m, 2.79H, Ar-H), 7.32−7.35 (m,
2.51H, Ar-H), 7.15−7.17 (m, 2H, Ar-H), 7.02−7.07 (m, 2H, Ar-H), 6.90−6.96 (m, 2H,
Ar-H), 6.39 (for Z isomer, s, 0.38H, Ar2-CH), 5.29 (for E isomer, s, 0.65H, Ar2-CH),
2.14−2.24 (m, 2H, CONHNCH-CH2), 1.43−1.55 (m, 2H, CONHNCHCH2-CH2),
13
0.86−0.93 (m, 3H, CH3); C NMR (100 MHz, DMSO-d6) δ 173.4, 168.2, 150.6, 146.5,
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136.15, 136.09, 126.7, 126.5, 123.9, 123.7, 120.9, 120.8, 118.81, 118.76, 118.3, 118.2,
113.5, 113.4, 111.4, 111.3, 34.6, 33.8, 33.7, 19.3, 19.1, 13.6, 13.5. C22H23N4O [M+H]+
359.1866, found (ESI+) 359.1860.
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Biological Assay. Each test was repeated three times at 25±1 °C. Activity expressed in
percentage scale of 0−100 (0: no activity; 100: total inhibited).
The tests of anti-TMV activity and mode of action20 and fungicidal activity25 were
carried out using reported methods, which also can be seen in Supporting Information.
RESULTS AND DISCUSSION
Chemistry.
We first constructed the diindole framework by the reaction of indole with ethyl
glyoxylate under the catalysis of I2 (Figure 2). Compound 3a was reduced to alcohol 4 by
LiAlH4, and then the natural product streptindole (5) was obtained by the reaction of
alcohol 4 with acetyl chloride (Figure 3). In order to investigate the influence of the
electronic effects on the biological activity, compound 8 with hydroxyl group of 4
changed into nitro group and compound 11 with hydroxyl group of 4 changed into amino
group were designed and synthesized (Figures 4 and 5). Nitroalkene 7 was obtained by
the reaction of indole formaldehyde with nitromethane, and compound 8 was obtained by
the addition of indole with 7. As the nitro group had a great influence on the reaction, the
yield of 8 could not be improved. The plan of preparing compound 11 by reducing
compound 8 was cancelled. We switched to Gabriel method to realize the efficient
preparation of compound 11. In order to investigate the effect of electronic effect,
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aromaticity and steric hindrance of amino region on biological activity, we designed and
synthesized compounds 12a−12d (Figure 5). Thiourea is a kind of pharmacophore
containing hydrogen bond donor and acceptor. Lu research group has done a very good
job in this respect. Based on the function of hydrogen bond, they designed and
synthesized a series of thiourea derivatives, and found that these compounds have very
good antiviral activities.26,27 Inspired by the above work, we designed and synthesized
thiourea derivatives 13a−13l by addition of compound 11 with isothiocyanate (Figure 6).
Acylhydrazone is a kind of good pharmacophore. In the previous work, we found that the
introduction of acylhydrazone can improve the antiviral activity of compounds. Under
the guidance of previous work experience, we designed and synthesized a series of
acylhydrazone derivatives 15a−15h via the reaction of 14 with corresponding aldehydes
1
(Figure 7). The analysis of the H NMR spectra revealed that compounds 15a−15h exist
as Z/E isomers, and the proportion of isomers can be determined according to the
literature methods.28,29
Phytotoxic Activity.
The phytotoxic-activity tests (according to the criterion of safety evaluation of
pesticide to crops: NYT 1965.1-2010) revealed that compounds 3a−3c, 4, 5, 8, 10, 11,
12a−12d, 13a−13l, 14 and 15a−15h were safe for testing on plants at 500 μg/mL.21
Antiviral Activity in vivo. The activities of compounds 3a−3c, 4, 5, 8, 10, 11,
12a−12d, 13a−13l, 14 and 15a−15h against TMV are listed in Table 1 with commercial
viral inhibitor ribavirin as control. The inactive activity can best reflect the interaction
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between compounds and TMV. We first tested the inactive activities of all compounds,
and further tested the curative activities and protective activities of the compounds with
good inactive activities (inactive effect > 40%).
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As can be seen in table 1, most of the streptindole derivatives showed good anti-TMV
activities, compounds 4, 5, 11, 12c, 12d, 13d and 13i–13l displayed higher activities than
ribavirin at 500 μg/mL, especially for compound 12d. Compounds 3a−3c displayed
about similar antiviral activities, which indicated that the substitution effect on indole
ring is not obvious, and the compound 3a without substituents on indole ring has better
activity. The antiviral activity is obviously improved after reduction of ester group to
alcohol (inhibitory effect: 4 > 3a). Natural product streptindole (5) showed 44% inactive
effect, which is about similar to compound 4. The antiviral activity decreased
significantly when the electron deficient nitro group or o-phthalimide group replaced the
acetoxy group of streptindole (inhibitory effect: 5 > 8 > 10). Compound 11 showed slight
higher activity than 4, which revealed that it is feasible to replace hydroxyl with amino
group. The main differences of compounds 12a−12d are the substituents on the amino
group. The introduction of benzoyl group or p-phenylsulfonyl group on amino group is
not conducive to the antiviral activity (inhibitory effect: 11 > 12a > 12b). However, the
introduction of fatty acyl group is beneficial to the improvement of activity and the larger
steric hindrance is better (inhibitory effect: 12d > 12c > 11). The introduction of thiourea
functional groups did not significantly improve the activities of these compounds,
compounds 13d and 13j−13l displayed similar activities as compound 11, while the other
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compounds showed lower activities. Conversion of ester group to hydrazide is beneficial
to the improvement of antiviral activity (inhibitory effect: 14 > 3a). However, further
conversion of hydrazide to hydrazone did not improve the biological activity. Only
compound 15a containing benzene ring and compound 15d containing trimethoxy
substituted benzene ring maintain antiviral activity at the same level as compound 14.
The above structure-activity relationship revealed that the ethyl in the structure of
streptindole (5) is very important to maintain the biological activity. The conversion of
ester group of streptindole (5) to fatty amide is beneficial to the improvement of activity.
Compound 12d with excellent antiviral activity emerged as new antiviral candidate.
Preliminary Mode of Action.
Compound 12d with excellent antiviral activity was further evaluated the mode of action
using our reported method.20,21 As shown in Figure 8, 20S CP and TMV RNA can be
assembled into TMV particles with a total length of 300 nm, and DMSO had no effect on
the assembly. Compound 12d can inhibit the assembly of the virus. No full-length virus
particles can be found in Figure 8C, most of them become fusion aggregates. Further
interaction test on the 20S CP disk and 12d revealed that TMV CP can be incubated into
20S CP disk (Figure 9A), DMSO had no effect on the incubation of 20S CP disk (Figure
9B). Compound 12d has strong interaction with 20S CP disk, which leads to the fusion
of 20S CP disk into aggregate (Figure 9C). These results suggest that compound 12d
may act on the amino acid residues of TMV CP through hydrogen bonds, thus destroying
their three-dimensional structures.
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Molecular Docking. To further confirm the interaction between these compounds and
TMV CP (PDB code: 1EI7), we chose compounds 5 and 12d for molecular docking via
AutoDock-vina 1.1.2.30 Compound 5 forms two conventional hydrogen bonds with the
active site of ARG 261 at a distance of 2.4 Å and ASN 73 at a distance of 2.3 Å (Figure
10A). Compound 12d forms three conventional hydrogen bonds with amino acids SER
138 (2.5 Å), GLY 135 (2.5 Å) and TYR 139 (2.7 Å). The above results further confirmed
the mode of action of these compounds, and pointed out the direction for the later target
determination.
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Fungicidal Activity.
Plant fungal diseases are also persistent diseases that seriously affect plant growth.3 We
also evaluated the fungicidal activities of compounds 3a−3c, 4, 5, 8, 10, 11, 12a−12d,
13a−13l, 14 and 15a−15h against 14 kinds of phytopathogenic fungi at 50 μg/mL with
commercial fungicides carbendazim and chlorothalonil as controls.
As shown in Table 2, streptindole and its derivatives exhibited broad-spectrum fungicidal
activities. Compounds 4 and 5 displayed higher fungicidal activities against Alternaria
solani than carbendazim and chlorothalonil. The inhibitory effects of 3b, 8, 13a and 15a
are better than that of chlorothalonil and carbendazim against Phytophthora capsici. The
activities of compounds 3a, 3b, 4, 5, 12a and 13i are higher than that of chlorothalonil
and carbendazim against Botrytis cinereal. These compounds have different
structure-activity relationships on different plant fungi. Take Botrytis cinereal as an
example: Compounds 3a−3c, 4, 5 and 8 shown good fungicidal activities; The fungicidal
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activity decreased significantly when the o-phthalimide group or amino group replaced
the acetoxy group of streptindole; Among amide substituted derivatives, benzamide
compound 12a showed higher fungicidal activity than the others; For thiourea derivatives,
the diphenyl derivative 13i displayed higher fungicidal activity; The fungicidal activities
of hydrazone derivatives are not very prominent.
In summary, natural product streptindole and its derivatives were synthesized and
evaluated for their antiviral activities and fungicidal activities. Compounds 4, 5, 11, 12c,
12d, 13d and 13i–13l displayed higher antiviral activities than ribavirin. A systematic
study on the structure-activity relationship of these compounds was carried out.
Compound 12d with significantly higher antiviral activities than ribavirin emerged as
new antiviral candidate. The preliminary mode of action studies revealed that compound
12d has strong interaction with 20S CP disk, which leads to the fusion of 20S CP disk
into aggregate. The molecular docking results further confirmed the mode of action of
these compounds. Streptindole and its derivatives also exhibited broad-spectrum
fungicidal activities against 14 kinds of plant fungi at 50 μg/mL. Some compounds
displayed higher fungicidal activities than chlorothalonil and carbendazim. Current
research is expected to promote the application of these simple compounds in plant
protection.
ASSOCIATED CONTENT
Supporting Information
The detailed bio-assay procedures. The spectra data of compounds 3a−3c, 4, 5, 8, 10, 11,
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12a−12d, 13a−13l, 14 and 15a−15h. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
*(Z.W.)
E-mail:
hxxywzw@tjnu.edu.cn;
Phone:
0086-22-23766531;
Fax:
0086-22-23766531.
*(Q.W.) E-mail: wangqm@nankai.edu.cn. Phone: 0086-22-23503952. Fax:
0086-22-23503952.
Funding
This study was supported by Natural Science Fund of China (21772145, 21732002,
21772104) and Training Program of Outstanding Youth Innovation Team of Tianjin
Normal University.
Notes
The authors declare no competing financial interest.
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