Optimization, Structure-Activity Relationship, and Mode of Action of Nortopsentin Analogues Containing Thiazole and Oxazole Moieties

Article abstract of DOI:10.1021/acs.jafc.9b04093

Plant diseases seriously endanger plant health, and it is very difficult to control them. A series of nortopsentin analogues were designed, synthesized, and evaluated for their antiviral activities and fungicidal activities. Most of these compounds displayed higher antiviral activities than ribavirin. Compounds 1d, 1e, and 12a, with excellent antiviral activities, emerged as novel antiviral lead compounds, among which 1e was selected for further antiviral mechanism research. The mechanism research results indicated that these compounds may play an antiviral role by aggregating viral particles to prevent their movement in plants. Further fungicidal activity tests revealed that nortopsentin analogues displayed broad-spectrum fungicidal activities. Compounds 2p and 2f displayed higher antifungal activities against Alternaria solani than the commercial fungicides carbendazim and chlorothalonil. Current research has laid a foundation for the application of nortopsentin analogues in plant protection.

Full text of DOI:10.1021/acs.jafc.9b04093

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Agricultural and Environmental Chemistry
Optimization, Structure-Activity Relationship and Mode of Action of
Nortopsentin Analogues Containing Thiazole and Oxazole Moieties
Jincheng Guo, Yanan Hao, Xiaofei Ji, Ziwen Wang, Yuxiu Liu, Dejun
Ma, Yongqiang Li, Huailin Pang, Jueping Ni, and Qingmin Wang
J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.9b04093 • Publication Date (Web): 26 Aug 2019
Downloaded from pubs.acs.org on August 26, 2019
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Optimization, Structure-Activity Relationship and Mode of Action of
Nortopsentin Analogues Containing Thiazole and Oxazole Moieties
†
,‡
‡
‡
†,
‡,
‡
Jincheng Guo , Yanan Hao , Xiaofei Ji , Ziwen Wang *, Yuxiu Liu *, Dejun Ma ,
‡
§
§
‡,
Yongqiang Li , Huailin Pang , Jueping Ni , Qingmin Wang *
†Tianjin Key Laboratory of Structure and Performance for Functional Molecules, MOE Key
Laboratory of Inorganic–Organic Hybrid Functional Material Chemistry, 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;
§CAC Nantong Chemical Co. Ltd, Shanghai 226400, 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 Yuxiu Liu, E-mail: liuyuxiu@nankai.edu.cn;
Phone: 0086-22-23503792; Fax: 0086-22-23503792; For Qingmin Wang, E-mail:
wangqm@nankai.edu.cn; Phone: 0086-22-23503952; Fax: 0086-22-23503952.
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ABSTRACT: Plant diseases seriously endanger plant health, it is very difficult to control
them. A series of nortopsentin analogues were designed, synthesized and evaluated for
their antiviral activities and fungicidal activities. Most of these compounds displayed
higher antiviral activities than ribavirin. Compounds 1d, 1e and 12a with excellent
antiviral activities emerged as novel antiviral lead compounds, among which, 1e was
selected for further antiviral mechanism research. The mechanism research results
indicated that these compounds may play an antiviral role by aggregating viral particles
to prevent their movement in plants. Further fungicidal activity tests revealed that
nortopsentin analogues displayed broad-spectrum fungicidal activities. Compounds 2p
and 2f displayed higher antifungal activities against Alternaria solani than commercial
fungicides carbendazim and chlorothalonil. Current research has laid a foundation for the
application of nortopsentin analogues in plant protection.
1
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KEYWORDS: structure optimization, nortopsentin analogues, anti-TMV activity,
fungicidal activity, mode of action
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INTRODUCTION
As the population continues to grow, the food problem will once again become a
rigid demand.1-5 Among the many factors contributing to the food shortage, plant diseases
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which reduce crop yield cannot be ignored. Tobacco mosaic virus (TMV) is the earliest
and deepest studied model virus. It can infect more than 400 crops including tobacco,
7
cucumber, banana and so on. As the widely used antiviral agent, ribavirin (Figure 1)
displayed less than 50% anti-TMV effect at 500 μg/mL. Control of tobacco mosaic virus
disease is very challenging. So developing novel structure, remarkable effect and
environmentally friendly pesticides are needed urgently.8
Leading discovery and optimization based on natural products are crucial means in
development of novel pesticides due to their immense structural diversity and wide
variety of biological activities.9−11 The biologically oriented synthesis seeks to elaborate
structural modifications onto a bio-active natural-product scaffold to improve its
1
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physicochemical property or inherent biological activity. Till now, only a small amount
of natural products are used as antiviral agents.13,14 Very few antivirals have been studied
the mechanism of action. The creation of new antiviral agents based on mechanism of
action is difficult to carry out. Development of new antiviral agents limited by backward
mechanism research. The antiviral mechanisms in plants involve a series of plant
signaling pathways, viral replication, nucleoprotein assembly and RNA-induced gene
silencing. Gossypol compounds could neither inhibit the multiplication of TMV nor
1
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induce the systemic acquired resistance of tobacco plants. Antofine was found to be
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favorable interaction with origin of TMV RNA to exert its virus inhibition. Gramine
analogues likely exerted their virus inhibition by crosslinking TMV CP and interfered
with virus assembly.17
The bisindole alkaloids nortopsentins A−C (Figure 1) were isolated from the
deep-water marine sponge Spongosorites ruetzleri by Sun firstly and showed in vitro
1
8
cytotoxicity against P388 cells and antifungal activity against Candida albicans. Due to
the interesting biological activities and unique chemical structures of the marine bisindole
alkaloids, the marine disindole alkaloids as lead compounds for discovery of new drugs
have became an attractive field in medicinal chemistry. So a series of nortopsentin
analogues containing five-membered heterocycles, such as bis-indolyl-thiophenes,19
-oxazoles,20 –pyrazole,21 -furans,22 -isoxazoles,22 -pyrroles,23 -thiazoles,24,25 and
-1,2,4-thiadiazoles26 were reported. But the study of nortopsentin analogues mainly
focused on antitumor activity.18-26 In previous work, we have found that nortopsentin
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alkaloids exhibit good activity in plant-disease prevention. In addition, thiazole and
oxazole as two kinds of important five-membered heterocycles are widely present in
pesticide molecules.28,29 Considering the above findings, we designed and synthesized a
series of bis(indolyl)-thiazole, bis(indolyl)-oxazole and mono(indolyl)-thiazole
compounds to explore the structure-activity relationship (SAR) in this work (Figure 2).
Finally, we evaluated for their antiviral, anti-phytopathogenic-fungus activities and
studied antiviral mechanism preliminarily by transmission electron microscope (TEM).
MATERIALS AND METHODS
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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. The intermediates 8a and 9o−9q were purchased from J&K Scientific Ltd.
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 CDCl or DMSO-d as the solvent.
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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 (Tecnai G2 F20).
General Procedures for the Preparation of Compounds 4a–4c. To a solution of
indoles 3a−3c (15 mmol) in CH CN was added 60% NaH (21 mmol) at 0 °C. The
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mixture was stirred for 10 min, and TsCl (16.5 mmol) was added. Then, the mixture was
allowed to reach room temperature and was stirred for 4 h. The reaction was quenched
with a saturated aqueous solution of NH Cl. The resulting solution was extracted with
4
ethyl acetate (3 × 100 mL). The combined organic phases were washed with brine (100
mL), dried over anhydrous Na SO , filtered, and concentrated in vacuo to provide the
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corresponding compounds 4a−4c.
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N-Tosylindole (4a). Brown solid; yield 99%; mp 76−78 °C; H NMR (400 MHz, CDCl )
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δ 7.99 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 3.6 Hz, 1H), 7.52 (d, J =
7.6 Hz, 1H), 7.36−7.27 (m, 1H), 7.24−7.18 (m, 3H), 6.65 (d, J = 3.6 Hz, 1H), 2.33 (s,
3H).
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N-Tosyl-6-bromoindole (4b). Brown solid; yield 99%; mp 131−132 °C; H NMR (400
MHz, CDCl ) δ 8.17 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 3.6 Hz, 1H), 7.38 (d, J
3
= 8.4 Hz, 1H), 7.33 (dd, J = 8.4, 1.6 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 3.6 Hz,
1H), 2.36 (s, 3H).
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N-Tosyl-5-bromoindole (4c). Brown solid; yield 99%; mp 133−134 °C; H NMR (400
MHz, CDCl ) δ 7.86 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 1.6 Hz,
3
1H), 7.56 (d, J = 3.6 Hz, 1H), 7.39 (dd, J = 8.8, 2.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H),
2.35 (s, 3H).
General Procedures for the Preparation of Compounds 5a−5c. To a mixture of AlCl3
(300 mmol) in dichloromethane was added acetic anhydride (150 mmol) at 0 °C. Then
compounds 4a−4c (50 mmol) were added, and the solution was allowed to reach room
temperature and stirred for 2 h. The resulting mixture was poured into ice water and
extracted with dichloromethane (3 × 200 mL). The combined organic phase was washed
with brine (200 mL), dried over anhydrous Na SO , filtered, and concentrated in vacuo to
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provide the corresponding compounds 5a−5c.
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N-Tosyl-3-acetylindole (5a). Red-brown solid; yield 99%; mp 143−145 °C; H NMR
(400 MHz, CDCl ) δ 8.33 (dd, J = 6.8, 1.6 Hz, 1H), 8.21 (s, 1H), 7.93 (dd, J = 7.0, 1.6 Hz,
3
1H), 7.84 (d, J = 8.4 Hz, 2H), 7.41−7.31 (m, 2H), 7.29 (d, J = 8.4 Hz, 2H), 2.58 (s, 3H),
2.37 (s, 3H).
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N-Tosyl-3-acetyl-6-bromoindole (5b). Brown solid; yield 96%; mp 159−160 °C; H
NMR (400 MHz, CDCl ) δ 8.19 (d, J = 8.8 Hz, 1H), 8.16 (s, 1H), 8.10 (d, J = 1.6 Hz,
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1H), 7.83 (d, J = 8.4 Hz, 2H), 7.45 (dd, J = 8.4, 1.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H),
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2.56 (s, 3H), 2.40 (s, 3H).
N-Tosyl-3-acetyl-6-bromoindole (5c). Light-brown solid; yield 98%; mp 159−160 °C;
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H NMR (400 MHz, CDCl ) δ 8.52 (d, J = 2.0 Hz, 1H), 8.20 (s, 1H), 7.85 (s, 1H),
3
7.82–7.78 (m, 3H), 7.49 (dd, J = 8.8, 2.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 2.56 (s, 3H),
2.39 (s, 3H).
Preparation of 3-Acetyl-1H-5- methoxyindole (7). Phosphoryl chloride (78 mmol) was
added to ice cold dimethylacetamide under stirring and cooling in ice. After stirring 0.5 h,
a solution of 5-methoxy-1H-indole 3d (60 mmol) in dimethylacetamide was added and
the reaction mixture was stirred at 90 ℃ for 2 h, then poured over ice and basified with 4
N aqueous sodium hydroxide solution. Finally, the suspension was filtered to give 7.
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Orange solid; yield 51%; mp 208−209 °C; H NMR (400 MHz, DMSO-d ) δ 11.81 (s,
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1H), 8.24 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.2
Hz, 1H), 3.77 (s, 3H), 2.43 (s, 3H).
Preparation of N-Tosyl-3-acetyl-6-methoxyindole (5d). To a solution of 7 (5 mmol) in
dichloromethane
was
added 4-toluene
sulfonyl
chloride
(5.5
mmol),
4-dimethylaminopyridine (0.5 mmol) and triethylamine (7.5 mmol), then the mixture was
stirred at room temperature for 3 h. The resulting mixture was washed with water (2 × 50
mL) and brine (50 mL), dried over anhydrous Na SO , filtered, and concentrated in vacuo
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to provide compound 5d. Brown solid; yield 82%; mp 162−165 °C; H NMR (400 MHz,
CDCl ) δ 8.16 (s, 1H), 7.84–7.78 (m, 4H), 7.29 (d, J = 8.0Hz, 2H), 6.97 (dd, J = 9.2, 2.8
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Hz, 1H), 3.85 (s, 3H), 2.56 (s, 3H), 2.37 (s, 3H).
General Procedures for the Preparation of Compounds 6a–6d. To a solution of 5a–5d
(12.7 mmol) in mixed solvent (ethyl acetate: chloroform = 1:1) was added CuBr (28
2
mmol). The mixture was heated at reflux for 20 min and continued to react for 2 h after
adding ethanol. The resulting mixture was filtered, and filtrate was washed with water (3
× 200 mL) and brine (200 mL). The organic phase was dried over anhydrous Na SO ,
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filtered, and concentrated in vacuo. The residue was purified by flash chromatography on
a silica gel using petroleum ether and ethyl acetate (5:1, v/v) as the eluent to give 6a−6d.
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N-Tosyl-3-(α-bromoacetyl)-indole (6a). Yellow solid; yield 89%; mp 118−119 °C; H
NMR (400 MHz, CDCl ) δ 8.35 (s, 1H), 8.30 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 7.6 Hz,
3
1H), 7.85 (d, J = 8.0 Hz, 2H), 7.45−7.33 (m, 2H), 7.30 (d, J = 8.0 Hz, 2H), 4.36 (s, 2H),
2.38 (s, 3H).
N-Tosyl-3-(α-bromoacetyl)-6-bromoindole (6b). Brown solid; yield 81%; mp 162−163
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°C; H NMR (400 MHz, CDCl ) δ 8.30 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.11 (s, 1H),
3
7.84 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 4.33 (s, 2H),
2.40 (s, 3H).
N-Tosyl-3-(α-bromoacetyl)-5-bromoindole (6c). Brown solid; yield 88%; mp 163−164
1
°C; H NMR (400 MHz, CDCl ) δ 8.47 (d, J = 1.4 Hz, 1H), 8.32 (s, 1H), 7.86–7.77 (m,
3
3H), 7.49 (dd, J = 8.8, 1.6 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 4.32 (s, 2H), 2.39 (s, 3H).
N-Tosyl-3-(α-bromoacetyl)-5-methoxyindole (6d). Yellow solid; yield 62%; mp
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171−172 °C; H NMR (400 MHz, CDCl ) δ 8.28 (s, 1H), 7.84–7.80 (m, 3H), 7.77 (d, J =
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2.8 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 6.99 (dd, J = 9.2, 2.4 Hz, 1H), 4.35 (s, 2H), 3.85 (s,
3H), 2.38 (s, 3H).
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General Procedures for the Preparation of Compounds 8b−8d. To a solution of
indoles 3b−3d (10 mmol) in DMF was added chlorosulfonamide isocyanate (12 mmol) at
-50 °C in an argon atmosphere. The temperature was raised to -10 °C, and then the
solution was brought to room temperature after it was stirred for 1.5 h. The resulting
solution was poured into ice water, and kept for 30 min, and filtered to give 8b−8d.
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3-Cyano-6-bromoindole (8b). Yellow solid; yield 99%; mp 189−190 °C; H NMR (400
MHz, DMSO-d ) δ 12.33 (s, 1H), 8.29 (d, J = 2.8 Hz, 1H), 7.76 (d, J = 1.2 Hz, 1H), 7.61
6
(d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.4, 1.6 Hz, 1H).
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3-Cyano-5-bromoindole (8c). Yellow solid; yield 97%; mp 178−179 °C; H NMR (400
MHz, DMSO-d ) δ 12.41 (s, 1H), 8.32 (d, J = 2.8 Hz, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.53
6
(d, J = 8.8 Hz, 1H), 7.42 (dd, J = 8.4, 1.6 Hz, 1H).
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3-Cyano-5-methoxyindole (8d). Brown solid; yield 99%; mp 155−156 °C; H NMR
(400 MHz, DMSO-d ) δ 12.06 (s, 1H), 8.16 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.07 (s, 1H),
6
6.90 (d, J = 8.6 Hz, 1H), 3.81 (s, 3H).
Preparation of N-Tosyl-3-cyano-6-methoxyindole (10). To a solution of 8d (5 mmol)
in dichloromethane was added 4-toluene sulfonyl chloride (5.5 mmol),
4-dimethylaminopyridine (0.5 mmol) and triethylamine (7.5 mmol), then the mixture was
stirred at room temperature for 3 h. The resulting mixture was washed with water (2 × 50
mL) and brine (50 mL), dried over anhydrous Na SO , filtered, and concentrated in vacuo
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to provide compound 10. Yellow solid; yield 88%; mp 157−158 °C; H NMR (400 MHz,
CDCl ) δ 8.04 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.0
3
Hz, 2H), 7.08 (d, J = 2.4 Hz, 1H), 7.05 (s, 1H, Ar-H), 3.84 (s, 3H), 2.39 (s, 3H).
General Procedures for the Preparation of Compounds 9a−9c, 11 and 9i−9m. To a
slurry of 70% sodium hydrosulfide hydrate (24 mmol) and magnesium chloride
hexahydrate (8 mmol) in 10 mL of DMF was added corresponding materials (8 mmol) in
one portion, and the mixture was stirred at 40 °C overnight. The resulting green slurry
was poured into 200 mL of water, and the resulting precipitates were collected by
filtration. The crude product was resuspended in 1 N HCl and stirred for 20 min, then
filtered and washed with water to give 9a−9c, 11 and 9i−9m.
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1H-Indole-3-carbothioamide (9a). Yellow solid; yield 89%; mp 141−142 °C; H NMR
(400 MHz, DMSO-d ) δ 11.78 (s, 1H), 8.96 (s, 1H), 8.82 (s, 1H), 8.71–8.54 (m, 1H), 8.09
6
(d, J = 2.8 Hz, 1H), 7.49–7.40 (m, 1H), 7.21–7.09 (m, 2H). 13C NMR (100 MHz,
DMSO-d ) δ 193.6, 136.8, 128.0, 1259, 122.0, 121.8, 120.7, 116.3, 111.9.
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1H-6-Bromoindole-3-carbothioamide (9b). Yellow solid; yield 87%; mp 195−196 °C;
1
H NMR (400 MHz, DMSO-d ) δ 11.87 (s, 1H), 9.05 (s, 1H), 8.92 (s, 1H), 8.60 (d, J =
6
8.8 Hz, 1H), 8.10 (d, J = 3.2 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.28 (dd, J = 8.8, 2.0 Hz,
1H).
1H-5-Bromoindole-3-carbothioamide (9c). Yellow solid; yield 85%; mp 141−142 °C;
1
H NMR (400 MHz, DMSO-d ) δ 11.98 (s, 1H), 9.04 (s, 1H), 8.94 (s, 1H), 8.90 (s, 1H),
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8.15 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H).
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N-Tosyl-5-methoxyindole-3-carbothioamide (11). Yellow oil; yield 85%; H NMR
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93
94
95
96
97
98
99
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01
02
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(400 MHz, DMSO-d ) δ 9.62 (s, 1H), 9.41 (s, 1H), 8.36 (s, 1H), 8.09 (d, J = 2.6 Hz, 1H),
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7.92 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 9.2 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 6.99 (dd, J =
1
3
8.8, 2.6 Hz, 1H), 3.75 (s, 3H), 2.33 (s, 3H). C NMR (100 MHz, DMSO-d ) δ 192.2,
6
156.2, 146.1, 133.5, 130.4, 129.4, 128.8, 127.0, 126.9, 121.4, 114.1, 113.8, 105.3, 55.3,
21.0.
1
Benzothioamide (9i). Yellow solid; yield 85%; mp 113–115 °C; H NMR (400 MHz,
DMSO-d ) δ 9.89 (s, 1H), 9.51 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.50 (t, J = 7.3 Hz, 1H),
6
7.41 (t, J = 7.6 Hz, 2H).
1
4-Fluorobenzothioamide (9j). Yellow solid; yield 76%; mp 143−144 °C; H NMR (400
MHz, DMSO-d ) δ 9.90 (s, 1H), 9.52 (s, 1H), 7.99–7.95 (m, 2H), 7.27–7.23 (m, 2H).
6
1
2-(Trifluoromethyl)benzothioamide (9k). Yellow solid; yield 94%; mp 76−77 °C; H
NMR (400 MHz, DMSO-d ) δ 10.18 (s, 1H), 9.72 (s, 1H), 7.72–7.63 (m, 2H), 7.54 (t, J =
6
7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H).
1
3, 4-Dichlorobenzothioamide (9l). Yellow solid; yield 89%; mp 133−134 °C; H NMR
(400 MHz, DMSO-d ) δ 10.11 (s, 1H), 9.68 (s, 1H), 8.09 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H),
6
7.71 (d, J = 8.4 Hz, 1H).
1
4-Penoxybenzothioamide (9m). Yellow solid; yield 89%; mp 158−159 °C; H NMR
(400 MHz, DMSO-d ) δ 9.78 (s, 1H), 9.43 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.44 (t, J =
6
7.8 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 7.09 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H).
Preparation of Heptanethioamide (9n). To a solution of heptanenitrile (3 mmol) in
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anhydrous ethanol was added P S (3.15 mmol) and stirred at room temperature overnight.
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The resulting mixture was quenched with water and extracted with chloroform. The
organic fractions were evaporated under reduce pressure and then, the evaporated fraction
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was recrystallized in hexane to give 9n. White solid; yield 35%; mp 57−58 °C; H NMR
(400 MHz, CDCl ) δ 7.54 (s, 1H), 6.84 (s, 1H), 2.67 (t, J = 7.8 Hz, 2H), 1.81–1.73(m,
3
2H), 1.41–1.25 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H).
General Procedures for the Preparation of Compounds 2a−2q. To a solution of
6a−6d (2 mmol) in anhydrous ethanol was added 9a−9c, 11 and 9i−9q (2 mmol). The
mixture was stirred at reflux for 0.5 h, then filtered to give 2a−2q.
2-(1H-Indol-3-yl)-4-(1-tosyl-1H-indol-3-yl)thiazole (2a). Yellow solid; yield 97%; mp
1
246−248 °C; H NMR (400 MHz, DMSO-d ) δ 11.87 (s, 1H), 8.38 (s, 1H), 8.36 (d, J =
6
7.2 Hz, 1H), 8.31–8.26 (m, 1H), 8.23 (d, J = 2.8 Hz, 1H), 8.05 (s, 1H), 8.03 (d, J = 7.2 Hz,
1H), 7.95 (d, J = 8.4 Hz, 2H), 7.54 (dd, J = 5.2, 3.6 Hz, 1H), 7.45 (m, 2H), 7.40 (d, J =
1
3
8.0 Hz, 2H), 7.30–7.24 (m, 2H), 2.30 (s, 3H). C NMR (100 MHz, DMSO-d ) δ 163.3,
6
147.5, 146.2, 137.1, 135.2, 134.4, 130.8, 128.5, 127.5, 127.3, 125.7, 124.9, 124.7, 124.5,
+
122.9, 122., 121.4, 120.5, 118.3, 113.9, 112.8, 111.9, 110.7, 21.5. C H N O S [M+H]
2
6
20
3
2 2
+
470.0991, found (ESI ) 470.1000.
2-(6-Bromo-1H-indol-3-yl)-4-(1-tosyl-1H-indol-3-yl)thiazole (2b). Orange solid; yield
1
96%; mp 192−194 °C; H NMR (400 MHz, DMSO-d ) δ 11.97 (s, 1H), 8.37 (s, 1H), 8.33
6
(d, J = 7.6 Hz, 1H), 8.26 (s, 1H), 8.24 (d, J = 8.0 Hz, 2H), 8.06 (s, 1H), 8.03 (d, J = 8.0
Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.48–7.37 (m, 5H), 7.39 (d, J = 8.0 Hz,
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2H), 2.31 (s, 3H). C NMR (100 MHz, DMSO-d ) δ 162.7, 147.7, 146.2, 138.0, 135.2,
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134.3, 130.8, 128.4, 127.3, 125.7, 125.0, 124.5, 124.3, 123.8, 122.4, 122.2, 118.3, 115.6,
+
+
115.4, 113.9, 112.3, 111.0, 21.5. C H BrN O S [M+H] 548.0097, found (ESI )
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6
19
3
2 2
548.0086.
4-(6-Bromo-1-tosyl-1H-indol-3-yl)-2-(1H-indol-3-yl)thiazole (2c). Orange solid; yield
1
84%; mp 236−237 °C; H NMR (400 MHz, DMSO-d ) δ 11.87 (s, 1H), 8.44 (s, 1H), 8.36
6
(d, J = 8.4 Hz, 1H), 8.28–8.23 (m, 1H), 8.23 (d, J = 2.8 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H),
8.06 (s, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.61 (dd, J = 8.4, 1.6 Hz, 1H), 7.56–7.52 (m, 1H),
7.44 (d, J = 8.4 Hz, 2H), 7.31–7.22 (m, 2H), 2.33 (s, 3H). 13C NMR (100 MHz,
DMSO-d ) δ 163.4, 147.1, 146.5, 137.1, 135.8, 134.1, 131.0, 127.7, 127.6, 127.4, 125.5,
6
124.7, 124.3, 122.9, 121.4, 120.5, 118.5, 118.1, 116.2, 112.8, 112.3, 110.7, 21.5.
+
+
C H BrN O S [M+H] 548.0097, found (ESI ) 548.0093.
2
6
19
3
2 2
4-(6-Bromo-1-tosyl-1H-indol-3-yl)-2-(6-bromo-1H-indol-3-yl)thiazole (2d). Yellow
1
solid; yield 85%; mp 223−224 °C; H NMR (400 MHz, DMSO-d ) δ 11.96 (s, 1H), 8.43
6
(s, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 2.8 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.15
(d, J = 1.6 Hz, 1H), 8.07 (s, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 1.6 Hz, 1H), 7.61
(dd, J = 8.4, 1.6 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.41 (dd, J = 8.4, 1.6 Hz, 1H), 2.33 (s,
1
3
3H). C NMR (100 MHz, DMSO-d ) δ 162.9, 147.3, 146.6, 137.9, 135.8, 134.1, 131.0,
6
128.4, 127.6, 127.4, 125.5, 124.4, 124.2, 123.7, 122.4, 118.5, 118.1, 116.2, 115.6, 115.3,
+
+
112.6, 110.9, 21.5. C H Br N O S [M+H] 625.9202, found (ESI ) 625.9178.
2
6
18
2
3
2 2
4-(5-Bromo-1-tosyl-1H-indol-3-yl)-2-(5-bromo-1H-indol-3-yl)thiazole (2e). Orange
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solid; yield 78%; mp 225−226 °C; H NMR (400 MHz, DMSO-d ) δ 12.06 (s, 1H), 8.62
6
(d, J = 1.8 Hz, 1H), 8.50 (s, 1H), 8.49 (d, J = 1.2 Hz, 1H), 8.28 (d, J = 2.8 Hz, 1H), 8.13
(s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.61 (dd, J = 8.8, 2.0 Hz, 1H),
7.52 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.38 (dd, J = 8.6, 2.0 Hz, 1H), 2.32 (s,
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3
3H). C NMR (100 MHz, DMSO-d ) δ 162.6, 146.9, 146.0, 135.3, 133.5, 133.4, 130.4,
6
129.9, 128.5, 127.9, 126.8, 125.9, 125.6, 125.1, 124.4, 122.5, 117.0, 116.8, 115.3, 114.3,
+
+
113.6, 112.0, 109.8, 21.0. C H Br N O S [M+H] 625.9202, found (ESI ) 625.9194.
2
6
18
2
3
2 2
4-(5-Bromo-1-tosyl-1H-indol-3-yl)-2-(6-bromo-1H-indol-3-yl)thiazole (2f). Orange
1
solid; yield 91%; mp 235−236 °C; H NMR (400 MHz, DMSO-d ) δ 11.94 (s, 1H), 8.61
6
(d, J = 2.0 Hz, 1H), 8.47 (s, 1H), 8.26 (d, J = 8.8Hz, 1H), 8.23 (d, J = 2.8Hz, 1H), 8.11 (s,
1H), 7.99 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 1.6 Hz, 1H), 7.60 (dd,
J = 8.8, 1.6 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.37 (dd, J = 8.5, 1.4 Hz, 1H), 2.32 (s, 3H).
1
3
C NMR (100 MHz, DMSO-d ) δ 162.9, 147.2, 146.4, 138.0, 134.1, 133.9, 130.9, 128.5,
6
128.3, 127.3, 126.1, 124.1, 123.8, 117.5, 117.3, 115.8, 115.6, 115.4, 112.6, 110.9, 21.5.
+
+
C H Br N O S [M+H] 625.9202, found (ESI ) 625.9200.
2
6
18
2
3
2 2
2,4-Bis(5-methoxy-1-tosyl-1H-indol-3-yl)thiazole (2g). Red solid; yield 79%; mp
1
236−238 °C; H NMR (400 MHz, DMSO-d ) δ 8.57 (s, 1H), 8.39 (s, 1H), 8.26 (s, 1H),
6
8.01−7.88 (m, 7H), 7.80 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz,
2H), 7.11 (dd, J = 9.2, 2.8 Hz, 1H), 7.07 (dd, J = 9.2, 2.8 Hz, 1H), 3.84 (s, 3H), 3.82 (s,
1
3
3H), 2.32 (s, 3H), 2.30 (s, 3H). C NMR (100 MHz, DMSO-d ) δ 160.2, 157.3, 157.0,
6
148.4, 146.4, 146.1, 134.3, 134.2, 130.84, 130.76, 129.8, 129.5, 129.4, 128.6, 127.6,
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127.5, 127.2, 126.0, 117.9, 116.9, 114.8, 114.4, 114.1, 110.0, 105.2, 105.0, 56.0, 55.8,
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21.5, 21.4. C H N O S [M+H] 684.1291, found (ESI ) 684.1293.
35 30 3 6 3
2-(6-Bromo-1H-indol-3-yl)-4-(5-methoxy-1-tosyl-1H-indol-3-yl)thiazole (2h). Orange
1
solid; yield 80%; mp 201−202 °C; H NMR (400 MHz, DMSO-d ) δ 11.98 (s, 1H), 8.36
6
(s, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 2.8 Hz, 1H), 8.08 (s, 1H), 7.93−7.89 (m,
3H), 7.87 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 1.2 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.36 (dd,
1
3
J = 8.4, 1.6 Hz, 1H), 7.05 (dd, J = 9.0, 2.8 Hz, 1H), 3.87 (s, 3H), 2.30 (s, 3H). C NMR
(100 MHz, DMSO-d ) δ 162.3, 156.4, 147.4, 145.5, 137.4, 133.8, 130.2, 129.2, 129.1,
6
127.9, 126.7, 125.0, 123.6, 123.3, 122.0, 117.8, 115.1, 114.9, 114.4, 114.3, 111.6, 110.5,
+
+
103.8, 55.4, 21.0. C H BrN O S [M+H] 578.0202, found (ESI ) 578.0202.
2
7
21
3
3 2
4-(6-Bromo-1-tosyl-1H-indol-3-yl)-2-phenylthiazole (2i). White solid; yield 75%; mp
1
173−175 °C; H NMR (400 MHz, DMSO-d ) δ 8.50 (s, 1H), 8.33 (d, J = 8.8 Hz, 1H),
6
8.29 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 8.07 (dd, J = 7.8, 1.8 Hz, 2H), 7.98 (d, J = 8.4 Hz,
1
3
2H), 7.61–7.53 (m, 4H), 7.44 (d, J = 8.2 Hz, 2H), 2.33 (s, 3H). C NMR (100 MHz,
DMSO-d ) δ 167.5, 148.6, 146.5, 135.7, 134.2, 133.2, 130.98, 130.95, 129.8, 127.6,
6
127.4, 127.3, 126.7, 125.8, 124.3, 118.5, 117.7, 116.2, 116.1, 21.5. C H BrN O S
2 2
2
4
18
2
+
+
[M+H] 508.9988, found (ESI ) 508.9984.
4-(6-Bromo-1-tosyl-1H-indol-3-yl)-2-(4-fluorophenyl)thiazole (2j). White solid; yield
1
82%; mp 229−230 °C; H NMR (400 MHz, DMSO-d ) δ 8.49 (s, 1H), 8.32 (d, J = 8.4 Hz,
6
1H), 8.29 (s, 1H), 8.14–8.11 (m, 3H), 7.98 (d, J = 8.4 Hz, 2H), 7.58 (dd, J = 8.4, 1.6 Hz,
1
3
1H), 7.47–7.37 (m, 4H), 2.33 (s, 3H). C NMR (100 MHz, DMSO-d ) δ 166.3, 163.8 (d,
6
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95
96
97
98
99
00
01
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J = 248.0 Hz), 148.6, 146.6, 135.7, 134.1, 131.0, 129.9, 129.1 (d, J = 7.8 Hz), 127.7,
127.6, 127.4, 125.9, 124.3, 118.6, 117.6, 116.8 (d, J = 22.0 Hz), 116.2, 110.0, 21.5.
+
+
C H BrFN O S [M+H] 526.9893, found (ESI ) 526.9888.
2
4
17
2
2 2
4-(6-Bromo-1-tosyl-1H-indol-3-yl)-2-(2-(trifluoromethyl)phenyl)thiazole (2k). White
1
solid; yield 64%; mp 152−153 °C; H NMR (400 MHz, DMSO-d ) δ 8.48 (d, J = 7.4 Hz,
6
2H), 8.25 (d, J = 8.6 Hz, 1H), 8.12 (s, 1H), 8.00–7.94 (m, 3H), 7.86 (d, J = 4.0 Hz, 2H),
7.81–7.78(m, 1H), 7.53 (dd, J = 8.4, 1.6 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 2.33 (s, 3H).
1
3
C NMR (100 MHz, DMSO-d ) δ 164.2, 148.3, 146.6, 135.7, 134.1, 133.3, 132.9, 132.2
6
(q, J = 2.0 Hz), 131.0, 128.3, 127.5 (q, J = 30.0 Hz),127.4, 127.3, 125.8, 124.2, 124.1(q, J
+
= 272.0 Hz), 118.5, 118.2, 117.5, 116.2, 21.5. C H BrF N O S [M+H] 576.9861,
2
5
17
3
2
2 2
+
found (ESI ) 576.9860.
4-(6-Bromo-1-tosyl-1H-indol-3-yl)-2-(3,4-dichlorophenyl)thiazole 2l. White solid;
1
yield 97%; mp 211−212 °C; H NMR (400 MHz, DMSO-d ) δ 8.51 (s, 1H), 8.35 (s, 1H),
6
8.28–8.26 (m, 2H), 8.13 (d, J = 1.6 Hz, 1H), 8.04–8.01 (m, 1H), 7.98 (d, J = 8.4 Hz, 2H),
7.80 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 2.33 (s, 3H).
1
3
C NMR (100 MHz, DMSO-d ) δ 164.1, 148.4, 146.1, 135.2), 133.7, 133.1, 132.8, 132.1,
6
131.4, 130.5, 127.5, 127.1, 126.9, 126.8, 126.3, 125.6, 123.6, 118.0, 116.9, 116.8, 115.7,
+
+
99.5, 21.0. C H BrCl N O S [M+H] 576.9208, found (ESI ) 576.9203.
2
4
16
2
2
2 2
4-(6-Bromo-1-tosyl-1H-indol-3-yl)-2-(4-phenoxyphenyl)thiazole (2m). White solid;
1
yield 68%; mp 189−190 °C; H NMR (400 MHz, DMSO-d ) δ 8.47 (s, 1H), 8.31 (d, J =
6
8.6 Hz, 1H), 8.24 (s, 1H), 8.13 (d, J = 1.4 Hz, 1H), 8.07 (d, J = 8.8 Hz, 2H), 7.97 (d, J =
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8.4 Hz, 2H), 7.57 (dd, J = 8.4, 1.6 Hz, 1H), 7.49–7.42 (m, 4H), 7.23 (t, J = 7.4 Hz, 1H),
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7.15−7.12 (m, 4H), 2.33 (s, 3H). C NMR (100 MHz, DMSO-d ) δ 166.4, 158. 8, 155.7,
6
148.0, 146.1, 135.2, 133.7, 130.5, 130.2, 128.2, 127.9, 127.1, 127.0, 126.8, 125.3, 124.2,
+
123.8, 119.4, 118.6, 118.0, 117.2, 115.7, 115.2, 21.0. C H BrN O S [M+H] 601.0250,
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0
22
2
3 2
+
found (ESI ) 601.0247.
4-(6-Bromo-1-tosyl-1H-indol-3-yl)-2-(4-hexylphenyl)thiazole (2n). White solid; yield
1
84%; mp 163−165 °C; H NMR (400 MHz, DMSO-d ) δ 8.35 (s, 1H), 8.21 (d, J = 8.6 Hz,
6
1H), 8.14 (d, J = 1.6 Hz, 1H), 8.08 (s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.54 (dd, J = 8.5, 1.7
Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 3.04 (t, J = 7.6 Hz, 2H), 2.31 (s, 3H), 1.73–1.75 (m,
1
3
2H), 1.35–1.27 (m, 6H), 0.85 (t, J = 7.0 Hz, 3H). C NMR (100 MHz, DMSO-d ) δ
6
171.3, 146.7, 146.5, 135.7, 134.1, 130.9, 127.4, 127.3, 125.3, 124.1, 118.4, 117.8, 116.2,
+
115.0, 33.0, 31.3, 29.8, 28.5, 22.4, 21.5, 14.3. C H BrN O S [M+H] 517.0614, found
2
4
26
2
2 2
+
(ESI ) 517.0620.
4-(6-Bromo-1-tosyl-1H-indol-3-yl)-2-(p-tolyl)thiazole (2o). White solid; yield 94%; mp
1
175−176 °C; H NMR (400 MHz, DMSO-d ) δ 8.31 (s, 1H), 8.19 (d, J = 8.6 Hz, 1H),
6
8.11 (d, J = 1.6 Hz, 1H), 8.04 (s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.54 (dd, J = 8.6, 1.8 Hz,
1
3
1H), 7.43 (d, J = 8.0 Hz, 2H), 2.74 (s, 3H), 2.33 (s, 3H). C NMR (100 MHz, DMSO-d )
6
δ 166.0, 146.0, 135.2, 133.6, 130.5, 126.9, 126.8, 125.0, 123.6, 118.0, 117.1, 115.7, 115.0,
+
+
21.0, 18.72. C H BrN O S [M+H] 446.9831, found (ESI ) 446.9824.
1
9
16
2
2 2
4-(6-Bromo-1-tosyl-1H-indol-3-yl)-2-(4-(tert-butyl)phenyl)thiazole (2p). White solid;
1
yield 75%; mp 114−115 °C; H NMR (400 MHz, DMSO-d ) δ 8.36 (s, 1H), 8.24 (d, J =
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8.8 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 8.06 (s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.55 (dd, J =
1
3
8.6, 2.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 2.31 (s, 3H), 1.45 (s, 9H). C NMR (100 MHz,
DMSO-d ) δ 180.8, 146.8, 146.4, 135.7, 134.1, 131.0, 127.7, 127.5, 127.3, 125.2, 124.3,
6
+
118.4, 118.1, 116.2, 114.6, 37.8, 31.0, 26.8, 21.5. C H BrN O S [M+H] 489.0301,
2
2
22
2
2 2
+
found (ESI ) 489.0299.
Ethyl 2-(4-(4-(6-bromo-1-tosyl-1H-indol-3-yl)thiazol-2-yl)phenyl)acetate (2q). White
1
solid; yield 68%; mp 138−139 °C; H NMR (400 MHz, DMSO-d ) δ 8.34 (s, 1H), 8.18 (d,
6
J = 8.8 Hz, 1H), 8.17(s, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.54 (dd,
J = 8.6, 1.8 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 4.27 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 2.33
1
3
(s, 3H), 1.23 (t, J = 7.2 Hz, 3H). C NMR (100 MHz, DMSO-d ) δ 168.9, 162.1, 146.4,
6
146.0, 135.2, 133.6, 130.5, 126.93, 126.90, 126.8, 124.9, 123.6, 118.0, 117.2, 116.3,
+
+
115.7, 61.0, 38.1, 21.0, 14.0. C H BrN O S [M+H] 519.0042, found (ESI ) 519.0046.
2
2
20
2
4 2
General Procedures for the Preparation of Compounds 1a−1p. To a solution of
compounds 2a−2p (1 mmol) in MeOH (40 mL) was added 2 N NaOH (10 mL). The
mixture was heated at reflux for 1.5 h, cooled to room temperature, and extracted with
dichloromethane (3 × 50 mL). The combined organic phases were washed with brine
(100 mL), dried over anhydrous Na SO , filtered, and concentrated in vacuo to give
2
4
1a−1p.
1
2,4-Di(1H-indol-3-yl)thiazole (1a). Yellow solid; yield 88%; mp 282−283 °C; H NMR
(400 MHz, DMSO-d ) δ 11.81 (s, 1H), 11.46 (s, 1H), 8.4–8.30 (m, 1H), 8.22 (d, J = 7.2
6
Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.60 (s, 1H), 7.54–7.50 (m,
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1H), 7.49 (d, J = 8.0 Hz, 1H), 7.25 (dd, J = 5.6, 3.2 Hz, 2H), 7.22–7.11 (m, 2H). C
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NMR (100 MHz, DMSO-d ) δ 162.2, 151.0, 137.1, 137.1, 126.8, 125.3, 125.2, 124.9,
6
122.8, 122.0, 121.2, 120.9, 120.6, 120.1, 112.7, 112.4, 111.8, 111.3, 106.4. C H N S
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9
14
3
+
+
[M+H] 316.0903, found (ESI ) 316.0909.
2-(6-Bromo-1H-indol-3-yl)-4-(1H-indol-3-yl)thiazole (1b). Light-green solid; yield
1
76%; mp 258−260 °C; H NMR (400 MHz, DMSO-d ) δ 11.87 (s, 1H), 11.42 (s, 1H),
6
8.35 (d, J = 8.4 Hz, 1H),8.21–8.18 (m, 2H), 8.01 (d, J = 2.0 Hz, 1H), 7.71 (s, 1H), 7.62 (s,
1
3
1H), 7.49 (d, J = 7.2 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.27–7.12 (m, 2H). C NMR
(100 MHz, DMSO-d ) δ 161.7, 151.1, 137.9, 137.1, 127.8, 125.4, 125.1, 124.1, 123.9,
6
122.8, 122.0, 120.6, 120.2, 115.5, 115.2, 112.4, 111.7, 111.5, 106.7. C H BrN S
1
9
13
3
+
+
[M+H] 394.0008, found (ESI ) 394.0008.
4-(6-Bromo-1H-indol-3-yl)-2-(1H-indol-3-yl)thiazole (1c). Light-pink solid; yield 97%;
1
mp 266−267 °C; H NMR (400 MHz, DMSO-d ) δ 11.78 (s, 1H), 11.56 (s, 1H),
6
8.41–8.31 (m, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 2.8 Hz, 1H), 8.04 (d, J = 2.4 Hz,
1H), 7.69 (d, J = 1.6 Hz, 1H), 7.63 (s, 1H), 7.60–7.46 (m, 1H), 7.30 (dd, J = 8.4, 1.6 Hz,
1
3
1H), 7.28–7.22 (m, 2H). C NMR (100 MHz, DMSO-d ) δ 162.5, 150.4, 138.0, 137.1,
6
126.9, 126.2, 124.8, 124.3, 123.0, 122.8, 122.5, 121.2, 120.9, 114.9 114.8, 112.7, 112.1,
+
+
111.2, 107.1. C H BrN S [M+H] 394.0008, found (ESI ) 394.0001.
1
9
13
3
2,4-Bis(6-bromo-1H-indol-3-yl)thiazole (1d). Light-pink solid; yield 88%; mp 265−266
1
°C; H NMR (400 MHz, DMSO-d ) δ 11.87 (s, 1H), 11.55 (s, 1H), 8.31 (d, J = 8.4 Hz,
6
1H), 8.18 (d, J = 2.8 Hz, 1H), 8.17 (d, J = 2.8 Hz, 1H). 8.03 (d, J = 2.8 Hz, 1H), 7.70 (d, J
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= 1.6 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.66 (s, 1H), 7.39 (dd, J = 8.4, 1.6 Hz, 1H), 7.29
1
3
(dd, J = 8.4, 1.6 Hz, 1H). C NMR (100 MHz, DMSO-d ) δ 161.9, 150.5, 138.0, 137.9,
6
127.9, 126.2, 124.2, 124.1, 123.9, 123.0, 122.7, 122.4, 115.5, 115.2, 114.9, 114.8, 111.9,
+
+
111.4, 107.4. C H Br N S [M+H] 471.9113, found (ESI ) 471.9106.
1
9
12
2
3
2,4-Bis(5-bromo-1H-indol-3-yl)thiazole (1e). Light-brown solid; yield 96%; mp
1
206−207 °C; H NMR (400 MHz, DMSO-d ) δ 11.96 (s, 1H), 11.63 (s, 1H), 8.56 (d, J =
6
1.7 Hz, 1H), 8.47 (d, J = 1.7 Hz, 1H), 8.21 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 2.6 Hz, 1H),
7.68 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.38 (dd, J = 8.6, 1.9 Hz,
1
3
1H), 7.31 (dd, J = 8.6, 1.9 Hz, 1H). C NMR (100 MHz, DMSO-d ) δ 162.1, 150.6,
6
135.8, 135.7, 128.5, 127.1, 126.5, 126.4, 125.5, 124.6, 123.3,123.1, 114.7, 114.3, 113.9,
+
+
112.9, 111.3, 110.8, 107.3. C H Br N S [M+H] 471.9113, found (ESI ) 471.9101.
1
9
12
2
3
4-(5-Bromo-1H-indol-3-yl)-2-(6-bromo-1H-indol-3-yl)thiazole (1f). Light-brown solid;
1
yield 83%; mp 219−221 °C; H NMR (400 MHz, DMSO-d ) δ 11.88 (s, 1H), 11.64 (s,
6
1H), 8.46 (s, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.18 (d, J = 2.6 Hz, 1H), 8.06 (d, J = 2.3 Hz,
1H), 7.72 (d, J = 1.1 Hz, 1H), 7.69 (s, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.37 (dd, J = 8.5, 1.5
1
3
Hz, 1H), 7.31 (dd, J = 8.6, 1.7 Hz, 1H). C NMR (100 MHz, DMSO-d ) δ 161.5, 149.9,
6
137.5, 135.2, 127.4, 126.5, 126.1, 124.0, 123.5, 123.4, 122.6, 122.2, 115.0, 114.8, 113.9,
+
+
112.4, 110.9,110.8, 106.9. C H Br N S [M+H] 471.9113, found (ESI ) 471.9121.
1
9
12
2
3
2,4-Bis(5-methoxy-1H-indol-3-yl)thiazole (1g). Light-brown solid; yield 91%; mp
1
198−200 °C; H NMR (400 MHz, DMSO-d ) δ 11.61 (s, 1H), 11.26 (s, 1H), 8.08 (d, J =
6
2.7 Hz, 1H), 7.97 (d, J = 2.3 Hz, 1H), 7.93 (d, J = 2.5 Hz, 1H), 7.79 (d, J = 2.2 Hz, 1H),
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7.56 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.92 (dd, J = 8.8, 2.4 Hz,
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1H), 6.86 (dd, J = 8.8, 2.3 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H). C NMR (100 MHz,
DMSO-d ) δ 162.0, 154.6, 153.9, 150.7, 131.8, 131.7, 126.8, 125.3, 125.1, 125.0, 112.8,
6
+
112.4, 112.0, 111.3, 111.2, 110.7, 105.2, 102.8, 102.7, 55.5, 55.4. C H N O S [M+H]
2
1
18
3
2
+
376.1114, found (ESI ) 376.1112.
2-(6-Bromo-1H-indol-3-yl)-4-(5-methoxy-1H-indol-3-yl)thiazole (1h). Light-brown
1
solid; yield 86%; mp 189−291 °C; H NMR (400 MHz, DMSO-d ) δ 11.81 (s, 1H), 11.23
6
(s, 1H), 8.40 (d, J = 8.5 Hz, 1H), 8.15 (s, 1H), 7.93 (s, 1H), 7.75 (s, 1H), 7.70 (s, 1H),
1
3
7.58 (s, 1H), 7.35 (m, 2H), 6.83 (d, J = 8.7 Hz, 1H), 3.88 (s, 3H). C NMR (100 MHz,
DMSO-d ) δ 161.2, 154.0, 150.9, 137.5, 131.7, 127.3, 125.2, 125.1, 123.5, 123.4, 122.3,
6
+
115.0, 114.8, 112.5,111.8, 111.1, 111.0, 105.8, 101.9, 99.5, 55.3. C H BrN OS [M+H]
2
0
15
3
+
424.0114, found (ESI ) 424.0118.
4-(6-Bromo-1H-indol-3-yl)-2-phenylthiazole (1i). White solid; yield 94%; mp 233−234
1
°C; H NMR (400 MHz, DMSO-d ) δ 11.61 (s, 1H), 8.21 (d, J = 8.6 Hz, 1H), 8.07 (dd, J
6
= 8.1, 1.4 Hz, 2H), 8.04 (d, J = 2.6 Hz, 1H), 7.88 (s, 1H), 7.68 (d, J = 1.7 Hz, 1H),
1
3
7.58–7.52 (m, 3H), 7.30 (dd, J = 8.5, 1.8 Hz, 1H). C NMR (100 MHz, DMSO-d ) δ
6
166.0, 151.4, 137.4, 133.2, 130.1, 129.2, 126.1, 125.8, 123.7, 122.6, 122.1, 114.42,
+
+
114.36, 111.0, 110.6. C H BrN S [M+H] 354.9899, found (ESI ) 354.9894.
1
7
12
2
4-(6-Bromo-1H-indol-3-yl)-2-(4-fluorophenyl)thiazole (1j). White solid; yield 97%;
1
mp 220−221 °C; H NMR (400 MHz, DMSO-d ) δ 11.60 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H),
6
8.12 (d, J = 6.0 Hz, 2H), 8.02 (s, 1H), 7.87 (s, 1H), 7.66 (s, 1H), 7.40 (t, J = 8.4 Hz, 2H),
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7.28 (d, J = 8.5 Hz, 1H). C NMR (100 MHz, DMSO-d ) δ 165.4, 163.6 (d, J = 246.0
6
Hz), 151.8, 137.9, 130.3 (d, J = 3.1 Hz), 128.9 (d, J = 8.6 Hz), 126.3, 124.2, 123.1, 122.6,
+
116.8 (d, J = 22.0 Hz), 114.9, 114.8, 111.4, 111.2. C H BrFN S [M+H] 372.9805,
1
7
11
2
+
found (ESI ) 372.9800.
4-(6-Bromo-1H-indol-3-yl)-2-(2-(trifluoromethyl)phenyl)thiazole (1k). White solid;
1
yield 87%; mp 181−182 °C; H NMR (400 MHz, DMSO-d ) δ 11.62 (s, 1H), 8.17 (d, J =
6
8.5 Hz, 1H), 8.04–7.97 (m, 3H), 7.90–7.76 (m, 3H), 7.69 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H).
1
3
C NMR (100 MHz, DMSO-d ) δ 163.2, 151.5, 137.9, 133.2, 132.7, 130.7, 127.5 (q, J =
6
5.5 Hz), 126.3, 124.3(q, J = 272.1 Hz), 124.2, 123.0, 122.5, 114.9, 113.0, 111.4.
+
+
C H BrF N S [M+H] 422.9733, found (ESI ) 422.9767.
1
8
11
3
2
4-(6-Bromo-1H-indol-3-yl)-2-(3,4-dichlorophenyl)thiazole (1l). White solid; yield 99%;
1
mp 228−229 °C; H NMR (400 MHz, DMSO-d ) δ 11.65 (s, 1H), 8.27 (d, J = 2.1 Hz, 1H),
6
8.16 (d, J = 8.6 Hz, 1H), 8.06 (s, 1H), 8.03 (dd, J = 8.4, 2.1 Hz, 1H), 7.97 (s, 1H), 7.82 (d,
1
3
J = 8.4 Hz, 1H), 7.66 (d, J = 1.7 Hz, 1H), 7.29 (dd, J = 8.5, 1.8 Hz, 1H). C NMR (100
MHz, DMSO-d ) δ 163.2, 151.7, 137.4, 133.5, 132.4, 132.0, 131.4, 127.3, 126.1, 126.1,
6
+
123.6, 122.6, 121.9, 114.5, 114.4, 111.7, 110.7. C H BrCl N S [M+H] 422.9120,
1
7
10
2
2
+
found (ESI ) 442.9122.
4-(6-Bromo-1H-indol-3-yl)-2-(4-phenoxyphenyl)thiazole (1m). White solid; yield 90%;
1
mp 203−204 °C; H NMR (400 MHz, DMSO-d ) δ 11.54 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H),
6
8.06 (d, J = 8.2 Hz, 2H), 7.99 (s, 1H), 7.82 (s, 1H), 7.65 (s, 1H), 7.46 (t, J = 7.7 Hz, 2H),
1
3
7.29–7.19 (m, 2H), 7.14 (t, J = 6.9 Hz, 4H). C NMR (100 MHz, DMSO-d ) δ 165.5,
6
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158.5, 155.8, 151.2, 137.40, 130.2, 128.4, 128.0, 125.8, 124.2, 123.7, 122.6, 122.1, 119.3,
+
+
43
44
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49
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58
59
60
61
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118.6, 114.4, 114.4, 111.1, 110.2. C H BrN OS [M+H] 447.0161, found (ESI )
23 16 2
447.0157.
4-(6-Bromo-1H-indol-3-yl)-2-(4-hexylphenyl)thiazole (1n). White solid; yield 83%; mp
1
79−80 °C; H NMR (400 MHz, CDCl ) δ 8.38 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.68 (d, J
3
= 2.8 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.32 (dd, J = 8.4, 1.6 Hz, 1H), 7.22 (s, 1H),
3.11–3.02 (m, 2H), 1.89–1.81 (m, 2H), 1.49–1.42 (m, 2H), 1.39–1.28 (m, 4H), 0.90 (t, J
1
3
= 6.9 Hz, 3H). C NMR (100 MHz, DMSO-d ) δ 165.9, 144.3, 132.0, 118.9, 118.7,
6
118.6, 116.3, 110.7, 109.1, 107.9, 104.5, 28.3, 26.3, 24.9, 23.6, 17.3, 8.8. C H BrN S
1
7
20
2
+
+
[M+H] 363.0525, found (ESI ) 363.0533.
4-(6-Bromo-1H-indol-3-yl)-2-(p-tolyl)thiazole (1o). White solid; yield 87%; mp
1
114−116 °C; H NMR (400 MHz, DMSO-d ) δ 11.50 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H),
6
7.88 (s, 1H), 7.62 (d, J = 1.7 Hz, 1H), 7.61 (s, 1H), 7.23 (dd, J = 8.5, 1.8 Hz, 1H), 2.72 (s,
1
3
3H). C NMR (100 MHz, DMSO-d ) δ 164.6, 149.6, 137.4, 125.4, 123.6, 122.4, 121.9,
6
+
+
114.3, 114.2, 111.2, 109.6, 18.8. C H BrN S [M+H] 292.9743, found (ESI ) 292.9736.
1
2
10
2
4-(6-Bromo-1H-indol-3-yl)-2-(4-(tert-butyl)phenyl)thiazole (1p). Brown solid; yield
1
78%; mp 129−131 °C; H NMR (400 MHz, DMSO-d ) δ 11.49 (s, 1H), 8.09 (d, J = 8.5
6
Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.63 (s, 1H), 7.62 (d, J = 1.3 Hz, 1H), 7.23 (dd, J = 8.5,
1
3
1.5 Hz, 1H), 1.46 (s, 9H). C NMR (100 MHz, DMSO-d ) δ 179.2, 149.5, 137.3, 125.3,
6
+
123.8, 122.4, 122.1, 114.3, 114.2, 111.42, 108.9, 37.2, 30.6. C H BrN S [M+H]
1
5
16
2
+
335.0212, found (ESI ) 335.0213.
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General Procedures for the Preparation of Compounds 14a−14b. To a solution of
indoles 3a−3b (20 mmol) in anhydrous ether was added (COCl) (26 mmol) dropwise at
2
0 °C. The mixture was stirred for 1.5 h, and filtered to give 13a−13b, which were used
for the next step directly. To a solution of compounds 13a−13b in anhydrous ether was
added ammonia dropwise at room temperature. The mixture was stirred for 5 min, and
then filtered. Filter cake was washed with water and cold anhydrous ether to provide
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1H-Indole-3-oxacin (14a). Yellow solid; yield 84%; mp 225−256 °C; H NMR (400
MHz, DMSO-d ) δ 12.21 (s, 1H), 8.69 (d, J = 3.2 Hz, 1H), 8.27–8.18 (m, 1H), 8.09 (s,
6
1H), 7.73 (s, 1H), 7.54–7.52 (m, 1H), 7.28–7.23 (m, 2H).
1
1H-6-Bromoindole-3-oxacin (14b). Yellow solid; yield 75%; mp 265−266 °C; H NMR
(400 MHz, DMSO-d ) δ 12.28 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H),
6
8.12 (s, 1H), 7.76 (s, 1H), 7.73 (d, J = 1.2 Hz, 1H), 7.40 (dd, J = 8.4, 1.6 Hz, 1H).
General Procedures for the Preparation of Compounds 15a–15b. To a solution of
compounds 14a−14b (0.5 mmol) in DMF was added SOCl (0.75 mmol) dropwise under
2
inert atmosphere. The mixture was stirred for 30 min at 0 ℃, then poured into 50 mL
water and extracted with EtOAc (3 × 30 mL). The combined organic phase was washed
with brine (3 mL), dried over anhydrous Na SO , filtered, and concentrated in vacuo to
2
4
give 15a−15b.
1
1H-Indole-3-carbonyl cyanide (15a). Yellow solid; yield 82%; mp 162−163 °C; H
NMR (400 MHz, DMSO-d ) δ 12.94 (s, 1H), 8.65 (d, J = 2.8 Hz, 1H), 8.05 (d, J = 7.6 Hz,
6
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1H), 7.60 (d, J = 7.6 Hz, 1H), 7.41–7.31 (m, 2H).
85
86
87
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97
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1H-6-Bromoindole-3-carbonyl cyanide (15b). Yellow solid; yield 71%; mp 131−133
1
°C; H NMR (400 MHz, DMSO-d ) δ 12.98 (s, 1H), 8.67 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H),
6
7.77 (d, J = 1.6 Hz, 1H), 7.48 (dd, J = 8.4, 1.6 Hz, 1H).
Preparation of 2-amino-1-(1H-indol-3-yl) ethan-1-one acetate (16). To a solution of
compound 15a (1.47 mmol) in AcOH was added Pb/C. The mixture was stirred for 1 h at
room temperature in a hydrogen atmosphere under atmospheric pressure, and
concentrated in vacuo, recrystallized with ether to give compound 16. Yellow solid; yield
1
78%; mp 146−148 °C; H NMR (400 MHz, DMSO-d ) δ 8.35 (s, 1H), 8.22–8.15 (m, 1H),
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7.53–7.45 (m, 1H), 7.26–7.16 (m, 2H), 3.98 (s, 2H), 1.86 (s, 3H). C NMR (100 MHz,
DMSO-d ) δ 192.4, 172.9, 137.0, 134.3, 125.7, 123.3, 122.3, 121.5, 114.2, 112.7, 46.9,
6
22.2.
General Procedures for the Preparation of Compounds 17a−17b. To a solution of
compound 16 (1 mmol) in DCM was added TEA. After stirred for 10 minutes,
compounds 15a−15b were added in two portions. The resulting mixture was allowed to
stir for 5 h at room temperature. Then the mixture was diluted with water and extracted
with dichloromethane (3 × 50 mL). The combined organic phase was washed with brine
(3 mL), dried over anhydrous Na SO , filtered, and concentrated in vacuo to give
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compounds 17a−17b.
N-(2-(1H-Indol-3-yl)-2-oxoethyl)-1H-indole-3-carboxamide (17a). Yellow solid; yield
1
98%; mp 285−287 °C; H NMR (400 MHz, DMSO-d ) δ 12.03 (s, 1H), 11.61 (s, 1H),
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8.52 (d, J = 2.8 Hz, 1H), 8.23 (t, J = 5.6 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.15 (d, J =
8.0 Hz, 1H), 8.13 (d, J = 2.8 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H),
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7.27–7.19 (m, 2H), 7.18–7.06 (m, 2H), 4.66 (d, J = 5.6 Hz, 2H). C NMR (100 MHz,
DMSO-d ) δ 191.2, 164.7, 136.4, 136.1, 133.5, 128.1, 126.0, 125.5, 122.8, 121.8, 121.8,
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121.2, 120.9, 120.4, 114.2, 112.1, 111.8, 110.4, 45.6. C H N O [M+H] 318.1237,
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+
found (ESI ) 318.1240.
N-(2-(1H-Indol-3-yl)-2-oxoethyl)-6-bromo-1H-indole-3-carboxamide (17b). Yellow
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solid; yield 98%; mp 295−296 °C; H NMR (400 MHz, DMSO-d ) δ 12.06 (s, 1H), 11.76
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(s, 1H), 8.52 (s, 1H), 8.34 (t, J = 5.6 Hz, 1H), 8.23–8.14 (m, 2H), 8.09 (d, J = 8.6 Hz, 1H),
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7.66 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.23 (m, 3H), 4.65 (d, J = 5.6 Hz, 2H). C NMR
(100 MHz, DMSO-d ) δ 191.0, 164.3, 137.0, 136., 133.5, 128.8, 125.4, 125.2, 123.3,
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122.8, 122.7, 121.8, 121.2, 114.6, 114.5, 114.1, 112.2, 110.6, 45.6. C H BrN O
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+
+
[M+H] 396.0342, found (ESI ) 396.0342.
General Procedures for the Preparation of Compounds 12a−12b. The compounds
17a−17b (1 mmol) was dissolved in POCl . The resulting mixture was heated to reflux
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and stirred for about 1 h. After the reaction was completed, the mixture was poured into
water, extracted with ethyl acetate and purified via column chromatography (PE: EA = 2:
1).
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2,5-Di(1H-indol-3-yl)oxazole (12a). Yellow solid; yield 84%; mp 249–251 °C. H NMR
(400 MHz, DMSO-d ) δ 11.79 (s, 1H), 11.60 (s, 1H), 8.28 (d, J = 6.8 Hz, 1H), 8.14 (d, J
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= 2.0 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.59–7.44 (m, 3H),
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7.30–7.14 (m, 4H). C NMR (100 MHz, DMSO-d ) δ 156.8, 145.4, 136.4, 136.4, 126.2,
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124.2, 123.5, 122.9, 122.3, 122.1, 120.6, 120.4, 120.0, 119.6, 112.1, 112.1, 104.1, 104.1.
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C H N O [M+H] 300.1131, found (ESI ) 300.1129.
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2-(6-Bromo-1H-indol-3-yl)-5-(1H-indol-3-yl)oxazole (12b). Yellow solid; yield 76%;
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mp 259–260 °C; H NMR (400 MHz, DMSO-d ) δ 11.90 (s, 1H), 11.61 (s, 1H), 8.21 (d, J
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= 7.6 Hz, 1H), 8.17 (s, 1H), 7.96 (d, J = 6.4 Hz, 1H), 7.91 (s, 1H), 7.72 (s, 1H), 7.51 (m,
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2H), 7.37 (d, J = 7.2 Hz, 1H), 7.28–7.13 (m, 2H). C NMR (100 MHz, DMSO-d ) δ
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156.7, 146.2, 137.7, 136.91, 127.6, 124.0, 123.8, 123.6, 122.7, 122.6, 120.6, 120.1, 115.6,
+
+
115.2, 112.6, 104.8, 104.5. C H BrN O [M+H] 378.0237, found (ESI ) 378.0236.
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Biological Assay. Each test was repeated three times at 25±1 °C. Active effect expressed
in percentage scale of 0−100 (0: no activity; 100: total inhibited).
Specific steps for the anti-TMV30 and fungicidal31 activities were carried out in
accordance with the literature method, also can be seen in Supporting Information.
Mode of Action Studies. The mode of action studies were carried out in accordance with
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the literature method, also can be seen in Supporting Information.
RESULTS AND DISCUSSION
Chemistry.
Till now, only one synthetic method of the corresponding bis-(indolyl)thiazole
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analogues has been reported by Jiang and Parrino . However, it has some shortcomings,
namely low yields and many steps. The route needs improvement. As shown in Figure 3,
commercially available indoles (3a−3c) were reacted with tosyl chloride to give the
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protected indoles (4a−4c), which were treated with acetic anhydride and brominated to
provide the key intermediate α-bromoketones (6a−6c). Due to the influence of electronic
effect, 5-methoxyindole (3d) can not be converted into 6d by the above steps.
3-Acetyl-1H-5-methoxyindole (7), provided by Vilsmeier–Haack reaction of
methoxyindole (3d) and dimethylacetamide, was reacted with tosyl chloride to give 5d.
Bromination of 5d gave N-tosyl-3-(α-bromoacetyl)-5-methoxyindole (6d). As depicted in
Figures 4 and 5, treatment of the indoles (3b−3d) with chlorosulfonyl isocyanate (CSI)
gave 3-cyanoindoles (8b−8d). Cyanoindoles (8a−8c) and nitriles 8i−8m were reacted
with sodium hydrosulfide hydrate and magnesium chloride hexahydrate to give the key
intermediate thioamides (9a−9c and 9i−9m). However, fatty nitriles are not suitable for
this method. Intermediate thioamide 9n was prepared from 8n using P S as vulcanization
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reagent. Cyanoindole (8d) needs to protect NH with tosyl chloride before it can be
converted to thioamide (11). As shown in Figures 6 and 7, the protected
bis-(indolyl)thiazole compounds (2a−2h) and indole-thiazole compounds (2i−2q) were
provided by condensation of the α-bromoketones (6) with the thioamides (9) using
Hantzsch reaction.24,25 The removal of the Ts group was carried out under refluxing
conditions in a solution of 2 N NaOH to afford bis-(indolyl)thiazole compounds (1a−1h)
and indole-thiazole compounds (1i−1p). The corresponding bis-(indolyl)oxazole
analogues (12a−12b) were synthesized by Horne’s method (Figures 8−10), which is
described in the literature.20
Phytotoxic Activity. The phytotoxic-activity tests showed that the nortopsentins
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analogues, namely bis-(indolyl)thiazole compounds 1a−1p, indole-thiazole compounds
2a−2q and bis-(indolyl)oxazole compounds 12a, 12b were safe for testing on plants at
500 μg/mL. The detailed test procedures can be seen in Supporting Information.
Antiviral Activity in vivo. The results of the anti-TMV activities of the nortopsentin
analogues containing thiazole 1a−1p and 2a−2q, oxazole 12a−12b are listed in Table 1
with nortopsentins A−D and the commercial plant virucide ribavirin as the controls. In
order to improve the efficiency of the antiviral activity test, we first test the inactive
activities of all compounds listed in Table 1 at 500 μg/mL, and further test the curative
activities and protective activities of compounds with good inactive activities (inactive
effect > 40%).
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As depicted in Table 1, the nortopsentin analogues containing thiazole 1a−1p and
2a−2q, oxazole 12a−12b showed good antiviral activities in vivo. Most of the analogues
exhibited higher in vivo TMV inhibitory effects than ribavirin, especially compounds 1d,
1e and 12a. The substitution of sulfur or oxygen atoms for nitrogen atom obviously
changed the structure-activity relationship of these compounds. The activities of these
alkaloids were significantly increased when the imidazole ring was changed to thiazole
ring, except compound 1a (inhibitory effect: 1a < nortopsentin D). Compound 12a
containing oxazole ring showed the same level of biological activity as nortopsentin D
but higher activity than 1a. Oxazole ring containing compound 12b showed the same
level of biological activity as 1b but higher activity than nortopsentin B. The mainly
difference between 1a−1h lies in substitutes on indole rings. Compound 1a without
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