Discovery of Pimprinine Alkaloids as Novel Agents against a Plant Virus

Article abstract of DOI:10.1021/acs.jafc.8b06175

Plant viral diseases cause tremendous decreases in crop yield and quality. Natural products have always been a valuable source for lead discovery in medicinal and agricultural chemistry. A series of pimprinine alkaloids and their derivatives were prepared and identified by nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HR-MS). The antiviral activities of these alkaloids against tobacco mosaic virus (TMV) were systematically investigated for the first time. Most of the compounds exhibited higher antiviral activities than ribavirin. Compounds 5l, 9h, and 10h, which had similar or higher antiviral activities than ningnanmycin (perhaps the most widely used antiviral agent at present), emerged as new antiviral pilot compounds. This systematic structure-activity-relationship research lays the foundation for simplifying the structure of these alkaloids. The ring-open products, acylhydrazones 9a-9u, were also found to possess good antiviral activities. Moreover, all the synthesized compounds displayed broad-spectrum fungicidal activities. This study provides important information for the research and development of pimprinine alkaloids as novel antiviral agents.

Full text of DOI:10.1021/acs.jafc.8b06175

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Agricultural and Environmental Chemistry
Discovery of Pimprinine Alkaloids as Novel Agents against a Plant Virus
Bin Liu, Rui Li, Yanan Li, Songyi Li, Jin Yu, Binfen Zhao, Ancai Liao,
Ying Wang, Ziwen Wang, Aidang Lu, Yuxiu Liu, and Qingmin Wang
J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.8b06175 • Publication Date (Web): 25 Jan 2019
Downloaded from http://pubs.acs.org on January 27, 2019
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Page 1 of 44
Journal of Agricultural and Food Chemistry
Discovery of Pimprinine Alkaloids as Novel Agents against a
Plant Virus
Bin Liu,† Rui Li,† Yanan Li,† Songyi Li,† Jin Yu,† Binfen Zhao,† Ancai Liao,† Ying
Wang,† Ziwen Wang,†,* Aidang Lu,‡,* Yuxiu Liu§ and 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 Normal University, Tianjin 300387, China
‡
School of Chemical Engineering and Technology, Hebei University of Technology,
Hebei Collaborative Innovation Center of Modern Marine Chemical Technology, Tianjin 300130,
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 Aidang Lu, E-mail:
luaidang@hebut.edu.cn; Phone: 0086-22-60302812; Fax: 0086-22-60204274.
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ABSTRACT: Plant viral diseases cause tremendous decreases in yield and quality.
Natural products have always been valuable source for lead discovery in medicinal and
agricultural chemistry. A series of pimprinine alkaloids and their derivatives were
prepared and identified by nuclear magnetic resonance (NMR) and high-resolution
mass spectrometer (HR-MS). The antiviral activities of these alkaloids against tobacco
mosaic virus (TMV) were systematically investigated for the first time. Most of the
compounds exhibited higher antiviral activities than ribavirin. Compounds 5l, 9h and
10h with similar or higher antiviral activities than ningnanmycin (perhaps the most
widely used antiviral agent at present) emerged as new antiviral pilot compounds. The
systematically structure-activity relationship research lays a foundation for simplifying
the structure of these alkaloids. As the ring open products, acylhydrazones 9a–9u were
also found to possess good antiviral activities. Moreover, all the synthesized
compounds displayed broad-spectrum fungicidal activities. This study provides
important information for the research and development of pimprinine alkaloids as
novel antiviral agents.
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KEYWORDS: natural product, alkaloid, pimprinine, anti-TMV activity, fungicidal
activity
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INTRODUCTION
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The recent population survey reveals that the population growth rate far exceeds
the growth rate of land production capacity, which will lead to the urgent need to
increase food production.1,2 Plant viruses often drastically damage crops and cause
serious reductions in crop yield and quality. Tobacco Mosaic Virus (TMV) is the
earliest discovered plant virus and widely used as a model virus in the study of new
antiviral agents. It is known to infect more than 400 crops, leading to yield reduction or
abortion.3 The management of these viruses has puzzled scientists for years. Few
chemical agents for controlling viruses have been commercialized as effective products.
As the most widely used antiviral agent at present, ribavirin and ningnanmycin can only
show moderate field control effect. The discovery of novel antiviral agents with
different scaffolds or modes of action are needed urgently.
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Natural products and their derivatives have always been valuable source for lead
discovery in medicinal and agricultural chemistry, because their novel scaffolds can
provide different action modes from the existing agents.4 Some natural products have
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been commercialized5,6 or found as lead compounds7–13 for plant virus control.
Pimprinine is an indole alkaloid first isolated from the filtrates of Streptomyces
pimprina cultures in 1963. Members of this family (Figure 1) display a range of
biological activities, such as anti-epileptic effect14,15, platelet aggregation inhibitory
effect16, anti-tumor activity17, and fungicidal activity18. Because of the low natural
content and difficult synthesis of these alkaloids, the research on their biological
activities is not deep enough, and there is no report on their anti-plant viral activities at
present.
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Our research group has been devoted to the development of new antiviral agents
based on natural products for a long time.10–13 In this work, pimprinine was taken as the
parent structure to carry out structural optimization for discovering simpler structure
analogues with higher activity. As shown in Figure 2, we designed and synthesized a
series of pimprinine analogues in which the indole nitrogen, 2-position of oxazole,
oxazole ring have been derivatised. The antiviral and fungicidal activities of these
compounds were systematically studied.
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MATERIALS AND METHODS
Chemicals. All the reagents used are purchased analytical pure reagents.
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Instruments. The melting points of the synthesized compounds were determined on an
X-4 binocular microscope (Beijing Tech Instruments Co., Beijing, China) without
temperature correction. 1H NMR and 13C NMR spectra of the compounds were obtained
on Bruker AV 400 spectrometer (Bruker Corp., Switzerland) in CDCl3 or DMSO-d6
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with tetramethylsilane as the internal standard. High-resolution mass spectra were
obtained with an FT-ICR MS spectrometer (Ionspec, 7.0 T).
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Preparation of Compound 2-(1H-Indol-3-yl)-2-oxoacetyl Chloride (2). The ether
solution (100 mL) of oxaloyl chloride (0.22 mol) was added to the ether solution (350
o
mL) of indole (0.17 mol) dropwise while maintaining the temperature at 0 C. The
yellowish mixture was stirred at 0 oC for 90 min and filtered, washed with cold ether to
give 2 (yield 90%) as a yellow solid, which was directly used for next reaction without
purification.
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Preparation of Compound 2-(1H-Indol-3-yl)-2-oxoacetaldehyde (3). Under Ar
atmosphere, the ethyl acetate solution (150 mL) of tributyltin hydride (0.15 mol) was
added to ethyl acetate solution (150 mL) of oxoacetyl chloride 2 (0.15 mol) drop by
drop at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and at 25 °C for 15 h.
To the mixture was added petroleum ether (700 mL), then filtered to afford 2-
oxoacetaldehyde 3 as a yellow powder in 80% yield, which was directly used for next
reaction without purification.
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General Methods for Synthesis of Compounds 5a–5l. The mixture of 2-
oxoacetaldehyde 3 (5.8 mmol), corresponding amino acids (11.6 mmol) and I2 (5.8
mmol) in dimethyl sulfoxide (DMSO, 30 mL) was stirred at 110 °C for 30 min, then
added 5% solution of Na2S2O3 (300 mL) and ethyl acetate (400 mL). Then the reaction
mixture was stirred for 30 min and separated. The organic layer was washed with
saturated NaCl solution (200 mL × 2), dried with anhydrous Na2SO4, filtered and
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concentrated in vacuum. The compounds 5a–5l were obtained by column
chromatography on silica gel.
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Pimprinine (5a). Brown solid; mp. 202−203 C (lit.14, 204−205 C); yield 66%; H
NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H, NH), 7.84 (d, J = 7.9 Hz, 1H, Ar-H), 7.74
(d, J = 2.6 Hz, 1H, Ar-H), 7.47 (d, J = 8.0 Hz, 1H, Ar-H), 7.30 (s, 1H, Ar-H), 7.12–
7.23 (m, 2H, Ar-H), 2.49 (s, 3H, CH3);13C NMR (100 MHz, DMSO-d6) δ 158.2, 147.3,
136.3, 123.5, 122.8, 122.0, 120.0, 119.4, 119.2, 112.0, 103.9, 13.6; HRMS (ESI) calcd
for C12H11N2O (M+H)+ 199.0866, found 199.0861.
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5-(1H-Indol-3-yl)oxazole (5b). Brown solid; mp. 152−154 C (lit.19, 156−157 C);
1
yield 68%; H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H, NH), 8.36 (s, 1H, Ar-H),
7.88 (d, J = 5.9 Hz, 1H, Ar-H), 7.83 (s, 1H, Ar-H), 7.49 (s, 2H, Ar-H), 7.17–7.23 (m,
2H, Ar-H);13C NMR (100 MHz, DMSO-d6) δ 149.6, 147.6, 136.4, 123.5, 122.1, 120.1,
119.4, 118.7, 112.1, 103.6.
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2-(tert-Butyl)-5-(1H-indol-3-yl)oxazole (5c). Brown solid; mp. 172−174 C; yield
57%; 1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H, NH), 7.84 (d, J = 7.8 Hz, 1H, Ar-
H), 7.77 (d, J = 2.6 Hz, 1H, Ar-H), 7.48 (d, J = 7.9 Hz, 1H, Ar-H), 7.26 (s, 1H, Ar-H),
7.14–7.23 (m, 2H, Ar-H), 1.41 (s, 9H, CH3); 13C NMR (100 MHz, DMSO-d6) δ 167.7,
147.1, 136.3, 123.6, 123.0, 122.0, 120.0, 119.4, 118.8, 112.0, 104.0, 33.2, 28.5; HRMS
(ESI) calcd for C15H17N2O (M+H)+ 241.1335, found 241.1339.
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5-(1H-Indol-3-yl)-2-isopropyloxazole (5d). Brown solid; mp. 125−126 C (lit.19,
100
125−126 oC); yield 72%; 1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H, NH), 7.85 (s,
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1H, Ar-H), 7.76 (s, 1H, Ar-H), 7.48 (s, 1H, Ar-H), 7.29 (s, 1H, Ar-H), 7.21 (s, 1H, Ar-
H), 7.17 (s, 1H, Ar-H), 3.15 (s, 1H, Ar-CH), 1.36 (s, 6H, CH3); 13C NMR (100 MHz,
DMSO-d6) δ 165.5, 147.1, 136.3, 123.6, 122.9, 122.0, 120.0, 119.4, 118.9, 112.0, 103.9,
27.6, 20.4.
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Labradorin 1 (5e). Brown solid; mp. 145−146 oC (lit.19, 147−148 oC); yield 78%; 1H
NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H, NH), 7.84 (d, J = 7.8 Hz, 1H, Ar-H), 7.73
(d, J = 2.6 Hz, 1H, Ar-H), 7.47 (d, J = 8.0 Hz, 1H, Ar-H), 7.30 (s, 1H, Ar-H), 7.12–
7.22 (m, 2H, Ar-H), 2.69 (d, J = 7.1 Hz, 2H, Ar-CH2), 2.09–2.19 (m, 1H, ArCH2-CH),
0.98 (d, J = 6.7 Hz, 6H, CH3); 13C NMR (100 MHz, DMSO-d6) δ 160.9, 147.2, 136.3,
123.5, 122.9, 122.0, 120.0, 119.4, 119.1, 112.0, 103.9, 36.2, 27.1, 22.1; HRMS (ESI)
calcd for C15H17N2O (M+H)+ 241.1135, found 241.1133.
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2-Cyclohexyl-5-(1H-indol-3-yl)oxazole (5f). Brown solid; mp. 169−170 C; yield
48%; 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H, NH), 8.19–8.24 (m, 1H, Ar-H),
7.83 (d, J = 7.7 Hz, 1H, Ar-H), 7.74 (d, J = 2.6 Hz, 1H, Ar-H), 7.46 (d, J = 7.9 Hz, 1H,
Ar-H), 7.28 (s, 2H, Ar-H), 2.84–2.90 (m, 1H, Ar-CH), 2.05–2.10 (m, 2H, CH-CH2),
1.76–1.80 (m, 2H, CH-CH2), 1.13–1.66 (m, 4H, CHCH2-CH2), 1.26–1.45 (m, 2H,
CHCH2CH2-CH2);13C NMR (100 MHz, DMSO-d6) δ 164.6, 146.9, 137.1, 136.3, 122.9,
122.0, 120.0, 119.4, 118.9, 112.0, 104.0, 36.5, 30.3, 25.0; HRMS (ESI) calcd for
C17H19N2O (M+H)+ 267.1492, found 267.1493.
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(5-(1H-Indol-3-yl)oxazol-2-yl)methanol (5g). Brown solid; mp. 187−189 C (lit.19,
189−190 oC); yield 39%; 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H, NH), 7.89 (d,
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J = 7.7 Hz, 1H, Ar-H), 7.79 (d, J = 1.4 Hz, 1H, Ar-H), 7.50 (d, J = 7.9 Hz, 1H, Ar-H),
7.39 (s, 1H, Ar-H), 7.22 (t, J = 7.1 Hz, 1H, Ar-H), 7.16 (t, J = 7.5 Hz, 1H, Ar-H), 5.71
(t, J = 5.9 Hz, 1H, OH), 4.59 (d, J = 5.8 Hz, 2H, CH2); 13C NMR (100 MHz, DMSO-
d6) δ 160.8, 147.9, 136.3, 123.5, 123.2, 122.1, 120.1, 119.5, 112.1, 103.7, 55.9.
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5-(1H-Indol-3-yl)-2-(2-(methylthio)ethyl)oxazole (5h). Brown solid; mp. 146−147
oC (lit.19, 149−150 oC); yield 47%; 1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H, NH),
7.86 (d, J = 7.7 Hz, 1H, Ar-H), 7.76 (s, 1H, Ar-H), 7.48 (d, J = 7.9 Hz, 1H, Ar-H), 7.34
(s, 1H, Ar-H), 7.13–7.23 (m, 2H, Ar-H), 3.12 (t, J = 6.9 Hz, 2H, CH2), 2.94 (t, J = 7.1
Hz, 2H, CH2), 2.11 (s, 3H, CH3);13C NMR (100 MHz, DMSO-d6) δ 160.0, 147.5, 136.3,
123.5, 123.0, 122.1, 120.0, 119.4, 119.1, 112.0, 103.8, 30.5, 27.9, 14.6.
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5-(1H-Indol-3-yl)-2-phenyloxazole (5i). Brown solid; mp. 226−228 C (lit.19,
226−228 oC); yield 83%; 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H, NH), 8.12 (d,
J = 1.4 Hz, 1H, Ar-H), 8.10 (s, 1H, Ar-H), 7.99 (s, 1H, Ar-H), 7.98 (d, J = 5.9 Hz, 1H,
Ar-H), 7.62 (s, 1H, Ar-H), 7.58 (t, J = 6.9 Hz, 2H, Ar-H), 7.52 (t, J = 6.8 Hz, 2H, Ar-
H), 7.19–7.27 (m, 2H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ 158.0, 148.3, 136.4,
130.0, 129.1, 127.2, 125.5, 123.8, 123.5, 122.2, 120.8, 120.3, 119.5, 112.1, 103.6.
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2-(4-Fluorophenyl)-5-(1H-indol-3-yl)oxazole (5j). Brown solid; mp. 205−206 C;
yield 51%; 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H, NH), 8.13 (dd, J = 6.3, 9.0
Hz, 2H, Ar-H), 7.97 (s, 1H, Ar-H), 7.96 (d, J = 9.0 Hz, 1H, Ar-H), 7.60 (s, 1H, Ar-H),
7.50 (d, J = 7.6 Hz, 1H, Ar-H), 7.41 (t, J = 8.2 Hz, 2H, Ar-H), 7.17–7.25 (m, 2H, Ar-
H);13C NMR (100 MHz, DMSO-d6) δ 164.3, 161.8, 157.2, 148.3, 136.4, 127.94, 127.86,
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123.9, 123.5, 122.2, 120.7, 120.3, 119.5, 116.4, 116.1, 112.1, 103.5; HRMS (ESI) calcd
for C17H12FN2O (M+H)+ 279.0928, found 279.0933.
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Pimprinaphine (5k). Brown solid; mp. 199−200 C (lit.19, 202−203 C); yield 56%;
1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H, NH), 7.82 (d, J = 7.4 Hz, 1H, Ar-H),
7.74 (s, 1H, Ar-H), 7.47 (d, J = 7.6 Hz, 1H, Ar-H), 7.32–7.40 (m, 5H, Ar-H), 7.29 (s,
1H, Ar-H), 7.20 (t, J = 6.9 Hz, 1H, Ar-H), 7.14 (t, J = 7.2 Hz, 1H, Ar-H), 4.22 (s, 2H,
Ar-CH2); 13C NMR (100 MHz, DMSO-d6) δ 160.0, 147.8, 136.3, 136.2, 128.7, 128.6,
127.2, 126.8, 123.5, 123.1, 122.1, 120.0, 119.4, 119.3, 112.0, 103.7, 33.7; HRMS (ESI)
calcd for C18H15N2O (M+H)+ 275.1179, found 275.1177.
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4-((5-(1H-Indol-3-yl)oxazol-2-yl)methyl)phenol (5l). Brown solid; mp. 165−166 oC;
yield 44%; 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H, NH), 9.45 (s, 1H, OH), 8.01
(s, 1H, Ar-H), 7.81 (d, J = 7.8 Hz, 1H, Ar-H), 7.72 (d, J = 2.4 Hz, 1H, Ar-H), 7.46 (d,
J = 7.5 Hz, 1H, Ar-H), 7.31 (s, 1H, Ar-H), 7.16 (d, J = 8.9 Hz, 2H, Ar-H), 6.75 (d, J =
8.3 Hz, 2H, Ar-H), 4.07 (s, 2H, Ar-CH2); 13C NMR (100 MHz, DMSO-d6) δ 166.4,
161.0, 156.6, 148.1, 136.9, 136.8, 132.8, 130.2, 126.7, 123.5, 122.6, 122.5, 121.0, 119.9,
115.8, 112.5, 104.2, 33.4; HRMS (ESI) calcd for C18H15N2O2 (M+H)+ 291.1128, found
291.1129.
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General Methods for the Synthesis of Compounds 6aa and 6ab. The 60% NaH (7
mmol) powder was batched into tetrahydrofuran solution of methyloxazole 5a (2 mmol)
at room temperature and stirred for 30 min. To the reaction solution was added
iodomethane or benzyl chloride (6 mmol) and stirred for 1 h at room temperature and
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refluxed for 1 h. Water (200 mL) was added and extracted with CH2Cl2 (80 mL × 3).
The organic layer was washed with saturated NaCl solution (50 mL), dried with
anhydrous Na2SO4, filtered and concentrated in vacuum. The compounds 6aa and 6ab
were obtained by column chromatography on silica gel.
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2-Methyl-5-(1-methyl-1H-indol-3-yl)oxazole (6aa). Yellow solid; mp. 71−73 C;
yield 86%; 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 7.8 Hz, 1H, Ar-H), 7.73 (s,
1H, Ar-H), 7.50 (d, J = 8.1 Hz, 1H, Ar-H), 7.30 (s, 1H, Ar-H), 7.27 (d, J = 7.5 Hz, 1H,
Ar-H), 7.19 (d, J = 7.5 Hz, 1H, Ar-H), 3.83 (s, 3H, N-CH3), 2.48 (s, 3H, Ar-CH3); 13C
NMR (100 MHz, DMSO-d6) δ 158.3, 147.0, 136.8, 126.8, 123.7, 122.1, 120.1, 119.6,
119.2, 110.3, 103.0, 32.6, 13.5; HRMS (ESI) calcd for C13H13N2O (M+H)+ 213.1022,
found 213.1027.
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5-(1-Benzyl-1H-indol-3-yl)-2-methyloxazole (6ab). Yellow solid; mp. 94−96 C;
yield 88%; 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H, Ar-H), 7.87 (d, J = 7.7 Hz,
1H, Ar-H), 7.55 (d, J = 8.1 Hz, 1H, Ar-H), 7.15–7.32 (m, 7H, Ar-H), 5.48 (s, 2H, Ar-
CH2), 2.48 (s, 3H, Ar-CH3); 13C NMR (100 MHz, DMSO-d6) δ 158.4, 146.8, 137.7,
136.1, 128.6, 127.5, 127.2, 126.2, 124.0, 122.3, 120.3, 119.8, 119.5, 110.8, 103.7, 49.2,
13.5; HRMS (ESI) calcd for C19H17N2O (M+H)+ 289.1335, found 289.1337.
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General Methods for the Synthesis of Compounds 9a–9u. The reaction mixture of
1H-indole-3-carbohydrazide (7, 6 mmol) and corresponding aldehydes 8a–8u (6 mmol)
in anhydrous ethanol (80 mL) was stirred and refluxed at 90 oC for 4 h, then cooled to
room temperature and filtered to give compounds 9a–9u.
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(E)-N'-Benzylidene-1H-indole-3-carbohydrazide (9a). White solid; mp. 233−234 oC
(lit.20, 232−234 oC); yield 79%; 1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H, NH),
11.38 (s, 1H, NH), 8.20–8.33 (m, 3H, Ar-H), 7.72 (d, J = 7.3 Hz, 2H, Ar-H), 7.47 (s,
1H, Ar-CH), 7.38–7.49 (m, 3H, Ar-H), 7.14–7.22 (m, 2H, Ar-H); 13C NMR (100 MHz,
DMSO-d6) δ 134.7, 129.5, 128.8, 126.7, 122.2, 120.8, 111.9.
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(E)-N'-(4-Methoxybenzylidene)-1H-indole-3-carbohydrazide (9b). White solid; mp.
242−243 oC (lit.20, 239−241 oC); yield 90%; 1H NMR (400 MHz, DMSO-d6) δ 11.72
(s, 1H, NH), 11.27 (s, 1H, NH), 8.20–8.29 (m, 3H, Ar-H, Ar-CH), 7.66 (d, J = 8.6 Hz,
2H, Ar-H), 7.45 (d, J = 7.8 Hz, 1H, Ar-H), 7.15–7.20 (m, 2H, Ar-H), 7.03 (d, J = 8.7
Hz, 2H, Ar-H), 3.82 (s, 3H, OCH3); 13C NMR (100 MHz, DMSO-d6) δ 160.4, 128.3,
127.3, 122.2, 120.7, 114.3, 111.9, 55.2.
196
197
198
199
200
201
202
(E)-N'-(2-Bromobenzylidene)-1H-indole-3-carbohydrazide (9c). White solid; mp.
294−296 oC; yield 92%; 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H, NH), 11.71 (s,
1H, NH), 8.68 (s, 1H, Ar-H), 8.30 (s, 1H, Ar-CH), 8.23 (d, J = 7.3 Hz, 1H, Ar-H), 8.02
(dd, J = 6.6, 1.2 Hz, 1H, Ar-H), 7.70 (d, J = 8.0 Hz, 1H, Ar-H), 7.46–7.51 (m, 2H, Ar-
H), 7.33–7.37 (m, 1H, Ar-H), 7.16–7.24 (m, 2H, Ar-H); 13C NMR (100 MHz, DMSO-
d6) δ 136.0, 133.5, 130.1, 131.2, 128.0, 127.0, 123.1, 122.3, 120.9, 112.0; HRMS (ESI)
calcd for C16H13BrN3O (M+H)+ 342.0237, found 342.0239.
203
204
205
(E)-N'-(4-Nitrobenzylidene)-1H-indole-3-carbohydrazide (9d). Yellow solid; mp.
287−288 oC (lit.20, 289−291 oC); yield 92%; 1H NMR (400 MHz, DMSO-d6) δ 11.83
(d, J = 1.4 Hz, 1H, NH), 11.73 (s, 1H, NH), 8.38–8.43 (m, 1H, Ar-H), 8.31 (d, J = 8.8
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Hz, 2H, Ar-H), 8.29 (s, 1H, Ar-CH), 8.21 (d, J = 7.5 Hz, 1H, Ar-H), 7.98 (d, J = 8.8
Hz, 2H, Ar-H), 7.51 (d, J = 7.5 Hz, 1H, Ar-H), 7.16–7.24 (m, 2H, Ar-H); 13C NMR
(100 MHz, DMSO-d6) δ 147.4, 141.2, 136.0, 127.6, 124.1, 122.4, 121.1, 120.9, 112.0.
209
210
211
212
213
214
215
(E)-N'-(4-(Trifluoromethyl)benzylidene)-1H-indole-3-carbohydrazide (9e). White
o
1
solid; mp. 298−300 C; yield 53%; H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H,
NH), 11.61 (s, 1H, NH), 8.20–8.39 (m, 3H, Ar-H, Ar-CH), 7.94 (d, J = 8.1 Hz, 2H, Ar-
H), 7.82 (d, J = 8.2 Hz, 2H, Ar-H), 7.49 (d, J = 8.1 Hz, 1H, Ar-H), 7.15–7.23 (m, 2H,
Ar-H); 13C NMR (100 MHz, DMSO-d6) δ 139.2, 129.9, 129.5, 127.8, 126.3, 126.19,
126.15, 126.0, 122.9, 121.4, 112.5; HRMS (ESI) calcd for C17H13F3N3O (M+H)+
332.1005, found 332.1001.
216
217
218
219
220
221
(E)-N'-(Furan-2-ylmethylene)-1H-indole-3-carbohydrazide (9f). White solid; mp.
284−286 oC; yield 89%; 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H, NH), 11.35 (s,
1H, NH), 8.10–8.30 (m, 3H, Ar-H, NHN-CH), 7.84 (s, 1H, Ar-H), 7.48 (d, J = 7.8 Hz,
1H, Ar-H), 7.13–7.21 (m, 2H, Ar-H), 6.88 (d, J = 3.3 Hz, 1H, Ar-H), 6.64 (dd, J = 3.0,
1.6 Hz, 1H, Ar-H);13C NMR (100 MHz, DMSO-d6) δ 149.8, 144.6, 122.2, 120.8, 112.3,
112.1, 111.9; HRMS (ESI) calcd for C14H12N3O2 (M+H)+ 254.0924, found 254.0925.
222
223
224
225
226
(E)-N'-(Naphthalen-1-ylmethylene)-1H-indole-3-carbohydrazide (9g). White solid;
o
1
mp. 279−281 C; yield 86%; H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H, NH),
11.52 (s, 1H, NH), 8.90–9.10 (m, 2H, Ar-H, NCH), 8.20–8.30 (m, 2H, Ar-H), 8.00–
8.04 (m, 2H, Ar-H), 7.94 (d, J = 7.0 Hz, 1H, Ar-H), 7.68 (d, J = 7.1 Hz, 1H, Ar-H),
7.60–7.63 (m, 2H, Ar-H), 7.50 (d, J = 7.5 Hz, 1H, Ar-H), 7.16–7.24 (m, 2H, Ar-H); 13C
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NMR (100 MHz, DMSO-d6) δ 133.5, 130.1, 130.0, 128.8, 127.1, 126.2, 125.6, 122.3,
228
120.8, 112.0; HRMS (ESI) calcd for C20H16N3O (M+H)+ 314.1288, found 314.1284.
229
230
231
232
233
234
(E)-N'-((5-Bromo-1H-indol-3-yl)methylene)-1H-indole-3-carbohydrazide
(9h).
o
o
1
Brown solid; mp. 230−231 C (lit.21, 232−233 C); yield 78%; H NMR (400 MHz,
DMSO-d6) δ 11.74 (s, 2H, NH), 11.19 (s, 1H, NH), 8.53 (d, J = 4.8 Hz, 2H, Ar-H), 8.24
(d, J = 7.4 Hz, 1H, Ar-H), 8.20 (s, 1H, Ar-CH), 7.87 (s, 1H, Ar-H), 7.15–7.51 (m, 5H,
Ar-H); 13C NMR (100 MHz, DMSO-d6) δ 136.2, 131.3, 126.4, 125.5, 122.6, 121.1.
114.3, 113.4, 112.4.
235
236
237
238
239
240
(E)-N'-(Cyclohexylmethylene)-1H-indole-3-carbohydrazide (9i). White solid; mp.
284−286 oC; yield 67%; 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H, NH), 10.90 (s,
1H, NH), 8.02–8.14 (m, 2H, Ar-H), 7.53 (s, 1H, NHN-CH), 7.45 (d, J = 7.8 Hz, 1H,
Ar-H), 7.11–7.19 (m, 2H, Ar-H), 2.22–2.32 (m, 1H, NCH-CH), 1.63–1.82 (m, 5H, CH2),
1.19–1.36 (m, 5H, CH2); 13C NMR (100 MHz, DMSO-d6) δ 122.1, 120.6, 111.8, 29.8,
25.5, 25.0; HRMS (ESI) calcd for C16H20N3O (M+H)+ 270.1601, found 270.1607.
241
242
243
244
245
246
247
(E)-N'-Octylidene-1H-indole-3-carbohydrazide (9j). White solid; mp. 260−266 oC;
1
yield 56%; H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H, NH), 10.93 (s, 1H, NH),
8.12–8.16 (m, 2H, Ar-H, NCH), 7.55–7.64 (m, 1H, Ar-H), 7.45 (d, J = 7.9 Hz, 1H, Ar-
H), 7.10–7.19 (m, 2H, Ar-H), 2.24–2.28 (m, 2H, CH2), 1.49–1.52 (m, 2H, CH2), 1.20–
1.35 (m, 8H, CH2), 0.87 (t, J = 5.5 Hz, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ
122.1, 120.5, 111.8, 31.9, 31.2, 28.6, 28.5, 26.2, 22.0, 13.9; HRMS (ESI) calcd for
C17H24N3O (M+H)+ 286.1914, found 286.1910.
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249
250
251
252
253
(E)-N'-(3,4,5-Trimethoxybenzylidene)-1H-indole-3-carbohydrazide (9k). White
o
o
1
solid; mp. 243−245 C (lit.21, 245−246 C); yield 77%; H NMR (400 MHz, DMSO-
d6) δ 11.79 (s, 1H, NH), 11.43 (s, 1H, NH), 8.21–8.28 (m, 3H, Ar-H, Ar-CH), 7.49 (d,
J = 7.9 Hz, 1H, Ar-H), 7.14–7.22 (m, 2H, Ar-H), 7.02 (s, 2H, Ar-H), 3.85 (s, 6H, CH3),
3.71 (s, 3H, CH3);13C NMR (100 MHz, DMSO-d6) δ 153.2, 138.7, 130.3, 122.3, 120.8,
112.0, 103.9, 60.1, 55.9.
254
255
256
257
258
259
260
(E)-N'-(3-Hydroxy-4-methoxybenzylidene)-1H-indole-3-carbohydrazide
(9l).
White solid; mp. 248−250 oC; yield 88%; 1H NMR (400 MHz, DMSO-d6) δ 11.74 (s,
1H, NH), 11.25 (s, 1H, NH), 9.49 (s, 1H, OH), 8.15–8.30 (m, 3H, Ar-H, NHNC-H),
7.48 (d, J = 8.0 Hz, 1H, Ar-H), 7.31 (s, 1H, Ar-H), 7.13–7.21 (m, 2H, Ar-H), 7.07 (dd,
J = 8.1, 1.4 Hz, 1H, Ar-H), 6.85 (d, J = 8.1 Hz, 1H, Ar-H), 3.84 (s, 3H, OCH3); 13C
NMR (100 MHz, DMSO-d6) δ 148.4, 148.0, 126.2, 122.2, 120.7, 115.4, 111.9, 108.8,
55.5; HRMS (ESI) calcd for C17H16N3O3 (M+H)+ 310.1186, found 310.1191.
261
262
263
264
265
266
267
(E)-N'-(4-Hydroxybenzylidene)-1H-indole-3-carbohydrazide (9m). White solid;
o
1
mp. 296−298 C; yield 88%; H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H, NH),
11.22 (s, 1H, NH), 9.88 (s, 1H, OH), 8.12–8.30 (m, 3H, Ar-H, NHNC-H), 7.55 (d, J =
8.5 Hz, 2H, Ar-H), 7.48 (d, J = 7.8 Hz, 1H, Ar-H), 7.13–7.21 (m, 2H, Ar-H), 6.85 (d, J
= 8.5 Hz, 2H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ 158.9, 128.5, 125.7, 122.2,
120.7, 115.7, 111.9; HRMS (ESI) calcd for C16H14N3O2 (M+H)+ 280.1081, found
280.1086.
268
(E)-N'-(4-Fluorobenzylidene)-1H-indole-3-carbohydrazide (9n). White solid; mp.
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248−252 oC; yield 91%; 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H, NH), 11.42 (s,
1H, NH), 8.19–8.40 (m, 3H, Ar-H, NHNC-H), 7.78 (dd, J = 8.6, 5.7 Hz, 2H, Ar-H),
7.48 (d, J = 7.6 Hz, 1H, Ar-H), 7.27–7.32 (m, 2H, Ar-H), 7.13–7.22 (m, 2H, Ar-H); 13C
NMR (100 MHz, DMSO-d6) δ 164.0, 161.5, 131.3, 128.9, 128.8, 122.2, 121.1, 120.8,
115.9, 115.7, 111.9; HRMS (ESI) calcd for C16H13FN3O (M+H)+ 282.1037, found
282.1042.
270
271
272
273
274
275
276
277
278
279
280
281
282
(E)-N'-(2-Nitrobenzylidene)-1H-indole-3-carbohydrazide (9o). Yellow solid; mp.
275−277 oC; yield 86%; 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H, NH), 11.79 (s,
1H, NH), 8.73 (s, 1H, Ar-H), 8.30 (s, 1H, Ar-CH), 8.23 (d, J = 7.5 Hz, 1H, Ar-H), 8.16
(d, J = 7.7 Hz, 1H, Ar-H), 8.08 (dd, J = 8.2, 1.0 Hz, 1H, Ar-H), 7.82 (t, J = 7.7 Hz, 1H,
Ar-H), 7.64–7.68 (m, 1H, Ar-H), 7.50 (d, J = 7.9 Hz, 1H, Ar-H), 7.16–7.24 (m, 2H, Ar-
H); 13C NMR (100 MHz, DMSO-d6) δ 148.0, 136.0, 133.6, 130.1, 129.1, 127.7. 124.6,
122.3, 121.1, 120.9, 112.0; HRMS (ESI) calcd for C16H13N4O3 (M+H)+ 309.0982,
found 309.0985.
283
284
285
286
287
288
289
(E)-N'-(Quinolin-4-ylmethylene)-1H-indole-3-carbohydrazide (9p). Yellow solid;
mp. > 300 oC; yield 77%; 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H, NH), 11.79
(s, 1H, NH), 8.99 (d, J = 4.5 Hz, 1H, Ar-H), 8.97 (s, 1H, Ar-H), 8.78 (s, 1H, NHNC-
H), 8.34 (s, 1H, Ar-H), 8.25 (d, J = 7.4 Hz, 1H, Ar-H), 8.12 (d, J = 8.4 Hz, 1H, Ar-H),
7.82–7.86 (m, 2H, Ar-H), 7.75 (t, J = 7.9 Hz, 1H, Ar-H), 7.52 (d, J = 7.9 Hz, 1H, Ar-
H), 7.18–7.25 (m, 2H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ 150.8, 148.9, 138.4,
136.5, 130.2, 130.1, 127.9, 125.2, 122.9, 121.5, 112.6; HRMS (ESI) calcd for
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C19H15N4O (M+H)+ 315.1240, found 315.1237.
291
292
293
294
295
296
(E)-N'-((1H-Pyrrol-2-yl)methylene)-1H-indole-3-carbohydrazide (9q). Gray solid;
o
1
mp. 253−255 C; yield 52%; H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H, NH),
11.45 (s, 1H, NH), 11.09 (s, 1H, NH), 8.13–8.20 (m, 3H, Ar-H, NHNC-H), 7.47 (d, J
= 7.8 Hz, 1H, Ar-H), 7.12–7.20 (m, 2H, Ar-H), 6.92 (s, 1H, Ar-H), 6.45 (s, 1H, Ar-H),
6.15 (s, 1H, Ar-H);13C NMR (100 MHz, DMSO-d6) δ 128.0, 122.6, 122.3, 121.1, 112.9,
112.4, 109.6; HRMS (ESI) calcd for C14H13N4O (M+H)+ 253.1084, found 253.1080.
297
298
299
300
301
302
(E)-N'-(Thiophen-2-ylmethylene)-1H-indole-3-carbohydrazide (9r). Yellow solid;
o
o
1
mp. 265−267 C (lit.21, 269−271 C); yield 93%; H NMR (400 MHz, DMSO-d6) δ
11.78 (s, 1H, NH), 11.36 (s, 1H, NH), 8.58 (s, 1H, Ar-H), 8.21 (s, 2H, Ar-H, NHNC-
H), 7.63 (s, 1H, Ar-H), 7.48 (d, J = 7.1 Hz, 1H, Ar-H), 7.43 (s, 1H, Ar-H), 7.14–7.20
(m, 3H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ 128.0, 122.6, 122.3, 121.1, 112.9,
112.4, 109.6.
303
304
305
306
307
308
(E)-N'-(Pyridin-4-ylmethylene)-1H-indole-3-carbohydrazide (9s). Gray solid; mp.
o
1
> 300 C; yield 54%; H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H, NH), 11.70 (s,
1H, NH), 8.65 (d, J = 5.6 Hz, 2H, Ar-H), 8.28–8.39 (m, 2H, Ar-H, NHNC-H), 8.23 (d,
J = 7.4 Hz, 1H, Ar-H), 7.67 (d, J = 5.7 Hz, 2H, Ar-H), 7.51 (d, J = 7.8 Hz, 1H, Ar-H),
7.16–7.24 (m, 2H, Ar-H);13C NMR (100 MHz, DMSO-d6) δ 150.6, 142.4, 122.9, 121.5,
121.3, 112.5; HRMS (ESI) calcd for C15H13N4O (M+H)+ 265.1084, found 265.1086.
309
310
(E)-N'-Butylidene-1H-indole-3-carbohydrazide (9t). White solid; mp. 238−240 oC;
1
yield 77%; H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H, NH), 10.95 (s, 1H, NH),
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8.02–8.34 (m, 2H, Ar-H), 7.60 (s, 1H, NHN-CH), 7.45 (d, J = 7.8 Hz, 1H, Ar-H), 7.11–
7.19 (m, 2H, Ar-H), 2.25 (dd, J = 6.9, 13.1 Hz, 2H, NCH-CH2), 1.49–1.58 (m, 2H, CH3-
CH2), 0.95 (t, J = 7.3 Hz, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ 122.1, 120.6,
111.8, 33.9, 19.5, 13.6; HRMS (ESI) calcd for C13H16N3O (M+H)+ 230.1288, found
230.1283.
312
313
314
315
316
317
318
319
320
321
(E)-N'-(2-Methylpropylidene)-1H-indole-3-carbohydrazide (9u). White solid; mp.
197−199 oC; yield 81%; 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H, NH), 10.93 (s,
1H, NH), 8.10–8.30 (m, 2H, Ar-H), 7.16 (s, 1H, NHNC-H), 7.44–7.47 (m, 1H, Ar-H),
7.12–7.19 (m, 2H, Ar-H), 2.50–2.55 (m, 1H, (CH3)2C-H), 1.10 (s, 3H, CH3), 1.08 (s,
3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ 122.6, 121.1, 112.3, 31.4, 20.2; HRMS
(ESI) calcd for C13H16N3O (M+H)+ 230.1288, found 230.1283.
322
323
324
325
326
327
328
General Methods for the synthesis of Compounds 10a–10j. The reaction mixture of
corresponding carbohydrazides 9a–9j (3 mmol) and iodobenzene diacetate (6 mmol) in
o
acetonitrile (60 mL) was stirred at 50 C for 2 h. The acetonitrile was removed in
vacuum. Ethyl acetate (150 mL) was added and washed with saturated Na2CO3 solution
(80 mL), brine (80 mL) and dried with anhydrous Na2SO4, filtered and concentrated in
vacuum. The compounds 10a–10j were obtained by column chromatography on silica
gel.
o
329
330
331
2-(1H-Indol-3-yl)-5-phenyl-1,3,4-oxadiazole (10a). White solid; mp. 269−271 C;
yield 72%; 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H, NH), 8.34 (d, J = 2.9 Hz,
1H, Ar-H), 8.20 (t, J = 5.0 Hz, 1H, Ar-H), 8.14–8.16 (m, 2H, Ar-H), 7.64–7.66 (m, 3H,
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332
333
334
335
Ar-H), 7.57–7.59 (m, 1H, Ar-H), 7.29–7.31 (m, 2H, Ar-H); C NMR (100 MHz,
DMSO-d6) δ 162.0, 161.8, 136.5, 131.5, 129.4, 128.6, 126.3, 124.1, 123.7, 122.9, 121.3,
120.2, 112.5, 99.4; HRMS (ESI) calcd for C16H12N3O (M+H)+ 262.0975, found
262.0971.
336
337
338
339
340
341
342
2-(1H-Indol-3-yl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole (10b). White solid; mp.
276−277 oC; yield 69%; 1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H, NH), 8.07 (d,
J = 8.8 Hz, 1H, Ar-H), 7.75 (d, J = 8.0 Hz, 2H, Ar-H), 7.56 (d, J = 8.1 Hz, 1H, Ar-H),
7.40 (t, J = 7.4 Hz, 1H, Ar-H), 7.27–7.31 (m, 1H, Ar-H), 7.19 (t, J = 7.7 Hz, 3H, Ar-
H), 3.88 (s, 3H, OCH3); 13C NMR (100 MHz, DMSO-d6) δ 172.5, 162.2, 137.6, 135.0,
131.1, 128.6, 128.2, 123.8, 122.1, 118.9, 115.3, 113.4, 56.0; HRMS (ESI) calcd for
C17H14N3O2 (M+H)+ 292.1081, found 292.1087.
343
344
345
346
347
348
349
2-(2-Bromophenyl)-5-(1H-indol-3-yl)-1,3,4-oxadiazole (10c). Brown solid; mp.
236−238 oC; yield 78%; 1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H, NH), 8.29 (s,
1H, Ar-H), 8.18 (d, J = 5.3 Hz, 1H, Ar-H), 8.07 (d, J = 7.2 Hz, 1H, Ar-H), 7.92 (d, J =
7.7 Hz, 1H, Ar-H), 7.64 (t, J = 6.8 Hz, 1H, Ar-H), 7.57 (d, J = 5.5 Hz, 2H, Ar-H), 7.29
(d, J = 5.9 Hz, 2H, Ar-H);13C NMR (100 MHz, DMSO-d6) δ 162.8, 161.6, 137.0, 134.8,
133.4, 132.1, 129.2, 128.7, 125.6, 124.6, 123.4, 121.9, 121.3, 120.6, 113.0, 99.6; HRMS
(ESI) calcd for C16H11BrN3O (M+H)+ 340.0080, found 340.0081.
350
351
352
2-(1H-Indol-3-yl)-5-(4-nitrophenyl)-1,3,4-oxadiazole (10d). Gray solid; mp. >300 oC;
1
yield 66%; H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H, NH), 8.47 (s, 1H, Ar-H),
8.45 (s, 1H, Ar-H), 8.35–8.39 (m, 3H, Ar-H), 8.18 (t, J = 5.0 Hz, 1H, Ar-H), 7.56–7.58
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(m, 1H, Ar-H), 7.29–7.31 (m, 2H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ 163.4,
161.1, 149.3, 137.0, 129.73, 129.70. 128.0, 125.1, 124.5, 123.5, 121.9, 120.7, 113.1,
99.5; HRMS (ESI) calcd for C16H11N4O3 (M+H)+ 307.0826, found 307.0822.
354
355
356
357
358
359
360
361
362
2-(1H-Indol-3-yl)-5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazole (10e). Light
yellow solid; mp. 288−290 oC; yield 82%; 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s,
1H, NH), 8.37 (d, J = 2.9 Hz, 1H, Ar-H), 8.34 (d, J = 8.1 Hz, 2H, Ar-H), 8.19 (t, J =
5.0 Hz, 1H, Ar-H), 8.01 (d, J = 8.3 Hz, 2H, Ar-H), 7.57–7.59 (m, 1H, Ar-H), 7.28–7.33
(m, 2H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ 163.0, 161.4, 136.9, 127.7, 126.8,
124.5. 123.5, 121.9, 120.6, 113.1, 99.6; HRMS (ESI) calcd for C17H11F3N3O (M+H)+
330.0849, found 330.0844.
363
364
365
366
367
368
369
2-(Furan-2-yl)-5-(1H-indol-3-yl)-1,3,4-oxadiazole (10f). Gray solid; mp. 214−216 oC;
yield 61%; 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H, NH), 8.27 (d, J = 2.9 Hz,
1H, Ar-H), 8.16 (dd, J = 3.4, 6.5 Hz, 1H, Ar-H), 8.09 (d, J = 1.1 Hz, 1H, Ar-H), 7.57
(dd, J = 2.0, 5.5 Hz, 1H, Ar-H), 7.41 (d, J = 3.5 Hz, 1H, Ar-H), 7.26–7.32 (m, 2H, Ar-
H), 6.84 (dd, J = 1.8, 3.5 Hz, 1H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ 161.7,
155.4, 147.0, 139.5, 136.9, 129.1. 124.5, 123.4, 121.8, 120.7, 114.3, 113.1, 113.0, 99.5;
HRMS (ESI) calcd for C14H10N3O2 (M+H)+ 252.0768, found 252.0765.
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371
372
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2-(1H-Indol-3-yl)-5-(naphthalen-1-yl)-1,3,4-oxadiazole (10g). Gray solid; mp.
186−188 oC; yield 70%; 1H NMR (400 MHz, CDCl3) δ 9.37 (d, J = 8.6 Hz, 1H, Ar-H),
9.23 (s, 1H, NH), 8.38 (d, J = 7.1 Hz, 1H, Ar-H), 8.30 (d, J = 7.2 Hz, 1H, Ar-H), 8.11
(d, J = 2.6 Hz, 1H, Ar-H), 8.06 (d, J = 8.3 Hz, 1H, Ar-H), 7.97 (d, J = 8.2 Hz, 1H, Ar-
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H), 7.70–7.76 (m, 1H, Ar-H), 7.61–7.66 (m, 2H, Ar-H), 7.53–7.58 (m, 2H, Ar-H), 7.34–
7.39 (m, 1H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ 161.8, 161.5, 136.5, 133.5,
132.2, 129.3, 128.9, 128.2, 128.1, 126.8, 125.7, 125.4, 124.2, 122.9, 121.3, 120.2, 120.0,
112.5. 99.3; HRMS (ESI) calcd for C20H14N3O (M+H)+ 312.1131, found 312.1137.
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2-(5-Bromo-1H-indol-3-yl)-5-(1H-indol-3-yl)-1,3,4-oxadiazole (10h). Gray solid;
o
1
mp. 291−292 C; yield 49%; H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H, NH),
12.04 (s, 1H, NH), 8.34 (s, 2H, Ar-H), 8.26 (s, 1H, Ar-H), 8.22 (d, J = 6.4 Hz, 1H, Ar-
H), 7.58 (d, J = 1.9 Hz, 1H, Ar-H), 7.55 (d, J = 8.6 Hz, 1H, Ar-H), 7.43 (d, J = 8.6 Hz,
1H, Ar-H), 7.29 (t, J = 3.6 Hz, 2H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ 160.4,
159.7, 137.0, 135.8, 129.7, 126.3. 124.5, 123.4, 123.0, 120.9, 115.0, 112.9, 100.1, 99.9;
HRMS (ESI) calcd for C18H12BrN4O (M+H)+ 379.0189, found 379.0181.
385
386
387
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389
390
391
2-Cyclohexyl-5-(1H-indol-3-yl)-1,3,4-oxadiazole (10i). White solid; mp. 197−198 oC;
yield 51%; 1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H, NH), 8.13 (d, J = 2.8 Hz,
1H, Ar-H), 8.08 (d, J = 7.0 Hz, 1H, Ar-H), 7.53 (dd, J = 6.5, 1.2 Hz, 1H, Ar-H), 7.23–
7.27 (m, 2H, Ar-H), 2.98–3.05 (m, 1H, Ar-CH), 2.07–2.11 (m, 2H, ArCH-CH2), 1.76–
1.81 (m, 2H, ArCH-CH2), 1.28–1.69 (m, 6H, ArCHCH2-(CH2)3); 13C NMR (100 MHz,
DMSO-d6) δ 167.7, 167.1, 136.9, 128.2, 123.2, 121.6. 120.6, 112.8, 100.1, 34.6, 30.2,
25.7, 25.2; HRMS (ESI) calcd for C16H18N3O (M+H)+ 268.1444, found 268.1449.
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393
394
2-Heptyl-5-(1H-indol-3-yl)-1,3,4-oxadiazole (10j). Gray solid; mp. 176−177 oC; yield
46%; 1H NMR (400 MHz, CDCl3) δ 9.23 (d, J = 108.1 Hz, 1H, NH), 8.25–8.38 (m, 1H,
Ar-H), 7.84 (dd, J = 2.6, 64.6 Hz, 1H, Ar-H), 7.46–7.57 (m, 1H, Ar-H), 7.32–7.35 (m,
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2H, Ar-H), 4.10–4.33 (m, 2H, CH2), 2.80–2.98 (m, 2H, CH2), 1.85–2.09 (m, 3H, CH2),
1.25–1.58 (m, 8H, CH2, CH3); 13C NMR (100 MHz, DMSO-d6) δ 164.3, 161.6, 136.4,
127.7, 124.1, 122.7, 121.0, 120.2, 112.3, 31.1, 28.3, 28.2, 26.0, 24.4, 22.0, 13.9; HRMS
(ESI) calcd for C17H22N3O (M+H)+ 284.1757, found 284.1752.
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400
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Biological Assay. The biological activity of target compounds were tested on the
corresponding test tissues. To ensure the accuracy of the data, each group of tests was
repeated at least three times. The activity data were expressed as percentage inhibition
rates ranging from 0 to 100 (0 means no activity, 100 means total inhibition).
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404
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Antiviral Biological Assay. The anti-TMV activities of target compounds were obtained
by using reported methods10 with tobacco (Nicotianatobaccum var. Xanthi-nc) as the
test plant. The detailed procedures also can be seen in Supporting Information.
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Phytotoxic Activity. The growing 5–6 leaf stage tobaccos (Nicotiana tabacum var
Xanthi nc) were selected. The compound solution (500 µg/mL) was smeared on the
leaves and calculated the number of lesions after 3-4 days.
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Antifungal Biological Assay. The fungicidal activities of target compounds were
obtained by using literature methods.22 The detailed procedures also can be seen in
Supporting Information.
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RESULTS AND DISCUSSION
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Chemistry. Till now, the synthesis of pimprinine has been accomplished by Joshi23,
Molina24, Wu19 and Zhou25. Considering a series of derivatives of pimprinine would be
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needed, Wu’s method was selected and optimized (Figure 3).25 2-Oxoacetaldehyde 3
and corresponding amino acids underwent decarboxylation coupling reaction to give
5a–5l in 39%–83% yields. Indole nitrogen substituted products 6aa and 6ab were
prepared (Figure 4) to evaluate the influence of the NH on activity.
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1,3,4-Oxadiazole is a very good bioisostere of amide and ester functional group.
Compounds containing a 1,3,4-oxadiazole ring often exhibit broad-spectrum biological
activities, such as anticancer26, antifungal27 and anti-HIV28. On the basis of the principle
of combination of active structural moieties, a series of pimprinine derivatives
containing a 1,3,4-oxadiazole ring were reasonably designed and prepared (Figure 5).
The reaction of hydrazide 7 with a number of aldehydes 8a–8u gave acylhydrazones
9a–9u (Figures 5 and 6). It is well known that acylhydrazone compounds may exist as
isomers (E/Z) due to the carbon-nitrogen double bonds and the rotamers (cis/trans)
caused by amide N–C(O) bond.29,30 The hydrazones prepared from aldehydes and
hydrazides exists in E-form in solution.29 For acylhydrazones 9a–9u, only E form were
detected by NMR in DMSO-d6. Acylhydrazones 9a–9j were transformed into
oxadiazoles 10a–10j by reacting with iodobenzene diacetate.
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Phytotoxic Activity. The first phytotoxic activity evaluation indicated that pimprinine
alkaloids and their derivatives 5a–5l, 6aa, 6ab, 7, 9a–9u and 10a–10j displayed no
phytotoxic activity to the tested tobaccos at 500 μg/mL. No local lesion appear on the
tobacco leaves.
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Antiviral Activity. The antiviral activities of pimprinine alkaloids and their derivatives
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5a–5l, 6aa, 6ab, 7, 9a–9u and 10a–10j against TMV was shown in Table 1. Currently
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widely used antivirals ribavirin and ningnanmycin were selected as the controls.
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In Vitro Anti-TMV Activity. The in vitro anti-TMV activities of pimprinines 5a–5l, 6aa,
6ab, 7, 9a–9u and 10a–10j were first tested. Compounds 5g, 5j–5l, 9d, 9e, 9h, 9m, 9o,
9p, 9s, 10c, 10d, 10g and 10h exhibited higher in vitro anti-TMV activities than
ribavirin, in which, compounds 5l, 9h and 10h displayed similar or higher antiviral
activities than ningnanmycin (perhaps the most widely used antiviral agent at present).
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Pimprinine (5a) showed about similar TMV inhibitory effect with compounds 6aa
and 6ab, which indicated that the modification of indole nitrogen is tolerant. The main
difference between 5a–5f lies in the size of alkyl substituents, 5c and 5e showed higher
inhibitory effect than the others which indicated that increasing steric hindrance is
beneficial to the activity. Compounds 5c and 5e exhibited higher inhibitory effect than
pimprinine (5a) which indicated that the introduction of hydroxyl and methylthio
groups is favorable for the activity. The replacement of methyl with phenyl maintained
activity (inhibitory effect: 5a ≈ 5i). However, the replacement of methyl with 4-F
phenyl significantly increased activity (inhibitory effect: 5j > 5a) which indicated that
the 2-position of pimprinine is a substituent effect sensitive region. Pimprinaphine (5k)
displayed significantly higher activity than pimprinine (5a) and 5i which indicated that
the benzyl is more beneficial to the activity. Introduction of hydroxy into benzyl further
increased antiviral activity (inhibitory effect: 5l > 5k). The replacement of oxazole ring
with oxadiazole ring increased antiviral activity (inhibitory effect: 10a > 5i, 10i > 5f).
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The mainly difference between 10a–10e lies in the phenyl substituents, electron
deficient substituents are more beneficial to the activity (inhibitory effect: 10d > 10e >
10b). Ortho bromophenyl substituent 10c showed higher inhibitory effect than the
others. The replacement of phenyl with furany and alkyls decreased antiviral activity
(inhibitory effect: 10a > 10f ≈ 10i ≈ 5j). Naphthyl and indolyl substituents 10g and 10h
displayed about similar activities with 10c.
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N-Acylhydrazones also play an important role in medicinal chemistry, as they
display broad-spectrum biological activities, such as antiviral31, anticonvulsant32 and
antitrypanosomal33. As the ring open products, 7 and 9a–9u were also tested for their
antiviral activities. The results revealed that acylhydrazones 9a–9u also showed good
antiviral activities. Compounds 9d, 9e, 9h, 9m, 9o, 9p and 9s showed higher activities
than ribavirin, especially for compound 9h displayed about similar activity to
ningnanmycin. As the ring open products of 10a–10j, 9a–9j displayed lower antiviral
activities than 10a–10j except for 9e (inhibitory effect: 9e > 10e) which indicated that
the open of oxadiazole ring is bad for antiviral activity. The alkyl substituted derivatives
9i, 9j, 9t and 9u exhibited relatively lower activities than the others. Among the phenyl
substituted derivatives 9a–9e and 9k–9o, electron deficient substituted compounds 9d,
9e, 9o and hydroxyl substituted compound 9m showed relatively higher activities.
Heterocyclic substituted derivatives 9f, 9q and 9r displayed about similar activities
with 9a. Compounds 9h and 9p exhibited excellent antiviral activities.
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In Vivo Anti-TMV Activity Pimprinine alkaloids and their derivatives 5a–5l, 6aa, 6ab,
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7, 9a–9u and 10a–10j also were evaluated for their in vivo anti-TMV activities. Most
of these compounds displayed good activities. Compounds 5l, 9h and 10h displayed
significantly higher in vivo activities than ribavirin. The SARs of in vivo activity are
similar to that of in vitro activity. The EC50 values of compounds 5l, 9h and 10h for
protection effect were further investigated to further confirm the activity data. As shown
in Table 2, ribavirin displayed 694 μg/mL EC50 value which is significantly higher than
that of compounds 5l, 9h and 10h. Ningnanmycin showed 203 μg/mL EC50 value which
is slightly lower than that of 5l (211 μg/mL) and higher than that of 9h (190 μg/mL)
and 10h (180 μg/mL). Compounds 5l, 9h and 10h with similar or higher antiviral
activities than ningnanmycin emerged as new lead compounds for antiviral research.
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Fungicidal Activity. The in vitro fungicidal activities of pimprinine alkaloids and their
derivatives 5a–5l, 6aa, 6ab, 7, 9a–9u and 10a–10j were also tested against 14 kinds of
phytopathogenic fungi. Currently widely used fungicides carbendazim and
chlorothalonil were selected as the controls.
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As shown in Table 3, all the tested compounds showed broad-spectrum in vitro
fungicidal activities at 50 µg/mL. The fungicidal activities of 5d, 6aa and 6ab are
higher than that of carbendazim against Cercospora arachidicola Hori. The fungicidal
activities of compounds 5b, 5k and 9i are higher than that of carbendazim against
Physalospora piricola. Compounds 5d, 5j, 6aa, 6ab and 9a exhibited higher fungicidal
activities than did carbendazim against Rhizoctonia cerealis. The fungicidal activities
of 5g against Bipolaris maydis were higher than that of chlorothalonil. The fungicidal
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activities of 6ab and 9a against Alternaria solani and 5c, 5g, 6aa, 6ab, 9h, 9i and 9o
against Botrytis cinerea were higher than that of carbendazim.
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In Summary, pimprinine alkaloids and their derivatives 5a–5l, 6aa, 6ab, 7, 9a–9u
and 10a–10j were synthesized and evaluated systematically for their antiviral and
fungicidal activities. The anti-TMV activities of these compounds were discovered for
the first time. Compounds 5l, 9h and 10h with simple structure showed similar or higher
in vivo anti-TMV activities than ningnanmycin, thus emerged as new antiviral pilot
compounds. The modification of indole nitrogen is tolerant for antiviral research. The
replacement of oxazole ring with oxadiazole ring increased antiviral activity. As the
ring open products, acylhydrazones 9a–9u were also found to possess good antiviral
activity. Moreover, all the synthesized compounds were found to have broad-spectrum
in vitro fungicidal activities. This study laid a solid foundation for the application of
pimprinine alkaloids and their derivatives in plant protection.
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FUNDING
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We gratefully acknowledge assistance from National Natural Science Foundation of
China (21772145, 21732002, 21672117), Tianjin Natural Science Foundation
(16JCZDJC32400), the Foundation of Development Program of Future Expert in
Tianjin Normal University (WLQR201703), Training Program of Outstanding Youth
Innovation Team of Tianjin Normal Uiversity and the Program for Innovative Research
Team in University of Tianjin (TD13-5074).
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NOTES
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The authors declare no competing financial interest.
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SUPPORTING INFORMATION
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Biological assay procedures, 1H and 13C NMR spectra of pimprinine alkaloids and their
derivatives 5a–5l, 6aa, 6ab, 7, 9a–9u and 10a–10j. This material is available free of
charge via the Internet at http://pubs.acs.org.
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