Design, synthesis, and antifungal activity of novel aryl-1,2,3-triazole-β-carboline hybrids

Article abstract of DOI:10.3390/molecules23061344

The copper catalytic azide and terminal alkyne cycloaddition reaction, namely “click chemistry”, gives a new and convenient way to create l,4-disubstitutd-l,2,3-triazoles. In this work, 2-pyrrolecarbaldiminato–Cu(II) complexes were established as efficient catalysts for the three-component 1,3-dipolar cycloaddition reaction of arylboronic acid and sodium azide (NaN₃) with terminal alkynes in ethanol at room temperature to 50 ^?C, 1,4-disubstituted 1,2,3-triazoles were synthesized. Following the optimized protocol, two series of new aryl-1,2,3-triazole-β-carboline hybrids have been designed and synthesized, and the chemical structures were characterized by ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry (HRMS). All of the target compounds were evaluated in vitro for their antifungal activity against Rhizoctorzia solani, Fusarium oxysporum, Botrytis cinerea Pers., sunflower sclerotinia rot, and rape sclerotinia rot by mycelia growth inhibition assay at 50 μg/mL. The antifungal evaluation of the novel hybrids showed that, among the tested compounds, 5a, 5b, 5c, and 9b showed good antifungal activity against sunflower sclerotinia rot. Specifically, compound 9b also exhibited high broad-spectrum fungicidal against all the tested fungi with inhibition rates of 58.3%, 18.52%, 63.07%, 84.47%, and 81.23%. However, for F. oxysporum, all the target compounds showed no in vitro antifungal activities with an inhibition rate lower than 20%. These results provide an encouraging framework that could lead to the development of potent novel antifungal agents.

Full text of DOI:10.3390/molecules23061344

molecules
Article
Design, Synthesis, and Antifungal Activity of Novel
Aryl-1,2,3-Triazole-β-Carboline Hybrids
Xin-Yu Huo 1,†, Liang Guo 1,†, Xiao-Fei Chen 1, Yue-Ting Zhou 2, Jie Zhang 1,*,
Xiao-Qiang Han 2,
*
and Bin Dai 1,
*
ID
1
School of Chemistry and Chemical Engineering, Key Laboratory for Green Processing of Chemical
Engineering of Xinjiang Bingtuan, Shihezi University, Shihezi 832003, China;
shz_hxy1993@sina.com (X.-Y.H.); guoliang_xj@163.com (L.G.); mykoob@163.com (X.-F.C.)
Key Laboratory at Universities of Xinjiang Uygur Autonomous Region for Oasis Agricultural Pest
Management and Plant Protection Resource Utilization, College of Agricultural, Shihezi University,
Shihezi 832003, China; zhouyueting@stu.shzu.edu.cn
2
*
Correspondence: zhangjie-xj@163.com (J.Z.); hanshz@shzu.edu.cn (X.-Q.H.); db_tea@shzu.edu.cn (B.D.);
Tel.: +86-993-205-7215 (J.Z.); +86-993-205-8060 (X.-Q.H.); +86-993-205-8176 (B.D.)
These authors contributed equally to this work.
†
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 4 May 2018; Accepted: 31 May 2018; Published: 4 June 2018
Abstract: The copper catalytic azide and terminal alkyne cycloaddition reaction, namely “click
chemistry”, gives a new and convenient way to create l,4-disubstitutd-l,2,3-triazoles. In this
work, 2-pyrrolecarbaldiminato–Cu(II) complexes were established as efficient catalysts for the
three-component 1,3-dipolar cycloaddition reaction of arylboronic acid and sodium azide (NaN3)
with terminal alkynes in ethanol at room temperature to 50 ◦C, 1,4-disubstituted 1,2,3-triazoles were
synthesized. Following the optimized protocol, two series of new aryl-1,2,3-triazole-β-carboline
hybrids have been designed and synthesized, and the chemical structures were characterized by
1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS). All of the target compounds
were evaluated in vitro for their antifungal activity against Rhizoctorzia solani, Fusarium oxysporum,
Botrytis cinerea Pers., sunflower sclerotinia rot, and rape sclerotinia rot by mycelia growth inhibition
assay at 50
µg/mL. The antifungal evaluation of the novel hybrids showed that, among the tested
compounds, 5a
,
5b 5c, and 9b showed good antifungal activity against sunflower sclerotinia rot.
,
Specifically, compound 9b also exhibited high broad-spectrum fungicidal against all the tested fungi
with inhibition rates of 58.3%, 18.52%, 63.07%, 84.47%, and 81.23%. However, for F. oxysporum, all the
target compounds showed no in vitro antifungal activities with an inhibition rate lower than 20%.
These results provide an encouraging framework that could lead to the development of potent novel
antifungal agents.
Keywords: β-carboline; 1,2,3-trizole; antifungal activity; structure–activity relationships
1. Introduction
Plant pathogenic microorganisms could infect crops and cause local or whole plant disease,
which leads to significant economic losses [
pesticides on the environment and human health has been of great concern, which highlights the
need for environmentally-friendly pesticides to protect crops from insect infestation [ ]. Therefore,
plant-derived extracts and their bioactive natural compounds have been considered bio-rational
alternatives [ ]. Additionally, further modification and structural optimization of novel insecticides
leading from the plant origin have recently been important methods for the research and development
of new pesticides [ ]. Harmine, harman, and harmol, belonging to the -carboline alkaloid class, are
1]. In recent years, the potential impact of synthetic
2
3
4
β
Molecules 2018, 23, 1344; doi:10.3390/molecules23061344
www.mdpi.com/journal/molecules

Molecules 2018, 23, 1344
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present in medicinal plants, such as Peganum harmala L. [5]. The reported biological applications
of
β-carboline alkaloids include sedative and anxiolytic [
6], antitumor [7,8], antimalarial [8],
antiparasitic [9], anti-HIV [10] agents, and other pharmacological activities. As for pest management,
the extracts of Peganum harmala L. plant species containing a mixture of harmine, harmaline,
and norharman, as well as their derivatives, had been proven to have excellent insecticidal,
fungicidal, and plant growth regulatory properties [11–17]. In our previous work [18], we found
that 9-fluorosubstituted-harmine displayed higher fungicidal activities against Rhizoctonia solani,
Rape sclerotinia rot, and Alternaria kikuchiana Tanaka.
l,2,3-Triazole and its derivatives as an important class of nitrogen-containing aromatic heterocyclic
compounds have attracted a great deal of interest due to their diverse biological activities, such
as anticancer [19,20] and antifungal [20] activities, and other properties [21,22]. Meanwhile, the
1,2,3-triazole moiety is stable with regard to metabolic degradation, and capable of hydrogen bonding,
which could be favorable in binding of biomolecular targets and increasing solubility [23]. Moreover,
1,2,3-triazoles can be attractive as linker units, which could connect two pharmacophores to give an
innovative bifunctional drug, and have become increasingly useful and important in constructing
bioactive molecules [24,25].
Accordingly, in an attempt to improve activity of
β-carboline derivatives, in this paper, we
synthesized two series of novel aryl-1,2,3-triazole-
activities were evaluated in vitro.
β-carboline hybrids (see Figure 1). Their antifungal
Figure 1. Designed strategy of aryl-1,2,3-triazole-β-carboline hybrids.
2. Results and Discussion
2.1. Chemistry
The synthesis of the desired key intermediate 1-methyl-9-(prop-2-yn-1-yl)-
performed in three steps starting from L-tryptophan, which was outlined in Scheme 1. The synthetic
step involved the Pictet–Spengler condensation [ ], and was followed by oxidation and decarboxylation
to afford the intermediate 1-methyl- -carboline (
). In the next step, the N9-alkylated of compound
was prepared by the action of sodium hydride (NaH) in anhydrous N,N-dimethylformamide (DMF)
β-carboline (3) was
6
β
2
2
followed by addition of propargyl bromide to afford compound
group required for click chemistry.
3, which incorporates an alkynyl
A number of synthetic methodologies [19
1,2,3-triazole. In our previous investigation [28
,
26
,27] are available in the literature for the synthesis of
,
29], we have found that 2-pyrrolecarbaldiminato-Cu(II)
complexes are efficient catalysts, which affords the 1-benzyl-1,2,3-triazoles in good yields. In order
to improve the selectivity of the reaction, we have studied the reaction conditions by screening
various catalysts. Initially, the cycloaddition reaction between phenylboronic acid, NaN3, and
1-methyl-9-propargyl-β-carboline (3) was selected as a model reaction to investigate the catalytic

Molecules 2018, 23, 1344
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activity of four different 2-pyrrolecarbaldiminato–Cu(II) complexes, and the results are summarized
in Table 1. It was found that the azidonation reaction of phenylboronic acid with NaN3 proceeded
smoothly within 8 h in the presence of the four Cu(II) complexes with 1 mol % loa◦ding. Subsequently,
we added intermediate 3 to the reaction mixture, and the solution was heated at 50 C for 2 h. The click
cyclization reaction was completed to give the 1,4-disubstituted 1,2,3-triazoles in the yields of 69% to
84%, and Cu(II)-complex L1 was found to be the best (Entries 1–4). The control experiment indicated
that the reaction could not occur without the Cu(II)-complex (Entry 5). When the amount of the
Cu(II)-complex, L1, was reduced from 1 mol % to 0.5 mol %, it resulted in a lower yield (Entry 6).
Therefore, the optimal conditions for aryl-1,2,3-triazole-β-carboline hybrid synthesis involves the use
of 1 mol % Cu(II)-complex L1 as the catalyst. and ethanol as the solvent.
Scheme 1. Synthesis of the key intermediate 3.
Table 1. Cu(II)-complex-catalyzed one-pot synthesis of aryl-1,2,3-triazole-
β-carboline hybrids from
phenylboronic acid in ethanol: optimization of the catalytic conditions.
N
BrCH2-C CH
NaH/DMF
N
N
CH3
N
H
CH3
N
3
2
N
Cu(II)-complex
CH3
+
N
R
NaN3
+
N
℃
Ethanol, 50
L1: R = CH3
L2: R = t-Bu
L3: R = Ph
L4: R = Bn
N
Cu
N
B(OH)2
N
R
Cu(II)-complex
4
Entry
Catalyst (mol %)
t/h
Yield/%
1
2
3
4
5
6
L1(1)
L2(1)
L3(1)
L4(1)
-
8 + 2
8 + 2
8 + 2
8 + 2
8 + 2
8 + 2
84
80
69
71
0
L1(0.5)
67
The generality of the optimized reaction condition was studied with a wide range of substrates,
using various substituted phenylboronic acid bearing electron-withdrawing and electron-donating
substituents, NaN3, and 1 mol % Cu(II)-complex L1 with 1-methyl-9-propargyl-
9-(1,2,3-triazolyl)- -carboline hybrids 5a , which are shown in Scheme 2. The synthetic routes
of novel 7-(1,2,3-triazolyl)- -carboline hybrids 9a
are outlined in Scheme 3. The N9-alkylated
harmine derivative was prepared according to the synthetic protocol described by our group [30].
The preparation of compound
demethylation of compound
Compound
by the action of NaH in dry DMF followed by addition of propargyl bromide in 81% yield. Lastly,
the synthesis of compounds 9a was carried out following the general procedure for the synthesis of
compounds 5a
. All structures of the final products were determined by 1H NMR, 13C NMR (see
Supplementary Materials), and HRMS.
β-carboline 3 to afford
β
–k
β
–f
6
7
followed a common synthetic scheme and was characterized by
6
using hydrobromic acid and acetic acid as the reaction solvent.
8, bearing alkoxy in postion-7 of β-carboline core, was synthesized from compound
7
–
f
–
k

Molecules 2018, 23, 1344
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Scheme 2. Synthesis of the 9-(1,2,3-triazolyl)-β-carboline hybrids 5a–k.
Scheme 3. Synthesis of the 7-(1,2,3-triazolyl)-β-carboline hybrids 9a–f. Reagents and conditions:
(i) DMF, NaH, n-iodobutane, stirred at RT; (ii) HBr, HOAc, reflux (iii) DMF, NaH, 3-bromopropyne,
◦
stirred at RT; (iv) Cu(II)-complex L1, ethanol, 50 C.
2.2. Fungicidal Activities
From the synthetic route mentioned above, we obtained two series of novel aryl-1,2,3-triazole-β-
carboline hybrids 5a–k, 9a–f. These compounds were evaluated in a series of fungicidal tests in vitro
against a range of phytopathogenic species including R. solani, Fusarium oxysporum, Botrytis cinerea
Pers., sunflower sclerotinia rot, and rape sclerotinia rot. The activity results obtained as an inhibition
rate are summarized in Table 2.
Generally, at 50 µg/mL, the target compounds exhibited different levels of antifungal activity
against these five tested fungi. Compared with that of the commercial fungicide carbendazim
and azoxystrobin, these compounds have exhibited a significant inhibitory effect against sunflower

Molecules 2018, 23, 1344
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sclerotinia rot (SCR) in which compounds 5a (Ar = phenyl), 5b (Ar = 4-trifluoromethylphenyl), 5c
(Ar 3,4,5-trifluorophenyl), and 9b (Ar = 3,4,5-trifluorophenyl) had inhibitory rates of 85.04%, 86.93%,
85.98%, and 84.47%, respectively, which displayed comparable antifungal activity than that of the
positive control, with an inhibition rate of 89.77% and 88.07%. In addition, compounds 5d 5i 9c
=
–
g,
–
k,
–d,
and 9f displayed moderate activity, with an inhibition rate ranging from 50% to 80%. For F. oxysporum,
all the target compounds showed inactive in vitro antifungal activities with an inhibition rate lower
than 20%. Similarly, for R. solani, the compounds showed weak antifungal activities with an inhibition
rate ranging from 20% to 50%, except for 9b, which exhibited moderate activity with an inhibition rate
of 58.30%. However, it was not as clear as the one drawn from the RSR data. Some of the compounds
exhibited significant activities in vitro toward RSR in which the compound 9b had control efficacy rates
of 81.23% and most of them showed weak to moderate activity. Of all aryl-1,2,3-triazole-β-carboline
hybrids, compound 9b displayed as broad a fungicidal spectrum as azoxystrobin and carbendazim
against these phytopathogens.
Table 2. Fungicidal activities of compounds 5a–k, 9a–f against four kinds of fungi (50 µg/mL) a.
Inhibition Ratio (%) b
Componds
ClogP c
RS
FO
BCP
SCR
RSR
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
9a
9b
9c
9d
9e
9f
35.57
30.68
33.52
25.23
28.07
27.84
33.52
35.80
30.45
34.09
34.09
36.59
58.30
39.20
28.75
47.72
35.34
81.82
54.55
−2.60
−0.28
0.65
−1.67
−2.37
1.11
−0.28
−2.60
1.81
51.14
38.64
34.85
36.36
15.53
14.02
15.91
19.70
16.29
7.39
85.04
86.93
85.98
58.14
71.78
73.48
67.99
44.70
65.34
67.80
70.08
40.53
84.47
79.31
76.70
44.51
75.57
89.77
88.07
22.22
0.00
53.26
0.00
4.251
5.435
4.788
3.468
8.437
5.063
4.976
5.588
4.479
4.750
4.566
7.306
6.659
7.459
6.350
6.621
6.437
17.05
35.44
26.05
55.36
19.54
35.25
0.00
10.76
81.23
52.11
47.31
28.91
19.28
100
−3.76
0.19
5.11
−0.97
18.52
7.85
12.69
63.07
16.86
63.45
28.03
24.43
88.07
83.71
2.27
−7.24
0.65
carbendazim
azoxystrobin
70.98
51.25
88.51
a
RS, R. solani; FO, F. oxysporum; BCP, B. cinerea Pers.; SCR, sunflower sclerotinia rot; RSR, rape sclerotinia rot.
b
The data in bold are used to emphasize that these compounds showed good activity. significant inhibitory effect:
inhibitory rate
≥
80%, moderate: inhibition rate ranges from 50% to 80%, weak: inhibition rate ranges from 20% to
c
50%. ClogP represent the calculated n-octanol/water partition coefficient (log Pow), and the values produced by
Chemdraw software.
3. Materials and Methods
3.1. General Information
All the reactions were monitored by TLC on silica gel F254 plates (Qingdao Haiyang Inc., Qingdao,
China) for detection of the spot. Column chromatography was performed with silica gel (200–300 mesh).
NMR spectra were recorded at room temperature on a Bruker Avance III HD 400 instrument at 400 MHz
for 1H NMR and 100 MHz for 13C NMR (Bruker Company, Bremen, Gemany). CDCl3, DMSO-d6,
Methanol-d4 or Pyridine-d5 was used as the solvent and TMS as the internal standard. High-resolution
mass spectrometry (HRMS) were measured on Bruker ultrafleXtreme MALDI-TOF/TOF-MS and
HCCA (alpha-cyano-4-hydroxycinnamic acid) is used as matrix.

Molecules 2018, 23, 1344
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All solvents were purified and dried using standard methods prior to use. The following
intermediates, 1-methyl- -carboline 31], 7-methoxy-9-n-butyl-1-methyl- -carboline 6 [30] and
β
2
[
β
9-n-butyl-1-methyl-β-carboline-7-ol 7 [32] were synthesized according to published procedures.
3.2. Synthesis of 1-Methyl-9-(prop-2-yn-1-yl)-β-carboline (3)
A mixture of 1-methyl-β-carboline (2, 1.82 g, 10 mmol) and anhydrous DMF (60 mL) was stirred
at room temperature for 0.5 h, and then 95% NaH (0.37 g, 15 mmol) and 3-bromopropyne (1.8 g, 15
mmol) were added. The mixture was stirred at room temperature for 15–45 min. After completion
of the reaction as indicated by TLC, the solution was poured into H2O (150 mL), and extracted with
ethyl acetate. The organic phase was washed with water and brine, then dried over anhydrous sodium
sulfate, filtered, and evaporated. The resulting oil was crystallized from ethyl ether. White crystals of
3
1
were obtained (1.93 g, 88%). H NMR (400 MHz, DMSO-d6)
δ
: 8.38–8.18 (m, 2H), 8.01 (s, 1H), 7.81 (d,
J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.32 (t, J = 6.8 Hz, 1H), 5.48 (s, 2H), 3.39 (d, J = 2.0 Hz, 1H), 3.09
(s, 3H). 13C NMR (100 MHz, DMSO-d6)
δ
: 142.22, 141.34, 138.80, 134.74, 129.05, 128.82, 122.07, 121.34,
120.62, 113.49, 110.86, 80.58, 76.10, 34.68, 23.10.
3.3. Synthesis of 9-Butyl-1-Methyl-7-(Prop-2-yn-1-yloxy)-β-Carboline (8)
Prepared by the same procedure as compound
(1.8 g, 15 mmol). White crystals of
3
from
7
(2.54 g, 10 mmol) and 3-bromopropyne
1
8
were obtained (2.37 g, 81%). H NMR (400 MHz, CDCl3)
δ
: 8.29 (d,
J = 5.2 Hz, 1H), 7.99 (dd, J = 8.1, 2.0 Hz, 1H), 7.73 (d, J = 5.2 Hz, 1H), 6.99 (t, J = 2.0 Hz, 1H), 6.95–6.92
(m, 1H), 4.84 (dd, J = 2.4, 1.2 Hz, 2H), 4.46 (t, J = 8.0 Hz, 2H), 3.02 (s, 3H), 2.57 (t, J = 2.4 Hz, 1H),
1.86–1.77 (m, 2H), 1.50–1.40 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ: 158.55,
142.81, 140.73, 138.28, 135.44, 129.17, 122.39, 115.97, 112.35, 108.92, 95.16, 78.5, 75.79, 56.35, 44.77, 32.77,
23.47, 20.23, 13.92.
3.4. General Procedure for the Synthesis of 1,2,3-Triazolyl-β-Carboline Hybrids (5 and 9)
A 50 mL Schlenk tube was charged with Cu(II)-complex L1 (0.025 mmol), arylboronic acid
(5 mmol), NaN3 (6 mmol) and dry alcohol (30 mL). The mixture was stirred at 30 ◦C and monitored
by TLC until the arylboronic acid was consumed. Compound
solution was continuously heated at 50 ◦C for 2 h. After completion of the reaction, water was added
to the reaction mixture, and the compound was extracted with ethyl acetate (3 100 mL). The organic
3 or 8 (2.5 mmol) was added, and the
×
phase was washed with water and brine, dried over anhydrous Na2SO4, and the solvent was removed
under reduced pressure. The crude product was purified by flash column chromatograph on silica gel
(ethyl acetate/petroleum ether as the eluent) to obtain the target products.
1-Methyl-9-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-
β
-carboline (5a): White crystals (0.71g, 84%) were
1
obtained. H NMR (400 MHz, DMSO-d6)
δ
: 8.79 (s, 1H), 8.24–8.27 (m, 2H), 8.02 (d, J = 5.2 Hz, 1H),
7.81–7.88 (m, 3H), 7.58–7.62 (m, 1H), 7.52–7.56 (m, 2H), 7.43–7.47 (m, 1H), 7.29 (t, J = 7.2 Hz, 1H), 5.99
(s, 2H), 3.13 (s, 3H). 13C NMR (100 MHz, DMSO-d6)
δ
: 145.53, 142.30, 141.46, 138.38, 136.89, 135.09,
130.25, 129.16, 128.67, 128.65, 121.94, 121.67, 121.38, 120.57, 120.34, 113.46, 111.18, 39.92, 23.89. HRMS
calcd for C21H18N5 [M + H]+ 340.1557, found 340.1569.
1-Methyl-9-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-
β
-carboline (5b): Slightly brown
1
crystals (0.87 g, 86%) were obtained. H NMR (400 MHz, DMSO-d6)
δ: 8.93 (s, 1H), 8.26 (d, J = 7.6 Hz,
2H), 8.10 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 5.2 Hz, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.4 Hz, 1H),
7.58–7.63 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 6.02 (s, 2H), 3.12 (s, 3H). 13C NMR (100 MHz, DMSO-d6)
δ
:
145.99, 142.27, 141.46, 135.09, 139.66 (q, J = 1.4 Hz), 138.41, 128.96 (q, J = 32.1 Hz), 128.71, 128.63, 127.55
(q, J = 3.7 Hz), 124.24 (q, J = 270.5 Hz), 121.95, 121.39, 121.03, 120.37, 113.47, 111.15, 23.86. 19F NMR
(376 MHz, DMSO-d6) δ: −61.04. HRMS calcd for C22H17F3N5 [M + H]+ 408.1431, found 408.1422.

Molecules 2018, 23, 1344
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1-Methyl-9-((1-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-
β
-carboline (5c): Slightly brown crystals
1
(0.79 g, 80%) were obtained. H NMR (400 MHz, DMSO-d6)
δ
: 8.78 (s, 1H), 8.26 (d, J = 6.0 Hz, 2H),
8.04 (d, J = 5.2 Hz, 1H), 7.98 (dd, J = 8.8, 6.0 Hz, 2H), 7.83 (d, J = 8.4 Hz, 1H), 7.58–7.62 (m, 1H), 7.30 (t,
J = 8.0 Hz, 1H), 6.01 (s, 2H), 3.09 (s, 3H). 13C NMR (100 MHz, DMSO-d6)
δ
: 150.43 (ddd, J = 240.5, 10.1,
5.6 Hz), 145.61, 141.61, 140.89, 138.53 (dt, J = 249, 14.9 Hz), 137.81, 134.44, 131.92 (td, J = 11.5, 4.3 Hz),
128.20, 128.15, 121.52, 121.40, 120.80, 119.84, 112.93, 110.55, 105.71 (m), 23.18. 19F NMR (376 MHz,
DMSO)
394.1274, found 394.1288.
δ
:
−
132.58 (d, J = 21.8 Hz),
−
161.09 (t, J = 21.8 Hz). HRMS calcd for C21H15F3N5 [M + H]+
1-Methyl-9-((1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-
β
-carboline (5d): Slightly yellow crystals (0.61 g,
1
72%) were obtained. H NMR (400 MHz, Methanol-d4)
δ: 8.66 (d, J = 5.6 Hz, 2H), 8.55 (s, 1H), 8.23–8.20
(m, 2H), 8.01 (d, J = 5.2 Hz, 1H), 7.89–7.88 (m, 2H), 7.74 (dt, J = 8.4, 0.8 Hz, 1H), 7.66–7.62 (m, 1H),
7.35–7.31 (m, 1H), 6.05 (s, 2H), 3.13 (s, 3H). 13C NMR (100 MHz, Methanol-d4)
δ
: 150.77, 146.20, 143.55,
141.82, 141.61, 137.19, 129.92, 128.60, 121.32, 121.27, 120.33, 120.26, 113.92, 113.08, 109.94, 39.85, 21.46.
HRMS calcd for C20H17N6 [M + H]+ 341.1509, found 341.1498.
1-Methyl-9-((1-(4-(9H-carbazol-9-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-
β
-carboline (5e): Slightly brown
1
crystals (0.73 g, 58%) were obtained. H NMR (400 MHz, Pyridine-d5)
δ: 8.67 (s, 1H), 8.59 (d, J = 5.2 Hz,
1H), 8.30–8.26 (m, 3H), 8.05 (d, J = 8.8 Hz, 2H), 8.00–7.95 (m, 2H), 7.68–7.64 (m, 5H), 7.49 (s, 2H),
7.41–7.36 (m, 3H), 6.18 (s, 2H), 3.36 (s, 3H). 13C NMR (100 MHz, Pyridine-d5) δ: 146.26, 142.22, 141.62,
140.61, 138.90, 137.55, 135.71, 135.32, 129.16, 128.49, 127.86, 126.45, 123.75, 121.97, 121.91, 121.74, 120.86,
120.66, 120.64, 120.35, 113.11, 110.53, 109.88, 40.75, 23.73. HRMS calcd for C33H25N6 [M + H]+ 505.2135,
found 505.2145.
1-Methyl-9-((1-(4-ethoxycarbonyl)phenyl-1H-1,2,3-triazol-4-yl)methyl)-
β
-carboline (5f): Yellow crystals (0.82
1
g, 80%) were obtained. H NMR (400 MHz, Methanol-d4)
δ
: 8.44 (s, 1H), 8.23–8.20 (m, 2H), 8.16–8.13
(m, 2H), 8.02 (d, J = 5.6 Hz, 1H), 7.92–7.89 (m, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.66–7.62 (m, 1H), 7.35–7.31
(m, 1H), 6.05 (s, 2H), 4.39 (q, J = 7.2 Hz, 2H), 3.15 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
Methanol-d4) δ: 165.38, 145.83, 141.88, 139.96, 137.15, 137.14, 130.73, 130.43, 129.93, 128.60, 121.33,
121.27, 120.57, 120.24, 119.76, 109.98, 61.08, 39.90, 21.49, 13.13. HRMS calcd for C24H22N5O2 [M + H]+
412.1768, found 412.1759.
1-Methyl-9-((1-(4-vinylphenyl)-1H-1,2,3-triazol-4-yl)methyl)-
β
-carboline (5g): Brown crystals (0.81 g, 89%)
1
were obtained. H NMR (400 MHz, Methanol-d4)
δ
: 8.32 (s, 1H), 8.25 (s, 1H), 8.22(d, J = 8.0 Hz, 1H),
8.03 (d, J = 5.2 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.72–7.70 (m, 2H), 7.66–7.62 (m, 1H), 7.58–7.56 (m,
2H), 7.35–7.31 (m, 1H), 6.77 (dd, J = 17.6, 10.8 Hz, 1H), 6.04 (s, 2H), 5.85 (d, J = 17.6 Hz, 1H), 5.32 (d,
J = 10.8 Hz, 1H), 3.15 (s, 3H). 13C NMR (100 MHz, Methanol-d4)
δ: 145.47, 141.90, 138.37, 135.99, 135.34,
129.88, 128.58, 127.05, 121.31, 121.25, 120.39, 120.23, 120.21, 120.20, 114.39, 109.99, 56.92, 39.91, 16.96.
HRMS calcd for C23H20N5 [M + H]+ 366.1713, found 366.1720.
1-Methyl-9-((1-(4-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-
crystals (0.84 g, 79%) were obtained. H NMR (400 MHz, Methanol-d4)
β
-carboline (5h): Slightly brown
: 6.83 (s, 1H), 6.69–6.66 (m,
1
δ
2H), 6.47 (d, J = 5.6 Hz, 1H), 6.35–6.31 (m, 2H), 6.21 (d, J = 8.4 Hz, 1H), 6.12–6.08 (m, 1H), 5.89 (d,
J = 8.4 Hz, 2H), 5.81–5.77 (m, 1H), 4.50 (s, 2H), 1.60 (s, 3H). 13C NMR (100 MHz, Methanol-d4)
δ
: 144.21,
140.35, 140.10, 135.61, 133.97, 133.57, 128.40, 127.06, 120.47, 120.40, 119.79, 119.74, 119.18, 118.70, 111.55,
108.44, 38.37, 19.94. 19F NMR (376 MHz, DMSO-d6)
424.1380, found 424.1388.
δ
:
−
59.68. HRMS calcd for C22H17F3N5O [M + H]+
1-methyl-9-((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-
β
-carboline (5i): Brown crystals (0.84 g,
1
91%) were obtained. H NMR (400 MHz, Methanol-d4)
δ
: 8.24–8.21 (m, 3H), 8.02 (d, J = 5.2 Hz, 1H),
7.75 (d, J = 8.4 Hz, 1H), 7.66–7.60 (m, 3H), 7.35–7.31 (m, 1H), 7.05–7.01 (m, 2H), 6.02 (s, 2H), 3.83 (s, 3H),
3.14 (s, 3H). 13C NMR (100 MHz, Methanol-d4)
δ
: 160.17, 145.23, 141.89, 130.10, 129.87, 128.58, 121.87,
121.86, 121.29, 121.24, 120.65, 120.20, 114.39, 110.00, 54.68, 39.90, 16.97. HRMS calcd for C22H20N5O
[M + H]+ 370.1662, found 370.1669.

Molecules 2018, 23, 1344
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1-Methyl-9-((1-(p-tolyl)-1H-1,2,3-triazol-4-yl)methyl)-
β
-carboline (5j): Slightly brown crystals (0.76 g, 86%)
δ
were obtained. 1H NMR (400 MHz, Methanol-d4)
: 8.36 (s, 1H), 8.26 (d, J = 8.0 Hz, 2H), 8.17 (d,
J = 5.6 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.72–7.68 (m, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.38 (t, J = 7.6 Hz,
1H), 7.30 (d, J = 8.4 Hz, 2H), 6.03 (s, 2H), 3.22 (s, 3H), 2.37 (s, 3H). 13C NMR (100 MHz, Methanol-d4)
δ
:
144.41, 143.31, 139.19, 134.49, 130.57, 129.89, 122.18, 121.40, 120.82, 120.55, 120.08, 114.41, 110.52, 39.87,
19.60. HRMS calcd for C22H20N5 [M + H]+ 354.1713, found 354.1703.
1-Methyl-9-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-
g, 80%) were obtained. 1H NMR (400 MHz, DMSO-d6)
J = 5.2 Hz, 1H), 7.90–7.86 (m, 3H), 7.63–7.58 (m, 1H), 7.43–7.38 (m, 2H), 7.29 (t, J = 7.6 Hz, 1H), 6.00 (s,
2H), 3.13 (s, 3H). 13C NMR (100 MHz, DMSO-d6)
: 162.04 (d, J = 244 Hz), 145.48, 142.33, 141.41, 138.34,
β
-carboline (5k): Slightly brown crystals (0.71
δ
: 8.82 (s, 1H), 8.27–8.24 (m, 2H), 8.03 (d,
δ
135.09, 133.43 (d, J = 2.6 Hz), 128.70, 128.64, 122.97, 122.88, 121.99 (d, J = 10 Hz), 121.33, 120.35, 117.11
(d, J = 23.1 Hz), 113.50, 111.20, 23.88. HRMS calcd for C21H17FN5 [M + H]+ 358.1463, found 358.1470.
9-Butyl-1-methyl-7-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-
β
-carboline (9a): Slightly
1
yellow crystals (0.41 g, 85%) were obtained. H NMR (400 MHz, DMSO-d6)
δ: 9.17 (s, 1H), 8.21–8.17
(m, 3H), 8.12 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 5.2 Hz, 1H), 7.40 (d, J = 2.4 Hz,
1H), 6.98 (dd, J = 8.8, 2.0 Hz, 1H), 5.45 (s, 2H), 4.56 (t, J = 7.6 Hz, 2H), 2.95 (s, 3H), 1.75–1.67 (m, 2H),
1.42–1.32 (m, 2H), 0.89 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6)
δ: 159.49, 144.80, 143.10,
141.07, 139.80 (q, J = 1.5 Hz), 138.22, 135.10, 129.40 (q, J = 32.4 Hz), 128.79, 127.73 (q, J = 3.6 Hz), 124.27
(q, J = 270.5 Hz) 123.63, 122.95, 121.04, 115.06, 112.76, 109.96, 95.37, 61.99, 44.38, 32.93, 23.55, 19.98,
14.19. HRMS calcd for C26H25F3N5O [M + H]+ 480.2017, found 480.2009.
9-Butyl-1-methyl-7-((1-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-
β
-carboline (9b): Slightly
1
brown crystals (0.43 g, 91%) were obtained. H NMR (400 MHz, DMSO-d6 )
δ
: 8.76 (s, 1H), 8.18–8.13 (m,
2H), 8.04 (s, 1H), 7.86–7.82 (m, 2H), 7.32 (s, 1H), 7.07 (d, J = 8.8 Hz, 1H), 5.47 (s, 2H), 4.63 (t, J = 7.6 Hz,
2H), 3.07 (s, 3H), 1.87–1.79 (m, 2H), 1.52–1.43 (m, 2H), 1.00 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz,
DMSO-d6) δ: 159.54, 152.34 (ddd, J = 246.6, 10.0, 5.2 Hz), 144.86, 143.17, 140.91, 138.70 (dt, J = 250,
18 Hz), 137.90, 135.02, 132.58 (td, J = 12.1, 3.6 Hz), 128.92, 123.64, 122.96, 115.02, 112.78, 110.00, 106.17
(m), 95.29, 62.01, 44.38, 32.91, 23.32, 19.97, 14.16. HRMS calcd for C25H23F3N5O [M + H]+ 466.1849,
found 466.1860.
9-Butyl-1-methyl-7-((1-(4-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-
β
-carboline (9c): Yellow
1
crystals (0.44 g, 88%) were obtained. H NMR (400 MHz, DMSO-d6)
δ
: 9.10 (s, 1H), 8.17 (d, J = 5.2 Hz,
1H), 8.15–8.04 (m, 3H), 7.89 (d, J = 5.2 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 2.0 Hz, 1H), 6.97 (dd,
J = 8.4, 2.0 Hz, 1H), 5.43 (s, 2H), 4.58 (t, J = 7.6 Hz, 2H), 2.95 (s, 3H), 1.74–1.66 (m, 2H), 1.41–1.32 (m,
2H), 0.89 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6)
δ: 159.46, 148.34, 144.55, 143.11, 141.05,
138.20, 135.87, 128.79, 123.77, 123.11, 122.95, 122.57, 121.73, 119.17, 114.97, 112.77, 110.06, 95.35, 61.87,
44.34, 32.96, 23.52, 19.93, 14.18. HRMS calcd for C26H25F3N5O2 [M + H]+ 496.1955, found 496.1962.
9-Butyl-7-((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-methyl-
β
-carboline (9d): White crystals
1
(0.39 g, 89%) were obtained. H NMR (400 MHz, DMSO-d6)
δ
: 8.55 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.89
(s, 1H), 7.76–7.69 (m, 2H), 7.20 (d, J = 2.0 Hz, 1H), 7.13–7.05 (m, 2H), 7.00 (dd, J = 8.4, 2.0 Hz, 1H), 5.40
(s, 2H), 4.53 (t, J = 7.6 Hz, 2H), 3.87 (s, 3H), 2.97 (s, 3H), 1.80–1.72 (m, 2H), 1.47–1.37 (m, 2H), 0.96 (t,
J = 7.2 Hz, 3H). 13C NMR (100 MHz, DMSO-d6)
δ: 159.77, 159.56, 144.10, 143.12, 141.08, 138.16, 130.45,
128.80, 123.35, 122.91, 122.22, 115.35, 114.97, 112.78, 109.99, 95.31, 62.02, 56.02, 44.36, 32.94, 23.57, 19.97,
14.20. HRMS calcd for C26H28N5O2 [M + H]+ 442.2238, found 442.2247.
9-Butyl-1-methyl-7-((1-(p-tolyl)-1H-1,2,3-triazol-4-yl)methoxy)-
(0.36 g, 86%) were obtained. H NMR (400 MHz, DMSO-d6)
β
-carboline (9e): Slightly yellow crystals
1
δ: 9.06 (s, 1H), 8.52 (d, J = 6.0 Hz, 1H),
8.41 (d, J = 8.8 Hz, 1H), 8.35 (d, J = 6.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.42 (d,
J = 8.4 Hz, 2H), 7.14 (dd, J = 8.8, 2.0 Hz, 1H), 5.49 (s, 2H), 4.69 (t, J = 8.0 Hz, 2H), 3.26 (s, 3H), 2.39 (s,
3H), 1.82–1.74 (m, 2H), 1.45–1.35 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, DMSO-d6)
δ:
161.94, 146.31, 143.74, 138.92, 137.71, 134.76, 133.82, 133.18, 130.74, 129.45, 125.00, 123.56, 120.48, 114.86,

Molecules 2018, 23, 1344
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113.71, 113.15, 95.24, 62.27, 44.83, 32.86, 21.06, 19.89, 17.93, 14.17. HRMS calcd for C26H28N5O [M + H]+
426.2288, found 426.2281.
9-Butyl-7-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-methyl-
β
-carboline (9f): White crystals (041
1
g, 87%) were obtained. H NMR (400 MHz, DMSO-d6)
δ
: 9.03 (s, 1H), 8.18 (d, J = 5.2 Hz, 1H), 8.12 (d,
J = 8.8 Hz, 1H), 8.03–7.96 (m, 2H), 7.89 (d, J = 5.2 Hz, 1H), 7.48 (t, J = 8.8 Hz, 2H), 7.41 (d, J = 2.0 Hz,
1H), 6.98 (dd, J = 8.8, 2.0 Hz, 1H), 5.43 (s, 2H), 4.56 (t, J = 7.6 Hz, 2H), 2.95 (s, 3H), 1.75–1.67 (m, 2H),
1.42–1.33 (m, 2H), 0.90 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6)
δ: 160.91(d, J = 245 Hz),
159.52, 144.39, 143.11, 141.05, 138.20, 135.08, 133.61 (d, J = 2.8 Hz), 128.80, 123.64, 122.98 (d, J = 8.7 Hz),
122.93, 117.22 (d, J = 23.3 Hz), 115.00, 112.75, 109.99, 95.33, 61.98, 44.36, 32.94, 23.54, 19.96, 14.20. HRMS
calcd for C25H25FN5O [M + H]+ 430.2038, found 430.2044.
3.5. Biological Assays
The antifungal activity of the synthesized compounds was performed according to previously
reported procedures [33]. The fungicidal activity of the target compounds against R. solani, F. oxysporum,
B. cinerea Pers., sunflower sclerotinia rot and rape sclerotinia rot were evaluated using a mycelium
growth rate test [17]. Carbendazim and azoxystrobin standard purchased from J&K Scientific Ltd.
(Beijing, China), were used as a control, treating it in the same way. The relative inhibition ratio (%)
was calculated using the following equation:
Colony diameter of control − colony diameter of treated)
The relative inhibition ratio (%) =
× 100%.
colony diameter of control mycelial disk diameter
4. Conclusions
In order to find potential activity from
β-carboline derivatives for further structural optimization,
in this study, two series of new aryl-1,2,3-triazole-
assayed for their fungicidal activities in vitro. The antifungal evaluation of the novel hybrids showed
that, among the tested compounds, 1-methyl-9-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)- -carboline
5a), 1-methyl-9-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)- -carboline 5b),
1-methyl-9-((1-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)- -carboline (5c), and 9-butyl-
1-methyl-7-((1-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)- -carboline 9b showed
β-carboline hybrids were synthesized, and first
β
(
β
(
β
β
(
)
satisfactory antifungal activity against sunflower sclerotinia rot. Specifically, compound 9b also
exhibited high broad-spectrum fungicidal activity against all the tested fungi with inhibition rates
of 58.3%, 18.52%, 63.07%, 84.47%, and 81.23%. However, for F. oxysporum, all the target compounds
showed no in vitro antifungal activities with an inhibition rate lower than 20%.
Supplementary Materials: The following are available online, 1H and 13C NMR spectra for the target compounds
are available online.
Author Contributions: J.Z., X.-Q.H. and B.D. conceived and designed the research; X.-Y.H., L.G. and X.-F.C.
performed the experiments; Y.-T.Z. performed the bioassay research; X.-Y.H. and X.-Q.H. analyzed the data;
J.Z. and L.G. wrote the paper.
Funding: This research was supported by the scientific research innovation project in Xinjiang Uygur Autonomous
Region under Grant (XJGRI2017045); the Program for Changjiang Scholars and Innovative Research Team in
University (No. IRT15R46), and Yangtze River Scholar Research Project of Shihezi University (No. CJXZ201601).
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Dayan, F.E.; Cantrell, C.L.; Duke, S.O. Natural products in crop protection. Bioorg. Med. Chem. 2009, 17,
4022–4034. [CrossRef] [PubMed]
2.
Rosell, G.; Quero, C.; Coll, J.; Guerrero, A. Biorational insecticides in pest management. J. Pestic. Sci. 2008
,
33, 103–121. [CrossRef]

Molecules 2018, 23, 1344
10 of 11
3.
4.
Petroski, R.J.; Stanley, D.W. Natural compounds for pest and weed control. J. Agric. Food Chem. 2009, 57,
8171–8179. [CrossRef] [PubMed]
Crombie, L. Natural product chemistry and its part in the defence against insects and fungi in agriculture.
Pestic. Sci. 1999, 55, 761–774. [CrossRef]
5.
6.
Meester, C.D. Genotoxic potential of β-carbolines: A review. Mutat. Res. 1995, 339, 139–153. [CrossRef]
Cain, M.; Weber, R.W.; Guzman, F.; Cook, J.M.; Barker, S.A.; Rice, K.C.; Crawley, J.N.; Paul, S.M.; Skolnick, P.
β-Carbolines: Synthesis and neurochemical and pharmacological actions on brain benzodiazepine receptors.
J. Med. Chem. 1982, 25, 1081–1091. [CrossRef] [PubMed]
7.
Bournine, L.; Bensalem, S.; Fatmi, S.; Bedjou, F.; Mathieu, V.; Iguer-Ouada, M.; Kiss, R.; Duez, P. Evaluation
of the cytotoxic and cytostatic activities of alkaloid extracts from different parts of Peganum harmala L.
(Zygophyllaceae). Eur. J. Integr. Med. 2017, 9, 91–96. [CrossRef]
8.
9.
Asgarpanah, J.; Ramezanloo, F. Chemistry, pharmacology and medicinal properties of Peganum harmala L.
Afr. J. Pharm. Pharmacol. 2012, 6, 1573–1580. [CrossRef]
Srivastava, S.K.; Agarwal, A.; Chauhan, P.M.S.; Agarwal, S.K.; Bhaduri, A.P.; Singh, S.N.; Fatima, N.;
Chatterjee, R.K. Potent 1,3-disubstituted-9H-pyrido[3,4-b] indoles as new lead compounds in antifilarial
chemotherapy. Bioorg. Med. Chem. 1999, 7, 1223–1236. [CrossRef]
10. Wang, Y.H.; Tang, J.G.; Wang, R.R.; Yang, L.M.; Dong, Z.J.; Du, L.; Shen, X.; Liu, J.K.; Zheng, Y.T. Flazinamide,
a novel -carboline compound with anti-HIV actions. Biochem. Biophys. Res. Commun. 2007, 355, 1091–1095.
β
[CrossRef] [PubMed]
11. Zhang, Z.J.; Zhang, J.J.; Jiang, Z.Y.; Zhong, G.H. Design, Synthesis and Bioactivity Evaluation of Novel
β-carboline 1,3,4-oxadiazole Derivatives. Molecules 2017, 22, 1811. [CrossRef] [PubMed]
12. Nenaah, G. Toxicity and growth inhibitory activities of methanol extract and the beta-carboline alkaloids
of Peganum harmala L. against two coleopteran stored-grain pests. J. Stored Prod. Res. 2011, 47, 255–261.
[CrossRef]
13. Abbasipour, H.; Mahmoudvand, M.; Rastegar, F.; Basij, M. Insecticidal activity of Peganum harmala seed
extract against the diamondback moth, Plutella xylostella. Bull. Insectol. 2010, 63, 259–263.
14. Shonouda, M.; Osman, S.; Salama, O.; Ayoub, A. Toxical effect of Peganum harmala L. leaves on the cotton
leaf worm, Spodoptera littoralis boisd and its parasitoids Microplitis rufiventris Kok. Pak. J. Biol. Sci. 2008, 11,
546–552. [CrossRef] [PubMed]
15. Song, H.J.; Liu, Y.X.; Liu, Y.X.; Wang, Q.M. Synthesis and antiviral and fungicidal activity evaluation of
β
-carboline, dihydro-
2014, 62, 1010–1018. [CrossRef] [PubMed]
16. Huang, Y.Q.; Liu, Y.X.; Liu, Y.X.; Song, H.J.; Wang, Q.M. C ring may be dispensable for
β-carboline, tetrahydro-β-carboline alkaloids, and their derivatives. J. Agric. Food Chem.
β-carboline:
Design, synthesis, and bioactivities evaluation of tryptophan analog derivatives based on the biosynthesis of
β-carboline alkaloids. Bioorg. Med. Chem. 2016, 24, 462–473. [CrossRef] [PubMed]
17. Li, Z.B.; Chen, S.H.; Zhu, S.W.; Luo, J.J.; Zhang, Y.M.; Weng, Q.F. Synthesis and fungicidal activity of
β-carboline alkaloids and their derivatives. Molecules 2015, 20, 13941–13957. [CrossRef] [PubMed]
18. Huo, X.Y.; Guo, L.; Wei, Y.T.; Zhang, J.; Han, X.Q. Synthesis and Fungicidal Activity of Novel β-Carboline
Derivatives. Agrochemicals 2018, 57, 3–6. [CrossRef]
19. Ruddarraju, R.R.; Murugulla, A.C.; Kotla, R.; Tirumalasetty, M.C.B.; Wudayagiri, R.; Donthabakthuni, S.;
Maroju, R.; Baburao, K.; Parasa, L.S. Design, synthesis, anticancer, antimicrobial activities and molecular
docking studies of theophylline containing acetylenes and theophylline containing 1,2,3-triazoles with
variant nucleoside derivatives. Eur. J. Med. Chem. 2016, 123, 379–396. [CrossRef] [PubMed]
20. Kant, R.; Kumar, D.; Agarwal, D.; Gupta, R.D.; Tilak, R.; Awasthi, S.K.; Agarwal, A. Synthesis of newer
1,2,3-triazole linked chalcone and flavone hybrid compounds and evaluation of their antimicrobial and
cytotoxic activities. Eur. J. Med. Chem. 2016, 113, 34–49. [CrossRef] [PubMed]
21. Huo, J.P.; Hu, H.W.; Zhang, M.; Hu, X.H.; Chen, M.; Chen, D.C.; Liu, J.W.; Xiao, G.F.; Wang, Y.; Wen, Z.L.
A mini review of the synthesis of poly-1,2,3-triazole-based functional materials. RSC Adv. 2017, 7, 2281–2287.
[CrossRef]
22. Floros, M.C.; Bortolatto, J.F.; Oliveira, J.O.B.; Salvador, S.L.; Narine, S.S. Antimicrobial activity of amphiphilic
triazole-linked polymers derived from renewable sources. ACS Biomater. Sci. Eng. 2016, 2, 336–343.
[CrossRef]

Molecules 2018, 23, 1344
11 of 11
23. Vatmurge, N.S.; Hazra, B.G.; Pore, V.S.; Shirazi, F.; Chavan, P.S.; Dehpande, M.V. Synthesis and antimicrobial
activity of -lactam-bile acid conjugates linked via triazole. Bioorg. Med. Chem. Lett. 2008, 18, 2043–2047.
β
[CrossRef] [PubMed]
24. Jagasia, R.; Holub, J.M.; Bollinger, M.; Kirshenbaum, K.; Finn, M.G. Peptide Cyclization and
Cyclodimerization by CuI-Mediated Azide
Alkyne Cycloaddition. J. Org. Chem. 2009, 74, 2964–2974.
−
[CrossRef] [PubMed]
0
25. Huber, D.; Hübner, H.; Gmeiner, P. 1,1 -Disubstituted Ferrocenes as Molecular Hinges in Mono- and Bivalent
Dopamine Receptor Ligands. J. Med. Chem. 2009, 52, 6860–6870. [CrossRef] [PubMed]
26. Dubovis, M.V.; Rudakov, G.F.; Kulagin, A.S.; Tsarkova, K.V.; Popkov, S.V.; Goloveshkin, A.S.; Cherkaev, G.V.
A new method of synthesis of substituted 1-(1H-imidazole-4-yl)-1H-1,2,3-triazoles and their fungicidal
activity. Tetrahedron 2018, 74, 672–683. [CrossRef]
27. Zheng, X.C.; Wan, Y.J.; Ling, F.; Ma, C. Copper-Catalyzed Tandem Reaction of Terminal Alkynes and Sulfonyl
Azides for the Assembly of Substituted Aminotriazoles. Org. Lett. 2017, 19, 3859–3862. [CrossRef] [PubMed]
28. Hao, C.B.; Zhou, C.J.; Xie, J.W.; Zhang, J.; Liu, P.; Dai, B. An Efficient Copper-Catalyzed One-Pot Synthesis
of 1-Aryl-1,2,3-triazoles from Arylboronic Acids in Water under Mild Conditions. Chin. J. Chem. 2015, 33,
1317–1320. [CrossRef]
29. Zhou, C.J.; Zhang, J.; Liu, P.; Xie, J.W.; Dai, B. 2-Pyrrolecarbaldiminato–Cu(II) complex catalyzed
three-component 1,3-dipolar cycloaddition for 1,4-disubstituted 1,2,3-triazoles synthesis in water at room
temperature. RSC Adv. 2015, 5, 6661–6665. [CrossRef]
30. Cao, R.H.; Chen, Q.; Hou, X.R.; Chen, H.S.; Guan, H.J.; Ma, Y.; Peng, W.L.; Xu, A.L. Synthesis, acute toxicities
and antitumor effects of novel 9-substituted
[CrossRef] [PubMed]
β-carboline derivatives. Bioorg. Med. Chem. 2004, 12, 4613–4623.
31. Xinjiang Huashidan Pharmaceutical Research Co., Ltd. Harmine Derivatives, Intermediates Used in Their
Preparation, Preparation Processes and Use Thereof. EP 1634881 A1, 15 March 2006.
32. Cao, R.H.; Guan, X.D.; Shi, B.X.; Chen, Z.Y.; Ren, Z.H.; Peng, W.L.; Song, H.C. Design, synthesis and
3D-QSAR of β-carboline derivatives as potent antitumor agents. Eur. J. Med. Chem. 2010, 45, 2503–2515.
[CrossRef] [PubMed]
33. Du, S.J.; Lu, H.Z.; Yang, D.Y.; Li, H.; Gu, X.L.; Wan, C.; Jia, C.Q.; Wang, M.; Li, X.Y.; Qin, Z.H. Synthesis,
Antifungal Activity and QSAR of Some Novel Carboxylic Acid Amides. Molecules 2015, 20, 4071–4087.
[CrossRef] [PubMed]
Sample Availability: Samples of the compounds 5a–k, 9a–f are available from the authors.
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