Synthesis of novel 1,2,3-triazole tethered 1,3-disubstituted β-carboline derivatives and their cytotoxic and antibacterial activities

Article abstract of DOI:10.1007/s00044-016-1622-y

In this paper new β-carboline derivatives possessing the 1,2,3-triazole ring at C-1 substituent were synthesized from L-tryptophan by Pictet–Spengler reaction followed by a Huisgen 1,3-dipolar addition. In vitro cytotoxicity and antibacterial activity of synthetic compounds were investigated. Methyl 1-(3-((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-β-carboline-3-carboxylate (7f) showed the highest cytotoxic activity with IC₅₀ values of 46 and 32 μM against Hela and HepG2 cell lines, respectively. Compounds 7d and 7i (possessing 4-bromophenyl substituent) and 5c showed excellent inhibition activity for Enterococcus faecium with MIC of 8 μg/mL. The results demonstrated that the presence of 1,2,3-triazole rings in β-carboline derivatives improve their biological activities.

Full text of DOI:10.1007/s00044-016-1622-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1622-y
ORIGINAL RESEARCH
Synthesis of novel 1,2,3-triazole tethered 1,3-disubstituted β-carboline
derivatives and their cytotoxic and antibacterial activities
1 ●
1 ●
1 ●
Peyman Salehi Kosar Babanezhad-Harikandei Morteza Bararjanian
2 ●
3 ●
3
Ahmed Al-Harrasi Mohammad-Ali Esmaeili Atousa Aliahmadi
Received: 7 April 2016 / Accepted: 24 June 2016
©
Springer Science+Business Media New York 2016
Abstract In this paper new β-carboline derivatives pos-
sessing the 1,2,3-triazole ring at C-1 substituent were syn-
thesized from L-tryptophan by Pictet–Spengler reaction
followed by a Huisgen 1,3-dipolar addition. In vitro cyto-
toxicity and antibacterial activity of synthetic compounds
were investigated. Methyl 1-(3-((1-(3,4-dichlorophenyl)-
Introduction
β-Carbolines, containing tricyclic pyrido[3, 4-0]indole ring
structure, are a large group of indole alkaloids, with variable
saturation degrees. These alkaloid compounds were ori-
ginally extracted from seeds of Pegannum harmala L., such
as harman, and found in nature including in plants, insects,
marine invertebrates, human tissues and body fluids (Cao
et al., 2007; Ikeda et al., 2012).
β-Carbolines have a great importance because of their
various pharmacological activities such as sedative, anxio-
lytic, anticonvulsant, hypnotic (Braestrup et al., 1980;
Meldrum et al., 1983; Nutt and Lister 1989), anticancer
(Daoud et al., 2014; Shen et al., 2011; Jiménez et al., 2008;
Boursereau and Coldham 2004; Guan et al., 2006), anti-
parasitic (Gohil et al., 2012), antiviral (anti-HIV) (Nazari
Formagio et al., 2009; Brahmbhatt et al., 2010), antith-
rombotic (Zhao et al., 2006a) and antimicrobial (Verdian
Rizi and Hadjiakhoondi 2007). Recent works have been
focused on the anticancer activity of these compounds
1
H-1,2,3-triazol-4-yl)methoxy)phenyl)-β-carboline-3-car-
boxylate (7f) showed the highest cytotoxic activity with
IC50 values of 46 and 32 μM against Hela and HepG2 cell
lines, respectively. Compounds 7d and 7i (possessing 4-
bromophenyl substituent) and 5c showed excellent inhibi-
tion activity for Enterococcus faecium with MIC of 8 μg/
mL. The results demonstrated that the presence of 1,2,3-
triazole rings in β-carboline derivatives improve their bio-
logical activities.
●
●
●
Keywords β-Carboline Triazole ring Cytotoxic activity
●
Antibacterial activity Click chemistry
(Chauhan et al., 2014; Dighe et al., 2015). β-Carboline
derivatives exert their antitumor activity through multiple
mechanisms such as intercalating into DNA, inhibiting
topoisomerases I and II, CDK, IKK, PLK1, MK-2 and
kinase Eg5 (Xiao et al., 2001; Barbosa et al., 2011; Cao
et al., 2004; Cuny et al., 2012). Structure–activity rela-
tionship (SAR) studies demonstrated that the planarity and
the presence of suitable substituents in 1, 2, 3, and 9 posi-
tions of β-carboline skeleton impressed the antitumor
effects of these molecules (Cao et al., 2010).
Electronic supplementary material The online version of this article
doi:10.1007/s00044-016-1622-y) contains supplementary material,
which is available to authorized users.
(
*
Peyman Salehi
p-salehi@sbu.ac.ir
1
Department of Phytochemistry, Medicinal Plants and Drugs
Research Institute, Shahid Beheshti University, G. C., Evin,
1
983963113 Tehran, Iran
2
3
UoN Chair of Oman’s Medicinal Plants and Marine Natural
Products, University of Nizwa, P.O Box 33, Birkat Al Mauz,
Nizwa Postal Code 616, Oman
1,2,3-Triazole ring is an important class of N-hetero-
cycles with a wide range of pharmacological activities, such
as antibacterial, anthelmintic, antifungal (Li et al., 2016),
antimalarial (Guantai et al., 2010; Vijai Kumar Reddy et al.,
2016), trypanocidal (Carvalho et al., 2010) and anticancer
Department of Biology, Medicinal Plants and Drugs Research
Institute, Shahid Beheshti University, G. C., Evin, 1983963113
Tehran, Iran

Med Chem Res
(
Kamal et al., 2008, 2011; Shankaraiah et al., 2016; Naresh
reaction conditions including reagent and its amount, sol-
vent and temperature were optimized (Table 2). The best
result was obtained with five equivalents of sulfur in 18 h
(Table 2, entry 5). Oxidation of other derivatives, 4a and
4b, were carried out by the same method in 68–70 % yields.
Then the terminal alkyne moiety of β-carboline deriva-
tives were reacted with alkyl and aryl azides (Pokhodylo
et al., 2009; Ingham et al., 1956; Wu et al., 2010) (Fig. 1) by
using CuSO ·5H O and sodium ascorbate as catalyst
Kumar et al., 2016; Narsimha et al., 2016). 1,2,3-Triazole
groups are used in pharmaceutical compounds as pharma-
cophores or linkers between two or more parts of the
molecule (de Luiza et al., 2014). They are easily prepared
by 1,3-dipolar cycloaddition called Huisgen reaction (Duan
et al., 2013). It is a type of click chemistry reaction that have
grown rapidly in last decade (Calderone et al., 2005 Díaz
et al., 2010; Zhao et al., 2015). Huisgen reaction includes
interaction between azides and terminal alkynes in the
presence of Cu(I) as catalyst (Luo et al., 2014; Kolb et al.,
4
2
(Kamal et al., 2008, 2011; Freitas et al., 2014; Duan et al.,
2013; Vijai Kumar Reddy et al., 2016; M. Heravi et al.,
2016). The Huisgen reaction was performed in t-BuOH:
H O (2:1) in the presence of 0.2 eq CuSO ·5H O and 0.4 eq
2
001).
In continuation of our research on the synthesis of new
,2,3-triazoles and evaluation of their biological activities
Mohebbi et al., 2014; Salehi et al., 2011; Salehi et al.,
012; Dabiri et al., 2010), here we report the synthesis of
2
4
2
1
(
2
1
NaAs. The results are summarized in Table 3. Six azides
(Fig. 1) were prepared and used for the synthesis of the
target molecules. No significant difference between aro-
matic and aliphatic azides was observed. The reactions
proceeded smoothly and all products obtained are in good
to excellent yields (Table 3).
,2,3-triazole tethered β-carbolines and investigation of
their cytotoxic and antimicrobial activities.
The chemical structures of all these novel products were
1
13
identified by H-NMR, C-NMR, HRESIMS and FTIR.
Results and discussion
Chemistry
Cytotoxic activity
The overall strategy for the synthesis of novel β-carboline
derivatives containing the 1,2,3-triazole ring is shown in
Scheme 1. 1,2,3,4-Tetrahydro-β-carboline compounds 4a–c
were synthesized by Pictet-Spengler reaction of L-trypto-
phan methyl ester (2) with O-propargylated benzaldehydes
The cytotoxic activity of novel β-carboline derivatives 4a–c,
5a–c and 7a–i were evaluated in vitro against two cancer cell
lines, namely Hela and HepG2, by the standard MTT assay.
Paclitaxel was used as the positive control. The results are
summarized in Table 4. As shown, compound
7f with 1-(3-(3,4-(dichlorophenyl)-1H-1,2,3-(triazole-4-yl)
metoxy)phenyl) substituent demonstrated the highest cyto-
toxicity against both cancer cell lines, Hela and HepG2, with
IC50 values equal to 46 and 32 μM, respectively. Compounds
4b, 5b, 7c, 7g and 7h displayed good cytotoxicity with IC50
o 100 μM. Other β-carboline derivatives 4a, 4c, 5a, 5c, 7b
and 7e exhibited moderate cytotoxic activity against cancer
(
3a–c) to yield 1,2,3,4-tetrahydro-β-carboline compounds
as mixture of two diasteromers (Table 1) (Zhao et al.,
2
006b).
We investigated several oxidizing reagents including
sulfur (Snyder et al., 1948; Cao et al., 2005), KMnO and
4
IBX for the conversion of 1,2,3,4-tetrahydro-β-carboline
derivative 4a–c to the corresponding β-carbolines 5a–c. The
CO CH
CO H
2
3
2
CHO
CO CH
2
3
NH2
NH2
[
i]
[ii]
NH
[iii]
+
N
O
N
H
H
N
H
O
1
2
3a-c
4
a-c
CO CH
CO CH
2
3
2
3
N
[iv]
N
R
N3
N
N
H
H
R
N
O
O
N
N
5
a-c
7a-i
6
a-e
3 2 2 2 4 2 2
Scheme 1 i CH OH, SOCl , reflux ii CH Cl , 10 % TFA, rt iii S, xylene, reflux iv 20 % CuSO · 5H O, 40 % sodium ascorbate, t-BuOH:H O (4:1)

Med Chem Res
Table 1 Synthesis of methyl 1-(α-(O-propargylated)-phenyl) 1,2,3,4-tetrahydro β-carboline carboxylate derivatives
2
CO CH3
CO CH3
2
CHO
NH2
NH
CH Cl , 10% TFA
2
2
+
N
rt
N
O
H
H
O
2
3a-c
4a-c
a
Aldehyde
Product
yield % (dr)
85(57:43)
CO CH3
2
NH
O
4a
3
a
N
H
CO CH
2
3
CHO
NH
4
b
87(57:43)
85(56:44)
N
O
O
CHO
O
H
3
b
4
c
3
c
a
dr diastereomeric ratio calculated by NMR spectroscopy
cell lines with 100 o IC50 o 200 μM (except for 7b and 7e
that were inactive against HepG2).
cell lines. These results showed that R group of 1,2,3-tria-
zole ring has a detrimental effect on the cytotoxic activity of
β-carbolines and their activity could be tuned by linking
appropriate groups.
Among 1,2,3,4-tetrahydro-β-carboline derivatives 4a–c
with propargyloxy moiety on phenyl group at C-1, com-
pound 4b possessing 1-(3-(prop-2-ynyloxy)phenyl) sub-
stituent was found to be the most active with IC50 values 88
and 54 μM for Hela and HepG2, respectively. β-Carbolines
Antibacterial activity
5
a and 5c showed better cytotoxic activity than their parent
Antibacterial activities of the synthesized β-carboline deri-
vatives were assessed against Staphylococcus aureus, van-
comycin resistant strain of Enterococcus faecium,
Enterococcus faecalis, and Bacillus cereus as Gram-
positive bacteria and one Gram-negative bacterium,
Escherichia coli. Chloramphenicol and cefixime were used
as the standard antibiotics. The results are presented in
Table 5. Compounds 5c, 7d and 7i exhibited excellent
antibacterial activity against vancomycin resistant strain of
E. faecium with MIC of 8 μg/mL which were even more
potent than chloramphenicol and cefixime. Compounds 4a,
compounds, 4a and 4c, but 5b demonstrated similar activity
as 4b. So these results confirm that aromatization improved
the cytotoxicity of β-carbolines (Zhao et al., 2006b). Syn-
thetic derivatives with 1,2,3-triazole ring possessing 3,4-
dichlorophenyl, 2-hydroxyethyl and 2-hydroxy propyl
groups at N-4 of triazole ring, 7c, 7g and 7h, were more
active than other derivatives and their parent compounds
with IC50 o 100 μM. Compounds 7a, 7d and 7i with
4
-bromophenyl group at N-4 position were found to be less
active with IC50 values of more than 400 μM against cancer

Med Chem Res
Table 2 Optimization of oxidation reaction conditions
Entry
Reagent
Equivalent
Solvent
CH CN
Temperature
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
IBX
S
2.5
3
3
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
rt
24
24
8
0
Toluene
Xylene
Xylene
Xylene
Xylene
DMF
0
S
3
35
40
55
67
20
45
S
3
18
8
S
5
S
5
18
14
14
KMnO
KMnO
4
4
1.5
3
DMF
rt
at 600 and 500 and 150 and 125 MHz, respectively in
DMSO-d as solvent. Silica gel F was used in analytical
6
254
thin-layer chromatography (TLC) and also column chro-
matography. HRESIMS spectra were obtained on a Bruker
microTOF ESIMS in positive mode. FT-IR spectra were
performed on a Bruker Tensor 27 spectrometer.
Fig. 1 Structure of the applied azides
Preparation of L-tryptophan methyl ester 2
5
a, 5b, 7a, 7b, 7e, 7f, 7g, and 7h displayed potent activity
At 0 °C, to a solution of 4 g (20 mmol) L-tryptophan in
methanol (20 mL), 4.5 mL thionyl chloride was added drop
wise. The mixture was stirred for 10 min and then was
refluxed for 16 h. Solvent was evaporated under reduced
pressure. The residue was made basic with 50 mL saturated
solution of sodium bicarbonate, and the aqueous mixture
extracted with ethyl acetate (3 × 50 mL). The organic phase
was washed with water, then dried over anhydrous sodium
sulfate, filtered, and concentrated. The product was obtained
in 80 % yield.
(
MICs 16–32 μg/mL) against E. faecium. Compounds 4b,
4
6
4
c and 7c demonstrated moderate antibacterial effect (MIC
4 μg/mL) against E. faecium. All compounds (except for
b, 4c and 7c) inhibited the growth of E. faecium better than
vancomycin. Compound 7d was found to be a more active
β-carboline derivative than others against E. faecalis (MIC
1
6 μg/mL). All synthetic compounds showed weak activity
against S. aureus, E. coli and B. cereus (MIC 4 64 μg/mL).
Experimental
General procedure for the preparation of methyl-1,2,3,4-
tetrahydro-β-carboline-3-carboxylate 4a–c
General chemistry
To a solution of 1 mmol L-tryptophan methyl ester, 1 mL
CH Cl and 10 % TFA, 1 mmol O-propargylated benzal-
Azides and aldehydes were prepared based on previously
reported procedures (Pokhodylo et al., 2009; Ingham et al.,
2
2
dehyde [(prop-2-ynyloxy) benzaldehyde derivatives] was
added and the reaction was stirred at room temperature. The
completion of the reaction was monitored by TLC (ethyl
acetate/petroleum ether (40–60) 1:3). After 24 h, the mix-
ture was neutralized with saturated Na CO and extracted
1
956; Wu et al., 2010). Other starting materials and solvents
were obtained from Merck and Sigma-Aldrich chemical
companies and used without further purification. Melting
points were measured on a Branstead/Electrothermal 9200
2
3
1
13
apparatus and were not corrected. HNMR and CNMR
spectra were recorded on a Bruker Avance III spectrometers
with dichloromethane (3 × 50 mL). The organic phase was
washed with water, dried over Na SO , and concentrated
2
4

Med Chem Res
Table 3 Synthesis of 1,2,3-triazole β-carboline derivatives
CO CH3
CO CH3
2
2
CuSO4. 5H O
2
N
N
NaAs
R
N3
N
t-BuOH, H O, rt
N
2
H
H
R
N
O
O
N N
5
a-c
6a-e
7a-i
Entry
Azide
β-Carboline
Time (h)
3
Product
Yield (%)
78
1
6b
5a
Br
N
CO CH
2
3
N
N
N
O
N
H
7
a
2
6c
5a
3
80
F
N
CO CH
2
3
N
N
N
O
N
H
7
b
3
6d
5a
1.5
95
N
OH
2
CO CH3
N
N
N
O
N
H
7
7
7
c
d
e
4
5
6
6b
6c
6a
5b
5b
5b
4
79
80
83
Br
CO
2 3
CH
N
N
N
N
H
N
O
3.5
2.5
F
CO
2 3
CH
N
N
N
N
H
N
O

Med Chem Res
Table 3 continued
CO CH3
CO CH3
2
2
CuSO4. 5H O
2
N
N
NaAs
R
N3
N
t-BuOH, H O, rt
N
H
2
H
R
N
O
O
N N
5
a-c
6a-e
7a-i
Entry
Azide
β-Carboline
Time (h)
Product
Yield (%)
Cl
Cl
CO CH
2
3
N
N
N
N
H
N
O
7
7
f
7
8
9
6d
6e
6c
5b
5b
5c
1.5
1.5
2.5
94
95
78
CO CH3
2
OH
N
N
N
N
H
N
O
g
CO CH
2
3
OH
N
N
N
N
H
N
O
7
h
CO CH3
Br
2
N
N
N
H
N
N
O
7
i
under reduced pressure to give two stereoisomers of the title
compound. The mixture of two diastereomers was separated
by preparative thin layer chromatography (PTLC) (silica gel
F254), eluting with hexane/ethyl acetate (4:1) (85 % yield).
J = 7.7 Hz, 1H, HAr (major isomer)], 7.44 [d, J = 7.7 Hz,
1H, HAr (minor isomer)], 7.33 [t, J = 7.8 Hz, 1H, HAr
(minor isomer)], 7.29 [t, J = 7.9 Hz, 1H, HAr (major iso-
mer)], 7.24 [t, J = 8.2 Hz, 2H, HAr (major isomer)], 7.19 [t,
J = 7.1 Hz, 2H, HAr (minor isomer)], 7.15 [d, J = 7.3 Hz,
Methyl 1-(2-(prop-2-ynyloxy)phenyl)-1,2,3,4-tetrahydro-β-
1H, HAr (minor isomer)], 6.92–7.09 (m, 5H, H ), 6.86 [t,
Ar
carboline-3-carboxylate (mixture of two isomer 57:43)
J = 7.4 Hz, 1H, HAr (major isomer)], 6.62 [d, J = 7.4 Hz,
1H, HAr (major isomer)], 5.66 [s, 1H, CH–N (major iso-
mer)], 5.61 [d, J = 5.2 Hz, 1H, CH–N (minor isomer)], 4.99
[s, 2H, CH –O (major isomer)], 4.92 [s, 2H, CH –O (minor
(
(
(
4a) Yield: 85 %, off white powder; m.p. 115–117 °C; IR
KBr, cm ): 1220, 1449, 1732, 2122, 3392; H NMR
DMSO-d6, 600 MHz): δ = 10.69 [s, 1H, NHindole (major
−1
1
2
2
isomer)], 10.31 [s, 1H, NHindole (minor isomer)], 7.47 [d,
isomer)], 3.88–3.94 [m, 1H, CH–CO Me (minor isomer)],
2

Med Chem Res
Table 4 Cytotoxicity of β-carboline derivatives by MTT assay (IC50
μM)
,
3
2
62–3.68 (m, 9H, mixture of two isomers), 2.99–3.12 [m,
H, CH (major isomer)], 2.91 [br s, 1H, NH (minor iso-
2
a
Compound
IC50
mer)], 2.76–2.88 [m, 2H, CH (minor isomer)], 2.51 [br s,
2
1H, NH (major isomer)]; C NMR (DMSO-d , 150 MHz):
1
3
b
b
Hela
HepG2
6
δ = 173.4(C=O), 172.9 (C=O), 155.3 (C –O), 154.8
Ar
4
4
4
5
5
5
7
7
7
7
7
7
7
7
7
a
b
c
a
b
c
a
b
c
d
e
f
187
88
215
54
(
(
(
CAr–O), 136.1 (C –NH), 136.1 (C –NH), 134.9
Ar Ar
C –NH), 133.3 (C –NH), 130.7 (C ), 130.2 (C ), 129.0
Ar
Ar
Ar
Ar
195
108
95
145
125
73
CH ), 128.9 (CH ), 128.6 (CH ), 128.5 (CH ), 126.5
Ar
Ar
Ar
Ar
(C ), 126.4 (C ), 121.3 (CH ), 120.8 (CH ), 120.6
Ar
Ar
Ar
Ar
(CH ), 120.5 (CH ), 118.3 (2CH ), 117.6 (CH ), 117.4
Ar
Ar
Ar
Ar
140
101
4400
_
(CH ), 112.8 (CH ), 112.6 (CH ), 111.1 (CH ), 111.0
Ar Ar Ar Ar
4400
142
(CH ), 107.6 (C ), 107.1(C ), 78.5 (-C≡), 78.4 (-C≡),
Ar
Ar
Ar
56.1 (CH –O), 56.0 (2CH–NH), 55.9 (CH –O), 51.7
2
2
83
66
(CH–COOMe), 51.7 (CH–COOMe), 51.2 (OCH ), 48.5
3
(
+
OCH ), 25.3 (CH ), 24.9 (CH ); HRMS [ESI+] m/z [M
4400
125
4400
_
3 2 2
+
Na] calcd for C H N NaO 383.1372, found: 383.1380,
22 20 2 3
+
[M+H] calcd for C H N O 361.1474, found: 361.1611.
46
32
22 21 2 3
g
h
i
92
105
87
74
Methyl 1-(3-(prop-2-ynyloxy)phenyl)-1,2,3,4-tetrahydro-β-
4400
4 nM
4400
25 nM
carboline-3-carboxylate (mixture of two isomers 57:43)
−
1
Paclitaxel
(4b) Yield: 87 %, yellow; m.p. 71-73 °C; IR (KBr, cm ):
1
a
1268, 1446, 1733, 2122, 3388; H NMR (DMSO-d , 600
6
Cytotoxicity as IC50 for each cell line, is the concentration of
compound, which reduced by 50 % the optical density of treated cells
with respect to untreated cells using the MTT assay
MHz): δ = 10.66 [s, 1H, NHindole (minor isomer)], 10.35 [s,
1H, NHindole (major isomer)], 7.46 (d, J = 4.5 Hz, 1H, HAr),
7.44 (d, J = 4.5 Hz, 1H, H ), 7.32 (t, J = 7.9 Hz, 1H, H ),
b
Cell lines include liver carcinoma (HepG2) and cervical carcinoma
Ar
Ar
(
Hela)
7
.21–7.28 (m, 3H, H ), 6.93–7.06 (m, 8H, H ), 6.91 (s,
Ar Ar
1
H, H ), 6.86 (d, J = 7.7 Hz, 1H, H ), 5.30 [s, 1H, CH–N
Ar
Ar
Table 5 In vitro antibacterial
activity of β-carboline
derivatives (MIC, μg/mL)
Compound
MIC (μg/mL)
S. aureus
E. faecalis
E. faecium
B. cereus
E. coli
4
4
4
5
5
5
7
7
7
7
7
7
7
7
7
a
b
c
a
b
c
a
b
c
d
e
f
64
64
64
64
64
64
32
64
32
32
16
32
32
64
32
32
1
32
64
64
16
32
8
64
4128
64
64
4128
4128
4128
4128
4128
4128
4128
4128
4128
4128
4128
4128
4128
4128
0.5
64
64
64
64
64
64
4128
4128
64
4128
4128
16
16
64
8
4128
4128
64
4128
4128
4128
4128
4128
4128
4128
8
16
16
32
32
8
4128
4128
64
g
h
i
4128
1
Chloramphenicol
Cefixime
32
32
64
2
4
0.25
8
Vancomycin
–
–
–
–
MIC minimum inhibitory concentration

Med Chem Res
(
minor isomer)], 5.20 [d, J = 5.7 Hz, 1H, CH–N (major
111.1 (CH ), 110.9 (CH ), 106.8 (C ), 106.5 (C ), 79.3
Ar
Ar
Ar
Ar
isomer)], 4.80 [d, J = 2.3 Hz, 2H, CH –O (major isomer)],
(2CH), 78.2(-C≡),78.1(-C≡), 57.1 (CH–NH), 56.2
(CH–NH), 55.3 (CH –O), 55.2 (CH –O), 53.3
2
4
.77 [d, J = 2.3 Hz, 2H, CH –O (minor isomer)], 3.85–3.89
2
2
2
[
m, 1H, CH–CO Me (major isomer)], 3.77–3.83 [m, 1H,
(CH–COOMe), 51.7(CH–COOMe), 51.6 (OCH ), 51.6
2
3
CH–CO Me (mior isomer)], 3.72 [s, 3H, OCH3 (major
(OCH ), 25.4 (CH ), 24.7(CH ); HRMS [ESI+] m/z [M
+H] calcd for C H N O 361.1474, found: 361.1594.
22 20 2 3
2
3
2
2
+
isomer)], 3.64 [s, 3H, OCH (minor isomer)], 3.56 [t, J =
3
2
1
.3 Hz, 1H, Hacetylene (major isomer)], 3.54 [t, J = 2.3 Hz,
H, Hacetylene (minor isomer)], 3.17 [br s, 1H, NH (minor
General procedure for the preparation of methyl-β-
carboline-3-carboxylate 5a–c
isomer)] 3.01–3.09 [m, 2H, CH (minor isomer)], 2.92–2.81
2
[
m, 2H, CH (major isomer)], 2.51 [br s, 1H, NH (major
2
1
3
isomer)];
C NMR (DMSO-d , 150 MHz): δ = 173.8
6
To 1 mmol of tetrahydro-β-carboline derivatives (4a–c),
160 mg (5 mmol) sulfur and 20 mL xylene was added and
the mixture was refluxed for 18 h until TLC (chloroform/
methanol 15:1) indicated disappearance of tetrahydro-β-
carboline derivative. After evaporation, the crude product
was purified by silica gel column chromatography (AcOEt
and Hexane as the eluent).
(
C=O), 172.9 (C=O), 157.2 (C –O), 157.2 (C –O), 144.7
Ar Ar
(
C ), 143.7 (C ), 136.3 (C –NH), 136.1(C –NH), 135.1
Ar Ar Ar Ar
(
C –NH), 134.1 (C –NH), 129.4 (CH ), 129.1 (CH ),
Ar Ar Ar Ar
1
1
1
1
1
26.5 (C ), 126.4 (C ), 121.4 (CH ), 121.1 (CH ),
Ar Ar Ar Ar
20.8 (CH ), 120.7 (CH ), 118.4 (CH ), 118.3 (CH ),
Ar
Ar
Ar
Ar
17.6 (CH ), 117.5 (CH ), 115.5 (CH ), 115.2 (CH ),
Ar
Ar
Ar
Ar
13.5 (CH ), 113.0 (CH ), 111.2 (CH ), 111.0 (CH ),
Ar
Ar
Ar
Ar
06.9 (C ), 106.5 (C ), 79.2 (2CH), 78.2 (-C≡), 78.1
Methyl
1-(2-(prop-2-ynyloxy)phenyl)-β-carboline-3-car-
Ar
Ar
(
(
-C≡), 57.6 (CH–NH), 56.2 (CH–NH), 55.4 (CH –O), 55.3
boxylate (5a) Yield: 60 %, off white powder; m.p. 187 °C
(Dec.); IR (KBr, cm ): 1261, 1444, 1707, 2118, 3422; H
2
−1
1
CH –O), 53.9 (2CH–COOMe), 51.7 (OCH3), 51.6
2
(
OCH ), 25.4 (CH ), 24.7 (CH ); HRMS [ESI+] m/z
NMR (DMSO-d , 600 MHz): δ = 11.53 (s, 1H, NH), 8.95
3
2
2
6
+
[
M+Na] calcd for C H N NaO 383.1376, found:
(s, 1H, H ), 8.42 (d, J = 7.9 Hz, 1H, H ), 7.55–7. 63 (m,
2
2
20
2
3
Ar
Ar
+
3
83.1380, [M+H] calcd for C H N O 361.1546, found:
3H, H ), 7.54 (d, J = 7.4 Hz, 1H, H ), 7.35 (d, J = 8.4 Hz,
2
2
21
2
3
Ar Ar
3
61.1563.
1H, H ), 7.32 (t, J = 7.3 Hz, 1H, H ), 7.22 (t, J = 7.4 Hz,
Ar Ar
1
H, H ), 4.83 (s, 2H, CH –O), 3.92 (s, 3H, OCH ), 3.43 (s,
Ar 2 3
1
3
Methyl 1-(4-(prop-2-ynyloxy)phenyl)-1,2,3,4-tetrahydro-β-
1H, Hacetylene); C NMR (DMSO-d , 150 MHz): δ = 166.1
6
carboline-3-carboxylate (mixture of two isomers 56:44)
(C=O), 155.1 (C –O), 141.0 (C -COOMe), 140.9
Ar
Ar
(
(
(
4c) Yield: 85 %, white powder; m.p. 146–149 °C; IR
KBr, cm ): 1224, 1447, 1737, 2119, 3388; H NMR
(C –N), 136.2 (C –NH), 135.8 (C –NH), 131.7 (CH ),
130.2 (CH ), 128.5 (CH ), 127.7 (C ), 126.8 (C ),
Ar Ar Ar Ar
122.0 (CH ), 121.0 (CH ), 120.9 (C ), 120.0 (CH ),
Ar Ar Ar Ar
Ar Ar Ar Ar
−1
1
DMSO-d , 600 MHz): δ = 10.68 [s, 1H, NHindole (major
6
isomer)], 10.40 [s, 1H, NHindole (minor isomer)], 7.46–7.53
116.7 (CH ), 112.9 (CH ), 112.4 (CH ), 79.1 (CH), 78.1
Ar Ar Ar
(
7
8
m, 2H, H ), 7.34 [d, J = 8.6 Hz, 2H, H ,(minor isomer)],
(–C≡), 55.8 (CH –O), 51.9 (OCH ); HRMS [ESI+] m/z [M
Ar
Ar
2
3
+
.29 [d, J = 8.0 Hz, 1H, H ,(major isomer)], 7.27 [d, J =
+Na]
calcd for C H N NaO 379.1059, found:
22 16 2 3
Ar
+
.0 Hz, 1H, H ,(minor isomer)], 7.23 [d, J = 8.6 Hz, 2H,
379.1072, [M+H] calcd for C H N O 357.1239, found:
Ar
22 17 2 3
H ,(major isomer)], 6.90–7.13 (m, 8H, H ), 5.33 [s, 1H,
357.1273.
Ar
Ar
CH–N (major isomer)], 5.23 [d, J = 5.4 Hz, 1H, CH–N
minor isomer)], 4.86 [d, J = 2.2 Hz, 2H, CH –O (minor
(
Methyl
1-(3-(prop-2-ynyloxy)phenyl)-β-carboline-3-car-
2
isomer)], 4.83 [d, J = 2.2 Hz, 2H, CH –O (major isomer)],
boxylate (5b) Yield: 63 %, off white powder; m.p.
2
−1
3
.91–3.94 [m, 1H, CH–CO Me (minor isomer)], 3.82 [dd,
185–188 °C (Dec.); IR (KBr, cm ): 1245, 1445, 1715,
2
1
J = 10.9, 5.5 Hz, 1H, CH–CO Me (major isomer)], 3.77 [s,
2126, 3322; H NMR (DMSO-d , 600 MHz): δ = 11.94
2
6
3
H, OCH3 (minor isomer)], 3.68 [s, 3H, OCH3 (major
(s, 1H, NH), 8.95 (s, 1H, H ), 8.45 (d, J = 7.9 Hz, 1H,
Ar
isomer)], 3.63 [t, J = 2.2 Hz, 1H, Hacetylene (minor isomer)],
H ), 7.71 (d, J = 8.2 Hz, 1H, H ), 7.63 (d, J = 7.3 Hz, 2H,
Ar
Ar
3
1
.60 [t, J = 2.2 Hz, 1H, Hacetylene (major isomer)], 3.15 [br s,
H ), 7.60 (d, J = 7.5 Hz, 1H, H ), 7.58 (s, 1H, H ), 7.35
(t, J = 7.4 Hz, 1H, H ), 7.22 (d, J = 6.9 Hz, 1H, H ), 4.96
Ar Ar
Ar Ar Ar
H, NH (minor isomer)], 3.02–3.15 [m, 2H, CH (major
2
isomer)], 2.84–2.99 [m, 2H, CH (minor isomer)], 2.56 [br
(s, 2H, CH –O), 3.95 (s, 3H, OCH ), 3.62 (s, 1H, Hacetylene);
2 3
2
3
1
13
s, 1H, NH (major isomer)]; C NMR (DMSO-d , 150
C NMR (DMSO-d , 150 MHz): δ = 165.9 (C=O), 157.4
6
6
MHz): δ = 173.8 (C=O), 172.9 (C–O), 156.8 (C –O),
(C –O), 141.7 (C –COOMe), 141.4 (C –N), 138.9
Ar Ar Ar
Ar
1
56.4 (C –O), 136.3 (C –NH), 136.0 (C –NH), 135.8
(C ), 136.6 (C –NH), 134.5 (C –NH),, 129.9 (CH ),
Ar Ar Ar Ar
Ar
Ar
Ar
(
C ), 135.6 (C ), 134.8 (C –NH), 134.5 (C –NH),
129.2 (C ), 128.7 (CH ), 122.0 (CH ), 121.6 (CH ),
Ar Ar Ar Ar
Ar
Ar
Ar
Ar
1
1
1
29.7 (CH ), 129.3 (CH ), 126.5 (C ), 126.4 (C ),
121.1 (C ), 120.4 (CH ), 116.8 (CH ), 115.3 (CH ),
Ar Ar Ar Ar
Ar
Ar
Ar
Ar
20.7 (CH ), 120.6 (CH ), 118.3 (CH ), 118.2 (CH ),
115.0 (CH ), 112.8 (CH ), 78.5 (–C≡), 55.6 (CH –O),
Ar
Ar
Ar
Ar
Ar
Ar
2
+
17.6 (CH ), 117.5 (CH ), 114.5 (CH ), 114.4 (CH ),
51.3 (OCH ); HRMS [ESI+] m/z [M+Na] calcd for
3
Ar
Ar
Ar
Ar

Med Chem Res
+
+
C H N NaO 379.1059, found: 379.1070, [M+H] calcd
51.9 (OCH ); HRMS [ESI+] m/z [M+Na] calcd for
3
2
2
16
2
3
7
9
+
for C H N O 357.1253, found: 357.1273.
C H
calcd for C H
BrN NaO 576.0647, found: 576.0674, [M+Na]
2
2
17
2
3
28 20
5
3
8
20
1
BrN NaO 578.0627, found: 578.0640.
2
8
5
3
Methyl
1-(4-(prop-2-ynyloxy)phenyl)-β-carboline-3-car-
boxylate (5c) Yield: 67 %, white powder; m.p. 215–218 °
Methyl
methoxy)phenyl)-β-carboline-3-carboxylate
80 %, off white powder; m.p. 210 °C (Dec.); IR(KBr,
1-(2-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)
−1
C (Dec.); IR (KBr, cm ): 1237, 1505, 1707, 2112, 3243;
(7b) Yield:
1
H NMR (DMSO-d , 600 MHz): δ = 11.98 (s, 1H, NH),
6
−1
1
8
.94 (s, 1H, H ), 8.47 (d, J = 7.9 Hz, 1H, H ), 8.06
Ar Ar
cm ): 1244,1509, 1715, 3241; H NMR (DMSO-d , 500
6
(
(
(
d, J = 8.4 Hz, 2H, H ), 7.76 (d, J = 8.2 Hz, 1H, H ), 7.66
Ar Ar
MHz): δ = 11.70 (s, 1H, NH), 8.92 (s, 1H, H ), 8.42 (d, J
Ar
t, J = 7.6 Hz, 1H, H ), 7.38 (t, J = 7.5 Hz, 1H, H ), 7.31
Ar
Ar
= 7.9 Hz, 1H, H ), 8.02 (s, 1H, Htriazole), 7.59–7.64 (m,
Ar
d, J = 8.4 Hz, 2H, H ), 5.00 (s, 2H, CH –O), 3.99 (s, 3H,
Ar
2
3H, H ), 7.55 (t, J = 7.6 Hz, 1H, H ), 7.50 (d, J = 8.2 Hz,
Ar
Ar
1
3
OCH ), 3.71 (s, 1H, Hacetylene); C NMR (DMSO-d , 150
MHz): δ = 166.1 (C=O), 157.8 (C –O), 141.8
3
6
1H, H ), 7.30–7.43 (m, 5H, H ), 7.23 (t, J = 7.4 Hz, 1H,
Ar Ar
1
3
Ar
H ), 5.37 (s, 2H, CH –O), 3.90 (s, 3H, OCH ); C NMR
Ar 2 3
(
(
(
(
(
C –COOMe), 141.4 (C –N), 136.5 (C –NH), 134.3
Ar Ar Ar
(DMSO-d , 125 MHz): δ = 166.1 (C=O), 165.5, 160.5,
6
C –NH),130.6 (C ), 129.8 (2CH ), 128.9 (C ), 128.5
Ar
Ar
Ar
Ar
155.7 (C –O), 144.2 (C–N
), 140.9 (C –COOMe),
triazole Ar
Ar
CH ), 121.9 (CH ), 121.1 (C ), 120.3 (CH ), 116.3
Ar
Ar
Ar
Ar
140.8 (C –N), 136.3 (C –NH), 135.7 (C –NH), 132.7
Ar Ar Ar
CH ), 115.1 (2CH ), 112.7 (CH ), 78.4 (–C≡), 55.5
Ar
Ar
Ar
(C –N
), 131.7 (CH ), 130.5 (CH ), 128.6 (CH ),
triazole Ar Ar Ar
Ar
+
CH –O), 52.0 (OCH ); HRMS [ESI+] m/z [M+Na] calcd
2
3
127.6 (C ), 126.7 (C ), 122.2 (CH ), 122.1 (CH ),
Ar Ar Ar Ar
122.1 (CH ), 121.9 (CH ), 121.1 (CH ), 120.8 (C ),
Ar Ar Ar Ar
+
for C H N NaO 379.1059, found: 379.1073, [M+H]
calcd for C H N O 357.1253, found: 357.1253.
2
2
16
2
3
2
2
17
2
3
120.1 (CH ), 116.8 (CH
), 116.7 (CH ), 116.5
triazole Ar
Ar
(
(
CH ), 112.9 (CH ), 112.2 (CH ), 61.6 (CH –O), 51.9
Ar
Ar
Ar
2
+
General procedure for the preparation of β-carboline
derivatives possessing 1,2,3-triazole ring by click chemistry
7a–i)
OCH3); HRMS [ESI+] m/z [M+Na]
calcd for
C H FN NaO 516.1448, found: 516.1456.
2
8
20
5
3
(
Methyl 1-(2-((1-(2-hydroxypropyl)-1H-1,2,3-triazol-4-yl)
methoxy)phenyl)-β-carboline-3-carboxylate (7c) Yield:
In a round–bottom flask, 0.5 mmol β-carboline (5a–c), 0.5
mmol azide derivatives, 0.1 mmol CuSO ·5H O, 0.2 mmol
−1
9
1
5 %, off white powder; m.p. 91.6 °C; IR (KBr, cm ):
4
2
1
252, 1613, 1717, 2925, 3416; H NMR (DMSO-d , 500
sodium ascorbate, 1 mL t-butyl alcohol and 500 μL H O
6
2
MHz): δ = 11.73 (s, 1H, NH), 8.97 (s, 1H, H ), 8.46 (d, J
were added. The reaction was stirred at room temperature.
The disappearance of β-carboline was monitored by TLC
Ar
=
7.9 Hz, 1H, H ), 7.78 (s, 1H, Htriazole), 7.71 (d, J = 8.2
Ar
Hz, 1H, H ), 7.58–7.68 (m, 3H, H ), 7.51 (d, J = 8.4 Hz,
(
CH Cl :EtOAc 10:1). Upon completion, 1 mL ammonia
Ar
Ar
2
2
1
1
H, H ), 7.37 (t, J = 7.4 Hz, 1H, H ), 7.25 (t, J = 7.4 Hz,
solution and 5 mL H O were added to reaction mixture and
it was extracted with CH Cl (3 × 25 mL). The combined
Ar Ar
2
H, H ), 5.35 (s, 2H, CH –O), 5.00 (d, J = 4.7 Hz, 1H,
Ar
2
2
2
OH), 4.11 (dd, J = 13.6, 4.7 Hz, 1H, CH ), 4.06 (dd, J =
organic layer was washed with brine, dried over anhydrous
Na SO and concentrated under vacuum to afford the crude
product. The product was purified by PTLC.
2
1
3.6, 6.9 Hz, 1H, CH ), 3.97 (s, 3H, OCH ), 3.79 (m, 1H,
2 3
1
2
4
3
CH-OH), 0.91 (d, J = 6.3 Hz, 3H, CH3); C NMR (DMSO-
d , 125 MHz): δ = 166.1 (C=O), 155.6 (C –O), 142.5
6
Ar
Methyl
1-(2-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)
(
C–Ntriazole), 140.9 (C –COOMe), 140.8 (C –N), 136.2
Ar Ar
methoxy)phenyl)-β-carboline-3-carboxylate
(7a) Yield:
(
C –NH), 135.7(C –NH), 131.9 (CH ), 130.4 (CH ),
Ar Ar Ar Ar
7
8 %, off white powder; m.p. 271–273 °C (Dec.); IR (KBr,
1
1
1
28.4 (CH ), 127.7 (C ), 126.7 (C ), 124.6 (CH ),
Ar Ar Ar Ar
−1
1
cm ): 1247, 1497, 1715, 3247; H NMR (DMSO-d , 500
6
22.0 (CH ), 120.8 (CH ), 120.8 (C ), 120.0 (CH ),
Ar
Ar
Ar
Ar
MHz): δ = 11.69 (s, 1H, NH), 8.93 (s, 1H, H ), 8.42 (d, J
Ar
16.7 (CHtriazole), 112.8 (CH ), 112.2 (CH ), 64.9
Ar
Ar
=
7.9 Hz, 1H, H ), 8.05 (s, 1H, Htriazole), 7.69 (d, J = 8.7
Ar
(
(
CH–OH), 61.4 (CH –O), 56.3 (CH –N
), 51.9
2
2
triazole
+
Hz, 2H, H ), 7.59–7.63 (m, 3H, H ), 7.56 (t, J = 7.6 Hz,
Ar
Ar
OCH ), 20.4 (CH ); HRMS [ESI+] m/z [M+Na] calcd for
3
3
1
H, H ), 7.50 (d, J = 8.2 Hz, 1H, H ), 7.33–7.35 (m, 3H,
+
Ar
Ar
C H N NaO 480.1648, found: 480.1663, [M+H] calcd
2
5
23
5
4
H ), 7.23 (t, J = 7.4 Hz, 1H, H ), 5.37 (s, 2H, CH –O),
Ar
Ar
2
for C H N O 458.1828, found: 458.1834.
2
5 24 5 4
1
3
3
1
.90 (s, 3H, OCH3); C NMR (DMSO-d 125 MHz): δ =
66.1 (C=O), 155.6 (C –O), 144.4 (C–Ntriazole), 140.9
6,
Methyl
methoxy)phenyl)-β-carboline-3-carboxylate
79 %, off white powder; m.p. 248–251 °C (Dec.); IR (KBr,
1-(3-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)
Ar
(
(
(
(
(
(
C –COOMe), 140.8 (C –N), 136.3 (C –NH), 135.7
(7d) Yield:
Ar Ar Ar
C –NH), 135.3 (C –N
), 132.6 (2CH ), 131.7
Ar
Ar
triazole
Ar
−1
1
CH ), 130.5 (CH ), 128.6 (CH ), 127.6 (C ), 126.7
cm ): 1259, 1349, 1497, 1698, 3440; H NMR (DMSO-d ,
Ar
Ar
Ar
Ar
6
C ), 122.2 (CH ), 121.7 (CH ), 121.6 (2CH ), 121.3
500 MHz): δ = 12.00 (s, 1H, NH), 9.07 (s, 1H, Htriazole),
8.95 (s, 1H, H ), 8.45 (d, J = 7.9 Hz, 1H, H ), 7.92 (d,
Ar
Ar
Ar
Ar
C ), 121.1 (CH ), 120.8 (C ), 120.1(CH ), 116.8
Ar
Ar
Ar
Ar
Ar
Ar
CHtriazole), 112.9 (CH ), 112.2 (CH ), 61.6 (CH –O),
J = 7.9 Hz, 2H, H ), 7.83 (d, J = 7.8 Hz, 2H, H ),
Ar Ar
Ar
Ar
2

Med Chem Res
7
.58–7.75 (m, 5H, H ), 7.35 (t, J = 7.5 Hz, 1H, H ), 7.29
121.9 (CH ), 121.4 (CH ), 121.1 (C ), 120.4 (CH ),
Ar
Ar
Ar
Ar
Ar
Ar
(
d, J = 7.4 Hz, 1H, H ), 5.43 (s, 2H, CH –O), 3.94 (s, 3H,
120.2 (CH ), 116.8 (CH
), 115.5 (CH ), 114.7
triazole Ar
Ar
2
Ar
1
3
OCH3); C NMR (DMSO-d , 125 MHz): δ = 166.0 (C=O),
1
1
(CH ), 112.7 (CH ), 60.9 (CH –O), 52.1 (OCH ); HRMS
Ar Ar 2 3
6
+
35
28 19 2 5
58.1(C –O), 143.9 (C–N
), 141.8 (C –COOMe),
[ESI+] m/z [M+Na]
calcd for C H
Cl N
Ar
triazole
Ar
+
41.4 (C –N), 138.9 (C ), 136.5 (C –NH), 135.7
NaO3 566.0774, found: 566.0766, [M+Na] calcd for
Ar
Ar
Ar
3
7
28 19 2 5 3
+
(
(
(
(
(
[
C –NH), 134.6 (C -N
), 132.8 (2CH ), 130.1
C H
Cl N NaO 568.0733, found: 566.0755, [M+H]
Ar
Ar triazole
Ar
3
28 20 2 5 3
5
CH ), 129.2 (C ), 128.7 (CH ), 123.1 (CH ), 122.1
calcd for C H
+H] calcd for C H
Cl N O 544.0943, found: 544.0943, [M
Ar
Ar
Ar
Ar
+
37
28 20 2 5 3
2CH ), 122.0 (CH ), 121.4 (C ), 121.4 (CH ), 121.1
Cl N O 546.0914, found:
Ar
Ar
Ar
Ar
C ), 120.4 (CH ), 116.8 (CH
), 115.5 (CH ), 114.7
546.0929.
Ar
Ar
triazole
Ar
CH ), 112.7 (CH ), 60.9 (CH –O), 52.0 (OCH ); HRMS
ESI+] m/z [M+Na] calcd for C H BrN NaO 576.0647,
Ar
Ar
+
2
3
79
20
Methyl 1-(3-((1-(2-hydroxypropyl)-1H-1,2,3-triazol-4-yl)
methoxy)phenyl)-β-carboline-3-carboxylate (7g) Yield:
2
8
5
3
+
81
found: 576.0666, [M+Na] calcd for C H BrN5
NaO3 578.0627, found: 578.0636, [M+H] calcd for
C H BrN O 554.0828, found: 554.0842, [M+H] calcd
for C H BrN O 556.0807, found: 556.0813.
2
+
8 20
−1
94 %, off white powder; m.p. 72 °C; IR (KBr, cm ): 1251,
1
7
9
+
1590, 1713, 3390; H NMR (DMSO-d6, 500 MHz): δ =
2
8
21
5 3
8
1
12.10 (s, 1H, NH), 9.00 (s, 1H, Htriazole), 8.50 (d, J = 7.9
Hz, 1H, H ), 8.30 (s, 1H, H ), 7.60–7.80 (m, 5H, H ),
2
8
21
5 3
Ar
Ar
Ar
Methyl
methoxy)phenyl)-β-carboline-3-carboxylate
0 %, off white powder; m.p. 218–220 °C (Dec.); IR (KBr,
1-(3-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)
7
5
.40 (t, J = 7.5 Hz, 1H, H ), 7.30 (d, J = 7.8 Hz, 1H, H ),
Ar Ar
(7e) Yield:
.38 (s, 2H, CH –O), 5.14 (d, J = 5.1 Hz, 1H, OH), 4.43
2
8
(dd, J = 13.7, 4.1 Hz, 1H, CH ), 4.32 (dd, J = 13.7, 7.4 Hz,
2
−1
1
cm ): 1257, 1512, 1699, 3241; H NMR (DMSO-d , 500
MHz): δ = 12.01 (s, 1H, NH), 9.02 (s, 1H, Htriazole), 8.95
(
Hz, 1H, H ), 7.98 (d, J = 4.2 Hz, 1H, H ), 7.69–7.73
(
6
1H, CH ), 4.05–4.13 (m, 1H, CH–OH), 4.00 (s, 3H, OCH ),
2
3
13
1.14 (d, J = 6.3 Hz, 3H, CH3);
MHz): δ = 166.0 (C=O), 158.1 (C –O), 142.2 (C–Ntriazole),
C NMR (DMSO-d , 125
6
s, 1H, H ), 8.45 (d, J = 7.9 Hz, 1H, H ), 8.00 (d, J = 4.9
Ar Ar
Ar
Ar
Ar
141.8 (C –COOMe), 141.4 (C –N), 138.8 (C ), 136.6
Ar
Ar
Ar
m, 2H, H ), 7.58–7.63 (m, 3H, H ), 7.48 (t, J = 8.6 Hz,
Ar Ar
(C –NH), 134.6 (C –NH), 130.0 (CH ), 129.2 (C ), 128.7
Ar Ar Ar Ar
(CH ), 125.5 (CH ), 122.0 (CH ), 121.2 (CH ), 121.1
Ar Ar Ar Ar
2
1
H, H ), 7.35 (t, J = 7.4 Hz, 1H, H ), 7.29 (d, J = 7.7 Hz,
Ar Ar
H, H ), 5.43 (s, 2H, CH –O), 3.94 (s, 3H, OCH );
Ar
2
3
(C ), 120.4 (CH ), 116.8 (CH
), 115.5 (CH ), 114.6
Ar
Ar
triazole
Ar
1
3
C NMR (DMSO-d , 125 MHz): δ = 166.9, 166.0 (C=O),
6
(CH ), 112.8 (CH ), 65.2 (CH–OH), 60.8 (CH –O), 56.5
Ar Ar 2
1
62.6, 160.7, 158.0 (C –O), 143.8 (C–Ntriazole), 141.8
Ar
(CH –N), 52.1 (OCH ), 20.7 (CH ); HRMS [ESI+] m/z [M
2 3 3
+
(
C –COOMe), 141.4 (C –N), 138.8 (C ), 136.5
Ar Ar Ar
+Na] calcd for C H N NaO 480.1648, found: 480.1655,
25 23 5 4
+
(
C –NH), 134.6 (C –NH), 133.1 (C –Ntriazole), 131.6,
Ar Ar Ar
[M+H] calcd for C H N O 458.1828, found: 458.1833.
25 24 5 4
1
1
1
1
(
[
31.5 (C ), 130.0 (CH ), 129.2 (C ), 128.7 (CH ),
Ar Ar Ar Ar
Methyl
1-(3-((1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)
28.6 (CH ), 123.3 (CH ), 122.6 (CH ), 122.5 (CH ),
Ar
Ar
Ar
Ar
methoxy)phenyl)-β-carboline-3-carboxylate (7h) Yield:
22.0 (CH ), 121.4(CH ), 121.1 (C ), 120.4 (CH ),
Ar
Ar
Ar
Ar
−1
9
1
5 %, white powder; m.p. 206–208 °C; IR (KBr, cm ):
258, 1716, 2928, 3415; H NMR (DMSO-d6, 500 MHz):
16.8 (CHtriazole), 116.6 (2CH ), 115.5 (CH ), 114.6
Ar
Ar
1
CH ), 112.7 (CH ), 60.9 (CH –O), 52.0 (OCH ); HRMS
Ar Ar 2 3
+
δ = 12.07 (s, 1H, NH), 8.95 (s, 1H, H ), 8.45 (d, J = 7.9
ESI+] m/z [M+Na] calcd for C H FN NaO 516.1448,
Ar
2
8
20
5
3
+
Hz, 1H, H ), 8.30 (s, 1H, Htriazole), 7.53 – 7.77 (m, 5H,
found: 516.1467, [M+H] calcd for C H FN O 494.1628,
Ar
2
8
21
5 3
H ), 7.34 (t, J = 7.5 Hz, 1H, H ), 7.25 (d, J = 7.8 Hz, 1H,
found:494.1634.
Methyl 1-(3-((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)
methoxy)phenyl)-β-carboline-3-carboxylate (7f) Yield:
8
1
Ar
Ar
H ), 5.33 (s, 2H, CH –O), 5.11 (br s, 1H, OH), 4.45 (t, J =
Ar
2
5
.2 Hz, 2H, CH -N), 3.95 (s, 3H, OCH ), 3.81 (t, J = 5.2
2 3
13
Hz, 2H, CH –OH); C NMR (DMSO-d , 125 MHz): δ =
2
6
−1
3 %, white powder; m.p. 206–208 °C; IR(KBr, cm ):
1
66.0 (C=O), 158.1 (C –O), 142.3 (C–Ntriazole), 141.8
Ar
1
257,1596, 1696, 3197; H NMR (DMSO-d , 500 MHz): δ
6
(
C –COOMe), 141.4 (C –N), 138.8 (C ), 136.5
Ar Ar Ar
=
11.99 (s, 1H, NH), 9.14 (s, 1H, Htriazole), 8.96 (s, 1H,
(
C –NH), 134.6 (C –NH), 129.9 (CH ), 129.2 (C ),
Ar Ar Ar Ar
H ), 8.45 (d, J = 7.9 Hz, 1H, H ), 8.32 (s, 1H, H ), 8.31
Ar
Ar
Ar
1
1
1
5
28.6 (CH ), 125.3 (CH ), 121.9 (CH ), 121.2 (CH ),
Ar Ar Ar Ar
(
s, 1H, H ), 8.01 (d, J = 8.7 Hz, 1H, H ), 7.90 (d, J = 8.8
Ar Ar
21.1 (C ), 120.3 (CH ), 116.8 (CHtriazole), 115.5 (CHAr),
Ar
Ar
Hz, 1H, H ), 7.55–7.78 (m, 4H, H ), 7.35 (t, J = 7.4 Hz,
1
CH –O), 3.94 (s, 3H, OCH ); C NMR (DMSO-d , 125
MHz): δ = 165.9 (C=O), 158.0 (C –O), 144.1 (C–Ntriazole),
Ar
Ar
14.5 (CH ), 112.8 (CH ), 60.8 (CH –O), 59.9 (CH –N),
Ar
Ar
2
2
H, H ), 7.29 (d, J = 7.7 Hz, 1H, H ), 5.44 (s, 2H,
+
Ar
Ar
2.3 (OCH ), 52.2 (CH –OH); HRMS [ESI+] m/z [M+Na]
3
2
1
3
2
3
6
calcd for C H N NaO 466.1491, found: 466.1502,
2
4
21
5
4
+
Ar
[
M+H] calcd for C H N O 444.1671, found: 444.1675.
24 22 5 4
1
41.8 (C –COOMe), 141.4 (C –N), 138.9 (C ), 136.5
Ar Ar Ar
(
C –NH), 136.0 (C –NH), 134.6 (C –Ntriazole), 132.3
Methyl
1-(4-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)
Ar
Ar
Ar
(
C –Cl), 131.8 (CH ), 131.1 (C –Cl), 130.1 (CH ),
methoxy)phenyl)- β-carboline-3-carboxylate (7i) Yield:
Ar
Ar
Ar
Ar
1
29.2 (C ), 128.7 (CH ), 123.3 (CH ), 122.0 (CH ),
78 %, off white powder; m.p. 141 °C; Off white powder; IR
Ar
Ar
Ar
Ar

Med Chem Res
−
1
1
(
5
KBr, cm ): 1246, 1503,1714, 3434; H NMR (DMSO-d6,
ATCC 29212, Vancomycin resistant strain of E. faecium
(MIC value: 64 µg/mL) and B. cereus PTCC 1015.
00 MHz): δ = 11.92 (s, 1H, NH), 9.08 (s, 1H, Htriazole),
8
.90 (s, 1H), 8.43 (d, J = 7.9 Hz, 1H, H ), 8.03 (d, J = 8.2
Ar
Hz, 2H, H ), 7.94 (d, J = 8.4 Hz, 2H, H ), 7.84 (d, J = 8.4
Ar
Ar
Hz, 2H, H ), 7.71 (d, J = 8.2 Hz, 1H, H ), 7.61 (t, J = 7.6
Determination of MICs
Ar
Ar
Hz, 1H, H ), 7.29 – 7.40 (m, 3H, H ), 5.40 (s, 2H,
Ar
Ar
1
3
CH –O), 3.94 (s, 3H, OCH ); C NMR (DMSO-d , 125
Antimicrobial activity of each synthetic material was
evaluated by broth micro-dilution susceptibility method
which was carried out according to the standard protocols
described by Clinical Laboratory Standard Institute
(CLSI) to determine the minimum concentration of each
antibacterial agent required for inhibition of visible
growth of mentioned bacteria (MIC). In brief, two fold
serial dilutions of each substance were made in a con-
centration range from 0.06 to 256 µg/mL in sterile plastic
micro-dilution trays containing Mueller Hinton broth
(MHB) medium. There after freshly cultured bacteria on
nutrient agar plates were used for preparation of the
inoculants of the bacterial strains using sterile normal
saline that were adjusted to 0.5 McFarland standard tur-
bidity using sterile normal saline, and were further dilu-
ted (1:100) by MHB just before adding to the trays
containing a serial dilution of each synthetic compound.
2
3
6
MHz): δ = 166.1 (C=O), 158.6 (C –O), 143.9 (C–Ntriazole),
Ar
1
41.8 (C –O), 141.4 (C –N), 136.5 (C –NH), 135.7
Ar Ar Ar
(
C –NH), 134.3 (C –N
), 132.8 (2CH ), 130.4
Ar
Ar
triazole
Ar
(
C ), 129.9 (2CH ), 129.0 (C ), 128.6 (CH ), 123.0
Ar Ar Ar Ar
(
CH ), 122.0 (2CH ), 121.9 (CH ), 121.4 (C ), 121.1
Ar Ar Ar Ar
(
C ), 120.3 (CH ), 116.2 (CHtriazole), 114.9 (2CHAr),
Ar Ar
1
12.7 (CH ), 61.2 (CH –O), 52.0 (OCH ); HRMS [ESI+]
Ar
2
3
+
79
m/z [M+Na] calcd for C H
found: 576.0666, [M+Na] calcd for C H
BrN NaO 576.0647,
2
8
20
5
3
81
+
BrN NaO
5 3
calcd for
2
8
20
+
5
78.0627, found: 578.0666, [M+H]
7
9
+
C H
calcd for C H
BrN O 554.0828, found: 554.0842, [M+H]
5 3
2
8
21
8
21
1
BrN O 556.0807, found: 556.0826.
5 3
2
8
MTT assay in vitro
Cell culture and treatment
8
So all experiments were carried out against 0.5–1 × 10
The human hepatocarcinoma (HepG2) and Hela cell lines
were purchased from National Cell Bank of Iran (NCBI),
Pasteur Institute of Iran (Tehran, Iran), and maintained in
DMEM medium supplemented with 10 % fetal bovine
serum and 100 U/mL penicillin and 100 μg/mL streptomy-
cin. These cells were kept at 37 °C in a humidified atmo-
CFU/mL of bacteria. The results of MIC determination
were recorded after 22 h incubation at 37 °C. All
experiments were done in triplicate.
sphere containing 5 % CO . β-carboline derivatives were
Conclusions
2
dissolved in DMSO to make a stock of 1 mM and further
diluted to final concentrations of 10–1000 µM with serum
free culture medium. The amount of DMSO added to the
cell culture was less than 0.1 % in all cases.
In this paper, β-carboline derivatives possessing the
1,2,3-triazole ring at C-1 position substituent were syn-
thesized and their cytotoxicities and antibacterial activ-
ities were evaluated. Compound 7f showed more potent
cytotoxic activity than other derivatives with IC50 values
of 46, 32 μM against Hela and HepG2 cell lines,
respectively. β-Carboline compounds 5a–c were more
active than their 1,2,3,4-tetrahydro-β-carboline parents,
demonstrated that aromatization improved their antitumor
activity in these cases. Compounds 7d, 7i which possess
4-bromophenyl substituent at N-4 and 5c exhibited
excellent inhibition against E. faecium with MIC of 8 μg/
mL. Comparison between cytotoxic and antibacterial
activity of these compounds showed that β-carboline
structures possessing 4-bromophenyl group on triazole
ring (7a, 7d and 7i) have good antibacterial activity and
weak cytotoxicity, so we can come to the conclusion that
they exhibit cell selectivity between bacteria and human
cells. These findings indicate that the nature of sub-
stituent on 1,2,3-triazole ring can tolerate cytotoxicity of
these compounds.
Cell viability assay
Cell viability was determined using the MTT assay. Briefly,
4
2
5
.5 × 10 cells were seeded in 96-well plates at 37 °C with
% CO for overnight incubation and treated with appro-
2
priate concentrations of β-carboline derivatives for 24 h.
The cells were then incubated with a serum-free medium
containing MTT at a final concentration of 0.5 mg/mL for 4
h. The dark formazan crystals formed were dissolved in
DMSO and the absorbance was measured at 570 nm.
Antibacterial activity
Bacterial strains
The following bacterial strains were included in the study:
E. coli ATCC 25922, S. aureus ATCC 25923, E. faecalis

Med Chem Res
Compliance with ethical standards
potential pharmacological chaperones for Gaucher disease. J Med
Chem 53:5248–55
Conflicts of interest The authors declare that they have no conflicts
of interest.
Dighe SU, Khan S, Soni I, Jain P, Shukla S, Yadav R, Sen P, Meeran
SM, Batra S (2015) Synthesis of β-carboline-based\nN\n-hetero-
cyclic carbenes and their antiproliferative and antimetastatic activ-
ities against human breast cancer cells. J Med Chem 58:3485–3499
Duan Y-C, Ma Y-C, Zhang E, Shi X-J, Wang M-M, Ye X-W, Liu H-
M (2013) Design and synthesis of novel 1,2,3-triazole-dithio-
carbamate hybrids as potential anticancer agents. Eur J Med
Chem 62:11–19
de Luiza BO, Borgati TF, de Freitas RP, Ruiz ALTG, Marchetti GM,
de Carvalho JE, da Cunha EFF, Ramalho TC, Alves RB (2014)
Synthesis and antiproliferative activity of 8-hydroxyquinoline
derivatives containing a 1,2,3-triazole moiety. Eur J Med Chem
84:595–604
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