Synthesis and cytotoxicity of novel 4-(4-(substituted)-1H-1,2,3-triazol-1- yl)-N-phenethylbenzenesulfonamides

Article abstract of DOI:10.1007/s00044-013-0777-z

A new series of 4-(4-(substituted)-1H-1,2,3-triazol-1-yl)-N- phenethylbenzenesulfonamide derivatives 5 were synthesized through the Click approach and evaluated for their cytotoxic activity against four cancer cell lines (HuCCA-1, HepG2, A549, and MOLT-3)

Full text of DOI:10.1007/s00044-013-0777-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:1768–1780
DOI 10.1007/s00044-013-0777-z
ORIGINAL RESEARCH
Synthesis and cytotoxicity of novel 4-(4-(substituted)-1H-1,2,3-
triazol-1-yl)-N-phenethylbenzenesulfonamides
•
Ratchanok Pingaew Supaluk Prachayasittikul
•
•
Somsak Ruchirawat Virapong Prachayasittikul
Received: 22 May 2013 / Accepted: 29 August 2013 / Published online: 13 September 2013
Ó Springer Science+Business Media New York 2013
Abstract A new series of 4-(4-(substituted)-1H-1,2,3-
triazol-1-yl)-N-phenethylbenzenesulfonamide derivatives 5
were synthesized through the Click approach and evaluated
for their cytotoxic activity against four cancer cell lines
(HuCCA-1, HepG2, A549, and MOLT-3). Most of the syn-
thesized triazoles 5 displayed cytotoxicity against MOLT-3
cell line, except for analogs 5a–c and 5e. Significantly,
4-phenyltriazoles (5a and 5n), 4-(naphthalen-2-yloxy)
methyltriazole 5d, as well as 4-((2-oxo-2H-chromen-7-
yl)oxy)methyltriazole 5l showed higher cytotoxic activity
against HepG2 cells than the reference drug, etoposide.
Interestingly, the 4-phenyltriazole 5a was the most potent
and promising compound with IC50 value of 9.07 lMagainst
HepG2 cell line. The analog 5a also exerted the highest
cytotoxic activity against HuCCA-1 cells. This finding pro-
vides the novel lead molecules for further development.
Keywords Sulfonamide ꢀ Triazole ꢀ Click reaction ꢀ
Cytotoxicity
Introduction
Nitrogen heterocycles display a vast arrays of bioactivities,
in particular, triazoles have been attracted considerable
interest due to their wide use as antitubercular, antibacte-
rial, antifungal, antiviral, anti-HIV, antiinflammatory, and
cytotoxic agents (Agalave et al., 2011). Triazoles showed
various promising structural features, such as stable to
metabolic degradation, capable of hydrogen bonding, high
selectivity, and less adverse effects. Furthermore, the tria-
zole scaffold can be used for the linkage of biomolecules
(e.g., polyamines, amino acids, and carbohydrates), drugs,
and other functional molecules with the point of improving
their pharmacological activities (Agalave et al., 2011).
The azide/alkyne dipolar cycloaddition, represented as
the Click-type reaction, is a significant route to the syn-
thesis of 1,2,3-triazoles. The approach has endowed with
high thermodynamic driving force (i.e., usually greater
than 20 kcal mol-1) (Kolb et al., 2001), therefore leading
to a powerful reaction of high yield, short reaction time,
and high selectivity.
R. Pingaew (&)
Department of Chemistry, Faculty of Science, Srinakharinwirot
University, Bangkok 10110, Thailand
e-mail: ratchanok@swu.ac.th
S. Prachayasittikul
Center of Data Mining and Biomedical Informatics, Faculty of
Medical Technology, Mahidol University, Bangkok 10700,
Thailand
S. Ruchirawat
Laboratory of Medicinal Chemistry, Chulabhorn Research
Institute, Bangkok 10210, Thailand
S. Ruchirawat
Program in Chemical Biology, Chulabhorn Graduate Institute,
Bangkok 10210, Thailand
S. Ruchirawat
Center of Excellence on Environmental Health and Toxicology,
Commission on Higher Education (CHE), Ministry of Education,
Bangkok, Thailand
Sulfonamide-containing molecules also possess a broad
spectrum of pharmacological actions including antitumor,
antibacterial, antimalarial, and antioxidative activities (Hu
et al., 2008; Scozzafava et al., 2003; Supuran et al., 2004;
Winum et al., 2008). A large number of novel sulfonamide
V. Prachayasittikul
Department of Clinical Microbiology and Applied Technology,
Faculty of Medical Technology, Mahidol University,
Bangkok 10700, Thailand
123

Med Chem Res (2014) 23:1768–1780
1769
R1
R1
NO2
R1
R1
NH2
SnCl2 2H2O
EtOH, reflux
O
S
O
S
HN
1
HN
O
O
2
1-3
R1
a
H
b
OMe
(i) NaNO2, HCl/CH3COOH, 0 o
(ii) NaN3, rt
C
R2
N
N
N
R1
R1
N3
R2
4
R1
R1
CuSO4 5H2O, sodium ascorbate
O
S
O
HN
3
HN
t-BuOH/H2O, rt
S
O
O
5
4-5 : R1, R2 = see tables 1 and 2
Scheme 1 Synthesis of 4-(4-(substituted)-1H-1,2,3-triazol-1-yl)-N-phenethylbenzenesulfonamides 5 through the Click reaction
derivatives as cytotoxic agent revealed several advantages
including simplicity of the synthesis and effectiveness
against multidrug resistant cell lines (MDR). Moreover,
some compounds have better pharmacological profiles such
as oral absorption with low side effects.
Reduction of the nitro derivatives 1 with stannous chloride
in refluxing ethanol provided the corresponding amino-
benzenesulfonamides 2 which were converted to the azi-
dobenzensulfonamides 3 using sodium nitrite and sodium
azide in a mixture of glacial acetic acid and concentrated
hydrochloric acid. Cycloaddition reaction of the azides 3
with various alkynes 4 readily afforded the triazoles 5 in
good yields (70–98 %) (Scheme 1; Table 1).
Furthermore, triazoles bearing sulfonamide moiety have
been reported to exert antimicrobial (Ezabadi et al., 2008;
Faidallah et al., 2011; Thomas et al., 2011; Wang et al.,
2010; Wilkinson et al., 2007), antimalarial (Boechat et al.,
2011), and antitumor (Ou et al., 2011) activities.
Structures of the desired triazoles 5 were characterized
by 1H NMR spectra which showed the existing of the
singlet of methine proton of triazole ring at d 8–10 ppm
indicating that the cycloadducts 5 were formed. The
1H NMR spectra displayed two methylene groups
(ArCH2CH2NH–) as triplet and as quartet at d in the range
of 2–4 ppm. The NH proton showed as triplet at d 4–5 ppm
(in CDCl3) or at d 7–8 ppm (in DMSO-d6). In the latter
case, the deshielded proton was observed due to the for-
mation of H-bonding with the solvent. In addition, the ether
derivatives (5b–5m and 5o–5p) showed the singlet of ether
methylene proton at d 5–6 ppm. The structures of all
obtained compounds were further supported by 2D NMR,
IR, and HRMS.
In the design of new bioactive agents, the development
of hybrid structures using a combination of two or more
pharmacophores that have different mechanisms of action
in the same molecule is the method of choice. These
merged pharmacophores offer the possibility to overcome
the current drug resistance and to reduce the appearance of
new resistant strains. In addition, the strategy can also
reduce unwanted side effects and may enhance biological
potency (Bektas et al., 2012; Hubschwerlen et al., 2003;
Kaplancikli et al., 2008; Solomon et al., 2010).
In this article, a novel series of target molecules that
contain both biologically active sulfonamide and triazole
entities have been designed and synthesized. A variety of
expected novel sulfonamide-triazole hybrids were evalu-
ated for their in vitro cytotoxic activity against HuCCA-1,
HepG2, A549, and MOLT-3 cell lines.
Cytotoxic activity
Cytotoxicity of the synthesized triazoles (5) as well as
amines (2) and azides (3) was assayed against HuCCA-1,
HepG2, A549, and MOLT-3 human cancer cell lines as
summarized in Table 2. Obviously, most of the triazoles
(5) displayed higher cytotoxicity than the amino (2) and
azido (3) derivatives, whereas the azido analogs (3) showed
twofold stronger activity than the amino compounds (2) in
MOLT-3 cells.
Results and discussion
Chemistry
A series of novel 4-substituted triazole sulfonamide
analogs 5 as target molecules were synthesized via azi-
dobenzenesulfonamides 3 as shown in Scheme 1. Nitro-
benzenesulfonamides 1 were prepared by treatment of
2-phenylethylamines with 4-nitrobenzenesulfonyl chloride
in the presence of sodium carbonate (Pingaew et al., 2013).
Substituents on the target 4-substituted triazoles 5 include
phenyl, phenoxymethyl, naphthalenoxymethyl, and couma-
rinoxymethyl groups. Significant results showed that triazoles
of various 4-substituents such as phenyl (5a and 5n), phen-
oxymethyl (5b, 5e–5f, and 5h–5k), naphthalenoxymethyl
123

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Med Chem Res (2014) 23:1768–1780
Table 1 Chemical yield of the 4-(4-(substituted)-1H-1,2,3-triazol-1-yl)-N-phenethylbenzenesulfonamides 5
Azide 3
Alkyne 4
Triazole 5
Yield (%)
94
3a
5a
4a
3a
3a
3a
3a
3a
3a
3a
O
O
5b
5c
5d
5e
5f
98
76
70
75
79
93
91
4b
4c
O
4d
O
O
O
Me 4e
CHO 4f
NO2 4g
5g
5h
Me
4h
O
MeO2C
O
3a
3a
5i
5j
88
76
4i
MeO
O
4j
CHO
MeO
O
4k
CHO
3a
3a
5k
5l
71
77
O
4l
O
O
123

Med Chem Res (2014) 23:1768–1780
1771
Table 1 continued
Azide 3
Alkyne 4
Triazole 5
Yield (%)
77
3a
5m
O
O
O
4m
3b
3b
5n
5o
94
90
4a
O
O
CHO 4f
NO2 4g
3b
5p
95
(5d), and coumarinoxymethyl (5l) displayed cytotoxicity
against HepG2 cell line. Among these cytotoxic compounds,
4-phenyltriazole (5a) exerted the highest cytotoxic activity
(IC50 = 9.07 lM) and higher than that of the reference drug,
etoposide (IC50 = 30.16 lM). The analog 5a also displayed
the highest cytotoxicity against HuCCA-1 cell line with IC50
of 8.65 lM. Cytotoxic activity of triazole 5a decreased
when dimethoxy groups were introduced to 3,4-positions on
NO2 substituents were placed on para-position of phen-
oxymethyl group as seen for triazole analogs (5e, 5f, and 5g).
The inhibition effect distinctively enhanced in MOLT-3
cells, when the triazole 5b contained CH3, CO2CH3, and
OCH3 groups on ortho-position of 4-phenoxytriazole as
noted for compounds 5h, 5i, 5j, and 5k. The ester derivative
of triazole (5i) was shown to be the most active compound
(MOLT-3 cells) with IC50 of 8.81 lM. The triazoles that
showed selective inhibition against MOLT-3 cells were p-
NO2 phenoxy (5g and 5p) and 4-coumaryloxy (5m) deriva-
tives. However, most of the investigated compounds exerted
cytotoxicity against MOLT-3 cell line, except for triazoles
5a–5c and 5e. In HuCCA-1 cell line, 3,4-dimethoxy groups
on phenethyl moiety of the triazole (5n) resulted in signifi-
cant loss of cytotoxicity as compared to phenethyltriazole
(5a). The results demonstrated that the insertion of
4-oxymethyl group between triazole and phenyl (or napht-
halenyl or coumarinyl) moieties makes most target com-
pounds lose their cytotoxic activity. From cytotoxicity
results of 4-substituted triazoles (5), obviously, 4-phenyl-
triazole (5a) was shown to be the most potent compound
against HepG2 cells. It is reasonable to assume that 4-phenyl
ring is an appropriate hydrophobic group for potent cyto-
toxicity. Other 4-aryl- and heteroaryloxymethyltriazoles
exhibited lower cytotoxicity, particularly, toward HepG2
cells. This could be possibly due to the steric effect of 4-a-
ryloxymethyl group that hindered the molecule in interacting
with the target site of action. It could be postulated that
cytotoxic activity of 4-substituted triazole (5) against HepG2
cells requires the planarity of 1-benzenesulfonamide and
4-phenyl moieties on the triazole ring together with unsub-
stituted phenethyl group. Therefore, both ends of the target
phenethyl moiety as observed for triazole 5n (IC50
=
23.89 lM). Similarly, when 4-phenyl group of compound 5a
was replaced by 4-phenoxymethyl group (5b), cytotoxic
activity was remarkably decreased. In addition, 2-naphtha-
lenoxymethyl (5d, IC50 = 28.21 lM) and 7-coumarin-
oxymethyl (5l, IC50 = 12.44 lM) displayed cytotoxic
activity, but weaker than the phenyltriazole 5a. It should be
noted that positions of naphthalenyl and coumaryl groups
linked to oxymethyl affect cytotoxic activity of the com-
pounds. Apparently, 1-naphthalenyloxymethyl moiety
afforded the triazole 5c with total loss of the cytotoxic
activity toward all the tested cells. It was also found that
4-coumaryloxymethyl triazole (5m) showed no inhibition
effect against the tested cells, except for MOLT-3 cells.
Interestingly, many 4-substituted triazoles 5 exerted prom-
isingly high cytotoxic activity against HepG2 cells as com-
pared to the etoposide. The order of decreasing cytotoxic
potency of these triazoles against HepG2 cells was
5a [ 5l [ 5n [ 5d. It was observed that 4-phenoxymeth-
yltriazole (5b) and its derivatives having substituents (CH3,
OCH3, CHO, CO2CH3, and NO2) on phenoxy moiety
exhibited cytotoxicity against different cell lines with dif-
ferent potencies. In HepG2 cell line, inhibition effect of
phenoxymethyltriazole (5b) decreased when CH3 CHO and
123

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Med Chem Res (2014) 23:1768–1780
Table 2 Cytotoxic activity of compounds (2–3 and 5) against four cancer cell lines
Compound
Cytotoxic activity (IC50, lM)a
HuCCA-1
Inactive
HepG2
A549
MOLT-3
Inactive
Inactive
166.60 1.96
NH2
O
S
HN
O
2a
MeO
MeO
NH2
O
S
Inactive
Inactive
Inactive
104.49 2.93
HN
2b O
N3
O
S
HN
3a
Inactive
Inactive
92.61 3.00
138.91 9.90
60.10 1.13
O
MeO
MeO
N3
O
HN
122.32 5.51
Inactive
48.51 0.81
S
O
3b
N
N
N
8.65 1.70
9.07 1.15
34.54 0.89
Inactive
Inactive
O
S
HN
HN
O
5a
5b
N
N
N
N
O
O
Inactive
57.54 8.66
Inactive
O
S
O
N
N
O
S
Inactive
Inactive
Inactive
Inactive
HN
HN
O
5c
5d
N
N
N
O
O
S
Inactive
28.21 2.89
Inactive
74.23 5.08
O
123

Med Chem Res (2014) 23:1768–1780
1773
Table 2 continued
Compound
Cytotoxic activity (IC50, lM)a
HuCCA-1
Inactive
HepG2
A549
MOLT-3
Inactive
N
N
81.75 2.89
Inactive
N
O
O
O
HN
S
O
5e
Me
N
N
N
O
HN
87.89 0.92
100.54 2.12
Inactive
32.02 0.76
S
5f
O
OHC
N
N
N
O
O
O
S
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
61.42 1.01
34.24 3.11
8.81 0.42
HN
HN
O
5g
O2N
N
N
N
41.62 1.15
O
S
Me
O
5h
N
N
N
N
O
O
O
S
49.40 4.04
HN
HN
CO2Me
O
5i
5j
N
N
O
S
Inactive
Inactive
57.52 6.51
79.18 14.15
9.22 0.48
OMe
O
OHC
34.51 4.36
39.04 0.37
10.33 0.08
N
N
N
O
O
S
HN
OHC
5k
OMe
O
123

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Med Chem Res (2014) 23:1768–1780
Table 2 continued
Compound
Cytotoxic activity (IC50, lM)a
HuCCA-1
HepG2
A549
MOLT-3
16.12 0.71
12.44 1.71
19.60 2.33
88.97 3.42
N
N
N
O
O
HN
S
O
5l
O
O
N
N
N
O
O
HN
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
10.65 0.48
60.99 6.66
17.43 0.41
10.10 0.27
S
O
O
O
5m
N
N
MeO
N
23.89 3.00
18.19 0.35
28.03 1.63
Inactive
O
S
HN
MeO
O
5n
N
N
MeO
MeO
N
O
O
O
Inactive
HN
S
O
5o
OHC
N
N
N
MeO
MeO
O
S
Inactive
HN
O
5p
O2N
Etoposideb
Doxorubicinc
ND
30.16 0.50
0.79 0.08
ND
0.051 0.002
ND
0.83 0.07
0.44 0.01
Inactive = IC50 [ 50 lg/mL. Cancer cell lines comprise the following: HuCCA-1 human cholangiocarcinoma cell line, HepG2 human hepa-
tocellular carcinoma cell line, A549 human lung carcinoma cell line, MOLT-3 human lymphoblastic leukemia cell line
ND not determined
a
The assays were performed in triplicate
b,c
Etoposide and doxorubicin were used as reference drugs
triazole require hydrophobic phenyl groups to bind lipophilic
sites of action. However, the effect of triazole core structure
on the target site of action and its mode of action remain to be
elucidated.
Conclusion
A series of triazoles-based sulfonamide (5) have been
accomplished via the Click reaction. Cytotoxic activity
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Med Chem Res (2014) 23:1768–1780
1775
testing revealed that most of the triazole analogs displayed
cytotoxicity against MOLT-3 cell line. It was observed that
the 4-phenoxymethyl-triazole scaffolds, especially meth-
ylbenzoate analog 5i, seem to be the most important core
structure responsible for strong cytotoxic activity (MOLT-3
cells). Significantly, triazoles (5a, 5d, 5l, and 5n) showed
higher cytotoxic activity against HepG2 cells than the con-
trol drug, etoposide. In particular, the 4-phenyl-triazole 5a
was the most potent and promising cytotoxic agent
(IC50 = 9.07 lM). The analog 5a also displayed the highest
(300 MHz, DMSO-d6) d 2.63 (t, J = 8.0 Hz, 2H, ArCH2),
2.82 (br q, 2H, CH2NH), 5.92 (s, 2H, NH2), 6.59 (d,
J = 8.6 Hz, 2H, C30-ArH and C50-ArH), 7.10–7.29 (m,
6H, ArH and NHSO2), 7.40 (d, J = 8.7 Hz, 2H, C20-
ArH and C60-ArH). 13C NMR (75 MHz, DMSO-d6) d 35.2
(CH2), 44.1 (CH2), 112.7 (CH), 126.1 (C), 128.3 (CH),
128.4 (CH), 128.6 (CH), 138.9 (C), 152.4 (C). HRMS–
TOF: m/z [M?Na]? 299.0814 (Calcd for C14H16N2NaO2S:
299.0825).
inhibition potency against HuCCA-1 cell line (IC50
=
4-Amino-N-(3,4-dimethoxyphenethyl)benzenesulfonamide
8.65 lM). The synthesis of the novel triazole analogs of
phenethylbenzenesulfonamides 5 provides potential lead
molecules for further drug discovery and development.
(2b)
Light brown solid. 94 %. mp 144–145 °C. IR (UATR)
cm-1: 3467 (NH), 3371 (NH), 3256 (NH), 1596 (ar C=C),
1515 (ar C=C), 1309 (S=O), 1145 (S=O). 1H NMR
(300 MHz, CDCl3) d 2.68 (t, J = 6.6 Hz, 2H, ArCH2),
3.12 (q, J = 6.6 Hz, 2H, CH2NH), 3.79, 3.83 (2s, 6H,
2 9 OCH3), 4.12 (s, 2H, NH2), 4.30 (br q, 1H, NHSO2),
6.55 (d, J = 1.8 Hz, 1H, C2-ArH), 6.58–6.65 (m, 3H, C6-
ArH, C30-ArH and C50-ArH), 6.74 (d, J = 8.1 Hz, 1H, C5-
ArH), 7.52 (d, J = 8.7 Hz, 2H, C20-ArH and C60-ArH).
13C NMR (75 MHz, CDCl3) d 35.2 (CH2), 44.2 (CH2),
55.8 (OCH3), 55.9 (OCH3), 111.4 (CH), 111.7 (CH), 114.0
(CH), 120.8 (CH), 127.8 (C), 129.2 (CH), 130.3 (C), 147.8
(C), 149.1 (C), 150.5 (C). HRMS–TOF: m/z [M?H]?
337.1224 (Calcd for C16H21N2O4S: 337.1216).
Experimental
Chemistry
Column chromatography was carried out using silica gel 60
(70–230 mesh ASTM). Analytical thin-layer chromatogra-
phy (TLC) was performed with silica gel 60 F254 aluminum
sheets. 1H- and 13C-NMR spectra were recorded on a Bruker
AVANCE 300 NMR spectrometer (operating at 300 MHz
1
for H and 75 MHz for 13C). FTIR spectra were obtained
using a universal attenuated total reflectance attached on a
Perkin-Elmer Spectrum One spectrometer. High-resolution
mass spectra (HRMS) were recorded on a Bruker Daltonics
(microTOF). Melting points were determined using a Griffin
melting point apparatus and were uncorrected.
General procedure for the synthesis of 4-azido-N-
phenethylbenzenesulfonamides (3)
Propynyoxy derivatives (4b–m) were prepared accord-
ing to the literature procedures (Banday et al., 2010) and
To a cool solution of amine 2 (3 mmol) in HCl:CH3COOH
(3:3 mL) at 0 °C, a solution of sodium nitrite (9 mmol) in
water (5 mL) was added. The stirred reaction mixture was
maintained for 15 min and then added dropwise a solution
of sodium azide (9 mmol) in water (5 mL). The reaction
mixture was allowed to stir at room temperature for 0.5 h,
then the precipitate was filtered, washed with cool water,
and recrystallized from methanol.
1
confirmed by H-NMR spectra.
General procedure for the synthesis of 4-amino-N-
phenethylbenzenesulfonamides (2)
A mixture of nitrosulfonamide 1 (4 mmol) and SnCl2ꢀ2
H2O (20 mmol) in absolute ethanol (20 mL) was stirred
under reflux for 4 h then concentrated under reduced
pressure. Water (20 mL) was added and extracted with
EtOAc (3 9 20 mL). The organic extracts were combined
and washed with water (20 mL) and brine (20 mL). The
organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated. The crude product was recrys-
tallized from methanol.
4-Azido-N-phenethylbenzenesulfonamide (3a)
Light brown solid. 95 %. mp 72–73 °C. IR (UATR) cm-1
:
3279 (NH), 2120 (N=N?=N-), 2097 (N=N?=N-), 1588
1
(ar C=C), 1490 (ar C=C), 1324 (S=O), 1155 (S=O). H
NMR (300 MHz, CDCl3) d 2.79 (t, J = 6.8 Hz, 2H,
ArCH2), 3.26 (q, J = 6.8 Hz, 2H, CH2NH), 4.42 (br s, 1H,
NHSO2), 7.08–7.33 (m, 7H, ArH), 7.79 (d, J = 8.5 Hz,
2H, C20-ArH and C60-ArH). 13C NMR (75 MHz, CDCl3) d
35.8 (CH2), 44.2 (CH2), 119.4 (CH), 126.9 (CH), 128.7
(CH), 128.8 (CH), 129.0 (CH), 137.5 (C), 144.6 (C).
HRMS–TOF: m/z [M?Na]? 325.0733 (Calcd for C14H14
N4NaO2S: 325.0741).
4-Amino-N-phenethylbenzenesulfonamide (2a)
Light brown solid. 82 %. mp 147–148 °C. IR (UATR)
cm-1: 3460 (NH), 3366 (NH), 3273 (NH), 1597 (ar C=C),
1497 (ar C=C), 1312 (S=O), 1153 (S=O). 1H NMR
123

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Med Chem Res (2014) 23:1768–1780
4-Azido-N-(3,4-dimethoxyphenethyl)benzenesulfonamide
N-Phenethyl-4-(4-(phenoxymethyl)-1H-1,2,3-triazol-1-
(3b)
yl)benzenesulfonamide (5b)
Light brown solid. 84 %. mp 76–77 °C. IR (UATR) cm-1
:
White solid. 98 %. mp 149–150 °C. IR (UATR) cm-1: 3278
(NH), 1597 (ar C=C), 1496 (ar C=C), 1331 (S=O), 1159
(S=O). 1H NMR (300 MHz, CDCl3) d 2.83 (t, J = 6.8 Hz,
2H, ArCH2), 3.31 (q, J = 6.8 Hz, 2H, CH2NH), 4.56 (t,
J = 6.1 Hz, 1H, NHSO2), 5.34 (s, 2H, CH2O), 7.00–7.38 (m,
10H, ArH), 7.90 (d, J = 8.9 Hz, 2H, ArH), 7.97 (d,
J = 8.9 Hz, 2H, ArH), 8.15 (s, 1H, CHN). 13C NMR
(75 MHz, CDCl3) d 35.8 (CH2), 44.3 (CH2), 61.9 (OCH2),
114.8 (CH), 120.6 (CH), 121.6 (CH), 127.0 (CH), 128.7
(CH), 128.9 (CH), 129.7 (CH), 137.3 (C), 139.7 (C), 140.2
(C), 145.9 (C), 158.0 (C). HRMS–TOF: m/z [M?H]?
435.1473 (Calcd for C23H23N4O3S: 435.1496).
3276 (NH), 2130 (N=N?=N-), 2101 (N=N?=N-), 1589 (ar
1
C=C), 1517 (ar C=C), 1329 (S=O), 1160 (S=O). H NMR
(300 MHz, CDCl3) d 2.69 (t, J = 6.6 Hz, 2H, ArCH2),
3.17 (q, J = 6.6 Hz, 2H, CH2NH), 3.80, 3.83 (2 s, 6H,
2 9 OCH3), 4.44 (t, J = 6.3 Hz, 1H, NHSO2), 6.55 (d,
J = 1.9 Hz, 1H, C2-ArH), 6.59 (dd, J = 8.0, 1.9 Hz, 1H,
C6-ArH), 6.74 (d, J = 8.0 Hz, 1H, C5-ArH), 7.06 (d,
J = 8.8 Hz, 2H, C30-ArH and C50-ArH), 7.73 (d, J =
8.8 Hz, 2H, C20-ArH and C60-ArH). 13C NMR (75 MHz,
CDCl3) d 35.3 (CH2), 44.3 (CH2), 55.8 (OCH3), 55.9
(OCH3), 111.4 (CH), 111.8 (CH), 119.4 (CH), 120.7 (CH),
129.0 (CH), 129.9 (C), 136.0 (C), 144.7 (C), 148.0 (C),
149.2 (C). HRMS–TOF: m/z [M?H]? 363.1119 (Calcd for
C16H19N4O4S: 363.1122).
4-(4-((Naphthalen-1-yloxy)methyl)-1H-1,2,3-triazol-1-yl)-
N-phenethylbenzenesulfonamide (5c)
White solid. 76 %. mp 166–167 °C. IR (UATR) cm-1
:
General procedure for the synthesis of 4-(4-
(substituted)-1H-1,2,3-triazol-1-yl)-N-
phenethylbenzenesulfonamides (5)
3250 (NH), 1596 (ar C=C), 1507 (ar C=C), 1331 (S=O),
1154 (S=O). 1H NMR (300 MHz, CDCl3) d 2.78 (t,
J = 6.8 Hz, 2H, ArCH2), 3.26 (q, J = 6.7 Hz, 2H,
CH2NH), 4.51 (t, J = 6.1 Hz, 1H, NHSO2), 5.50 (s, 2H,
CH2O), 6.95 (d, J = 7.5 Hz, 1H, ArH), 7.11 (dd, J = 7.9,
1.6 Hz, 2H, ArH), 7.17–7.29 (m, 3H, ArH), 7.38 (t,
J = 7.6 Hz, 1H, ArH), 7.42–7.52 (m, 3H, ArH), 7.77–7.96
(m, 5H, ArH), 8.20 (s, 1H, CHN), 8.23–8.28 (m, 1H, ArH).
13C NMR (75 MHz, CDCl3) d 35.8 (CH2), 44.3 (CH2),
62.3 (OCH2), 105.4 (CH), 120.6 (CH), 120.7 (CH), 121.2
(CH), 121.8 (CH), 125.4 (CH), 125.8 (CH), 126.6 (CH),
127.0 (CH), 127.6 (CH), 128.7 (CH), 128.9 (CH), 134.6
(C), 137.3 (C), 139.7 (C), 140.2 (C), 145.9 (C), 153.7 (C).
HRMS–TOF: m/z [M?H]? 485.1652 (Calcd for C27H25
N4O3S: 485.1642).
To a stirred solution of azido 3 (0.2 mmol) and alkyne
4 (0.2 mmol) in t-BuOH:H2O (3:3 mL), CuSO4ꢀ5H2O
(0.2 mmol) and ascorbic acid (0.5 mmol) were added. The
reaction mixture was stirred at room temperature for 2 h,
then concentrated under reduced pressure. The residue was
added water (10 mL) and extracted with dichloromethane
(3 9 20 mL). The combined organic phases were washed
with water (20 mL), dried over anhydrous sodium sulfate,
and evaporated to dryness. The crude product was purified
using silica gel column chromatography and eluted with
methanol:dichloromethane (1:50).
4-(4-((Naphthalen-2-yloxy)methyl)-1H-1,2,3-triazol-1-yl)-
N-Phenethyl-4-(4-phenyl-1H-1,2,3-triazol-1-
N-phenethylbenzenesulfonamide (5d)
yl)benzenesulfonamide (5a)
White solid. 70 %. mp 179–180 °C. IR (UATR) cm-1
3247 (NH), 1598 (ar C=C), 1505 (ar C=C), 1312 (S=O),
:
White solid. 94 %. mp 219–220 °C. IR (UATR) cm-1
3315 (NH), 1597 (ar C=C), 1504 (ar C=C), 1328 (S=O),
:
1
1154 (S=O). H NMR (300 MHz, DMSO-d6) d 2.70 (t,
1
1153 (S=O). H NMR (300 MHz, DMSO-d6) d 2.71 (t,
J = 7.6 Hz, 2H, ArCH2), 3.03 (q, J = 7.0 Hz, 2H,
CH2NH), 5.39 (s, 2H, CH2O), 7.12–7.29 (m, 6H, ArH),
7.37 (t, J = 8.1 Hz, 1H, ArH), 7.49 (t, J = 7.9 Hz, 1H,
ArH), 7.56 (d, J = 2.2 Hz, 1H, ArH), 7.81–7.95 (m, 4H,
ArH and NHSO2), 7.98 (d, J = 8.6 Hz, 2H, ArH), 8.16 (d,
J = 8.7 Hz, 2H, ArH), 9.14 (s, 1H, CHN). 13C NMR
(75 MHz, DMSO-d6) d 35.7 (CH2), 44.5 (CH2), 61.5
(OCH2), 107.8 (CH), 119.1 (CH), 121.1 (CH), 123.7 (CH),
124.3 (CH), 126.7 (CH), 127.0 (CH), 127.3 (CH), 128.0
(CH), 128.8 (CH), 128.9 (CH), 129.1 (CH), 129.9 (CH),
134.6 (C), 139.1 (C), 139.4 (C), 140.7 (C), 144.7 (C), 156.3
J = 7.5 Hz, 2H, ArCH2), 3.04 (q, J = 6.9 Hz, 2H,
CH2NH), 7.13–7.30 (m, 5H, ArH), 7.41 (t, J = 7.5 Hz, 1H,
ArH), 7.52 (t, J = 7.2 Hz, 2H, ArH), 7.87–8.05 (m, 5H,
ArH and NHSO2), 8.17 (d, J = 8.7 Hz, 2H, ArH), 9.42 (s,
1H, CHN). 13C NMR (75 MHz, DMSO-d6) d 35.7 (CH2),
44.5 (CH2), 120.3 (CH), 120.9 (CH), 125.9 (CH), 126.7
(CH), 128.8 (CH), 128.9 (CH), 129.1 (CH), 129.5 (CH),
130.4 (C), 139.1 (C), 139.5 (C), 140.6 (C), 148.1 (C).
HRMS–TOF: m/z [M?H]? 405.1371 (Calcd for C22H21N4
O2S: 405.1380).
123

Med Chem Res (2014) 23:1768–1780
1777
(C). HRMS–TOF: m/z [M?H]? 485.1635 (Calcd for
(C), 141.7 (C), 143.8 (C), 163.6 (C). HRMS–TOF: m/
z [M?H]? 480.1337 (Calcd for C23H22N5O5S: 480.1336).
C27H25N4O3S: 485.1642).
N-Phenethyl-4-(4-((p-tolyloxy)methyl)-1H-1,2,3-triazol-1-
N-Phenethyl-4-(4-((o-tolyloxy)methyl)-1H-1,2,3-triazol-1-
yl)benzenesulfonamide (5e)
yl)benzenesulfonamide (5h)
White solid. 75 %. mp 150–151 °C. IR (UATR) cm-1
3273 (NH), 1597 (ar C=C), 1508 (ar C=C), 1331 (S=O),
:
White solid. 91 %. mp 172–173 °C. IR (UATR) cm-1
:
3187 (NH), 1594 (ar C=C), 1496 (ar C=C), 1333 (S=O),
1161 (S=O). 1H NMR (300 MHz, DMSO-d6) d 2.16 (s, 3H,
ArCH3), 2.70 (t, J = 7.6 Hz, 2H, ArCH2), 3.02 (q,
J = 7.1 Hz, 2H, CH2NH), 5.26 (s, 2H, CH2O), 6.83–6.90
(m, 1H, ArH), 7.12–7.29 (m, 8H, ArH), 7.91 (t, J =
5.7 Hz, 1H, NHSO2), 7.98 (d, J = 8.8 Hz, 2H, ArH), 8.15
(d, J = 8.8 Hz, 2H, ArH), 9.06 (s, 1H, CHN). 13C NMR
(75 MHz, DMSO-d6) d 16.5 (CH3), 35.7 (CH2), 44.5
(CH2), 61.7 (OCH2), 112.4 (CH), 121.1 (CH), 121.2 (CH),
123.3 (CH), 126.5 (C), 126.7 (CH), 127.4 (CH), 128.8
(CH), 129.1 (CH), 131.0 (CH), 139.0 (C), 139.4 (C), 140.7
(C), 145.2 (C), 156.5 (C). HRMS–TOF: m/z [M?H]?
449.1629 (Calcd for C24H25N4O3S: 449.1642).
1
1159 (S=O). H NMR (300 MHz, CDCl3) d 2.32 (s, 3H,
ArCH3), 2.82 (t, J = 6.8 Hz, 2H, ArCH2), 3.30 (q,
J = 6.4 Hz, 2H, CH2NH), 4.55 (br s, 1H, NHSO2), 5.31 (s,
2H, CH2O), 6.94 (d, J = 8.6 Hz, 2H, ArH), 7.08–7.17 (m,
4H, ArH), 7.22–7.33 (m, 3H, ArH), 7.90 (d, J = 8.8 Hz,
2H, ArH), 7.97 (d, J = 8.8 Hz, 2H, ArH), 8.14 (s, 1H,
CHN). 13C NMR (75 MHz, CDCl3) d 20.5 (CH3), 35.8
(CH2), 44.3 (CH2), 62.0 (OCH2), 114.6 (CH), 120.6 (CH),
127.0 (CH), 128.7 (CH), 128.9 (CH), 130.1 (CH), 130.9
(C), 137.3 (C), 139.7 (C), 140.2 (C), 146.0 (C), 155.9 (C).
HRMS–TOF: m/z [M?H]? 449.1641 (Calcd for C24H25N4
O3S: 449.1642).
Methyl 2-((1-(4-(N-phenethylsulfamoyl)phenyl)-1H-1,2,3-
4-(4-((4-Formylphenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-
triazol-4-yl)methoxy)benzoate (5i)
phenethylbenzenesulfonamide (5f)
White solid. 88 %. mp 135–136 °C. IR (UATR) cm-1
3275 (NH), 1717 (C=O), 1599 (ar C=C), 1490 (ar C=C),
:
White solid. 79 %. mp 141–142 °C. IR (UATR) cm-1
3267 (NH), 1687 (C=O), 1597 (ar C=C), 1507 (ar C=C),
:
1
1307 (S=O), 1159 (S=O). H NMR (300 MHz, CDCl3) d
1
1330 (S=O), 1158 (S=O). H NMR (300 MHz, CDCl3) d
2.82 (t, J = 6.8 Hz, 2H, ArCH2), 3.31 (br t, 2H, CH2NH),
3.92 (s, 3H, CO2CH3), 4.62 (br s, 1H, NHSO2), 5.44 (s, 2H,
CH2O), 7.04–7.33 (m, 7H, ArH), 7.49–7.57 (m, 1H, ArH),
7.85–8.00 (m, 5H, ArH), 8.36 (s, 1H, CHN). 13C NMR
(75 MHz, CDCl3) d 35.8 (CH2), 44.3 (CH2), 52.0 (OCH3),
63.4 (OCH2), 114.1 (CH), 120.6 (CH), 121.1 (C), 121.3
(CH), 127.0 (CH), 128.7 (CH), 128.9 (CH), 131.8 (CH),
133.8 (C), 137.4 (C), 139.7 (C), 140.1 (C), 157.8 (C), 166.2
(C=O). HRMS–TOF: m/z [M?Na]? 515.1359 (Calcd for
C25H24N4NaO5S: 515.1371).
2.83 (t, J = 6.8 Hz, 2H, ArCH2), 3.31 (q, J = 6.8 Hz, 2H,
CH2NH), 4.62 (t, J = 6.1 Hz, 1H, NHSO2), 5.42 (s, 2H,
CH2O), 7.08–7.34 (m, 7H, ArH), 7.85–8.01 (m, 6H, ArH),
8.19 (s, 1H, CHN), 9.92 (s, 1H, CHO). 13C NMR (75 MHz,
CDCl3) d 35.8 (CH2), 44.3 (CH2), 62.0 (OCH2), 115.1
(CH), 120.7 (CH), 120.9 (CH), 127.0 (CH), 128.7 (CH),
128.9 (CH), 129.0 (CH), 130.6 (C), 132.1 (CH), 137.3 (C),
139.5 (C), 140.5 (C), 144.8 (C), 162.9 (C), 190.7 (C=O).
HRMS–TOF: m/z [M?H]? 463.1428 (Calcd for C24H23N4
O4S: 463.1434).
4-(4-((4-Formyl-2-methoxyphenoxy)methyl)-1H-1,2,3-
4-(4-((4-Nitrophenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-
triazol-1-yl)-N-phenethylbenzenesulfonamide (5j)
phenethylbenzenesulfonamide (5g)
Pale yellow solid. 76 %. mp 100–101 °C. IR (UATR)
cm-1: 3300 (NH), 1677 (C=O), 1586 (ar C=C), 1504 (ar
C=C), 1334 (S=O), 1156 (S=O). 1H NMR (300 MHz,
CDCl3) d 2.78 (t, J = 6.8 Hz, 2H, ArCH2), 3.26 (q,
J = 6.7 Hz, 2H, CH2NH), 3.92 (s, 3H, OCH3), 4.67 (t,
J = 6.1 Hz, 1H, NHSO2), 5.44 (s, 2H, CH2O), 7.06 (dd,
J = 7.9, 1.7 Hz, 2H, ArH), 7.18–7.28 (m, 4H, ArH),
7.40–7.47 (m, 2H, ArH), 7.85 (d, J = 8.8 Hz, 2H, ArH),
7.92 (d, J = 8.7 Hz, 2H, ArH), 8.18 (s, 1H, CHN), 9.84 (s,
1H, CHO). 13C NMR (75 MHz, CDCl3) d 35.8 (CH2), 44.3
(CH2), 56.1 (OCH3), 62.7 (OCH2), 109.5 (CH), 112.6
(CH), 120.7 (CH), 121.2 (C), 126.6 (CH), 127.0 (CH),
White solid. 93 %. mp 192–193 °C. IR (UATR) cm-1
3280 (NH), 1590 (ar C=C), 1506 (ar C=C), 1338 (S=O),
:
1
1158 (S=O). H NMR (300 MHz, DMSO-d6) d 2.70 (t,
J = 7.6 Hz, 2H, ArCH2), 3.03 (q, J = 6.9 Hz, 2H,
CH2NH), 5.45 (s, 2H, CH2O), 7.13–7.35 (m, 7H, ArH),
7.91 (t, J = 5.7 Hz, 1H, NHSO2), 7.98 (d, J = 8.7 Hz, 2H,
ArH), 8.14 (d, J = 8.7 Hz, 2H, ArH), 8.25 (d, J = 9.0 Hz,
2H, ArH), 9.11 (s, 1H, CHN). 13C NMR (75 MHz, DMSO-
d6) d 35.7 (CH2), 44.5 (CH2), 62.2 (OCH2), 115.9 (CH),
121.2 (CH), 124.0 (CH), 126.4 (CH), 126.7 (CH), 128.8
(CH), 128.9 (CH), 129.1 (CH), 139.0 (C), 139.3 (C), 140.8
123

1778
Med Chem Res (2014) 23:1768–1780
128.7 (CH), 128.9 (CH), 130.9 (C), 137.4 (C), 139.5 (C),
140.4 (C), 150.0 (C), 152.8 (C), 190.9 (C=O). HRMS–
TOF: m/z [M?H]? 493.1545 (Calcd for C25H25N4O5S:
493.1540).
CH2NH), 5.56 (s, 2H, CH2O), 6.22 (s, 1H, COCH),
7.13–7.46 (m, 5H, ArH), 7.36 (t, J = 8.0, 1H, ArH), 7.43
(d, J = 7.8 Hz, 1H, ArH), 7.66 (dt, J = 8.0, 1.4 Hz, 1H,
ArH), 7.85 (dd, J = 7.9, 1.4 Hz, 1H, ArH), 7.92 (t,
J = 5.7 Hz, 1H, NHSO2), 7.99 (d, J = 8.8 Hz, 2H, ArH),
8.18 (d, J = 8.8 Hz, 2H, ArH), 9.21 (s, 1H, CHN). 13C
NMR (75 MHz, DMSO-d6) d 35.7 (CH2), 44.5 (CH2), 63.2
(OCH2), 92.0 (CH), 115.5 (CH), 116.9 (CH), 121.2 (CH),
123.5 (CH), 124.1 (CH), 124.7 (CH), 126.7 (CH), 128.8
(CH), 128.9 (CH), 133.3 (C), 139.0 (C), 139.3 (C), 140.9
(C), 143.1 (C), 153.3 (C), 162.0 (C), 164.8. HRMS–TOF:
m/z [M?H]? 503.1383 (Calcd for C26H23N4O5S:
503.1384).
4-(4-((5-Formyl-2-methoxyphenoxy)methyl)-1H-1,2,3-
triazol-1-yl)-N-phenethylbenzenesulfonamide (5k)
Light brown solid. 71 %. mp 204–205 °C. IR (UATR)
cm-1: 3304 (NH), 1686 (C=O), 1583 (ar C=C), 1514 (ar
C=C), 1335 (S=O), 1162 (S=O). 1H NMR (300 MHz,
DMSO-d6) d 2.70 (t, J = 6.8 Hz, 2H, ArCH2), 3.02 (q,
J = 6.8 Hz, 2H, CH2NH), 3.87 (s, 3H, OCH3), 5.33 (s, 2H,
CH2O), 7.13–7.30 (m, 6H, ArH), 7.62 (dd, J = 8.2, 1.7 Hz,
1H, ArH), 7.66 (d, J = 1.7 Hz, 1H, ArH), 7.90 (t,
J = 5.7 Hz, 1H, NHSO2), 7.98 (d, J = 8.7 Hz, 2H, ArH),
8.15 (d, J = 8.7 Hz, 2H, ArH), 9.07 (s, 1H, CHN), 9.86 (s,
1H, CHO). 13C NMR (75 MHz, DMSO-d6) d 35.7 (CH2),
44.5 (CH2), 56.4 (OCH3), 62.1 (OCH2), 112.2 (CH), 112.3
(CH), 121.1 (CH), 123.9 (CH), 126.7 (CH), 126.9 (CH),
128.8 (CH), 129.1 (CH), 130.1 (C), 139.1 (C), 139.4 (C),
140.8 (C), 144.3 (C), 148.2 (C), 155.0 (C), 191.8 (C=O).
HRMS–TOF: m/z [M?H]? 493.1536 (Calcd for C25H25
N4O5S: 493.1540).
N-(3,4-Dimethoxyphenethyl)-4-(4-phenyl-1H-1,2,3-triazol-
1-yl)benzenesulfonamide (5n)
Pale yellow solid. 94 %. mp 147–148 °C. IR (UATR)
cm-1: 3271 (NH), 1596 (ar C=C), 1516 (ar C=C), 1330
(S=O), 1157 (S=O). 1H NMR (300 MHz, CDCl3) d 2.74 (t,
J = 6.8 Hz, 2H, ArCH2), 3.26 (q, J = 6.8 Hz, 2H,
CH2NH), 3.78, 3.81 (2s, 6H, 2 9 OCH3), 4.59 (t,
J = 6.2 Hz, 1H, NHSO2), 6.56 (d, J = 1.7 Hz, 1H, C2-
ArH), 6.61 (dd, J = 8.1,1.7 Hz, 1H, C6-ArH), 6.74 (d,
J = 8.1 Hz, 1H, C5-ArH), 7.35–7.50 (m, 3H, ArH),
7.87–7.98 (m, 6H, ArH), 8.27 (s, 1H, CHN). 13C NMR
(75 MHz, CDCl3) d 35.4 (CH2), 44.4 (CH2), 55.9 (OCH3),
56.0 (OCH3), 111.6 (CH), 111.9 (CH), 117.3 (CH), 120.5
(CH), 120.8 (CH), 126.0 (CH), 128.8 (CH), 128.9 (CH),
129.7 (C), 129.9 (C), 139.7 (C), 140.0 (C), 148.1 (C), 149.0
(C), 149.2 (C). HRMS–TOF: m/z [M?H]? 465.1590
(Calcd for C24H25N4O4S: 465.1591).
4-(4-(((2-Oxo-2H-chromen-7-yl)oxy)methyl)-1H-1,2,3-
triazol-1-yl)-N-phenethylbenzenesulfonamide (5l)
White solid. 77 %. mp 130–131 °C. IR (UATR) cm-1
3246 (NH), 1718 (C=O), 1618 (C=C), 1595 (ar C=C), 1505
:
1
(ar C=C), 1277 (S=O), 1153 (S=O). H NMR (300 MHz,
CDCl3) d 2.79 (t, J = 6.8 Hz, 2H, ArCH2), 3.27 (q,
J = 6.6 Hz, 2H, CH2NH), 4.60 (t, J = 5.8 Hz, 1H,
NHSO2), 5.35 (s, 2H, CH2O), 6.26 (d, J = 9.5, 1H,
COCH=CH), 6.91–6.98 (m, 2H, ArH), 7.07 (d, J = 6.6 Hz,
2H, ArH), 7.17–7.29 (m, 3H, ArH), 7.40 (d, J = 9.2 Hz,
1H, ArH), 7.63 (d, J = 9.5 Hz, 1H, COCH=CH), 7.87 (d,
J = 8.7 Hz, 2H, ArH), 7.93 (d, J = 8.7 Hz, 2H, ArH),
8.50 (s, 1H, CHN). 13C NMR (75 MHz, CDCl3) d 35.8
(CH2), 44.3 (CH2), 62.2 (OCH2), 102.2 (CH), 112.7 (CH),
113.2 (CH), 113.7 (CH), 120.7 (CH), 121.0 (C), 127.0
(CH), 128.7 (CH), 128.9 (CH), 129.0 (CH), 137.4 (C),
139.5 (C), 140.4 (C), 143.2 (C), 155.8 (C), 161.0 (C), 161.1
(C). HRMS–TOF: m/z [M?H]? 503.1392 (Calcd for
C26H23N4O5S: 503.1384).
N-(3,4-Dimethoxyphenethyl)-4-(4-((4-
formylphenoxy)methyl)-1H-1,2,3-triazol-1-
yl)benzenesulfonamide (5o)
Light brown solid. 90 %. mp 143–144 °C. IR (UATR)
cm-1: 3262 (NH), 1688 (C=O), 1597 (ar C=C), 1508 (ar
C=C), 1330 (S=O), 1159 (S=O). 1H NMR (300 MHz,
CDCl3) d 2.73 (t, J = 6.5 Hz, 2H, ArCH2), 3.24 (q,
J = 6.2 Hz, 2H, CH2NH), 3.76, 3.80 (2s, 6H, 2 9 OCH3),
4.58 (t, J = 6.0 Hz, 1H, NHSO2), 5.38 (s, 2H, CH2O), 6.55
(br d, 1H, C2-ArH), 6.60 (d, J = 7.8 Hz, 1H, C6-ArH),
6.73 (d, J = 8.1 Hz, 1H, C5-ArH), 7.81–7.96 (m, 6H,
ArH), 7.12 (d, J = 8.6 Hz, 2H, ArH), 8.17 (s, 1H, CHN),
9.88 (s, 1H, CHO). 13C NMR (75 MHz, CDCl3) d 35.4
(CH2), 44.4 (CH2), 55.8 (OCH3), 55.9 (OCH3), 62.0
(OCH2), 111.5 (CH), 111.8 (CH), 115.1 (CH), 120.6 (CH),
120.7 (CH), 120.8 (C), 121.0 (C), 128.9 (C), 129.8 (C),
130.6 (C), 132.0 (CH), 139.5 (C), 140.4 (C), 144.7 (C),
148.1 (C), 149.2 (C), 162.9 (C), 190.7 (C=O). HRMS–
4-(4-(((2-Oxo-2H-chromen-4-yl)oxy)methyl)-1H-1,2,3-
triazol-1-yl)-N-phenethylbenzenesulfonamide (5m)
White solid. 77 %. mp 181–182 °C. IR (UATR) cm-1
:
3147 (NH), 1719 (C=O), 1624 (C=C), 1328 (S=O), 1157
(S=O). 1H NMR (300 MHz, DMSO-d6) d 2.70 (t,
J = 6.8 Hz, 2H, ArCH2), 3.02 (q, J = 6.8 Hz, 2H,
123

Med Chem Res (2014) 23:1768–1780
1779
TOF: m/z [M?H]? 523.1650 (Calcd for C26H27N4O6S:
References
523.1646).
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Banday AH, Shameem SA, Gupta BD, Sampath Kumar HM (2010)
D-ring substituted 1,2,3-triazolyl 20-keto pregnenanes as
potential anticancer agents: synthesis and biological evalua-
tion. Steroids 75:801–804
N-(3,4-Dimethoxyphenethyl)-4-(4-((4-
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Light brown solid. 95 %. mp 183–184 °C. IR (UATR)
cm-1: 3257 (NH), 1593 (ar C=C), 1519 (ar C=C), 1343
(S=O), 1160 (S=O). 1H NMR (300 MHz, DMSO-d6) d
2.62 (t, J = 7.4 Hz, 2H, ArCH2), 3.03 (q, J = 7.0 Hz, 2H,
CH2NH), 3.65, 3.68 (2s, 6H, 2 9 OCH3), 5.45 (s, 2H,
CH2O), 6.64 (dd, J = 8.1, 1.8 Hz, 1H, C6-ArH), 6.72 (d,
J = 1.7 Hz, 1H, C2-ArH), 6.78 (d, J = 8.2 Hz, 1H, C5-
ArH), 7.32 (d, J = 9.3 Hz, 2H, C200-ArH and C600-ArH),
7.85 (t, J = 5.6 Hz, 1H, NHSO2), 7.94 (d, J = 8.7 Hz, 2H,
C30-ArH and C50-ArH), 8.11 (d, J = 8.7 Hz, 2H, C20-
ArH and C60-ArH), 8.25 (d, J = 9.2 Hz, 2H, C300-ArH and
C500-ArH), 9.09 (s, 1H, CHN). 13C NMR (75 MHz,
DMSO-d6) d 35.3 (CH2), 44.7 (CH2), 55.8 (OCH3), 55.9
(OCH3), 62.2 (OCH2), 112.2 (CH), 113.0 (CH), 115.9
(CH), 121.0 (CH), 123.9 (CH), 126.4 (CH), 128.8 (CH),
131.4 (C), 139.2 (C), 140.9 (C), 141.7 (C), 143.8 (C), 147.8
(C), 149.0 (C), 163.6 (C). HRMS–TOF: m/z [M?H]?
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were inoculated in 96-well microtiter plates (Corning Inc.,
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medium containing either the serial dilutions of the test
compounds, positive control (etoposide and/or doxorubi-
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final concentrations, and the microtiter plates were further
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Acknowledgments We gratefully acknowledge the research grants
from Srinakharinwirot University under the Government Budget
(B.E. 2557) and the Thailand Research Fund under the Young
Scholars Research Fellowship (MRG5680001 to R.P.). This project is
supported by the office of the Higher Education Commission and
Mahidol University under the National Research Universities Initia-
tive. We are also indebted to the Chulabhorn Research Institute for
recording mass spectra and bioactivity testing.
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