Synthesis and Anticancer Activity of 1,2,3-Triazole Fused N-Arylpyrazole Derivatives

Article abstract of DOI:10.1134/S1070363219040315

A novel series of triazole derivatives 11a–11j is synthesized. Structures of the products are confirmed by ¹H and ¹³C NMR, and mass spectral data. The anticancer activities of compounds 11a–11j are evaluated against three human cance

Full text of DOI:10.1134/S1070363219040315

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 4, pp. 831–835. © Pleiades Publishing, Ltd., 2019.
Synthesis and Anticancer Activity of 1,2,3-Triazole
Fused N-Arylpyrazole Derivatives
R. Lakkakulaa, A. Roya*, K. Mukkantib, and G. Sridharc
a
GVK Biosciences Private Limited, Medicinal Chemistry Division, 28A, Nacharam,
IDA-Mallapur, Hyderabad, Telangana, 500076 India
*e-mail: sridhar1org@gmail.com
b Department of Chemistry, Jawaharlal Nehru Technological University–Hyderabad, Kukatpally,
Hyderabad, Telangana, 500085 India
c Organic and Biomolecular Chemistry Division, CSIR–Indian Institute of Chemical Technology,
Hyderabad, 50010 India
Received February 3, 2019; revised April 3, 2019; accepted April 9, 2019
Abstract—A novel series of triazole derivatives 11a–11j is synthesized. Structures of the products are
1
confirmed by H and 13C NMR, and mass spectral data. The anticancer activities of compounds 11a–11j are
evaluated against three human cancer cell lines (MCF-7, A549, and A375) using the standard MTT assay in
vitro, using doxorubicin as the positive control. All the compounds exhibit significant activity against cancer
cell lines. The compounds 11a, 11d, 11e, 11g, and 11j demonstrate more potent activity than the positive
control.
Keywords: celecoxib, rimonabant, pyrazole, 1,2,3-triazole and anticancer activity
DOI: 10.1134/S1070363219040315
INTRODUCTION
In view of the above we have synthesized a novel
series of 1,2,3-triazole derivatives combined with N-
arylpyrazoles 11a–11j. The synthesized compounds
11a–11j were tested for their anticancer activity
against different human cancer cell lines.
Pyrazole derivatives demonstrate a broad spectrum
of biological activities, including anticancer [1], anti-
inflammatory [2], anticonvulsant [3], antipyretic [4],
and antimicrobial [5, 6]. Celecoxib 1 [7] and
Rimonabant 2 [8] are pyrazole core containing drugs
available on the market (see the figure).
RESULTS AND DISCUSSION
Synthesis of the key intermediate 1-(4-azidophenyl)-
1,2,3-Triazole derivatives also play an important
role in pharmaceutical chemistry [9]. Generally, 1,2,3-
triazoles are synthesized by the Huisgen 1,3-dipolar
cycloaddition reaction catalyzed by Cu(I) [10].
3,5-bis(3,4,5-trimethoxyphenyl)-1H-pyrazole
(9)
(Scheme 1) started with the reaction of 1-(3,4,5-
trimethoxyphenyl)ethanone (3) with ethyl 3,4,5-
trimethoxybenzoate (4) which gave 1,3-bis(3,4,5-
(a)
(b)
SO2NH2
Cl
Cl
N
NH
O
N
N
N
N
Me
F3C
Cl
Structures of compounds (a) 1 and (b) 2.
831

832
LAKKAKULA et al.
Scheme 1.
H2N
NH
O
O
O
OEt
O
MeO
MeO
OMe
OMe
MeO
THF, NaH
room temparature, 6 h
MeO
MeO
OMe
NO2
OMe
OMe
OMe
OMe
3
6
4
5
EtOH, reflux,
20 h
O2N
H2N
OMe
OMe
OMe
OMe
N
N
LAH, THF
N
N
MeO
MeO
room temparature, 2 h
MeO
MeO
OMe
OMe
OMe
OMe
8
7
NaNO2, aqueous HCl,
NaN3, acetone,
80°C, 15 min, 85%
R
N3
N
N
N
CuSO4·5H2O,
potassium ascorbate,
t-BuOH/H2O,
70°C, 13 h
OMe
N
OMe
OMe
OMe
N
N
N
MeO
MeO
OMe
OMe
R
MeO
MeO
OMe
OMe
9
10a−10j
11a−11j
R = H (10a, 11a), 3,4,5-trimethoxy (10b, 11b), 4-methoxy (10c, 11c), 4-bromo (10d, 11d), 4-trifluoro (10e, 11e), 3,5-
ditrifluoro (10f, 11f), 3,5-difluoro (10g, 11g), 2,4,6-trimethyl (10h, 11h), 3,5-dimethoxy (10i, 11i), 4-nitro (10j, 11j).
trimethoxyphenyl)propane-1,3-dione (5). Its following
reaction with 1-(4-nitrophenyl)hydrazine (6) led to
pyrazole intermediate (7) with high yield. Reduction of
compound 7 by LiAlH4 in THF gave the amine
intermediate 8, diazotation of which followed by the
Sand Mayer reaction afforded the azide 9. The
Huisgen 1,3-dipolar cycloaddition of intermediate 9
with substituted aromatic alkynes 10a–10j upon
prolonged heating at 70°C afforded the corresponding
final compounds 11a–11j.
In vitro cytotoxicity. The newly synthesized com-
pounds were tested for their cytotoxicity against three
human tumor cell lines: breast (MCF-7), lung (A-549),
and melanoma (A-375) cells using the 3-(4,5-dimethyl-
thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
assay. Here doxorubicin was used as a positive control
(see the table). All tested compounds exhibited potent
anticancer activity with IC50 values ranging from 0.13 to
9.34 µM. Activity of the compounds 11a, 11d, 11e, 11g,
and 11j was higher than that of the positive control.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 4 2019

SYNTHESIS AND ANTICANCER ACTIVITY OF 1,2,3-TRIAZOLE
833
In vitro cytotoxicity data of target compounds 11a–11j
EXPERIMENTAL
IC50, µM
A-549
2.90
All chemicals were obtained from Aldrich (Sigma–
Aldrich, St. Louis, MO, USA), Lancaster (Alfa Aesar,
Johnson Matthey Company, Ward Hill, MA, USA)
and used without further purification. Progress of the
reactions was monitored by TLC, performed on silica
gel glass plates containing 60 F-254, and visualized
Compound
11a
MCF-7
1.78
3.78
3.67
1.90
0.10
7.65
0.22
8.12
9.34
0.34
2.02
A375
0.23
2.22
11b
2.98
11c
5.60
Not active
1.44
1
under UV light or by iodine indicator. H and 13C
11d
1.11
NMR spectra were measured on a Bruker UXNMR/
XWIN-NMR (300 MHz) spectrometer using DMSO-
d6 as a solvent and TMS as an internal standard. ESI
spectra were measured on a Micro mass, Quattro LC
using ESI+ software with capillary voltage 3.98 kV
and ESI mode positive ion trap detector. Melting
points were determined on an electrothermal melting
point apparatus, and are uncorrected.
11e
0.13
1.20
11f
2.11
4.56
11g
2.44
0.33
11h
2.09
3.23
11i
Not active
0.76
Not active
0.89
11j
Doxorubicin
2.18
5.51
1,3-Di(3,4,5-trimethoxyphenyl)-1,3-propanedione
(5). To a solution of 3,4,5-trimethoxyacetophenone 3
(30 g, 142.7 mmol) in dry THF (300 mL), NaH (6.8 g,
285.4 mmol) was added in portions under the
atmosphere of N2 maintaining temperature below –5°C.
After stirring the mixture at this temperature for
30 min, ethyl 3,4,5-trimethoxybenzoate (4) (51.4 g,
214 mmol) was added, and the reaction mixture was
stirred at room temperature for 6 h. After completion
of reaction, the solvent was evaporated, and the residue
was mixed with ice-water, acidified with HCl (1N) to
pH 6 and extracted with ethyl acetate (3 ×100 mL).
The combined organic layers were washed with water
(50 mL) and dried over Na2SO4. The solvent was
evaporated, the solid residue was washed with hexane
and dried under high vacuum to provide a solid mass,
which was re-dissolved in CH2Cl2 and dried under
high vacuum to give diketone 5 as white solid, yield
(2H, J = 8.13 Hz), 7.30 s (2H), 7.57 d (2H, J =
8.13 Hz). MS (ESI): 522 [M + H]+.
4-[3,5-Di(3,4,5-trimethoxyphenyl)-1H-1-pyrazolyl]-
aniline (8). To a solution of 1-(4-nitrophenyl)-3,5-di-
(3,4,5-trimethoxyphenyl)-1H-pyrazole
7
(46 g,
88.2 mmol) in dry THF (150 mL) was added LiAlH4
(13.4 g, 353.1 mmol). The mixture was vigorously
stirred at room temperature for 2 h. The mixture was
then cooled down, quenched with aq Na2SO4, filtered
on acelite pad, and concentrated under reduce pressure
to remove THF. The aqueous layer was extracted with
ethyl acetate (30 mL). The organic extracts were dried,
and the solvent was evaporated to give a pure
1
compound 8 (yield 96%). H NMR spectrum, δ, ppm:
3.86 s (6H), 3.91 s (3H), 3.93 s (6H), 3.95 s (3H), 6.45
br.s (2H), 6.93 s (1H), 7.13 d (2H, J = 8.10 Hz), 7.19 s
(2H), 7.28 s (2H), 7.54 d (2H, J = 8.10 Hz). MS (ESI):
492 [M + H]+.
1
94%. H NMR spectrum, δ, ppm: 3.93 s (12H), 3.95 s
(6H), 6.61 s (1H), 7.19 s (4H), 16.94 br.s (1H). MS
(ESI): 405 [M + H]+.
1-(4-Azidophenyl)-3,5-bis(3,4,5-trimethoxyphenyl)-
1H-pyrazole (9). A solution of HCl (0.2 N, 50 mL)
was added to a solution of 4-[3,5-di(3,4,5-trimeth-
oxyphenyl)-1H-1-pyrazolyl]aniline 8 (39 g, 79.4 mmol)
in acetone (100 mL) at 0°C. After 20 min of stirring,
NaNO2 (16.4 g, 238.2 mmol) was added to the mixture
within 20 min followed by addition of NaN3 (15.4 g,
238.2 mmol). After 15 min of stirring, the product was
extracted by diethyl ether (100 mL), the combined
extracts were dried (Na2SO4) and concentrated. The
crude product was purified by column chromatography
with ethyl acetate–hexane (2 : 8) to afford pure com-
pound 9 (yield 79%). 1H NMR spectrum, δ, ppm: 3.86
1-(4-Nitrophenyl)-3,5-di(3,4,5-trimethoxyphenyl)-
1H-pyrazole (7). 4-Nitrophenylhydazine (6) (20.4 g,
133.6 mmol) was added upon stirring to a solution of
diketone 5 (45 g, 111.3 mmol) in ethanol (100 mL).
The reaction mixture was stirred upon refluxing for
20 h, then it was concentrated in vacuum. The residue
was mixed with ethyl acetate, washed with water and
dried over Na2SO4. The crude product was purified by
column chromatography with ethyl acetate–hexane
1
(6 : 4) to afford pure compound 7 (yield 85%). H
NMR spectrum, δ, ppm: 3.87 s (6H), 3.91 s (3H), 3.93
s (6H), 3.96 s (3H), 6.93 s (1H), 7.20 s (2H), 7.27 d
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 4 2019

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LAKKAKULA et al.
s (6H), 3.91 s (3H), 3.93 s (6H), 3.96 s (3H), 6.94 s
(1H), 7.20 s (2H), 7.29 d (2H, J = 8.14 Hz), 7.36 s
(2H), 7.56 d (2H, J = 8.14 Hz). MS (ESI): 518 [M + H]+.
1-{4-[3,5-Bis(3,4,5-trimethoxyphenyl)-1H-pyrazol-
1-yl]phenyl}-4-(4-bromophenyl)-1H-1,2,3-triazole
(11d). Yield 76%, mp 330–332°C. 1H NMR spectrum,
δ, ppm: 3.87 s (6H), 3.93 s (3H), 3.94 s (6H), 3.96 s
(3H), 6.96 s (1H), 7.21 s (2H), 7.29–7.35 m (4H), 7.57
d (2H, J = 8.15 Hz), 7.62 d (2H, J = 8.13 Hz), 8.12 d
Synthesis of compounds 11a–11j. Compound 9
(500 mg, 9.67 mmol) and an ethynylbenzene 10a–10j
(9.67 mmol) were mixed in n-BuOH–H2O (1 : 1,
10 mL) in a sealed tube in presence of CuSO4·5H2O
(24 mg, 0.096 mmol) and potassium ascorbate
(207 mg, 0.967 mmol). The reaction mixture was
stirred at 70°C for 13 h. Upon cooling down, the
reaction mixture was poured into H2O (16 mL) at 0°C,
and the precipitate was filtered off and washed with
H2O. The crude product was purified by column
chromatography with ethyl acetate–hexane (3 : 7) to
afford the corresponding pure compound 11a–11j.
13
(2H, J = 8.13 Hz), 8.28 s (1H). C NMR spectrum, δ,
ppm: 57.7, 57.8, 61.8, 61.9, 106.7, 107.6, 108.7, 116.7,
122.4, 125.6, 125.9, 127.3, 128.5, 129.5, 131.4, 132.6,
137.5, 141.4, 142.7, 144.5, 147.2, 147.8, 151.1, 154.2,
155.7. MS (ESI): 699 [M + H]+.
1-{4-[3,5-Bis(3,4,5-trimethoxyphenyl)-1H-pyrazol-
1-yl]phenyl}-4-[4-(trifluoromethyl)phenyl]-1H-1,2,3-
1
triazole (11e). Yield 71%, mp 305–307°C. H NMR
spectrum, δ, ppm: 3.88 s (6H), 3.93 s (3H), 3.94 s
(6H), 3.96 s (3H), 6.95 s (1H), 7.20 s (2H), 7.28 s
(2H), 7.34 d (2H, J = 8.13 Hz), 7.56 d (2H, J =
8.16 Hz), 7.60 d (2H, J = 8.16 Hz), 8.11 d (2H, J =
8.13 Hz), 8.27 s (1H). 13C NMR spectrum, δ, ppm:
57.8, 57.9, 61.7, 61.9, 106.5, 107.5, 108.7, 116.7,
121.5, 125.6, 125.8, 126.7, 127.5, 128.6, 129.3, 129.7,
133.5, 137.5, 141.4, 142.6, 144.3, 147.4, 147.9, 151.5,
154.6, 155.7. MS (ESI): 688 [M + H]+.
1-{4-[3,5-Bis(3,4,5-trimethoxyphenyl)-1H-pyrazol-
1-yl]phenyl}-4-phenyl-1H-1,2,3-triazole (11a). Yield
69%, mp 310–312°C. 1H NMR spectrum, δ, ppm: 3.87
s (6H), 3.91 s (3H), 3.93 s (6H), 3.95 s (3H), 6.95 s
(1H), 7.21 s (2H), 7.36 s (2H), 7.40–7.47 m (3H), 7.52
d (2H, J = 8.10 Hz), 7.56 d (2H, J = 8.14 Hz), 8.12 d
13
(2H, J = 8.14 Hz), 8.28 s (1H). C NMR spectrum, δ,
ppm: 57.4, 57.9, 61.6, 61.9, 106.5, 107.4, 108.3, 116.7,
125.6, 125.8, 126.2, 127.8, 128.3, 129.4, 129.6, 132.2,
137.4, 141.3, 142.6, 144.4, 147.5, 148.2, 151.6, 154.8,
155.6. MS (ESI): 620 [M + H]+.
1-{4-[3,5-Bis(3,4,5-trimethoxyphenyl)-1H-pyrazol-
1-yl]phenyl}-4-[3,5-bis(trifluoromethyl)phenyl]-1H-
1
1,2,3-triazole (11f). Yield 64%, mp 309–311°C. H
NMR spectrum, δ, ppm: 3.88 s (6H), 3.93 s (3H), 3.94
s (6H), 3.96 s (3H), 6.96 s (1H), 7.21 s (2H), 7.29 s
(2H), 7.35 d (2H, J = 8.13 Hz), 7.39 s (1H), 7.42 s
1-{4-[3,5-Bis(3,4,5-trimethoxyphenyl)-1H-pyrazol-
1-yl]phenyl}-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-
triazole (11b). Yield 65%, mp 321–323°C. H NMR
1
13
(2H), 8.11 d (2H, J = 8.13 Hz), 8.27 s (1H). C NMR
spectrum, δ, ppm: 3.87 s (6H), 3.89 s (6H), 3.91 s
(3H), 3.93 s (6H), 3.95 s (3H), 3.96 s (3H), 6.95 s
(1H), 7.20 s (2H), 7.35 s (2H), 7.41 s (2H), 7.55 d (2H,
J = 8.13 Hz), 8.11 d (2H, J = 8.13 Hz), 8.27 s (1H).
13C NMR spectrum, δ, ppm: 56.4, 57.6, 57.9, 60.3,
61.6, 61.9, 106.2, 106.7, 108.2, 111.4, 116.4, 125.7,
126.3, 127.4, 128.5, 129.1, 137.4, 141.6, 142.8, 144.3,
144.7, 147.4, 149.6, 151.4, 154.6, 154.8, 156.7. MS
(ESI): 710 [M + H]+.
spectrum, δ, ppm: 57.6, 57.8, 61.6, 61.8, 106.8, 107.6,
108.6, 116.7, 119.6, 123.5, 125.6, 125.9, 127.4, 129.6,
130.6, 131.5, 134.6, 137.7, 141.3, 142.4, 144.7, 147.6,
150.5, 151.6, 154.8, 155.9. MS (ESI): 756 [M + H]+.
1-{4-[3,5-Bis(3,4,5-trimethoxyphenyl)-1H-pyrazol-
1-yl]phenyl}-4-(3,5-difluorophenyl)-1H-1,2,3-triazole
(11g). Yield 66%, mp 290–292°C. 1H NMR spectrum,
δ, ppm: 3.86 s (6H), 3.92 s (3H), 3.94 s (6H), 3.95 s
(3H), 6.96 s (1H), 7.20–7.27 m (3H), 7.30 s (2H), 7.34
s (2H), 7.39 d (2H, J = 8.10 Hz), 8.11 d (2H, J =
8.10 Hz), 8.27 s (1H). 13C NMR spectrum, δ, ppm:
57.6, 57.8, 61.6, 61.8, 104.5, 106.4, 107.5, 108.7,
114.7, 116.8, 125.7, 125.9, 127.3, 129.5, 135.3, 136.4,
137.6, 141.3, 142.6, 144.5, 147.5, 151.3, 154.7, 155.8,
159.4. MS (ESI): 656 [M + H]+.
1-{4-[3,5-Bis(3,4,5-trimethoxyphenyl)-1H-pyrazol-
1-yl]phenyl}-4-(4-methoxyphenyl)-1H-1,2,3-triazole
(11c). Yield 70%, mp 317–319°C. 1H NMR spectrum,
δ, ppm: 3.78 s (3H), 3.86 s (6H), 3.91 s (3H), 3.93 s
(6H), 3.95 s (3H), 6.95 s (1H), 7.21 s (2H), 7.28 d (2H,
J = 8.09 Hz), 7.34 s (2H), 7.54–7.65 m (4H), 8.10 d
(2H, J = 8.13 Hz), 8.27 s (1H). 13C NMR spectrum, δ,
ppm: 55.5, 57.4, 57.6, 61.6, 61.7, 106.4, 107.7, 108.6,
115.6, 116.7, 124.4, 125.6, 125.9, 127.3, 128.6, 129.4,
137.5, 141.3, 142.7, 144.6, 147.6, 148.6, 151.3, 154.6,
155.6, 160.5. MS (ESI): 650 [M + H]+.
1-{4-[3,5-Bis(3,4,5-trimethoxyphenyl)-1H-pyrazol-
1-yl]phenyl}-4-mesityl-1H-1,2,3-triazole (11h). Yield
65%, mp 296–298°C. 1H NMR spectrum, δ, ppm: 2.23
s (3H), 2.32 s (6H), 3.86 s (6H), 3.90 s (3H), 3.93 s
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 4 2019

SYNTHESIS AND ANTICANCER ACTIVITY OF 1,2,3-TRIAZOLE
835
(6H), 3.94 s (3H), 6.94 s (1H), 7.20 s (2H), 7.24 s
All target compounds 11a–11j are evaluated for their
antitumor activity against MCF-7, A549 and A375
cancer cell lines by the MTT assay. Among these, com
-pounds 11a, 11d, 11e, 11g, and 11j demonstrate more
potent activity than the positive control doxorubicin.
(2H), 7.29 s (2H), 7.34 d (2H, J = 8.09 Hz), 8.07 d
13
(2H, J = 8.09 Hz), 8.26 s (1H). C NMR spectrum, δ,
ppm: 21.6, 22.7, 57.6, 57.8, 61.6, 61.8, 106.3, 107.4,
108.6, 116.5, 125.6, 125.9, 127.3, 129.5, 129.6, 130.8,
136.5, 137.6, 138.5, 141.3, 142.3, 144.7, 147.5, 148.6,
151.8, 154.3, 155.2. MS (ESI): 662 [M + H]+.
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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1
azole (11i). Yield 67%, mp 327–329°C. H NMR
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spectrum, δ, ppm: 3.76 s (6H), 3.86 s (6H), 3.90 s
(3H), 3.93 s (6H), 3.94 s (3H), 6.67 s (1H), 6.95 s
(1H), 7.20 s (2H), 7.27 s (2H), 7.31 s (2H), 7.35 d (2H,
J = 8.10 Hz), 8.08 d (2H, J = 8.10 Hz), 8.25 s (1H).
13C NMR spectrum, δ, ppm: 54.3, 57.6, 57.8, 61.5,
61.7, 99.5, 106.5, 107.4, 108.4, 111.7, 116.7, 125.7,
125.9, 127.4, 129.6, 133.4, 137.6, 141.3, 142.7, 144.7,
147.4, 149.2, 151.3, 154.8, 155.9, 158.7. MS (ESI):
680 [M + H]+.
1-{4-[3,5-Bis(3,4,5-trimethoxyphenyl)-1H-pyrazol-
1-yl]phenyl}-4-(4-nitrophenyl)-1H-1,2,3-triazole (11j).
1
Yield 78%, mp 337–339°C. H NMR spectrum, δ,
ppm: 3.87 s (6H), 3.92 s (3H), 3.93 s (6H), 3.95 s
(3H), 6.95 s (1H), 7.21 s (2H), 7.28 s (2H), 7.32 d (2H,
J = 8.16 Hz), 7.37 d (2H, J = 8.14 Hz), 8.12–8.17 m
(4H), 8.27 s (1H). 13C NMR spectrum, δ, ppm: 57.6,
57.8, 61.7, 61.9, 106.7, 107.8, 108.6, 116.8, 125.6,
125.8, 126.7, 127.8, 129.4, 131.4, 137.4, 138.3, 141.3,
142.5, 144.5, 147.2, 147.8, 148.1, 151.6, 154.6, 155.9.
MS (ESI): 665 [M + H]+.
MTT assay. Cytotoxic activity of the compounds
11a–11j was determined using MTT assay. 1×
104 cells/well were seeded in 200 mL DMEM,
supplemented with 10% FBS in each well of 96-well
microculture plates and incubated for 24 h at 37°C in a
CO2 incubator. Compounds, diluted to the desired
concentrations in culture medium, were added to the
wells with respective vehicle control. After 48 h of
incubation, 10 mL of MTT [3-(4,5-dimethylthiazol-2-
yl)-2,5-diphenyl tetrazolium bromide] (5 mg/mL) were
added to each well and the plates were further
incubated for 4 h. Then the supernatant from each well
was carefully removed, formazan crystals were
dissolved in 100 mL of DMSO and absorbance at
540 nm wavelength was recorded.
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CONCLUSIONS
A series of 1,2,3-triazole containing N-arylpyrazole
derivatives 11a–11j is synthesized, and their structures
1
are confirmed by H and 13C NMR, and mass spectra.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 4 2019