Regioselective synthesis and evaluation of novel sulfonamide 1,2,3-triazole derivatives as antitumor agents

Article abstract of DOI:10.1007/s13738-019-01796-y

A novel series of 1,2,3-triazole containing sulfonamide moiety was synthesized. Treatment of 4-acetyl 1,2,3-triazole 3 with different aldehydes gave α,β-unsaturated ketones 4a–c. Condensation of 3 with dimethylformamide dimethylacetal (DMF-DMA) gave formi

Full text of DOI:10.1007/s13738-019-01796-y

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-019-01796-y
ORIGINAL PAPER
Regioselective synthesis and evaluation of novel sulfonamide
1,2,3‑triazole derivatives as antitumor agents
Sameh R. Elgogary2,3 · Rizk E. Khidre1,2 · Emad M. El‑Telbani1,2
Received: 2 July 2018 / Accepted: 20 October 2019
©
Iranian Chemical Society 2020
Abstract
A novel series of 1,2,3-triazole containing sulfonamide moiety was synthesized. Treatment of 4-acetyl 1,2,3-triazole 3
with diꢀerent aldehydes gave α,β-unsaturated ketones 4a–c. Condensation of 3 with dimethylformamide dimethylacetal
(
DMF-DMA) gave formimidamide 5. Chalcone 7 was achieved via two ways from the reaction of 5 with benzaldehyde or
from treatment of 4a with DMF-DMA. Reaction of 7 with hydrazine hydrate aꢀorded pyrazoline 8. 5-Methyl pyrazole 12
was synthesized from Claisen condensation reaction of 3 or 5 with ethyl acetate to give 1,3-diketone adduct 9 or 10, respec-
tively, followed by treatment with hydrazine hydrate. 5-Aminopyrazole 17 was synthesized from the reaction of ester 13 or
formimidamide ester 13a with acetonitrile to aꢀord cyanoacetyl derivatives 14 or 15, respectively, followed by treatment with
hydrazine hydrate. The new compounds were screened for their in vitro antitumor activity. The results of this investigation
revealed that compounds 12, 7, and 17 had a signiꢁcant anticancer activity against MCF-7 cancer cell line with IC values
5
0
1
2.4, 19.8, and 23.4 µM, respectively, in relation to the standard drug, doxorubicin.
Keywords 1,2,3-Triazole · Sulfonamide · Chalcone · Pyrazole · Anticancer activity · Molecular docking
Introduction
applied in therapy for more than 70 years, still more than
0 drugs containing this functionality are in clinical use
3
Sulfa drugs are sulfonamide antibiotics largely used as pre-
ventive and chemotherapeutic agents against various infec-
tious diseases [1–3]. Due to the mechanism of sulfonamides,
antimicrobial action involves competitive inhibition of folic
acid synthesis, which prevents the growth and reproduction
of microorganisms, and sulfonamides belong to the group
of bacteriostatic agents [4]. Although sulfonamides were
and drugs of choice for the treatment of several conditions
and diseases including antibacterial [3], antifungal [5], anti-
inꢂammatory [6], anti-protozoal [7], antihypertensive agent
bosentan [8], nonpeptidic vasopressin receptor antagonists
[9], and translation initiation inhibitors [10]. Some important
modiꢁed sulfonamides with various heterocyclic rings are
used as carbonic anhydrase inhibitors of commercial impor-
tance [11]. They are also eꢀective for the treatment of uri-
nary, intestine, and ophthalmic infections, scalds, ulcerative
colitis [12], male erectile dysfunction as the phosphodies-
terase-5 inhibitor sildenaꢁl—better known under its com-
mercial name, Viagra [13], rheumatoid arthritis [14], and
obesity [15]. Recently, sulfonamides are performed as an
anticancer agent [16], as the antiviral HIV protease inhibitor
amprenavir [17] and in Alzheimer’s disease [12]. There are
many drugs containing sulfonamide moiety (Fig. 1).
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-019-01796-y) contains
supplementary material, which is available to authorized users.
*
Rizk E. Khidre
rizkkhidre@yahoo.com
*
Emad M. El-Telbani
dremad1966@yahoo.co.uk
In addition, 1,2,3-triazole derivatives are known to exhibit
various pharmacological applications such as antimicrobial
1
2
3
Chemical Industries Division, National Research Centre,
Dokki, Giza 12622, Egypt
[
18–20], anti-inꢂammatory [21], anti-convulsant [19], anti-
Chemistry Department, Faculty of Science, Jazan University,
Jazan 2079, Saudi Arabia
malarial [22], antiviral [23, 24], anti-proliferative [25, 26],
as carbonic anhydrase I, II, IV, and IX inhibitors [27], and
anticancer activities [28–30]. For the design and search of
Chemistry Department, Faculty of Science, Damietta
University, Damietta, Egypt
Vol.:(0
1
123456789)
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Journal of the Iranian Chemical Society
Fig. 1 Structures of some sul-
SO NH
2
2
fonamide drugs
F3C
NH2
NH2
N
N
N N
NH2
SO NH
SO
N
NH
2
2
OCH3
N
SO NH
N
2
2
NH2
S
N
Prontosil
Celecoxib
Sulfametrazole
Sulfamethazine
new drugs, the development of hybrid molecules through the
binding of various pharmacophores in one frame could lead
to molecules with interesting pharmaceutical properties.
Taking into account all previous commentaries of the
biological activities of sulfonamide, 1,2,3-triazole deriva-
tives, and in continuation of our interest in the synthesis of
biologically active heterocycles [31–37], eꢀorts have been
made to synthesize a series of new 1,2,3-triazole derivatives
incorporating sulfonamide moiety to evaluate their antitumor
activity.
of the N,N-dimethylformimidamide residue. The presence
of two signals at δ 10.21 (s, 1H, NH) and 7.60 ppm (s, 2H,
NH ), with the other protons in their expected locations,
2
supported the suggested structure (see “Experimental” sec-
tion). To prove the structure of 8, it was prepared by another
two pathways of its preparation either by the reaction of
4a directly with hydrazine hydrate or by the reaction of 4a
ꢁrstly with DMF-DMA followed by treatment with hydra-
zine hydrate (Scheme 1).
The regioselective reaction of 3 with DMF-DMA was
widely studied; to this aim, Claisen–Schmidt condensation
of 3 with ethyl acetate in the presence of a sodium sand gave
the corresponding 1,3-diketone derivative 9. The structure
of 9 was elucidated on the basis of spectral and analytical
analyses. The IR spectrum exhibited two absorption peaks at
Results and discussion
Diazotization of the sulfonamide 1 using sodium nitrite fol-
lowed by coupling with sodium azide gave the correspond-
ing azido derivative 2. Reaction of 2 with acetyl acetone in
the presence of piperidine aꢀorded triazolobenzenesulfona-
mide derivative 3 in fairly good yield. The structure of 3 was
established using both spectral and analytical analyses; the
−
1
1
1703 and 1618 cm (2CO), while H-NMR showed a new
singlet signal at δ 4.25 ppm (2H, CH ), with the disappear-
2
ance of the acetyl group previously detected at δ 2.64 ppm
of the parent 3. Treatment of 9 with DMF-DMA in dioxane
gave sulfonyl formimidamide derivative 10 rather than 11.
The disappearance of the amino group with the appearance
of a new singlet signals at δ 6.59 (N=CH) supported the
suggested structure. Reaction of 10 with hydrazine hydrate
−1
IR spectrum exhibited an absorption peak at 1689 cm cor-
1
responding to the acetyl group, while the H-NMR revealed
a singlet signal at 2.64 ppm owing to acetyl group. Treat-
1
ment of 3 with diꢀerent aldehydes, namely benzaldehyde,
gave pyrazole benzenesulfonamide 12. H-NMR spectrum
4
-chlorobenzaldehyde, and thiophene-2-carbaldehyde, gave
showed two exchangeable signals at 12.90 (s, 1H, NH) and
1
the corresponding chalcone derivative 4a–c. The H-NMR
of 4a (as a represented example) shows two doublet protons
at 8.02 and 7.87 ppm with J coupling 16 Hz, indicating that
the chalcone derivatives exist in E-conꢁguration (Scheme 1).
Condensation of 3 with dimethylformamide dimethylacetal
6.42 (s, 2H, NH ) which indicated the cleavage of N,N-
2
dimethylformimidamide residue. To prove the structure
of compound 12, it was prepared by another method of its
preparation by application of Claisen condensation on com-
pound 5 followed by treatment with hydrazine hydrate (see
Scheme 2 and “Experimental” section).
(
DMF-DMA) gave N,N-dimethylformimidamide derivative
5
6
as a sole product without any detection of the compound
. The disappearance of the amino group with the presence
To demonstrate regioselective performance of reac-
tion of DMF-DMA with amino group rather than active
methylene groups, Claisen condensation was success-
fully achieved by treatment of ethyl 5-methyl-1-(4-
sulfamoylphenyl)-1H-1,2,3-triazole-4-carboxylate 13,
which was synthesized from the reaction of azide 2
with ethyl acetoacetate in EtOH containing piperidine
at reꢂux temperature [38], with acetonitrile in the pres-
ence of a sodium sand to give cyanoacetyl benzenesul-
fonamide derivative 14. Then compound 14 was reacted
of the acetyl group at δ=2.55 ppm indicates that the con-
densation occurred with a great performance at the amino
group rather than the acetyl group and supported the sug-
gested structure by X-ray analysis (Fig. 2). The adduct 7
was achieved by the treatment of the acetyl derivative 5 with
benzaldehyde in aqueous basic medium and readily reacted
with an equimolar amount of hydrazine hydrate in boiling
ethanol to give the pyrazoline derivative 8 with the cleavage
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Journal of the Iranian Chemical Society
H
N
Hc
Ph
Hb
O
N
O
Ar
N
N
Ha
N
N
N3
NH2
N
N
NaNO / HCl
N
N
i)
2
N
NH NH .H O
2 2 2
acetylacetone
piperidine
ArCHO/NaOH
NaN3
Ar = Ph
ii)
SO NH
SO NH
2
2
2
2
SO NH
4a-c
SO
NH
2 2
8
SO NH
2
2
2
2
1
2
3
Ar = Ph, 4ClC H ,
6
4
2-thienyl
NH NH .H O
2
2
2
DMF-DMA/dioxane
O
Ar = Ph
DMF-DMA
dioxane
O
O
Ph
N
N
N
N
N
N
N
N
N
N
PhCHO
NaOH
SO N
2
SO N
SO NH
2
2
2
N
6
N
5
7
Scheme 1 Synthesis of triazolosulfonamide derivatives 3, 4, 5, 7, and 8
Fig. 2 X-ray structure of 5
with DMF-DMA followed by treatment with hydrazine
hydrate to give 5-amino pyrazole benzenesulfonamide 17
with the cleavage of N,N-dimethylformimidamide resi-
due. On the other hand, the structure of pyrazole 17 was
proved either by spectral data or by its preparation from
Claisen condensation of enamine 13a with acetonitrile to
give 15, which either was prepared from cyanoacetyl 14,
followed by treatment with hydrazine hydrate (Scheme 3
and “Experimental” section).
Anticancer activity screening
Cytotoxicity assay
Cytotoxicity assays were done to govern the level of
sensitivity as well as the selectivity of malignancy and
normal cells to the experimental compound. Some of
the newly synthesized compounds were tested for their
anticancer activity against MCF-7 cancer cell line using
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Journal of the Iranian Chemical Society
Scheme 2 Synthesis of triazol
derivatives 9, 10, and 8
O
O
N
O
N
N
N
N
N
NH NH .H O
CH CO Et
DMF-DMA
dioxane
2
2
2
3
2
Sodium sand
SO NH2
2
SO NH2
9
2
O
3
H
N
N
N
N
DMF-DMA/dioxane
N
N
N
O
O
N
N
N
N
N
SO2
O
N
N
O
5
SO NH
2
2
12
N
N
N
SO NH2
2
11
NH NH .H O
CH CO Et
3
2
2
2
2
Sodium sand
SO N
2
10
N
high-throughput screening technique, and the outcomes
are presented in Table 1.
dock them into the active site of the CDK2 enzyme. Start-
ing from a triazole scaꢀold, eight analogs were designed
based on the structure (active site) of the CDK2 enzyme.
Molecular docking studies were performed with the default
parameter of CDOCKER. For docking simulation of CDK2,
ꢁve optimized inhibitors were docked with the enzyme
(PDB:2FVD). Top-ranked conformations were selected
for further analysis and visual interaction studies. Binding
energy calculations are used to evaluate the compound’s
overall potential to qualify a ligand as a potential drug candi-
date. Compound 12 ranks highest among all studied triazole
derivatives from the docking methodologies as shown in
Table 1. The most active compound 12 is ranked as second
by considering its binding energy obtained from the exten-
sible protocol of Accelrys Discovery studio 2.5.
The investigation of the IC results in Table 1 dis-
5
0
played that compound 12 exhibited high anticancer
activity against MCF-7 cancer cell line with IC values
5
0
1
2.41 µM. Since this compound has the uppermost IC
50
values, it can be considered as primary hits. Compounds
and 17 showed high proliferative activity against the
cell line taken for the study with IC values 19.8 and
7
5
0
2
3.41 µM, respectively. Compounds 4a and 8 displayed
poor anticancer activity against MCF-7 cancer cell line
with IC values 105.47 and 99.54 µM, respectively. From
5
0
the formerly mentioned study, we could accomplish that
compounds 12, 17, and 7 showed a good anticancer activ-
ity among all the tested compounds expressed by their
IC values related to doxorubicin IC = 1.19 µM. These
5
0
50
compounds can be used as lead compounds and by further
Receptor–ligand interaction analysis
optimization could have a high biological profile.
Results obtained from interaction analysis of all newly
designed ligands have proposed that a group of amino
acid residues located on the binding cavity such as Ile10,
Ala31, Val64, Phe80, Asp86, and Leu134 in the target
CDK2 enzyme play an important role in ligand binding.
Molecular docking
To understand the variability of the biological results of the
newly synthesized compounds as antitumor, we decided to
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Journal of the Iranian Chemical Society
Scheme 3 Synthesis of triazol
derivatives 13, 13a, 14, 15,
and 17
O
O
CN
OEt
N
N
N
N
N
N
NH NH .H O
CH CN
2
2
2
3
H
N
Sodium sand
NH2
N
SO NH2
SO NH
2 2
4
2
1
N
N
1
3
N
DMF-DMA/dioxane
DMF-DMA
dioxane
O
CN
O
CN
O
N
SO NH
2
2
N
OEt
N
N
17
N
N
N
N
N
NH NH .H O
2 2 2
N
SO N
2
SO NH
2
2
N
SO N
15
2
1
6
CH CN
N
3
1
3a
Sodium sand
Best ranked compounds 6 and 3 are docked deeply into
the active site region, forming interactions with the res-
idues Asp86, Ile10, Ala31, Val64, Phe80, and Phe146
FTIR-440 spectrometer using KBr pellets. Mass spectra
were performed at 70 eV on an MS-50 Kratos (A.E.I.)
1
spectrometer provided with a data system. H NMR
1
3
(
Table 1).
(500 MHz) and CNMR (125 MHz) were recorded on a
Bruker model UltraShield NMR spectrometer in DMSO-
d6 using tetramethylsilane (TMS) as an internal standard;
chemical shifts are reported as ppm units. The elemental
analyses (% C, H, N) were done at the Microanalytical
Center, Cairo University, Cairo, Egypt. The appropriate
precautions in handling moisture-sensitive compounds
were taken. Solvents were dried by standard techniques.
The monitoring of the progress of all reactions and homo-
geneity of the synthesized compounds was carried out and
was run using thin-layer chromatography (TLC) aluminum
sheets silica gel 60 F254 (Merck).
From the interactive analysis, it can be concluded that
top-ranked inhibitor 12 mainly interacts with main chain
residues Asp86 (hydrogen bond), Ile10, Ala31, Val64,
Phe80, and Leu134 (electrostatic and hydrophobic inter-
actions) during the docking simulation by CDOCKER
programs (Figs. 2, 3; Table 1).
The binding sites of CDK2 enzyme were explored to
be located in the active site near to Leu83 and Asp86.
Compounds 4a and 8 which contain a phenyl pyrazole
and α,β-unsaturated ketone in their structure have not
obtained comparatively good docking scores in all 10
poses (Fig. 4).
Synthesis of 4‑(4‑acetyl‑5‑methyl‑1H‑1,2,3‑triazol‑1‑yl)
benzenesulfonamide (3)
Experimental
Azide compound (2) (0.01 mol) has been cautiously added
to a cold solution of acetyl acetone (0.01 mol, 1.3 g) and
piperidine (1 ml) in ethanol (100 ml), and the mixture
has been heated under reꢂux on a water bath for 3 h. The
resulting solid was separated and recrystallized from acetic
Chemistry
Melting points were determined on a digital Gallen-
KampMFB-595 instrument using open capillary tubes and
are uncorrected. IR spectra were recorded on Shimadzu
−
1
acid. M.p. 292–294 °C. Yield: 86%. FT-IR (KBr, ν, cm ):
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Journal of the Iranian Chemical Society
Table 1 Docking, binding energy calculations, and antitumor activity assay against MCF-7 of the newly synthesized compounds
No. MCF-7 IC50 (µM) Docking score Binding energy 3D interaction
4
a
105.47
−19.7064
−10.2719
7
19.8
−9.68375
−28.709-S3
8
99.54
−15.87
−9.414
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Journal of the Iranian Chemical Society
Table 1 (continued)
No.
12
MCF-7 IC50 (µM) Docking score Binding energy 3D interaction
12.41
−17.3531
−31.407
1
7
23.41
−16.3296
−12.6568
Doxorubicin
1.19
–
–
–
Fig. 3 Hydrogen bonding and electrostatic and hydrophobic interac-
tions of compound 12 with the CDK2 active site
ν = 3278, 3197 (NH ), 1689 (C=O), 1357, 1168 (SO ).
2
2
1
H-NMR (500 MHz, δ, ppm, DMSO-d ): δ = 8.0 (d, 2H,
6
Fig. 4 Hydrogen bonding and electrostatic and hydrophobic interac-
tions of compound 17 with the CDK2 active site
J=8.6 Hz, Ar–H), 7.84 (d, 2H, J=8.6 Hz, Ar–H), 7.59 (s,
2
H, NH ), 2.60 (s, 3H, CH CO), 2.56 (s, 3H, CH ); MS, m/z
2 3 3
+
(
%): 280 [M ] (15), 210 (100). Anal. Calcd for C H N O S
11 12 4 3
(
280.30): C, 47.14; H, 4.32; N, 19.99. Found C, 47.10; H,
.50; N, 19.80.
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Journal of the Iranian Chemical Society
General procedure for the preparation of compounds 4a–c
To a well-stirred solution of 3 (10 mmol) in alcoholic NaOH
CH=CH), 7.66 (d, 1H, J = 4 Hz, thiophene–H), 7.62 (s,
2
H, NH ), 7.20 (d, 1H, J = 4 Hz, thiophene–H), 2.63 (s,
2
1
3
3H, CH ). C NMR (125 MHz, DMSO-d6) δc 9.99 (CH ),
3
3
(
5%, 25 ml) at 0–5 °C, a solution of the appropriate alde-
121.03 (CH=), 126.96, 127.32, 128.93, 130.54, 133.63,
hydes (10 mmol) was added gradually. Stirring was contin-
ued for 24 h at r.t. The resulting precipitate after neutraliza-
tion with diluted HCl was ꢁltrated, washed with water, and
crystallized from ethanol to give 4a–c.
136.02, 137.40, 139.12, 139.66, 143.15, 145.34 (=CH),
+
182.68 (C=O). MS, m/z (%): 374 [M ] (10%), 197 (100%).
Anal. Calcd for C H N O S (374.43): C, 51.32; H, 3.77;
1
6
14
4
3 2
N, 14.96. Found C, 51.50; H, 3.60; N, 14.80.
Synthesis of N′‑[(4‑(4‑Acetyl‑5‑methyl‑1H‑1,2,3‑triazol‑1yl)
phenyl)sulfonyl]‑N,N‑dimethylformimidamide (5)
(
E)‑4‑(4‑Cinnmoyl‑5‑methyl‑1H‑1,2,3‑triazol‑1‑yl)benzene‑
sulfonamide (4a)
To a well-stirred solution of 3 (10 mmol) in dioxane, dimeth-
ylformamide dimethylacetal (10 mmol) was added gradually.
Stirring was continued for 6 h at r.t. The resulting precipi-
tate was ꢁltrated and crystallized from ethanol to give 5 as
colorless crystals, M.p. 298–299 °C, yield (77%). FT-IR
As colorless needles, M.p. 238–240 °C, yield (81%). FT-IR
−
1
(
(
KBr, ν, cm ): ν = 3284, 3163 (NH ), 1658(C=O), 1595
2
1
C=C), 1350, 1168 (SO ). H-NMR (500 MHz, δ, ppm,
2
DMSO-d ): δ=8.09 (d, 2H, J=8.6 Hz, Ar–H), 8.02 (d, 1H,
6
J=16 Hz, CH=CH), 7.90 (d, 2H, J=8.6 Hz, Ar–H), 7.87
−
1
(
KBr, ν, cm ): ν = 1658(C=O), 1587 (C=C), 1330, 1172
(
d, 1H, J=16 Hz, CH=CH), 7.82 (m, 2H, Ar–H), 7.63 (s,
1
13
(SO ). H-NMR (500 MHz, δ, ppm, DMSO-d ): δ=8.00 (s,
2
6
2
H, NH ), 7.47 (m, 3H, Ar–H), 2.64 (s, 3H, CH ). C NMR
2
3
1
H, N=CH), 7.98 (d, 2H, J= 8.6 Hz, Ar–H), 7.80 (d, 2H,
(
125 MHz, DMSO-d6) δc 10.01 (CH ), 122.65 (CH=),
3
J=8.6 Hz, Ar–H), 2.91 (s, 3H, NCH ), 2.60 (s, 3H, NCH ),
3
3
1
1
1
25.72, 126.0, 127.24, 128.75, 129.11, 130.65, 134.11,
34.34, 137.40, 139.26, 143.25, 143.29, 145.35 (=CH),
2
.55 (s, 3H, CH CO), 2.52 (s, 3H, CH ). MS: m/z = 335
3
3
+
+
[M ]. Anal. Calcd for C H N O S (335.38): C, 50.14; H,
14 17 5 3
82.89 (C=O). MS, m/z (%): 368 [M ] (12), 197 (100).
5
.11; N, 20.88. Found C, 50.20; H, 5.20; N, 20.80.
Anal. Calcd for C H N O S (368.41): C, 58.68; H, 4.38;
1
8
16
4
3
N, 15.21. Found C, 58.60; H, 4.50; N, 15.10.
Synthesis of (E)‑N′‑[(4‑(4‑cinnamoyl‑5‑methyl‑1H‑1,2,3‑triaz
ol‑1yl)phenyl)sulfonyl]‑N,N‑dimethylformimidamide (7)
(E)‑4‑(4‑(3‑(4‑chlorophenyl)acryloyl)‑5‑methyl‑1H‑1,2,3‑tri‑
azol‑1‑yl)benzenesulfonamide (4b)
To a well-stirred solution of 5 (10 mmol) in alcoholic NaOH
(
5%, 25 ml) at 0–5 °C, benzaldehyde (10 mmol) was added
As a pale brown color, M.p. 240–241 °C, yield (79%). FT-IR
gradually. Stirring was continued for 24 h at r.t. The result-
ing precipitate after neutralization with diluted HCl was ꢁl-
trated, washed with water, and crystallized from ethanol to
give 7 as a pale yellow color, M.p.>300 °C, yield (79%).
−
1
(
(
KBr, ν, cm ): ν=3352, 3251 (NH ), 1662 (C=O), 1591
2
1
C=C), 1357, 1163 (SO ). H-NMR (500 MHz, δ, ppm,
2
DMSO-d ): δ=8.07 (d, 2H, J=9 Hz, Ar–H), 8.02 (d, 1H,
6
J=16.5 Hz, CH=CH), 7.92 (d, 2H, J=9 Hz, Ar–H), 7.88 (d,
−1
FT-IR (KBr, ν, cm ): ν=1658 (C=O), 1622 (N=CH), 1595
2
7
3
1
1
1
H, J=8.5 Hz, Ar–H), 7.83 (d, 1H, J=16.5 Hz, CH=CH),
1
(
C=C), 1336, 1151 (SO ); H-NMR (500 MHz, δ, ppm,
2
.62 (s, 2H, NH ), 7.52 (d, 2H, J=8.5 Hz, Ar–H), 2.62 (s,
2
DMSO-d ): δ=8.79 (s, 1H, N=CH), 8.03 (d, 1H, J=16 Hz,
6
1
3
H, CH ). C NMR (125 MHz, DMSO-d ) δc 10.00 (CH ),
3
6
3
CH=CH), 7.90 (d, 2H, J = 8.5 Hz, Ar–H), 7.87-7.83 (m,
23.32 (CH=), 125.70, 127.22, 129.12, 130.43, 133.28,
3
H, CH=CH, Ph-H), 7.76 (d, 2H, J =8.5 Hz, Ar–H), 7.47
35.33, 137.36, 139.31, 141.82, 143.18, 145.35 (=CH),
13
(
m, 3H, Ph-H), 2.64 (s, 3H, CH ), 2.48 (s, 6H, 2NCH ).
C
3
3
+
83.16 (C=O). MS, m/z (%): 402 [M ] (10), 197 (100).
NMR (125 MHz, DMSO-d ) δc 9.97 (CH ), 39.00 (NCH ),
6
3
3
Anal. Calcd for C H ClN O S (402.85): C, 53.67; H, 3.75;
18
15
4
3
122.70 (CH=), 125.55, 126.93, 128.78, 129.15, 130.89,
N, 13.91. Found C, 53.60; H, 3.60; N, 13.80.
1
1
34.36, 136.16, 139.23, 143.18, 143.27, 147.86 (=CH),
+
69.68 (N=CH), 183.35 (C=O). MS: m/z = 423 [M ].
(E)‑4‑(5‑methyl‑4‑(3‑(thiophen‑2‑yl)acryloyl)‑1H‑1,2,3‑tria‑
Anal. Calcd for C H N O S (423.49): C, 59.56; H, 5.00;
2
1
21
5
3
zol‑1‑yl)benzenesulfonamide (4c)
N, 16.54. Found C, 59.50; H, 5.10; N, 16.60.
As a pale yellow color, M.p. 262–264 °C, yield (77%). FT-IR
4
‑(5‑Methyl‑4‑(5‑phenyl‑4,5‑dihy‑
−
1
(
(
KBr, ν, cm ): ν=3363, 3217 (NH ), 1658 (C=O), 1587
2
dro‑1H‑pyrazol‑3‑yl)‑1H‑1,2,3‑triazol‑1‑yl)benzenesulfona‑
mide (8)
1
C=C), 1330, 1172 (SO ). H-NMR (500 MHz, δ, ppm,
2
DMSO-d ): δ=8.09 (d, 2H, J=8.5 Hz, Ar–H), 8.02 (d, 1H,
6
J=15.00 Hz, CH=CH), 7.90 (d, 2H, J=8.5 Hz, Ar–H), 7.80
A mixture of compounds 4a or 7 (10 mmol) and hydra-
(
d, 1H, J=5.5 Hz, thiophene–H), 7.71 (d, 1H, J=15.5 Hz,
zine hydrate (10 mmol) in ethanol (50 ml) was reꢂuxed for
1
3

Journal of the Iranian Chemical Society
−
1
5
h. The resulting precipitate formed after cooling, ꢁltered
nol to give 10, yield (82%). FT-IR (KBr, ν, cm ): ν=1695
1
oꢀ, dried, and crystallized from ethanol to give as color-
less crystals, M.p. >300 °C, yield (80% and 77%). FT-IR
and 1633 (2C=O), 1593 (C=C), 1332, 1153 (SO ). H-NMR
2
(500 MHz, δ, ppm, DMSO-d ): δ=8.13 (d, 2H, J=8.6 Hz,
6
−
1
(
(
KBr, ν, cm ): ν = 3358, 3251 (NH ), 3185 (NH), 1595
Ar–H), 7.91 (d, 1H, J=8.6 Hz, Ar–H), 6.59 (s, 1H, N=CH),
2
1
C=C), 1348, 1168 (SO ). H-NMR (500 MHz, δ, ppm,
4.25 (s, 2H, CH ), 3.13 (s, 3H, NCH ), 2.90 (s, 3H, NCH ),
2
2
3
3
+
DMSO-d ): δ=10.21 (s,1H, NH), 8.04 (d, 2H, J=8.5 Hz,
2.56 (s, 3H, CH ), 2.25 (s, 3H, CH ); MS: m/z (%): 327 [M ]
6
3 3
Ar–H), 7.87 (d, 2H, J=8.5 Hz, Ar–H), 7.60 (s, 2H, NH ),
(27). Calcd for C H N O S (327.42): C, 50.92; H, 5.07; N,
16 19 5 4
2
7
2
3
.59 (s, 1H, Ph-H), 7.33 (d, 2H, J=7.5 Hz, Ph-H), 7.27 (d,
H, J=7.5 Hz, Ph-H), 4.83 (dd, 1H, J=20.5, 10.5 Hz, Hc),
.59 (dd, 1H, J=16, 10 Hz, Hb), 3 (dd, 1H, J=16, 10 Hz,
18.56. Found C, 50.80; H, 5.20; N, 18.60.
Synthesis of 4‑(5‑methyl‑4‑(5‑methyl‑1H‑pyrazol‑3‑yl)‑1H‑1
1
3
Ha), 2.57 (s, 3H, CH ); C NMR (125 MHz, DMSO-d )
3
6
,2,3‑triazol‑1‑yl) benzenesulfonamide (12)
δc 10.02 (CH ), 41.97 (CH ), 62.65 (CH), 125.51, 126.61,
3
2
1
1
27.17, 128.45, 131.86, 132.5, 138.06, 139.34, 142.82,
A mixture of compound 10 (10 mmol) and hydrazine hydrate
+
43.32, 144.85; MS, m/z: 382 [M ] (20). Anal. Calcd for
(
10 mmol) in ethanol (50 ml) was reꢂuxed for 5 h. The
C H N O S (382.4 4): C, 56.53; H, 4.74; N, 21.98. Found
1
8
18
6
2
resulting precipitate formed after cooling, ꢁltered oꢀ, dried,
and crystallized from ethanol to give colorless crystals M.p.
C, 56.33; H, 4.80; N, 21.54.
−
1
2
86-288 °C, yield (79%). FT-IR (KBr, ν, cm ): ν=3325,
Synthesis of 4‑(5‑methyl‑4‑(3‑oxobutanoyl)‑1H‑1,2,3‑tria‑
zol‑1‑yl) benzenesulfonamide (9)
3
180 (NH ), 3120 (NH), 1597 (C=C), 1300, 1166 (SO ).
2
2
1
H-NMR (500 MHz, δ, ppm, DMSO-d ): δ=12.90 (s,1H,
6
NH), 8.01 (d, 2H, J=8.6 Hz, Ar–H), 7.85 (d, 2H, J=8.6 Hz,
A mixture of compound 3 (10 mmol) and ethyl acetate
Ar–H), 7.57 (s, 1H, pyrazole-H4), 6.42 (s, 2H, NH ), 2.56 (s,
2
(
50 ml) was cautiously added to a freshly prepared sodium
+
3
H, CH ), 2.26 (s, 3H, CH ). MS: m/z=318 [M ]. Calcd for
3
3
sand (15 mmol) and heated on a water bath for 2 h. After
the reaction is complete, methanol (5 ml) is added, poured
into ice-cold water, and neutralized with diluted hydrochlo-
ric acid. The resulting precipitate was ꢁltered oꢀ, dried, and
crystallized from ethanol to give as a colorless crystal M.p.
C H N O S (318.36): C, 49.05; H, 4.43; N, 26.40. Found
1
3
14
6
2
C, 49.10; H, 4.20; N, 26.60.
Ethyl‑1‑(4‑(N‑((dimethylamino)methylene)sulfamoyl)
phenyl)‑5‑methyl‑1H‑1,2,3‑triazole‑4‑carboxylate (13a)
−
1
2
3
65-267 °C, yield (82%). FT-IR (KBr, ν, cm ): ν=3390,
222 (NH ), 1703 and 1618 (CO), 1591(C=C), 1340, 1153
2
1
(
(
SO ). H-NMR (500 MHz, δ, ppm, DMSO-d ): δ = 8.11
To a well-stirred solution of 13 (10 mile) in dioxane, dimeth-
ylformamide dimethylacetal (10 mmol) was added gradually.
Stirring was continued for 8 h at r.t. The resulting precipitate
was ꢁltrated and crystallized from ethanol to give 13a, yield
2
6
d, 2H, J=8.6 Hz, Ar–H), 7.91 (d, 1H, J=8.6 Hz, Ar–H),
6
2
.80 (s, 2H, NH ), 4.25 (s, 2H, CH ), 2.46 (s, 3H, CH ),
2 2 3
+
.17 (s, 3H, CH ). MS, m/z (%): 322 [M ] (34). Calcd for
3
−1
C H N O S (322.34): C, 48.44; H, 4.38; N, 17.38. Found
(79%). FT-IR (KBr, ν, cm ): ν=1726 (C=O), 1589 (C=C),
1
3
14
4
4
1
C, 48.60; H, 4.20; N, 17.20.
1342, 1149 (SO ). H-NMR (500 MHz, δ, ppm, DMSO-d ):
2
6
δ=8.00 (s, 1H, N=CH), 7.98 (d, 2H, J=8.6 Hz, Ar–H), 7.80
Synthesis of N′N′‑dimethyl‑N′‑[(4‑(5‑methyl‑4‑(3‑oxobutan
oyl)‑1H‑1,2,3‑triazol‑1‑yl)phenyl)sulfonyl] formimidamide
(d, 2H, J=8.6 Hz, Ar–H), 4.31(q, 2H, J=6.7 Hz, OCH ),
2
3.14 (s, 3H, NCH ), 2.91 (s, 3H, NCH ), 2.56 (s, 3H, CH ),
3
3
3
1
3
(10)
1.29 (t, 3H, J=6.7 Hz, CH ); C NMR (125 MHz, DMSO-
3
d ) δc 9.80 (CH ), 14.18 (CH ), 35.18 (NCH ), 41 (NCH ),
6
3
3
3
3
Method A A mixture of compound 5 (10 mmol) and ethyl
acetate (50 ml) was cautiously added to a freshly prepared
sodium sand (15 mmol) and heated on a water bath for 2 h.
After the reaction is complete, methanol (5 ml) is added,
poured into ice-cold water, and neutralized with diluted
hydrochloric acid. The resulting precipitate was ꢁltered oꢀ,
dried, and crystallized from ethanol to give 10 as pale yel-
low crystals, M.p. 189–190 °C, yield (75%).
60(CH ), 125.99, 127.17, 127.47, 136.07, 137.43, 139.59,
2
+
144.33 (CH=N), 161 (C=O); MS: m/z= 365 [M ]. Anal.
Calcd for C H N O S (365.41): C, 49.31; H, 5.24; N,
1
5
19
5
4
19.17. Found C, 49.13; H, 5.32; N, 18.97.
Synthesis of 4‑(4‑(2‑cyanoacetyl)‑5‑methyl‑1H‑1,2,3‑tria‑
zol‑1‑yl)benzenesulfonamide (14)
A mixture of compound 13 (10 mmol) and acetonitrile
(50 ml) was cautiously added to a freshly prepared sodium
sand (15 mmol) and heated on a water bath for 2 h. After the
reaction is complete, methanol (5 ml) is added, poured into
ice-cold water, and neutralized with diluted hydrochloric
Method B To a well-stirred solution of 9 (10 mmol) in
dioxane, dimethylformamide dimethylacetal (10 mmol) was
added gradually. Stirring was continued for 8 h at r.t. The
resulting precipitate was ꢁltrated and crystallized from etha-
1
3

Journal of the Iranian Chemical Society
acid. The resulting precipitate was ꢁltered oꢀ, dried, and
crystallized from ethanol to give as colorless crystals M.p.
Nonius, Deꢂt and Mac Science, Japan) [39]. Mo Kα radia-
tion (λ = 0.71073 Ǻ) and a graphite monochromator were
used for data collection. The chemical formula and ring
labeling system are shown in Fig. 2. Crystal data for com-
pound 5: C H N O S, Mr, 335.386; system, monoclinic;
−1
2
25–227 °C, yield (80%). FT-IR (KBr, ν, cm ): 3390, 3210
(
(
(
NH ), 2210 (CN), 1703 (C=O), 1596(C=C), 1340, 1153
2
1
SO ). H-NMR (500 MHz, δ, ppm, DMSO-d ): δ = 8.04
2
6
14 17
5
3
d, 2H, J=7.65 Hz, Ar–H), 7.92 (d, 2H, J=7.65 Hz, Ar–H),
space group, P2 /c; unit cell dimensions, a, 7.7615 (2)Å; b,
1
7
.60 (s, 2H, NH ), 4.72 (s, 2H, CH ), 2.46 (s, 3H, CH ). MS:
26.1958 (7)Å; c, 8.0542 (2)Å; α, 90.00° (2)°; β, 106.455
2
2
3
+
3
−3
m/z=305 [M ]. Calcd for C H N O S (305.31): C, 47.21;
(2)°; γ, 90.00°; V, 1570.50 (7)Å ; Z, 4; Dx, 1.419 Mg m ;
1
2
11
5
3
H, 3.63; N, 22.94. Found C, 47.40; H, 3.70; N, 22.80.
θ range for data collection, 2.910–30.034°; μ (Mo–Kα),
−
1
0
.23 mm ; T = 298 K; independent reflections, 4479;
Synthesis of N′‑((4‑(4‑(2‑cyanoacetyl)‑5‑methyl‑1H‑1,2,3‑t
riazol‑1‑yl)phenyl)sulfonyl)‑N,N‑dimethylformimidamide
measured reflections, 9424; observed reflections, 2595;
R(all), 0.1230; R(gt), 0.0652; wR(ref), 0.2099; wR(gt),
3
(15)
0.1835; S(ref), 1.163; δ/σ , 0.001; δρ , 0.410eÅ ; δρ
,
min
max
max
3
−
0.409eÅ . Crystallographic data for the structure 5 have
To a well-stirred solution of 14 (10 mmol) in dioxane,
dimethylformamide dimethylacetal (10 mmol) was added
gradually. Stirring was continued for 6 h at r.t. The result-
ing precipitate was ꢁltrated, washed with water, and crys-
tallized from ethanol to give 15 as colorless crystals, M.p.
been deposited with the Cambridge Crystallographic Data
Center (CCDC) under the number 1574930. Copies of the
data can be obtained, free of charge, on application to CCDC
12 Union Road, Cambridge CB2 1EZ, UK [Fax: +44-1223-
336033; e-mail: deposit@ccdc.cam.ac.uk or at www.ccdc.
cam.ac.uk.
−
1
2
63–265 °C, yield (77%). FT-IR (KBr, ν, cm ): ν=2208
(
CN), 1716 (C=O), 1635 (N=CH), 1589 (C=C), 1342, 1148
1
(
SO ); H-NMR (500 MHz, δ, ppm, DMSO-d ): δ=8.28 (s,
2
6
1
H, N=CH), 8.02 (d, 2H, J= 8.5 Hz, Ar–H), 7.82 (d, 2H,
Materials and methods
J=8.5 Hz, Ar–H), 4.34 (s, 2H, CH ), 3.16 (s, 3H, NCH ),
2
3
13
2
.93 (s, 3H, NCH ), 2.54 (s, 3H, CH ). C NMR (125 MHz,
Three-dimensional structure of human cycline-dependant
kinase CDK2, PDB:2FVD, was obtained from protein data
bank. Energy minimization of newly designed compounds
was done by employing discovery studio 2.5 for structure
reꢁnement. Geometry of all designed analogues is typed
with CHARMm [40] force ꢁeld; then partial charges are
calculated by Momany Rone method [41]. Further, they
are optimized through a smart minimizer algorithm, which
performs 1000 steps of steepest descent with a root mean
square (RMS) gradient tolerance of 0.1. Same as the prepa-
ration of ligands for the target, its active site was also passed
with the energy minimization process and it was done using
CHARMm force ꢁeld which is deꢁned by equation given
below:
3
3
DMSO-d ) δc 9.82 (CH ), 14.19 (CH ), 41.05 [N(CH ) ],
6
3
2
3 2
1
26, 127.48, 136.06, 137.44, 139.61, 144.33, 159.9, 160.98
+
(
N=C), 183.16 (C=O). MS: m/z=360 [M ]. Anal. Calcd for
C H N O S (360.39): C, 49.99; H, 4.48; N, 23.32. Found
1
5
16
6
3
C, 49.80; H, 4.30; N, 23.40.
Synthesis of 4‑(4‑(5‑amino‑1H‑pyra‑
zol‑3‑yl)‑5‑methyl‑1H‑1,2,3‑triazol‑1‑yl)benzenesulfona‑
mide (17)
A mixture of compound 15 (10 mmol) and hydrazine
hydrate (10 mmol) in ethanol (50 ml) was reꢂuxed for 5 h.
The resulting precipitate formed after cooling, ꢁltered oꢀ,
dried, and crystallized from ethanol to give colorless crystals
E = E + E + E + E + E + E + E + E + E
cj
−
1
b
q
f
w
vdw
el
hd
cr
M.p.>300 °C, yield (79%). FT-IR (KBr, ν, cm ): ν 3325,
1
3
180 (NH ), 3120 (NH), 1597(C=C), 1300, 1166 (SO ); H-
2
2
where E = total energy, E = bond potential energy, E
b
q
NMR (500 MHz, δ, ppm, DMSO-d ): δ=9.79 (s, 1H, NH),
6
and E =bond angle potential energy, E =torsion energy,
f
w
8
2
2
.01 (d, 2H, J=8.5 Hz, Ar–H), 7.95 (s, 2H, NH ), 7.87 (d,
2
E
=van der Waals interaction energy, E =electrostatic
vdw
el
H, J=8.5 Hz, Ar–H), 7.52 (s, 1H, pyrazole-H4), 7.42 (s,
potential energy, E =hydrogen bond energy, E =energy
hb
cr
1
3
H, NH ), 2.56 (s, 3H, CH ); C NMR (125 MHz, DMSO-
2
3
constraints, and E =energy function [40].
cj
d ) δc 9.39 (CH ), 125.41, 127.16, 136.48, 137.77, 137.85,
6
3
+
1
38.51, 145.11, 160.07, 162.67. MS: m/z=319 [M ]. Calcd
CDOCKER
for C H N O S (319.34): C, 45.13; H, 4.10; N, 30.70.
1
2
13
7
2
Found C, 45.10; H, 4.20; N, 30.60.
CDOCKER (CHARMm-based DOCKER), a docking pro-
gram provided by discovery studio 2.5, uses a CHARMm-
based molecular dynamics (MD) scheme to dock ligands
into a receptor binding site and then random conformations
X-ray crystallography of compound 5 A single crystal
of compound 5 was obtained by slow evaporation at room
temperature, from dimethylformamide (DMF). The crys-
tal structure was solved and reꢁned using MaXus (Bruker
1
3

Journal of the Iranian Chemical Society
will be produced using high-temperature molecular
dynamics. When these conformations are translated to the
active site, candidate poses are then generated using ran-
dom rigid body rotations followed by simulated annealing.
CDOCKER oꢀers all the advantages of full ligand ꢂexibil-
ity (including bonds, angles, and dihedrals) and reasonable
computation times. CDOCKER uses soft core potentials,
which are found to be eꢀective in exploring the conforma-
tional space of macromolecules used in various docking
studies. The nonbonded interactions which involve van
der Waals (vdW) and electrostatics are softened at diꢀer-
ent levels, except during the ꢁnal minimization step [42].
Initially, ten conformations for each inhibitor are generated
in the active site of the target enzyme, which is created
as a spherical region with a diameter of 10 Ǻ. Simulated
annealing is performed using a ꢂexible ligand and a rigid
protein. Receptor–ligand interactions are calculated from
grid extension 8.0, random conformations are generated
using speciꢁc molecular dynamics steps, and the system
is heated to 700 K in 2000 steps, cooling steps to 5000,
and cooling temperature to 300 K. The ꢁnal reꢁnement
step of minimization is performed using full potential.
Minimized docking poses are then clustered, based on a
heavy atom RMSD approach. The ranking is based on the
total docking energy, which is composed of the ligand’s
intramolecular energy and the ligand–receptor interaction.
3. C. Hansch, P.G. Sammes, J.B. Taylor, Comprehensive medicinal
chemistry, vol. 2 (Pergamon Press, Oxford, 1990)
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A. Natarajan, Y. Guo, F. Harbinski, Y.-H. Fan, H. Chen, L.
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1. D. Vullo, V. De Luca, A. Scozzafava, V. Carginale, M. Rossi,
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(
2001)
In summary, new 1,2,3-triazole derivative containing sul-
fonamide moiety was synthesized, in good yields, start-
ing from 4-acetyl 1,2,3-triazole 3 and ethyl-1,2,3-tria-
zole-4-carboxylate 13. A number of prepared compounds
showed moderate-to-good anticancer activities. Pyrazolyl
1
6. L.-Y. Ma, B. Wang, L.-P. Pang, M. Zhang, S.-Q. Wang, Y.-C.
Zheng, K.-P. Shao, D.-Q. Xue, H.-M. Liu, Bioorg. Med. Chem.
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1
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4639 (2010)
1
,2,3-triazole 12 showed excellent anticancer activity with
against MCF-7 cancer cell line with IC values 12.4
19. A. Rajasekaran, S. Murugesan, K. AnandaRajagopal, Arch.
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0
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Acknowledgements The authors like to thank Dr. Aly Fahmy, Vacsera,
(
2015)
Cairo, Egypt, for handling the antitumor properties.
1. R. Paprocka, M. Wiese, A. Eljaszewicz, A. Helmin-Basa, A.
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Compliance with ethical standards
2
Conflict of interest The authors declare that they have no conꢂict of
interest.
23. Y.-W. He, C.-Z. Dong, J.-Y. Zhao, L.-L. Ma, Y.-H. Li, H.A.
Aisa, Eur. J. Med. Chem. 76, 245–255 (2014)
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