Synthesis and biological evaluation of novel tamoxifen-1,2,4-triazole conjugates

Article abstract of DOI:10.1007/s11030-016-9677-8

Abstract: A new class of compounds, structurally related to the breast cancer drug tamoxifen, was designed and synthesized. The McMurry coupling reaction was used as the key synthetic step in the preparation of these analogs, and the structural assignment

Full text of DOI:10.1007/s11030-016-9677-8

Mol Divers
DOI 10.1007/s11030-016-9677-8
ORIGINAL ARTICLE
Synthesis and biological evaluation of novel
tamoxifen-1,2,4-triazole conjugates
1
1
2
M. S. R. Murty · Mohana Rao Katiki · Jagadeesh Babu Nanubolu ·
3
3
3
Srujana Garimella · Sowjanya Polepalli · Nishant Jain ·
4
4
Sudheer Kumar Buddana · R. S. Prakasham
Received: 16 October 2015 / Accepted: 22 May 2016
©
Springer International Publishing Switzerland 2016
Abstract A new class of compounds, structurally related to
the breast cancer drug tamoxifen, was designed and synthe-
sized. The McMurry coupling reaction was used as the key
synthetic step in the preparation of these analogs, and the
tigated for their antibacterial activity against six bacterial
strains. Preliminary results indicate that some of the newly
synthesized title compounds exhibited promising antibacte-
rial activity compared with the standard drug, vancomycin.
1
structural assignments were made on the basis of H NMR,
1
3
Graphical Abstract
A new class of compounds were
C NMR, and HRMS studies. The absolute stereochem-
designed rationally by the replacement of a ethyl group
in tamoxifen with a methylene (1H-1,2,4-triazole) group.
The absolute stereochemistry of E and Z isomers were
unambiguously confirmed by a single-crystal X-ray diffrac-
tion analysis. The title compounds were evaluated for their
antiproliferative and antibacterial activities.
istry of E and Z isomers was unambiguously confirmed by a
single-crystal X-ray diffraction analysis. Water was found to
be an inexpensive nontoxic and effective medium for the C–
N bond formation. Utilizing this protocol, various tamoxifen
derivatives were synthesized in good yields. Environmental
acceptability, low cost, and high yields are the important fea-
tures of this protocol. These compounds were evaluated for
their antiproliferative activity on five human tumor cell lines.
Compound 4p (GI50 = 0.23 μM) showed improved antipro-
liferative activity against breast cancer cell line (MDA-MB-
Ether linkage
Triphenylethylene
O
R
2
31) compared to tamoxifen (GI50 = 0.24 μM), while the
compound 4o (GI50 = 0.12 μM) exhibited similar activ-
ity against SiHa compared to the reference drug, tamoxifen
N
(
GI50 = 0.12 μM). In addition, these analogs were inves-
N
N
Electronic supplementary material The online version of this
article (doi:10.1007/s11030-016-9677-8) contains supplementary
material, which is available to authorized users.
1
,2,4-Triazole
R = Secondary amines
E-isomers: 4a-r & Z-isomers: 5a-r
B M. S. R. Murty
msrmurty@ymail.com
Keywords Tamoxifen · 1,2,4-Triazole · McMurry cou-
pling · Piperazines · Antibacterial
1
Medicinal Chemistry & Pharmacology Division, Discovery
Laboratory, CSIR–Indian Institute of Chemical Technology,
Hyderabad, India
2
Centre for X-Ray Crystallography, CSIR–Indian Institute of
Chemical Technology, Hyderabad, India
Introduction
3
Centre for Chemical Biology, CSIR–Indian Institute of
Chemical Technology, Hyderabad, India
Cancer is one of the major health problems in the world
for decades. Breast cancer is the most commonly diagnosed
cancer and the leading cause of morbidity and mortality in
4
Bioengineering & Environmental Sciences, CSIR–Indian
Institute of Chemical Technology, Hyderabad, India
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Mol Divers
O
O
N
N
here we describe the synthesis of novel tamoxifen derivatives
containing a 1,2,4-triazole moiety.
The McMurry coupling reaction is an important method-
ology for the synthesis of functionalized olefins and has been
usedforthesynthesisoftitlecompoundsthatmimicthestruc-
tural core of tamoxifen [9–13]. A structural characteristic
of most nonsteroidal antiestrogens is the presence of basic
ether side chain/group at a given position in space, which is
required for the molecule to be an effective estrogen antag-
onist [14,15]. The basic group may be important in evoking
estrogenantagonismduetoits ionicinteractionwithanacidic
amino acid residue in the binding site of the estrogen receptor
Cl
Tamoxifen
Toremifene
CN
N
N
N
[
16]. To probe the importance of the aminoethyl side chain,
CN
N
N
NC
CN
we evaluated the antiproliferative activity of a newly pre-
pared series of tamoxifen analogs in which the side chain
basicity was varied over a wide range.
N
Anastrozole
Letrozole
The triphenylethylene moiety and the side chain are
prerequisites for tamoxifen binding to the ER, although mod-
ification of the ethyl group linked to the ethylenic carbon does
not seem to drastically affect the affinity for the antiestrogen
binding site [17]. Toremifene differs from tamoxifen by the
introduction of a chlorine atom for a hydrogen atom in the
ethyl group and has been proven to be clinically effective
[18]. The fluorotamoxifen analogs with fluorine atom posi-
tioned on the ethyl substituent of tamoxifen had similar or
superior binding affinities compared with tamoxifen [19].
They were found to be most active on the MCF-7 cell line
[20]. Based on these observations, new tamoxifen analogs
4a–r and 5a–r were designed rationally by the replacement
of an ethyl group in tamoxifen with a methylene (1H-1,2,4-
triazole) group to furnish novel tamoxifen analogs with high
antiproliferative activity.
Fig. 1 Structures of the selective estrogen receptor modulators
SERMs) tamoxifen and toremifene, and the aromatase inhibitors (AIs)
anastrozole and letrozole
(
women worldwide [1]. It is generally believed that estrogen
can directly stimulate the growth of breast cancer; there-
fore, its inhibition with antiestrogens at the estrogen receptor
(
ER) can provide a particularly useful strategy for the treat-
ment of hormone-dependent breast cancer. Antiestrogens
AEs) and aromatase inhibitors (AIs) are used clinically to
(
arrestestrogen-dependentgrowthofbreastcancer. Moreover,
triphenylethylene antiestrogens, which have more recently
been designated as selective estrogen receptor modulators
(
[
SERMs), are widely used to treat all stages of breast cancer
2]. Tamoxifen is a synthetic nonsteroidal triphenylethylene
The construction of the C–N bond is of great importance
because of its relevance in compounds with interesting and
diverse biological activities [21]. The classical methods for
the C–N bond formation involves the use of strong bases
like alkali metal hydroxides, carbonates, and phosphates as
well as organic bases like DBU or tertiary amines. Hence,
the construction of the C–N bond employing mild and inex-
pensive reaction conditions is of particular interest. Water
is a unique medium to perform catalyst-free organic reac-
tions [22] and also offers practical advantages over organic
solvents because it is readily available, safe, nontoxic, non-
flammable, and environmentally benign. Herein, we report
an environmentally friendly and efficient method for the
formation of C–N bond under catalyst-free conditions in
aqueous medium. In addition, the title compounds were
evaluated for their in vitro antiproliferative activity against
five human tumor cell lines, SiHa (cervical cancer), MDA-
MB-231 (breast cancer), PANC-1 (pancreatic carcinoma),
IMR-32 (neuroblastoma), and Hep G2 (liver carcinoma).
All the compounds were subjected to in vitro antibacter-
ial activity against Bacillus subtilis, Bacillus megaterium,
antiestrogen drug and is widely used in the treatment of breast
cancer (Fig. 1) [3,4]. Tamoxifen is an SERM, which acts as
either an agonist or an antagonist depending on the target
tissue. Toremifene is a chlorinated derivative of tamoxifen,
which is an alternative to tamoxifen in the first-line treat-
ment of hormone-responsive metastatic breast cancer (Fig. 1)
[
5,6].
Aromatase inhibitors lower the production of estrogen
levels in the body by blocking aromatase, an enzyme that
converts the hormone androgen into estrogen. Suppres-
sion of estrogen biosynthesis by aromatase inhibition is a
valuable approach for the treatment of hormone-responsive
breast cancer. The third-generation nonsteroidal aromatase
inhibitors have shown important benefits in postmenopausal
women with estrogen receptor-positive (ER+) breast cancer.
The reversible nonsteroidal AIs anastrozole and letrozole
(1,2,4-triazole derivatives) (Fig. 1) are widely accepted
as alternatives to tamoxifen as an initial therapy in post-
menopausal women with advanced breast cancer, because
of their improved clinical effectiveness [7,8]. Accordingly,
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Scheme 1 Synthesis of
1
-phenyl-2-(1H-1,2,4-triazol-1-
N
N
HN
HO
Triethyl amine
yl)ethanone
N
Br
N
acetone, reflux, 8 h
O
O
N
1
Scheme 2 Synthesis of (4-(2-
O
Br
bromoethoxy)benzophenone
1
0% aq. NaOH
Br
Br
reflux, 18 h
O
O
2
O
O
Br
Br
Zn, TiCl4, THF
10 °C to reflux, 6 h
N
N
-
O
N
O
N
N
1
2
N
3
RH, H2O, reflux, 3 h
O
O
R
R
N
N
N
N
N
N
E-isomer:4a−r
Z-isomer:5a−r
R= Secondary amines
Scheme 3 Synthesis of tamoxifen containing 1,2,4-triazole and its side chain analogs. Compounds 4a–r are presented as E-isomers and compounds
5a–r are presented as Z-isomers
Micrococcus luteus, Escherichia coli, Salmonella typhi, and
Pseudomonas aeruginosa and their minimal inhibitory con-
centrations were determined.
ketone 1 was prepared by the reaction of 1H-1,2,4-triazole
with phenacyl bromide in the presence of Et3N [23]. The
synthesis of 4-(2-bromoethoxy)benzophenone 2 was accom-
plished by the reaction of 4-hydroxybenzophenone with 1,2-
dibromoethane using sodium hydroxide [24]. The (E,Z)-1-
(3-(4-(2-bromoethoxy)phenyl)-2,3-diphenylallyl)-1H-1,2,4-
triazole 3 was afforded via implementation of the tita-
nium tetrachloride/zinc-mediated McMurry coupling reac-
tion of 1-phenyl-2-(1H-1,2,4-triazol-1-yl)ethanone 1 with
4-(2-bromoethoxy)benzophenone 2 [10]. The mixture of E,
Z isomers 3 proved difficult to separate by column chro-
matography. However, upon alkylation, the resulting E, Z
isomers 4a–r and 5a–r were readily separable.
Results and discussion
Chemistry
The synthetic routes adopted for the preparation of target
molecules (4a–r & 5a–r) are shown in Schemes 1, 2, and
3. McMurry coupling was used as the key synthetic step in
the preparation of these compounds. The required ketones 1
and 2 necessary for the McMurry coupling reaction were
prepared as outlined in Schemes 1 and 2. The triazole-
Initially, compound 3 and phenyl piperazine were selected
as the model substrates to determine the optimized reac-
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Table 1 Optimization of the
reaction conditions
O
O
Br
N
N
HN
2
H O
N
reflux, 3 h
N
N
N
N
N
N
3
m
4m+5m
◦
a
Entry
Solvent
Temperature ( C)
Yield (%)
1
2
3
4
5
6
7
8
9
H2O
rt
0
28
82
42
39
43
47
54
51
63
H2O
50
H2O
100
82
CH3CN
DCM
40
DMSO
DMF
100
100
100
100
100
1,4-Dioxan
Toluene
PEG-400
10
Reaction conditions: 3 (0.0005 mol), m (0.001 mol) in solvent (3mL) were refluxed for 3h
Bold value indicates the best optimized reaction conditions
a
Isolated yield after column chromatography
tion conditions and the results are summarized in Table 1.
The reaction proceeds under catalyst-free conditions and, in
order to ascertain the effect of solvent on N-alkylation, the
reaction was carried out using different solvents (Table 1,
entries 3–10). The results, as shown in Table 1, unveil that
water is superior to the other solvent systems. In aqueous
medium, no reaction was observed at room temperature but
mined to be in the E configuration based on its chemical shift
between 3.92 and 4.03ppm. Similarly, the chemical shift
between 4.07 and 4.18ppm establishes the stereochemical
assignment of series 5a–r to be in the Z configuration (trans
(E) and cis (Z) are used in this paper to designate the relative
positions of the methylene (1H-1,2,4-triazole) group and the
ringbearingtheaminoethylsidechain). Thesamepatternwas
observed for N-methylene protons attached to the triazole
ring (chemical shift between 5.13 and 5.15ppm for series 4a–
rand5.19and5.21ppmforseries5a–r). Single-crystalX-ray
diffraction of compounds 4h, 4i, and 5k (each recrystallized
from EtOAc) confirms the stereochemical assignment for
these compounds (Fig. 2).
◦
by performing the reaction at 50 C (Table 1, entry 2) encour-
agingly the reaction afforded the corresponding product in
◦
2
8% yield. With a further increase in temperature to 100 C,
the yield increased to 82% (Table 1, entry 3). Thus, the best
◦
result was obtained when the reaction was pursued at 100 C
under catalyst-free conditions in water for 3h. In order to
investigate the scope of this reaction, a variety of secondary
amines were subjected to this reaction (Table 2, entries 1–18)
which afforded the corresponding products in good yields.
The results suggest that, irrespective of the nature of the sec-
ondary amine, the reaction proceeds well in the optimized
conditions (Table 2). The C–N bond formation reaction pro-
vided a mixture of E, Z isomers (4a–r and 5a–r) that were
separated by column chromatography in good yields (74–
The analysis of the E and Z isomers of the tamox-
ifen derivatives by reversed-phase high-performance liquid
chromatography (RP-HPLC) has been reported. A typical
chromatogram of compound 3 spiked with Eand Z isomers
is shown in Fig. 3a. The retention times of E and Z were
17.7 and 18.9min, respectively. The signals were provision-
ally assigned on the basis of UV spectra of compound 3. The
separation of the isomers in compound 3 is not possible at
this stage and hence the precise identification of individual
signals is difficult. However, after alkylation of 3 it is possible
to discriminate between each of the isomers on the basis of
82%).
Theconfigurationoffinalcompoundswasreadilyassigned
on the basis of the relative chemical shift of basic side chain
O-methylene protons in NMR spectra. In trans-tamoxifen,
the resonance of the O-methylene protons is at higher field
compared to cis-tamoxifen due to the shielding influence of
unsubstituted phenyl rings [25]. This relation holds for all
tamoxifen derivatives and related triphenylethylenes [26,27].
Accordingly, the stereochemistry of series 4a–r was deter-
1
H NMR data of tamoxifen derivatives 4m and 5m (Table 2,
entry 13). Both compounds 4m and 5m exhibited signals
with well- separated retention times of 20.7 and 24.2min,
respectively, as shown in Fig. 3b. The spectrum of 4m con-
tained an O-methylene triplet centered at δ 4.03 ppm. This
was assigned to the E configuration (retention time of 20.7,
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Table 2 Synthesis of
O
O
(EZ)-2-(4-(1,2-diphenyl-3-(1H-
R
R
1,2,4-triazol-1-yl)prop-1-en-1-
yl)phenoxy)ethyl amines (4a–r
and 5a–r)
N
N
N
N
N
N
E- isomer: 4a−r
Z- isomer: 5a−r
Producta
4a+5a
Yieldb
E:Z ratioc
2.8:1
R
Entry
1
(%)
N
a
b
c
d
e
f
78
81
79
76
N
2
4b+5b
4c+5c
4d+5d
3:1
3
4
2.9:1
3.2:1
N
N
5
6
4e+5e
4f+5f
80
77
3.1:1
3:1
N
N
O
O
7
N
g
75
4.8:1
4
g+5g
8
9
S
N
N
N
N
N
N
h
i
4h+5h
4i+5i
82
81
4.1:1
3.3:1
1
1
0
1
N
N
N
79
80
3.2:1
3:1
j
4j+5j
O
O
k
4k+5k
1
2
l
4l+5l
74
3.1:1
O
1
1
3
4
N
N
N
N
m
n
4m+5m
4n+5n
82
79
3.3:1
3.6:1
N
N
N
1
1
5
6
N
N
N
N
o
p
4o+5o
79
78
2.7:1
2.9:1
O
4
4
p+5p
q+5q
O
1
1
7
8
q
r
80
77
3.5:1
2.8:1
N
N
N
N
4r+5r
a
b
c
Reaction conditions: 3 (0.0005 mol), RH (0.001mol) in water (3mL) were refluxed for 3h
Isolated yield after column chromatography
E/Z ratio determined from the integral of the respective NCH2 singlet in the NMR spectra
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Biological evaluation
Antiproliferative activity
The title compounds were evaluated by an in vitro assay,
which was carried out with a panel of five human cancer cell
lines including cervical cancer (SiHa), breast cancer (MDA-
MB-231), pancreatic carcinoma (PANC-1), neuroblastoma
(IMR-32), and liver carcinoma (Hep G2), using tamoxifen as
a reference compound. The screening procedure was based
on the standard SRB assay. The results are summarized in
Table 3 and expressed as the concentration, in μM, of drug
inhibiting the cell growth by 50% (GI50).
Theinvestigationoftheantiproliferativeeffectonestrogen
independent human tumor cell lines SiHa, MDA-MB-231,
PANC-1, IMR-32, and Hep G2 showed a significant decrease
of sensitivity toward tamoxifen. A direct comparison of
antiproliferative activity of compound 4a containing the
N-dimethyl basic side chain to the activity recorded for
tamoxifen resulted in a significant loss in activity indicat-
ing that the replacement of an ethyl group in tamoxifen for a
methylene (1H-1,2,4-triazole) group may not be necessary.
Interestingly, compound 4p bearing a piperonyl piperazine
moietyshowedaslightincreaseinactivity(GI50 = 0.23 μM)
against the breast cancer cell line (MDA-MB-231) compared
to tamoxifen. Compound 4o having a pyrimidyl piperazine
group maintained similar activity against SiHa compared
to the reference drug. Compound 4m, with phenyl piper-
azine group, was close to the standard (GI50 = 0.39 μM) in
IMR-32. Among the screened tamoxifen derivatives, com-
pound 4e, with a homopiperidine substitution, was found to
be active against PANC-1 and Hep G2. It is well known that
E-tamoxifen (cis isomer) is not antiestrogenic but functions
as an estrogen agonist, whereas Z-tamoxifen (trans isomer)
behaves as an antagonist and is effective in treating estrogen-
dependent breast cancer [28]. The antiproliferative activity
results of title compounds revealed that E-tamoxifen deriv-
atives were more active toward the tested cells compared to
Z-tamoxifen derivatives (Table 3).
Fig. 2 ORTEP diagram of compounds a 4h, CCDC number 1028923,
b 4i, CCDC number 1028922, and c 5k, CCDC number 1028921 with
the atom-numbering scheme. Displacement ellipsoids are drawn at the
Antibacterial activity
In addition to antiproliferative activity studies, we studied
the antibacterial properties of the new tamoxifen deriva-
tives. Thus, the newly synthesized compounds and tamoxifen
were screened for their in vitro activity against three Gram-
positive (B. subtilis, B. megaterium, M. luteus) and three
Gram-negative (E. coli, S. typhi, Pseudomonas aeruginosa)
bacterial strains using the well diffusion and microdilution
methods. Antibacterial activity was determined by measur-
ing the diameter of inhibition zone in mm. The minimum
inhibitory concentration (MIC) was noted by considering the
lowest concentration of the drug at which there was no visi-
3
0% probability level and H atoms are shown as small spheres of arbi-
trary radius
Fig. 3c). The triplet at δ 4.18ppm is due to the OCH2 of
compound 5m, which was assigned as the Z configuration
(retention time of 23.8, Fig. 3d). On this basis, the signal
identities were further established by the retention times of
compounds 4m and 5m.
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Mol Divers
Fig. 3 HPLC chromatograms (a) of compound 3, (b) reaction mixture of 4m:5m, (c) compound 4m, and (d) compound 5m
ble growth. The activity of each compound was compared to
vancomycin (standard). The inhibitory effects of compounds
compared with the standard drug, vancomycin. Besides, the
compounds 4e, 5d, and 5e each having MIC = 62.5 μg/mL
against B. subtilis, compound 4e (MIC = 62.5 μg/mL)
against B. megatherium exhibited exceptional activity com-
pared to the standard drug, vancomycin. Compounds 4a and
4e showed potent and broad-spectrum antibacterial activity
against representatives of both Gram-positive and Gram-
negative bacteria except P. aeruginosa.
The antibacterial activity results revealed that the title
compounds with dimethyl amine, piperidine, and
homopiperidine substitutions exhibited promising antibac-
terial activity compared to other substituted tamoxifen
derivatives. In addition, taking the stereochemistry into con-
sideration, E isomers 4a–r proved to be more active toward
the tested bacterial strains, with respect to Z isomers 5a–r.
The data from Table 4 indicate that tamoxifen has in vitro
antibacterial properties against E. coli, B. subtilis, and B.
megatherium when compared with the standard drug, van-
comycin. Tamoxifen exhibited potent antibacterial activity
against B. megatherium (MIC = 62.5 μg/mL). Overall, the
data from Table 4 suggest that tamoxifen and some of its
derivatives may represent attractive new chemical entities
(NCEs) for antibacterial drug development.
4
a–r and 5a–r against these organisms are summarized in
Table 4.
The screening results from Table 4 indicate that some
of the compounds exhibited moderate to good antibacterial
activity when compared with the standard drug, vancomycin.
Amongthetestedorganisms, thecompoundsshowedtwofold
better activity for Gram-positive bacteria (B. subtilis and B.
megatherium) than the Gram-negative bacteria (E. coli and
S. typhi). This may be due to their diffusibility nature against
the cell wall bacteria. One of the Gram-negative bacteria (P.
aeruginosa)wasresistanttoalmostallcompoundsalongwith
the standard drug, vancomycin. Among the newly synthe-
sized compounds, the inhibitory efficiency of compounds 4a
and 4d with MIC = 125 μg/mL against Gram-negative bac-
teria, E. coli, and compounds 4a–4e, 5d, and 5e each having
MIC = 31.25 μg/mL against S. typhi were comparable to
that of the standard drug, vancomycin. Further observation
of the data indicated that compound 4e (MIC = 62.5 μg/mL)
showed twofold more potent activity than the standard drug,
vancomycin (MIC = 125 μg/mL) against E. coli. In general,
the resistance to naturally available drugs may be associ-
ated with the tough cell wall and spore forming nature of
gram-positive organisms. It was observed from Table 4 that
the compounds 4a–4d, 4i, 4j, and 5c each having MIC =
Conclusions
125 μg/mL showed equivalent antibacterial activity against
In summary, we have developed a straightforward synthetic
strategy for the preparation of novel tamoxifen scaffolds
incorporating a methylene (1H-1,2,4-triazole) with good
yields. The replacement of a dimethyl amino moiety in
B. subtilis, compounds 4a, 4d, 5d, 5e, and 5k each having
MIC = 125 μg/mL against B. megatherium, and compounds
5d and 5e with MIC = 31.25 μg/mL against M. luteus when
1
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Hep G2
Table 3 Growth inhibition
activity of compounds 4a–r and
Compound
Antiproliferative activity (GI50 in μM)
5a–r on five different human
SiHa
MDA-MB-231
PANC-1
IMR-32
cancer cell lines
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
0.21 ± 0.01
11.99 ± 0.02
7.47 ± 0.01
4.81 ± 0.02
15.96 ± 0.01
0.93 ± 0.02
20.53 ± 0.02
0.44 ± 0.03
9.59 ± 0.01
0.51 ± 0.02
14.12 ± 0.01
0.59 ± 0.03
2.03 ± 0.01
0.51 ± 0.01
5.62 ± 0.02
5.48 ± 0.01
0.23 ± 0.01
5.32 ± 0.02
4.17 ± 0.03
3.85 ± 0.02
4.33 ± 0.01
2.73 ± 0.02
11.04 ± 0.03
18.63 ± 0.02
1.53 ± 0.01
3.39 ± 0.02
1.77 ± 0.01
12.41 ± 0.02
1.88 ± 0.02
2.04 ± 0.03
7.10 ± 0.02
4.71 ± 0.01
5.99 ± 0.02
1.63 ± 0.02
8.65 ± 0.01
9.03 ± 0.02
4.57 ± 0.02
0.24 ± 0.01
5.44 ± 0.02
7.02 ± 0.01
0.41 ± 0.02
5.62 ± 0.01
0.31 ± 0.02
3.26 ± 0.01
1.67 ± 0.03
1.51 ± 0.02
9.41 ± 0.03
5.99 ± 0.01
4.41 ± 0.02
8.37 ± 0.01
0.61 ± 0.01
7.49 ± 0.02
0.49 ± 0.03
3.13 ± 0.02
1.34 ± 0.01
0.71 ± 0.02
9.71 ± 0.01
14.67 ± 0.03
5.38 ± 0.02
7.27 ± 0.01
18.01 ± 0.02
5.11 ± 0.03
0.73 ± 0.02
3.64 ± 0.01
11.89 ± 0.02
3.81 ± 0.01
0.89 ± 0.03
3.02 ± 0.02
7.66 ± 0.01
2.29 ± 0.01
4.21 ± 0.03
1.77 ± 0.02
1.03 ± 0.01
1.49 ± 0.02
0.15 ± 0.02
7.32 ± 0.01
2.61 ± 0.09
3.21 ± 0.07
6.47 ± 0.03
2.01 ± 0.04
24.68 ± 0.02
5.67 ± 0.03
5.49 ± 0.08
6.98 ± 0.06
7.54 ± 0.09
4.92 ± 0.07
6.92 ± 0.07
0.39 ± 0.03
6.39 ± 0.09
2.88 ± 0.01
3.75 ± 0.06
7.95 ± 0.06
6.33 ± 0.05
8.13 ± 0.03
11.84 ± 0.07
9.42 ± 0.05
16.7 ± 0.04
13.42 ± 0.06
3.35 ± 0.01
4.81 ± 0.09
1.58 ± 0.01
9.57 ± 0.05
6.32 ± 0.08
1.45 ± 0.07
4.19 ± 0.02
5.97 ± 0.05
9.74 ± 0.06
3.43 ± 0.08
3.12 ± 0.01
6.31 ± 0.09
10.82 ± 0.05
0.35 ± 0.01
16.39 ± 0.07
6.14 ± 0.08
3.42 ± 0.06
12.43 ± 0.02
0.71 ± 0.01
12.68 ± 0.01
2.45 ± 0.05
6.19 ± 0.03
7.64 ± 0.02
12.95 ± 0.07
2.87 ± 0.03
5.36 ± 0.03
0.94 ± 0.01
4.83 ± 0.06
3.76 ± 0.04
4.95 ± 0.03
4.74 ± 0.02
5.11 ± 0.09
6.54 ± 0.04
9.73 ± 0.06
3.58 ± 0.01
14.61 ± 0.02
10.92 ± 0.03
6.75 ± 0.03
5.11 ± 0.02
8.78 ± 0.02
16.42 ± 0.01
9.36 ± 0.01
0.93 ± 0.03
8.37 ± 0.02
4.95 ± 0.03
11.46 ± 0.01
6.25 ± 0.02
13.58 ± 0.03
7.12 ± 0.01
8.94 ± 0.03
0.54 ± 0.02
5.19 ± 0.02
4.45 ± 0.01
0.59 ± 0.02
3.69 ± 0.03
7.24 ± 0.02
3.75 ± 0.01
0.59 ± 0.02
3.50 ± 0.01
9.15 ± 0.03
8.99 ± 0.02
5.19 ± 0.01
0.31 ± 0.02
3.87 ± 0.01
0.12 ± 0.02
3.34 ± 0.03
8.35 ± 0.02
7.02 ± 0.01
3.63 ± 0.02
12.48 ± 0.01
6.81 ± 0.02
3.00 ± 0.01
12.79 ± 0.02
2.05 ± 0.01
2.04 ± 0.03
4.13 ± 0.02
0.89 ± 0.01
11.15 ± 0.02
2.12 ± 0.03
8.65 ± 0.02
1.91 ± 0.02
2.07 ± 0.01
3.03 ± 0.02
12.84 ± 0.01
8.68 ± 0.02
12.49 ± 0.03
0.12 ± 0.01
g
h
i
j
k
l
m
n
o
p
q
r
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Tamoxifen
Bold value indicates the most potent compounds
tamoxifen by various secondary amines can be used as a tool
to prepare novel tamoxifen analogs with high antiprolifera-
tive activity. We have also developed a simple, convenient,
and effective method for the facile C–N bond formation in
aqueous medium. The new tamoxifen analogs 4a–r and 5a–
r were designed for evaluation as antiproliferative agents.
Compound 4p bearing a piperonyl piperazine moiety showed
a slight increase in activity (GI50 = 0.23 μM) against breast
cancer cell line (MDA-MB-231) compared to tamoxifen.
Compound 4o having a pyrimidyl piperazine group main-
tained similar activity against SiHa compared to the reference
drug, tamoxifen. In addition, all the synthesized compounds
were evaluated for their in vitro antimicrobial activity and
compounds 4a, 4d, 4e, 5d, and 5e were found to be promis-
ing antibacterial agents.
1
23

Mol Divers
Table 4 In vitro antibacterial
activity of compounds 4a–r and
Compounds
Antibacterial activity (zone of inhibition in mm and MIC in mg/mL)
Gram-positive bacteria Gram-negative bacteria
5a–r on different bacterial
strains
B. subtilis
B. megaterium
M. luteus
E. coli
S. typhi
P. aeruginosa
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
17 (125)
15 (125)
19 (62.5)
16 (125)
23 (31.25)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
14
12
0
0
0
0
0
15 (125)
12
17
14
24 (31.25)
17 (125)
12
17
14
25 (31.25)
16 (125)
15 (125)
16
17 (125)
23 (31.25)
20 (62.5)
18 (62.5)
19 (62.5)
19 (62.5)
25 (31.25)
12
12
0
13
15
g
h
i
11
10
0
11
14
0
0
0
0
13
15 (125)
0
15
12
21 (62.5)
j
15 (125)
10
17
13
22 (62.5)
k
l
0
0
0
10
13
0
0
0
0
12
m
n
o
p
q
r
a
b
c
d
e
f
0
0
0
0
0
0
0
0
12
0
0
0
0
0
0
0
0
0
10
12
0
0
11
0
11
0
0
0
0
0
13
0
12
0
18
11
0
0
0
10
16 (125)
0
15
0
22 (62.5)
18 (62.5)
14 (125)
21 (31.25)
14
25 (31.25)
18 (62.5)
15 (125)
21 (31.25)
14
25 (31.25)
14
13
16
15
21 (62.5)
g
h
i
12
12
16
0
18
0
12
13
0
11
13
12
17
0
22 (62.5)
j
12
12
17
0
21 (62.5)
k
l
11
15 (125)
14
0
16
0
0
0
0
12
m
n
o
p
q
r
0
0
0
0
11
0
0
12
0
14
0
0
13
0
15
0
0
15
0
14
0
0
16
0
16
0
0
11
0
0
DMSO
0
0
0
0
0
Tamoxifen
Vancomycin
15 (125)
16 (125)
17 (62.5)
14 (125)
20 (125)
22 (31.25)
17 (125)
17 (125)
18 (125)
24 (31.25)
The table shows the zone of inhibition in mm and the corresponding MIC values in μg/mL
Bold value indicates the most potent compounds
1
23

Mol Divers
Experimental
Chemistry
between EtOAc and H2O. The aqueous phase was further
extracted with EtOAc, and the combined organic phases were
successively washed with H2O, brine, and dried over anhy-
drous Na2SO4. The solvent was evaporated under vacuum,
the resulting residue was purified by column chromatogra-
phy using ethyl acetate/hexane (8:2) as an eluent to get pure
compound as a yellow crystalline solid (52% yield).
General Information
All chemicals and reagents were obtained from commercial
suppliers and were used without further purification. Tetrahy-
drofuran was dried over Na metal and distilled prior to use.
Glassware was oven-dried, assembled while hot, and cooled
under an inert atmosphere. Unless otherwise noted, all reac-
tions were conducted in an inert atmosphere. The progress of
the reactions were monitored by thin-layer chromatography
◦
1
M.p. 114–115 C; H NMR (300MHz, CDCl3): δ 8.26
(s, 1H), 8.10–7.91 (m, 3H), 7.68 (t, J = 7.4 Hz, 1H), 7.55
1
3
(t, J = 7.5 Hz, 2H), 5.69 (s, 2H); C NMR (126 MHz,
CDCl3): δ 190.6, 151.9, 144.9, 134.6, 134.0, 129.2, 128.1,
+
55.1; MS (ESI) 188 (M+H ).
Synthesis of 4-(2-bromoethoxy)benzophenone(2)
(TLC) using Merck silica gel glass plate (60 F254, 0.25mm),
To
a
solution of 4-hydroxybenzophenone (5.0g,
and TLC plates were visualized by UV light (254nm) or I2
stain. Column chromatography was carried out with Merck
0.025mol), tetra-n-butyl ammonium iodide (0.37g,
0.001mol), and sodium hydroxide (2.0g, 0.05mol) in water
(15mL), 1,2-dibromoethane (9.4g, 0.05) was added. The
mixture was heated to reflux and stirred for 18h. The cooled
solution was partitioned between ethyl acetate and water.
The organic layer was washed with water, brine, and dried
over Na2SO4. After removal of the solvent in vacuo, the
residue was purified by silica gel chromatography using ethyl
acetate/hexane (20:1) as an eluent to give pure compound as
a white solid (63% yield).
60–120 sized mesh silica gel or aluminum oxide active neu-
tral with 100–300 mesh using ethyl acetate and hexane as
an eluent. All products were characterized by their NMR,
1
IR, and HRMS spectra. The H NMR spectra were recorded
on a Bruker Avance 500 (500 MHz) Nuclear Magnetic Res-
onance spectrometer or on a Bruker Avance spectrometer
(
300MHz), and 13C NMR spectra were recorded on a Bruker
Avance 500 (126 MHz) Nuclear Magnetic Resonance spec-
trometer or on a Bruker Avance spectrometer (75 MHz)
taking the compounds in CDCl3 using TMS as an inter-
nal standard. The chemical shifts (δ) were reported in parts
per million (ppm) downfield from TMS, and the values of
◦
1
M.p. 68–69 C; H NMR (300 MHz, CDCl3): δ 7.89–7.69
(m, 4H), 7.58 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.4 Hz, 2H),
6.98 (d, J = 8.7 Hz, 2H), 4.38 (t, J = 6.2 Hz, 2H), 3.68
1
3
(t, J = 6.2 Hz, 2H). C NMR (126 MHz, CDCl3): δ 195.5,
n
coupling constants J were expressed in Hz. The following
161.7, 138.1, 132.6, 132.4, 132.1, 130.8, 129.8, 128.4, 128.3,
+
abbreviations are used for NMR signals: s = singlet, d = dou-
blet, t = triplet, q = quartet, m = multiplet, dd = doublet of
doublets, qd = quartet of doublets, ddd = doublet of doublet
of doublets, dqd = doublet of quartet of doublets. IR spectra
114.2, 67.9, 28.7; MS (ESI) 306 (M+H ).
Synthesis of (E,Z)-1-(3-(4-(2-bromoethoxy)phenyl)-2,3-
diphenylallyl)-1H-1,2,4-triazole(3)
Zinc powder (1.56g, 0.024mol) was suspended in dry THF
◦
(
KBr) were recorded on a Thermo Nicolet Nexus 670 FTIR
(10mL), and the mixture was cooled to −10 C. TiCl4
−1
Spectrometer (ν in cm ). HRMS spectra were recorded on
a Thermo Scientific Exactive Orbitrap Mass Spectrometer
under Electron Spray Ionization conditions preparing sam-
ple solution in methanol. Melting points were measured on an
Electro thermal 9100 Melting point apparatus and are uncor-
rected.
(1.32mL, 0.012 mol) was added dropwise under nitrogen.
When the addition was completed, the reaction mixture
was heated to reflux for 2h. A solution of 1-phenyl-2-
(1H-1,2,4-triazol-1-yl)ethanone (0.75 g, 0.004 mol) and
4-(2-bromoethoxy) benzophenone (1.22 g, 0.004 mol) in dry
THF (10mL) was added to a cooled suspension of the tita-
◦
nium reagent at 0 C, and the reaction mixture was heated to
◦
Synthetic methods and spectroscopic data
reflux for 2.5h. After cooling to 25 C, the reaction mixture
waspouredintoa10%aqueousK2CO3 solution(30mL), this
mixture was stirred vigorously for 15min, and the dispersed
insoluble material was filtered off. The organic fraction was
separated and the aqueous layer was extracted with EtOAc
(3 × 30 mL). The combined organic fractions were dried
(Na2SO4). Removal of the solvent in vacuo gave a residue
which was purified by silica gel column chromatography
using EtOAc:hexane (1:3) as an eluent to furnish a mixture of
Synthesisof1-phenyl-2-(1H-1,2,4-triazol-1-yl)ethanone(1)
To a cooled solution of 1,2,4-1H-triazole (1.52 g, 0.022
mol) and Et3N (2.02 g, 0.02 mol) in acetone (5mL) was
added dropwise a solution of phenacyl bromide (3.98 g, 0.02
mol) in acetone (10mL). The reaction mixture was heated
to reflux for 6h. The progress of the reaction was monitored
by thin-layer chromatography (TLC). After completion of
the reaction, indicated by TLC, the reaction mixture was
cooled to room temperature. The solvent was removed under
reduced pressure, and the resulting residue was partitioned
1
the E:Z stereoisomers in a ratio of 3:1 ( H NMR integrals)
◦
in 44% yield (1.0 g), m.p. 125–126 C. All attempts to sep-
arate these stereoisomers by fractional crystallization from
1
23

Mol Divers
solvents of different polarity (diethyl ether, ethyl acetate, iso-
propanol, and ethanol) were unsuccessful. Therefore, this
mixture was used for a subsequent reaction without further
purification.
General procedure for the synthesis of (E & Z)-2-(4-(1,2-
diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-en-1-yl)phenoxy)
ethyl amines(4a–r & 5a–r)
The mixture of (E) and (Z) stereoisomers 3 (0.0005 mol)
was added to an appropriate secondary amine (0.001 mol)
in water (3mL). The mixture was heated under reflux for
54.0, 23.5; HRMS (ESI) calcd for C29H31ON4, 451.24820
+
[M+H] ; found, 451.24827.
(E)-1-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
en-1-yl)phenoxy)ethyl)piperidine(4d)
◦ −1
White crystalline solid, M.p. 155–156 C; IR (KBr) ν/cm
3031, 2924, 1603, 1507, 1247; 1H NMR (500 MHz,
CDCl3):δ 7.87 (s, 1H), 7.69 (s, 1H), 7.44–7.30 (m, 5H),
7.18–7.04 (m, 5H), 6.82 (d, J = 8.8 Hz, 2H), 6.58 (d,
J = 8.8 Hz, 2H), 5.14 (s, 2H), 3.99 (t, J = 6.0 Hz, 2H),
2.71 (t, J = 6.0 Hz, 2H), 2.48 (s, 4H), 1.62–1.54 (m, 4H),
1
3
3
h. After completion of the reaction, indicated by TLC, the
1.43 (d, J = 5.0 Hz, 2H); C NMR (126 MHz, CDCl3):δ
157.7, 151.7, 145.2, 143.3, 141.8, 139.4, 133.9, 131.9, 131.4,
129.6, 129.5, 128.7, 128.5, 127.8, 127.2, 113.7, 65.7, 57.9,
55.1, 54.1, 25.9, 24.2; HRMS (ESI) calcd for C30H33ON4,
reaction mixture was cooled to room temperature. The aque-
ous phase was extracted with EtOAc (3 × 10 mL), and then
the combined organic phases were successively washed with
H2O, brine, and dried over anhydrous Na2SO4. The solvent
was evaporated under vacuum to give the crude product,
which was purified by neutral alumina column chromatogra-
phy using ethyl acetate/hexane (1:4) as an eluent to give the
separated (E)-(4a–r) and (Z)-(5a–r) stereoisomers.
+
465.26400 [M+H] ; found, 465.26403.
(E)-1-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
en-1-yl)phenoxy)ethyl)azepane(4e)
−
1
Yellow oil; IR (KBr) ν/cm 3050, 2933, 1605, 1508, 1247,
1
1142; H NMR (300 MHz, CDCl3): δ 7.87 (s, 1H), 7.69 (s,
(
E)-2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
1H), 7.46–7.29 (m, 5H), 7.12 (tt, J = 7.8, 4.3 Hz, 5H), 6.82
(d, J = 8.8 Hz, 2H), 6.58 (d, J = 8.8 Hz, 2H), 5.14 (s, 2H),
3.94 (t, J = 6.2 Hz, 2H), 2.87 (t, J = 6.2 Hz, 2H), 2.78–
en-1-yl)phenoxy)-N,N-dimethyl ethanamine(4a)
Yellow oil; IR (KBr) ν/cm 3054, 2924, 1605, 1508, 1240,
1
1
2
2
−1
1
13
137; H NMR (500 MHz, CDCl3):δ 7.87 (s, 1H), 7.69 (s,
H), 7.43–7.31 (m, 5H), 7.17–7.03 (m, 5H), 6.85–6.80 (m,
H), 6.62–6.56 (m, 2H), 5.14 (s, 2H), 3.95 (t, J = 5.7 Hz,
2.65 (m, 4H), 1.58 (s, 8H); C NMR (75 MHz, CDCl3): δ
157.8, 151.7, 145.1, 143.3, 141.8, 139.4, 133.8, 131.9, 131.3,
129.6, 129.5, 128.6, 128.5, 127.8, 127.2, 113.7, 66.3, 56.3,
55.9, 54.0, 27.9, 27.1; HRMS (ESI) calcd for C31H ON4,
1
3
H), 2.67 (t, J = 5.7 Hz, 2H), 2.30 (s, 6H); C NMR
3
5
+
(126 MHz, CDCl3):δ 157.7, 151.7, 145.2, 143.3, 141.8,
479.27858 [M+H] ; found, 479.27863.
1
39.4, 134.0, 131.9, 131.4, 129.6, 129.5, 128.7, 128.5, 127.8,
(E)-4-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
1
27.2, 113.7, 65.7, 58.2, 54.1, 45.8; HRMS (ESI) calcd for
en-1-yl)phenoxy)ethyl)morpholine(4f)
+
◦
−1
C27H29ON4, 425.23341 [M+H] ; found, 425.23339.
White solid, M.p. 105–106 C; IR (KBr) ν/cm 3035, 2931,
1
(
1
E)-2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-en-
-yl)phenoxy)-N,N-diethyl ethanamine(4b)
1604, 1507, 1245, 1145; H NMR (500 MHz, CDCl3): δ 7.87
(s, 1H), 7.69 (s, 1H), 7.44–7.31 (m, 5H), 7.19–7.04 (m, 5H),
6.83 (d, J = 8.7 Hz, 2H), 6.58 (d, J = 8.7 Hz, 2H), 5.14 (s,
2H), 3.98 (t, J = 5.7 Hz, 2H), 3.73–3.67 (m, 4H), 2.72 (t,
−1
Yellow oil; IR (KBr) ν/cm 2924, 1605, 1508, 1245, 1138;
1
H NMR (500 MHz, CDCl3):δ 7.87 (s, 1H), 7.70 (s, 1H),
1
3
7
6
2
.43–7.31 (m, 5H), 7.18–7.05 (m, 5H), 6.84–6.80 (m, 2H),
.60–6.55 (m, 2H), 5.14 (s, 2H), 3.92 (t, J = 6.4 Hz, 2H),
.79 (t, J = 6.4 Hz, 2H), 2.59 (q, J = 7.1 Hz, 4H), 1.02 (t,
J = 5.7 Hz, 2H), 2.53 (d, J = 4.1 Hz, 4H); C NMR (126
MHz, CDCl3): δ 157.5, 151.7, 145.0, 143.3, 141.7, 139.3,
134.0, 131.9, 131.5, 129.6, 129.5, 128.6, 128.5, 127.8, 127.2,
113.7, 66.9, 65.6, 57.6, 54.1, 54.0; HRMS (ESI) calcd for
1
3
J = 7.1 Hz, 6H); C NMR (126 MHz, CDCl3): δ 157.5,
+
1
1
4
51.7, 145.1, 143.3, 141.8, 139.3, 134.0, 131.9, 131.4, 129.6,
29.5, 128.7, 128.5, 127.8, 127.2, 113.7, 65.9, 54.0, 51.5,
7.8, 11.4; HRMS (ESI) calcd for C29H33ON4, 453.26342
C29H31ON4, 467.24432 [M+H] ; found, 467.24442.
(E)-4-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
en-1-yl)phenoxy)ethyl)-2,6-dimethylmorpholine(4g)
+
−1
[
M+H] ; found, 453.26320.
Yellow oil; IR (KBr) ν/cm 2972, 1606, 1508, 1245, 1140;
1
(
E)-1-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
H NMR (500MHz, CDCl3): δ 7.87 (s, 1H), 7.69 (s, 1H),
en-1-yl)phenoxy)ethyl)pyrrolidine(4c)
Yellow oil; IR (KBr) ν/cm 3036, 2930, 1606, 1508, 1246,
7.43–7.32 (m, 5H), 7.17–7.02 (m, 5H), 6.86–6.81 (m, 2H),
6.60–6.56 (m, 2H), 5.14 (s, 2H), 3.98 (t, J = 5.8 Hz, 2H),
3.68 (dqd, J = 12.5, 6.3, 2.0 Hz, 2H), 2.77 (t, J = 9.1 Hz,
2H), 2.73–2.68 (m, 2H), 1.88–1.80 (m, 2H), 1.14 (d, J =
6.3 Hz, 6H); 13C NMR (126 MHz, CDCl3): δ 157.6, 151.7,
145.0, 143.3, 141.7, 139.3, 134.0, 131.9, 131.5, 130.9, 130.6,
129.6, 129.5, 128.6, 128.5, 127.8, 127.2, 113.7, 71.6, 65.5,
−1
1
1
1
2
2
1
1
1
145; H NMR (500 MHz, CDCl3): δ 7.87 (s, 1H), 7.69 (s,
H), 7.45–7.29 (m, 5H), 7.19–7.04 (m, 5H), 6.86–6.79 (m,
H), 6.63–6.55 (m, 2H), 5.14 (s, 2H), 3.98 (t, J = 6.0 Hz,
H), 2.82 (t, J = 6.0 Hz, 2H), 2.62–2.54 (m, 4H), 1.81–
.74 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 157.7, 151.7,
45.1, 143.3, 141.8, 139.3, 133.8, 131.9, 131.4, 129.6, 129.5,
28.6, 128.6, 128.5, 127.8, 127.2, 113.7, 66.9, 55.1, 54.8,
59.8, 57.2, 54.0, 19.2; HRMS (ESI) calcd for C31H O2N4,
3
5
+
495.27360 [M + H] ; found, 495.27353.
1
23

Mol Divers
−
1
(
E)-4-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
Yellow oil; IR (KBr) ν/cm 3056, 2925, 1508, 1244, 1138;
1
en-1-yl)phenoxy)ethyl)thiomorpholine(4h)
White crystalline solid, M.p. 166–167 C; IR (KBr) ν/cm
3
H NMR (500 MHz, CDCl3): δ 7.87 (s, 1H), 7.69 (s, 1H),
◦
−1
7.49–7.45 (m, 1H), 7.43–7.31 (m, 5H), 7.17–7.05 (m, 5H),
6.98 (d, J = 3.5 Hz, 1H), 6.84 (d, J = 8.6 Hz, 2H), 6.58
(d, J = 8.7 Hz, 2H), 6.48–6.45 (m, 1H), 5.14 (s, 2H), 3.99
(t, J = 5.5 Hz, 2H), 3.80 (s, 4H), 2.77 (t, J = 5.5 Hz,
2H), 2.63–2.54 (m, 4H); 13C NMR (126 MHz, CDCl3): δ
159.1, 157.5, 151.7, 148.0, 145.0, 143.7, 143.4, 141.7, 139.3,
134.2, 131.9, 131.6, 129.6, 129.5, 128.7, 128.5, 127.8, 127.2,
1
033, 2930, 1601, 1505, 1242, 1139; H NMR (500 MHz,
CDCl3):δ 7.87(s, 1H), 7.69(s, 1H), 7.42–7.31(m, 5H), 7.18–
.05 (m, 5H), 6.86–6.80 (m, 2H), 6.60–6.54 (m, 2H), 5.14
7
(
4
s, 2H), 3.95 (t, J = 5.8 Hz, 2H), 2.80 (dd, J = 6.1, 3.9 Hz,
1
3
H), 2.76 (t, J = 5.8 Hz, 2H), 2.67–2.63 (m, 4H); C NMR
(75 MHz, CDCl3): δ 157.5, 151.7, 145.0, 143.3, 141.7, 139.3,
1
34.0, 131.9, 131.4, 129.6, 129.5, 128.6, 128.5, 127.8, 127.2,
116.5, 113.7, 111.3, 65.7, 57.1, 54.0; HRMS (ESI) calcd for
+
113.7, 65.5, 57.9, 55.3, 54.0, 27.9; HRMS (ESI) calcd for
C34H34O3N , 560.26467 [M+H] ; found, 560.26470.
5
+
C29H31ON4S, 483.21801 [M+H] ; found, 483.21836.
(E)-1-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1
(
E)-1-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
-en-1-yl)phenoxy)ethyl)-4-phenylpiperazine(4m)
−
1
en-1-yl)phenoxy)ethyl)-4-methylpiperazine(4i)
Yellow crystalline solid, M.p. 165–166 C; IR (KBr) ν/cm
Yellow oil; IR (KBr) ν/cm 3057, 2931, 1601, 1503, 1241,
◦
1
−1
1
1141; H NMR (500 MHz, CDCl3): δ 7.87 (s, 1H), 7.69 (s,
3052, 2935, 1607, 1509, 1241, 1155; H NMR (500 MHz,
1H), 7.44–7.31 (m, 5H), 7.29–7.23 (m, 3H), 7.18–7.05 (m,
5H), 6.92 (d, J = 8.3 Hz, 2H), 6.88–6.81 (m, 3H), 6.60 (t,
J = 5.7 Hz, 2H), 5.14 (s, 2H), 4.03 (t, J = 5.7 Hz, 2H),
3.23–3.16 (m, 4H), 2.80 (t, J = 5.7 Hz, 2H), 2.74–2.66 (m,
CDCl3): δ 7.87 (s, 1H), 7.69 (s, 1H), 7.43–7.30 (m, 5H),
7
5
2
.17–7.05 (m, 5H), 6.85–6.80 (m, 2H), 6.60–6.55 (m, 2H),
.14 (s, 2H), 3.97 (t, J = 5.8 Hz, 2H), 2.74 (t, J = 5.8 Hz,
1
3
13
H), 2.65–2.35 (m, 8H), 2.28 (s, 3H); C NMR (126 MHz,
4H); C NMR (126 MHz, CDCl3): δ 157.6, 151.8, 151.3,
CDCl3): δ 157.7, 151.7, 145.1, 143.3, 141.8, 139.4, 134.0,
145.1, 143.4, 141.8, 139.4, 134.1, 131.9, 131.5, 129.6, 129.5,
129.2, 128.7, 128.6, 127.8, 127.3, 119.9, 116.2, 113.8, 65.8,
131.9, 131.4, 129.6, 129.5, 128.7, 128.5, 127.8, 127.2, 113.7,
6
5.8, 57.2, 55.0, 54.0, 53.6, 46.0; HRMS (ESI) calcd for
57.3, 54.1, 53.7, 49.2; HRMS (ESI) calcd for C H36ON ,
3
5
5
+
+
C30H34ON , 480.27404 [M+H] ; found, 480.27395.
542.29135 [M+H] ; found, 542.29135.
5
(
E)-1-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
(E)-1-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
en-1-yl)phenoxy)ethyl)-4-ethylpiperazine(4j)
Yellow oil; IR (KBr) ν/cm 3055, 2942, 1606, 1508, 1237,
en-1-yl)phenoxy)ethyl)-4-(pyridin-2-yl)piperazine(4n)
−1
−1
Yellow oil; IR (KBr) ν/cm 3054, 2925, 1595, 1505, 1244,
1
1
1
1
6
2
1
1
1
5
144; H NMR (300 MHz, CDCl3): δ 7.87 (s, 1H), 7.69 (s,
H), 7.44–7.30 (m, 5H), 7.12 (qd, J = 8.2, 4.2 Hz, 5H),
.83 (d, J = 8.7 Hz, 2H), 6.57 (d, J = 8.8 Hz, 2H), 5.14 (s,
H), 3.98 (t, J = 5.8 Hz, 2H), 2.81–2.31 (m, 12H), 1.13–
.01 (m, 3H); 13C NMR (126 MHz, CDCl3): δ 157.6, 151.7,
45.0, 143.3, 141.7, 139.3, 133.9, 131.8, 131.4, 129.5, 129.5,
28.6, 128.5, 127.7, 127.2, 113.7, 65.7, 57.1, 54.0, 53.6, 52.7,
1139; H NMR (500 MHz, CDCl3): δ 8.18 (ddd, J = 4.9,
1.9, 0.7 Hz, 1H), 7.87 (s, 1H), 7.68 (s, 1H), 7.49–7.31 (m,
6H), 7.18–7.05 (m, 5H), 6.87–6.81 (m, 2H), 6.65–6.56 (m,
4H), 5.14 (s, 2H), 4.02 (t, J = 5.7 Hz, 2H), 3.56–3.51 (m,
13
4H), 2.78 (t, J = 5.7 Hz, 2H), 2.67–2.61 (m, 4H);
C
NMR (75 MHz, CDCl3): δ 160.9, 159.5, 157.6, 151.7, 148.0,
145.0, 143.3, 141.7, 139.3, 137.5, 134.0, 131.9, 131.5, 129.5,
129.5, 128.6, 128.5, 127.7, 127.2, 113.7, 113.3, 107.1, 65.7,
57.3, 54.0, 53.4, 45.1; HRMS (ESI) calcd for C34H ON6,
2.3, 12.0; HRMS (ESI) calcd for C31H36ON , 494.28999
5
+
[
M+H] ; found, 494.28997.
3
5
+
(
E)-1-(4-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop- 543.28671 [M+H] ; found, 543.28718.
1
-en-1-yl)phenoxy)ethyl) piperazin-1-yl)ethanone(4k)
(E)-2-(4-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)
prop-1-en-1-yl)phenoxy)ethyl) piperazin-1-yl)pyrimidine
(4o)
−1
Yellow oil; IR (KBr) ν/cm 2926, 1607, 1508, 1244, 1138;
H NMR (500 MHz, CDCl3): δ 7.87 (s, 1H), 7.69 (s, 1H),
1
−
1
7
6
3
2
.46–7.31 (m, 5H), 7.19–7.03 (m, 5H), 6.87–6.80 (m, 2H),
.61–6.54 (m, 2H), 5.14 (s, 2H), 3.98 (t, J = 5.6 Hz, 2H),
.67–3.56 (m, 2H), 3.49–3.39 (m, 2H), 2.75 (t, J = 5.5 Hz,
Yellow oil; IR (KBr) ν/cm 2926, 1585, 1505, 1245, 1139;
1
H NMR (500 MHz, CDCl3): δ 8.29 (d, J = 4.7 Hz, 2H),
7.87 (s, 1H), 7.69 (s, 1H), 7.45–7.31 (m, 5H), 7.18–7.05 (m,
5H), 6.87–6.80 (m, 2H), 6.63–6.56 (m, 2H), 6.48 (t, J =
4.7 Hz, 1H), 5.15 (s, 2H), 4.03 (t, J = 5.7 Hz, 2H), 3.88–
3.78 (m, 4H), 2.79 (t, J = 5.7 Hz, 2H), 2.65–2.56 (m, 4H);
1
3
H), 2.58–2.44 (m, 4H), 2.07 (s, 3H); C NMR (126 MHz,
CDCl3): δ 168.9, 157.5, 151.7, 145.0, 143.3, 141.7, 139.3,
134.1, 131.9, 131.6, 129.6, 129.5, 128.6, 128.5, 127.8, 127.2,
1
3
113.7, 65.7, 57.1, 54.0, 53.7, 53.2, 46.3, 41.4, 21.3; HRMS
C NMR (126 MHz, CDCl3): δ 161.6, 157.7, 157.5, 151.6,
+
(
5
ESI) calcd for C31H34O2N , 508.26905 [M+H] ; found,
145.0, 143.3, 141.7, 139.3, 134.0, 131.8, 131.4, 129.5, 129.5,
128.6, 128.5, 127.7, 127.2, 113.7, 109.9, 65.6, 57.3, 54.0,
53.5, 43.6; HRMS (ESI) calcd for C33H34ON7, 544.28159
5
08.26892.
(
-
E)-(4-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1
en-1-yl)phenoxy)ethyl) piperazin-1-yl)(furan-2-yl)
+
[M+H] ; found, 544.28161.
methanone(4l)
1
23

Mol Divers
−
1
(
E)-1-(Benzo[d][1,3]dioxol-5-ylmethyl)-4-(2-(4-(1,2-
Yellow oil; IR (KBr) ν/cm 3053, 2925, 1606, 1507, 1245,
1
diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-en-1-yl)phenoxy)
ethyl)piperazine(4p)
1138; H NMR (300 MHz, CDCl3): δ 7.88 (d, J = 3.9 Hz,
1H), 7.71 (s, 1H), 7.34 (d, J = 8.7 Hz, 2H), 7.18–6.99 (m,
10H), 6.96–6.89 (m, 4H), 5.21 (s, 2H), 4.07 (t, J = 6.3 Hz,
2H), 2.90 (t, J = 6.3 Hz, 2H), 2.66 (q, J = 7.1 Hz, 4H),
−1
Yellow oil; IR (KBr) ν/cm 2927, 1605, 1505, 1244, 1138;
1
H NMR (500 MHz, CDCl3): δ 7.87 (s, 1H), 7.69 (s, 1H),
.42–7.31 (m, 5H), 7.17–7.04 (m, 4H), 6.86–6.79 (m, 3H),
.74 (d, J = 7.6 Hz, 3H), 6.56 (d, J = 8.8 Hz, 2H), 5.94
1
3
7
6
1.08 (t, J = 7.1 Hz, 6H); C NMR (75 MHz, CDCl3):
δ 158.35, 151.75, 145.37, 143.40, 141.91, 139.29, 134.01,
132.00, 130.95, 130.66, 129.53, 128.45, 127.69, 127.26,
126.94, 114.57, 66.06, 54.09, 51.60, 47.76, 11.46; HRMS
(
d, J = 10.5 Hz, 2H), 5.14 (s, 2H), 3.97 (t, J = 5.8 Hz,
2
2
1
1
1
H), 3.43–3.37 (m, 2H), 2.74 (t, J = 5.8 Hz, 2H), 2.66–
.31 (m, 8H); 13C NMR (126 MHz, CDCl3): δ 157.6, 151.7,
47.6, 146.6, 145.1, 143.3, 141.7, 139.3, 133.9, 131.8, 131.4,
29.5, 129.5, 128.6, 128.5, 127.7, 127.2, 122.3, 113.7, 109.6,
+
(ESI) calcd for C29H33ON4, 453.26318 [M+H] ; found,
453.26290.
(Z)-1-(2-(4-(1,2-diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
en-1-yl)phenoxy)ethyl)pyrrolidine(5c)
07.9, 100.9, 65.6, 62.7, 57.1, 54.0, 53.6, 52.8; HRMS
+
−1
(
6
ESI) calcd for C37H38O3N , 600.29795 [M+H] ; found,
Yellow oil; IR (KBr) ν/cm 3053, 2928, 1606, 1508, 1244,
5
1
00.29780.
1138; H NMR (500 MHz, CDCl3): δ 7.88 (s, 1H), 7.71 (s,
(
E)-1-Benzyl-4-(2-(4-(1,2-diphenyl-3-(1H-1,2,4-triazol-1-
1H), 7.34 (d, J = 8.6 Hz, 2H), 7.15–7.02 (m, 8H), 6.97–6.89
yl)prop-1-en-1-yl)phenoxy) ethyl)piperazine(4q)
Yellow oil; IR (KBr) ν/cm 3027, 2935, 1604, 1504, 1243,
1
1
2
2
(m, 4H), 5.20(s, 2H), 4.15(t, J = 5.6 Hz, 2H), 2.88–2.88(m,
−1
13
2H), 2.63–2.48 (s, 4H), 1.70–1.57 (m, 4H); C NMR (126
1
139; H NMR (500 MHz, CDCl3): δ 7.87 (s, 1H), 7.69 (s,
H), 7.42–7.21 (m, 11H), 7.16–7.05 (m, 5H), 6.85–6.78 (m,
H), 6.59–6.53 (m, 2H), 5.14 (s, 2H), 3.96 (t, J = 5.9 Hz,
H), 3.50 (s, 2H), 2.73 (t, J = 5.9 Hz, 2H), 2.65–2.39
MHz, CDCl3): δ 158.0, 151.7, 145.3, 143.4, 141.9, 139.3,
132.1, 131.0, 130.6, 129.5, 128.4, 127.7, 127.3, 127.0, 114.6,
54.7, 54.6, 54.1, 23.5; HRMS (ESI) calcd for C29H31ON4,
+
451.24741 [M+H] ; found, 451.24743.
(
m, 8H); 13C NMR (126 MHz, CDCl3): δ157.6, 151.7,
(Z)-1-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
1
1
6
45.1, 143.3, 141.8, 139.3, 138.0, 133.9, 131.9, 131.4, 129.6,
29.5, 129.3, 128.6, 128.5, 128.3, 127.8, 127.2, 127.1, 113.7,
en-1-yl)phenoxy)ethyl)piperidine(5d)
−1
Yellow oil; IR (KBr) ν/cm 2924, 1605, 1503, 1244, 1137;
1
5.7, 63.1, 57.2, 54.0, 53.6, 53.0; HRMS (ESI) calcd for
H NMR (300 MHz, CDCl3): δ 7.88 (s, 1H), 7.71 (s, 1H),
+
C36H38ON , 556.30799 [M + H] ; found, 556.30779.
7.34 (d, J = 8.7 Hz, 2H), 7.13–7.00 (m, 8H), 6.93 (dd,
J = 9.1, 4.3 Hz, 4H), 5.20 (s, 2H), 4.14 (t, J = 6.0 Hz,
2H), 2.80 (t, J = 6.0 Hz, 2H), 2.54 (s, 4H), 1.68–1.56 (m,
5
(E)-1-Benzhydryl-4-(2-(4-(1,2-diphenyl-3-(1H-1,2,4-
triazol-1-yl)prop-1-en-1-yl)phenoxy)ethyl)piperazine(4r)
White solid, M.p. 166–167 C; IR (KBr) ν/cm 3026, 2959,
◦
−1
13
6H); C NMR (126 MHz, CDCl3): δ 158.5, 151.8, 145.4,
1
1603, 1504, 1252, 1137; H NMR (500 MHz, CDCl3): δ 7.87
143.4, 141.9, 139.3, 134.0, 132.0, 130.9, 130.7, 129.6, 128.4,
127.7, 127.3, 126.9, 114.7, 65.9, 57.9, 55.1, 54.1, 25.8, 24.1;
(s, 1H), 7.69 (s, 1H), 7.43–7.30 (m, 9H), 7.28–7.22 (m, 5H),
+
7.19–7.03 (m, 7H), 6.84–6.78 (m, 2H), 6.58–6.52 (m, 2H),
HRMS (ESI) calcd for C30H33ON4, 465.26585 [M+H] ;
5
.13 (s, 2H), 4.20 (s, 1H), 3.96 (t, J = 5.9 Hz, 2H), 2.73
found, 465.26568.
1
3
(
t, J = 5.8 Hz, 2H), 2.66–2.24 (m, 8H); C NMR (126
(Z)-1-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
en-1-yl)phenoxy)ethyl) azepane(5e)
MHz, CDCl3): δ 157.7, 151.7, 145.1, 143.3, 142.8, 141.8,
−
1
139.4, 133.9, 131.9, 131.4, 129.6, 129.5, 128.7, 128.5, 128.0,
Yellow oil; IR (KBr) ν/cm 3056, 2923, 1607, 1509, 1247,
1
127.8, 127.2, 127.0, 113.7, 76.3, 65.8, 57.2, 54.1, 54.0, 51.9;
1137; H NMR (500 MHz, CDCl3): δ 7.89 (s, 1H), 7.71
+
HRMS (ESI) calcd for C42H42ON , 632.33720 [M+H] ;
(s, 1H), 7.36–7.31 (m, 2H), 7.14–7.02 (m, 8H), 6.95–6.90
(m, 4H), 5.21 (s, 2H), 4.09 (t, J = 6.2 Hz, 2H), 2.97 (t,
J = 6.2 Hz, 2H), 2.82–2.76 (m, 4H), 1.67 (s, 4H), 1.63–1.58
(m, 4H);13CNMR(126MHz, CDCl3):δ 158.6, 151.7, 145.4,
143.4, 141.9, 139.3, 133.8, 132.0, 130.9, 130.6, 129.5, 128.4,
127.7, 127.2, 126.9, 114.6, 66.5, 56.4, 55.9, 54.1, 27.9, 27.1;
5
found, 632.33729.
(
Z)-2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
en-1-yl)phenoxy)-N,N-dimethylethanamine(5a)
−1
Yellow oil; IR (KBr) ν/cm 2924, 1606, 1508, 1243, 1142;
1
H NMR (300 MHz, CDCl3): δ 7.89 (s, 1H), 7.71 (s, 1H),
+
7
.34 (d, J = 8.7 Hz, 2H), 7.15–7.00 (m, 8H), 6.93 (d, J =
HRMS (ESI) calcd for C31H ON4, 479.27940 [M+H] ;
3
5
8
.5 Hz, 4H), 5.21 (s, 2H), 4.11 (t, J = 5.7 Hz, 2H), 2.78
found, 479.27936.
1
3
(
t, J = 5.6 Hz, 2H), 2.37 (s, 6H); C NMR (126 MHz,
(Z)-4-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
CDCl3): δ 158.4, 151.7, 145.4, 143.4, 141.9, 139.3, 134.0,
en-1-yl)phenoxy)ethyl)morpholine(5f)
◦
−1
1
6
4
32.0, 130.9, 130.6, 129.5, 128.4, 127.7, 127.2, 126.9, 114.6,
5.7, 58.0, 54.1, 45.6; HRMS (ESI) calcd for C27H29ON4,
25.23167 [M+H] ; found, 425.23188.
White solid, M.p. 129–130 C; IR (KBr) ν/cm 3036, 2929,
1
1606, 1508, 1243, 1137; H NMR (300 MHz, CDCl3): δ
+
7.88 (s, 1H), 7.70 (s, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.09
(dd, J = 12.8, 7.8 Hz, 8H), 6.92 (d, J = 8.6 Hz, 4H), 5.20
(s, 2H), 4.13 (t, J = 5.6 Hz, 2H), 3.79–3.70 (m, 4H), 2.82
(
Z)-2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
en-1-yl)phenoxy)-N,N-diethyl ethanamine(5b)
1
23

Mol Divers
(
t, J = 5.6 Hz, 2H), 2.65–2.54 (m, 4H); 13C NMR (126
(Z)-1-(4-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-
MHz, CDCl3): δ 158.4, 151.8, 145.3, 143.4, 141.9, 139.3,
1
1
1-en-1-yl)phenoxy)ethyl) piperazin-1-yl)ethanone(5k)
◦
−1
34.0, 132.0, 130.9, 130.6, 129.5, 128.4, 127.7, 127.2, 126.9,
Yellow crystalline solid, M.p. 167–168 C; IR (KBr) ν/cm
1
14.6, 67.0, 65.8, 57.7, 54.2, 54.1; HRMS (ESI) calcd for
3055, 2921, 1508, 1246, 1138; H NMR (500 MHz, CDCl3):
δ 7.89 (s, 1H), 7.70 (s, 1H), 7.38–7.32 (m, 2H), 7.14–7.02 (m,
8H), 6.96–6.89 (m, 4H), 5.20 (s, 2H), 4.13 (t, J = 5.5 Hz,
2H), 3.68–3.62 (m, 2H), 3.52–3.46 (m, 2H), 2.85 (t, J =
+
C29H31ON4, 467.24442 [M+H] ; found, 467.24480.
(
-
Z)-4-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1
en-1-yl)phenoxy)ethyl)-2,6-dimethylmorpholine(5g)
−1
13
Yellow oil; IR (KBr) ν/cm 2932, 1607, 1508, 1244, 1141;
5.5 Hz, 2H), 2.62–2.53 (m, 4H), 2.09 (s, 3H); C NMR (126
1
H NMR (300 MHz, CDCl3): δ 7.89 (s, 1H), 7.71 (s, 1H),
MHz, CDCl3): δ 169.0, 158.3, 151.8, 145.3, 143.4, 141.9,
7
(
3
.35 (d, J = 8.6 Hz, 2H), 7.16–6.99 (m, 8H), 6.97–6.87
m, 4H), 5.21 (s, 2H), 4.13 (t, J = 5.7 Hz, 2H), 3.81–
.64 (m, 2H), 2.82 (dd, J = 14.8, 8.9 Hz, 4H), 1.90 (t,
J = 10.8 Hz, 2H), 1.17 (d, J = 6.3 Hz, 6H); C NMR
126 MHz, CDCl3): δ 158.4, 151.8, 145.4, 143.4, 141.9,
139.3, 134.1, 132.1, 130.9, 130.6, 129.5, 128.4, 127.7, 127.3,
126.9, 114.6, 65.9, 57.2, 54.1, 53.7, 53.2, 46.3, 41.4, 21.4;
+
HRMS (ESI) calcd for C31H34O2N , 508.26889 [M+H] ;
5
1
3
found, 508.26919.
(
(Z)-(4-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-
1-en-1-yl)phenoxy)ethyl)piperazin-1-yl)(furan-2-yl)
methanone5l)
139.3, 134.0, 132.0, 130.9, 130.6, 129.5, 128.4, 127.7, 127.3,
126.9, 114.6, 71.6, 65.7, 59.9, 57.3, 54.1, 19.3; HRMS
+
−1
(
4
ESI) calcd for C31H O2N4, 495.27357 [M+H] ; found,
Yellow oil; IR (KBr) ν/cm 2924, 1605, 1508, 1243, 1138;
3
5
1
95.27378.
H NMR (500 MHz, CDCl3): δ 7.89 (s, 1H), 7.70 (s, 1H),
(
Z)-4-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
7.48 (t, J = 2.6 Hz, 1H), 7.37–7.33 (m, 2H), 7.15–7.02
(m, 8H), 7.01–6.99 (m, 1H), 6.96–6.90 (m, 4H), 6.48 (dd,
J = 3.4, 1.8 Hz, 1H), 5.20 (s, 2H), 4.15 (t, J = 5.5 Hz,
2H), 3.91–3.79 (m, 4H), 2.88 (t, J = 5.5 Hz, 2H), 2.70–2.64
(m, 4H); 13C NMR (75 MHz, CDCl3): δ 158.3, 151.7, 148.0,
145.3, 143.7, 143.4, 141.9, 139.3, 134.1, 132.1, 131.0, 130.6,
129.5, 128.4, 127.7, 127.3, 126.9, 116.5, 114.6, 111.3, 65.9,
en-1-yl)phenoxy)ethyl)thiomorpholine(5h)
White solid, M.p. 135–136 C; IR (KBr) ν/cm 3035, 2921,
1
7
◦
−1
1
607, 1508, 1242, 1136; H NMR (300 MHz, CDCl3): δ
.89 (s, 1H), 7.70 (s, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.08
(
dd, J = 19.0, 4.9 Hz, 8H), 6.93 (dd, J = 9.9, 5.7 Hz, 4H),
5
2
1
1
.20 (s, 2H), 4.11 (t, J = 5.6 Hz, 2H), 2.86 (s, 6H), 2.75–
.66 (m, 4H); 13C NMR (126 MHz, CDCl3): δ 158.4, 151.8,
45.4, 143.4, 141.9, 139.3, 134.1, 132.0, 130.9, 130.6, 129.5,
57.2, 54.1; HRMS (ESI) calcd for C34H34O3N , 560.26318
5
+
[M+H] ; found, 560.26253.
28.4, 127.7, 127.3, 126.9, 114.6, 65.8, 58.0, 55.4, 54.1, 28.0;
(Z)-1-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
+
HRMS (ESI) calcd for C29H31ON4S, 483.22230 [M+H] ;
en-1-yl)phenoxy)ethyl)-4-phenylpiperazine(5m)
−
1
found, 483.22226.
Yellow oil; IR (KBr) ν/cm 3040, 2922, 1600, 1507, 1239,
1
(
-
Z)-1-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1
en-1-yl)phenoxy)ethyl)-4-methylpiperazine(5i)
1150; H NMR (500 MHz, CDCl3): δ 7.89 (s, 1H), 7.71 (s,
1H), 7.35 (d, J = 8.7 Hz, 2H), 7.30–7.23 (m, 4H), 7.14–7.01
(m, 7H), 6.94 (d, J = 7.7 Hz, 6H), 6.86 (t, J = 7.3 Hz, 1H),
5.21 (s, 2H), 4.18 (t, J = 5.7 Hz, 2H), 3.26–3.21 (m, 4H),
◦
−1
Yellow solid, M.p. 135–136 C; IR (KBr) ν/cm 2927,
1
1
(
6
609, 1506, 1245, 1169; H NMR (500 MHz, CDCl3): δ 7.89
s, 1H), 7.71 (s, 1H), 7.36–7.32 (m, 2H), 7.14–7.01 (m, 8H),
.95–6.89 (m, 4H), 5.20 (s, 2H), 4.15–4.10 (m, 2H), 2.85 (t,
1
3
2.90 (t, J = 5.6 Hz, 2H), 2.81–2.73 (m, 4H); C NMR (126
MHz, CDCl3): δ 158.4, 151.8, 151.3, 145.4, 143.4, 141.9,
139.3, 134.0, 132.1, 130.9, 130.6, 129.5, 129.2, 128.4, 127.7,
127.3, 126.9, 119.8, 116.2, 114.7, 66.0, 57.3, 54.1, 53.8, 49.2;
1
3
J = 5.7 Hz, 2H), 2.77–2.51 (m, 8H), 2.34 (s, 3H); C NMR
(75 MHz, CDCl3): δ 158.3, 151.6, 145.3, 143.3, 141.8, 139.2,
+
1
1
34.0, 131.9, 130.9, 130.6, 129.5, 128.4, 127.6, 127.2, 126.9,
HRMS (ESI) calcd for C H36ON , 542.29166 [M+H] ;
3
5
5
14.5, 65.7, 56.9, 54.3, 54.0, 52.7, 45.2; HRMS (ESI) calcd
found, 542.29176.
+
for C30H34ON , 480.27390 [M+H] ; found, 480.27384.
(Z)-1-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
5
(
Z)-1-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-
en-1-yl)phenoxy)ethyl)-4-(pyridin-2-yl)piperazine(5n)
◦
−1
en-1-yl)phenoxy)ethyl)-4-ethylpiperazine(5j)
White solid, M.p. 135–136 C; IR (KBr) ν/cm 2923, 1599,
−1
1
Yellow oil; IR (KBr) ν/cm 2929, 1606, 1508, 1245, 1138;
1507, 1243, 1150; H NMR (500 MHz, CDCl3): δ 8.19 (dd,
1
H NMR (300 MHz, CDCl3): δ 7.89 (s, 1H), 7.71 (s, 1H),
J = 4.9, 1.2 Hz, 1H), 7.88 (s, 1H), 7.70 (s, 1H), 7.48 (ddd,
J = 8.9, 7.2, 2.0 Hz, 1H), 7.37–7.33 (m, 2H), 7.14–7.02
(m, 8H), 6.96–6.91 (m, 4H), 6.67–6.61 (m, 2H), 5.20 (s,
2H), 4.19 (t, J = 5.5 Hz, 2H), 3.60 (s, 4H), 2.91 (t, J =
7
6
.34 (d, J = 8.6 Hz, 2H), 7.17–7.00 (m, 8H), 6.93 (t, J =
.8 Hz, 4H), 5.20(s, 2H), 4.13(t, J = 5.7 Hz, 2H), 2.91–2.33
1
3
(
m, 12H), 1.10 (t, J = 7.2 Hz, 3H); C NMR (126 MHz,
1
3
CDCl3): δ 158.4, 151.7, 145.4, 143.4, 141.9, 139.3, 133.9,
5.4 Hz, 2H), 2.74 (s, 4H); C NMR (126 MHz, CDCl3): δ
159.6, 158.4, 151.8, 148.0, 145.4, 143.4, 141.9, 139.3, 137.5,
134.0, 132.0, 130.9, 130.6, 129.5, 128.4, 127.7, 127.2, 126.9,
114.6, 113.4, 107.1, 66.0, 57.4, 54.1, 53.5, 45.2; HRMS
1
6
32.0, 130.9, 130.6, 129.5, 128.4, 127.7, 127.2, 126.9, 114.6,
5.9, 57.2, 54.1, 53.5, 52.7, 52.3, 11.9; HRMS (ESI) calcd
+
for C31H36ON , 494.28996 [M+H] ; found, 494.28983.
5
1
23

Mol Divers
+
(
5
(
ESI) calcd for C34H ON6, 543.28634 [M+H] ; found,
127.2, 127.0, 126.9, 114.6, 76.3, 66.0, 57.2, 54.1, 54.0, 51.9;
3
5
+
43.28658.
HRMS (ESI) calcd for C42H42ON , 632.33770 [M+H] ;
5
Z)-2-(4-(2-(4-(1,2-Diphenyl-3-(1H-1,2,4-triazol-1-yl)
prop-1-en-1-yl)phenoxy)ethyl) piperazin-1-yl)pyrimidine
5o)
found, 632.33769.
(
X-ray crystallographic data of compounds 4h, 4i and 5k
Crystal data for compound 4h C H N OS, M = 482.63,
−1
Yellow oil; IR (KBr) ν/cm 3031, 1588, 1506, 1245, 1149;
1
H NMR (300 MHz, CDCl3): δ 8.32 (t, J = 5.9 Hz, 2H),
2
9
30
4
3
7
7
5
2
.89 (s, 1H), 7.71 (s, 1H), 7.37 (t, J = 7.9 Hz, 2H), 7.16–
.01(m, 8H), 6.99–6.89 (m, 4H), 6.48 (t, J = 4.7 Hz, 1H),
.21 (s, 2H), 4.17 (t, J = 5.7 Hz, 2H), 3.92–3.82 (m, 4H),
colorless block, 0.42 × 0.40 × 0.31 mm , monoclinic, space
group Pc (No. 7), a = 8.8130(4) Å, b = 15.0717(8) Å, c =
◦
3
10.3342(5) Å, β = 112.0480(10) , V = 1272.28(11) Å ,
1
3
3
.88 (t, J = 5.7 Hz, 2H), 2.71–2.61 (m, 4H); C NMR (75
Z = 2, D = 1.260 g/cm , F
= 512, λ = 0.71073 Å,
c
000
MHz, CDCl3): δ 161.7, 158.4, 157.8, 151.7, 145.3, 143.4,
CCDareadetector, MoK αradiation, T = 293(2)K, 2θ
=
=
max
int
◦
1
1
41.9, 139.3, 134.0, 132.1, 130.9, 130.6, 129.6, 129.5, 128.4,
27.7, 127.2, 126.9, 114.6, 109.9, 65.9, 57.4, 54.1, 53.6, 43.7;
HRMS (ESI) calcd for C33H34ON7, 544.28177 [M+H] ;
50.0 , 12,027 reflections collected, 4461 unique (R
0.0204), final GooF = 1.046, R1=0.0283, wR2=0.0738,
+
R indices based on 4344 reflections with I > 2σ(I) (refine-
2
−1
found, 544.28179.
(
ment on F ), 316 parameters, μ = 0.156 mm , CCDC
Z)-1-(Benzo[d][1,3]dioxol-5-ylmethyl)-4-(2-(4-(1,2-
number 1028923.
diphenyl-3-(1H-1,2,4-triazol-1-yl)prop-1-en-1-yl)phenoxy)
Crystal data for compound 4i C H N O, M = 479.61,
3
0
33
5
3
ethyl)piperazine(5p)
colorless block, 0.43 × 0.38 × 0.26 mm , monoclinic, space
group Pn (No. 7), a = 9.1314(5) Å, b = 15.5515(9) Å, c =
−1
Yellow oil; IR (KBr) ν/cm 2923, 1605, 1505, 1244, 1138;
1
◦
3
H NMR (500 MHz, CDCl3): δ 7.88 (s, 1H), 7.71 (s, 1H),
10.3830(6) Å, β = 115.6080(10) , V = 1329.63(13) Å ,
3
7.37–7.31 (m, 2H), 7.15–7.01 (m, 8H), 6.96–6.88 (m, 4H),
Z = 2, D = 1.198 g/cm , F = 512, CCD area detector,
c
000
6
.85 (d, J = 6.0 Hz, 1H), 6.78–6.70 (m, 2H), 5.96–5.92
MoK α λ = 0.71073 Å, radiation, T = 293(2) K, 2θ
=
=
max
◦
(
m, 2H), 5.20 (s, 2H), 4.13 (q, J = 6.0 Hz, 2H), 3.44 (d,
50.0 , 12,624 reflections collected, 2349 unique (R
int
J = 4.1 Hz, 2H), 2.85 (t, J = 5.7 Hz, 2H), 2.76–2.40 (m,
0.0208), final GooF = 1.146, R1=0.0265, wR2=0.0709,
1
3
8
1
1
1
H); C NMR (126 MHz, CDCl3): δ 158.4, 151.8, 147.7,
46.7, 145.4, 143.4, 141.9, 139.3, 134.0, 132.0, 130.9, 130.6,
29.5, 128.4, 127.7, 127.2, 126.9, 122.4, 114.6, 109.7, 108.0,
R indices based on 2301 reflections with I > 2σ(I) (refine-
2
−1
ment on F ), 326 parameters, μ = 0.075 mm , CCDC
number 1028922.
01.0, 65.9, 62.8, 57.2, 54.1, 53.6, 52.8; HRMS (ESI) calcd
Crystal data for compound 5k C H N O , M = 507.62,
3
1
33
5
2
+
3
for C37H38O3N , 600.29795 [M+H] ; found, 600.29774.
colorless block, 0.49 × 0.38 × 0.33 mm , triclinic, space
5
¯
(
Z)-1-Benzyl-4-(2-(4-(1,2-diphenyl-3-(1H-1,2,4-triazol-1-
group P(1) (No. 2), a = 9.3539(7) Å, b = 10.3002(8) Å,
◦
◦
yl)prop-1-en-1-yl)phenoxy) ethyl)piperazine(5q)
c = 14.5900(11)Å, α = 104.8220(10) , β = 90.9440(10) ,
−
1
◦
3
Yellow oil; IR (KBr) ν/cm 3029, 2934, 1603, 1504, 1244,
γ = 90.1160(10) , V = 1358.72(18) Å , Z = 2, D =
c
1
3
1
1
4
136; H NMR (500 MHz,CDCl3): δ 7.88 (s, 1H), 7.71 (s,
H), 7.35–7.29 (m, 6H), 7.14–7.00 (m, 9H), 6.95–6.88 (m,
H), 5.20 (s, 2H), 4.12 (t, J = 5.8 Hz, 2H), 3.53 (s, 2H), 2.84
1.241 g/cm , F
= 540, CCD area detector, MoK α λ =
0
00
◦
0.71073 Å, radiation, T = 293(2) K, 2θ
max
= 50.0 , 13,168
reflections collected, 4788 unique (R = 0.0181), final
int
1
3
(
t, J = 5.8 Hz, 2H), 2.76–2.42(m, 8H); CNMR(126MHz,
GooF = 1.031, R1=0.0464, wR2=0.1191, R indices
2
CDCl3): δ 158.4, 151.8, 145.4, 143.4, 141.9, 139.3, 138.0,
based on 4093 reflections with I > 2σ(I) (refinement on F ),
−
1
133.9, 132.0, 130.9, 130.6, 129.5, 129.3, 128.4, 128.3, 127.7,
344 parameters, μ = 0.080 mm , CCDC number 1028921.
Experimental biology
1
27.2, 127.2, 126.9, 114.6, 65.9, 63.1, 57.2, 54.1, 53.7, 53.0;
+
HRMS (ESI) calcd for C36H38ON , 556.30793 [M+H] ;
5
found, 556.30775.
(Z)-1-Benzhydryl-4-(2-(4-(1,2-diphenyl-3-(1H-1,2,4-
Cell culture, maintenance, and antiproliferative evaluation
triazol-1-yl)prop-1-en-1-yl)phenoxy)ethyl)piperazine(5r)
◦
−1
White solid, M.p. 201–202 C; IR (KBr) ν/cm 3025, 2961,
1
(
The cell lines, SiHa, MDA-MB-231, PANC1, IMR-32, and
Hep G2 which were used in this study were procured
from American Type Culture Collection (ATCC), United
States. The synthesized test compounds were evaluated for
their in vitro antiproliferative activity against five differ-
ent human cancer cell lines. A protocol of 48-h continuous
drug exposure was used, and a sulforhodamine B (SRB)
cell proliferation assay was used to estimate cell viability
or growth. All cell lines were grown in Dulbecco’s mod-
1
604, 1507, 1249, 1136; H NMR (500MHz, CDCl3): δ 7.88
s, 1H), 7.70 (s, 1H), 7.41 (d, J = 7.7 Hz, 4H), 7.33 (d,
J = 8.4 Hz, 2H), 7.29–7.24 (m, 7H), 7.17 (t, J = 7.3 Hz,
2
6
2
H), 7.13–7.07 (m, 2H), 7.03 (t, J = 4.1 Hz, 4H), 6.95–
.86 (m, 4H), 5.19 (s, 2H), 4.22 (s, 1H), 4.14–4.08 (m,
1
3
H), 2.83 (s, 2H), 2.72–2.34 (m, 8H); C NMR (126 MHz,
CDCl3): δ 158.4, 151.8, 145.4, 143.4, 142.8, 141.9, 139.3,
34.0, 132.0, 130.9, 130.6, 129.5, 128.6, 128.4, 128.0, 127.7,
1
1
23

Mol Divers
ified Eagle’s medium (containing 10% fetal bovine serum
rial activity. The MTCC (Microbial Type Culture Collection)
cultures were provided by the Institute of Microbial Tech-
nology, Chandigarh. All the compounds were dissolved in
dimethylsulfoxide(DMSO)togetafinalconcentrationofone
mg/mL. The antibacterial potency of the compounds under
conditions was compared with the activity of the antibac-
terial drug vancomycin 50 μg/mL. In order to ensure that
the solvent had no effect on bacteria, a control test was also
performed with DMSO.
◦
(FBS) in a humidified atmosphere of 5% CO2 at 37 C). Cells
weretrypsinized whensub-confluent from T25flasks/60-mm
dishes and seeded in 96-well plates in 100 − μL aliquots at
plating densities depending on the doubling time of individ-
◦
ual cell lines. The microtiter plates were incubated at 37 C,
5
% CO2, 95% air, and 100% relative humidity for 24 h
prior to addition of experimental drugs and were incubated
for 48 h with different doses (0.01, 0.1, 1, 10, 100 μM) of
◦
the prepared derivatives. After 48-h incubation at 37 C, cell
monolayers were fixed by the addition of 10% (wt/vol) cold
trichloroaceticacid, incubatedat4 Cfor1h, andthenstained
Disk diffusion method
◦
with 0.057% SRB dissolved in 1% acetic acid for 30 min
at room temperature. Unbound SRB was washed with 1%
acetic acid. The protein-bound dye was dissolved in 10 mM
Tris base solution for OD determination at 510 nm using
a microplate reader (Enspire, Perkin Elmer, USA). Using
the seven absorbance measurements [time zero, (Tz), con-
trol growth, (C), and test growth in the presence of drug at
the five concentration levels (Ti)], the percentage growth was
calculated at each of the drug concentrations levels. Percent-
age growth inhibition was calculated as
The antibacterial activity of the synthesized compounds was
evaluated by the disk diffusion method. A standard inoculum
7
(1 − 2 × 10 cfu/mm 0.5 McFarland standards) was intro-
duced onto the surface of sterile agar plates, and a sterile
glass spreader was used for even distribution of the inocu-
lum. The disks measuring 6 mm in diameter were prepared
from Whatman no. 1 filter paper and sterilized by dry heat
◦
at 140 C for an hour. The sterile disks previously soaked
in a known concentration of the test compounds (in DMSO)
were placed in nutrient agar medium. Solvent and growth
controls were kept. The plates were inverted and incubated
◦
[
[
(Ti−Tz)/(C−Tz)] × 100 for concentrations for which Ti
/ = Tz
(Ti − Tz)/Tz] × 100 for concentrations for which Ti
Tz.
for 24 h at 37 C. After incubation, the zone of growth inhi-
bition was measured using a calibrated scale and expressed
in mm. Experiment was performed in triplicate to minimize
the deviations, and the average values are reported in Table 4.
>
<
Microdilution broth method
The dose–response parameters were calculated for each
experimental agent. Growth inhibition of 50% (GI50) was
calculated from [(Ti−Tz)/(C−Tz)] × 100 = 50, which is
the drug concentration resulting in a 50% reduction in the
net protein increase (as measured by SRB staining) in control
cells during the drug incubation. The values were calculated
for this parameter if the level of activity is reached; however,
if the effect is not reached or is exceeded, the value for that
parameter was expressed as greater or less than the maximum
or minimum concentration tested.
The minimal inhibitory concentration (MIC) values for the
tested compounds were determined using the microdilution
broth method. The inoculum of microorganisms was pre-
pared from 24-h broth cultures, and the suspensions were
adjusted to 0.5 McFarland standard turbidity. The test com-
pounds dissolved in DMSO were diluted to the highest
concentration (1000 μg/mL) to be tested. Then serial twofold
dilutions were made in the concentration range from 1.95 to
1000 μg/mL in 10-mL sterile tubes. A prepared suspension
of the standard microorganisms was added to each dilution
in a 1:1 ratio. Growth of the microorganisms was determined
visually after incubation for 24 h at 37 C. It corresponds to
the well with the lowest concentration of the tested substance
where microbial growth was clearly inhibited. The MIC val-
ues (in micro molars) are shown in Table 4.
Microorganisms and growth conditions
◦
The newly synthesized compounds were screened for their
antibacterial activity against three Gram-positive (B. subtilis
MTCC 736, B. megaterium MTCC 2412, M. luteus MTCC
106) and three Gram-negative (E. coli MTCC 40, S. typhi
Isolated strain, Pseudomonas aeruginosa MTCC 4673) bac-
terial strains by well diffusion method. The microdilution
method for estimation of MIC value (the lowest concen-
tration of compound required to inhibit the growth of the
tested microorganism) was applied to evaluate the antibacte-
Acknowledgments MRK is thankful to the Council of Scientific &
Industrial Research (CSIR), New Delhi, India, for the award of fellow-
ships. We thank CSIR for the financial support under the 12th Five Year
plan projects “Affordable Cancer Therapeutics (ACT)” (CSC 0301) and
“Screening Molecules in Lead Exploration (SMiLE)” (CSC 0111).
1
23

Mol Divers
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