1,2,3-Triazole tethered β-lactam-Chalcone bifunctional hybrids: Synthesis and anticancer evaluation

Article abstract of DOI:10.1016/j.ejmech.2011.10.033

The manuscript describes the synthesis of novel 1,2,3-triazole tethered β-lactam-chalcone bifunctional hybrids via click chemistry approach utilizing azide-alkyne cycloaddition reactions and their evaluation as anticancer agents against four human cancer

Full text of DOI:10.1016/j.ejmech.2011.10.033

European Journal of Medicinal Chemistry 47 (2012) 594e600
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
1,2,3-Triazole tethered b-lactam-Chalcone bifunctional hybrids:
Synthesis and anticancer evaluation
,
a,
Pardeep Singh a, Raghu Raj a, Vipan Kumar a , Mohinder P. Mahajan d, P.M.S. Bedi b, Tandeep Kaur c,
*
A.K. Saxena c
a Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India
b Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, India
c Cancer Pharmacology Division, Indian Institute of Integrative Medicine, Jammu 180001, J & K, India
d Apeejay Stya Research Foundation, Gurgaon, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The manuscript describes the synthesis of novel 1,2,3-triazole tethered b-lactam-chalcone bifunctional
hybrids via click chemistry approach utilizing azide-alkyne cycloaddition reactions and their evaluation
as anticancer agents against four human cancer cell lines. The presence of a cyclohexyl substituent at N-1
Received 8 August 2011
Received in revised form
28 September 2011
Accepted 14 October 2011
Available online 21 October 2011
of
b-lactam ring and methoxy substituents, preferably ortho on ring A and para on ring B on chalcones
markedly improved the anticancer profiles of the synthesized scaffolds with the most potent of the test
compound exhibiting an IC50 value of <1, 67.1, <1 and 6.37 mM against A-549(lung), PC-3(prostate), THP-
1(leukemia), and Caco-2(colon) cell lines, respectively.
Keywords:
Ó 2011 Elsevier Masson SAS. All rights reserved.
Bifunctional hybrids
b-Lactam
Chalcone
Anticancer evaluation
Triazole
1. Introduction
drugs with different mechanisms or by single chemical entity that
could modulate several targets of a multi-factorial disease. As
a result, there is increasing interest in the discovery of agents that
concomitantly address more than one biological target for cancer
treatment [7,8].
Cancer, the uncontrolled, rapid and pathological proliferation of
abnormal cells, is one of the most formidable afflictions in the
world [1,2]. Despite immense advances in the field of basic and
clinical research, which have resulted in higher cure rates for
a number of malignancies, cancer remains the second leading cause
of death after heart disorders in developing as well as advanced
countries. Many of the currently available anticancer drugs are
unable to differentiate between normal and neoplastic cells or to
overcome primary or secondary resistance mechanisms evolved in
the cancer cells. Thus, there is a pressing need for new anticancer
agents with high potency, less toxicity in non-cancerous cells, and
unique targets of action [3]. Currently, cancer therapy interfering
with a single biological molecule or pathway has been successfully
utilized [4]. However, there is general belief that agents modulating
more than one target could have superior efficacy compared to
single target drugs [5,6]. Therefore, modulating multiple targets
simultaneously can be achieved by the combination of multiple
Molecular hybridization is the rational design of new chemical
entities by the fusion of two drugs, both active compounds and/or
pharmacophoric units recognized and derived from known bioac-
tive molecules [9,10]. Pharmacophore hybridization is believed to
be analogous to conventional combination therapy, with the
exception that the two drugs are covalently linked and available as
a single entity [11]. The selection of the two principles in the dual
drug is usually based on their observed (or anticipated) synergistic
or additive pharmacological activities to enable the identification of
highly active novel chemical entities. Chalcones (1,3-diaryl-2-
propen-1-ones) constitute an important class of natural products
belonging to the flavonoids family, display interesting biological
activities [12e17]. The appeal of working with chalcones stems
from their synthetic accessibility, the various ways the core struc-
ture can be diversified and their ability to confer drug-like prop-
erties to compound libraries modelled on them [18]. Chalcones
received significant attention for their anti-tumor properties,
particularly in view of their similar mode of action to the
* Corresponding author. Tel.: þ91 183225880209x3320; fax: þ91 183225881920.
E-mail address: vipan_org@yahoo.com (V. Kumar).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.10.033

P. Singh et al. / European Journal of Medicinal Chemistry 47 (2012) 594e600
595
structurally related natural combretastatin [19]. Recent studies
have shown that triazole based chalcone-pyrrolo[2,1-c] [1,4]
benzodiazepine (PBD) hybrids resulted in G1 cell cycle arrest and
exhibited inhibitory effect on NF-kB, Bcl-XL proteins which are vital
for breast cancer cell proliferation [20]. Chalcone is also considered
to be a promising template to develop inhibitors of HIF-1 [21],
a major mechanism for the survival and evasion of tumor cells.
Triazoles constitute another important class of heterocycles
because of their varied biological activities [22] and being regarded
as an interesting unit with significant anticancer profile in many of
the human cell lines [23e25]. The triazoles are more than just
passive linkers, and confer properties like moderate dipole char-
acter, hydrogen bonding capability, rigidity and stability under
in vivo conditions [26].
b-lactams with functionalized chalcones via azide-alkyne cyclo-
addition reaction (Fig. 1) and their evaluation as anticancer agents
against four human cancer cell lines viz. A-549(lung), PC-
3(prostate), THP-1(leukemia), and Caco-2(colon).
2. Synthetic chemistry and pharmacology
2.1. Synthetic chemistry
The acetylenic chalcones (1aec, 2aeb and 3) required for the
synthesis of desired target compounds were prepared according to
reported procedures [31] while 3-azido-2-azetidinones (4 and 5)
were synthesized by Staudinger reaction of appropriately func-
tionalized 1-azadienes with azido-ketene[29]. The target
compounds (6e11) were synthesized by utilizing azide-alkyne
cycloaddition reaction of appropriate precursors in the presence
of CuSO4.5H2O/sodium ascorbate in ethanol: water mixture. The
methodology involved the initial stirring of an equimolar mixture
of acetylenic chalcones (1aec or 2aeb) or acetylenic vanillin 3 with
3-azido-2-azetidinones (4, 5) in ethanol: water mixture with
subsequent addition of CuSO4$5H2O (0.05 mmol) and sodium
ascorbate (0.13 mmol) (Schemes 1 and 2). The reaction mixture was
stirred at room temperature for 7e8 h and the progress was
monitored using tlc. The purification of the reaction mixture, after
usual work up, via column chromatography resulted in the isolation
of desired scaffolds, the structures to which are assigned on the
basis of spectral data and analytical evidences.
b-Lactam compounds are ‘evergreen’ bioactive molecules with
activity ranging from the antimicrobial potency of naturally
occurring bicyclic compounds (penicillins and cephalosporins), to
the new variants with monocyclic structure (azetidinones) having
specific biological activities. Since, b-lactams are widely and safely
used without significant toxicity, synthesis and utilization of these
molecules as new, novel anticancer agents could be timely and
significant. Recent relevant studies on b-lactams have shown their
potential as anti-tumor agents against a number of human tumor
and normal cell lines [27]. The 1,4-diaryl-2-azetidinones specifi-
cally, have shown anti-proliferative activity against the MCF-7 and
MDA-MB-231 human breast carcinoma cell lines exerting anti-
mitotic effects through inhibition of tubulin polymerisation and
subsequent G2/M arrest of the cell cycle [28].
Recent revelation from our lab has shown triazole tethered 2-
azetidinones as potential anticancer agent against different
human cancer cell lines with marked dependency of activity on the
2.2. Pharmacology
The human cancer cell lines were procured from National
Cancer Institute, Frederick, PO Box B, Frederick, MD 21702-1201,
U.S.A. Cells were grown in tissue culture flasks in complete growth
medium (RPMI-1640 medium with 2 mM glutamine, pH 7.4, sup-
substituents at N-1 of the b-lactam ring and C-3 substituted triazole
ring [29]. In continuation of our pursuit towards the synthesis of
biologically potent novel functional entities [30], we report herein
the synthesis of 1,2,3-triazole tethered novel bifunctional hybrids of
plemented with 10% fetal calf serum, 100 mg/ml streptomycin and
O
O
R1
O
MeO
O
N
R
R
N3
O
Hybridization
O
O
MeO
O
B
R
A
R
A
B
O
N
N
N
R = -OCH3
N
N
N
4, R1 = Cyclohexyl
5, R1 = p-tolyl
O
O
N
N
R1
R1
Fig. 1. General structure of lead compound and target hybrid compounds

596
P. Singh et al. / European Journal of Medicinal Chemistry 47 (2012) 594e600
O
O
MeO
O
MeO
O
R
R
N
N
N
N
N
O
N
MeO
O
O
O
R
N
N
1a-c
7 a-c
CH3
6 a-c
( i )
O
O
O
R
R
O
O
R
N
N
O
N
N
N
N
2 a-b
O
O
N
N
CH3
8 a-b
9 a-b
Scheme 1. Reagent and conditions: (i) 4 (for 6aec and 8aeb) or 5 (for 7aec and 9aeb), Sodium ascorbate (0.13 mmol), CuSO4$5H2O (0.05 mmol), EtOH/H2O, rt, 8 h.
100 units/ml penicillin) in a carbon dioxide incubator (37 ꢀC, 5%
CO2, 90% RH). The cells at subconfluent stage were harvested from
the flask by treatment with trypsin [0.05% in PBS (pH 7.4) con-
taining 0.02% EDTA]. Cells with viability of more than 98% as
determined by trypan blue exclusion, were used for determination
of cytotoxicity. The cell suspension of 1 ꢁ105 cells/ml was prepared
in complete growth medium. Stock solutions (2 ꢁ 10ꢂ2 M) of
compounds were prepared in DMSO. The stock solutions were
complete growth medium (100 ml) were added after 24 h of incu-
bation to the wells containing cell suspension. The plates were
further incubated for 48 h in a carbon dioxide incubator. The cell
growth was stopped by gently layering trichloroacetic acid (50%,
50 ml) on top of the medium in all the wells. The plates were
incubated at 4 ꢀC for 1 h to fix the cells attached to the bottom of the
wells. The liquid of all the wells was gently pipetted out and dis-
carded. The plates were washed five times with distilled water to
remove trichloroacetic acid, growth medium low molecular weight
metabolites, serum proteins, etc. and air-dried. The plates were
serially diluted with complete growth medium containing 50 mg/ml
of gentamycin to obtain working test solutions of required
concentrations.
stained with Sulforhodamine B dye (0.4% in 1% acetic acid, 100 ml)
In vitro cytotoxicity against human cancer cell lines of different
tissues was determined [32,33] using 96-well tissue culture plates.
for 30 min. The plates were washed five times with 1% acetic acid
and then air-dried [33]. The adsorbed dye was dissolved in TriseHCl
The 100
ml of cell suspension was added to each well of the 96-well
Buffer (100 ml, 0.01 M, pH 10.4) and plates were gently stirred for
tissue culture plate. The cells were allowed to grow in carbon
10 min on a mechanical stirrer. The optical density (OD) was
recorded on ELISA reader at 540 nm. The cell growth was
dioxide incubator (37 ꢀC, 5% CO2, 90% RH) for 24 h. Test materials in
O
O
MeO
O
H
MeO
O
H
O
O
N
MeO
O
H
N
MeO
HO
H
( ii )
( i )
N
N
N
N
O
O
N
N
Vanilline
3
CH3
11
10
Scheme 2. Reagent and conditions: (i) K2CO3, DMF, propargyl bromide, rt, 12 h (ii) 4 (for 10) or 5 (for 11), sodium ascorbate (0.13 mmol), CuSO4$5H2O (0.05 mmol), EtOH/H2O, rt,
8 h.

P. Singh et al. / European Journal of Medicinal Chemistry 47 (2012) 594e600
597
determined by subtracting mean OD value of respective blank from
the mean OD value of experimental set. Percent growth in presence
of test material was calculated considering the growth in absence of
any test material as 100% and in turn percent growth inhibition in
presence of test material was calculated.
shown better cytotoxic activity compared to N-aryl-
b
-lactams
(7ae7c) against all the cell lines tested. The trend reverses on
comparing 8aeb and 9aeb where N-aryl substituted bifunctional
hybrids showed better growth inhibition than their cyclohexyl
counterparts. Further, vanillin based chalcones (6aec and 7aec)
showed better growth inhibition compared to 8aeb and 9aeb
which might be either because of the presence of an ortho-
methoxy substituent on ring A.
3. Result and discussions
The presence of methoxy substituent and its position on ring B
has shown to play an important role on the observed growth inhi-
bition. Evidently, a single methoxy group on ring B, preferably at the
para-position considerably improves the activity profile (compare
6a and 6b) while a decrease in activity has been observed especially
in case of PC-3 and THP-1 cell lines when un-substituted phenyl ring
B was employed (6c). The favourable effect of 4-methoxy on activity
profiles is further authenticated on comparing 7a and 7b especially
in case of Caco-2 cell lines. As illustrated in Table 1, the introduction
of an additional methoxy group at ortho position in case of 7b
resulted in the decrease in activity in case of Caco-2 cell lines.
However the compound 7c (un-substituted ring B) shows an
exception and was found to be more potent than 7a and 7b in case of
A-549 cell line and was also more potent than 7a and 7b in case of
Caco-2 cell line especially at higher concentrations. A comparison
The synthesized b-lactam-chalcone hybrids were evaluated for
their anticancer activity against four human cancer cell lines viz. A-
549(lung), PC-3 (prostate), THP-1(leukemia) and Caco-2 (colon)
using sulforhodamine B assay. The concentration dependent cyto-
toxicity of these scaffolds against human cancer cell lines is shown
in Table 1. Paclitexal has been used as standard in case of lung (A-
549), 5-fluorouracil in case of THP-1(leukemia) and Caco-2(colon)
while mitomycin in case of PC-3(prostate). As evident from
Table 1, the tested compounds were not as active as paclitexal and
mitomycin C in terms of %age growth inhibition against A-549 and
PC-3 cell lines. However, the compound 6a has shown twice the %
growth inhibition than 5-fluorouracil in case of THP-1 cell line and
comparable growth inhibition with 5-fluorouracil against Caco-2
cell lines. The careful analysis of Table 1 reveals interesting struc-
ture activity relationship (SAR) and substituent effect with
between activity profiles of 10 and 11 (vanillin tethered b-lactams)
revealed that compound 10 with N-cyclohexylsubstituent was more
considerable % growth inhibition at 10 mM. The compounds with
cyclohexyl substituent (6ae6c) on Nꢂ1 of
b-lactam ring have
Table 1
In vitro cytotoxicity against human cancer cell lines.
Compound
R
Concentration
Tissues
A549
2
ꢀ
PC-3
THP-1
Caco-2
C log P
6.72
PSA (A )
%age growth inhibition
6a
6b
6c
7a
7b
7c
8a
8b
9a
9b
10
11
4-OCH3
2,4-OCH3
H
10
50
100
10
50
100
10
50
100
10
50
100
10
50
100
10
50
100
10
50
100
10
50
100
10
89
93
95
68
78
85
39
67
82
0
10
33
79
29
40
43
0
1
15
1
17
23
10
18
18
15
21
26
0
76
78
83
61
71
77
5
11
28
3
54
57
72
16
49
99
27
36
61
26
28
47
0
95.78
6.81
6.80
7.27
7.36
7.35
7.04
7.04
7.59
7.59
4.73
5.28
105.01
86.55
95.78
105.01
86.55
86.55
86.55
86.55
86.55
86.55
86.55
4-OCH3
2,4-OCH3
H
10
11
4
6
11
11
14
25
0
1
20
0
0
10
8
11
22
2
15
23
26
74
83
15
49
80
0
0
0
4
27
77
18
46
55
0
0
10
9
44
98
10
25
47
33
38
65
7
4-OCH3
2-OCH3
4-OCH3
2-OCH3
0
22
17
28
37
8
8
9
8
10
14
7
19
39
12
38
54
e
0
0
11
73
93
43
50
84
39
62
64
45
53
61
69
e
50
100
10
50
100
10
50
100
10
4
6
0
0
3
10
12
25
0
22
53
e
50
32
42
e
100
1
Paclitaxel
5-Flourouracil
Mitomycin-C
20
1
e
70
e
68
e
e
60

598
P. Singh et al. / European Journal of Medicinal Chemistry 47 (2012) 594e600
potent than 11 in case of Caco-2 cell lines while compound 11 with
N-aryl substituent was observed to be more potent than 10 in case of
PC-3 and THP-1 cell lines.
indicated as s: singlet, d: doublet, t: triplet, m: multiplet, dd: double
doublet, ddd: doublet of a doublet of a doublet, and br: broad peak.
13C NMR spectra were recorded on Jeol 300 (75 MHz) spectrome-
ters in deuterochloroform using TMS as internal standard. Mass
spectra were recorded on Shimadzu GCMS-QP-2000 mass spec-
trometer. Elemental analyses were performed on Heraus CHN-O-
Rapid Elemental Analyzer. Column chromatography was per-
formed on a silica gel (60e120 mesh). All the starting materials as
well as the products were racemates.
The IC50 values, which is the concentration required to inhibit
50% of cell viability by the test compounds after exposure to cells, of
the test compounds against the human cell lines werecalculatedand
the results are summarized in Table 2. Most of the compounds have
show activity on A-549 and Caco-2 cell lines except 7a, 7b and 8b.
The tested compounds proved to be inactive against PC-3 and THP-1
cell lines except 6a and 6b. The vanillin based bifunctional hybrid 6a
with N-cyclohexyl substituent showed best IC50 value among the
4.1. General method for the preparation of compounds 6, 7, 8, and 9
tested compounds with values of <1, 67.1, <1 and 6.37 mM against A-
549, PC-3, THP-1 and Caco-2 cell lines. The compound 6b showed
a poor activity compared to 6a except in case of A-549 cell lines
where it has the comparable activity profile with 6a. The further
decrease in activity observed in case of 6c is indicative of the role of
methoxy substituent on the desired cytotoxicity.
To a stirred solution of appropriate acetylenic chalcone 1 or 2
(1 mmol) in ethanol-water mixture and azide 4 or 5 (1 mmol) was
added added copper sulphate (0.05 mmol) and sodium ascorbate
(0.13 mmol). The reaction mixture was allowed to stir at room
temperature for 8 h and the progress was monitored using tlc. After
the completion of reaction, water (25 ml) was added and the
reaction mixture was extracted twice with dichloromethane
(2 ꢁ 30 ml). The combined organic layers were dried over anhy-
drous sodium sulphate and concentrated under reduced pressure
to yield a crude product which was purified via column chroma-
tography using 50:50 (EtOAc: hexane) mixture.
Thus, the present communication describes the synthesis of
a range of triazole tethered bifunctional hybrids of b-lactam with
chalcones and their evaluation against a panel of four human
cancer cell lines. The preliminary studies show that most of these
compounds are active against A-549 and Caco-2 cell lines but only
two of the tested compounds viz. 6a and 6b showed cytotoxic
activity against PC-3 and THP-1 cell lines. The compound 6a proved
to be nearly twice as active as 5-flourouracil in case of THP-1 cell
lines. These preliminary results indicate a marked dependence of
cytotoxicity on the presence of cyclohexyl/aryl substituent on N-1
4.1.1. 1-Cyclohexyl-3(RS)-(4-{2-methoxy-4-[3-(4-methoxy-
phenyl)-3-oxo-propenyl]-phenoxymethyl}-[1,2,3]triazol-1-yl)-
4(SR)-styryl-azetidin-2-one(6a)
of the
b
-lactam and 4-methoxy substituent on ring B of the chal-
Yield 84%; yellow solid; mp120-122 ꢀC; IR nmax (KBr)/cmꢂ1
:
cone. Further, vanillin based chalcones showed better activity
profiles compared to other analogues suggestive of the importance
of 2-methoxy on ring A in improving cytotoxic profiles. Based on
these observations, the compound 6a may be considered as a good
hit in terms of %age growth inhibition, IC50, C log P (6.72) and PSA
1742,1513,1689. 1H NMR (CDCl3, 300 MHz):
d 1.23e1.96 (m, 10H,
cyclohexyl H), 3.58 (m, 1H, cyclohexyl H), 3.91 (s, 6H, 2x-OCH3),
4.72 (dd, 5.1 Hz, 8.7 Hz, 1H, Hb), 5.33 (s, 2H, eOCH2e), 5.65 (dd,
8.7 Hz, 15.6 Hz, 1H, Hc), 5.99 (d, 5.1 Hz, 1H, Ha), 6.64(d, 15.6 Hz, 1H,
Hd), 6.93e7.26(m, 10H, eArH), 7.36(d, 15.6 Hz, 1H, He), 7.69 (d,
15.6 Hz, 1H, Hf), 7.79 (s, 1H, triazole-H) 8.03 (d, 9.0 Hz, 2H, eArH),
13C NMR (CDCl3, 75 Hz): 22.4, 27.4, 30.9, 47.5, 50.2, 55.9, 56.0, 65.3,
72.5, 113.0, 114.5, 115.3, 116.2, 118.6, 123.4,124.5 126.1, 127.3, 128.2,
128.4, 129.2, 130.6, 132.3, 134.9, 142.9, 145.3, 146.7, 147.8, 166.9,
172.3, 186.9. MS m/z 619 (M)þ. Analysis calculated for C37H38N4O5:
C, 71.82; H, 6.19; N, 9.06. Found: C, 71.79; H, 6.15; N, 9.02.
2
ꢀ
(95.78 A ) [34] values. Further studies in order to generalize,
substantiate and improve the activity profiles of the scaffolds are
underway in the lab and will soon be communicated.
4. Experimental section
Melting points were determined by open capillary using Veego
Precision Digital Melting Point apparatus (MP-D) and are uncor-
rected. IR spectra were recorded on a Shimadzu D-8001 spectro-
photometer. 1H NMR spectra were recorded in deuterochloroform
with Jeol 300 (300 MHz) spectrometers using TMS as internal
standard. Chemical shift values are expressed as parts per million
downfield from TMS and J values are in hertz. Splitting patterns are
4.1.2. 1-Cyclohexyl-3(RS)-(4-{4-[3-(2,4-dimethoxy-phenyl)-3-oxo-
propenyl]-2-methoxy-phenoxymethyl}-[1,2,3]triazol-1-yl)-4(SR)-
styryl-azetidin-2-one(6b)
Yield 85%; yellow solid; mp 112e114 ꢀC; IR nmax (KBr)/cmꢂ1: 1738,
1520, 1688. 1H NMR (CDCl3, 300 MHz):
d 1.09e1.96 (m, 10H, cyclo-
hexyl ring), 3.56 (m, 1H, cyclohexyl ring), 3.90 (s, 9H, 3 eOCH3), 4.71
(dd, 5.4 Hz, 8.4 Hz, 1H, Hb), 5.34(s, 2H, eOCH2e), 5.66 (dd, 8.4 Hz,
15.9 Hz, 1H, Hc), 5.97 (d, 5.4 Hz, 1H, Ha), 6.65 (d, 15.9 Hz, 1H, Hd),
6.92e7.28 (m, 9H, eArH), 7.36 (d,15.6 Hz,1H, He), 7.69 (d,15.6 Hz,1H,
Hf), 7.79 (s,1H, triazole-H) 8.04 (d, 8.7 Hz, 2H, eArH),13C NMR (CDCl3,
75 Hz): 22.3, 27.5, 31.0, 47.6, 51.0, 55.2, 55.9, 56.2, 65.4, 72.5, 102.0,
105.1, 113.1, 114.7, 115.7, 117.7, 123.3, 126.0, 127.3, 124.5, 127.0, 128.5,
129.2, 131.3, 131.0, 135.6, 143.1, 145.2, 146.7, 147.7, 165.8, 167.3, 172.4,
186.9. MS m/z 649 (M)þ. Analysis calculated for C38H40N4O6: C, 70.35;
H, 6.21; N, 8.64. Found: C, 70.47; H, 6.33; N,8.60.
Table 2
IC50 determination of cytotoxicity of compounds against human cancer cell lines
Compound
R
Tissues
Lung
Prostate
PC-3
Leukemia
THP-1
Colon
A-549
Caco-2
IC50 (mM)
6a
6b
6c
7a
7b
7c
8a
8b
9a
9b
10
11
4-OCH3
2,4-OCH3
H
4-OCH3
2,4-OCH3
H
4-OCH3
2-OCH3
4-OCH3
2-OCH3
<1
<1
67.1
<1
1.39
6.37
45.2
79.5
>100
>100
75.1
71.9
>100
53.8
>100
64
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
83.2
4.1.3. 1-Cyclohexyl-3(RS)-{4-[2-methoxy-4-(3-oxo-3-phenyl-
propenyl)-phenoxymethyl]-[1,2,3]triazol-1-yl}-4(SR)-styryl-
azetidin-2-one (6c)
21.2
>100
>100
31.5
52
>100
43.9
22.8
26.9
24.7
>100
>100
>100
>100
>100
>100
>100
>100
>100
89.3
Yield 78%; yellow solid; mp 113e115 ꢀC; IR nmax (KBr)/cmꢂ1
:
1745,1584,1692. 1H NMR (CDCl3, 300 MHz):
d 1.23e1.99 (m, 10H,
cyclohexyl ring), 3.58 (m, 1H, cyclohexyl ring), 3.91 (s, 3H, eOCH3),
4.73 (dd, 5.1 Hz, 9.0 Hz, 1H, Hb), 5.33 (s, 2H, eOCH2e), 5.64 (dd,
9.0 Hz, 15.3 Hz, 1H, Hc), 5.98 (d, 5.1 Hz, 1H, Ha), 6.64(d, 15.3 Hz, 1H,
Hd), 6.93e7.26(m, 11H, eArH), 7.36(d, 15.6 Hz, 1H, He), 7.68 (d,
>100

P. Singh et al. / European Journal of Medicinal Chemistry 47 (2012) 594e600
599
15.6 Hz, 1H, Hf), 7.79 (s, 1H, triazole-H) 8.01 (d, 7.5 Hz, 2H, eArH),
13C NMR (CDCl3, 75 Hz): 22.4, 27.4, 30.9, 47.5, 50.2, 55.9, 65.3, 72.5,
113.0, 114.6, 115.3, 118.6, 121.5, 123.4, 124.4, 126.1, 127.3, 128.2, 128.4,
129.2, 130.6, 132.4, 134.2, 134.9, 142.9, 145.3, 146.6, 147.9, 172.3,
187.2. MS m/z 619 (M)þ. Analysis calculated for C36H36N4O4: C,
73.45; H, 6.16; N, 9.52. Found: C, 73.49; H, 6.26; N, 9.47.
7.96 (d, 8.4 Hz, 2H, eArH), 13C NMR (CDCl3, 75 Hz): 22.3, 27.4,
30.8, 47.5, 50.1, 55.9, 65.3, 72.4, 113.0, 114.6, 115.3, 118.6, 123.4, 126.1,
127.4, 128.2, 128.4, 129.1, 130.5, 132.4, 134.9, 142.8, 145.2, 147.6,
146.9, 163.2, 172.3, 186.9. MS m/z 619 (M)þ. Analysis calculated for
C36H36N4O4: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.61; H, 6.26; N,
9.42.
4.1.4. 3(RS)-(4-{2-Methoxy-4-[3-(4-methoxy-phenyl)-3-oxo-
propenyl]-phenoxymethyl}-[1,2,3]triazol-1-yl)-4(SR)-styryl-1-p-
tolyl-azetidin-2-one(7a)
4.1.8. 1-Cyclohexyl-3(RS)-(4-{4-[3-(2-methoxy-phenyl)-acryloyl]-
phenoxymethyl}-[1,2,3]triazol-1-yl)-4(SR)-styryl-azetidin-2-
one(8b)
Yield 83%; yellow solid; mp 137e139 ꢀC; IR nmax (KBr)/
Yield 80%; yellow solid; mp 127e129 ꢀC; IR nmax (KBr)/cmꢂ1
:
cmꢂ1:1752, 1517, 1693. 1H NMR (CDCl3, 300 MHz):
d
2.32 (s, 3H,
1735, 1523, 1689. 1H NMR (CDCl3, 300 MHz):
d 1.09e1.98 (m, 10H,
eCH3), 3.91 (s, 6H, 2xeOCH3), 5.19 (dd, 4.5 Hz, 7.8 Hz, 1H, Hb), 5.24
(s, 2H, eOCH2e), 5.81 (dd, 7.5 Hz, 15.6 Hz, 1H, Hc), 6.25 (d, 4.5 Hz,
1H, Ha), 6.72 (d, 15.6 Hz, 1H, Hd), 6.93e7.26 (m, 14H, eArH), 7.36 (d,
15.6 Hz, 1H, He), 7.69 (d, 15.6 Hz, 1H, Hf), 7.79 (s, 1H, triazole-H) 8.03
(d, 9.0 Hz, 2H, eArH), 13C NMR (CDCl3, 75 Hz): 20.9, 50.6, 55.9, 56.2,
65.4, 72.4, 113.3, 114.6, 115.4, 117.8, 121.3, 123.1, 124.3, 126.2, 127.6,
128.1, 128.7, 129.0, 129.3, 130.8, 131.2, 132.3, 133.6, 135.1, 138.6,
143.4, 145.6, 146.6, 147.8, 166.9, 172.2, 186.8. MS m/z 627 (M)þ.
Analysis calculated for C38H34N4O5: C, 71.82; H, 6.19; N, 9.06.
Found: C, 71.93; H, 6.08; N, 9.00.
cyclohexyl H), 3.56 (m, 1H, cyclohexyl H), 3.91 (s, 3H, eOCH3), 4.75
(dd, 5.1 Hz, 8.7 Hz, 1H, Hb), 5.31 (s, 2H, eOCH2e), 5.66 (dd, 8.7 Hz,
15.9 Hz, 1H, Hc), 5.95 (d, 5.1 Hz, 1H, Ha), 6.60 (d, 15.9 Hz, 1H, Hd),
6.85e7.40 (m, 9H, eArH), 7.39 (d, 15.9 Hz, 1H, He), 7.60 (d, 7.5 Hz,
2H, eArH), 7.79 (s,1H, triazole-H), 7.96 (d, 7.5 Hz, 2H, eArH),8.09 (d,
15.9 Hz, 1H, Hf), 13C NMR (CDCl3,75 Hz): 22.4, 27.4, 30.9, 47.4, 50.2,
55.9, 65.2, 72.4, 113.0, 114.6, 115.3, 118.6, 121.5, 121.7, 123.4, 126.1,
127.3, 128.2, 128.4, 129.1, 130.6, 132.4, 134.9, 142.9, 145.3, 147.6,
146.9, 158.8, 172.3, 186.8. MS m/z 589 (M)þ. Analysis calculated for
C36H36N4O4: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.51; H, 6.07; N,
9.41.
4.1.5. 3(RS)-(4-{4-[3-(2,4-Dimethoxy-phenyl)-3-oxo-propenyl]-2-
methoxy-phenoxymethyl}-[1,2,3]triazol-1-yl)-4(SR)-styryl-1-p-
tolyl-azetidin-2-one(7b)
4.1.9. 3(RS)-(4-{4-[3-(4-Methoxy-phenyl)-acryloyl]-
phenoxymethyl}-[1,2,3]triazol-1-yl)-4(SR)-styryl-1-p-tolyl-
azetidin-2-one(9a)
Yield 80%; yellow solid; mp 133e135 ꢀC; IR nmax (KBr)/cmꢂ1
:
1750, 1521, 1692. 1H NMR (CDCl3, 300 MHz):
d
2.32 (s, 3H, eCH3),
Yield 80%; Yellow solid; mp 136e138 ꢀC; IR nmax (KBr)/cmꢂ1
:
3.90 (s, 9H, 3xeOCH3), 5.17 (dd, 5.1 Hz, 7.8 Hz, 1H, Hb), 5.25 (s, 2H,
eOCH2e), 5.80 (dd, 7.8 Hz, 15.9 Hz, 1H, Hc), 6.23 (d, 5.1 Hz, 1H, Ha),
6.72 (d, 15.9 Hz, 1H, Hd), 6.91e7.25(m, 13H, eArH), 7.36 (d, 15.6 Hz,
1H, He), 7.69 (d, 15.6 Hz, 1H, Hf), 7.79 (s, 1H, triazole-H) 8.02 (d,
8.7 Hz, 2H, eArH), 13C NMR (CDCl3, 75 Hz): 21.0, 50.3, 55.7, 56.1,
56.7, 65.3, 72.5, 101.3, 107.3, 112.9, 113.6, 116.1, 118.4, 119.8, 122.3,
123.5, 124.2, 127.4, 128.1, 128.5, 129.3, 129.5, 131.1, 132.4, 133.6,
135.8, 137.4, 143.8, 144.9, 146.8, 148.5, 165.9, 167.5, 172.2, 187.0. MS
m/z 657 (M)þ. Analysis calculated for C39H36N4O6: C, 71.33; H, 5.53;
N, 8.53. Found: C, 71.47; H, 5.58; N, 8.40.
1750,1527,1689. 1H NMR (CDCl3, 300 MHz):
d 2.32 (s, 3H, -CH3), 3.90
(s, 3H, eOCH3), 5.17 (dd, 5.4 Hz, 8.7 Hz, 1H, Hb), 5.24 (s, 2H,
eOCH2e), 5.80 (dd, 8.7 Hz, 15.9 Hz, 1H, Hc), 6.26 (d, 5.4 Hz, 1H, Ha),
6.70 (d, 15.9 Hz, 1H, Hd), 6.92e7.42 (m, 15H, eArH), 7.59 (d, 15.9 Hz,
1H, He), 7.83 (s, 1H, triazole-H) 7.94 (d, 8.7 Hz, 2H, eArH), 8.09 (d,
15.9 Hz, 1H, Hf), 13C NMR (CDCl3, 75 Hz), 20.7, 50.5, 55.9, 65.2, 72.5,
112.9, 115.0, 115.2, 117.7, 121.2, 122.4, 125.8, 126.7, 128.0, 128.6, 129.3,
129.6, 131.5, 132.7, 134.1, 134.9, 136.7, 143.9, 146.1, 147.6, 149.1, 167.3,
172.3, 186.3. MS m/z 597 (M)þ. Analysis calculated for C37H32N4O4:
C, 74.48; H, 5.41; N, 9.39. Found: C, 74.61; H, 5.56; N, 9.50.
4.1.6. 3(RS)-{4-[2-Methoxy-4-(3-oxo-3-phenyl-propenyl)-
phenoxymethyl]-[1,2,3]triazol-1-yl}-4(SR)-styryl-1-p-tolyl-
azetidin-2-one(7c)
4.1.10. 3(RS)-(4-{4-[3-(2-Methoxy-phenyl)-acryloyl]-
phenoxymethyl}-[1,2,3]triazol-1-yl)-4(SR)-styryl-1-p-tolyl-
azetidin-2-one(9b)
Yield 83%; yellow solid; mp 142e144 ꢀC; IR nmax (KBr)/cmꢂ1
:
Yield 78%; yellow solid; mp 140e142 ꢀC; IR nmax (KBr)/cmꢂ1
:
1752, 1513, 1688. 1H NMR (CDCl3, 300 MHz):
d
2.32 (s, 3H, eCH3),
1752, 1517, 1691. 1H NMR (CDCl3, 300 MHz):
d 2.31 (s, 3H, eCH3),
3.90 (s, 3H, eOCH3), 5.19 (dd, 5.7 Hz, 7.5 Hz, 1H, Hb), 5.23 (s, 2H,
eOCH2e), 5.81 (dd, 7.5 Hz, 15.9 Hz, 1H, Hc), 6.25 (d, 5.7 Hz, 1H, Ha),
6.71 (d, 15.9 Hz, 1H, Hd), 6.91e7.25 (m, 15H, eArH), 7.35 (d, 15.6 Hz,
1H, He), 7.67 (d, 15.6 Hz, 1H, Hf), 7.82 (s, 1H, triazole-H) 8.03 (d,
8.7 Hz, 2H, eArH), 13C NMR (CDCl3, 75 Hz), 21.0, 49.8, 56.0, 66.4,
72.5, 113.1, 115.0, 115.4, 117.9, 119.2, 121.3, 123.3, 124.4127.1, 127.3,
128.0,128.6, 129.1, 129.3, 130.6,131.4, 134.1,134.5, 134.9, 137.6, 141.9,
145.3, 146.5, 147.0, 171.7, 187.05. MS m/z 597 (M)þ. Analysis calcu-
lated for C37H32N4O4: C, 74.48; H, 5.41; N, 9.39. Found: C, 74.57; H,
5.29; N, 9.51.
3.91 (s, 3H, eOCH3), 5.16 (dd, 5.4 Hz, 8.7 Hz, 1H, Hb), 5.25 (s, 2H,
eOCH2e), 5.80 (dd, 8.7 Hz, 15.9 Hz, 1H, Hc), 6.25 (d, 5.4 Hz, 1H, Ha),
6.71 (d, 15.9 Hz, 1H, Hd), 6.93e7.40 (m, 15H, eArH), 7.58 (d, 15.6 Hz,
1H, He), 7.83 (s, 1H, triazole-H) 7.93 (d, 8.7 Hz, 2H, eArH), 8.10 (d,
15.9 Hz, 1H, Hf), 13C NMR (CDCl3, 75 Hz), 20.7, 49.8, 55.7, 65.3, 72.5,
113.0, 114.4, 116.0, 117.4, 121.3, 123.2, 124.6, 125.8, 127.4, 128.1, 128.6,
129.5, 130.4, 130.8, 132.5, 134.3, 133.6, 135.0, 137.3, 141.8, 144.6,
147.6, 147.9,166.8, 172.6, 187.1. MS m/z 597 (M)þ. Analysis calculated
for C37H32N4O4: C, 74.48; H, 5.41; N, 9.39. Found: C, 74.61; H, 5.33;
N, 9.47.
4.1.7. 1-Cyclohexyl-3(RS)-(4-{4-[3-(4-methoxy-phenyl)-acryloyl]-
phenoxymethyl}-[1,2,3]triazol-1-yl)-4(SR)-styryl-azetidin-2-
one(8a)
4.1.11. 4-[1-(1-Cyclohexyl-2-oxo-4(SR)-styryl-azetidin-3(RS)-yl)-
1H-[1,2,3]triazol-4-ylmethoxy]-3-methoxy-benzaldehyde(10)
Yield 80%; white solid; mp 155e156 ꢀC; IR nmax (KBr)/cmꢂ1
:
Yield 78%; Yellow solid; mp 132e134 ꢀC; IR nmax (KBr)/
1735, 1523, 1689. 1H NMR (CDCl3, 300 MHz):
d 1.09e1.96 (m, 10H,
cmꢂ1:1743,1577,1688. 1H NMR (CDCl3, 300 MHz):
d
1.28e1.97 (m,
cyclohexyl ring), 3.57 (m, 1H, cyclohexyl ring), 3.90 (s, 3H, eOCH3),
4.73 (dd, 5.1 Hz, 8.7 Hz, 1H, Hb), 5.36 (s, 2H, eOCH2e), 5.65 (dd,
8.7 Hz, 15.6 Hz, 1H, Hc), 5.90 (d, 5.1 Hz, 1H, Ha), 6.62 (d, 15.6 Hz, 1H,
Hd), 7.06e7.25 (m, 7H, eArH), 7.38 (s, 1H, eArH), 7.79 (s, 1H,
triazole-H), 9.78 (s, 1H, eCHO), 13C NMR (CDCl3, 75 Hz): 22.3, 27.3,
30.9, 47.5, 50.2, 56.4, 66.4, 72.5, 115.2, 116.8, 123.0, 123.3, 126.3,
10H, cyclohexyl H), 3.57 (m, 1H, cyclohexyl H), 3.86 (s, 3H, -OCH3),
4.75 (dd,5.4 Hz, 8.4 Hz, 1H, Hb), 5.31 (s, 2H, eOCH2e), 5.66 (dd,
8.4 Hz, 15.9 Hz, 1H, Hc), 5.96 (d, 5.4 Hz, 1H, Ha), 6.66(d, 15.9 Hz, 1H,
Hd),6.92e7.26(m, 9H, eArH), 7.39 (d, 15.3 Hz, 1H, He), 7.60 (d,
8.4 Hz, 2H, eArH),7.69 (d, 15.3 Hz, 1H, Hf), 7.79 (s, 1H, triazole-H),

600
P. Singh et al. / European Journal of Medicinal Chemistry 47 (2012) 594e600
15 (2005) 4858;
127.2, 127.4, 128.4, 130.0, 132.4, 135.2, 145.3, 148.3, 152.2, 172.8,
189.9. MS m/z 487 (M)þ. Analysis calculated for C28H30N4O4: C,
69.12; H, 6.21; N, 11.51. Found: C, 69.00; H, 6.31; N, 11.40.
(d) M.L. Go, M. Liu, P. Wilairat, P.J. Rosenthal, K.J. Saliba, Antimicrob. Agents
Chemother. 48 (2004) 3241.
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(b) A. Friis-Moller, M. Chen, K. Fuursted, S.B. Christensen, A. Kharazmi, Planta
Med. 68 (2002) 416;
(c) L.D. Chiaradia, A. Mascarello, M. Purificação, J. Vernal, M.N.S. Cordeiro,
M.E. Zenteno, A. Villarino, R.J. Nunes, R.A. Yunes, H. Terenzi, Bioorg. Med.
Chem. Lett. 18 (2008) 6227.
4.1.12. 3-Methoxy-4-[1-(2-oxo-4(SR)-styryl-1-p-tolyl-azetidin-
3(RS)-yl)-1H-[1,2,3]triazol-4-ylmethoxy]-benzaldehydeYield (11)
78%; Yellow solid; mp 140e142 ꢀC; IR nmax (KBr)/cmꢂ1: 1752,
1517, 1691. 1H NMR (CDCl3, 300 MHz):
d 2.30 (s, 3H, eCH3), 3.90 (s,
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26 (1983) 251;
3H, eOCH3), 5.16 (dd, 5.4 Hz, 8.4 Hz, 1H, Hb), 5.25 (s, 2H, eOCH2e),
5.80 (dd, 8.4 Hz, 15.9 Hz, 1H, Hc), 6.25 (d, 5.4 Hz, 1H, Ha), 6.71(d,
15.9 Hz, 1H, Hd), 6.93e7.25 (m, 11H, eArH), 7.37 (s, 1H, eArH), 7.82
(s, 1H, triazole-H), 9.80 (s, 1H, eCHO), 13C NMR (CDCl3, 75 Hz), 20.3,
54.8, 56.4, 65.7, 72.3, 115.3, 115.7, 119.8, 122.2, 123.6, 125.6, 126.4,
127.3, 127.7, 128.0, 128.9, 129.5, 131.7, 133.4, 136.1, 144.5, 147.9, 152.2,
171.3, 189.9. MS m/z 495 (M)þ. Analysis calculated for C29H26N4O4:
C, 70.43; H, 5.30; N, 11.33. Found: C, 70.57; H, 5.41; N, 11.37.
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Acknowledgement
Financial assistance from Board of Research in Nuclear Sciences
under DAE Research Award for Young Scientist Scheme (VK) is
gratefully acknowledged.
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