Synthesis, characterization and antiamoebic activity of chalcones bearing N -substituted ethanamine tail

Article abstract of DOI:10.1016/j.ejmech.2015.05.013

A series of chalcones (4-21) possessing N-substituted ethanamine were synthesized by the aldol condensation reaction of 1-(4-(2-substituted ethoxy)phenyl)ethanones with different aldehydes preceded by the reaction of 2-chloro N-substituted ethanamine hydr

Full text of DOI:10.1016/j.ejmech.2015.05.013

European Journal of Medicinal Chemistry 98 (2015) 179e189
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis, characterization and antiamoebic activity of chalcones
bearing N-substituted ethanamine tail
Saadia Leeza Zaidi a, Sonam Mittal b, Maitreyi S. Rajala b, Fernando Avecilla c,
,
*
Mohammad Husain d, Amir Azam a
a Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
b School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
c
~
~
Departamento de Química Fundamental, Universidade da Coruna, Campus da Zapateira s/n, 15071 A Coruna, Spain
d Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of chalcones (4e21) possessing N-substituted ethanamine were synthesized by the aldol
condensation reaction of 1-(4-(2-substituted ethoxy)phenyl)ethanones with different aldehydes pre-
ceded by the reaction of 2-chloro N-substituted ethanamine hydrochloride and 4-hydroxy acetophenone.
The structure of all the synthesized compounds was elucidated by various spectral and X-ray diffraction
studies. The compounds were screened against HM1: IMSS strain of Entamoeba histolytica and cyto-
toxicity was performed on A549 (non-small cell lung cancer cell line) cells by MTT assay. Out of eighteen
compounds twelve showed better activity then the standard drug metronidazole. The compound 9, 14
and 19 showed good cell viability, hence were least toxic.
Received 6 February 2015
Received in revised form
4 May 2015
Accepted 8 May 2015
Available online 18 May 2015
Keywords:
Chalcones
Amoebiasis
E. histolytica
MTT assay
A549
© 2015 Elsevier Masson SAS. All rights reserved.
1. Introduction
promising structural motif to be explored in the quest for newer
drugs. Literature review revealed that chalcones have been studied
Amoebiasis, the devastating disease of the gastrointestinal tract
is caused by a parasitic protozoan Entamoeba histolytica. It is
responsible for 100,000 fatalities worldwide per annum [1]. The
spread of the infection is accelerated by poor sanitation. The
treatment is usually done by nitroimidazoles such as metronida-
zole (MNZ) and tinidazole but they have shown several side effects
[2]. MNZ is known to be carcinogenic in rodents and some major
side effects such as irritation of the gastric mucus lining, sperma-
tozoid damage, convulsions, central nervous system disorders,
blood in urine [3e7]. Recent reports have shown clinical resistance
towards the conventional drugs [8].
Chalcones are 1, 3-diaryl-2-propen-1-ones possessing a diverse
range of biological activities including anticancer [9,10], antimi-
crobial [11,12], anti-HIV [13,14], anti-oxidant [15,16], anti-
inflammatory [17,18] and anti-protozoal activities [19,20]. Modifi-
cation in their structure leads to an enhancement in their biological
activity and therapeutic efficacy [21]. Thus chalcones are a very
for their activity against various protozoal diseases but their po-
tential against the neglected diseases such as amoebiasis remains
to be explored. Previously, we have reported antiprotozoal activity
of a series of chloroquinoline based chalcones (Fig. 1) which
showed some promising results against E. histolytica [22]. Com-
pounds containing morpholine, piperadine (Fig. 2) and N, N-
dimethylamino scaffolds have shown promising antiprotozoal and
antibacterial activities [23e25].
In our continuous effort towards the development of more potent
antiamoebic agents and taking into consideration that aliphatic and
cyclic amine bearing heterocycles and chalcones are biologically
active. We herein, report the synthesis, characterization, antiamoebic
activity and toxicity of a series of hybrid molecules containing chal-
cone and N-substituted ethanamine tail (Fig. 3).
2. Results and discussion
2.1. Chemistry
A series of chalcones (4e21) containing N-substituted ethan-
* Corresponding author.
E-mail address: amir_sumbul@yahoo.co.in (A. Azam).
amine were synthesized as outlined in Scheme 1. 4-hydroxy
http://dx.doi.org/10.1016/j.ejmech.2015.05.013
0223-5234/© 2015 Elsevier Masson SAS. All rights reserved.

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S. Leeza Zaidi et al. / European Journal of Medicinal Chemistry 98 (2015) 179e189
Scheme 1. Synthesis of N-substituted ethanamine chalcones. Reagents and Conditions:
(a) THF, t-BuOK, Reflux (b) NaOH, EtOH, rt.
Fig. 1. Structures of antiprotozoal chalcones showing promising antiamoebic activity.
compounds with J values around 15 Hz. In the IR spectra the
carbonyl group appeared in the range 1650e1700 cmꢀ1 and at
around 1580 cmꢀ1for the alkenylic proton was also observed for
the final compounds. The values of the 13C NMR are also in good
agreement with the proposed structure. The characteristic peak
[Mþ1] in the mass spectra for chalcones helped to further
establish the structure.
2.2. Single crystal structures of 1, 8 and 9
1-(4-(2-morpholinoethoxy)phenyl)ethanone(1),
3-(2-methyl-
thiophen-2-yl)-1-(4-(2-morpholino ethoxy)phenyl)prop-2-en-1-one
(8) and 3-(3-bromo-4,5 dimethoxyphenyl)-1-(4-(2-morpholino
ethoxy)phenyl)ethanone (9) crystallize from methanol as colorless
prism in 1, as yellow prism in 8 and as orange prism in 9. Figs. 4e6
show an ORTEP representation of 1, 8 and 9 respectively. Hydrogen
bonds were not found in the structures. In the crystal packing of 8,
Fig. 2. Structures of compounds containing N-substituted ethanamine side chain
showing good antiamoebic activity.
the compound forms parallel dimers through
pep interactions
between the C]C bonds of propene groups and phenyl rings [26].
The distances between the centroids is for 8:dc1ec2 ¼ 3.532 Å [c1
(C14AeC15A), c2 (C7BeC8BeC9BeC10BeC11BeC12B)] (Fig. 7).
Instead the compound 9 prefers to form antiparallel dimers in su-
pramolecular structure (Fig. 8). pep stacking interactions between
phenyl rings predominate in this case. The distance between cen-
troids are: dc3ec4 ¼ 3.427 Å [c3 (C7AeC8AeC9AeC10AeC11Ae
C12A), c4 (C16LeC17LeC18LeC19LeC20LeC21L)] and dc5-c6
¼
3.427
Å
[c5 (C7LeC8LeC9LeC10LeC11LeC12L), c6 (C16Ae
C17AeC18AeC19AeC20AeC21A)]. Crystal data and details of the
data collection and refinement for the new compounds are
collected in Table 1 and Table 2 contains selected bond lengths and
angles for compound 1, 8 and 9.
Fig. 3. Designing of hybrid molecule.
2.3. Pharmacological screening
acetophenone is converted to 1-[4-(2-dimethylamino/piperidino/
morpholinoethoxy)phenyl)ethanone derivative by the reaction
with 2-chloro N-substitued ethanamine hydrochloride salts un-
der basic conditions using potassium tert-butoxide (t-BuOK) as a
base. The aldol condensation reaction of 1-(4-(2-substituted
ethoxy)phenyl)ethanones with different aldehydes resulted in
the desired chalcones. All the compounds synthesized were
characterized by 1H NMR, 13C NMR, IR and mass spectroscopy.
The molecular composition of the synthesized compounds was
established on the basis of their CHNS elemental analysis data. A
good agreement between the calculated and the observed values
for various elements supported the formation of expected com-
pounds as given in the experimental section. The structures of 1-
(4-(2-substituted ethoxy) phenyl) ketones and their chalcones
containing N-substituted ethanamine were also supported by
their 1H NMR spectra. The chemical shift values for all the com-
pounds are given in the experimental section. The signals due to
2.3.1. Antiamoebic activity
Preliminary experiments were carried out to determine the
in vitro antiamoebic activity of all the compounds (4e21) by
microdilution method using HM1: IMSS strain of E. histolytica and
their IC50 values are reported in Table 3. Metronidazole was used as
reference drug having IC50 ¼ 1.86
mM in our experiment. The results
were estimated as the percentage of growth inhibition compared
with the untreated controls and plotted as probit values as a
function of the drug concentration. IC50 and 95% confidence limits
were interpolated in the corresponding dose response curve. Out of
the 18 compounds synthesized 12 showed better antiamoebic ac-
tivity than MNZ. Compounds containing electron withdrawing
nitro group were found to have IC50 value greater than MNZ.
Compound 4, 10, 16 had IC50 values 4.76 mM, 4.17 mM and 2.33 mM
respectively. Compound 12 containing piperidinoethoxy side chain
and anisaldehyde as R1 was found to have the least IC50 value of
characteristic olefinic protons (
a and b) were found in all the
0.03
0.01 mM. The activity decreased tenfold when the

S. Leeza Zaidi et al. / European Journal of Medicinal Chemistry 98 (2015) 179e189
181
Fig. 4. ORTEP plot of compound 1-(4-(2-morpholinoethoxy)phenyl)ethanone (1). All the non-hydrogen atoms are presented by their 30% probability ellipsoids. Hydrogen atoms are
omitted for clarity.
Fig. 5. ORTEP plot of compound 3-(2-methylthiophen-2-yl)-1-(4-(2-morpholinoethoxy)phenyl)prop-2-en-1-one (8). All the non-hydrogen atoms are presented by their 30% proba-
bility ellipsoids. Hydrogen atoms are omitted for clarity.
Fig. 6. ORTEP plot of compound 3-(3-bromo-4, 5dimethoxyphenyl)-1-(4-(2-morpholinoethoxy)phenyl)ethanone (9). All the non-hydrogen atoms are presented by their 30% proba-
bility ellipsoids. Hydrogen atoms are omitted for clarity.
piperidinoethoxy side chain was replaced with dimethylaminoe-
thoxy side chain (18; IC50 ¼ 0.12 M) but for 6 with similar R1
substitution having morpholinoethoxy side chain the activity
decreased further (IC50 ¼ 2.86 M) and was comparable to MNZ. A
similar trend was also observed for compounds 13, 19 and 7 having
1 as dimethylamino group with IC50 values 0.05 M, 0.11 M and
2.38 M respectively. Compound 11, 17 and 5 were all found to be
active (IC50 ¼ 0.10 M, 0.20 M and 0.85 M respectively) but the
piperidinoethoxy and dimethylaminoethoxy side chain respec-
tively showed comparable antiamoebic activity (IC50 ¼ 0.20 M,
0.22 M) but the activity decreased sharply and compound 8 was
M) with morpholinoethoxy side chain.
Compound 15 and 21 with R1 2-bromo-4, 5-dimethoxyphenyl
showed very good and comparable antiamoebic activity
m
m
m
m
inactive (IC50 ¼ 9.93
m
R
m
m
m
(IC50 ¼ 0.07, IC50 ¼ 0.08
mM) and compound 9 had (IC50 ¼ 0.37
mM).
m
m
m
activity showed a trend of gradual decrease of tenfold while mov-
ing from piperidinoethoxy side chain to dimethylaminoethoxy side
chain and a further fourfold decrease in the morpholinoethoxy side
chain. Compound 14 and 20 with R1 as 2-methylthiophene in
2.3.2. Cytotoxicity
In vitro toxicity is to analyze the effect of synthetic and natural
chemical compounds on cultured bacterial and mammalian cells.
This method is primarily used to identify potentially hazardous

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S. Leeza Zaidi et al. / European Journal of Medicinal Chemistry 98 (2015) 179e189
Fig. 7. Intermolecular
pep interactions in 8. Dashed lines link the centres of the p clouds involved in each interaction.
Fig. 8. Intermolecular
pep interactions in 9. Dashed lines link the centres of the p clouds involved in each interaction.
Table 1
Crystal data and structure refinement for 1-(4-(2-morpholinoethoxy)phenyl)ethanone (1), for 3-(2-methylthiophen-2-yl)-1-(4-(2-morpholinoethoxy)phenyl)prop-2-en-1-
one (8) and for 3-(3-bromo-4,5 dimethoxyphenyl)-1-(4-(2-morpholinoethoxy)phenyl)ethanone (9).
1
C
8
9
Formula
Formula weight
T, K
14H19NO3
C20H23NO3S
357.45
100(2)
C23H26BrNO5
476.36
100(2)
249.30
100(2)
Wavelength, Å
Crystal system
Space group
a/Å
b/Å
c/Å
0.71073
Monoclinic
C2/c
20.4886(12)
6.3550(4)
20.0370(12)
90
101.203(4)
90
2559.2(3)
8
0.71073
Monoclinic
C2/c
34.479(3)
4.9814(4)
23.268(2)
90
117.892(5)
90
3532.1(5)
8
0.71073
Triclinic
P‾1
7.4199(9)
11.8414(15)
12.8403(16)
74.226(8)
79.908(8)
76.582(8)
1048.4(2)
2
a
/º
/º
b
g
/º
V/Å3
Z
F000
1072
1.294
0.091
2.03 to 22.24
0.0385
1520
1.344
0.202
1.34 to 26.45
0.1540
492
1.509
1.996
1.66 to 26.50
0.1078
Dcalc/g cmꢀ3
m
/mmꢀ1
q
/(ꢁ)
Rint
Crystal size/mm3
0.30 ꢂ 0.23 ꢂ 0.15
0.32 ꢂ 0.17 ꢂ 0.05
0.18 ꢂ 0.13 ꢂ 0.11
Goodness-of-fit on F2
1.104
1.026
1.069
R1[I > 2
s
(I)]a
0.0270
0.0742
0.133 and ꢀ0.133
0.0598
0.1951
0.522 and ꢀ0.397
0.0396
0.1102
0.500 and ꢀ0.544
wR2 (all data)b
Largest differences peak and hole (eÅꢀ3
)
P
P
a
R1
¼
jjFojejFcjj= jFoj.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
P
P
b
2
2
2
wR2 ¼ f ½wð jFoj ejFcj Þ ꢃ = ½wðF4oÞꢃg1=2
.
compounds and their toxic effect in the early stage of development
of therapeutics drugs. Cytotoxic effects of the compounds (4e21)
and standard drug MNZ were tested in A549 (non small cell lung
cancer) cells. Few compound of the morpholinoethoxy side tail
bearing series, such as 6, 7 and 8 didn't dissolve completely in
DMSO. We tried to dissolve in other solvents such as ethanol,
methanol and chloroform, but homogeneous drug suspension was
not obtained. Thus, we failed to determine the toxic effects of these
three compounds. Cytotoxic effects of each compound were
measured by calculating percentage of cell viability in dose
dependent manner (Figs. 9A, 10A and 11A) subsequently IC50 value
of each compound was determined. The IC50 values of the mor-
pholinoethoxy side chain bearing series compounds 4e9 are in the
range of 48e94.5 mM concentration while value of 9 was found to

S. Leeza Zaidi et al. / European Journal of Medicinal Chemistry 98 (2015) 179e189
183
Table 2
Electrospray (ES) mass spectra were carried out on Microtof-Q II
10262. Melting points were recorded on a Veego melting point
apparatus (model REC-2203882) and were uncorrected. IR spectra
were recorded on a Perkin Elmer model 1600 FT-IR RX1 spectro-
photometer. 1H NMR and 13C NMR spectra were obtained at
ambient temperature using a Bruker spectrospin DPX-300 MHz
instrument, in CDCl3 using tetramethylsilane as an internal stan-
dard. Splitting patterns are designated as follows: s, singlet; d;
doublet; t, triplet; m, multiplet. Chemical shift values are given in
ppm.
Bond lengths [Å] and angles [ꢁ] for 1-(4-(2-morpholinoethoxy)phenyl)ethanone (1),
for 3-(2-methylthiophen-2-yl)-1-(4-(2-morpholinoethoxy)phenyl)prop-2-en-1-one(8)
and for 3-(3-bromo-4,5 dimethoxyphenyl)-1-(4-(2-morpholinoethoxy)phenyl)etha-
none (9).
Bond lengths
1
8
9
O(1)eC(1)
O(1)eC(3)
N(1)eC(5)
N(1)eC(2)
N(1)eC(4)
O(2)eC(7)
O(2)eC(6)
O(3)eC(13)
S(1)eC(19)
S(1)eC(16)
O(4)eC(20)
O(4)eC(22)
Br(1)eC(17)
1.4281(18)
1.4297(18)
1.4580(18)
1.4679(18)
1.4697(18)
1.3621(17)
1.4377(17)
1.2242(17)
1.418(4)
1.420(4)
1.464(4)
1.461(4)
1.463(4)
1.363(3)
1.440(3)
1.220(4)
1.716(3)
1.730(3)
1.426(4)
1.425(4)
1.461(4)
1.467(4)
1.463(4)
1.364(3)
1.436(4)
1.222(4)
4.1. X-ray crystal structure determination
Three-dimensional X-ray data were collected on a Bruker
Kappa Apex CCD diffractometer at low temperature for 1, 8 and 9
1.355(4)
1.427(4)
1.901(3)
by the
hemisphere of data collected from frames, each of them covering
0.5ꢁ in
. Of the 19,611 for 1, 62,019 for 8 and 54641 for 9 re-
feuscan method. Reflections were measured from a
Angles
1
8
9
u
C(1)eO(1)eC(3)
C(5)eN(1)eC(2)
C(5)eN(1)eC(4)
C(2)eN(1)eC(4)
C(7)eO(2)eC(6)
C(19)eS(1)eC(16)
C(20)eO(4)eC(22)
C(18)eC(17)eBr(1)
C(16)eC(17)eBr(1)
108.90(11)
110.2(3)
110.3(2)
110.0(2)
108.7(2)
116.6(2)
91.37(16)
109.5(2)
110.9(2)
111.1(2)
107.8(2)
117.8(2)
flections measured, all were corrected for Lorentz and polariza-
tion effects and for absorption by multi-scan methods based on
symmetry-equivalent and repeated reflections, 1445, 2300 and
3476 respectively, independent reflections exceeded the signifi-
109.14(11)
111.06(12)
108.72(11)
119.73(10)
cance level (rFr/srFr) > 4.0. Complex scattering factors were taken
117.0(2)
116.0(2)
121.1(2)
from the program package SHELXTL [27]. The structures were
solved by direct methods and refined by full matrix least-squares
on F2. In 1, hydrogen atoms were located in difference Fourier
map and left to refine freely, except for C (11), which was
included in calculation position and refined in the riding mode. In
8, hydrogen atoms were located in difference Fourier map and
left to refine freely, except for C(6) and C(20), which were
included in calculation positions and refined in the riding mode.
In 9, hydrogen atoms were located in difference Fourier map and
left to refine freely, except for C(8), C(22), and C(23), which were
included in calculation positions and refined in the riding mode.
Refinements were done with allowance for thermal anisotropy of
all non-hydrogen atoms. A final difference Fourier map showed
no residual density outside: 0.133 and ꢀ0.133 e Åꢀ3 for 1, 0.522
and ꢀ0.397 e Åꢀ3 for 8 and 0.500 and ꢀ0.544e Åꢀ3 for 9. A
weighting scheme w ¼ 1/[s2ðF2oÞ þ (0.039400 P)2 þ 1.210700 P]
for 1, w ¼ 1/[s2ðFo2Þ þ (0.116400 P)2 þ 0.618300P] for 8 and
w ¼ 1/[s2ðF2oÞ þ (0.063800P)2 þ 0.000000 P] for 9, where
P ¼ (jFoj2 þ 2jFcj2)/3, were used in the latter stages of refinement.
CCDC 1035422 for 1, 1035420 for 8 and 1035421 for 9 contain the
supplementary crystallographic data for the structures reported
in this paper. These data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: (þ44) 1223 336 033; or e-mail: deposit@ccdc.
cam.ac.uk.
be very high i.e., 94.5
(non-small cell lung cancer cell line) cells remained 100% viable at
24 h post drug treatment. IC50 values of compounds processing
mM. Even at 2.5 mM concentration of 9, A549
dimethylaminoethoxy side chain (16e21) ranged from 36.4
69.3 M. Compound 19 was found to be the least toxic against A549
lung cancer cell line with IC50 value 69.3 M. The IC50 values of
piperidinoethoxy side tail bearing compounds ranged from 24.5 to
69.0 M. In this series compounds 14 was found to be the least
cytotoxic with IC50 value 69.0 M. Thus out of the three series of
mM to
m
m
m
m
compounds 9, 14 and 19 showed the least toxic effect against A549
lung cancer cell line. Corresponding IC50 values of each compound
was given in Table 3 and graphical representation was also shown
besides the graph showing percentage of viability (Figs. 9B, 10B and
11B).
3. Conclusion
In summary chalcones bearing N-substituted ethanamine side
chain were synthesized. The in vitro antiamoebic activity was
examined using HM1:1MSS strain of E. histolytica and results
showed that out of 18 compounds synthesized 12 exhibited
better antiamoebic activities than the reference drug metroni-
dazole. Cytotoxicity of the compounds on A549 (non small cell
lung cancer cell line) cells was measured by MTT assay. Based on
percentage of cell viability IC50 values of the compounds was
determined. Compound 9, 14 and 19 were found to be the least
toxic on lung cancer cell line. It is hoped that these studies will
fuel further efforts towards the development of effective anti-
amoebic agents.
4.2. General procedure for the synthesis of ketone (1, 2, 3)
To a stirred solution of t-BuOK (2.5 eq) in tetrahydrofuran
(250 mL) and 4-hydroxyacetophenone (1 eq) was added in por-
tions which resulted in
a white precipitate. Different N-
substituted 2-chloroethanamine hydrochloride (1 eq) were sub-
sequently added. The reaction mixture was refluxed for 15 h and
the reaction was monitored using TLC. The reaction mixture was
then concentrated in vacuo. The crude solid thus obtained was
treated with water, extracted with dichloromethane and dried
over anhydrous sodium sulphate. 1, 2 were recrystallized with
ethanol and 3 was purified by column chromatography using
ethyl acetate:hexane (1:9) as eluent. The compounds were ob-
tained in approximately 70e80 % yield.
4. Experimental protocol
All the chemicals were purchased from Aldrich Chemical Com-
pany (USA). Precoated aluminum sheets (silica gel 60 F254, Merck
Germany) were used for thin-layer chromatography (TLC) and
spots were visualized under UV light. Elemental analysis (C, H and
N) was carried out on CHNS Elementar analyzer (Vario EL-III).

184
S. Leeza Zaidi et al. / European Journal of Medicinal Chemistry 98 (2015) 179e189
Table 3
In vitro antiamoebic activity of chalcones (4e21) against HM1: IMSS strain of E. histolytica and measurement of cell viability by MTT assay.
O
R1
O
R
Compound code
R
R1
Antiamoebic activity (IC50 S.D.)
4.76 0.02
Cytotoxicity (IC50 S.D.)
48.86 1.23
4
O
NO2
N
O
5
6
7
0.85 0.01
2.86 0.02
2.38 0.01
49.76 0.03
CH3
N
O
N.D
OMe
N
O
N.D
CH3
N
N
O
CH3
8
9
9.93 0.01
0.37 0.01
N.D
S
N
O
H3C
94.53 0.80
N
10
11
12
13
4.17 0.01
0.10 0.01
0.03 0.01
0.05 0.01
24.54 1.20
30.96 3.03
28.57 0.02
39.45 1.70
N
N
N
N
NO2
CH3
OMe
CH3
N
CH3
14
15
0.20 0.01
0.07 0.01
69.00 0.03
47.84 0.40
S
N
N
H3C
16
17
18
2.33 0.01
0.20 0.01
0.12 0.02
N.D
N
N
N
NO2
CH3
40.95 0.20
36.45 1.82

S. Leeza Zaidi et al. / European Journal of Medicinal Chemistry 98 (2015) 179e189
185
Table 3 (continued )
Compound code
R
R1
Antiamoebic activity (IC50 S.D.)
Cytotoxicity (IC50 S.D.)
OMe
19
0.11 0.02
69.32 0.50
N
CH3
N
CH3
20
21
0.22 0.01
0.08 0.01
44.54 2.30
36.82 1.20
S
N
N
H3C
MNZ
1.86 0.02
>160
Fig. 9. (A) Measurement of cell viability following treatment with morpholinoethoxy side chain bearing compounds by MTT assay (B) IC50 values of corresponding compounds.
Fig. 10. (A) Measurement of cell viability following treatment with piperidinoethoxy side chain bearing compounds by MTT assay (B) IC50 values of corresponding compounds.
4.2.1. 1-(4-(2-morpholinoethoxy)phenyl)ethanone (1)
4.2.2. 1-(4-(2-(piperidin-1-yl)ethoxy)phenylethanone (2)
Yield: 82%; m.p. 80 ꢁC; Anal. Calc. (%) for C14H19NO3: C 67.45, H
Yield: 87%; m.p.76 ꢁC; Anal. Calc. (%) for: C14H21NO2: C 72.84, H
7.68, N 5.62; found: C 67.67, H 7.66, N 5.75; 1H NMR (300 MHz,
8.56, N 5.66; found: C 72.76, H 8.45, N 5.76; 1H NMR (300 MHz,
CDCl3,
d
ppm): 7.94 (d, 2H, J ¼ 9.0 Hz, AreH), 6.95 (d, 2H, J ¼ 9.0 Hz,
CDCl3,
d
ppm): 7.94 (d, 2H, J ¼ 8.7 Hz, AreH), 6.95 (d, 2H, J ¼ 8.7 Hz,
AreH), 2.84 (t, 2H, J ¼ 5.7 Hz), 4.19 (t, 2H, J ¼ 4.8 Hz, CH2O), 3.75 (t,
AreH), 4.18 (t, 2H, J ¼ 6.0 Hz, CH2O), 2.81 (t, 2H, J ¼ 6.0 Hz, CH2N),
4H, J ¼ 5.7 Hz, CH2O), 2.60e2.53 (7H, CH2N, CH3); 13C NMR
2.56 -2.51 (m, 7H), 1.63e1.57 (m, 6H, CH2); 13C NMR (75 MHz,
(75 MHz, CDCl3,
d
ppm): 196.71, 162.58, 130.40, 129.67, 114.83,
CDCl3,
d ppm): 196.72, 162.65, 131.71, 130.35, 129.69, 66.11, 57.62,
66.88, 66.45, 54.54, 53.67, 27.70. ES-MS: m/z: 250 [Mþ1].
54.98, 26.90, 25.02; ES-MS: m/z: 248 [Mþ1].

186
S. Leeza Zaidi et al. / European Journal of Medicinal Chemistry 98 (2015) 179e189
Fig. 11. (A) Measurement of cell viability following treatment with dimethylaminoethoxy side chain bearing compounds by MTT assay (B) IC50 values of corresponding compounds.
4.2.3. 1-(4-(2-(Dimethylamino)ethoxy)phenyl)ethanone (3)
4.3.3. 3-(4-methoxyphenyl)-1-(4-(2-morpholinoethoxy)phenyl)
prop-2-en-1-one (6)
Yield: 75%; Anal. Calc. (%) for C12H17NO2: C 69.54, H 8.27,N 6.76;
found: C 69.91, H 8.32, N 6.75; 1H NMR (300 MHz, CDCl3,
d
ppm):
Yield: 85%; m.p.: 83 ꢁC; Anal. Calc. (%) for C22H25NO4: C 71.91, H
6.86, N 3.81; found: C 71.87, H 6.78, N 3.59; FT-IR nmax (cmꢀ1): 1740
7.94 (d, 2H, J ¼ 7.4 Hz, AreH), 7.27 (d, 2H, J ¼ 7.4 Hz, AreH), 4.15 (t,
2H, J ¼ 5.4 Hz, CH2), 2.78 (t, 2H, J ¼ 5.4 Hz, CH2), 2.56 (s, 3H, CH3),
(C]O), 1595 (C]C); 1H NMR (300 MHz, CDCl3,
d ppm): 8.04 (d, 2H,
2.35 (s, 6H, CH3); 13C NMR (75 MHz, CDCl3,
d
ppm): 196.80, 162.64,
J ¼ 8.4 Hz, AreH), 7.81 (d, 1Ha, J ¼ 15.6 Hz), 7.62 (d, 2H, J ¼ 9.9 Hz,
AreH), 7.45 (d, 1Hb, J ¼ 15.6 Hz), 7.00e6.92 (m, 4H, AreH), 4.21 (t,
2H, J ¼ 5.4 Hz, CH2O), 3.86 (s, 3H, OCH3), 3.76e3.73 (m, 4H, CH2O),
2.86 (t, 2H, J ¼ 5.7 Hz, CH2), 2.61e2.59 (m, 4H, CH2N); 13C NMR
130.52, 115.55, 114.187, 65.97, 57.91, 45.67, 26.24; ES-MS: m/z: 208
[Mþ1].
(75 MHz, CDCl3,
d ppm):188.66, 162.38, 161.53, 143.83, 131.49,
4.3. General procedure for the synthesis of chalcones (4e21)
130.67, 130.10, 127.79, 119.52, 114.39, 114.34, 66.88, 66.05, 57.35,
55.38, 54.10; ES-MS: m/z: 368 [Mþ1].
A mixture of 4-substituted acetophenone derivatives (1 eq),
aromatic ketones (1 eq), and sodium hydroxide (2 mL, 40%
aqueous) in 10 mL ethanol was stirred at room temperature for
24 h. The reaction was monitored by TLC. After the completion of
the reaction the solvent was evaporated in vacuo. The concentrate
was extracted with dichloromethane and dried over anhydrous
sodium sulphate. The product was recrystallized from methanol.
Compound 19 has been reported earlier [25].
4.3.4. 3-(4-(dimethylamino) -1-(4-(2-morpholinoethoxy)phenyl)
prop-2-en-1-one (7)
Yield: 82%; m.p.: 78,C; Anal. Calc. (%) for C23H28N2O3: C 72.61, H
7.42, N 7.36; found: C 72.45, H 7.44, N 7.62; FT-IR nmax (cmꢀ1): 1646
(C]O), 1596 (C]C); 1H NMR (300 MHz, CDCl3,
d ppm): 8.03 (d, 2H,
J ¼ 8.7 Hz, AreH), 7.80 (d, 1Ha, J ¼ 15.6 Hz), 7.56 (d, 2H, J ¼ 8.7 Hz,
AreH), 7.37 (d, 1H, J ¼ 15.3 Hz), 6.98 (d, 2H, J ¼ 9.0 Hz, AreH), 6.71
(d, 2H, J ¼ 8.7 Hz, AreH), 4.20 (t, 2H, J ¼ 5.7 Hz, CH2O), 3.75 (t, 4H,
J ¼ 4.8 Hz, CH2O), 3.04 (s,6H, (CH3)2N), 2.85 (t, 2H, J ¼ 5.7 Hz, CH2N),
2.60 (t, 4H, J ¼ 4.5 Hz, CH2N); 13C NMR (75 MHz, CDCl3,
4.3.1. 1-(4-(2-morpholinoethoxy)phenyl)-3-(4-nitrophenyl)prop-2-
en-1-one (4)
d
ppm):188.86, 162.07,151.94, 144.98,132.06,130.52,130.25, 122.89,
Yield: 78%; m.p.: 94 ꢁC; Anal. Calc. (%) for C21H22N2O5: C 65.96, H
5.80, N 7.33; found: C 65.76, H 5.65, N 7.45; FT-IR nmax (cmꢀ1): 1655
116.72, 114.24, 111.86, 66.91, 66.03, 57.50, 54.12, 40.13; ES-MS: m/z:
381[Mþ1].
(C]O), 1583 (C]C); 1H NMR (300 MHz, CDCl3,
d ppm): 8.28 (d, 2H,
J ¼ 8.7 Hz, AreH), 8.06 (d, 2H, J ¼ 8.7 Hz, AreH), 7.83e7.78 (m, 3H),
7.67 (d, 1H, J ¼ 15.6 Hz, 1Hb), 7.02 (d, 2H, J ¼ 8.7 Hz), 4.22 (t, 2H,
J ¼ 5.7 Hz, CH2O), 3.76 (t, 4H, J ¼ 4.2 Hz, CH2O), 2.88 (t, 2H,
J ¼ 5.7 Hz, CH2N), 2.61 (t, 4H, J ¼ 4.5 Hz, CH2N); 13C NMR (75 MHz,
4.3.5. 3-(3-Methylthiophen-2-yl)-1-(4-(2-morpholinoethoxy)
phenyl)prop-2-en-1-one (8)
Yield: 77%; m.p.: 110 ꢁC; Anal. Calc. (%) for C20H23NO3S: C 67.20,
H 6.49, N 3.92, S 8.97; found: C 67.34, H 6.66, N 4.01, S 9.12; FT-IR
nmax (cmꢀ1): 1643 (C]O), 1547 (C]C); 1H NMR (300 MHz, CDCl3,
CDCl3,
d ppm): 187.69, 162.97, 148.44, 141.27, 140.71, 130.61, 128.83,
125.61, 124.16, 114.59, 66.84, 66.13, 57.41, 54.09; ES-MS: m/z: 383
[Mþ1].
d
ppm): 8.08e8.00 (m, 2H, AreH), 7.61 (d, 1Hb, J ¼ 15.9 Hz), 7.17 (s,
1H, AreH), 6.99 (d, 2H, J ¼ 8.7 Hz, AreH), 6.99 (d, 2H, J ¼ 8.7 Hz,
ArH), 6.88 (d, 2H, J ¼ 9.0 Hz), 4.21 (t, 1H, J ¼ 5.7 Hz, CH2O),
3.87e3.82 (m, 4H, CH3), 3.75 (t, 3H, J ¼ 4.5 Hz, CH2O), 2.85 (t, 2H,
J ¼ 5.7 Hz, CH2N), 2.60 (t, 3H, J ¼ 4.5 Hz, CH2N); 13C NMR (75 MHz,
4.3.2. 1-(4-(2-morpholinoethoxy)phenyl)-3-p-tolylprop-2-en-1-
one (5)
Yield 73%; m.p.: 81 ꢁC; Anal. Calc. (%) for C22H25NO3: C 75.19, H
7.17, N 3.99; found: C 75.21, H 7.23, N 3.89; FT-IR nmax (cmꢀ1): 1648
CDCl3, d ppm): 188.02, 162.43, 142.41, 134.87, 134.67, 131.42, 131.34,
130.65, 126.97, 119.64, 114.37, 66.83, 66.00, 57.44, 54.08, 14.28; ES-
MS: m/z: 358 [Mþ1].
(C]O), 1583 (C]C); 1H NMR (300 MHz, CDCl3,
d ppm): 8.04 (d, 2H,
J ¼ 8.7 Hz, AreH), 7.81 (d, 1Hb, J ¼ 15.6 Hz), 7.55e7.47 (m, 3H), 7.23
(d, 2H, J ¼ 8.1 Hz), 7.00 (d, 2H, J ¼ 9.0 Hz), 4.217 (t, 2H, J ¼ 5.7 Hz,
CH2O), 3.76 (t, 4H, J ¼ 4.2 Hz, CH2O), 2.85 (t, 2H, J ¼ 5.7 Hz, CH2N),
2.61 (t, 4H, J ¼ 4.5 Hz, CH2N), 2.39 (s, 3H, CH3); 13C NMR (75 MHz,
4.3.6. 3-(2-Bromo-4, 5-dimethoxyphenyl)-1-(4-(2-
morpholinoethoxy)phenyl)prop-2-en-1-one (9)
Yield: 76%; m.p.: 93,C; Anal. Calc. (%) for C23H26BrNO5: C 57.99,
CDCl3, d ppm): 188.68, 162.47, 144.05, 140.80, 132.33, 131.36, 130.74,
H 5.50, N 2.94; found: C 57.69, H 5.80, N 3.14; FT-IR nmax (cmꢀ1):
129.66, 128.38, 120.85, 114.37, 66.90, 66.08, 57.46, 54.11, 21.50; ES-
1750 (C]O), 1620 (C]C); 1H NMR (300 MHz, CDCl3,
d
ppm): 8.07-
MS: m/z: 352 [Mþ1].
8.00 (m, 2H, J ¼ 15 Hz, 1Hb, AreH), 7.27e7.26 (m, 1H, AreH), 7.19 (s,

S. Leeza Zaidi et al. / European Journal of Medicinal Chemistry 98 (2015) 179e189
187
1H, AreH), 7.08 (s, 1H, AreH), 7.00 (d, 2H, J ¼ 8.7 Hz, AreH),
4.21e4.18 (m, 2H), 3.95 (s, 3H, CH3O), 3.92 (s, 3H, CH3O), 3.76e3.73
(m, 4H), 2.86 (t, 2H, J ¼ 6.0 Hz), 2.61e2.58 (m, 4H); 13C NMR
1 Hb AreH), 6.99 (d, 2H, J ¼ 9.0 Hz, AreH), 6.90 (d, 1H, J ¼ 8.0 Hz,
,
AreH), 4.20 (t, 2H, J ¼ 6.0 Hz), 2.82 (t, 2H, J ¼ 6.0 Hz), 2.53 (t, 2H,
J ¼ 4.8 Hz), 2.39 (s, 3H), 1.66e1.58 (m, 6H), 1.49e1.45 (m, 2H); 13C
(75 MHz, CDCl3,
d
ppm): 188.77, 162.73, 148.99, 142.84, 130.92,
NMR (75 MHz, CDCl3, d ppm): 187.99,162.63,142.30, 134.75, 134.69,
127.65, 122.93, 115.83, 114.39, 66.72, 57.43, 56.24, 54.05; ES-MS: m/
z: 477 [Mþ1].
131.38, 131.57, 130.67, 126.92, 119.69, 114.39, 66.25, 57.73, 55.07,
25.91, 24.14, 14.26; ES-MS: m/z: 356 [Mþ1].
4.3.7. 3-(4-nitrophenyl)-1-(4-(2-(piperidin-1-yl)ethoxy)phenyl)
prop-2-en-1-one (10)
4.3.12. 3-(2-Bromo-4,5-dimethoxyphenyl)-1-(4-(2-(piperidin-1-yl)
ethoxy)phenyl)prop-2-en-1-one (15)
Yield: 88%; m.p.: 76 ꢁC; Anal. Calc. (%) for C22H24N2O4: C 69.46, H
Yield: 76%; m.p.: 78 ꢁC; Anal. Calc. (%) for C24H28BrNO4: C 60.76,
H 5.95, N 2.95; found: C 60.88, H 5.76, N 3.01; FT-IR nmax (cmꢀ1):
6.36, N 7.36; found: C 69.56, H 6.54, N 7.56; FT-IR nmax (cmꢀ1):
1676(C]O), 1589(C]C); 1H NMR (300 MHz, CDCl3,
d
ppm): 8.28 (d,
1771 (C]O), 1600 (C]C); 1H NMR (300 MHz, CDCl3,
d ppm):
2H, J ¼ 8.7 Hz, AreH), 7.96 (d, 2H, J ¼ 8.4 Hz, AreH), 7.88e7.76 (m,
3H, AreH), 7.67 (d, 1Hb, J ¼ 15.6 Hz), 6.99 (d, 2H, J ¼ 6.9 Hz, AreH),
4.22e4.13 (m, 2H), 2.84 (t, 2H), 2.55e2.53 (m, 2H), 1.64e1.61 (m,
8.00e7.84 (m, 2H, J ¼ 15.3 Hz, 1Ha, ArH), 7.25e7.19 (m, 2H, AreH),
7.01 (s, 1H, AreH), 6.93 (s, 1H, AreH), 6.87 (d, 2H, J ¼ 8.40 Hz,
AreH), 4.22e4.12 (m, 2H), 3.85 (s, 3H, OCH3), 3.74 (s, 3H, OCH3),
2.83e2.81 (m, 2H), 2.58e2.31 (m, 4H), 1.62e1.59 (m, 6H); 13C NMR
6H), 1.47e1.46 (m, 2H); 13C NMR (75 MHz, CDCl3,
d ppm): 187.72,
163.15, 148.42, 141.31, 140.63, 130.95, 130.44, 128.83, 125.68, 124.16,
(75 MHz, CDCl3, d ppm): 188.66, 162.63, 151.42, 148.68,142.45,
114.61, 66.33, 57.66, 55.07, 25.84, 24.08; ES-MS: m/z: 381[Mþ1].
141.61, 131.03, 130.86, 125.79,122.90, 115.78, 114.40, 109.62, 66.17,
57.67, 56.16, 55.04, 25.79, 24.06; ES-MS: m/z: 474 [Mþ1].
4.3.8. 1-(4-(2-(piperidin-1-yl)ethoxyphenyl-3-p-tolylprop-2-en-1-
one (11)
4.3.13. 1-(4-(2-(diethymlamino)ethoxy)phenyl)-3-(4-nitrophenyl)
prop-2-en-1-one (16)
Yield: 87%; m.p.: 84 ꢁC; Anal. Calc. (%) for C23H27NO2: C 79.05, H
7.79, N 4.01; found: C 79.32, H 7.56, N 3.98; FT-IR nmax (cmꢀ1): 1633
Yield: 75%; m.p: 117 ꢁC; Anal. Calc. (%) for C19H20N2O4: C 67.05, H
5.92, N 8.23; found: C 67.07, H 5.90, N 8.22; FT-IR nmax (cmꢀ1): 1660
(C]O), 1540 (C]C); 1H NMR (400 MHz, CDCl3,
d ppm): 8.02 (d, 2H,
J ¼ 8.8 Hz, AreH), 7.78 (d, 1Ha, J ¼ 15.2 Hz), 7.54e7.51 (m, 2H, 1Hb,
AreH), 7.47 (s, 1H, AreH), 6.97 (d, 2H, J ¼ 8.8 Hz, AreH), 4.19 (t, 2H,
J ¼ 6.0 Hz, CH2O), 2.81 (t, 2H, J ¼ 5.6 Hz, CH2N), 2.51 (bs, 4H, CH2),
(C]O), 1567 (C]C); 1H NMR (400 MHz, CDCl3,
d ppm): 8.31 (d, 2H,
J ¼ 8.7 Hz, AreH), 8.03 (d, 2H, J ¼ 8.6 Hz, AreH), 7.90e7.80 (m, 3H,
AreH), 7.63 (d, 1Hb), 7.02 (d, 2H), 4.15 (t, 2H, J ¼ 5.7 Hz, CH2O), 2.511
(t, 2H, J ¼ 5.0 Hz, CH2O), 2.21 (s, 6H); 13C NMR (75 MHz, CDCl3,
2.38 (s, 3H, CH3), 1.62e1.59 (m, 6H, CH2), 1.45e1.44 (m, 2H, CH2);13
C
NMR (75 MHz, CDCl3,
d
ppm): 188.78, 162.65, 144.01, 140.79, 132.37,
d ppm): 188.87, 162.73,161.40, 144.34,131.60,130.06,129.99,127.76,
131.23, 130.74, 129.66, 128.38, 120.91, 114.40, 66.29, 57.76, 55.10,
53.32, 50.28 25.96, 24.16, 21.51; ES-MS: m/z: 350 [Mþ1].
119.87, 115.06, 66.34, 58.43, 55.32, 45.86; ES-MS: m/z: 340 [Mþ1].
4.3.14. 1-(4-(2-(dimethylamino)ethoxy)phenyl)-3-p-tolylprop-2-
en-1-one (17)
4.3.9. 3-(4-methoxyphenyl)-1-(4-(2-(pipeidin-1-yl)ethoxy)phenyl)
prop-2-en-1-one (12)
Yield: 80%; m.p: 87 ꢁC; Anal. Calc. (%) for C20H23NO3: C 77.64, H
7.49, N 4.53; found: C 77.66, H 7.45, N 4.20; FT-IR nmax (cmꢀ1): 1653
Yield: 70%; m.p.: 43 ꢁC; Anal. Calc. (%) for C23H27NO3: C 75.59, H
7.45, N 3.83; found: C 75.65, H 7.43, N 3.82; FT-IR nmax (cmꢀ1):1649
(C]O), 1586 (C]C); 1H NMR (400 MHz, CDCl3,
d ppm): 8.02 (d, 2H,
(C]O), 1592 (C]C); 1H NMR (300 MHz, CDCl3,
d, ppm): 8.03 (d, 2H,
J ¼ 8.8 Hz, AreH), 7.79 (d, 1Ha, J ¼ 16.0 Hz), 7.53e7.51 (m, 2H, 1Hb,
AreH), 7.47 (s, 1H, AreH), 7.21 (d, 2H, J ¼ 8.0 Hz, AreH), 6.99 (d, 2H,
J ¼ 8.8 Hz, AreH), 4.15 (t, 2H, J ¼ 5.6 Hz, CH2O), 2.77 (t, 2H,
J ¼ 5.6 Hz, CH2N), 2.37 (s, 3H, CH3), 2.34 (s, 6H, CH3); 13C NMR
J ¼ 9.0 Hz, AreH), 7.80 (d, 1Ha, J ¼ 14.4 Hz), 7.61 (d, 2H, J ¼ 9.0 Hz,
ArH), 7.45 (d, 1Hb, J ¼ 16.2 Hz), 6.99e6.92 (m, 4H, AreH), 4.20 (t, 2H,
J ¼ 6.0 Hz, CH2O), 3.85 (s, 3H, OCH3), 2.82 (t, 2H, J ¼ 6.3 Hz, CH2N),
2.53 (t, 2H, J ¼ 4.5 Hz, CH2N), 1.65e1.58 (m, 6H, CH2), 1.49 (t, 2H,
(75 MHz, CDCl3,
d ppm): 188.66, 162.54, 161.50, 143.73, 131.40,
J ¼ 5.4 Hz); 13C NMR (75 MHz, CDCl3,
d
ppm): 188.76,162.65,143.98,
130.64, 130.07, 127.82, 119.58, 114.37, 66.27, 58.12, 55.36, 45.89; ES-
MS: m/z: 310 [Mþ1].
140.76, 132.38, 131.23, 130.72, 129.65, 128.37, 120.93, 114.39, 66.31,
57.75, 55.09, 25.95, 24.16, 21.49; ES-MS: m/z: 366[Mþ1].
4.3.15. 1-(4-(2-(dimethylamino)ethoxy)phenyl)-3-(4-
methoxyphenyl)propan-1-one (18)
4.3.10. 3-(4-(dimethylamino)phenyl)-1-(4-(2-(piperidin-1-yl)
ethoxy)phenyl)prop-2-en-1-one (13)
Yield: 75%; m.p: 89 ꢁC; Anal. Calc. (%) for C20H23NO3: C 73.82, H
7.12, N 4.30; found: C 73.67, H 7.21, N 4.33; FT-IR nmax (cmꢀ1): 1652
Yield: 86%; m.p.: 65 ꢁC; Anal. Calc. (%) for C24H30N2O2: C 76.16, H
7.99, N 7.40; found: C 76.24, H 7.87, N 7.34; FT-IR nmax (cmꢀ1): 1664
(C]O), 1594 (C]C); 1H NMR (300 MHz, CDCl3,
d ppm): 8.04 (d, 2H,
(C]O), 1593 (C]C); 1H NMR (300 MHz, CDCl3,
d
ppm): 8.02 (d, 2H,
J ¼ 8.7 Hz, AreH), 7.81 (d, 1Ha, J ¼ 15.6 Hz), 7.62 (d, 2H, J ¼ 8.7 Hz,
AreH), 7.46 (d, 1Hb, J ¼ 15.6 Hz), 7.01 (d, 2H, J ¼ 9.0 Hz, AreH), 6.95
(d, 2H, J ¼ 8.7 Hz, AreH), 4.16 (t, 2H, J ¼ 5.4 Hz, AreH), 3.86 (s, 3H,
OCH3), 2.78 (t, 2H, J ¼ 5.7 Hz, AreH), 2.35 (s, 6H, CH3); 13C NMR
J ¼ 7.7 Hz, AreH), 7.80 (d, 1Ha, J ¼ 16.0 Hz), 7.55 (d, 2H, J ¼ 9.0 Hz,
2AreH), 7.37 (d,1Hb, J ¼ 16.0 Hz), 6.98 (d, 2H, J ¼ 9.0 Hz, AreH), 6.70
(d, 2H, J ¼ 9.0 Hz, AreH), 4.20 (t, 2H, J ¼ 5.7 Hz, CH2O), 3.07 (s, 6H,
NCH3), 2.82 (t, 2H, J ¼ 6.0 Hz, CH2N), 2.54e2.52 (m, 4H, CH2),
1.63e1.61 (m, 4H, CH2), 1.46e1.45 (m, 2H); 13C NMR (75 MHz,
(75 MHz, CDCl3,
d ppm): 188.75, 162.63, 143.97, 140.74, 132.40,
131.32, 130.70, 129.64, 128.35, 120.96, 114.38, 66.32, 58.13, 45.90,
CDCl3,
d
ppm): 188.85, 162.25, 151.90,144.88, 130.87, 130.49, 130.24,
21.46; ES-MS: m/z: 325 [Mþ1].
122.89, 116.72, 114.26, 111.84, 66.20, 57.76, 55.07, 40.13, 26.32, 25.91,
24.15; ES-MS: m/z: 378 [Mþ1].
4.3.16. 1-(4-(2-(dimethylamino)ethoxy)phenyl)-3-
(4(dimethylamino)phenyl)prop-2-en-1-one (19)
4.3.11. 3-(3-Methylthiophen-2-yl)-1-(4-(2-(piperidin-1-yl)ethoxy)
phenyl)prop-2-en-1-one (14)
Yield: 77%; m.p: 162 ꢁC; Anal. Calc. (%) for C21H26N2O2: C 74.53,
H 7.74, N 8.28; found: C 74.36, H 7.76, N 8.34; FT-IR nmax (cmꢀ1):
Yield: 85%; m.p.: 45 ꢁC; Anal. Calc. (%) for C21H25NO2S: C 70.95, H
7.09, N 3.94, S 9.02 found: C 71.12, H 7.23, N 4.12, S 9.32; FT-IR nmax
(cmꢀ1): 1643 (C]O), 1597 (C]C); 1H NMR (300 MHz, CDCl3,
1652 (C]O), 1597 (C]C); 1H NMR (300 MHz, CDCl3,
d ppm): 8.02
(d, 2H, J ¼ 8.4 Hz, AreH), 7.80 (d, 1H , J ¼ 15.3 Hz), 7.55 (d, 2H,
a
J ¼ 8.7 Hz, AreH), 7.36 (d, 1Hb, J ¼ 15.6 Hz), 7.00 (d, 2H, J ¼ 8.7 Hz,
d
ppm): 8.04e7.99 (m, 3H, AreH), 7.31e7.26 (m, 2H, J ¼ 12.3 Hz,
AreH), 6.70 (d, 2H, J ¼ 8.7 Hz, AreH), 4.20 (t, 2H, J ¼ 5.7 Hz, CH2O),

188
S. Leeza Zaidi et al. / European Journal of Medicinal Chemistry 98 (2015) 179e189
3.08 (s, 6H, N(CH3)2), 2.84 (t, 2H, J ¼ 5.4 Hz, CH2N), 2.40 (s, 6H,
N(CH3)2); 13C NMR (75 MHz, CDCl3,
ppm): 188.85, 162.08, 151.94,
144.94, 132.02, 130.48, 130.24, 122.85, 116.71, 114.25, 111.85, 65.95,
57.98, 45.69, 40.08; ES-MS: m/z: 339 [Mþ1].
observed at 160 mM concentrations. Compounds were recon-
d
stituted initially in DMSO, but further dilutions were made in cul-
ture medium. A549 cells were cultured in 96 well plates at a density
of 4000cells/well in Ham's F-12 medium (Hi Media) supplemented
with 10% FBS. Once the cells attached to 60e70% confluence, me-
dium was aspirated off and replaced with medium containing
desired concentration of each drug and 2% FBS. Each drug con-
centration was taken in triplicates. Cells treated only with medium
were used as negative controls. Plates were incubated at 37 ꢁC with
5% CO2. At 24 h post drug treatment, the cell viability was measured
by MTT assay [30]. In brief, cells in each well were incubated with
4.3.17. 1-(4-(2-(dimethylamino)ethoxy)phenyl)-3-(3-
methylthiophen-2-yl)prop-2-en-1-one (20)
Yield: 81%; m.p.: 83 ꢁC; Anal. Calc. (%) for C18H21NO2S: C 68.54, H
6.71, N 4.44, S 10.16; found: C 68.57, H 6.67, N 4.34, S 10.23; FT-IR
nmax (cmꢀ1): 1655 (C]O), 1594 (C]C); 1H NMR (300 MHz, CDCl3,
d
ppm): 8.06 (d, 2H, J ¼ 8.7 Hz, AreH), 7.90 (d, 1Ha, J ¼ 15.3 Hz,
AreH), 7.65e7.62 (m,1H, AreH), 7.42 (d,1Hb, J ¼ 15.0 Hz), 7.07e7.00
(m, 3H, AreH), 4.15 (t, 2H, J ¼ 5.7 Hz, CH2O), 2.62 (t, 2H, J ¼ 4.5 Hz,
CH2N), 2.34 (s, 3H, CH3), 2.19 (s, 6H, CH3N); 13C NMR (75 MHz,
20 ml of MTT (3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-
tetrazolium bromide) reagent at a concentration of 5 mg/ml in
methanol for 4hr. Then, MTT reagent was removed and the
CDCl3,
d
ppm): 188.06, 162.32, 142.34, 134.85, 134.65, 131.39, 130.62,
resulting formazan crystals were solubilized in 200 ml of DMSO. The
126.96, 119.70, 114.39, 65.76, 57.81, 54.67, 45.51, 14.24; ES-MS: m/z:
316 [Mþ1].
quantity of formazan which is directly proportional to the number
of cells viable was measured by recording absorbance at wave-
length of 560 nm. The percentage of viability was calculated taking
negative controls into account and plotted against the concentra-
tion of the drug. IC50 value for each compound was determined by
linear interpolation of the drug concentration and the corre-
sponding percentage of viability [31] using the given formula:
IC50 ¼ (50% e Low inhibition %)/(High inhibition% e Low inhibition
%) X (HighConcꢀLow Conc) þ Low Conc..
4.3.18. 3-(2-Bromo-4,5-dimethoxyphenyl)-1-(4-(2-
(dimethylamino)ethoxy)phenyl)prop-2-en-1-one (21)
Yield: 66%; m.p.: 142 ꢁC; Anal. Calc. (%) for C21H24BrNO4: C 58.07,
H 5.57, N 3.22; found: C 58.12, H 5.55, N 3.21; FT-IR nmax (cmꢀ1):
1645 (C]O), 1582 (C]C); 1H NMR (300 MHz, CDCl3,
d ppm):
8.07e7.99 (m, 3H, J ¼ 14.1 Hz, 1 Ha, AreH), 7.27e7.26 (m, 1H, AreH),
7.19 (s, 1H, AreH), 7.08 (s, 1H, AreH), 7.00 (d, 2H, J ¼ 8.7 Hz, AreH),
4.17 (t, 2H, J ¼ 5.7 Hz, CH2O), 3.94 (s, 3H, CH3O), 3.91 (s, 3H, CH3O),
2.78 (t, 2H, CH2N), 2.35 (s, 6H, CH3N); 13C NMR (75 MHz, CDCl3,
Acknowledgments
d
ppm): 188.86, 162.59, 151.40, 148.30, 142.47, 131.11, 130.86, 127.13,
This work was supported by University Grants Commission
(grant # 41-275/2012(SR), New Delhi, India.
122.88, 117.83, 115.82, 114.39, 109.65, 66.14, 58.04, 56.23, 45.80; ES-
MS: m/z: 435 [Mþ1].
Appendix A. Supplementary data
4.4. Pharmacological procedures
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2015.05.013.
4.4.1. Antiamoebic activity
The chalcones (4e21) were screened against the HM1: IMSS
strain of E. histolytica by using the microdilution method [28]. All
the experiments were carried out in triplicates at each concentra-
tion level and repeated thrice. E. histolytica trophozoites were
cultured in TYI-S-33 growth medium in wells of 96-well microtiter
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