Synthesis and in vitro antiplasmodial evaluation of 7-chloroquinoline-chalcone and 7-chloroquinoline-ferrocenylchalcone conjugates

Article abstract of DOI:10.1016/j.ejmech.2015.03.045

Abstract The manuscript describes the synthesis of novel amide tethered 7-chloroquinoline-chalcone and 7-chloroquinoline-ferrocenylchalcone bifunctional hybrids and their evaluation as antimalarial agents against W2 resistant strain of Plasmodium falciparum. The antiplasmodial activity of 7-chloroquinoline-ferrocenylchalcones was found to be less than their corresponding simple chalcone conjugates. The presence of a methoxy substituent at para position of ring B on chalcones and longer alkyl chain length markedly improved the antiplasmodial profiles of the synthesized scaffolds with the most potent of the test compound exhibiting an IC₅₀ value of 17.8 nM. Synthesis of 7-chloroquinoline-chalcone and 7-chloroquinoline-ferrocenylchalcone conjugates.Antimalarial potency of synthesized conjugates was evaluated against W2 strain.Most potent and non-cytotoxic conjugate exhibited IC₅₀ of 17.8 nM.

Full text of DOI:10.1016/j.ejmech.2015.03.045

European Journal of Medicinal Chemistry 95 (2015) 230e239
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Preliminary communication
Synthesis and in vitro antiplasmodial evaluation of 7-
chloroquinolineechalcone and 7-chloroquinolineeferrocenylchalcone
conjugates
,
*
Raghu Raj a, Anu Saini a, Jiri Gut b, Philip J. Rosenthal b, Vipan Kumar a
a Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India
b Department of Medicine, University of California, San Francisco, CA, USA
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 amide tethered 7-chloroquinolineechalcone and 7-
chloroquinolineeferrocenylchalcone bifunctional hybrids and their evaluation as antimalarial agents
against W2 resistant strain of Plasmodium falciparum. The antiplasmodial activity of 7-chloroquinoline
eferrocenylchalcones was found to be less than their corresponding simple chalcone conjugates. The
presence of a methoxy substituent at para position of ring B on chalcones and longer alkyl chain length
markedly improved the antiplasmodial profiles of the synthesized scaffolds with the most potent of the
test compound exhibiting an IC50 value of 17.8 nM.
Received 31 January 2015
Received in revised form
18 March 2015
Accepted 19 March 2015
Available online 20 March 2015
Keywords:
7-Chloroquinoline
Chalcone
© 2015 Elsevier Masson SAS. All rights reserved.
Ferrocenylchalcone
Antiplasmodial activity
IC50 value
1. Introduction
significance and extensively utilized in malaria chemotherapy due
to its excellent clinical efficacy, limited host toxicity, simple and
Malaria poses a major public health threat, especially in devel-
oping countries, where it has huge economic and social costs, with
an estimated 207 million cases of infection and 627,000 deaths
worldwide in 2012 [1]. In Africa alone, ~90% of malaria deaths
occur, with the vast majority of them being young children under
the age of five years [2]. Among Plasmodium species that cause
disease in humans, Plasmodium falciparum is most fatal and
responsible for majority of deaths. The major obstacle in the control
of malaria is resistance of P. falciparum to common antimalarials
including quinolines, antifolates, and artemisinin and its semi
synthetic derivatives, potentially limiting the ability of artemisinin-
based combination therapy (ACT) to contribute importantly to
control and eventually eradicate the disease [3e8]. Thus, the syn-
thesis of new antimalarials with the ability to overcome
P. falciparum resistance is an urgent priority.
cost effective synthesis [9]. Unfortunately, emergence of resistant
strains of P. falciparum to CQ led to its replacement by ACTs for the
treatment of falciparum malaria [10,11]. However, recent studies
have revealed that the resistance to CQ seems compound specific
[12], and certain synthetic modifications around the quinoline
nucleus have yielded many quinolines active against CQ-resistant
parasites [13e17].
The quinoline hybridization strategy may allow us to circumvent
quinoline resistance. The strategy involves covalently linking a
quinoline nucleus with other drugs to result in a single hybrid
molecule with improved efficacy compared to the parent drugs
[18e21]. The potential of the hybridization strategy in malaria
chemotherapy can be exemplified with the recent success of fer-
roquine (FQ) (7-chloroquinolineeferrocene conjugate) and triox-
aquine (7-chloroquinolineetrioxane conjugate). The hybrid FQ is
an organometallic molecule active against CQ-sensitive as well as
CQ-resistant strains of P. falciparum [22,23], and it has recently
completed phase IIb clinical trials for the treatment of malaria [24].
Based on the success of FQ, a variety of ferrocenyl analogues of CQ
have been synthesized [23,25] due to its favourable properties such
as stability in aqueous and aerobic media and lipophilicity to
Since the discovery of quinine, the quinoline based drugs
continued as the mainstay in the fight against malaria for many
years. Among quinolines, chloroquine (CQ) has immense
* Corresponding author.
E-mail address: vipan_org@yahoo.com (V. Kumar).
http://dx.doi.org/10.1016/j.ejmech.2015.03.045
0223-5234/© 2015 Elsevier Masson SAS. All rights reserved.

R. Raj et al. / European Journal of Medicinal Chemistry 95 (2015) 230e239
231
enhance penetration into cellular membranes. In addition to inhi-
bition of hemozoin formation, ferrocene was shown to create
oxidative stress due to the redox property of the ferrocene (Fe2þ)/
ferricinium (Fe3þ) system, generating reactive oxygen species via a
Fenton-like reaction in the parasite digestive vacuole, resulting in
parasite death [26].
abilities, as this has been shown to enhance antimalarial efficacy
against both CQ-sensitive and CQ-resistant strains of P. falciparum
[33].
2. Result and discussion
Chalcones represent key structural motifs among biologically
active molecules, and they are key intermediates for combinatorial
assembly of heterocyclic scaffolds. Synthetic manoeuvring of
chalcones or their isolation from natural sources are being inves-
tigated because of their many relevant properties including anti-
oxidant, antitumour, anti-inflammatory, antibacterial, and
antiprotozoan activities [27,28]. The discovery of the oxygenated
chalcone Licochalcone A as a potential antimalarial agent [29]
encouraged researchers to design and synthesize variably func-
tionalized chalcones and to assess their antimalarial efficacies. The
antimalarial potential of chalcones is augmented by their ability to
inhibit both plasmodial aspartate and cysteine proteases [30],
which are potential novel chemotherapeutic targets [31].
Continuing our efforts in the synthesis of molecular conjugates and
their antimalarial evaluation [32], we now describe the synthesis
and characterization of amide tethered 7-chloroquinolinee
chalcones and 7-chloroquinolineeferrocenyl chalcones. The intro-
duction of an amide as linker is based on its hydrogen bonding
2.1. Synthetic chemistry
The synthetic methodology involved an initial base-promoted
treatment of 4-hydroxybenzaldehyde 1 with bromoacetic acid in
water as solvent under refluxing conditions for 4e5 h to yield (4-
Formyl-phenoxy)-acetic acid 2. The aldol condensation of 2 with
substituted acetophenones afforded the substituted chalcones 3
and 4. These precursors were then utilized to provide an access to
the desired amide tethered 7-chloroquinolineechalcone conju-
gates. However, no significant reaction was observed, possibly
because of the poor solubility of these chalcones in DMF. The
approach was thus refined, with an initial DCC-HOBt promoted
coupling of 2 with 4-diamino-7-chloroquinolines 5 having varied
spacer length, to yield the corresponding amide 6. Aldol conden-
sation of 6 with varied acetophenones at room temperature for
0.5e2 h yielded the desired conjugates 7 and 8 in good to excellent
yields (Scheme 1).
The structures of the synthesized conjugates were assigned on
Scheme 1. Synthesis of amide-tethered 7-chloroquinoline chalcone conjugates 7ae7h and 7-chloroquinoline ferrocenylchalcone conjugates 8ae8d.

232
R. Raj et al. / European Journal of Medicinal Chemistry 95 (2015) 230e239
the basis of spectral data and analytical evidence. For example, 7c
showed a molecular ion peak [M]þ at 513.1813 in its mass spectrum,
while the 1H NMR spectrum showed the presence of multiplets at
chalcone, confirming the structure assigned to the desired product
15b.
d
1.87 and 3.45 due to four methylene protons of the butyl diamine
of chloroquinoline along with a singlet at 4.58 corresponding to
methylene ether protons, and the characteristic quinoline ring
protons. The presence of the required number of carbons in the 13
2.2. In vitro antiplasmodial activity
d
The synthesized conjugates were assayed for their antimalarial
activities against the CQ-resistant W2 strain of P. falciparum
(Table 1). The synthesized conjugates were not as active as arte-
misinin, and few of the conjugates showed activity comparable to
that of chloroquine. The substituted chalcones 3, 11 and their fer-
rocenyl counterparts 4, 12 were ineffective in inhibiting the growth
of P. falciparum even at the highest tested concentrations. The
precursors 6ae6d with a 7-chloroquinoline nucleus, exhibited
antimalarial activity dependent upon the length of the alkyl chain
introduced as a linker. The conjugate 6b, with propyl linker, proved
to be the most potent of these precursors, exhibiting an IC50 of
73.4 nM. Activity decreases substantially with increase in chain
length.
C
NMR spectrum along with two carbonyls at
further confirmed the assigned the structure.
The approach was then extended using 4-hydroxyacetophenone
9 as the starting material. The initial treatment of 9 with bromo-
acetic acid led to the isolation of corresponding (4-Acetyl-phe-
noxy)-acetic acid 10, which upon DCC-HOBt promoted coupling
d 162.0 and 187.9
with 4-diamino-7-chloroquinolines
5 and subsequent aldol
condensation with variedly substituted aldehydes led to the syn-
thesis of 7-chloroquinolineechalcone conjugates 14 and 15 in good
to excellent yields (Scheme 2). Amide coupling was also attempted
between 5 and chalcones 11 and 12, but without success, likely due
to solubility issues. The structures of the synthesized hybrids were
assigned on the basis of spectral data and analytical evidence,
discussed in detail in the experimental section, while some salient
Analysing the activity profiles among conjugates 7ae7h
revealed an interesting structureeactivity relationship, with ac-
tivity showing marked dependence upon the length of the alkyl
chain as well as the nature of the substituent present. The conju-
gates 7ae7d (R]H) showed improvement in activity profiles with
features include the appearance of two doublets at
with a J value of 15.7 Hz, corresponding to the trans protons of
d 7.86 and 8.15
Scheme 2. Synthesis of amide-tethered 7-chloroquinoline chalcone conjugates 14ae14h and 7-chloroquinoline ferrocenylchalcone conjugates 15ae15d.

R. Raj et al. / European Journal of Medicinal Chemistry 95 (2015) 230e239
233
Table 1
Table 2
Antimalarial activities of synthesized compounds.
Cytotoxicity and Selective index of conjugates 7h and 14h.
Compound
R
n
W2 (CQ-R)a
IC50(nM) Std. deviation
Compound
Cytotoxicitya
M)
P. falciparumb
SIc
(
m
IC50(nM)
3a
3b
4
6a
6b
6c
6d
7a
7b
7c
7d
7e
7f
7g
7h
8a
H
OCH3
e
e
e
e
1
2
3
5
1
2
3
5
1
2
3
5
1
2
3
5
e
e
e
1
2
3
5
1
2
3
5
1
2
3
5
1
2
3
5
>10,000
>10,000
>10,000
7h
14h
40
25
35.4
17.8
1129
1404
a
e
419.4 40.7
73.4 11.1
443.7 8.1
875.2 59.3
905.3 75.0
109.4 20.8
139.4 156.4
ND
CQ-R: Chloroquine resistant strain.
Cytotoxicity against HeLa cell line.
SI: Selective index is ratio of IC50 value of HeLa cell line to that of W2 resistant
b
c
e
e
e
strain.
H
H
H
H
OCH3
OCH3
OCH3
OCH3
e
and therefore had selectivity for inhibition of P. falciparum.
In conclusion, we describe herein the synthesis of amide
tethered 7-chloroquinolineechalcone and 7-chloroquinolinee
ferrocenylchalcone conjugates along with their antimalarial eval-
uation against cultured P. falciparum. Antiplasmodial activity
profiles of tested compounds showed the dependence of activity
on the length of the alkyl chain. The 7-chloroquinolineechalcone
conjugates were more potent than their corresponding 7-
chloroquinolineeferrocenylchalcone counterparts. The most
potent of the synthesized compounds, which had along alkyl
chain (n ¼ 5) and a methoxy substituent present on the para
position of ring B, exhibited activity comparable to that of CQ,
with an IC50 value of 17.8 nM. Further work on the improvement
of activity profiles of the reported amide-tethered 7-
chloroquinoline chalcone conjugates is currently underway.
378.9 1.1
221.1 18.2
63.0 2.9
35.4 8.0
1039.7 96.5
330.2 177.1
692.0 50.3
382.6 41.9
>10,000
8b
8c
8d
11a
11b
12
e
e
e
H
OCH3
e
>10,000
>10,000
13a
13b
13c
13d
14a
14b
14c
14d
14e
14f
14g
14h
15a
15b
15c
15d
CQ
ART
e
558.0 8.5
173.2 12.7
147.6 10.9
71.1 5.8
840.2 221.7
46.3 4.9
398.3 17.7
4074.0 502.0
2735.0 338.0
50.5 1.1
170.1 21.1
17.8 8.0
3540.0 328.1
729.0 122.8
575.4 166.3
157.0 0.7
15.9 1.8
e
e
e
H
H
H
H
OCH3
OCH3
OCH3
OCH3
e
3. Experimental section
Melting points were determined by open capillary using a 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
and dimethylsulfoxide-d6 with a Jeol 300 (300 MHz) spectrometer
using TMS as an internal standard. Chemical shift values are
expressed as parts per million downfield from TMS and J values are
in hertz. Splitting patterns are 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
Bruker500 (125 MHz) spectrometer in dimethylsulfoxide using
TMS as internal standard. High resolution mass spectra were
recorded on Bruker-micrOTOF-Q II spectrometer.
e
e
e
6.5 0.2
a
CQ-R: Chloroquine-resistant strain.
increase in chain length. The introduction of a methoxy substituent
on ring B resulted in considerable improvement in antimalarial
efficacy, with conjugates 7ee7h showing IC50s in the range of
35.5e378 nM. The activity improved considerably with chain
length, with the most potent of the synthesized conjugates along
with n ¼ 5, exhibiting an IC50 of 35.5 nM. The introduction of a
ferrocene ring among synthesized conjugates 8ae8d did not
improve the activity profiles compared to their organic
counterparts.
Similar comparison among the precursors 13ae13d again
revealed the dependence of activity profiles upon the length of the
alkyl chain, with conjugate 13d (n ¼ 5) exhibiting an IC50 of 71.1 nM.
Structure activity relationship analysis among conjugates, 14ae14h
showed the dependence of activity on the length of the alkyl chain
introduced as a spacer as well as the substituent on the ring. Among
the conjugates 14ae14d (R]H), compound 14b, with propyl linker,
displayed an IC50 value of 46.3 nM. The introduction of a methoxy
substituent enhanced the activity profiles, with conjugates 14f
(propyl linker) and 14h (hexyl linker) exhibiting an IC50s of 50.5 and
17.8 nM. The introduction of a ferrocene nucleus again did not
improve the antimalarial efficacy, except for conjugate 15d (n ¼ 5),
with an IC50 value of 157 nM.
3.1. General procedure for the synthesis of precursor 6
To the stirred solution of (4-Formyl-phenoxy)-acetic acid
(1 mmol), prepared by reacting p-salicyaldehyde and bromoacetic
acid in presence of sodium hydroxide under refluxing conditions,
and diaminochloroquinoline (1 mmol) in DCM:DMF (20:80)
mixture was added triethylamine (1.5 mmol), HOBt (1.2 mmol) and
DCC (1.1 mmol). The reaction mixture was allowed to stir overnight
at room temperature and the progress was monitored using TLC.
After usual workup in ethyl acetate and water, combined organic
layers were collected, dried over anhydrous sodium sulphate and
evaporated under reduced pressure to yield crude product which
was purified via coloumn chromatography in neutral alumina using
95:5 (CHCl3: MeOH) mixture.
3.1.1. N-[2-(7-chloro-quinolin-4-ylamino)-ethyl]-2-(4-formyl-
phenoxy)-acetamide (6a)
Yield 85%; Off White Solid; 1H NMR (DMSO-d6, 300 MHz):
Cytotoxicity of two most potent compounds viz. 7h and 14h
were assessed against mammalian HeLa cells. As depicted in
Table 2, compounds were non-cytotoxic against mammalian cells
d
3.38e3.44 (m, 4H, 2ꢀ eCH2e), 4.64 (s, 2H, eOeCH2e), 6.58 (d,
J ¼ 5.4 Hz,1H, H2), 7.11 (d, J ¼ 8.7 Hz, 2H, ArH),7.44 (d, J ¼ 8.4 Hz, 2H,
H4 þ eNHe exchangeable with D2O), 7.78e7.83 (m, 3H, H5 þ 2ArH),

234
R. Raj et al. / European Journal of Medicinal Chemistry 95 (2015) 230e239
8.15 (d, J ¼ 8.7 Hz, 1H, H3), 8.40 (d, J ¼ 5.4 Hz, 2H, H1 þ eNHe
exchangeable with D2O), 9.83 (s, 1H, eCHO); 13C NMR (DMSO-d6,
125 MHz): 42.4, 47.9, 67.4, 99.0, 115.6, 117.8, 124.3, 124.6, 127.8,
130.5, 132.1, 149.2, 150.6, 152.1, 157.0, 162.9, 168.1, 191.7; HRMS:
Calcd for C20H18ClN3O3 [M]þ 383.1037, found 383.1030; Anal. Calcd
(%) for: C, 62.58; H, 4.73; N, 10.95, found: C, 62.64; H, 4.78; N, 10.87.
3.2.1. N-[2-(7-chloro-quinolin-4-ylamino)-ethyl]-2-[4-(3-oxo-3-
phenyl-propenyl)-phenoxy]-acetamide (7a)
Yield 93%; Light Yellow Solid; 1H NMR (CDCl3, 300 MHz):
d
3.36e3.46 (m, 4H, 2ꢀ eCH2e), 4.20 (s, 1H, eNHe exchangeable
with D2O), 4.62 (s, 2H, eOeCH2e), 6.40 (d, J ¼ 5.4 Hz, 1H, H2), 6.85
(s, 1H, eNHe exchangeable with D2O), 6.88e6.95 (m, 4H,
H4 þ 2ArH þ olefinic-H), 7.34 (d, J ¼ 7.8 Hz, 1H, H3), 7.40 (d,
J ¼ 15.6 Hz, 1H, olefinic-H), 7.47e7.55 (m, 3H, ArH),7.81 (d,
J ¼ 9.0 Hz, 2H, ArH),7.89 (s,1H, H5), 8.05 (d, J ¼ 8.7 Hz, 2H, ArH), 8.49
(d, J ¼ 5.4 Hz, 1H, H1); 13C NMR (DMSO-d6, 125 MHz): 39.6, 46.5,
67.1, 99.0, 114.9, 117.3, 120.1, 123.8, 124.6, 125.1, 126.4, 127.8, 130.5,
131.2, 132.0, 135.1, 143.8, 147.1, 150.2, 151.6, 157.3, 162.1, 167.7, 188.0;
HRMS: Calcd for C28H24ClN3O3 [M]þ 485.1506 found 485.1516;
Anal. Calcd (%) for: C, 69.20; H, 4.98; N, 8.65, found: C, 69.07; H,
4.91; N, 8.72.
3.1.2. N-[3-(7-chloro-quinolin-4-ylamino)-propyl]-2-(4-formyl-
phenoxy)-acetamide (6b)
Yield 76%; Off White Solid; 1H NMR (DMSO-d6, 300 MHz):
d
1.80e1.86 (m, 2H, eCH2e), 3.28e3.38 (s, 4H, 2ꢀ eCH2e), 4.60 (s,
2H, eOeCH2e), 6.59 (d, J ¼ 5.1 Hz, 1H, H2), 7.14 (d, J ¼ 8.7 Hz, 2H,
ArH),7.44 (d, J ¼ 8.4 Hz, 2H, H4 þ eNHe exchangeable with D2O),
7.80e7.85 (m, 3H, H5 þ 2ArH), 8.12 (d, J ¼ 8.7 Hz, 1H, H3), 8.40 (d,
J ¼ 5.1 Hz, 2H, H1 þ eNHe exchangeable with D2O), 9.80 (s, 1H,
eCHO); 13C NMR (DMSO-d6, 125 MHz): 29.8, 41.0, 47.3, 67.5, 99.2,
114.9, 117.4, 124.3, 124.7, 127.9, 130.8, 132.3, 149.1, 150.7, 152.3, 157.2,
162.8, 168.4, 191.5; HRMS: Calcd for C21H20ClN3O3 [M]þ 397.1193,
found 397.1202; Anal. Calcd (%) for: C, 63.40; H, 5.07; N, 10.56,
found: C, 63.52; H, 5.15; N, 10.45.
3.2.2. N-[3-(7-chloro-quinolin-4-ylamino)-propyl]-2-[4-(3-oxo-3-
phenyl-propenyl)-phenoxy]-acetamide (7b)
Yield 85%; Light Yellow Solid; 1H NMR (CDCl3, 300 MHz):
d1.92e2.06 (m, 2H, eCH2-), 3.35e3.47 (m, 4H, 2ꢀ eCH2e), 4.22 (s,
1H, eNHe exchangeable with D2O), 4.52 (s, 2H, eOeCH2e), 6.40 (d,
J ¼ 5.1 Hz, 1H, H2), 6.81 (s, 1H, eNHe exchangeable with D2O),
6.90e6.98 (m, 4H, H4 þ 2ArH þ olefinic-H), 7.29 (d, J ¼ 7.8 Hz, 1H,
H3), 7.46 (d, J ¼ 15.6 Hz, 1H, olefinic-H), 7.48e7.56 (m, 3H, ArH),7.80
(d, J ¼ 9.0 Hz, 2H, ArH),7.96 (s, 1H, H5), 8.06 (d, J ¼ 8.7 Hz, 2H, ArH),
8.53 (d, J ¼ 5.1 Hz, 1H, H1); 13C NMR (DMSO-d6, 125 MHz): 30.9,
37.0, 47.1, 67.5, 99.1, 115.3, 117.7, 119.9, 124.8, 125.4, 125.7, 126.4,
128.0, 130.9, 131.3, 132.2, 135.1, 143.6, 147.3, 150.6,151.5, 157.3, 162.2,
167.5, 187.8; HRMS: Calcd for C29H26ClN3O3 [M]þ 499.1663, found
499.1651; Anal. Calcd (%) for: C, 69.66; H, 5.24; N, 8.40, found: C,
69.75; H, 5.31; N, 8.50.
3.1.3. N-[4-(7-chloro-quinolin-4-ylamino)-butyl]-2-(4-formyl-
phenoxy)-acetamide (6c)
Yield 81%; Off White Solid; 1H NMR (DMSO-d6, 300 MHz):
d1.65e1.71 (m, 2H, eCH2e),1.80e1.89 (m, 2H, eCH2e),3.25e3.37 (s,
4H, 2ꢀ eCH2e), 4.63 (s, 2H, eOeCH2e), 6.57 (d, J ¼ 5.1 Hz, 1H, H2),
7.13 (d, J ¼ 8.7 Hz, 2H, ArH),7.45 (d, J ¼ 8.4 Hz, 1H, H4), 7.49 (s, 1H,
eNHe exchangeable with D2O), 7.79e7.84 (m, 3H, H5 þ 2ArH), 8.11
(d, J ¼ 8.7 Hz, 1H, H3), 8.40 (d, J ¼ 5.1 Hz, 1H, H1), 8.42 (s, 1H, eNHe
exchangeable with D2O), 9.82 (s, 1H, eCHO); 13C NMR (DMSO-d6,
125 MHz): 25.4, 26.3, 41.6, 47.8, 67.4, 99.1, 115.2, 117.5, 124.5, 124.7,
127.8, 130.4, 132.7, 149.3, 150.4, 152.9, 157.0, 162.6, 168.1, 191.7;
HRMS: Calcd for C22H22ClN3O3 [M]þ 411.1350, found 411.1345; Anal.
Calcd (%) for: C, 64.15; H, 5.38; N, 10.20, found: C, 64.07; H, 5.49; N,
10.26.
3.2.3. N-[4-(7-chloro-quinolin-4-ylamino)-butyl]-2-[4-(3-oxo-3-
phenyl-propenyl)-phenoxy]-acetamide (7c)
Yield 85%; Light Yellow Solid; 1H NMR (CDCl3, 300 MHz):
d1.70e2.05 (m, 4H, 2ꢀ eCH2e), 3.40e3.51 (m, 4H, 2ꢀ eCH2e), 4.25
(s, 1H, eNHe exchangeable with D2O), 4.58 (s, 2H, eOeCH2e), 6.37
(d, J ¼ 5.7 Hz, 1H, H2), 6.77 (s, 1H, eNHe exchangeable with D2O),
6.85e6.92 (m, 4H, H4 þ 2ArH þ olefinic-H), 7.36 (d, J ¼ 7.8 Hz, 1H,
H3), 7.40 (d, J ¼ 15.6 Hz, 1H, olefinic-H), 7.45e7.53 (m, 3H, ArH),7.81
(d, J ¼ 9.0 Hz, 2H, ArH),7.91 (s, 1H, H5), 8.02 (d, J ¼ 8.7 Hz, 2H, ArH),
8.56 (d, J ¼ 5.1 Hz, 1H, H1); 13C NMR (DMSO-d6, 125 MHz): 27.0,
28.2, 37.3, 47.8, 67.5, 99.3, 115.1, 117.6, 119.8, 124.5, 125.2, 125.6,
126.0, 127.9, 130.9, 131.2, 132.4, 134.9, 143.8, 147.2, 150.1, 151.7, 157.2,
162.0, 167.8, 187.9; HRMS: Calcd for C30H28ClN3O3 [M]þ 513.1819,
found 513.1813; Anal. Calcd (%) for: C, 70.10; H, 5.49; N, 8.17, found:
C, 70.23; H, 5.41; N, 8.08.
3.1.4. N-[6-(7-chloro-quinolin-4-ylamino)-hexyl]-2-(4-formyl-
phenoxy)-acetamide (6d)
Yield 80%; Off White Solid; 1H NMR (DMSO-d6, 300 MHz):
d
1.42e1.59 (m, 6H, 3ꢀ eCH2e), 1.76e1.85 (m, 2H,
eCH2e),3.30e3.45 (m, 4H, 2ꢀ eCH2e), 4.65 (s, 2H, eOeCH2e), 6.61
(d, J ¼ 5.4 Hz, 1H, H2), 7.11 (d, J ¼ 8.7 Hz, 2H, ArH),7.45 (d, J ¼ 8.4 Hz,
2H, H4 þ eNHe exchangeable with D2O), 7.82e7.87 (m, 3H,
H5 þ 2ArH), 8.13 (d, J ¼ 8.7 Hz, 1H, H3), 8.39 (d, J ¼ 5.4 Hz, 1H, H1),
8.43 (s, 1H, eNHe exchangeable with D2O), 9.87 (s, 1H, eCHO); 13
C
NMR (DMSO-d6, 125 MHz): 25.4, 25.7, 28.9, 30.2, 41.9, 46.8, 67.4,
99.0, 115.0, 117.5, 124.1, 124.5, 127.7, 130.5, 132.6, 149.3, 150.9, 152.4,
157.2, 162.6, 168.1, 191.8; HRMS: Calcd for C24H26ClN3O3 [M]þ
439.1663, found 439.1670; Anal. Calcd (%) for: C, 65.52; H, 5.96; N,
9.55, found: C, 65.66; H, 6.04; N, 9.62.
3.2.4. N-[6-(7-chloro-quinolin-4-ylamino)-hexyl]-2-[4-(3-oxo-3-
phenyl-propenyl)-phenoxy]-acetamide (7d)
Yield 89%; Light Yellow Solid; 1H NMR (CDCl3 þ DMSO-d6,
300 MHz):
d1.52e1.72 (m, 6H, 3ꢀ eCH2e), 1.90e2.03 (m, 2H,
3.2. General procedure for the synthesis of amide-tethered 7-
chloroquinoline chalcone conjugates 7 and 7-chloroquinoline
ferrocenylchalcone conjugates 8
eCH2e),3.36e3.47 (m, 4H, 2ꢀ eCH2e), 4.18 (s, 1H, eNHe
exchangeable with D2O), 4.61 (s, 2H, eOeCH2e), 6.39 (d, J ¼ 5.4 Hz,
1H, H2), 6.82 (s, 1H, eNHe exchangeable with D2O), 6.91e6.98 (m,
4H, H4 þ 2ArH þ olefinic-H), 7.28 (d, J ¼ 7.8 Hz, 1H, H3), 7.40 (d,
J ¼ 15.6 Hz, 1H, olefinic-H), 7.44e7.53 (m, 3H, ArH),7.77 (d,
J ¼ 9.3 Hz, 2H, ArH),7.91 (s,1H, H5), 8.00 (d, J ¼ 8.7 Hz, 2H, ArH), 8.47
(d, J ¼ 5.4 Hz, 1H, H1); 13C NMR (DMSO-d6, 125 MHz): 26.1, 26.6,
29.2, 30.4, 37.5, 47.7, 67.1, 99.0, 115.0, 117.4, 120.1, 124.7, 125.3, 125.8,
126.1, 127.8, 130.9, 131.6, 132.3, 134.7, 143.9, 147.0, 150.1, 151.6, 157.3,
162.2, 167.6, 188.0; HRMS: Calcd for C32H32ClN3O3 [M]þ 541.2132,
found 541.2144; Anal. Calcd (%) for: C, 70.90; H, 5.95; N, 7.75, found:
C, 70.97; H, 5.86; N, 7.83.
To a well stirred solution of 6 (1 mmol) in ethanol, appropriate
acetophenone (acetophenone/4-methoxyacetophenone/ferroce-
nylacetophenone) (1 mmol) along with 40% (w/v) sodium hy-
droxide solution was added sequentially into the reaction mixture.
The progress of the reaction was monitored using TLC. The pre-
cipitates obtained were washed with dilute HCl solution, excess of
water, dried in air and finally recrystallized with methanol to obtain
conjugates 7 or 8.

R. Raj et al. / European Journal of Medicinal Chemistry 95 (2015) 230e239
235
3.2.5. N-[2-(7-chloro-quinolin-4-ylamino)-ethyl]-2-{4-[3-(4-
3.2.9. N-[2-(7-chloro-quinolin-4-ylamino)-ethyl]-2-[4-(3-oxo-3-
methoxy-phenyl)-3-oxo-propenyl]-phenoxy}-acetamide (7e)
ferrocenyl-propenyl)-phenoxy]-acetamide (8a)
Yield 89%; Light Yellow Solid; 1H NMR (CDCl3, 300 MHz):
Yield 79%; Dark Red Solid; 1H NMR (CDCl3 þ DMSO-d6,
d3.37e3.48 (m, 4H, 2ꢀ eCH2e), 3.89 (s, 3H, eOCH3), 4.21 (s, 1H,
300 MHz):
d
3.35e3.43 (m, 4H, 2ꢀ eCH2e), 4.12 (s, 5H, Ferrocenyl-
eNHe exchangeable with D2O), 4.58 (m, 2H, eOeCH2e), 6.36 (d,
J ¼ 5.7 Hz, 1H, H2), 6.83 (s, 1H, eNHe exchangeable with D2O),
6.90e6.97 (m, 4H, H4 þ 2ArH þ olefinic-H), 7.30 (d, J ¼ 7.8 Hz, 1H,
H3), 7.42 (d, J ¼ 15.6 Hz, 1H, olefinic-H), 7.58 (d, J ¼ 8.4 Hz, 2H,
ArH),7.80 (d, J ¼ 9.0 Hz, 2H, ArH),7.94 (s, 1H, H5), 8.02 (d, J ¼ 8.7 Hz,
2H, ArH), 8.46 (d, J ¼ 5.1 Hz, 1H, H1); 13C NMR (DMSO-d6, 125 MHz):
39.2, 46.6, 55.9, 67.3, 99.1, 114.8, 117.2, 119.7, 123.9, 124.8, 125.2,
126.2, 127.7, 130.7, 131.3, 132.2, 135.0, 144.1, 147.4, 150.3, 151.5, 157.2,
162.0, 167.9, 187.9; HRMS: Calcd for C29H26ClN3O4 [M]þ 515.1612
found 515.1605; Anal. Calcd (%) for: C, 67.50; H, 5.08; N, 8.14, found:
C, 67.42; H, 5.20; N, 8.08.
H), 4.49 (s, 2H, Ferrocenyl-H), 4.59 (s, 2H, Ferrocenyl-H), 4.70 (s, 2H,
eOeCH2e), 5.57 (s, 1H, eNHe exchangeable with D2O), 6.42 (s, 1H,
eNHe exchangeable with D2O), 6.57 (d, J ¼ 5.4 Hz, 1H, H2),
6.96e7.04 (m, 3H, 2ArH þ olefinic-H),7.42 (d, J ¼ 8.4 Hz, 1H, H4),
7.59 (d, J ¼ 15.9 Hz, olefinic-H), 7.86 (d, J ¼ 8.1 Hz, 2H, 2ArH), 8.02 (d,
J ¼ 8.1 Hz, 1H, H3), 8.13 (s, 1H, H5), 8.33 (d, J ¼ 5.4 Hz, 1H, H1); 13C
NMR (DMSO-d6, 125 MHz): 42.0, 47.4, 67.6, 68.5, 69.5, 69.8, 71.6,
99.5, 115.6, 117.8, 120.3, 124.3, 125.0, 127.8, 130.5, 132.1, 144.5, 149.2,
150.6, 152.1, 157.0, 162.9, 167.2, 188.3; HRMS: Calcd for
C
32H28ClFeN3O3 [M]þ 593.1169, found 593.1160; Anal. Calcd (%) for:
C, 64.72; H, 4.75; N, 7.08, found: C, 64.84; H, 4.89; N, 7.01.
3.2.10. N-[3-(7-chloro-quinolin-4-ylamino)-propyl]-2-[4-(3-oxo-3-
ferrocenyl-propenyl)-phenoxy]-acetamide(8b)
3.2.6. N-[3-(7-chloro-quinolin-4-ylamino)-propyl]-2-{4-[3-(4-
methoxy-phenyl)-3-oxo-propenyl]-phenoxy}-acetamide (7f)
Yield 80%; Light Yellow Solid; 1H NMR (CDCl3, 300 MHz):
Yield 84%; Dark Red Solid; 1H NMR (CDCl3 þ DMSO-d6,
300 MHz):
d
1.99e2.08 (m, 2H, eCH2e),3.38e3.46 (m, 4H, 2ꢀ
d
1.90e2.04 (m, 2H, eCH2e), 3.40e3.51 (m, 4H, 2ꢀ eCH2e), 3.85 (s,
eCH2e), 4.15 (s, 5H, Ferrocenyl-H), 4.50 (s, 2H, Ferrocenyl-H), 4.61
(s, 2H, Ferrocenyl-H), 4.68 (s, 2H, eOeCH2e), 5.53 (s, 1H, eNHe
exchangeable with D2O), 6.44 (s, 1H, eNHe exchangeable with
D2O), 6.56 (d, J ¼ 5.4 Hz, 1H, H2), 6.95e7.03 (m, 3H, 2ArH þ olefinic-
H),7.41 (d, J ¼ 8.4 Hz,1H, H4), 7.59 (d, J ¼ 15.9 Hz, olefinic-H), 7.85 (d,
J ¼ 8.1 Hz, 2H, 2ArH), 8.01 (d, J ¼ 8.1 Hz,1H, H3), 8.14 (s, 1H, H5), 8.32
(d, J ¼ 5.4 Hz, 1H, H1); 13C NMR (DMSO-d6, 125 MHz): 29.8, 37.2,
47.5, 67.4, 68.4, 69.3, 69.7, 71.5, 99.3, 115.0, 117.2, 120.1, 124.4, 125.1,
127.7, 130.4, 132.2, 143.9, 149.3, 150.5, 152.0, 157.1, 162.9, 167.6,
188.2; HRMS: Calcd for C33H30ClFeN3O3 [M]þ 607.1325, found
607.1315; Anal. Calcd (%) for: C, 65.20; H, 4.97; N, 6.91, found: C,
65.32; H, 5.05; N, 6.82.
3H, eOCH3), 4.20 (s, 1H, eNHe exchangeable with D2O), 4.56 (s, 2H,
eOeCH2e), 6.41 (d, J ¼ 5.1 Hz, 1H, H2), 6.80 (s, 1H, eNHe
exchangeable with D2O), 6.88e6.95 (m, 4H, H4 þ 2ArH þ olefinic-
H), 7.30 (d, J ¼ 7.8 Hz, 1H, H3), 7.42 (d, J ¼ 15.6 Hz, 1H, olefinic-H),
7.57 (d, J ¼ 8.4 Hz, 2H, ArH),7.79 (d, J ¼ 9.0 Hz, 2H, ArH),7.97 (s,
1H, H5), 8.03 (d, J ¼ 8.7 Hz, 2H, ArH), 8.50 (d, J ¼ 5.1 Hz, 1H, H1); 13
C
NMR (DMSO-d6, 125 MHz): 30.5, 36.5, 47.8, 55.4, 67.6, 99.2, 115.1,
117.6, 119.8,124.5, 125.3,125.6,126.2,127.9,130.6,131.4, 132.1, 135.0,
144.1, 147.4, 150.3, 151.7, 157.2, 161.8, 167.7, 188.0; HRMS: Calcd for
C
30H28ClN3O4 [M]þ 529.1768, found 529.1752; Anal. Calcd (%) for: C,
67.98; H, 5.32; N, 7.93, found: C, 68.08; H, 5.38; N, 7.78.
3.2.7. N-[4-(7-chloro-quinolin-4-ylamino)-butyl]-2-{4-[3-(4-
methoxy-phenyl)-3-oxo-propenyl]-phenoxy}-acetamide (7g)
Yield 86%; Light Yellow Solid; 1H NMR (CDCl3, 300 MHz):
3.2.11. N-[4-(7-chloro-quinolin-4-ylamino)-butyl]-2-[4-(3-oxo-3-
ferrocenyl-propenyl)-phenoxy]-acetamide(8c)
Yield 76%; Dark Red Solid; 1H NMR (CDCl3 þ DMSO-d6,
d
1.66e2.07 (m, 4H, 2ꢀ eCH2e), 3.33e3.47 (m, 4H, 2ꢀ eCH2e), 3.88
300 MHz):
d1.66e1.91 (m, 4H, 2ꢀ eCH2e), 3.32e3.41 (m, 4H, 2ꢀ
(s, 3H, eOCH3), 4.25 (s, 1H, eNHe exchangeable with D2O), 4.54 (s,
2H, eOeCH2e), 6.37 (d, J ¼ 5.7 Hz, 1H, H2), 6.80 (s, 1H, eNHe
exchangeable with D2O), 6.91e6.98 (m, 4H, H4 þ 2ArH þ olefinic-
H), 7.32 (d, J ¼ 7.8 Hz, 1H, H3), 7.43 (d, J ¼ 15.6 Hz, 1H, olefinic-H),
7.58 (d, J ¼ 8.4 Hz, 2H, ArH),7.77 (d, J ¼ 9.0 Hz, 2H, ArH),7.92 (s,
eCH2e), 4.17 (s, 5H, Ferrocenyl-H), 4.47 (s, 2H, Ferrocenyl-H), 4.60
(s, 2H, Ferrocenyl-H), 4.69 (s, 2H, eOeCH2e), 5.59 (s, 1H, eNHe
exchangeable with D2O), 6.42 (s, 1H, eNHe exchangeable with
D2O), 6.54 (d, J ¼ 5.4 Hz, 1H, H2), 6.99e7.06 (m, 3H, 2ArH þ olefinic-
H),7.45 (d, J ¼ 8.4 Hz,1H, H4), 7.58 (d, J ¼ 15.9 Hz, olefinic-H), 7.83 (d,
J ¼ 8.1 Hz, 2H, 2ArH), 8.00 (d, J ¼ 8.4 Hz,1H, H3), 8.12 (s,1H, H5), 8.30
(d, J ¼ 5.4 Hz, 1H, H1); 13C NMR (DMSO-d6, 125 MHz): 27.3, 28.2,
36.9, 47.3, 67.5, 68.3, 69.6, 69.9, 71.6, 99.1, 115.4, 117.8, 120.2, 124.4,
125.2, 127.9, 130.4, 132.2, 144.2, 149.3, 150.7, 152.2, 157.2, 162.7,
167.5, 187.9; HRMS: Calcd for C34H32ClFeN3O3 [M]þ 621.1482, found
621.1490; Anal. Calcd (%) for: C, 65.66; H, 5.19; N, 6.76, found: C,
65.59; H, 5.30; N, 6.68.
1H, H5), 8.01 (d, J ¼ 8.7 Hz, 2H, ArH), 8.49 (d, J ¼ 5.1 Hz, 1H, H1); 13
C
NMR (DMSO-d6, 125 MHz): 26.8, 28.1, 36.7, 47.9, 55.8, 67.4, 99.0,
115.0, 117.4, 119.8, 124.7, 125.1, 125.4, 126.1, 127.8, 130.8, 131.1, 132.2,
134.8,143.7,147.1, 150.4,151.6, 157.1, 161.9,167.8, 187.7; HRMS: Calcd
for C31H30ClN3O4 [M]þ 543.1925, found 543.1938; Anal. Calcd (%)
for: C, 68.44; H, 5.56; N, 7.72, found: C, 68.53; H, 5.48; N, 7.60.
3.2.8. N-[6-(7-chloro-quinolin-4-ylamino)-hexyl]-2-{4-[3-(4-
methoxy-phenyl)-3-oxo-propenyl]-phenoxy}-acetamide(7h)
Yield 91%; Light Yellow Solid; 1H NMR (CDCl3 þ DMSO-d6,
3.2.12. N-[6-(7-chloro-quinolin-4-ylamino)-hexyl]-2-[4-(3-oxo-3-
ferrocenyl-propenyl)-phenoxy]-acetamide (8d)
300 MHz):
d
1.50e1.70 (m, 6H, 3ꢀ eCH2e), 1.92e2.05 (m, 2H,
Yield 81%; Dark Red Solid; 1H NMR (CDCl3 þ DMSO-d6,
eCH2e),3.37e3.48 (m, 4H, 2ꢀ eCH2e), 3.90 (s, 3H, eOCH3), 4.23 (s,
1H, eNHe exchangeable with D2O), 4.55 (s, 2H, eOeCH2e), 6.36 (d,
J ¼ 5.4 Hz, 1H, H2), 6.84 (s, 1H, eNHe exchangeable with D2O),
6.93e7.00 (m, 4H, H4 þ 2ArH þ olefinic-H), 7.31 (d, J ¼ 7.8 Hz, 1H,
H3), 7.42 (d, J ¼ 15.6 Hz, 1H, olefinic-H), 7.61 (d, J ¼ 8.4 Hz, 2H,
ArH),7.76 (d, J ¼ 9.0 Hz, 2H, ArH),7.93 (s, 1H, H5), 7.99 (d, J ¼ 8.7 Hz,
2H, ArH), 8.49 (d, J ¼ 5.4 Hz,1H, H1); 13C NMR (DMSO-d6,125 MHz):
26.2, 26.7, 29.3, 30.1, 37.0, 47.8, 55.6, 67.5, 99.1, 114.9, 117.3, 120.0,
124.8, 125.2, 125.5, 126.2, 127.9, 130.8, 131.3, 132.5, 134.8, 143.6,
147.2, 150.3, 151.7, 157.4, 162.1, 167.4, 188.1; HRMS: Calcd for
300 MHz):
d1.01e1.74 (m, 8H, 4ꢀ eCH2e),3.24e3.33 (m, 4H, 2ꢀ
eCH2e), 4.13 (s, 5H, Ferrocenyl-H), 4.48 (s, 2H, Ferrocenyl-H), 4.54
(s, 2H, Ferrocenyl-H), 4.78 (s, 2H, eOeCH2e), 5.56 (s, 1H, eNHe
exchangeable with D2O), 6.43 (s, 1H, eNHe exchangeable with
D2O), 6.51 (d, J ¼ 5.1 Hz, 1H, H2), 6.98e7.05 (m, 3H, 2ArH þ olefinic-
H),7.40 (d, J ¼ 8.4 Hz,1H, H4), 7.58 (d, J ¼ 15.9 Hz, olefinic-H), 7.88 (d,
J ¼ 8.1 Hz, 2H, 2ArH), 8.03 (d, J ¼ 8.1 Hz,1H, H3), 8.12 (s,1H, H5), 8.30
(d, J ¼ 5.1 Hz, 1H, H1); 13C NMR (DMSO-d6, 125 MHz): 25.8, 26.6,
29.7, 30.8, 37.6, 47.4, 67.5, 68.0, 69.1, 69.6, 71.3, 99.2, 115.5, 117.7,
120.0, 124.2, 125.1, 127.6, 130.7, 132.4, 144.3, 149.0, 150.6, 152.4,
157.2, 162.7, 167.3, 188.1; HRMS: Calcd for C36H36ClFeN3O3 [M]þ
649.1795, found 649.1809; Anal. Calcd (%) for: C, 66.52; H, 5.58; N,
C
33H34ClN3O4 [M]þ 571.2238, found 571.2244; Anal. Calcd (%) for: C,
69.28; H, 5.99; N, 7.34, found: C, 69.36; H, 6.10; N, 7.49.

236
R. Raj et al. / European Journal of Medicinal Chemistry 95 (2015) 230e239
6.46, found: C, 66.64; H, 5.61; N, 6.40.
J ¼ 8.4 Hz, 1H, H4), 7.46 (s, 1H, eNHe exchangeable with D2O),
7.80e7.84 (m, 3H, H5 þ 2ArH), 8.16 (d, J ¼ 8.7 Hz, 1H, H3), 8.42 (d,
3.3. General procedure for the synthesis of precursor 13
J ¼ 5.4 Hz, 1H, H1), 8.46 (s, 1H, eNHe exchangeable with D2O); 13
C
NMR (DMSO-d6, 125 MHz): 22.5, 25.3, 25.9, 29.1, 30.0, 42.1, 47.1,
67.7, 99.4, 115.3, 117.6, 124.7, 125.1, 127.8, 130.6, 132.7, 149.2, 151.0,
152.3,157.4,162.5,168.2,195.0; HRMS: Calcd for C25H28ClN3O3 [M]þ
453.1819, found 453.1828; Anal. Calcd (%) for: C, 66.14; H, 6.22; N,
9.26, found: C, 66.26; H, 6.14; N, 9.35.
To the stirred solution of (4-Acetyl-phenoxy)-acetic acid
(1 mmol) and diaminochloroquinoline (1 mmol) in DCM:DMF
(20:80) mixture was added triethylamine (1.5 mmol), HOBt
(1.2 mmol) and DCC (1.1 mmol). The reaction mixture was allowed
to stir overnight at room temperature. On the completion of reac-
tion, as monitored by TLC, water (30 mL) was added into the re-
action mixture and extracted with ethyl acetate (2 ꢀ 60 mL).
Organic layers were collected, dried over anhydrous sodium sul-
phate and evaporated under reduced pressure to yield the crude
product which was purified via column chromatography on neutral
alumina using 95:5 (CHCl3: MeOH) mixture as eluent.
3.4. General procedure for the synthesis of amide-tethered 7-
chloroquinoline chalcone conjugates 14 and 7-chloroquinoline
ferrocenylchalcone conjugates 15
To the well stirred solution of 13 (1 mmol) in ethanol, appro-
priate acetophenone (acetophenone/4-methoxyacetophenone/fer-
rocenylacetophenone) (1 mmol) was added followed by the
addition of 40% (w/v) sodium hydroxide solution. The reaction
mixture was stirred till completion of starting material as evi-
denced by TLC. The precipitates obtained were washed with dilute
HCl solution and excess of water and finally recrystallized with
methanol to obtain conjugates 14 or 15.
3.3.1. 2-(4-Acetyl-phenoxy)-N-[2-(7-chloro-quinolin-4-ylamino)-
ethyl]-acetamide (13a)
Yield 73%; Off White Solid; 1H NMR (DMSO-d6, 300 MHz):
d2.45
(s, 3H, -CH3), 3.36e3.44 (m, 4H, 2ꢀ eCH2e), 4.66 (s, 2H, eOeCH2e),
6.57 (d, J ¼ 5.4 Hz, 1H, H2), 7.13 (d, J ¼ 8.7 Hz, 2H, ArH),7.43 (d,
J ¼ 8.4 Hz, 1H, H4), 7.47 (s, 1H, eNHe exchangeable with D2O),
7.77e7.82 (m, 3H, H5 þ 2ArH), 8.18 (d, J ¼ 8.7 Hz, 1H, H3), 8.40 (d,
3.4.1. N-[2-(7-chloro-quinolin-4-ylamino)-ethyl]-2-[4-(3-phenyl-
acryloyl)-phenoxy]-acetamide(14a)
J ¼ 5.4 Hz, 1H, H1), 8.42 (s, 1H, eNHe exchangeable with D2O); 13
C
NMR (DMSO-d6, 125 MHz): 21.9, 42.6, 48.0, 67.6, 99.4, 115.5, 117.7,
124.2, 124.9, 127.6, 130.6, 132.3, 149.0, 150.5, 152.2, 157.4, 163.1,
168.4, 194.9; HRMS: Calcd for C21H20ClN3O3 [M]þ 397.1193, found
397.1205; Anal. Calcd (%) for: C, 63.40; H, 5.07; N, 10.56, found: C,
63.56; H, 4.99; N, 10.47.
Yield 88%; Light Yellow Solid; 1H NMR (CDCl3, 300 MHz):
d
3.39e3.48 (m, 4H, 2ꢀ eCH2e), 4.20 (s, 1H, eNHe exchangeable
with D2O), 4.60 (s, 2H, eOeCH2e), 6.38 (d, J ¼ 5.4 Hz, 1H, H2), 7.01
(d, J ¼ 8.7 Hz, 2H, 2ArH), 7.24 (s,1H, eNHe exchangeable with D2O),
7.31 (d, J ¼ 9.0 Hz, 1H, H4), 7.41e7.45 (m, 3H, ArH), 7.53 (d,
J ¼ 15.6 Hz, 1H, olefinic-H), 7.64 (d, J ¼ 8.4 Hz, 2H, ArH),7.79 (d,
J ¼ 15.6 Hz, 1H, olefinic-H),7.92 (s, 1H, H5), 7.99 (d, J ¼ 9.0 Hz, 1H,
H3), 8.03 (d, J ¼ 8.4 Hz, 2H, ArH), 8.42 (d, J ¼ 5.1 Hz,1H, H1); 13C NMR
(DMSO-d6, 125 MHz): 40.7, 47.4, 67.4, 99.1, 115.2, 117.6, 119.8, 124.1,
125.2, 125.8, 126.4, 128.3, 130.7, 131.9, 132.4, 134.6, 143.6, 147.0,
150.3, 151.6, 157.5, 162.0, 167.9, 187.8; HRMS: Calcd for
3.3.2. 2-(4-Acetyl-phenoxy)-N-[3-(7-chloro-quinolin-4-ylamino)-
propyl]-acetamide(13b)
Yield 77%; Off White Solid; 1H NMR (DMSO-d6, 300 MHz):
d
1.81e1.88 (m, 2H, eCH2e), 2.49 (s, 3H, -CH3), 3.35e3.43 (m, 4H, 2ꢀ
eCH2e), 4.58 (s, 2H, eOeCH2e), 6.60 (d, J ¼ 5.4 Hz, 1H, H2), 7.16 (d,
J ¼ 8.7 Hz, 2H, ArH),7.45 (d, J ¼ 8.4 Hz, 2H, H4 þ eNHe
exchangeable with D2O), 7.81e7.86 (m, 3H, H5 þ 2ArH), 8.09 (d,
J ¼ 8.7 Hz, 1H, H3), 8.38 (d, J ¼ 5.4 Hz, 1H, H1), 8.41 (s, 1H, eNHe
exchangeable with D2O);13C NMR (DMSO-d6, 125 MHz): 21.8, 30.1,
41.2, 47.6, 67.8, 99.1, 115.2, 117.7, 124.2, 124.6, 127.8, 130.7, 132.4,
149.0, 150.6, 152.1, 157.4, 162.6, 168.5, 195.0; HRMS: Calcd for
C
28H24ClN3O3 [M]þ 485.1506, found 485.1516; Anal. Calcd (%) for: C,
69.20; H, 4.98; N, 8.65, found: C, 69.29; H, 5.07; N, 8.80.
3.4.2. N-[3-(7-chloro-quinolin-4-ylamino)-propyl]-2-[4-(3-phenyl-
acryloyl)-phenoxy]-acetamide(14b)
Yield 80%; Light Yellow Solid; 1H NMR (CDCl3, 300 MHz):
C
22H22ClN3O3 [M]þ 411.1350, found 411.1360; Anal. Calcd (%) for: C,
d
1.91e2.00 (m, 2H, eCH2e),3.44e3.52 (m, 4H, 2ꢀ eCH2e), 4.19 (s,
64.15; H, 5.38; N, 10.20, found: C, 64.22; H, 5.28; N, 10.08.
1H, eNHe exchangeable with D2O), 4.62 (s, 2H, eOeCH2e), 6.36 (d,
J ¼ 5.7 Hz, 1H, H2), 7.00 (d, J ¼ 8.7 Hz, 2H, 2ArH), 7.20 (s, 1H, eNHe
exchangeable with D2O), 7.32 (d, J ¼ 9.0 Hz, 1H, H4), 7.42e7.46 (m,
3H, ArH), 7.51 (d, J ¼ 15.3 Hz, 1H, olefinic-H), 7.63 (d, J ¼ 8.4 Hz, 2H,
ArH),7.81 (d, J ¼ 15.6 Hz, 1H, olefinic-H),7.91 (s, 1H, H5), 7.99 (d,
J ¼ 9.0 Hz, 1H, H3), 8.04 (d, J ¼ 8.4 Hz, 2H, ArH), 8.38 (d, J ¼ 5.1 Hz,
1H, H1); 13C NMR (DMSO-d6, 125 MHz): 28.1, 36.8, 47.9, 67.5, 99.1,
114.2, 114.4, 115.5, 117.9, 120.3, 124.5, 125.7, 127.9, 130.9, 131.0, 131.2,
133.8, 143.3, 149.5, 150.4, 152.3, 157.1, 163.5, 167.9, 187.7; HRMS:
Calcd for C29H26ClN3O3 [M]þ 499.1663, found 499.1670; Anal. Calcd
(%) for: C, 69.66; H, 5.24; N, 8.40, found: C, 69.56; H, 5.29; N, 8.49.
3.3.3. 2-(4-Acetyl-phenoxy)-N-[4-(7-chloro-quinolin-4-ylamino)-
butyl]-acetamide(13c)
Yield 71%; Off White Solid; 1H NMR (DMSO-d6, 300 MHz):
d
1.60e1.70 (m, 2H, eCH2e), 1.86e1.90 (m, 2H, 2ꢀ eCH2e), 2.46 (s,
3H, -CH3), 3.37e3.46 (m, 4H, 2ꢀ eCH2e), 4.62 (s, 2H, eOeCH2e),
6.59 (d, J ¼ 5.4 Hz, 1H, H2), 7.12 (d, J ¼ 8.7 Hz, 2H, ArH),7.42 (d,
J ¼ 8.4 Hz, 1H, H4), 7.46 (s, 1H, eNHe exchangeable with D2O),
7.78e7.83 (m, 3H, H5 þ 2ArH), 8.12 (d, J ¼ 8.7 Hz, 1H, H3), 8.41 (d,
J ¼ 5.1 Hz, 1H, H1), 8.45 (s, 1H, eNHe exchangeable with D2O); 13
C
NMR (DMSO-d6, 125 MHz): 22.1, 25.5, 26.3, 41.1, 47.7, 67.8, 99.0,
115.6, 117.4, 124.2, 124.8, 127.7, 130.5, 132.9, 149.2, 150.5, 153.1, 157.3,
162.8, 168.0, 195.2; HRMS: Calcd for C23H24ClN3O3 [M]þ 425.1506,
found 425.1520; Anal. Calcd (%) for: C, 64.86; H, 5.68; N, 9.87, found:
C, 64.97; H, 5.74; N, 9.78.
3.4.3. N-[4-(7-chloro-quinolin-4-ylamino)-butyl]-2-[4-(3-phenyl-
acryloyl)-phenoxy]-acetamide(14c)
Yield 82%; Light Yellow Solid; 1H NMR (CDCl3, 300 MHz):
d
1.71e2.10 (m, 4H, 2ꢀ eCH2e), 3.40e3.50 (m, 4H, 2ꢀ eCH2e), 4.21
(s, 1H, eNHe exchangeable with D2O), 4.59 (s, 2H, eOeCH2e), 6.36
(d, J ¼ 5.4 Hz, 1H, H2), 7.00 (d, J ¼ 8.7 Hz, 2H, 2ArH), 7.22 (s, 1H,
eNHe exchangeable with D2O), 7.30 (d, J ¼ 9.0 Hz, 1H, H4),
7.40e7.45 (m, 3H, ArH), 7.55 (d, J ¼ 15.6 Hz, 1H, olefinic-H), 7.63 (d,
J ¼ 8.4 Hz, 2H, ArH),7.80 (d, J ¼ 15.6 Hz, 1H, olefinic-H),7.90 (s, 1H,
H5), 7.97 (d, J ¼ 9.0 Hz, 1H, H3), 8.02 (d, J ¼ 8.4 Hz, 2H, ArH), 8.40 (d,
J ¼ 5.4 Hz, 1H, H1); 13C NMR (DMSO-d6, 125 MHz): 27.3, 28.0, 36.9,
3.3.4. 2-(4-Acetyl-phenoxy)-N-[6-(7-chloro-quinolin-4-ylamino)-
hexyl]-acetamide (13d)
Yield 80%; Off White Solid; 1H NMR (DMSO-d6, 300 MHz):
d
1.45e1.56 (m, 6H, 3ꢀ eCH2e), 1.77e1.86 (m, 2H, eCH2e), 2.48 (s,
3H, -CH3), 3.34e3.42 (m, 4H, 2ꢀ eCH2e), 4.62 (s, 2H, eOeCH2e),
6.60 (d, J ¼ 5.4 Hz, 1H, H2), 7.12 (d, J ¼ 8.7 Hz, 2H, ArH),7.43 (d,

R. Raj et al. / European Journal of Medicinal Chemistry 95 (2015) 230e239
237
47.6, 67.3, 99.0, 115.1, 117.5, 119.9, 123.9, 125.2, 126.3, 128.4, 130.8,
131.3, 131.6, 132.5, 134.7, 143.5, 147.2, 150.1, 151.6, 157.4, 162.1, 168.1,
187.9; HRMS: Calcd for
513.1827; Anal. Calcd (%) for: C, 70.10; H, 5.49; N, 8.17, found: C,
70.01; H, 5.56; N, 8.30.
J ¼ 9.0 Hz, 1H, H4), 7.40 (d, J ¼ 8.4 Hz, 2H, ArH), 7.56 (d, J ¼ 15.6 Hz,
1H, olefinic-H), 7.62 (d, J ¼ 8.4 Hz, 2H, ArH),7.82 (d, J ¼ 15.6 Hz, 1H,
olefinic-H),7.89 (s, 1H, H5), 7.99 (d, J ¼ 9.0 Hz, 1H, H3), 8.05 (d,
J ¼ 8.4 Hz, 2H, ArH), 8.44 (d, J ¼ 5.4 Hz, 1H, H1); 13C NMR (DMSO-d6,
125 MHz): 27.2, 28.1, 36.8, 47.5, 55.2, 67.1, 99.3, 114.9, 117.6, 119.9,
124.0, 125.3, 125.8, 126.4, 128.6, 130.9, 131.9, 132.6, 134.8, 143.7,
147.3, 150.2, 151.6, 157.5, 162.2, 168.3, 188.0; HRMS: Calcd for
C
30H28ClN3O3 [M]þ 513.1819, found
3.4.4. N-[6-(7-chloro-quinolin-4-ylamino)-hexyl]-2-[4-(3-phenyl-
acryloyl)-phenoxy]-acetamide(14d)
C
31H30ClN3O4 [M]þ 543.1925, found 543.1937; Anal. Calcd (%) for: C,
Yield 79%; Light Yellow Solid; 1H NMR (CDCl3, 300 MHz):
68.44; H, 5.56; N, 7.72, found: C, 68.54; H, 5.49; N, 7.80.
d1.52e1.70 (m, 6H, 3ꢀ eCH2e), 1.93e1.99 (m, 2H,
eCH2e),3.41e3.51 (m, 4H, 2ꢀ eCH2e), 4.15 (s, 1H, eNHe
exchangeable with D2O), 4.58 (s, 2H, eOeCH2e), 6.35 (d, J ¼ 5.4 Hz,
1H, H2), 7.01 (d, J ¼ 8.7 Hz, 2H, 2ArH), 7.18 (s, 1H, eNHe
exchangeable with D2O), 7.31 (d, J ¼ 9.0 Hz, 1H, H4), 7.40e7.45 (m,
3H, ArH), 7.52 (d, J ¼ 15.6 Hz, 1H, olefinic-H), 7.62 (d, J ¼ 8.4 Hz, 2H,
ArH),7.80 (d, J ¼ 15.6 Hz, 1H, olefinic-H),7.88 (s, 1H, H5), 7.98 (d,
J ¼ 9.0 Hz, 1H, H3), 8.02 (d, J ¼ 8.4 Hz, 2H, ArH), 8.41 (d, J ¼ 5.1 Hz,
1H, H1); 13C NMR (DMSO-d6, 125 MHz): 25.9, 26.8, 29.1, 29.8, 37.1,
47.8, 67.4, 99.2, 115.0, 117.6, 120.1, 124.1, 125.1, 126.4, 128.3, 130.8,
131.3, 131.7, 132.6, 134.8, 144.0, 147.6, 150.3, 151.8, 157.5, 162.1, 167.7,
3.4.8. N-[6-(7-chloro-quinolin-4-ylamino)-hexyl]-2-{4-[3-(4-
methoxy-phenyl)-acryloyl]-phenoxy}-acetamide(14h)
Yield 88%; Light Yellow Solid; 1H NMR (CDCl3, 300 MHz):
d1.66e1.83 (m, 6H, 3ꢀ eCH2e), 1.92e1.99 (m, 2H,
eCH2e),3.39e3.48 (m, 4H, 2ꢀ eCH2e), 3.90 (s, 3H, eOCH3), 4.20 (s,
1H, eNHe exchangeable with D2O), 4.62 (s, 2H, eOeCH2e), 6.40 (d,
J ¼ 5.4 Hz, 1H, H2), 7.04 (d, J ¼ 8.4 Hz, 2H, 2ArH), 7.22 (s, 1H, eNHe
exchangeable with D2O), 7.32 (d, J ¼ 9.0 Hz, 1H, H4), 7.44 (d,
J ¼ 8.4 Hz, 2H, ArH), 7.51 (d, J ¼ 15.6 Hz, 1H, olefinic-H), 7.62 (d,
J ¼ 8.4 Hz, 2H, ArH),7.77 (d, J ¼ 15.6 Hz, 1H, olefinic-H),7.90 (s, 1H,
H5), 8.00 (d, J ¼ 9.0 Hz, 1H, H3), 8.04 (d, J ¼ 8.4 Hz, 2H, ArH), 8.43 (d,
J ¼ 5.4 Hz, 1H, H1); 13C NMR (DMSO-d6, 125 MHz): 25.9, 26.7, 29.7,
30.5, 37.4, 47.6, 55.6, 67.3, 99.1, 115.1, 117.4, 120.2, 124.0, 125.2, 125.7,
126.4, 128.2, 131.3, 131.8, 132.5, 134.9, 144.2, 147.5, 150.1, 151.9, 157.7,
161.7, 167.5, 187.6; HRMS: Calcd for C33H34ClN3O4 [M]þ 571.2238,
found 571.2233; Anal. Calcd (%) for: C, 69.28; H, 5.99; N, 7.34, found:
C, 69.36; H, 5.83; N, 7.44.
188.2; HRMS: Calcd for
541.2140; Anal. Calcd (%) for: C, 70.90; H, 5.95; N, 7.75, found: C,
70.80; H, 5.82; N, 7.82.
C
32H32ClN3O3 [M]þ 541.2132, found
3.4.5. N-[2-(7-chloro-quinolin-4-ylamino)-ethyl]-2-{4-[3-(4-
methoxy-phenyl)-acryloyl]-phenoxy}-acetamide(14e)
Yield 90%; Light Yellow Solid; 1H NMR (CDCl3, 300 MHz):
d3.36e3.47 (m, 4H, 2ꢀ eCH2e), 3.89 (s, 3H, eOCH3), 4.24 (s, 1H,
eNHe exchangeable with D2O), 4.56 (s, 2H, eOeCH2e), 6.34 (d,
J ¼ 5.4 Hz, 1H, H2), 7.00 (d, J ¼ 8.7 Hz, 2H, 2ArH), 7.19 (s, 1H, eNHe
exchangeable with D2O), 7.33 (d, J ¼ 9.0 Hz, 1H, H4), 7.42 (d,
J ¼ 8.4 Hz, 2H, ArH), 7.52 (d, J ¼ 15.6 Hz, 1H, olefinic-H), 7.66 (d,
J ¼ 8.4 Hz, 2H, ArH),7.80 (d, J ¼ 15.6 Hz, 1H, olefinic-H),7.88 (s, 1H,
H5), 7.96 (d, J ¼ 9.0 Hz, 1H, H3), 8.01 (d, J ¼ 8.4 Hz, 2H, ArH), 8.48 (d,
J ¼ 5.4 Hz, 1H, H1); 13C NMR (DMSO-d6, 125 MHz): 38.5, 47.5, 55.2,
67.3, 99.0, 115.1, 117.6, 119.9, 123.7, 125.2, 125.6, 126.5, 128.4, 130.6,
131.7, 132.2, 134.7, 143.7, 147.1, 150.4, 151.5, 157.4, 161.8, 167.4, 188.2;
HRMS: Calcd for C29H26ClN3O4 [M]þ 515.1612, found 515.1617; Anal.
Calcd (%) for: C, 67.50; H, 5.08; N, 8.14, found: C, 67.58; H, 5.21; N,
8.20.
3.4.9. N-[2-(7-chloro-quinolin-4-ylamino)-ethyl]-2-[4-(3-
ferrocenyl-acryloyl)-phenoxy]-acetamide(15a)
Yield 80%; Dark Red Solid; 1H NMR (CDCl3 þ DMSO-d6,
300 MHz):
d
3.38e3.47 (m, 4H, 2ꢀ eCH2e), 4.13 (s, 5H, Ferrocenyl-
H), 4.51 (s, 2H, Ferrocenyl-H), 4.62 (s, 2H, Ferrocenyl-H), 4.69 (s, 2H,
eOeCH2e), 5.55 (s, 1H, eNHe exchangeable with D2O), 6.46 (s, 1H,
eNHe exchangeable with D2O), 6.56 (d, J ¼ 5.4 Hz, 1H, H2),
7.00e7.07 (m, 3H, 2ArH þ olefinic-H),7.40 (d, J ¼ 8.4 Hz, 1H, H4),
7.58 (d, J ¼ 15.9 Hz, olefinic-H), 7.87 (d, J ¼ 8.1 Hz, 2H, 2ArH), 8.05 (d,
J ¼ 8.1 Hz, 1H, H3), 8.12 (s, 1H, H5), 8.31 (d, J ¼ 5.4 Hz, 1H, H1); 13C
NMR (DMSO-d6, 125 MHz): 42.4, 47.6, 67.5, 68.3, 69.4, 70.0, 71.8,
99.1, 115.4, 117.8, 120.5, 124.2, 125.1, 127.9, 130.4, 132.3, 144.2, 149.3,
150.7, 152.0, 157.2, 163.0, 167.4, 188.4; HRMS: Calcd for
3.4.6. N-[3-(7-chloro-quinolin-4-ylamino)-propyl]-2-{4-[3-(4-
methoxy-phenyl)-acryloyl]-phenoxy}-acetamide(14f)
C
32H28ClFeN3O3 [M]þ 593.1169, found 593.1180; Anal. Calcd (%) for:
C, 64.72; H, 4.75; N, 7.08, found: C, 64.64; H, 4.81; N, 7.17.
Yield 80%; Light Yellow Solid; 1H NMR (CDCl3, 300 MHz):
d
1.95e2.01 (m, 2H, eCH2e),3.32e3.41 (m, 4H, 2ꢀ eCH2e), 3.92 (s,
3.4.10. N-[3-(7-chloro-quinolin-4-ylamino)-propyl]-2-[4-(3-
ferrocenyl-acryloyl)-phenoxy]-acetamide(15b)
3H, eOCH3), 4.21 (s, 1H, eNHe exchangeable with D2O), 4.57 (s, 2H,
eOeCH2e), 6.35 (d, J ¼ 5.4 Hz,1H, H2), 7.00 (d, J ¼ 8.7 Hz, 2H, 2ArH),
7.16 (s, 1H, eNHe exchangeable with D2O), 7.31 (d, J ¼ 9.0 Hz, 1H,
H4), 7.41 (d, J ¼ 8.4 Hz, 2H, ArH), 7.53 (d, J ¼ 15.6 Hz, 1H, olefinic-H),
7.62 (d, J ¼ 8.4 Hz, 2H, ArH),7.80 (d, J ¼ 15.6 Hz, 1H, olefinic-H),7.87
(s, 1H, H5), 7.98 (d, J ¼ 9.0 Hz, 1H, H3), 8.03 (d, J ¼ 8.4 Hz, 2H, ArH),
8.46 (d, J ¼ 5.4 Hz,1H, H1); 13C NMR (DMSO-d6,125 MHz): 30.1, 37.0,
47.7, 55.0, 67.4, 99.1, 115.3, 117.4, 120.1, 124.1, 125.2, 125.8, 126.3,
128.2,130.8,131.9, 132.6,135.0, 143.6,147.2, 150.2,151.8, 157.9, 161.9,
167.8, 187.9; HRMS: Calcd for C30H28ClN3O4 [M]þ 529.1768, found
529.1760; Anal. Calcd (%) for: C, 67.98; H, 5.32; N, 7.93, found: C,
67.92; H, 5.45; N, 8.02.
Yield 81%; Dark Red Solid; 1H NMR (CDCl3 þ DMSO-d6,
300 MHz):
d
1.90e2.01 (m, 2H, eCH2e),3.32e3.41 (m, 4H, 2ꢀ
eCH2e), 4.16 (s, 5H, Ferrocenyl-H), 4.49 (s, 2H, Ferrocenyl-H), 4.60
(s, 2H, Ferrocenyl-H), 4.67 (s, 2H, eOeCH2e), 5.54 (s, 1H, eNHe
exchangeable with D2O), 6.43 (s, 1H, eNHe exchangeable with
D2O), 6.53 (d, J ¼ 5.4 Hz, 1H, H2), 6.98e7.05 (m, 3H, 2ArH þ olefinic-
H),7.43 (d, J ¼ 8.4 Hz,1H, H4), 7.58 (d, J ¼ 15.9 Hz, olefinic-H), 7.84 (d,
J ¼ 8.1 Hz, 2H, 2ArH), 8.04 (d, J ¼ 8.1 Hz,1H, H3), 8.10 (s, 1H, H5), 8.34
(d, J ¼ 5.4 Hz, 1H, H1); 13C NMR (DMSO-d6, 125 MHz): 30.1, 37.5,
47.6, 67.2, 68.5, 69.4, 69.8, 71.7, 99.5, 115.4, 117.6, 120.2, 124.6, 125.0,
127.8, 130.3, 132.1, 144.1, 149.2, 150.6, 152.1, 157.2, 162.8, 167.5, 187.8;
HRMS: Calcd for C33H30ClFeN3O3 [M]þ 607.1325, found 607.1319;
Anal. Calcd (%) for: C, 65.20; H, 4.97; N, 6.91, found: C, 65.28; H,
4.86; N, 7.03.
3.4.7. N-[4-(7-chloro-quinolin-4-ylamino)-butyl]-2-{4-[3-(4-
methoxy-phenyl)-acryloyl]-phenoxy}-acetamide (14g)
Yield 85%; Light Yellow Solid; 1H NMR (CDCl3, 300 MHz):
d
1.72e1.99 (m, 4H, 2ꢀ eCH2e), 3.38e3.46 (m, 4H, 2ꢀ eCH2e), 3.88
3.4.11. N-[4-(7-chloro-quinolin-4-ylamino)-butyl]-2-[4-(3-
ferrocenyl-acryloyl)-phenoxy]-acetamide(15c)
(s, 3H, eOCH3), 4.26 (s, 1H, eNHe exchangeable with D2O), 4.60 (s,
2H, eOeCH2e), 6.37 (d, J ¼ 5.4 Hz, 1H, H2), 6.98 (d, J ¼ 8.4 Hz, 2H,
2ArH), 7.19 (s, 1H, eNHe exchangeable with D2O), 7.33 (d,
Yield 78%; Dark Red Solid; 1H NMR (CDCl3 þ DMSO-d6,
300 MHz):
d
1.71e1.92 (m, 4H, 2ꢀ eCH2e), 3.37e3.46 (m, 4H, 2ꢀ

238
R. Raj et al. / European Journal of Medicinal Chemistry 95 (2015) 230e239
eCH2e), 4.14 (s, 5H, Ferrocenyl-H), 4.48 (s, 2H, Ferrocenyl-H), 4.62
(s, 2H, Ferrocenyl-H), 4.71 (s, 2H, eOeCH2e), 5.58 (s, 1H, eNHe
exchangeable with D2O), 6.41 (s, 1H, eNHe exchangeable with
D2O), 6.58 (d, J ¼ 5.4 Hz, 1H, H2), 6.97e7.04 (m, 3H, 2ArH þ olefinic-
H),7.44 (d, J ¼ 8.4 Hz, 1H, H4), 7.59 (d, J ¼ 15.9 Hz, olefinic-H), 7.81
(d, J ¼ 8.1 Hz, 2H, 2ArH), 8.03 (d, J ¼ 8.4 Hz, 1H, H3), 8.15 (s, 1H, H5),
8.31 (d, J ¼ 5.4 Hz, 1H, H1); 13C NMR (DMSO-d6, 125 MHz): 27.6,
28.3, 37.2, 47.5, 67.6, 68.2, 69.4, 70.1, 71.4, 99.0, 115.3, 117.7, 120.1,
124.5, 125.3, 127.8, 130.2, 132.1, 143.8, 149.4, 150.5, 152.2, 157.6,
162.6, 167.8, 188.0; HRMS: Calcd for C34H32ClFeN3O3 [M]þ 621.1482,
found 621.1477; Anal. Calcd (%) for: C, 65.56; H, 5.19; N, 6.76, found:
C, 65.49; H, 5.10; N, 6.91.
PBS and transferred to a microcentrifuge tube. 100 mL of trypan blue
solution were added to the re-suspended cells and allowed to
incubate at room temperature for approximately 10 min. Viable and
dead cells were visualized and counted with a hemacytometer. IC50
values were determined using GraphPad PRISM.
Acknowledgement
Financial assistance from Board of Research in Nuclear Sciences
under DAE Research Award for Young Scientist Scheme (VK) is
gratefully acknowledged.
Appendix A. Supplementary data
3.4.12. N-[6-(7-chloro-quinolin-4-ylamino)-hexyl]-2-[4-(3-
ferrocenyl-acryloyl)-phenoxy]-acetamide (15d)
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2015.03.045.
Yield 81%; Dark Red Solid; 1H NMR (CDCl3 þ DMSO-d6,
300 MHz):
d1.11e1.76 (m, 8H, 4ꢀ eCH2e),3.30e3.39 (m, 4H, 2ꢀ
eCH2e), 4.19 (s, 5H, Ferrocenyl-H), 4.49 (s, 2H, Ferrocenyl-H), 4.58
(s, 2H, Ferrocenyl-H), 4.70 (s, 2H, eOeCH2e), 5.55 (s, 1H, eNHe
exchangeable with D2O), 6.45 (s, 1H, eNHe exchangeable with
D2O), 6.49 (d, J ¼ 5.4 Hz, 1H, H2), 6.99e7.06 (m, 3H, 2ArH þ olefinic-
H),7.41 (d, J ¼ 8.4 Hz,1H, H4), 7.57 (d, J ¼ 15.9 Hz, olefinic-H), 7.85 (d,
J ¼ 8.1 Hz, 2H, 2ArH), 7.99 (d, J ¼ 8.4 Hz,1H, H3), 8.09 (s,1H, H5), 8.29
(d, J ¼ 5.1 Hz, 1H, H1); 13C NMR (DMSO-d6, 125 MHz): 25.6, 26.5,
29.8, 30.7, 37.5, 47.4, 67.6, 68.4, 69.5, 70.2, 71.6, 99.3, 115.6, 117.8,
120.0, 124.1, 125.3, 127.5, 130.7, 132.3,144.1, 149.2, 150.4, 152.6,157.1,
162.9, 167.4, 188.2; HRMS: Calcd for C36H36ClFeN3O3 [M]þ 649.1795,
found 649.1801; Anal. Calcd (%) for: C, 66.52; H, 5.58; N, 6.46,
found: C, 66.65; H, 5.45; N, 6.58.
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