Cinnamoylated chloroquine analogues: A new structural class of antimalarial agents

Article abstract of DOI:10.1016/j.ejmech.2017.04.063

A novel series of cinnamoylated chloroquine hybrid analogues were synthesized and evaluated as antimalarial agents. The trans cinnamic acid derivatives (3–8) were synthesized by utilizing substituted aldehydes and malanoic acid in DMF catalysed by DABCO. The final cinnamoylated chloroquine analogues (9–14) were synthesized by utilizing DCC coupling reagent. The amido chloroquine (17) was prepared from acid (16) and compound 2 in benzene using SOCl₂ as chlorinating agent. The corresponding ester (15) was prepared from 2-hydroxy acetophenone and 2-bromoacetates in actonitrile in presence of K₂CO₃?as?base followed by basic hydrolysis. The preparation of amide based chloroquine-chalcone analogues (18–22), were obtained by the combination of amido chloroquine (17) and aldehydes in 10% aq. KOH in methanol at room temperature. Further we prepared epichlorohydrin based chloroquine-chalcone analogues (25–28), by reacting the epoxide (24a, 24b and 24c) with 2 and methelenedioxy aniline. In?vitro antimalarial activity against chloroquine sensitive strain 3D7, chloroquine resistant strain K1 of P.?falciparum and in?vitro cytotoxicity of compounds using VERO cell line was carried out. The synthesized molecules showed significant in?vitro antimalarial activity especially against CQ resistant strain (K1). Among tested compounds, 13, 9 and 10 were found to be the most potent compounds of the series with IC₅₀ value of 44.06, 48.04 and 59.37?nM against chloroquine resistant K1 strain.

Full text of DOI:10.1016/j.ejmech.2017.04.063

Accepted Manuscript
Cinnamoylated chloroquine analogues: A new structural class of antimalarial agents
Venkatareddy Gayam, Subban Ravi
PII:
S0223-5234(17)30337-9
10.1016/j.ejmech.2017.04.063
EJMECH 9414
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 31 December 2016
Revised Date: 21 April 2017
Accepted Date: 22 April 2017
Please cite this article as: V. Gayam, S. Ravi, Cinnamoylated chloroquine analogues: A new
structural class of antimalarial agents, European Journal of Medicinal Chemistry (2017), doi: 10.1016/
j.ejmech.2017.04.063.
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ACCEPTED MANUSCRIPT
Cinnamoylated chloroquine analogues: a new structural class of
antimalarial agents
*
Venkatareddy Gayam and Subban Ravi
Department of Chemistry, Karpagam University, Karpagam Academy of Higher
Education, Coimbatore, Tamilnadu, India.
Graphical Abstract

ACCEPTED MANUSCRIPT
Cinnamoylated chloroquine analogues: a new structural class of
antimalarial agents
*
Venkatareddy Gayam and Subban Ravi
Department of Chemistry, Karpagam University, Karpagam Academy of Higher Education,
Coimbatore, Tamilnadu, India.
*
Corresponding Author
Dr.S.Ravi
Professor and Head
Department of Chemistry
Karpagam University
Coimbatore-641021
Mobile:+91 9047174142
E-mail: ravisubban@rediffmail.com

ACCEPTED MANUSCRIPT
Cinnamoylated chloroquine analogues: a new structural class of
antimalarial agents
*
Venkatareddy Gayam and Subban Ravi
Department of Chemistry, Karpagam University, Karpagam Academy of Higher Education,
Coimbatore, Tamilnadu, India.
Abstract
A novel series of cinnamoylated chloroquine hybrid analogues were synthesized and evaluated as
antimalarial agents. The trans cinnamic acid derivatives (3-8) were synthesized by utilizing substituted
aldehydes and malanoic acid in DMF catalysed by DABCO. The final cinnamoylated chloroquine
analogues (9-14) were synthesized by utilizing DCC coupling reagent. The amido chloroquine (17)
2
was prepared from acid (16) and compound 2 in benzene using SOCl as chlorinating agent. The
corresponding ester (15) was prepared from 2-hydroxy acetophenone and 2-bromoacetates in
actonitrile in presence of K CO as base followed by basic hydrolysis. The preparation of amide based
2
3
chloroquine-chalcone analogues (18-22), were obtained by the combination of amido chloroquine (17)
and aldehydes in 10% aq. KOH in methanol at room temperature. Further we prepared
epichlorohydrin based chloroquine-chalcone analogues (25-28), by reacting the epoxide (24a, 24b and
2
4c) with 2 and methelenedioxy aniline. In vitro antimalarial activity against chloroquine sensitive
strain 3D7, chloroquine resistant strain K1 of P. falciparum and in vitro cytotoxicity of compounds
using VERO cell line was carried out. The synthesized molecules showed significant in vitro
antimalarial activity especially against CQ resistant strain (K1). Among tested compounds, 13, 9 and

ACCEPTED MANUSCRIPT
1
0 were found to be the most potent compounds of the series with IC50 value of 44.06, 48.04 and 59.37
nM against chloroquine resistant K1 strain.
Key words: Cinnamoylated chloroquine hybrid, antimalarial activity
1
.
Introduction
The enormity of malaria in terms of morbidity and mortality in humans makes it a major public
health problem in tropical and subtropical countries. It is estimated that 149–303 million people are
affected worldwide every year and 1.5–2.7 million people die of malaria every year, which include
approximately one million children below the age of five years [1]. One of the fundamental reason for
this is the fast spread of Plasmodium falciparum that is resistant to antimalarial drugs including
quinolines, antifolates, and artemisinin and its semi synthetic derivatives and potentially limits in
control and eradication of the diseases [2-5]. Thus, the synthesis of new antimalarials which can
overcome P. falciparum resistance becomes the need of the hour. Since the discovery of quinine,
chloroquine (CQ) is extensively utilized in malaria chemotherapy due to its marvelous efficacy, less
toxicity and cost effective synthesis. Unfortunately, emergence of resistant strains of P. falciparum to
CQ were observed and recent studies have revealed that the resistance seems compound specific.
Certain synthetic modifications around the quinoline nucleus have yielded many quinolines active
against CQ-resistant parasites [6-9]. A recent but now common strategy in the search for new
antimalarials drugs is the design of hybrids [10].
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. It is exemplified with the
recent success of ferroquine (FQ) (7-chloroquinolineeferrocene conjugate) and trioxaquine

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(7-chloroquinolineetrioxane conjugate) [11-13]. Based on the success of FQ, a variety of ferrocenyl
analogues of CQ have been synthesized [14] and evaluated for their antimalarial activities. Some of
the FQ have completed phase IIb clinical trials for the treatment of malaria [13]. Similar
organometallic compounds like gold(I) complexes containing quinoline functionalized N-heterocyclic
carbene were reported to be potent against the Leishmania parasites [15]. The design and synthesis of
aminoquinoline-containing dual activity that would potentially inhibit haemozoin formation and
another target within Plasmodium falciparum, are very productive in the generation of new chemical
entities that are effective against drug resistant parasites in the long term [16-18]. Some potent
antimalarial drugs in current use are provided in Fig. 1. Previous reports have also demonstrated that
hybrid structures resulting from cinnamic acid conjugation with heterocyclic moieties from well
known antimalarials present improved antimalarial activity [19, 20]. Herein we report the synthesis
and antimalarial assessment of a series of new chloroquine-cinnamic conjugates.
2
. Results and Discussion
2
.1. Chemistry.
The synthesis of target and intermediate compounds were performed as outlined in Schemes 1-3.
th
Synthesis of one of the common intermediate 2 was achieved by the nucleophilic substitution at the 4
position of 4, 7- dichloroquinoline (1) with 1, 2-diaminoethane.The trans cinnamic acid derivatives (3-
8
) were synthesized by utilizing substituted aldehydes and malanoic acid in DMF. The reaction was
catalysed by DABCO. The final cinnamoylated chloroquine analogues (9-14) were synthesized by
utilizing DCC coupling reagent, the complete path was shown in Scheme 1. The preparation of amide
based chloroquine-chalcone analogues (18-22), which were obtained by the combination of amido
chloroquine (17) and aldehydes in 10% aq. KOH in methanol at room temperature. The amido
chloroquine (17) was prepared from acid (16) and compound 2 in benzene using SOCl as chlorinating
2

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agent. The corresponding ester (15) was prepared from 2-hydroxy acetophenone, 2-bromoacetates in
actonitrile and K CO as base followed by basic hydrolysis; the details were shown in scheme-2.
2
3
Further we prepared epichlorohydrin based chloroquine-chalcone analogues (25-28), for this we
synthesized 4-hydroxy chalcones from 4-hydroxy acetophenone and aldehydes followed by reaction
with epichlorohydrin. Subsequently the epoxide (24a, 24b and 24c) was reacted with compound 2
and methelenedioxy aniline to get corresponding chloroquine-chalcone analogues (25-28) as shown in
Scheme 3.
3 2
All the compounds were characterized by spectral data. The compound 10 analysed for C21H20ClN O
+
by exhibiting a pseudo molecular ion peak at m/z 382.13 for [M+H] ion. The structure of the trans-
1
cinnamoyl moiety was established by H NMR data which showed two vicinal olefinic protons [δ
6
6
.40 and 7.53 (J= 15.69Hz)] and four aromatic protons at δ 7.46 - 7.44 (m, 2H), 7.40-7.36 (m, 1H),
.88 (d, 1H, J =8.70), The four other aromatic protons at δ 8.32(d, 1H, J =5.76 Hz), 7.97(d, 1H, J
=
9.0 Hz), 7.77 (d, 1H, J =2.07 Hz), 6.49 (d, 1H, J =5.70) are attributed to the quinine moiety protons.
The pair of multiplets at δ 3.68 - 3.64 (m, 2H) and 3.51-3.47 (m, 2H) are assigned to two N-methylene
group protons and the singlet signal exhibited at δ 3.79 (s, 3H) is assigned to the methoxy group
1
3
protons. Consistent with the above data the C NMR spectra exhibited characteristic signals at δ 54.84
for methoxy carbon, δ 43.99 and 38.06 for N-methylene carbons, δ 117.29 and 147.36 for cinnamoyl
unsaturated carbons and at δ 168.96 for the cinnamoyl carbonyl group. The compound 18 analysed for
+
C H ClN O by exhibiting a pseudo molecular ion peak at m/z 516.31 for [M+H] ion. In addition to
29
26
3
4
1
the signals as discussed above, the H NMR spectra exhibited characteristic signals at δ 4.67 (s, 2H)
for a methylene group present in between amide carbonyl group and oxygen atom. The corresponding
1
3
signal in the C NMR spectra appeared at δ 68.01. Further the carbonyl carbon of the cinnamoyl
moiety appeared at δ 193.78. The compound 28 analysed for C30 by exhibiting a pseudo
3 4
H30ClN O

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+
1
molecular ion peak at m/z 533.21 for [M+H] ion. In H NMR spectra the signals at δ 3.82 (m, 1H) is
attributed to the hydroxyl methane proton, between 4.11- 4.01 (m, 2H) for oxymethylene protons and
1
3
at δ 2.96 (m, 2H) for N-methylene protons. The C NMR spectra complemented the above data by
exhibiting signals at δ 67.68 for hydroxyl methane carbon, 71.25 for oxymethylene carbon and at δ
5
5.82 for N-methylene carbon.
2
2
.2. Pharmacology
.2.1 In vitro antimalarial assay:
The synthesised compounds were dissolved in DMSO at 5 mg/mL. Two fold serial dilutions of test
samples were made in 96 well plates and incubated with 1.0% parasitized cell suspension containing
0
.8% parasitaemia (Asynchronous culture with more than 80% ring stages). The plates were incubated
at 37 ºC in CO incubator in an atmosphere of 5% CO and air mixture. 72 hour later 100 µL of lyses
2
2
buffer containing 2x concentration of SYBR Green-I (Invitrogen) was added to each well and
incubated for one hour at 37 ºC . The plates were examined at 485 ± 20 nm of excitation and 530 ± 20
nm of emission for relative fluorescence units (RFUs) per well using the fluorescence plate reader
(
FLX800, BIOTEK). Data was transferred into a graphic programme (EXCEL) and IC values were
50
obtained by Logit regression analysis of dose response curves. Chloroquine was used as the standard
reference drug. [8].
2
.2.2. Cytotoxicity assay
Cytotoxicity of the compounds was carried out using Vero cell line (C1008; Monkey kidney
fibroblast) following the method of Mosmann [21] with certain modifications. The cells were
incubated with different dilutions of test agents for 72 hour and MTT was used as reagent for the
detection of cytotoxicity. 50% cytotoxic concentration (CC ) was determined using nonlinear
50
regression analysis of dose response curves. Selectivity Index (SI) was calculated as: SI = CC /IC .
5
0
50

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All synthesized cinnamoylated and chalcone - chloroquine based hybrids (9-14), (18-22), (25-
8) and intermediate compounds 17, 24a, 24b and 24c were evaluated for their in vitro antimalarial
2
efficacy against 3D7 (CQ sensitive) and K1 (CQ resistant) strains of Plasmodium falciparum[19].
Most of the compounds showed potent antimalarial activity as compared to CQ against K1 strain, on
the other hand some of the compounds showed comparable activity to CQ against 3D7 strain. The
results have been summarized in Table 1. Among tested compounds, 13, 9 and 10 were found to be
the most potent compounds of the series with IC50 value of 44.06, 48.04 and 59.37 nM against
chloroquine resistant K1 strain. It was almost tenfold more potent than chloroquine. Four compounds
of the series (20, 21, 27 and 22) showed IC in the range of 100-155 nM and six compounds (7, 8, 11
5
0
and 15–17) showed IC50 ranging between 200-260 nM.
The structure-activity relationship studies for these compounds suggest that the presence of halogen
functionality on phenyl ring (13) showed remarkable activity with IC50 44.06 nM. The compounds 9
and 10 consisting methyl and methoxy groups on phenyl ring showed IC50 48.04 and 59.37 nM,
respectively. The replacement of phenyl group with furan resulted in reduced antimalarial activity as
shown by compound 14 (Table 1). In case of amide based chalcone - chloroquine analogues (18-22),
in which the intermediate compound 17 showed IC value of >1300 nM against chloroquine resistant
5
0
K1 strain but it showed comparable IC value of 10.44 nM against chloroquine CQ-sensitive 3D7
5
0
strain. Upon introduction of chalcone moiety with different aldehydes these derivatives showed
activity against chloroquine resistant K1 strain. In the compounds with methoxy groups on phenyl ring
the activity was found to increase remarkably when compared with intermediate 17 with IC50 value
1
34.1, 147.7, 160.8, 224.4 and 252.7 nM. The substitution patterns as well as number of substituents
on the phenyl ring also alter the activity profile. Compound 20 consisting three methoxy groups on
nd th
th
phenyl ring at 2 ,4 and 5 positions showed IC value of 160.8 nM, whereas the compound 21
5
0

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rd
th
th
consisting three methoxy groups at 3 , 4 , and 5 positions showed IC50 value 124.4 nM, suggesting
that steric factor also played a crucial role in the antimalarial activity of these hybrids against CQ-
resistant K1 strain. When the methoxy group was replaced with chlorine group on the phenyl ring 22
the activity was found to be decreasing, with IC50 value 252.7 nM as shown in table-1. Next we
observed that there was no activity in the case of epoxy chalcones 24a, 24b, and 24c
and
methelenedioxy aniline chalcones 25 against both chloroquine sensitive 3D7 and resistant K1 strain.
The epoxide open compound 26, showed activity against CQ-resistant K1 strain with IC50 values
ranging from 229.1 to >900 nM depending upon the number of methoxy groups and position. From
these results showed that chloroquine moiety was crucial for the anti-malarial activity.
These compounds were further tested for their cytotoxicity against VERO cells using MTT
assay [20]. Among all the synthesized hybrid derivatives, compound 17, which was more potent
against CQ-sensitive 3D7 strain showed good selectivity index of 10150.0 in comparison with other
derivatives. The most potent compounds 13 and 14 having IC 44.06 and 101.2 nM against CQ-
5
0
resistant strain showed selectivity index of 356.95 and 6696.98. Rest of compounds showed SI values
ranging between 19.0 and 1531.31. Compounds with selectivity index (SI) value greater than 50 are
generally considered safe. Although these hybrid compounds have exhibited higher IC50 values against
3
D7 strain but unlike CQ they have exhibited lower IC values against K1 strain. These findings make
50
these hybrid compounds worth pursuing as promising leads.
. Conclusion
In summary, a novel series of cinnamoylated and chalcone-chloroquine based hybrid
3
antimalarials were designed and synthesized. The synthesized molecules showed significant in vitro
antimalarial activity especially against CQ resistant strain (K1). Activity results indicated that
compounds 13, 9 and 10 could be utilized as lead molecules for further chemical modifications to

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enhance their therapeutic potential as antimalarial agents in the emergence of rapid resistance against
existing antimalarial. Further pharmacological and pharmacokinetic development of these hybrid
molecules is currently in progress.
4
. Experimental Section
4
.1 General Information
All reagents are of commercial grade and were used without further purification. Chromatography was
carried on silica gel (60-120 and 100-200 mesh). All the reactions were monitored by TLC; silica gel
1
13
plates with fluorescence F254 were used. . H NMR and C NMR spectra were recorded using Bruker
1
Supercon Magnet DPX-200 or DPX-300 spectrometers (operating at 300 and 400 MHz for H; 75 and
1
3
1
00 MHz for C) using pyridine-d5, CDCl , and DMSO-d as solvents and TMS as internal standard.
3 6
Elemental analysis was carried out using Perkin-Elemer 240C model Instrument. Electrospray
ionization mass spectra (ESI-MS) were recorded on Thermo Lcq Advantage.
4
.2 Preparation of compound (2)
, 7-dichloroquinoline (100g) was taken in a 500 ml round bottom flask and to this 200 ml of
4
ethylenediamine was added and maintained at 110 ºC under stirring for overnight. After completion of
reaction, the reaction mass was poured into cold water, the resulted solid was stirred for 2.0 hr and
then filtered. The solid compound was washed with 100 ml of n-hexane and dried in vacuum tray
dryer at 40 ºC for 10.0 hr (110 g, yield 97.5%).
4
.3 General synthetic procedure for compound (3-8)
The trans cinnamic acid derivatives (3-8) were synthesized by utilizing substituted benzaldehydes
1.0g, 1.0eq) in 100.0 ml round bottom flask containing 15.0 ml dimethylformide and malanoic acid
(

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(1.1eq). Diaza bicyclooctane (DABCO 1.0eq) was added as a catalyst and the temperature was raised
to 110.0 ºC and maintained for 2.0 hr. The reaction was monitored by thin layer chromatography.
After the completion of the reaction the reaction mass was quenched into cold water 40.0 ml and
extracted with ethyl acetate 2x25ml. The organic layer was dried with anhydrous sodium sulfate and
concentrated under high vacuum, the resulted solid was washed with hexane (5.0 ml), suck dry for
1
5.0 min and then dried under vacuum at 45 ºC for 5.0 hr to yield the solid compound.
4
.3.1. (E)-3-p-tolylacrylic acid (3)
-1
White solid; Yield:78.0%, IR (KBr, cm ) : 3650, 3021, 2930, 2401, 1722, 1600, 1512, 1449, 1210,
1
7
7
68; H NMR (C
3
D
6
CO,300 MHz) δ :7.65 (d, J = 15.9 Hz, 1H), 7.56 (d, J = 8.0Hz, 2H), 7.25 (d, J =
+
.8Hz, 2H), 6.47 (d, J = 15.9Hz, 1H) and 2.36 (s, 3H); Mass spectra ESI (m/z) : 162 [M+H] .
4
.3.2. (E)-3-(4-methoxyphenyl)acrylic acid (4)
-1
White solid; Yield: 80.0%,IR (KBr, cm ) :3687, 3021, 2936, 2401, 1729, 1600, 1512, 1427, 1216,
1
7
68; H NMR (C
3
D
6
CO, 300 MHz) δ :7.66 - 7.61 (m, 3H), 6.99 (d, J = 8.7 Hz, 2H), 6.38 (d, J = 16.0
+
Hz, 1H) and 3.85 (s, 3H); Mass spectra ESI (m/z):178 [M+H] .
4
.3.3. (E)-3-(3,4-dimethoxyphenyl) acrylic acid (5):
-1
Pale yellow solid; Yield:75.6%, IR (KBr, cm ) : 3684, 3021, 2927, 2402, 1684, 1525, 1424, 1216,
1
7
8
67, 670; H NMR (CDCl , 300 MHz) δ : 7.73 (d, J = 15.8 Hz, 1H), 7.15 - 7.07 (m, 2H), 6.79 (d, J =
3
+
.3 Hz, 1H), 6.32 (d, J = 15.8 Hz, 1H) and 3.92 (s, 6H); Mass spectra ESI (m/z): 208 [M+H] .
4
.3.4. (E)-3-(3,4, 5-trimethoxyphenyl)acrylic acid (6):
-1
Pale yellow solid; Yield: 80.0%, IR (KBr, cm ): 3694, 3021, 2946, 2366, 1686, 1590, 1426, 1268,
1
1
095, 794; H NMR (CDCl , 300 MHz) δ : 7.98 (d, J = 16.0 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 6.70
3
1
3
(
d, J = 8.7 Hz, 1H), 6.43 (d, J = 16.0 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.88(s, 3H); C NMR

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(
CDCl
3
, 75 MHz) δ: 172.9, 153.9, 153.5, 142.3, 141.9, 123.5, 121.1, 116.1, 107.6, 61.4, 60.8, 56.0;
+
MS: ESI (m/z): 238 [M+H] .
4
.3.5. (E)-3-(4-chlorophenyl) acrylic acid (7):
-1
1
White solid; Yield: 70.2%, IR (KBr, cm ) :3687, 3022, 1625, 1525, 1425,1216, 766; H NMR
(
CD
6
CO, 300 MHz) δ :7.71 (d, J = 8.3Hz, 2H), 7.66 (d, J = 15.9Hz, 1H), 7.47 (d, J = 8.3Hz, 2H), 6.55
+
(
d, J = 15.9Hz, 1H); MS: ESI (m/z):182 [M+H] .
4
.3.6. (E)-3-(furan-2-yl) acrylic acid (8):
-1
1
White solid; Yield:73.7%, IR (KBr, cm ) : 3628, 3121, 1628, 1556, 1481, 1225, 755; H NMR
(
CDCl ,300 MHz) δ : 7.55 - 7.49 (m, 2H), 6.67 (d, J = 3.3Hz, 1H), 6.49 (dd, J = 1.7 Hz, 1H), 6.32 (d,
3
1
3
J = 15.7 Hz, 1H); C NMR (CDCl , 75 MHz) δ: 172.6, 150.6, 145.3, 133.0, 115.7, 114.9, 112.4; MS:
3
+
ESI (m/z): 138 [M+H] .
4
.4. General synthetic procedure for cinnamoyl compounds (9-14)
To the substituted cinnamic acid (1.0eq) derivatives (3-8) 15 ml of tetrahydrofuran was added
and cooled to 0-5 ºC, to this cooled solution 1.0eq of dicyclohexyl dicarbodimide (DCC) was added
and stirred for 15 min. Then (1.0eq of N-hydroxy benzo triazine) HOBT was added, stirred for 30 min
and the solution of compound-2 (1.1eq) was added at 0-5 ºC for 60 min. The resulted mixture was
maintained overnight at 25-30ºC and the reaction was monitored by TLC. After completion of
reaction the reaction mass was quenched into cold water 40 ml and extracted with dichloro methane
2
x25ml. The organic layer was dried with sodium sulfate, concentrated under high vacuum, charged
into 10 ml THF and kept at 0-5 ºC over night. The resulted solid was filtered under vacuum and also
dried under vacuum at 45 ºC for 5 hr to obtain dried solid compound.
4
.4.1. Compound- (E)-N-(2-(7-chloroquinolin-4-ylamino) ethyl)-3-p-tolylacrylamide (9)
1
)
White solid; Yield: 60.5%, HNMR (CDCl + DMSO-d , 300MHz; δ:8.35(d, 1H, J =6.52 Hz), 8.20
3
6
(bs, NH), 8.01(d, 1H, J =12 Hz), 7.73(t, 1H, J =2.8 Hz), 7.47(d, 1H, J =21 Hz), 7.34(m, 3H), 7.21( bs,
NH), 7.10(d, 1H, J =10.4), 6.48(d, 1H, J =21) 6.37(d, 1H, J=7.2), 3.59-3.57(m, 2H), 3.39-3.37(m, 2H),

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1
3
2
1
.28(s, 3H).; C NMR DMSO-d
6
, 75MHz : δ 169.01, 150.80, 147.95, 141.16, 139.97, 135.05, 131.66,
+
29.23, 127.52, 126.54, 125.09, 118.75 MS: ESI (m/z) 366.3[M+H] and Anal. Calcd. for
C H ClN O: C,68.94; H, 5.51; N, 11.49; Found: C,68.98; H, 5.52; N, 11.42.
21
20
3
4
.4.2. (E)-N-(2-(7-chloroquinolin-4-ylamino) ethyl)-3-(4-methoxyphenyl) acrylamide (10)
1
White solid; Yield: 60.0%, HNMR (CDCl
3
+ DMSOD
6
, 300MHz); δ:8.32(d, 1H, J =5.76 Hz),
7
7
3
1
4
1
.97(d, 1H, J =9.0 Hz), 7.77(d, 1H, J =2.07 Hz), 7.53(d, 1H, J =15.69 Hz), 7.46-7.44(m, 2H), 7.40-
.36(m, 1H), 6.88(d, 1H, J =8.70), 6.49(d, 1H, J =5.70) 6.40(d, 1H, J=15.66), 3.79 (s, 3H) , 3.68-
1
3
.64(m, 2H), 3.51-3.47(m, 2H).; C NMR (DMSO-d , 75MHz) δ : 168.96, 160.82, 151.06, 150.33,
6
47.36, 140.83, 135.26, 129.12, 127.07, 126.05, 125.17, 122.44, 117.29, 116.91, 113.92, 97.91, 54.84,
+
3.99, 38.06.; MS: ESI (m/z) 382.3 [M+H] and Anal. Calcd. for C21
1.00; Found: C,66.07; H, 5.26; N, 11.03.
3 2
H20ClN O : C,66.05; H, 5.28; N,
4
.4.3. (E)-N-(2-(7-chloroquinolin-4-ylamino)ethyl)-3-(3,4-dimethoxyphenyl) acrylamide (11)
1
White solid; Yield: 58.0%, HNMR (CDCl
3
+ DMSOD
6
, 300MHz), δ:8.32(d, 1H, J =5.52 Hz),
7
7
2
5
.96(d, 1H, J =8.76 Hz), 7.77(d, 1H, J =2.07 Hz), 7.53(d, 1H, J =15.69 Hz), 7.55-7.50(m, 1H), 7.41-
.37(m, 1H), 7.11-7.07(m, 2H), 6.88(d, 1H, J =8.34) 6.48-6.38(m, 2H), 3.86 (s, 6H) , 3.69-3.65(m,
+
H), 3.50-3.46(m, 2H).;MS: ESI (m/z) 412.3[M+H] and Anal. Calcd. for C22
.38; N, 10.20; Found: C,64.12; H, 5.39; N, 10.24.
3 3
H22ClN O : C,64.15; H,
4
.4.4. (E)-N-(2-(7-chloroquinolin-4-ylamino) ethyl)-3-(2,4,5-trimethoxyphenyl) acrylamide (12)
1
White solid; Yield: 55.0%, HNMR (CDCl
3
, 300MHz), δ:8.36(d, 1H, J =5.49), 7.91-7.87(m, 3H),
7
3
1
1
.35-7.26 (m, 2H), 6.94(bs, 2H), 6.53-6.45(m, 2H), 6.18(d, 1H, J =4.98), 3.89(s, 3H), 3.82(s, 3H),
1
3
3 6
.80(s, 3H), 3.39(bs, 2H), 2.42(bs, 2H).; C NMR (CDCl + DMSOD , 75MHz),:169.63, 153.68,
51.59, 149.45, 146.38, 142.87, 136.27, 135.83, 125.58, 125.39, 122.78, 117.84, 116.76, 114.91,
+
11.31, 97.96, 96.80, 56.26, 55.98, 55.74, 44.47, 38.15. MS: ESI (m/z) 442.3[M+H] and Anal. Calcd.
for C23
H24ClN
3
O
4
: C,62.51; H, 5.47; N, 9.51; Found: C,62.56; H, 5.44; N, 9.48.
4
.4.5. (E)-N-(2-(7-chloroquinolin-4-ylamino) ethyl)-3-(4-chlorophenyl) acrylamide (13).

ACCEPTED MANUSCRIPT
1
White solid; Yield: 50.0%, HNMR (CDCl
3 3
+CD OD, 300MHz) δ:8.33(d, 1H, J =5.61), 7.96(d, 1H, J
=
8.97), 7.77(d, 1H, J =2.04), 7.53(d, 1H, J =15.71), 7.46 (d, 2H, J =8.49), 7.38(dd, 1H, J =7.90, 2.13),
7
3
4
.32(d, 2H, J =8.49), 6.55-6.48(m, 2H), 3.68-3.64(m, 2H), 3.52-3.48(m, 2H). MS: ESI (m/z)
+
86.5[M+H] and Anal. Calcd. for C20
.47; N, 10.85.
2 3
H17Cl N O: C,62.19; H, 4.44; N, 10.88; Found: C,62.18; H,
4
.4.6. (E)-N-(2-(7-chloroquinolin-4-ylamino) ethyl)-3-(furan-2-yl) acrylamide (14)
1
White solid; Yield:58.0%, HNMR (CDCl
3
+CD
3
OD, 300MHz) δ:8.32(d, 1H, J =5.43), 7.92(d, 1H, J
=
8.91), 7.77(d, 1H, J =1.74), 7.46(d, 1H, J =13.20), 7.36-7.33(m, 2H), 6.58(d, 1H, J =3.06), 6.43-
1
3
6
.35(m, 3H), 3.67-3.64(m, 2H), 3.47-3.42(m, 2H),; C NMR (CDCl +CD OD, 75MHz) δ:168.66,
3 3
1
51.15, 150.96, 150.46, 147.47, 144.14, 135.44, 128.12, 126.31, 125.40, 122.44, 117.46, 117.00,
+
1
14.05, 112.10, 98.03, 44.34, 38.29.MS: ESI (m/z) 342.3[M+H] and Anal. Calcd. for C H ClN O :
1
8
16
3
2
C,63.25; H, 4.72; N, 12.29; Found: C,63.21; H, 4.72; N, 12.32.
4
.5. Synthesis of (15)
-hydroxy acetophenone (20 g) and actonitrile (200 ml) were taken into a 500 ml round bottom
2
flask then added potassium carbonate (2.0eq) under stirring. Then ethyl bromoacetate (1.1eq) was
slowly added for 30 min at room temperature was raised to 65-70 ºC and maintained for 4 hr. After the
completion of the reaction it was filtered and the clear filtrate for concentrated under vacuum at 45 ºC
up to complete removal of solvent. The resulted compound was washed with hexane 10 ml twice and
dried for 2 hr at 45 ºC to yield a white solid compound.
1
White solid; Yield: 90.0%, HNMR (CDCl
3
, 300MHz) δ: 7.77-7.46(m, 1H), 7.47-7.41(m, 1H)
7
3
.07-7.02(m, 1H), 6.83(d, 1H, J =8.31), 4.72(s, 2H), 4.28(q, J =7.14, 2H), 2.71(s, 3H), 1.30(t, J =7.14,
+
H).; MS: ESI (m/z) 223.0 [M+H] .
4
.6. Synthesis of (16)
Compound 15 (20.0g) was dissolved in 100 ml methanol in a 500 ml round bottom flask at RT under
stirring. Then 10% aqueous potassium hydroxide solution was added into the solution. The
temperature was 60-65 ºC and maintained for 3 hr. Reaction mass was quenched into water 200ml

ACCEPTED MANUSCRIPT
and stirred for 15 min and then adjusted to pH 2-3 with 17.5% HCl solution. The it was stirred for 2-3
hr, filtered, washed with 20 ml acetone and dried under vacuum at 45 ºC for 8 hr to bring the
moisture content less than 0.5% to obtain the compound 16.
1
White solid; Yield: 85.0%, HNMR (CDCl , 300MHz) δ: 7.82-7.79,(m, 1H), 7.56-7.51(m, 1H) 7.16-
3
7
1
.11(m, 1H), 6.96(d, 1H, J =8.31), 6.13-6.11(bs, OH), 4.78(s, 2H), 2.69(s, 3H).; MS: ESI (m/z)
+
95.2[M+H] .
4
.7. Synthesis of (17)
Compound-16(15g) was taken in a 250 ml round bottom flask containing 75 ml of tetrahydrofuran
°
under stirring and cooled to 0-5 C. to this cooled solution Dicyclohexyl dicarbodimide (DCC)(1.0eq)
°
was added at 0-5 C, stirred for 15 min and then added (N-hydroxyl benzo trizine) HOBT(1.0eq) and
°
stirred for 30 min. Then added a prepared solution of compound-2 (1.1eq) in THF 30 ml at 0-5 C for
°
6
0 min and maintained for overnight at r.t (25-30 C). After completion of reaction the reaction mass
was quenched into cold water and extracted with dichloromethane (2x150ml). The organic layer was
dried with sodium sulfate and concentrated under high vacuum the solid obtained was charged into 10
ml THF and kept at 0-5 ºC over night. The resulted solid was filtered and dried under vacuum at 45
ºC for 5 hr to obtain a solid compound.
4
.7.1. 2-(2-acetylphenoxy)-N-(2-((7-chloroquinolin-4-yl)amino)ethyl)acetamide (17)
1
White solid; Yield: 80.0%, HNMR (CD OD, 300MHz) δ:8.90,(bs, NH), 8.48(d, 1H, J =5.2), 7.91(d,
3
1
1
H, J =1.98), 7.84(d, 1H, J =9), 7.77-7.74(m, 1H), 7.50-7.45(m, 1H), 7.36-7.33(m, 1H), 7.09-7.04(m,
H), 6.90 (d, 1H, J =8.3), 6.56(bs, NH), 6.33 (d, 1H, J =5.3) 4.62(s, 3H),3.86-3.80 (m, 2H),3.51-3.48
+
(
m, 2H), 2.61(s, 3H).; MS:ESI (m/z) 398.2[M+H] and Anal. Calcd. for C H ClN O : C,63.40; H,
21
20
3
3
5
.07; N, 8.91; Found: C,63.46; H, 5.01; N, 8.93.
.
4
.8. General synthetic procedure for preparation of cinnamoyl compounds (18-22)

ACCEPTED MANUSCRIPT
Compound-17 (1.0g 1.0eq) was taken in a round bottom flask containing 10 ml methanol and then
added 10% aq KOH solution under stirring followed by the addition of differently substituted
aldehydes at room temperature. The solution was refluxed for 12 hrs and monitored by TLC. After the
completion of the reaction the mass was poured into purified water 20ml and extracted with ethyl
acetate 2x40ml. The extract was concentrated and purified by chromatography using silica 230-
4
4
00mesh size in methylene dichloride and methanol (95:5%) as solvent system to yield the product.
.8.1.(E)-N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-2-(2-(3-(4-methoxyphenyl)acroyloly)
phenoxy)acetamide (18)
1
White solid; Yield: 80.0%, HNMR (CDCl , 300MHz) δ:8.62,(bs, 1H), 8.47(d, 1H, J =5.1), 7.92(d,
3
1
7
H, J =2.04), 7.81(d, 1H, J =8.94), 7.59-7.56 (m, 1H), 7.50(d, 2H, J =9.09), 7.46-7.40(m, 1H),
.31(dd, 1H, J =8.88, 1.98), 7.10-7.04 (m, 2H), 6.90 (m, 4H), 6.54( bs, 1H), 6.27(d, 1H, J =5.4), 4.67
1
3
(
s, 2H), 3.85 (s, 3H), 3.73-3.70(m, 2H), 3.40-3.39 (m, 2H).;C NMR (CDCl
3
, 75MHz) δ: 193.78,
1
1
5
70.72, 162.34, 155.95, 151.68, 150.33, 146.61, 135.09, 133.34, 130.55, 130.46, 128.7`4, 128.20,
26.93, 125.50, 123.67, 122.20, 121.88, 114.77, 113.79, 68.00, 55.59, 44.88, 38.41.; MS: ESI (m/z)
+
16.3[M+H] and Anal. Calcd. for C29
H26ClN
3
4
O : C,67.50; H, 5.08; N, 8.14; Found: C,67.46; H, 5.09;
N, 8.19
.8.2. (E)-N-(2-((7-chloroquinolin-4-yl) amino)ethyl)-2-(2-(3-(3,4-dimethoxy phenyl)
4
acroyloly)phenoxy)acetamide (19)
1
White solid; Yield: 76.0%, HNMR (CDCl , 300MHz) δ:8.67,(s, 1H), 8.46(d, 1H, J =5.56), 7.92(d,
3
1
1
3
H, J =1.95), 7.83(d, 1H, J =8.94), 7.58(m, 2H), 7.45(m, 1H), 7.33-7.29(m, 1H), 7.09(m, 4H), 6.98(d,
H, J =8.28), 6.88(d, 1H, J=8.37), 6.59(s, 1H), 6.28(d, 1H, J =5.43), 4.68(s, 2H), 3.93(s, 3H), 3.91(s,
+
H) 3.75-3.74(m, 2H), 3.43-3.41(m, 2H).; MS:ESI (m/z) 546.5[M+H] and Anal. Calcd. for
30 3 5
C H28ClN O : C,65.99; H, 5.17; N, 7.70; Found: C,65.96; H, 5.19; N, 7.72.
4
.8.3. (E)-N-(2-((7-chloroquinolin-4-yl) amino)ethyl)-2-(2-(3-(2,4,5-trimethoxy phenyl) acroyloly)
phenoxy)acetamide (20)
1
White solid; Yield: 72.0%, HNMR (CDCl , 300MHz) δ:8.75(s, 1H), 8.46(d, 1H, J =5.34), 7.95-
3
7
.84(m, 3H), 7.60-7.57(m, 1H), 7.46-7.40(m, 1H), 7.33-7.29(m, 1H), 7.13(d, 1H, J =16.0),7.08-7.04

ACCEPTED MANUSCRIPT
(m, 2H), 6.98(d, 1H, J =8.3) 6.69(bs, 1H), 6.47(s, 1H), 4.68(s, 2H), 3.94(s, 3H), 3.86(s, 3H), 3.82(s,
13
3
H), 3.74(bs, 2H), 3.42(bs, 2H). ; C NMR (CDCl , 75MHz) δ: 194.38, 170.73, 55.89, 154.97, 153.45,
3
1
51.11, 150.62, 148.13, 143.56, 142.18, 135.25, 133.05, 130.48, 129.10. 127.61, 125.54, 123.78,
22.36, 121.84, 117.25, 114.69, 113.81, 111.24, 98.39, 96.72, 68.05, 56.67, 56.32, 56.22, 44.77,
1
+
3
8.36.; MS: m/z value 576.5[M+H] and Anal. Calcd. for C H ClN O : C,64.64; H, 5.25; N, 7.29;
31
30
3
6
Found: C,64.65; H, 5.21; N, 7.35.
4
.8.4. (E)-N-(2-((7-chloroquinolin-4-yl) amino) ethyl)-2-(2-(3-(3,4,5-trimethoxy phenyl) acroyloly)
phenoxy)acetamide (21)
1
White solid; Yield: 80.0%, HNMR (CDCl , 300MHz) δ:8.63(bs, 1H), 8.47(d, 1H, J =5.22), 7.92(d,
3
1
6
6
1
1
3
H, J =1.41), 7.82(d, 1H, J =8.91), 7.60(d, 1H, J =7.38), 7.47(m, 1H) 7.32-7.29(m, 1H) 7.10(m, 2H),
.98(d, 1H, J =8.19), 6.77(s, 2H), 6.52(bs, 1H), 6.30(d, 1H, J =5.46), 4.67(s, 2H), 3.90(s, 3H), 3.88(s,
1
3
3 6
H), 3.75-3.74(m, 2H), 3.44-3.42(m, 2H).; C NMR, (CDCl +DMSOD , 75MHz) δ :193.81, 170.38,
55.70, 153.29, 150.73, 147.76, 146.57, 140.55, 135.18, 132.27, 130.18, 129.63, 128.05, 126.56,
25.17, 125.03, 122.29, 121.61, 117.03, 113.43, 106.68, 105.74, 98.17, 67.56, 60.63, 55.90, 43.29,
+
7.79, 33.44, 25.35, 24.65.;MS: ESI (m/z) 576.2[M+H] and Anal. Calcd. for C31
H30ClN
3
O
6
: C,64.64;
H, 5.25; N, 7.29; Found: C,64.65; H, 5.21; N, 7.35.
4
.8.5. (E)-N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-2-(2-(3-(4-chlorophenyl)
acroyloly)phenoxy)acetamid (22)
1
White solid; Yield: 76.0%, HNMR (CDCl , 300MHz) δ:8.22-8.15(m, 2H), 7.92-7.90( br.s, 1H), 7.55-
3
7
1
.42(m, 6H), 7.37-7.33(m, 2H), 7.19(d, 1H, J =15.9), 7.08-7.03(m, 1H), 6.96(d, 1H, J =8.2), 6.62(d,
1
3
3 6
H, J =6.42), 4.63(s, 2H), 3.70-3.68(m, 2H), 3.63-3.61(m, 2H).;C NMR (CDCl +DMSO-d , 75MHz)
δ; 193.16, 170.77, 155.96, 155.72, 144.36, 142.41, 139.62, 138.74, 136.75, 133.59, 132.69, 130.35,
1
29.64, 129.18, 127.96, 127.66, 126.06, 124.41, 121.79, 119.68, 115.34, 113.56, 97.92, 67.67, 43.90,
+
3
7.58, 33.52, 25.41, 24.75.; MS: ESI (m/z) 520.5[M+H] and Anal. Calcd. for C H Cl N O :
2
8
23
2
3
3
C,64.62; H, 4.45; N, 8.07; Found: C,64.65; H, 4.41; N, 8.09
4
.9. General synthetic procedure for preparation of cinnamyl compounds (23a, 23b, and 23c)

ACCEPTED MANUSCRIPT
4
- hydroxy benzaldehyde (1.0g ,1.0eq) was dissolved in 10 ml of methanol in a round bottom flask
and added 10% aq KOH solution and differently substiuted aldehydes (1.1eq) into reaction mixture
under stirring at room temperature. The reaction mixture was refluxed for overnight and poured into
purified water 20ml and extracted with ethyl acetate 2x40ml. The extract was concentrated to yield the
compound.
4
.10. Synthesis of 24a, 24b and 24c
The prepared Chalcones (1.0g 1.0eq) were taken in a 100ml round bottom flask; added
epichlorohydrine (1.5eq) followed by dimethyl formamide and potassium carbonate (2.0eq) and
refluxed for 3hr. After the completion of the reaction the mass was cooled to room temperature and
poured into cold water. The compound was extracted with ethyl acetate (2x25ml), the organic layer
was dried with sodium sulphate and concentrated under vacuum at 40°c. Obtained crude compound
was purified by column chromatography using ethyl acetate and hexane 50% solvent system. The pure
compound was obtained as a white solid (yield: 65-75%).
4
.10.1. (E)-1-(4-(oxiram-2-yl) phenyl)-3-(3,4,5-trimethoxy phenyl) prop-2-en-1-one (24a)
1
Solid; Yield: 75.0%, HNMR (CDCl , 300MHz) δ:8.09-8.00(m, 3H), 7.45(d, 1H, J =15.0), 7.12(s,
3
1
3
H), 6.99(d, 2H, J =8.76), 6.52(s, 1H), 4.34-4.29(m, 1H), 4.04-3.99(m, 1H), 3.93-3.89(m, 9H), 3.38-
+
.35(m, 1H), 2.94-2.91(m, 1H), 2.79-2.76(m, 1H).;MS: ESI (m/z) 357.2 [M+H] and Anal. Calcd. for
C H O : C,67.41; H, 5.56; Found: C,67.46; H, 5.52.
20
20
6
4
.11. Synthesis of (25)
The epoxide compound 24a (1.0g, 1.0eq) was dissolved in 10ml ethanol in a round bottom flask and
then added 5-amino benzodioxol compound (1.0eq). The reaction mixture was refluxed for 3hr,
concentrated and purified by column chromatography using dichloro methane and methanol (95:5)
solvent system. The purified compound was obtained as a solid (Yield: 75%).

ACCEPTED MANUSCRIPT
4
.11.1. (E)-1-(4-(3-(benzo[d][1, 3] dioxol-5-ylamino)-2-hydroxy prop oxy) phenyl) -3-(3,4,5-
trimethoxy phenyl) prop-2-en-1-one (25)
1
White solid; Yield: 75.0%, HNMR (CDCl ,300MHz) δ:8.02(d, 2H, J =8.82), 7.71(d, 1H, J =15.57),
3
7
.40(d, 1H, J =15.51), 6.99(d, 2H, J =8.85), 6.85(s, 2H), 6.66(d, 1H, J =8.28), 6.31(s, 1H), 6.11(d, 1H,
J =8.31), 5.85(s, 2H), 4.31-4.24(bs, 1H), 4.15-4.07(m, 2H), 3.91-3.89(m, 9H), 3.41-3.35(m, 1H), 3.27-
+
3
2
.21(m, 1H),; MS:ESI (m/z) 508.1 [M+H] and Anal. Calcd. for C H NO : C,66.26; H, 5.76; N,
2
8
29
8
.76; Found: C,66.21; H, 5.78; N, 2.79.
4
.12. Synthesis of 26-28
The epoxides 24a-c (1.0g) were dissolved in 10 ml ethanol in a 50ml round bottom flask along with
the amine compound-2 (1.0eq) and refluxed for 3hr. After the completion of the reaction mass was
concentrated and purified by column chromatography using dichloro methane and methanol (95:5%)
solvent system. The pure compound was obtained as a colorless solid (Yield: 80%).
4
.12.1.(E)-1-(2-(3-((2-((7-chloroquinolin-4-yl)amino)ethyl)amino)-2-hydroxy propoxy) phenyl)-3-
(3,4,5-trimethoxy phenyl) prop-2-en-1-one (26)
1
White solid; Yield: 80.0%, HNMR (DMSO-d
6
, 300MHz) δ:8.39 (d, 1H, J =5.34), 8.26(d, 1H, J
=
9.03), 8.14(d, 1H, J =8.76), 7.87(d, 1H, J =15.5), 7.79-7.77(m, 1H), 7.66(d, 1H, J =15.4), 7.43-
7
3
1
1
.40(m, 1H), 7.21(s, 2H), 6.51(d, 2H, J =8.76), 6.52(d, 1H, J =5.43), 4.11-4.00(m, 3H), 3.86(s, 6H),
13
.71(s, 3H), 3.62-3.59(m, 2H), 3.42-3.41(m, 2H),; CNMR (DMSO-d , 75MHz) δ:187.29, 162.59,
6
53.12, 151.83, 150.18, 148.98, 143.63, 139.64, 133.42, 130.89, 130.51, 130.38, 127.37, 124.22,
24.07, 121.21, 117.50, 114.43, 106.46, 98.76, 70.845, 67.53, 60.14, 56.14, 51.63, 47.11, 41.80.; MS:
+
ESI (m/z) 592.2[M+H] and Anal. Calcd. for C H ClN O : C,64.91; H, 5.79; N, 7.10; Found:
32
34
3
6
C,64.89; H, 5.76; N, 7.16
.12.2. (E)-1-(2-(3-((2-((7-chloroquinolin-4-yl)amino)ethyl)amino)-2-hydroxy propoxy)phenyl)-3-
4
(3,4,-di methoxy phenyl) prop-2-en-1-one (27)
1
White solid; Yield: 76.0%, HNMR (DMSO-d , 300MHz) δ:8.40 (d, 1H, J =5.37), 8.31-8.26(m, 2H),
6
8
.13(d, 2H, J =8.73), 7.84-7.78(m, 2H), 7.66(d, 1H, J =15.42), 7.53(s, 1H), 7.53(s, 1H), 7.44-7.36(m,

ACCEPTED MANUSCRIPT
2
H), 7.07-7.00(m, 3H), 6.54(d, 1H, J =5.43), 4.11-4.02(m, 3H), 3.86(s, 3H), 3.81(s, 3H), 3.74-3.45(m,
1
3
3
H), 3.02-2.99(m, 2H), 2.95-2.81 (m, 2H).; C NMR (DMSO-d , 75MHz) δ: 187.70, 162.84, 152.19,
6
1
51.60, 150.64, 149.49, 149.30, 144.12, 133.96, 131.23, 131.19, 128.11, 127.72, 124.79, 124.60,
24.18, 120.01, 117.96, 114.86, 112.02, 111.23 99.26, 79.64, 71.12, 67.41, 56.21, 56.05, 51.74, 47.23,
1
+
4
1.84.; MS: ESI (m/z) 562.2[M+H] and Anal. Calcd. for C H ClN O : C,66.24; H, 5.74; N, 7.48;
3
1
32
3
5
Found: C,66.26; H, 5.76; N, 7.44
4
.12.3. (E)-1-(2-(3-((2-((7-chloroquinolin-4-yl)amino)ethyl)amino)-2-hydroxy propoxy) phenyl)-3-(4-
methoxy phenyl) prop-2-en-1-one (28)
1
White solid; Yield: 80.0%, HNMR (DMSOD , 300MHz) δ: 8.40(d, 1H, J =5.43), 8.31-8.26(m, 2H),
6
8
6
2
1
9
.12(d, 2H, J =8.88), 7.85-7.77(m, 4H), 7.67(d, 1H, J =15.45), 7.44-7.41(m, 1H), 7.07-6.99(m, 4H),
.54(d, 1H, J =5.49), 4.11-4.01(m, 3H), 3.82(s, 3H), 3.47-3.43(m, 3H), 3.00-2.96(m, 2H), 2.87-
1
3
6
.76(m, 2H).;C NMR (DMSO-d , 75MHz) δ: 187.69, 162.88, 161.68, 152.25, 150.63, 149.38,
43.58, 133.93, 131.20, 131.15, 131.10, 127.92, 127.80, 124.72, 124.57, 119.95, 117.96, 114.85,
+
9.26, 79.65, 71.25, 67.68, 55.82, 51.85, 47.36, 41.90.; MS: ESI (m/z) 533.2[M+H] and Anal. Calcd.
3 4
for C30H30 ClN O : C,67.73; H, 5.68; N, 7.90; Found: C,67.74; H, 5.66; N, 7.93.
References
[
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Figure, Table and Scheme captions
Figure 1. Chemical structures of some potent antimalarial agents.
Table 1. In vitro antimalarial activity against chloroquine sensitive strain 3D7, chloroquine resistant
strain K1 of P. falciparum and in vitro cytotoxicity of compounds using VERO cell line.
Table 2. Obtained Compound yield percentage.
Scheme 1. Reagents and conditions: (a) Ethylenediamine, 110 ºC, overnight; (b) Malonic acid,
DABCO, DMF, 110 ºC, 2.0 h; (c) DCC, HOBT, THF, 0 ºC, 1.0 h then r.t overnight.
Scheme 2. Reagents and conditions:(a) K CO , AcCN, reflux, 4.0h; (b) 10% aq. KOH, Methanol, r.t
2
3
2
.0h; (c) DCC, HOBT, THF, 0 ºC, 1.0 h then r.t overnight; (d) 10% aq. KOH, Methanol, Overnight.
Scheme 3. Reagents and conditions: (a) 10% aq. KOH, Methanol, Overnight; (b) Epichlorohydrin,
CO , DMF, Reflux, 3.0 h; (c) Ethanol, Reflux, 2.0 hr.
K
2
3

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Table 1.
In vitro antimalarial activity against chloroquine sensitive strain 3D7, chloroquine resistant strain K1
of P. falciparum and in vitro cytotoxicity of compounds using VERO cell line
In vitro antimalarial
S.No
Compound structure
activity
Cytotoxicity Selectivity
a
IC (nM)
CC (µM)
index
5
0
50
a
a
3
D7
K1
(SI)
Cl
O
H
9
N
N
22.01±0.07 48.04±0.07 4.00±0.02
13.43±0.05 59.37±0.12 20.56±0.05
181.81
H
N
H C
3
Cl
O
H
N
N
H
1531.31
N
1
1
0
1
3
H CO
Cl
O
H
H CO
N
3
N
H
14.15±0.03 156.8±0.09 5.60±0.07
21.31±0.10 142.6±0.07 16.11±0.12
396.28
756.44
N
H CO
3
1
2
1
1
3
4
19.43±0.04 44.06±0.14 6.93±0.03
93.99±0.08 101.2±0.03 629.44±0.05
356.95
Cl
O
H
N
6696.98
N
H
O
N
O
N
1
7
10.44±0.05 1300±0.07 105.96±0.17
10150.0
Cl
HN
O
NH
O

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OCH3
Cl
1
1
8
9
134.3±0.14 147.7±0.09 25.04±0.03
186.46
55.26
H
O
N
HN
O
N
O
OCH3
OCH3
N
Cl
96.14±0.10 134.1±0.06 5.31±0.04
O
HN
NH
O
O
H CO
OCH3
OCH3
3
H
N
O
Cl
O
2
2
2
0
1
2
94.11±0.09 160.8±0.04 12.25±0.16
69.11±0.12 224.4±0.14 3.92±0.03
255.4±0.07 252.7±0.06 4.98±0.14
130.27
56.73
19.53
O
N
H
N
OCH3
OCH3
OCH3
H
N
O
O
Cl
O
N
H
N
O
Cl
N
O
HN
O
Cl
NH
O
OCH3
OCH3
O
2
2
4a
5
NA
NA
NA
NA
NA
NA
NA
NA
O
OCH3
O
OH
O
OCH3
OCH3
HN
OCH3
O
O
Cl
H
N
O
N
OH
OCH
3
3
N
H
2
6
13.48±0.12 800±0.05 1.91±0.02
141.78
O
OCH
OCH
3

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Cl
H
N
2
2
7
8
O
79.86±0.07 229.1±0.09 10.21±0.12
127.87
169.92
N
OH
O
OCH
3
N
H
OCH
3
Cl
H
47.3±0.08
7.68±0.06
900±0.12 8.03±0.16
N
O
N
OH
O
N
H
OCH
3
2
9
CQ
463±0.07
ND
30612
a
Experiments conducted in triplicate
IC : Concentration corresponding to 50% growth inhibition of the parasite.
5
0
CC : Concentration corresponding to 50% Cytotoxicity.
50
SI: CC50 values of cytotoxic activity/IC 50 values of antimalarial activity.
NA: Not active
ND: Not Done

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Fig. 1.

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NH2
Cl
N
HN
N
a
NH2
H N
2
Cl
Cl
2
1
NH2
O
HN
O
O
Cl
OH
H
R
b
c
N
H
N
R
H
3-8
R
Cl
N
9-14
R= 4-Methyl phenyl
N
R = 4-Methyl phenyl
R = 4-methoxy phenyl
4
3
2
4
-methoxy phenyl
,4-dimethoxy phenyl
,4,5-trimethoxy phenyl R = 3,4-dimethoxy phenyl
-chloro
furan
3
2
R = 4-Methyl phenyl
R10= 4-methoxy phenyl
R11= 3,4-dimethoxy phenyl
R12= 2,4,5-trimethoxy phenyl
R13= 4-chloro
9
4
5
R = 2,4,5-trimethoxy phenyl
R = 4-chloro
R = furan
6
7
8
R14= furan
Scheme 1.
Scheme 2.