4-Aminoquinoline-ferrocenyl-chalcone conjugates: Synthesis and anti-plasmodial evaluation

Article abstract of DOI:10.1016/j.ejmech.2016.09.044

A series of aliphatic and aromatic substituted 1H-1,2,3-triazole-tethered 4-amino-quinoline-ferrocenylchalcone conjugates has been synthesized and evaluated for anti-plasmodial activity. The conjugates with flexible aliphatic (aminoethanol or aminopropano

Full text of DOI:10.1016/j.ejmech.2016.09.044

Accepted Manuscript
4-Aminoquinoline-ferrocenyl-chalcone conjugates: Synthesis and anti-plasmodial
evaluation
Amandeep Singh, Jiri Gut, Philip J. Rosenthal, Vipan Kumar
PII:
S0223-5234(16)30774-7
10.1016/j.ejmech.2016.09.044
EJMECH 8910
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 29 July 2016
Revised Date: 13 September 2016
Accepted Date: 14 September 2016
Please cite this article as: A. Singh, J. Gut, P.J. Rosenthal, V. Kumar, 4-Aminoquinoline-ferrocenyl-
chalcone conjugates: Synthesis and anti-plasmodial evaluation, European Journal of Medicinal
Chemistry (2016), doi: 10.1016/j.ejmech.2016.09.044.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
-Aminoquinoline-ferrocenyl-chalcone conjugates: Synthesis and Anti-
Plasmodial Evaluation
4
a
b
b
a*
Amandeep Singh, Jiri Gut, Philip J. Rosenthal, Vipan Kumar,
a
Department of Chemistry, Guru Nanak Dev University, Amritsar-143005, Punjab, India.
b
Department of Medicine, University of California, San Francisco, CA, USA
N
HN
N
O
O
N
N
Cl
O
Fe
Most potent conjugate IC = 0.37 µM (W2 strain)
5
0
Synthesis and anti-plasmodial evaluation of 1H-1,2,3-triazole-tethered 4-aminoquinoline -
ferrocenenylchalcone conjugates with the most potent and non-cytotoxic conjugate
exhibiting an IC of 0.37 µM against CQ-R W2 strain of P. falciparum.
5
0

ACCEPTED MANUSCRIPT
4-Aminoquinoline-ferrocenyl-chalcone conjugates: Synthesis and Anti-
Plasmodial Evaluation
a
b
b
a*
Amandeep Singh, Jiri Gut, Philip J. Rosenthal, Vipan Kumar
a
Department of Chemistry, Guru Nanak Dev University, Amritsar-143005, Punjab, India
b
Department of Medicine, University of California, San Francisco, CA, USA
Abstract: A series of aliphatic and aromatic substituted 1H-1,2,3-triazole-tethered 4-amino-
quinoline-ferrocenylchalcone conjugates has been synthesized and evaluated for anti-plasmodial
activity. The conjugates with flexible aliphatic (aminoethanol or aminopropanol) substituents on the
quinoline ring showed better anti-plasmodial activities compared to those with cyclic (piperazine or
aminophenol) substituents. The conjugate 17j was the most potent and non-cytotoxic, with an IC50
value of 0.37 µM against the chloroquine-resistant W2 strain of Plasmodium falciparum.
Keywords: 4-amino-quinoline-ferrocenylchalcone, 1,3-dipolar cycloaddition, antiplasmodial
activities, Structure-activity relationship,
1
.
Introduction
Plasmodium falciparum, the causative organism for the most severe form of malaria,
poses significant global health and socio-economic burdens.[1] The disease remains a
major cause of illness and deaths in tropical and sub-tropical countries including Asia,
Africa and South America.[2] According to the World Health Organization, an
estimated 3.3 billion people are at risk of being infected with malaria while 1.2 billion
are at high risk.[3] In 2015, 214 million cases of malaria were estimated world-wide,
with 438,000 deaths.[4] Chloroquine (CQ) was the most accessible, effective and safe
drug in the history of malaria chemotherapy.[5-7] The drug was used for many years
as the principle treatment of faciparum malaria, and it is still the drug of choice for
the treatment of uncomplicated malaria caused by Plasmodium vivax and other
species.[8] The development of CQ-resistance in P. falciparum[9] paved the way for
its replacement with artemisinin-based combination therapy (ACT).[10] However,
resistance has been reported to both
artemisinins and key partner drugs in
southeast Asia, providing impetus for the development of new anti-plasmodial
agents.[11-14]

ACCEPTED MANUSCRIPT
Among strategies for new anti-plasmodial drug development is 4-
aminoquinoline hybridization. Quinoline-hybridization is an extension of the concept
of combination therapy, combining two pharmacophoric groups via a covalent bond
to create a single entity.[15] The success of quinoline-hybridization in malaria
chemotherapy is exemplified by ferroquine (7-chloroquinoline-ferrocene). The
organometallic conjugate ferroquine has shown activity against CQ-sensitive and CQ-
resistant strains of P. falciparum[16-19] and has recently completed phase IIb clinical
trials.[20] Ferroquine has been suggested to generate oxidative stress due to redox
2
+
3+
properties of the ferrocene (Fe )/ferrocenium (Fe ) system,[21-24] creating a
reactive oxygen species through a Fenton-like reaction in the digestive vacuole of the
parasite.[25-30] The high anti-plasmodial potency of ferroquine can be attributed
because of its higher fraction of neutral and monoprotonated form compared to
chloroquine and non-covalent interactions with hemozoin because of the presence
of a ferrocene core.[31]1,2,4-trioxane-ferrocene conjugates had IC values ranging
5
0
from 7.2-30.2 nM against the 3D7 strain of P. falciparum.[32] A carbosilane congener
of ferroquine exhibited better activity than ferroquine against the NF54 strain of P.
falciparum.[33]
Chalcones represent a key structural motif, belonging to the flavonoid class of
natural products and exhibiting a myriad of pharmacological properties.[34-35]The
discovery of the promising antiplasmodial activity of Licochalcone A from Chinese licorice
root prompted researchers to study the anti-plasmodial efficacies of variedly functionalized
synthetic chalcones.[36] Structure-activity relationship (SAR) studies confirmed the
presence of α,β-unsaturated ketone linkers and the E-configuration as critical pre-requisites
for good antiplasmodial activity.[37-38] The antiplasmodial activity of chalcones is
potentially augmented by their ability to act as inhibitors of plasmodial aspartate
proteases,[39] cysteine proteases[40] and cyclin-dependent protein kinases[41] along with
their inhibition of new permeation pathways induced by the parasite in erythrocytic
membranes.[42]
In continuation with our interest in the synthesis of biologically relevant molecular
conjugates,[43] the present manuscript describes the synthesis of a series of 1H-
1,2,3-triazole linked 4-aminoquinoline-ferrocenyl-chalcone conjugates as depicted in
Figure 1 and evaluation of their antiplasmodial activity. 1H-1,2,3-triazole core was

ACCEPTED MANUSCRIPT
introduced as a linker due to its stability under basic, acidic, reductive and oxidative
conditions, as well as favourable properties including high dipole moment, hydrogen
bonding, and rigidity in binding with bio-molecular targets.[44] The nature of the
substituent as well as the length of the alkyl chain between the two pharmacophores
(
7-chloroquinoline and ferrocenylchalcone) was altered to study the SAR of the
synthesized conjugates.
2
. Results and Discussion:
The precursor O-alkylazido-ferrocenyl chalcone 4, was prepared by a recently reported
protocol,[43] involving an initial alkylation of 4-hydroxy-acetophenone 1 using dibromo-
alkanes and subsequent reaction with sodium azide in dry DMF to afford O-alkylazido-
acetophenones 3. Aldol-condensation of 3 with ferrocene-carboxaldehyde afforded the
desired O-alkylazido-ferrocenyl chalcones 4 in good yields. For the synthesis of desired
piperazine-linked 4-aminoquinoline-ferrocenylchalcone conjugates 8, 4,7-dichloroquinoline
5
was initially reacted with piperazine to yield 7-chloro-4-piperazinequinoline6 [45] which
was N-propargylated to afford precursor 7. Cu-promoted azide-alkyne cycloaddition of 4
with 7 resulted in the formation of desired 8 in good to excellent yields (Scheme 2).
Structures to the conjugates were assigned on the basis of spectral studies and analytical
evidence. For example, compound 8a exhibited a molecular ion peak at 686.1849 in its high
1
resolution mass spectrum (HRMS). Its H NMR spectrum showed the presence of a singlet at
δ 4.18 corresponding to 5H (cyclopentadiene ring of ferrocene) along with singlets at δ 4.50
(4H) and δ 4.59 (2H) due to the presence of ferrocene ring and methylene protons. The
presence of two singlets at δ 2.86 (4H) and 3.29 (4H) corresponding to the piperazine ring
protons and a characteristic singlet at δ 8.07 (1H) corresponding to the triazole ring proton
supported the assigned structure. The presence of characteristic peaks at δ 49.7 and 51.8
ppm corresponding to the piperazine ring and an α,β-unsaturated carbonyl carbon at δ
13
1
87.8 in C NMR spectrum further corroborated the assigned structure.
Another precursor, (7-Chloro-quinolin-4-yl)-(4-prop-2-ynyloxy-phenyl)-amine
1
2
, was prepared via an initial propargylation of 4-nitrophenol
reduction with iron powder in ethanol:water (90:10) mixture to yield 4-Prop-2-
ynyloxy-phenylamine 11.[46] Heating a mixture of 11 with 4,7-dichloroquinoline in
refluxing ethanol yielded 12. Cu-promoted click chemistry of 12 with O-alkylazido-
ferrocenyl chalcones led to the isolation of crude solids, which were purified on
9 followed by its
5
4

ACCEPTED MANUSCRIPT
silica gel (60:120) using CHCl :methanol (95:5) mixture as eluent, to yield 13 in good
3
to excellent yields (Scheme 3).The structure of the compound was assigned on the
basis of spectral studies and analytical evidence. For example, compound 13a
exhibited a molecular ion peak at 709.1543 in its high resolution mass spectrum
1
HRMS). Its H NMR spectrum showed the presence of a singlet at δ 4.17
(
corresponding to 5H (cyclopentadiene ring of ferrocene) along with singlets at δ 4.49
2H) and δ 4.58 (2H) due to the presence of ferrocene ring protons. The appearance
(
of a doublet at δ 7.75 (1H, J=15.3Hz) confirmed the presence of the trans-olefinic
proton of ferrocenylchalcone, along with a characteristic singlet at δ 7.85 (1H)
corresponding to the triazole ring proton.The appearance of absorption peaks at δ
1
9.0, 69.7, 71.4 and 79.1 in the C NMR spectrum corresponding to ferrocene ring
3
6
carbons and the presence of an α,β-unsaturated carbonyl carbon at δ 188.1
supported the assigned structure.
The developed protocol was extended to synthesize a series of amino-alcohol
tethered 4-aminoquinoline-ferrocenylchalcone conjugates 17. The protocol involved initial
treatment of 4,7-dichloroquinoline 5 with aminoethanol/aminopropanol, with subsequent
propargylation to result in the formation of 16. Huisgen’s azide-alkyne cycloaddition of 16
with 4 gave the desired amino-alcohol-tethered-7-chloroquinoline-ferrocenylchalcone
conjugates 17 in excellent yields (Scheme 4). The structures of the conjugates were assigned
on the basis of spectral data and analytical evidence. For example, compound 17e exhibited
1
a molecular ion peak at 717.2129 in its high resolution mass spectrum (HRMS). Its H NMR
spectrum showed the presence of multiplets at δ 1.43 (2H) and 1.54 (2H) along with triplets
at δ 1.80 (2H), 1.94 (2H), and singlets at δ 3.54 (2H) and 4.70 (2H) due to the presence of n-
hexyl chain protons. The appearance of doublets at δ 6.94 (2H) and 8.05 (2H) confirmed the
presence of aromatic ring protons, and a characteristic singlet at δ 7.51 (1H) corresponded
to the triazole ring protons.The appearance of characteristic peaks corresponding to the
ferrocenyl ring and theα,
β
- unsaturated carbonyl carbon confirmed the assigned structure.
13 and 17
The synthesized 4-aminoquinoline-ferrocenylchalcone conjugates
8
,
were evaluated for their antiplasmodial activities against the chloroquine-resistant
W2 strain of P. falciparum (Table 1). All of the compounds showed good anti-
plasmodial activity with IC values ranging from 0.37-5.08 µM. Inspection of the data
5
0
revealed an interesting SAR, with activities largely dependent upon the nature of

ACCEPTED MANUSCRIPT
substituents introduced on the quinoline ring and on the length of the alkyl chain
introduced as a linker between two pharmacophores. In the case of piperazine-linked
conjugates 8a-8f, the compounds exhibited IC values in the range of 2.55-5.08 µM.
50
Conjugate 8a (n=2) was most potent in this series, while activity seems to be
independent upon the length of the alkyl chain introduced. Replacement of the
piperazine ring with 4-aminophenol did not improve antiplasmodial efficacy except in
the cases of 13e (n= 6) and 13f (n=8), with IC50s of 2.40 and 1.16 µM respectively,
indicating an improvement in antiplasmodial activity with increasing alkyl chain
length. Introduction of amino-alcohols as substituents on the quinoline core
improved the activity profiles, as evident for conjugates 17a
substituted scaffolds 17a , the conjugates showed a decrease in activity with
increase in chain length, as evident for compounds 17a (n=2, IC = 0.95 µM) and 17d
-l. Among amino-ethanol-
-
f
5
0
(
n=5, IC = 2.92 µM), while a further increase in chain length improved the activity, as
50
shown for conjugates 17e and 17f. Similar comparison among amino-propanol-
substituted compounds 17g revealed the conjugates to be the most potent among
-
l
the tested compounds, with activities largely independent of the length of alkyl chain
linker. Conjugate 17j, with an optimum combination of amino-propanol as
substituent and an n-pentyl chain linker, was the most potent of the tested
compounds, with an IC of 0.37 µM. Comparing the anti-plasmodial activities of the
5
0
present conjugates with amide-tethered similar scaffolds reported earlier by our
group revealed the preference for an amide functionality over the 1H-1,2,3-triazole
linker with the most potent 4-aminoquinoline-ferrocenylchalcone conjugate of the
series exhibiting an IC of 0.15 µM.[43e] Cytotoxicity of the most potent conjugates
5
0
viz. 17g-k was determined against mammalian HeLa cells in order to ascertain
whether the observed activities are due to their antiplasmodial efficacy or
cytotoxicity (Table 2). As evident, the synthesized conjugates exhibited IC values in
5
0
the range of 16.12-23.34
µM while doxorubicin displayed an IC50 of 8.3 µM
suggestive of the fact that these conjugates can act as starting points for the
synthesis of new pharmacological templates against P. falciparum.

ACCEPTED MANUSCRIPT
3
. Conclusion
In conclusion, a series of 1H-1,2,3-triazole tethered 7-chloroquinoline-ferrocenyl
chalcones with varied substituents on the quinoline core was prepared and evaluated
for activity against P. falciparum. The presence of a flexible chain as a substitutent on
the quinoline core improved antiplasmodial activity compared to the presence of
cyclic piperazine/aminophenol functionalities. The conjugates with amino alcohols
(
amino-propanol) as substituents were non-cytotoxic and had activities in the sub-
micromolar range (0.37-1.78 µM), and can be seen as templates for further design of
new antiplasmodial scaffolds.
4
. Experimental Section
General Information
Melting points were determined by an open capillary using a Veego Precision Digital
1
Melting Point apparatus (MP-D) and are uncorrected. H NMR spectra were recorded
in CDCl with a BRUKER AVANCE II (500 MHz) spectrometer using TMS as internal
3
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,
1
and br: broad peak. C NMR spectra were recorded in CDCl with a BRUKER AVANCE
3
3
II (125 MHz) using TMS as internal standard. Mass spectra were recorded on a
BRUCKER high resolution mass spectrometer (micrOTOF-QII). Elemental analyses
were performed on a Heraus CHN-O-Rapid Elemental Analyzer. Column
chromatography was performed on a silica gel (60–120 mesh) using ethyl
chloroform:hexane mixture as eluent.
4
.1 Procedure for synthesis of 1H-1,2,3-triazole-tethered piprazine-linked 4-
aminoquinoline-ferrocenylchalcone conjugates (8a-f):To a stirred solution of o-
alkylazido chalcones (1 mmol) and N-propargylated 7-chloro-4-
piprazinequinoline (1 mmol) in an ethanol−water (90:10) mixture was added copper
4
7

ACCEPTED MANUSCRIPT
sulfate (0.05 mmol) and sodium ascorbate (0.13 mmol).The reaction mixture was
allowed to stir at room temperature for 7−10 h, and the progress was monitored
using TLC. After the reaction was complete, water (20 mL) was added, and the
reaction mixture was extracted twice with dichloromethane (2 × 30 mL). The
combined organic layers were dried over anhydrous sodium sulfate and concentrated
under reduced pressure to yield a crude product, which was purified via column
chromatography using 10:90 (methanol:chloroform) mixture.
4
.1.1 1-[4-(2-{4-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-ylmethyl]-[1,2,3]triazol-1-yl}-
ethoxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (8a): Yield 74%. Dark red solid,
o
m.p: 150-151 C; H NMR (CDCl , 500MHz): 2.86 (s, 4H, piprazine-H), 3.29 (s, 4H,
1
3
9
1
2
7
piprazine-H), 3.89 (s, 2H, H ), 4.18 (s, 5H, H ), 4.49-4.51 (m, 4H, H +H ), 4.59 (s, 2H,
3
H ), 4.84 (t, J=4.9 Hz, 2H, H ), 6.84 (d, J=4.8 Hz, 1H, Ar-H), 6.96 (d, J=8.5 Hz, 2H, Ar-H),
6
5
4
.10 (d, J=15.2 Hz, 1H, H ), 7.43 (d, J=7.8 Hz, 1H, Ar-H), 7.74 (d, J=15.3 Hz, 1H, H ),
7
8
.81 (s, 1H, H ), 7.92 (d, J=8.9 Hz, 1H, Ar-H), 7.99 (d, J=8.5 Hz, 2H, Ar-H), 8.07 (s, 1H,
7
1
Ar-H), 8.72 (d, J=5.0 Hz, 1H, Ar-H). C NMR (CDCl , 125MHz):49.7, 51.8, 52.6, 53.0,
3
3
66.4, 68.9, 69.7, 71.3, 79.2, 99.9, 108.9, 114.1, 118.5, 121.7, 124.2, 125.1, 126.2,
128.6, 130.6, 132.4, 135.1, 146.3, 149.8, 151.6, 151.8, 161.1, 187.8. HRMS calcd for
+
C H ClFeN O [M] 686.1859,found 686.1868.Anal Calcd(%) for: C,64.69; H,5.13; N,
3
7
35
6
2
12.23. found: C,64.62; H,5.19; N,12.30.
4
.1.2 1-[4-(3-{4-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-ylmethyl]-[1,2,3]triazol-1-yl}-
propoxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (8b): Yield 80%. Dark red solid,
o
m.p: 145-146 C; H NMR (CDCl , 500MHz): 2.06-2.09 (m, 2H, H ), 2.83 (s, 4H,
1
7
3
1
0
8
piprazine-H), 3.27 (s, 4H, piprazine-H),3.85 (s, 2H, H ), 4.00 (t, J=5.3 Hz, 2H, H ), 4.16
1
s, 5H, H ), 4.49 (s, 2H, H ), 4.60-4.66 (m, 4H, H +H ), 6.82 (d, J=4.6 Hz, 1H, Ar-H), 6.92
2
3
6
(
(
5
d, J=8.4 Hz, 2H, Ar-H), 7.13 (d, J=15.1 Hz, 1H, H ), 7.41 (d, J=7.6 Hz, 1H, Ar-H), 7.75 (d,
4
J=15.2 Hz, 1H, H ), 7.81 (s, 1H, H ), 7.91 (d, J=8.9 Hz, 1H, Ar-H), 7.97 (d, J=8.4 Hz, 2H,
8
1
Ar-H), 8.05 (s, 1H, Ar-H), 8.77 (d, J=4.9 Hz, 1H, Ar-H). C NMR (CDCl , 125MHz): 28.0,
3
3
4
1
1
9.5, 51.6, 52.7, 64.2, 64.3, 68.9, 69.7, 71.3, 79.3, 99.5, 108.4, 114.4, 118.3, 121.5,
24.6, 125.3, 126.5, 128.4, 130.4, 132.6, 135.3, 146.6, 149.7, 151.5, 151.8, 161.4,
+
87.7. HRMScalcd for C H ClFeN O [M] 700.2016,found 700.2028.Anal Calcd(%)
3
8
37
6
2
for: C,65.10; H,5.32; N, 11.99. found: C,65.14; H,5.29; N, 11.83.

ACCEPTED MANUSCRIPT
4
.1.3 1-[4-(4-{4-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-ylmethyl]-[1,2,3]triazol-1-yl}-
butoxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (8c): Yield 79%. Dark red solid,
o
m.p: 140-141 C; H NMR (CDCl , 500MHz):1.87-1.91 (m, 2H, H ), 2.16-2.21(m, 2H,
1
8
3
7 11
H ), 2.92 (s, 4H, piprazine-H), 3.32 (s, 4H, piprazine-H), 3.92(s, 2H, H ), 4.09 (t, J=5.7
9
Hz, 2H, H ), 4.19 (s, 5H, H ), 4.49-4.50 (m, 4H, H +H ), 4.60 (s, 2H, H ), 6.85 (d, J=4.5
1
2
6
3
5
Hz, 1H, Ar-H), 6.95 (d, J=8.5 Hz, 2H, Ar-H), 7.14 (d, J=15.1 Hz, 1H, H ), 7.42 (d, J=7.5
4
10
Hz, 1H, Ar-H), 7.76 (d, J=15.1 Hz, 1H, H ), 7.82 (s, 1H, H ), 7.94 (d, J=8.6 Hz, 1H, Ar-H),
1
.98 (d, J=8.5 Hz, 2H, Ar-H), 8.07 (s, 1H, Ar-H), 8.72 (d, J=4.0 Hz, 1H, Ar-H). C NMR
3
7
(
CDCl , 125MHz): 26.1, 27.1, 29.6, 31.6, 50.0, 52.9, 67.1, 68.9, 69.7, 71.2, 79.4, 99.4,
3
1
1
7
08.9, 114.1, 118.8, 121.6, 124.0, 125.0, 126.3, 128.3, 130.5, 132.4, 135.2, 146.4,
+
49.5, 151.6, 151.7, 161.5, 187.9. HRMS
calcd for C H ClFeN O [M]
39 39 6 2
14.2176,found 714.2188.Anal Calcd(%) for: C,65.51; H,5.50; N, 11.75. found:
C,65.54; H,5.59; N,11.83.
4
.1.4 1-[4-(5-{4-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-ylmethyl]-[1,2,3]triazol-1-yl}-
pentyloxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (8d): Yield 84%. Dark red solid,
o
1
m.p: 139-140 C; H NMR (CDCl , 500MHz):1.54-1.56 (m, 2H, H ), 1.85-1.87 (m, 2H,
8
3
9
H ), 2.00-2.03 (m, 2H, H ), 2.95 (s, 4H, piprazine-H), 3.37 (s, 4H, piprazine-H), 4.02 (s,
7
1
H, H ), 4.09 (t, J=5.4 Hz, 2H, H ), 4.18 (s, 5H, H ), 4.49-4.51 (m, 4H, H +H ), 4.62 (s,
2
10
1
2
6
2
2
1
3
H, H ), 6.82 (d, J=4.1 Hz, 1H, Ar-H), 6.92 (d, J=8.4 Hz, 2H, Ar-H), 7.16 (d, J=15.3 Hz,
5
H, H ), 7.46 (d, J=7.4 Hz, 1H, Ar-H), 7.74 (d, J=15.3 Hz, 1H, H ), 7.84 (s, 1H, H ), 7.93
4
11
(
d, J=8.4 Hz, 1H, Ar-H), 7.83 (d, J=8.4 Hz, 2H, Ar-H), 8.05 (s, 1H, Ar-H), 8.74 (d, J=4.5
1
Hz, 1H, Ar-H). C NMR (CDCl , 125MHz):23.1, 26.3, 27.5, 29.2, 31.7, 50.1, 52.6, 67.3,
3
3
68.5, 69.5, 71.4, 79.2, 99.5, 108.6, 114.5, 118.6, 121.4, 124.4, 125.5, 126.6, 128.2,
130.3, 132.6, 135.6, 146.6, 149.3, 151.3, 151.5, 161.6, 187.7. HRMS calcd for
+
C H ClFeN O [M] 728.2329,found 728.2338.Anal Calcd(%) for: C,65.89; H,5.67; N,
4
0
41
6
2
11.53. found: C,65.81; H,5.62; N,11.63.
4
.1.5 1-[4-(6-{4-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-ylmethyl]-[1,2,3]triazol-1-yl}-
hexyloxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (8e): Yield 74%. Dark red solid,
o
m.p: 135-136 C; H NMR (CDCl , 500MHz):1.39-1.43 (m, 2H, H ), 1.51-1.55(m, 2H,
1
9
3

ACCEPTED MANUSCRIPT
8
H ), 1.79-1.82(m, 2H, H ), 1.92-1.96 (m, 2H, H ), 2.92 (s, 4H, piprazine-H), 3.35 (s, 4H,
10
7
1
piprazine-H), 4.03 (s, 2H, H ), 4.05 (t, J=5.2 Hz, 2H, H ), 4.17 (s, 5H, H ), 4.47-4.49
3
11
1
2
6
3
m, 4H, H +H ), 4.64 (s, 2H, H ), 6.84 (d, J=4.2 Hz, 1H, Ar-H), 6.95 (d, J=8.6 Hz, 2H, Ar-
(
5
H), 7.14 (d, J=15.2 Hz, 1H, H ), 7.44(d, J=7.3 Hz, 1H, Ar-H), 7.71 (d, J=15.2 Hz, 1H, H ),
4
1
.82 (s, 1H, H ), 7.85 (d, J=8.4 Hz, 1H, Ar-H), 7.88 (d, J=8.4 Hz, 2H, Ar-H), 8.03 (s, 1H,
2
7
1
3
Ar-H), 8.72 (d, J=5.1 Hz, 1H, Ar-H). C NMR (CDCl , 125MHz): 22.5, 23.1, 26.5, 27.8,
3
2
1
1
9.6, 31.4, 50.8, 52.9, 67.6, 68.4, 69.7, 71.8, 79.1, 99.1, 108.4, 114.7, 118.2, 121.2,
24.7, 125.9, 126.2, 128.5, 130.6, 132.7, 135.7, 146.3, 149.8, 151.4, 151.6, 161.6,
+
87.9. HRMS calcd for C H ClFeN O [M] 743.2485,found 743.2498.Anal Calcd(%)
4
1
43
6
2
for: C,66.27; H,5.83; N, 11.31. found: C,66.32; H,5.94; N,11.43.
4
.1.6 1-[4-(8-{4-[4-(7-Chloro-quinolin-4-yl)-piperazin-1-ylmethyl]-[1,2,3]triazol-1-yl}-
octyloxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (8f): Yield 77%. Dark red solid,
o
1
9
10
m.p: 120-121 C; H NMR (CDCl , 500MHz):1.39-1.42 (m, 4H, H +H ), 1.43-1.45 (m,
3
1
H, H ), 1.46-1.47 (m, 2H, H ), 1.80-1.82 (m, 2H, H ), 1.95-2.00 (m, 2H, H ), 2.98 (s,
1
8
12
7
2
4
4
1
H, piprazine-H), 3.38 (s, 4H, piprazine-H), 3.98 (s, 2H, H ), 4.03 (t, J=5.8 Hz, 2H, H ),
5
13
1
.18 (s, 5H, H ), 4.38 (t, J=6.2 Hz. 2H, H ), 4.48 (s, 2H, H ), 4.60 (s, 2H, H ), 6.85 (d,
6
2
3
5
J=4.2 Hz, 1H, Ar-H), 6.96 (d, J=8.2 Hz, 2H, Ar-H), 7.18 (d, J=15.3 Hz, 1H, H ), 7.48 (d,
4 15
J=7.3 Hz, 1H, Ar-H), 7.77 (d, J=15.3 Hz, 1H, H ), 7.89 (s, 1H, H ), 7.93 (d, J=8.2 Hz, 1H,
1
3
Ar-H), 7.87 (d, J=8.2 Hz, 2H, Ar-H), 8.38 (s, 1H, Ar-H), 8.78 (d, J=4.7 Hz, 1H, Ar-H). C
NMR (CDCl , 125MHz):22.6, 25.8, 26.4, 28.8, 29.0, 29.6, 30.2, 31.6, 50.4, 52.4, 68.0,
3
68.9, 69.7, 71.1, 79.4, 99.5, 108.2, 114.5, 118.5, 121.1, 124.3, 125.8, 126.1, 128.3,
130.8, 132.3, 135.4, 146.5, 149.5, 151.6, 151.7, 161.9, 187.3. HRMS calcd for
+
C H ClFeN O [M] 770.2798,found 770.2788.Anal Calcd(%) for: C,66.97; H,6.14; N,
4
3
47
6
2
10.90. found: C,66.88; H, 6.23; N,10.83.
4
.2 Procedure for synthesis of 1H-1,2,3-triazole-tethered 7-Chloro-quinolin-4-yl)-(4-
prop-2-ynyloxy-phenyl)-amine ferrocenylchalcone conjugates (13a-f): To a stirred
solution of O-alkylazide ferrocenyl chalcone (1 mmol) ,and 7-Chloro-quinolin-4-yl)-
4-prop-2-ynyloxy-phenyl)-amine 12 (1 mmol) in an ethanol:water(90:10) mixture
4
(
was added copper sulfate (0.05 mmol) and sodium ascorbate (0.13 mmol). The
reaction mixture was allowed to stir at room temperature for 10−11 h, and the
progress was monitored using TLC. After the reaction was complete, water (20 mL)

ACCEPTED MANUSCRIPT
was added, and the reaction mixture was extracted twice with dichloromethane (2 ×
30 mL). The combined organic layers were dried over anhydrous sodium sulfate and
concentrated under reduced pressure to yield a crude product, which was purified
via column chromatography using a 10:90 (methanol:chloroform) mixture.
4
.2.1 1-[4-(2-{4-[4-(7-Chloro-quinolin-4-ylamino)-phenoxymethyl]-[1,2,3]triazol-1-yl}-
ethoxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (13a): Yield 90%. Dark red solid,
o
1
1
2
6
m.p: 170-171 C; H NMR (CDCl , 500MHz): 4.17 (s, 5H, H ), 4.49 (s, 4H, H +H ), 4.58
3
3
7
9
s, 2H, H ), 4.83 (s, 2H, H ), 5.24 (s, 2H, H ), 6.65 (s, 1H, Ar-H), 6.89 (d, J=8.0 Hz, 2H,
(
4
Ar-H), 7.02 (d, J=7.3 Hz, 2H, Ar-H), 7.10 (d, J=15.3 Hz, 1H, H ), 7.21 (d, J=6.9 Hz, 2H,
5
Ar-H), 7.44 (d, J=6.9 Hz, 1H, Ar-H), 7.75 (d, J=15.3 Hz, 1H, H ), 7.85 (s, 1H, H ), 7.94 (d,
8
1
J=8.0 Hz, 2H, Ar-H), 8.02-8.05 (m, 2H, Ar-H), 8.44 (s, 1H, Ar-H). C NMR (CDCl ,
3
3
1
1
1
7
25MHz): 49.8, 62.1, 66.5, 69.0, 69.7, 71.4, 79.1, 101.2, 114.2, 115.9, 117.4, 118.5,
21.7, 124.0, 125.9, 126.1, 128.0, 130.6, 132.3, 132.4, 135.5, 144.2, 146.5, 149.5,
+
50.9, 151.0, 156.1, 161.1, 188.1. HRMS
calcd for C H ClFeN O [M]
39 32 5 2
09.1543,found 709.1532.Anal Calcd(%) for: C,66.97; H,4.54; N, 9.88. found: C,66.88;
H, 4.63; N,9.75.
4
.2.2 1-[4-(3-{4-[4-(7-Chloro-quinolin-4-ylamino)-phenoxymethyl]-[1,2,3]triazol-1-yl}-
propoxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (13b): Yield 89%. Dark red solid,
o
m.p: 167-168 C H NMR (CDCl , 500MHz): 2.04-2.06 (m, 2H, H ), 4.15 (s, 5H, H ), 4.47
1
7
1
3
2
6
3
8
10
s, 4H, H +H ), 4.56 (s, 2H, H ), 4.83 (s, 2H, H ), 5.25 (s, 2H, H ), 6.64 (s, 1H, Ar-H),
(
4
.88 (d, J=8.1 Hz, 2H, Ar-H), 7.04 (d, J=7.2 Hz, 2H, Ar-H), 7.11 (d, J=15.2 Hz, 1H, H ),
6
7
7
5
.22 (d, J=7.0 Hz, 2H, Ar-H), 7.46 (d, J=6.9 Hz, 1H, Ar-H), 7.76 (d, J=15.2 Hz, 1H, H ),
9
.83 (s, 1H, H ), 7.94 (d, J=8.1 Hz, 2H, Ar-H), 8.03-8.06 (m, 2H, Ar-H), 8.42 (s, 1H, Ar-
1
H). C NMR (CDCl , 125MHz) 27.8, 49.4, 62.4, 66.6, 69.2, 69.5, 71.2, 79.5, 101.4,
3
3
114.6, 115.6, 117.6, 118.7, 121.8, 124.5, 125.6, 126.3, 128.6, 130.7, 132.5, 132.6,
135.5, 144.6, 146.7, 149.8, 150.8, 150.9, 156.4, 161.3, 188.2. HRMS calcd for
+
C H ClFeN O [M] 723.1700,found 723.1712.Anal Calcd(%) for: C,66.35; H,4.73; N,
4
0
34
5
3
9.67. found: C,66.45; H, 4.63; N,9.75.

ACCEPTED MANUSCRIPT
4
.2.3 1-[4-(4-{4-[4-(7-Chloro-quinolin-4-ylamino)-phenoxymethyl]-[1,2,3]triazol-1-yl}-
butoxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (13c): Yield 93%. Dark red solid,
o
m.p: 159-160 C H NMR (CDCl , 500MHz):1.83-1.85(m, 2H, H ), 2.13-2.17(m, 2H, H ),
1
8
7
3
1
2
6
3
9
11
.14 (s, 5H, H ), 4.45 (s, 4H, H +H ), 4.57 (s, 2H, H ), 4.85 (s, 2H, H ), 5.27 (s, 2H, H ),
4
6.65 (s, 1H, Ar-H), 6.84 (d, J=8.2 Hz, 2H, Ar-H), 7.03 (d, J=7.1 Hz, 2H, Ar-H), 7.12 (d,
4
J=15.3 Hz, 1H, H ), 7.25 (d, J=7.1 Hz, 2H, Ar-H), 7.48 (d, J=6.8 Hz, 1H, Ar-H), 7.72 (d,
5 10
J=15.3 Hz, 1H, H ), 7.86 (s, 1H, H ), 7.96 (d, J=8.2 Hz, 2H, Ar-H), 8.05-8.08 (m, 2H, Ar-
1
3
H), 8.45 (s, 1H, Ar-H). C NMR (CDCl , 125MHz) 26.6, 27.6,49.4, 62.8, 66.4, 69.6, 69.9,
3
71.8, 79.8, 101.8, 114.9, 115.8, 117.8, 118.4, 121.4, 124.9, 125.8, 126.8, 128.9, 130.6,
132.4, 132.8, 135.4, 144.4, 146.6, 149.5, 150.8, 151.1, 156.3, 161.5, 188.6. HRMS
+
calcd for C H ClFeN O [M] 737.1856,found 737.1862.Anal Calcd(%) for: C,66.72;
4
1
36
5
3
H,4.92; N, 9.49. found: C,66.65; H, 4.83; N,9.55.
4
.2.4 1-[4-(5-{4-[4-(7-Chloro-quinolin-4-ylamino)-phenoxymethyl]-[1,2,3]triazol-1-yl}-
pentyloxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (13d): Yield 90%. Dark red
o
solid, m.p: 160-161 C H NMR (CDCl , 500MHz):1.51-1.54 (m, 2H, H ), 1.85-1.85 (m,
1
8
3
9
7
1
2
6
H, H ), 2.01-2.03 (m, 2H, H ), 4.14 (s, 5H, H ), 4.47 (s, 4H, H +H ), 4.57 (s, 2H, H ),
3
2
1
.86 (s, 2H, H ), 5.27 (s, 2H, H ), 6.67 (s, 1H, Ar-H), 6.87 (d, J=8.0 Hz, 2H, Ar-H), 7.04
0
12
4
4
d, J=7.3 Hz, 2H, Ar-H), 7.11 (d, J=15.3 Hz, 1H, H ), 7.22 (d, J=6.9 Hz, 2H, Ar-H), 7.41 (d,
(
5
8
J=6.9 Hz, 1H, Ar-H), 7.73 (d, J=15.3 Hz, 1H, H ), 7.83 (s, 1H, H ), 7.93 (d, J=8.0 Hz, 2H,
1
Ar-H), 8.04-8.07 (m, 2H, Ar-H), 8.46 (s, 1H, Ar-H). C NMR (CDCl , 125MHz) 23.1,
3
3
2
1
1
7
6.3, 27.5, 49.6, 61.8, 65.3, 69.9, 69.2, 71.5, 78.9, 101.6, 114.7, 116.0, 117.5, 117.8,
21.2, 123.8, 126.0, 126.5, 127.7, 130.1, 132.2, 132.7, 135.9, 144.9, 146.8, 148.8,
+
50.9, 151.1, 156.4, 161.6, 188.5. HRMS
calcd for C H ClFeN O [M]
42 38 5 3
51.2013,found 751.2022.Anal Calcd(%) for: C,67.07; H,5.09; N, 9.31. found: C,67.15;
H, 5.13; N,9.45.
4
.2.5 1-[4-(6-{4-[4-(7-Chloro-quinolin-4-ylamino)-phenoxymethyl]-[1,2,3]triazol-1-yl}-
hexyloxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (13e): Yield 91%. Dark red solid,
o
m.p: 150-152 C; H NMR (CDCl , 500MHz):1.35-1.38 (m, 2H, H ), 1.53-1.57(m, 2H,
1
9
3
8
10
7
1
2
6
H ), 1.77-1.80(m, 2H, H ), 1.94-1.96 (m, 2H, H ), 4.15 (s, 5H, H ), 4.45 (s, 4H, H +H ),
3
.54 (s, 2H, H ), 4.84 (s, 2H, H ), 5.23 (s, 2H, H ), 6.66 (s, 1H, Ar-H), 6.88 (d, J=8.1 Hz,
11
13
4

ACCEPTED MANUSCRIPT
H, Ar-H), 7.03 (d, J=7.2 Hz, 2H, Ar-H), 7.14 (d, J=15.2 Hz, 1H, H ), 7.26 (d, J=7.0 Hz,
4
2
2
7
5 12
H, Ar-H), 7.45 (d, J=6.9 Hz, 1H, Ar-H), 7.75 (d, J=15.3 Hz, 1H, H ), 7.81 (s, 1H, H ),
1
.91 (d, J=8.0 Hz, 2H, Ar-H), 8.03-8.06 (m, 2H, Ar-H), 8.44 (s, 1H, Ar-H). C NMR
3
(
CDCl , 125MHz): 22.3, 23.4, 26.4, 27.7, 49.7, 61.7, 65.5, 69.5, 69.6, 71.8, 78.7, 101.8,
3
114.5, 116.7, 117.4, 117.7, 121.6, 123.5, 126.5, 126.8, 127.6, 130.6, 132.4, 132.5,
135.7, 144.8, 146.6, 148.7, 150.8, 151.3, 156.2, 161.5, 188.7. HRMS calcd for
+
C H ClFeN O [M] 765.2169,found 765.2175.Anal Calcd(%) for: C,67.41; H,5.26; N,
4
3
40
5
3
9.14. found: C,67.55; H, 5.17; N,9.25.
4
.2.6 1-[4-(8-{4-[4-(7-Chloro-quinolin-4-ylamino)-phenoxymethyl]-[1,2,3]triazol-1-yl}-
octyloxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (13f): Yield 90%. Dark red solid,
o
m.p: 139-141 C H NMR (CDCl , 500MHz):1.40-1.43 (m, 4H, H +H ), 1.45-1.47 (m,
1
9
10
3
1
1
8
12
7
H, H ), 1.48-1.49 (m, 2H, H ), 1.84-1.86 (m, 2H, H ), 1.93-1.95 (m, 2H, H ), 4.16 (s,
2
5
1
1
1
1
6
1
1
1
2
6
3
13
15
H, H ), 4.47 (s, 4H, H +H ), 4.53 (s, 2H, H ), 4.84 (s, 2H, H ), 5.26 (s, 2H, H ), 6.65 (s,
H, Ar-H), 6.87 (d, J=8.0 Hz, 2H, Ar-H), 7.05 (d, J=7.1 Hz, 2H, Ar-H), 7.13 (d, J=15.3 Hz,
4
H, H ), 7.24 (d, J=7.0 Hz, 2H, Ar-H), 7.41 (d, J=6.7 Hz, 1H, Ar-H), 7.76 (d, J=15.3 Hz,
5 14
H, H ), 7.83 (s, 1H, H ), 7.91 (d, J=8.0 Hz, 2H, Ar-H), 8.01-8.03 (m, 2H, Ar-H), 8.41 (s,
1
3
H, Ar-H). C NMR (CDCl , 125MHz): 22.1, 22.7, 24.4, 25.4, 27.8, 49.2, 61.2, 65.9,
3
9.4, 69.8, 71.4, 78.3, 101.3, 114.1, 116.4, 117.7, 117.8, 122.3, 123.8, 126.5, 126.8,
27.2, 130.9, 132.2, 132.6, 135.2, 144.4, 145.6, 148.3, 151.1, 151.6, 154.2, 156.1,
+
61.7, 188.1. HRMS calcd for C H ClFeN O [M] 793.2482,found 793.2475.Anal
4
5
44
5
3
Calcd(%) for: C,66.06; H,5.58; N, 8.82. found: C,66.15; H, 5.67; N,8.91.
4
.3 Procedure for synthesis of 1H-1,2,3-triazole-tethered 4-aminoquinoline-
ferrocenylchalcone conjugates-ferrocenylchalcone conjugates (17a-l): To a stirred
solution of O-alkylazide ferrocenyl chalcone (1 mmol) ,and 7-chloro-N-(2-(prop-
4
zynyloxy)ethyl)quinolin-4-amine 16 (1 mmol) in an ethanol:water (90:10) mixture
was added copper sulfate (0.05 mmol) and sodium ascorbate (0.13 mmol). The
reaction mixture was allowed to stir at room temperature for 10−12 hrs, and the
progress was monitored using TLC. After the reaction was complete, water (20 mL)
was added, and the reaction mixture was extracted twice with dichloromethane (2 ×
30 mL). The combined organic layers were dried over anhydrous sodium sulfate and

ACCEPTED MANUSCRIPT
concentrated under reduced pressure to yield a crude product, which was purified
via column chromatography using a 10:90 (methanol:chloroform) mixture.
4
.3.1 1-[4-(2-{4-[2-(7-Chloro-quinolin-4-ylamino)-ethoxymethyl]-[1,2,3]triazol-1-yl}-
ethoxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (17a): Yield 82%. Dark red solid,
o
m.p: 160-161 C; H NMR (CDCl , 500MHz): 3.54 (s, 2H, H ), 3.94 (s, 2H, H ), 4.02 (s,
1
11
10
3
9
1
6
2
3
H, H ), 4.18 (s, 5H, H ), 4.36 (t, J= 4.3 Hz, 2H, H ), 4.48 (s, 2H, H ), 4.60 (s, 2H, H ),
2
7
.75 (s, 2H, H ), 6.40 (s, 1H, Ar-H), 6.71 (s, 1H, Ar-H), 6.94 (d, J=8.4 Hz, 2H, Ar-H), 7.15
4
4
d, J=15.3 Hz, 1H, H ), 7.40-7.51 (m, 2H, Ar-H+H ), 7.74 (d, J= 15.3Hz, 1H, H ), 8.00-
8
5
(
1
3
.07 (m, 3H, Ar-H), 8.45 (s, 1H, Ar-H). C NMR (CDCl , 125MHz): 30.1, 43.2, 50.3,
8
6
1
3
4.1, 67.8, 68.9, 69.7, 71.2, 79.4,98.7, 114.1, 116.9, 118.8, 118.9, 122.1, 122.5, 125.8,
26.5, 130.5, 131.3, 136.0, 144.6,145.8, 149.6, 151.3, 162.5, 188.0. HRMS calcd for
+
C H ClFeN O [M] 661.1543,found 661.1555.Anal Calcd(%) for: C,63.50; H,4.87; N,
3
5
32
5
3
10.58. found: C,63.59; H, 4.77; N,10.48.
4
.3.2 1-[4-(3-{4-[2-(7-Chloro-quinolin-4-ylamino)-ethoxymethyl]-[1,2,3]triazol-1-yl}-
propoxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (17b): Yield 82%. Dark red solid,
o
m.p: 153-154 C; H NMR (CDCl , 500MHz): 2.13-2.16 (m, 2H, H ), 3.52 (s, 2H, H ),
1
7
12
3
1
1
10
1
6
.91 (s, 2H, H ), 4.04 (s, 2H, H ), 4.15 (s, 5H, H ), 4.37 (t, J= 4.1 Hz 2H, H ), 4.43 (s,
3
2
H, H ), 4.64 (s, 2H, H ), 4.75 (s, 2H, H ), 6.43 (s, 1H, Ar-H), 6.73 (s, 1H, Ar-H), 6.91 (d,
3
8
2
4
J=8.3 Hz, 2H, Ar-H), 7.12 (d, J=15.2 Hz, 1H, H ), 7.43-7.46 (m, 2H, Ar-H+H ), 7.77 (d,
9
5 13
J=15.2, 1H, H ), 8.00-8.02 (m, 3H, Ar-H), 8.41 (s, 1H, Ar-H). C NMR (CDCl , 125MHz):
3
2
1
1
6.1, 30.4, 43.7, 50.8, 64.4, 67.5, 68.4, 69.3, 71.7, 79.8, 98.4, 114.5, 116.4, 118.4,
18.4, 122.5, 122.7, 125.5, 126.3, 130.3, 131.7, 136.5, 144.1, 145.9, 149.9, 151.8,
+
62.9, 188.1. HRMS calcd for C H ClFeN O [M] 675.1700,found 661.1715.Anal
3
6
34
5
3
Calcd(%) for: C,63.96; H,5.07; N, 10.36. found: C,63.85; H, 5.17; N,10.48.
4
.3.3 1-[4-(4-{4-[2-(7-Chloro-quinolin-4-ylamino)-ethoxymethyl]-[1,2,3]triazol-1-yl}-
butoxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (17c): Yield 86%. Dark red solid,
o
m.p: 152-153 C; H NMR (CDCl , 500MHz):1.82-1.87(m, 2H, H ), 2.13-2.17(m, 2H,
1
8
3
1
3
13
12
11
1
H ), 3.56 (s, 2H, H ), 3.91 (s, 2H, H ), 4.06 (s, 2H, H ), 4.16 (s, 5H, H ), 4.35 (t, J= 4.3
6
Hz 2H, H ), 4.46 (s, 2H, H ), 4.65 (s, 2H, H ), 4.75 (s, 2H, H ), 6.42 (s, 1H, Ar-H), 6.75 (s,
2
3
9
4
H, Ar-H), 6.97 (d, J=8.2 Hz, 2H, Ar-H), 7.12 (d, J=15.3 Hz, 1H, H ), 7.45-7.52 (m, 2H,
1

ACCEPTED MANUSCRIPT
1
Ar-H+H ), 7.71 (d, J= 15.3Hz, 1H, H ), 8.06-8.08 (m, 3H, Ar-H), 8.41 (s, 1H, Ar-H). C
0
5
13
NMR (CDCl , 125MHz):25.8, 26.3, 30.1, 43.5, 50.6, 64.1, 67.7, 68.6, 69.5, 71.4, 79.7,
3
9
1
6
8.5, 114.4, 116.6, 118.5, 118.8, 122.4, 122.7, 125.6, 126.2, 130.8, 131.9, 135.6,
+
44.5, 145.7, 149.8, 151.7, 162.6, 188.3. HRMS calcd for C H ClFeN O [M]
3
3
7
36
5
89.1856,found 689.1865.Anal Calcd(%) for: C,64.40; H,5.26; N, 10.15. found:
C,64.35; H, 5.17; N,10.23.
4
.3.4 1-[4-(5-{4-[2-(7-Chloro-quinolin-4-ylamino)-ethoxymethyl]-[1,2,3]triazol-1-yl}-
pentyloxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (17d): Yield 90%. Dark red
o
solid, m.p: 147-148 C H NMR (CDCl , 500MHz):1.43-1.46 (m, 2H, H ), 1.81-1.84 (m,
1
8
3
9
7
14
13
12
H, H ), 2.01-2.04 (m, 2H, H ), 3.52 (s, 2H, H ), 3.89 (s, 2H, H ), 4.06 (s, 2H, H ), 4.13
2
1
s, 5H, H ), 4.31 (t, J= 4.3 Hz 2H, H ), 4.42 (s, 2H, H ), 4.62 (s, 2H, H ), 4.71 (s, 2H, H ),
6
2
3
10
(
6.45 (s, 1H, Ar-H), 6.71 (s, 1H, Ar-H), 6.95 (d, J=8.2 Hz, 2H, Ar-H), 7.15 (d, J=15.1 Hz,
4
H, H ), 7.41-7.46 (m, 2H, Ar-H+H ), 7.71 (d, J= 15.1Hz, 1H, H ), 8.04-8.07 (m, 3H, Ar-
11
5
1
1
H), 8.46 (s, 1H, Ar-H). C NMR (CDCl , 125MHz): 23.6, 25.3, 26.6, 30.6, 43.3, 50.3,
3
3
64.4, 67.4, 68.5, 69.3, 71.3, 79.8, 98.3, 114.1, 116.4, 118.4, 118.5, 122.2, 122.6, 125.4,
126.6, 130.5, 131.6, 134.2, 144.2, 145.5, 149.7, 151.9, 162.3, 188.7. HRMS calcd for
+
C H ClFeN O [M] 703.2013,found 703.2021.Anal Calcd(%) for: C,64.83; H,5.44; N,
3
8
38
5
3
9.95. found: C,64.75; H, 5.37; N,9.83.
4
.3.5 1-[4-(6-{4-[2-(7-Chloro-quinolin-4-ylamino)-ethoxymethyl]-[1,2,3]triazol-1-yl}-
hexyloxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (17e): Yield 85%. Dark red solid,
o
1
9
m.p: 140-142 C H NMR (CDCl , 500MHz):1.40-1.46 (m, 2H, H ), 1.53-1.57 (m, 2H,
3
8
H ), 1.78-1.83 (m, 2H, H ), 1.92-1.98 (m, 2H, H ), 3.54 (s, 2H, H ), 3.95 (s, 2H, H ),
10
7
15
14
1
3
1
6
2
.02 (t,J= 6.2 Hz, 2H, H ), 4.19 (s, 5H, H ), 4.37 (t, J=7.0 Hz, 2H, H ), 4.49 (s, 2H, H ),
4
4
2
3 11
.60 (s, 2H, H ), 4.75 (s, 2H, H ), 6.40 (s, 1H, Ar-H), 6.66-6.70 (s, 1H, Ar-H), 6.94 (d,
4
H, 8.4 Hz, Ar-H), 7.15 (d, J= 15.2, 1H, H ), 7.41 (d,J=7.5 Hz, 1H, Ar-H), 7.51 (s, 1H,
1
2
5
13
H ), 7.75 (d, J=15.3 Hz, 1H, H ), 7.99-8.06 (m, 3H, Ar-H), 8.47 (s, 1H, Ar-H). C NMR
CDCl , 125MHz): 25.4, 26.1, 28.8, 29.6, 30.1, 43.2, 50.3, 64.1, 67.8, 68.9, 69.7, 71.2,
(
3
7
1
7
9.4, 98.7, 114.1, 116.9, 118.8, 118.9, 122.1, 122.5, 125.8, 126.5, 130.5, 131.3, 136.0,
+
44.6, 145.8, 149.6, 151.3, 162.5, 188.0. HRMS calcd for C H ClFeN O [M]
3
9
40
5
3
17.2169,found 717.2176.Anal Calcd(%) for: C,64.75; H,5.61; N, 9.75. found: C,64.83;
H, 5.52; N,9.83.

ACCEPTED MANUSCRIPT
4
.3.6 1-[4-(8-{4-[2-(7-Chloro-quinolin-4-ylamino)-ethoxymethyl]-[1,2,3]triazol-1-yl}-
octyloxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (17f): Yield 79%. Dark red solid,
o
m.p: 135-136 C; H NMR (CDCl , 500MHz):1.40-1.44 (m, 4H, H +H ), 1.45-1.47 (m,
1
9
10
3
1
1
8
12
H, H ), 1.48-1.50 (m, 2H, H ), 1.83-1.85 (m, 2H, H ), 1.93-1.96 (m, 2H, H ), 3.52 (s,
7
2
2
4
6
7
1
7
1
7
1
H, H ), 3.90 (s, 2H, H ), 4.08 (s, 2H, H ), 4.17 (s, 5H, H ), 4.33 (t, J= 4.2 Hz 2H, H ),
7
16
15
1
6
2
.45 (s, 2H, H ), 4.65 (s, 2H, H ), 4.74 (s, 2H, H ), 6.43 (s, 1H, Ar-H), 6.75 (s, 1H, Ar-H),
3
13
4
14
.92 (d, J=8.4 Hz, 2H, Ar-H), 7.13 (d, J=15.1 Hz, 1H, H ), 7.43-7.47 (m, 2H, Ar-H+H ),
5 13
.75 (d, J= 15.1 Hz, 1H, H ), 8.04 (m, 3H, Ar-H), 8.43 (s, 1H, Ar-H). C NMR (CDCl ,
3
25MHz): 22.2, 25.5, 26.5, 28.8, 29.2, 29.9, 30.1, 43.5, 49.4, 62.5, 66.4, 69.5, 69.8,
1.7, 79.4, 101.6, 118.8, 121.5, 124.4, 125.5, 126.5, 128.4, 130.6, 132.7, 132.7, 135.8,
+
44.6, 146.3, 149.8, 150.4, 156.3, 161.4, 188.4. HRMS calcd for C H ClFeN O [M]
4
1
44
5
3
45.2482,found 745.2476.Anal Calcd(%) for: C,66.00; H,5.94; N, 9.39. found: C,66.12;
H, 5.84; N,9.45.
4
.3.7 1-[4-(2-{4-[3-(7-Chloro-quinolin-4-ylamino)-propoxymethyl]-[1,2,3]triazol-1-yl}-
ethoxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (17g): Yield 74%. Dark red solid,
o
m.p: 142-143 C; H NMR (CDCl , 500MHz): 1.23-1.25 (m, 2H, H ), 2.43 (s, 2H, H ),
1
11
12
3
1
0
6
9
1
2
.45 (s, 2H, H ), 3.75 (s, 2H, H ), 4.02 (s, 2H, H ), 4.18 (s, 5H, H ), 4.47 (s, 2H, H ), 4.60
3
3
s, 2H, H ), 4.66 (s, 2H, H ), 6.38 (s, 1H, Ar-H), 6.90 (d, J=8.0 Hz, 2H, Ar-H), 7.12 (d,
7
(
4
J=15.3 Hz, 1H, H ), 7.28 (s, 2H, Ar-H), 7.54 (s, 1H, H ), 7.73-7.82 (m, 2H, Ar-H+H ), 7.97
8
4
1
3
(
d, J=8.0 Hz, Ar-H), 8.41 (s, 1H, Ar-H). C NMR (CDCl , 125MHz): 29.1, 42.4, 47.2,
3
6
1
6
4.2, 64.6, 68.3, 69.3, 71.2, 79.6, 98.4, 114.6, 116.2, 118.2, 122.6, 123.7, 125.2, 130.2,
+
31.2, 136.2, 144.1, 146.2, 151.2, 161.2, 188.2. HRMS calcd for C H ClFeN O [M]
3
6
34
5
3
75.1700,found 675.1712.Anal Calcd(%) for: C,63.96; H,5.07; N, 10.36. found:
C,63.83; H, 5.14; N, 10.42.
4
.3.8 1-[4-(3-{4-[3-(7-Chloro-quinolin-4-ylamino)-propoxymethyl]-[1,2,3]triazol-1-yl}-
propoxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (17h): Yield 78%. Dark red solid,
o
m.p: 130-131 C H NMR (CDCl , 500MHz): 1.26-1.29 (m, 2H, H ), 2.06 (s, 2H, H ),
1
12
7
3
1
3
11
6
10
1
.41 (s, 2H, H ), 3.48 (s, 2H, H ), 3.78 (s, 2H, H ), 4.00 (s, 2H, H ), 4.18 (s, 5H, H ),
2
2
.49 (s, 2H, H ), 4.60 (s, 2H, H ), 4.66 (s, 2H, H ), 6.38 (s, 1H, Ar-H), 6.90 (d, J=8.0, 2H,
3
8
4
4
Ar-H), 7.12 (d, J=15.3 Hz, H ), 7.28 (s, 2H, Ar-H), 7.54 (s, 1H, H ), 7.73-7.82 (m, 2H, Ar-
9

ACCEPTED MANUSCRIPT
13
5
H+H ), 7.97 (d, J=8.0 Hz, 2H, Ar-H), 8.41 (s, 1H, Ar-H). C NMR (CDCl , 125MHz): 28.0,
3
2
1
1
9.6, 31.5, 42.1, 47.0, 64.2, 64.3, 68.9, 69.7, 71.3, 79.3, 98.1, 114.1, 116.6, 117.2,
18.7, 122.7, 123.0, 125.8, 126.3, 128.2, 130.6, 131.9, 136.3, 144.5, 146.1, 151.7,
+
61.7, 188.0. HRMS calcd for C H ClFeN O [M] 689.1856,found 689.1844.Anal
3
7
36
5
3
Calcd(%) for: C,64.40; H,5.26; N, 10.15. found: C,64.33; H, 5.14; N, 10.22.
4
.3.9 1-[4-(4-{4-[3-(7-Chloro-quinolin-4-ylamino)-propoxymethyl]-[1,2,3]triazol-1-yl}-
butoxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (17i): Yield 80%. Dark red solid,
o
m.p: 125-127 C H NMR (CDCl , 500MHz):1.23-125 (m, 2H, H ), 1.83-1.89 (m, 2H,
1
13
3
8
7
14
12
6
H ), 2.14-2.19 (m, 2H, H ), 2.39 (s, 2H, H ), 3.43 (s, 2H, H ), 3.73 (s, 2H, H ), 4.04 (s,
1
H, H ), 4.15 (s, 5H, H ), 4.45 (s, 2H, H ), 4.62 (s, 2H, H ), 4.65 (s, 2H, H ), 6.32 (s, 1H,
1
1
2
3
9
2
4
Ar-H), 6.93 (d, J=8.1, 2H, Ar-H), 7.14 (d, J=15.2 Hz, H ), 7.25 (s, 2H, Ar-H), 7.52 (s, 1H,
1
H ), 7.72-7.81 (m, 2H, Ar-H+H ), 7.93 (d, J=8.1 Hz, 2H, Ar-H), 8.43 (s, 1H, Ar-H). C
0
5
13
NMR (CDCl , 125MHz): 28.0, 29.5, 30.2, 31.2, 42.6, 47.4, 64.8, 64.1, 68.3, 69.9, 71.2,
3
7
1
7
9.8, 98.4, 114.5, 116.6, 117.6, 118.9, 122.6, 123.3, 125.4, 126.7, 128.3, 130.4, 131.5,
+
36.7, 144.7, 146.4, 151.7, 161.4, 188.3. HRMS calcd for C H ClFeN O [M]
3
3
8
38
5
03.2013,found 703.2024.Anal Calcd(%) for: C,64.83; H,5.44; N, 9.95 found: C,64.73;
H, 5.34; N, 9.84.
4
.3.10 1-[4-(5-{4-[3-(7-Chloro-quinolin-4-ylamino)-propoxymethyl]-[1,2,3]triazol-1-
yl}-pentyloxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (17j): Yield 83%. Dark red
o
solid, m.p: 120-121 C H NMR (CDCl , 500MHz): 1.25-1.27 (m, 2H, H ), 1.53-1.57 (m,
1
14
3
8
9
7
15
13
H, H ), 1.82-1.85 (m, 2H, H ), 2.01-2.04 (s, 2H, H ), 2.34 (s, 2H, H ), 3.45 (s, 2H, H ),
2
6
12
1
2
3
.75 (s, 2H, H ), 4.06 (s, 2H, H ), 4.17 (s, 5H, H ), 4.43 (s, 2H, H ), 4.62 (s, 2H, H ), 4.62
3
1
s, 2H, H ), 6.32 (s, 1H, Ar-H), 6.95 (d, J=8.2, 2H, Ar-H), 7.16 (d, J=15.1 Hz, H ), 7.27 (s,
0
4
(
1
H, Ar-H), 7.52 (s, 1H, H ), 7.73-7.79 (m, 2H, Ar-H+H ), 7.91 (d, J=8.1 Hz, 2H, Ar-H),
1
5
2
8
6
1
1
3
.46 (s, 1H, Ar-H). C NMR (CDCl , 125MHz): 26.3, 28.4, 29.4, 30.5, 31.4, 42.5, 47.4,
3
4.3, 64.8, 68.4, 69.4, 71.8, 79.4, 98.6, 114.7, 116.8, 117.3, 118.7, 122.9, 123.6, 125.5,
26.7, 128.4, 130.4, 131.6, 136.7, 144.6, 146.5, 151.4, 161.5, 188.4. HRMS calcd for
+
C H ClFeN O [M] 717.2169,found 717.2154.Anal Calcd(%) for: C,65.23; H,5.61; N,
3
9
40
5
3
9.75 found: C,65.33; H, 5.54; N, 9.84.

ACCEPTED MANUSCRIPT
4
.3.11 1-[4-(6-{4-[3-(7-Chloro-quinolin-4-ylamino)-propoxymethyl]-[1,2,3]triazol-1-
yl}-hexyloxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (17k): Yield 74%. Dark red
o
solid, m.p: 110-111 C H NMR (CDCl , 500MHz): 1.25-1.27 (m, 2H, H ), 1.32-137 (m,
1
15
3
9
8
10
7
H, H ), 1.52-1.56 (m, 2H, H ), 1.83-1.86 (m, 2H, H ), 2.03-2.05 (s, 2H, H ), 2.36 (s, 2H,
2
1
H ), 3.42 (s, 2H, H ), 3.78 (s, 2H, H ), 4.08 (s, 2H, H ), 4.14 (s, 5H, H ), 4.46 (s, 2H,
6
14
6
13
1
2
3
11
H ), 4.66 (s, 2H, H ), 4.66 (s, 2H, H ), 6.31 (s, 1H, Ar-H), 6.98 (d, J=8.0, 2H, Ar-H), 7.14
4
d, J=15.3 Hz, H ), 7.24 (s, 2H, Ar-H), 7.55 (s, 1H, H ), 7.75-7.79 (m, 2H, Ar-H+H ), 7.94
12
5
(
(
1
3
d, J=8.0 Hz, 2H, Ar-H), 8.43 (s, 1H, Ar-H). C NMR (CDCl , 125MHz): 25.7, 26.5, 28.7,
3
2
1
1
7
9.7, 30.3, 31.7, 42.7, 47.9, 64.7, 64.8, 68.8, 69.6, 71.6, 79.7, 98.8, 114.5, 116.4,
17.3, 118.7, 122.7, 123.7, 125.9, 126.6, 128.4, 130.5, 131.6, 136.5, 144.7, 146.8,
+
51.5, 161.7, 188.3. HRMS calcd for C H ClFeN O [M] 731.2326,found
4
0
42
5
3
31.2334.Anal Calcd(%) for: C,65.62; H,5.78; N, 9.75 found: C,65.73; H, 5.64; N, 9.84.
4
.3.12 1-[4-(8-{4-[3-(7-Chloro-quinolin-4-ylamino)-propoxymethyl]-[1,2,3]triazol-1-
yl}-octyloxy)-phenyl]-3-ferrocenyl-1,3-dienyl-propenone (17l): Yield 69%. Dark red
o
solid, m.p: 105-106 C; H NMR (CDCl , 500MHz): 1.25-1.27 (m, 2H, H ), 1.41-143 (m,
1
17
3
9
10
11
8
8
H, H +H ), 1.46-1.49 ( m, 2H, H ), 1.51-1.55 (m, 2H, H ), 1.85-1.87 (m, 2H, H ), 2.05-
4
2
4
6
7
7
.07 (s, 2H, H ), 2.38 (s, 2H, H ), 3.45 (s, 2H, H ), 3.73 (s, 2H, H ), 4.03 (s, 2H, H ),
18
16
6
15
1
2
.15 (s, 5H, H ), 4.48 (s, 2H, H ), 4.69 (s, 2H, H ), 4.70 (s, 2H, H ), 6.34 (s, 1H, Ar-H),
3
13
4 14
.95 (d, J=8.1 Hz, 2H, Ar-H), 7.17 (d, J=15.3 Hz, H ), 7.27 (s, 2H, Ar-H), 7.58 (s, 1H, H ),
5
13
.73-7.75 (m, 2H, Ar-H+H ), 7.96 (d, J=8.1 Hz, 2H, Ar-H), 8.43 (s, 1H, Ar-H). C NMR
CDCl , 125MHz): 22.5, 25.1, 25.6, 26.4, 28.4, 29.8, 30.6, 31.4, 42.4, 47.6, 64.4, 64.5,
(
3
68.4, 69.3, 71.8, 79.4, 98.5, 114.8, 116.2, 117.5, 118.4, 122.5, 123.8, 125.5, 126.4,
128.8, 130.6, 131.8, 136.4, 144.6, 146.5, 151.8, 161.3, 188.5. HRMS calcd for
+
C H ClFeN O [M] 746.2560,found 746.2554.Anal Calcd(%) for: C,65.91; H,6.07; N,
4
1
45
5
3
9.37 found: C,65.83; H, 6.14; N, 9.47.
4
.4 Methods for assessment of antiplasmodial activity of test compounds:
The W2 strain of P. falciparum was cultured in RPMI-1640 medium with 10% human
serum, following standard methods, and parasites were synchronized with 5% D-
sorbitol.[47] Beginning at the ring stage, microwell cultures were incubated with
different concentrations of compounds for 48 h. The compounds were added from
DMSO stocks; the maximum concentration of DMSO used was 0.1%. Controls

ACCEPTED MANUSCRIPT
without inhibitors included 0.1% DMSO. After 48 h when control cultures had
progressed to new rings, the culture medium was removed, and cultures were
incubated for 48 h with 1% formaldehyde in PBS, pH 7.4, at room temperature. Fixed
parasites were then transferred to 0.1% Triton X-100 in PBS containing 1 nM YOYO-
1
dye (Molecular Probes). Parasitemia was determined from dot plots (forward scatter
vs. fluorescence) acquired on a FACSort flow cytometer using Cell Quest software
Beckton Dickinson). IC values for growth inhibition were determined from plots of
(
50
percent control parasitemia over inhibitor concentration using the Prism 3.0 program,
GraphPad Software), with data from duplicate experiments fitted by non-linear
regression.[48]
(
4
.5 In vitro analysis of cytotoxicity on HeLa cells:
HeLa cells were cultured in 60 mm x 15 mm tissue culture dishes containing 5 mL of
Dulbecco's Modified Eagle's Medium (DMEM) supplemented with penicillin and
streptomycin. Compounds were dissolved in DMSO to 100
µM concentrations. Once
cell cultures reached 70% confluency, 5 µL of compound was added to the DMEM in
the tissue culture dish for a final concentration of 100 µM. Cells were incubated for
ο
2
4 h in a 37 C CO incubator. After 24 h incubation, the media was removed from
2
the HeLa cells and the cells were then washed with 5 mL of 1 x PBS. The cells were
then cleaved off of the bottom of the plate via 5-min incubation with 0.5 mL of 0.25%
trypsin. Cells were re-suspended in 1mL of 1 x PBS and transferred to a
microcentrifuge tube. 100 µL 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. IC values were
5
0
determined using GraphPad PRISM.
References
[
1]C.J.L. Murray, L.C. Rosenfeld, S.S. Lim, K.G. Andrews, K.J. Foreman, D. Haring, N.
Fullman, M. Naghavi, R. Lozano, A.D. Lopez. Lancet, 379 (2012) 413.
2]R. Raj, K. M. Land, V. Kumar. RSC Adv. 5 (2015) 82676.
[
[
3]M. Njoroge, N. M. Njuguna, P. Mutai, D.S.B. Ongarora, P.W. Smith, K. Chibale,
Chem. Rev., 114 (2014) 11138.

ACCEPTED MANUSCRIPT
[
4] World
http://who.int/malaria/publications/world-malaria-report-2015/report/en.
5]R. W. Steketee, J. J. Wirima, L. Slutsker, C. O. Khoromana, D. L. Heymann, J. G .
Breman, Am. J. Trop. Med. Hyg., 55 (1996) 50.
Malaria
Report,
World
Health
Organization
Online
2015.
[
[
[
6]R. G. Ridley. Nature, 415 (2002) 686.
7]A. Mishra, H. Batchu, K. Srivastava, P. Singh, P. K. Shukla, S. Batra, Bioorg. Med.
Chem. Lett., 24 (2014) 1719.
8]M. Sinha, V. R. Dola, A. Soni, P. Agarwal, K. Srivastava, W. Haq, S. K. Puri, S. B. Katti,
Bioorg. Med. Chem., 22 (2014) 5950.
9](a) J.K. Baird, Antimicrob. Agents Chemother., 48 (2004) 4075 (b) A. O. Talisuna, P.
[
[
Bloland, U. D’Alessandro, Clin. Microbiol. Rev., 17 (2004) 235. (c) T. Mita, K. J. Tanabe,
Infect. Dis., 65 (2012) 465.
[
[
[
[
10]R. M. Beteck, F. J. Smit, R. K. Haynes, D.D. N’Da, Malar. J., 13 (2014) 339.
11]A. M. Dondorp, F. Nosten, P. Yi, D. Das, A. P. N. Phyo. Eng. J. Med., 361 (2009) 455.
12]J.T. Lin, J.J. Juliano, C. Wongsrichanalai, Curr. Infect. Dis. Rep., 12 (2010) 165.
13]H. Noedl, Y. Se, S. Sriwichai, K. Schaecher, P. Teja-Isavadharm, B. Smith, W.
Rutvisuttinunt, D. Bethell, S. Surasri, M. M. Fukuda, Clin. Infect. Dis. 51 (2010) 82.
14] C. Amaratunga, P. Lim, S. Suon, S. Sreng, S. Mao, C. Sopha, B. Sam, D. Dek, V. Try, R.
[
Amato, D. Blessborn, L. Song, G. S. Tullo, M. P. Fay, J. M. Anderson, J. Tarning, R. M.
Fairhurst, Lancet Infect Dis., 16 (2016) 357.
[
15] R.R. Soares, J.M.F. Da Silva, B.C. Carlos, C.C. Da-Fonseca, L.S.A. De Souza, F.V.
Lopes, R.M. De Paula Dias, P.O.L. Moreira, C. Abramo, G. Viana, H.R.V.F. De Pila,
Bioorg. Med. Chem. Lett., 25 (2015) 2308.
[
16] C. Atteke, J. M. Ndong, A. Aubouy, L. A. Maciejewski, J. S. Brocard, J. Lebibi, P.
Deloron, J. Antimicrob. Chemother., 51 (2005) 1021.
17] C. Biot, L. Delhaes, H. Abessolo, O. Domarle, L.A. Maciejewski, M. Mortuaire, P.
Delcourt, P. Deloron, D. Camus,; D. Dive, J. S. Brocard, J. Organomet. Chem., 589
[
(1999) 59.
[
18] C. Biot, L. Delhaes, C. M. Diaye, L. A. Maciejewski, D. Camus, D. Dive, J.S Brocard,
Bioorg. Med. Chem., 7 (1999) 2843.
19] F. Dubar, T. J. Egan, B. Pradines, D. Kuter, K.K. Ncokazi, ACS Chem. Biol., 6 (2011)
75.
[
2

ACCEPTED MANUSCRIPT
[
20] G. Mombo-Ngoma, C. Supan, M.P. Dal-Bianco, M.A. Missinou, P.B. Matsiegui,
C.L.O. Salazar, S. Issifou, D. Ter-Minassian, M. Ramharter, M. Kombila, P.G. Kremsner, B.
Lell, Malar. J., 10 (2011) 53.
[
21] C. Biot, G. Glorian, L. A. Maciejewski, J.S. Brocard, O. Domarle, G. Blampain, P.
Millet, A. J. Georges, H. Abessolo, D. Dive. J. Med. Chem. 40 (1997) 3715.
22]F. Dubar, C. Solmianny, J. Khalife, D. Dive, H. Kalamou, Y. Guerardel, P. Grellier,
C. Biot, Angew. Chem. Int. Ed., 52 (2013) 7690.
[
[
[
23]D. Dive, C. Biot. Curr. Top. Med. Chem. 14 (2014) 1684.
24]N. Chavain, H. Vezin, D. Dive, N. Touati, J. F. Paul, E. Buisine, C. Biot, Mol. Pharm.,
5
(2008) 710.
[
(
[
25]W.A. Wani, E. Jameel, U. Baig, S. Mumtazuddin, L.T. Hun, Eur. J. Med. Chem. 101
2015) 534.
26]J. Manosroi, K. Rueanto, K. Boonpisuttinant, W. Manosroi, C. Biot, J. Med. Chem.
5
3(2010) 3937.
27]C.L. Ferreira, C.B. Ewart, C.A. Barta, S. Little, V. Yardley, C. Martins, E. Polishchuk,
P.J. Smith, J.R. Moss, M.Merkel, M. J. Adam, C. Orvig, Inorg. Chem., 45 (2006) 659.
[
[
[
28] B. Long, S. Liang, D. Xin, Y. Yang, J. Xiang, Eur. J. Med. Chem. 44 (2009) 2572.
29]M. F. R. Fouda, M. M. Abd-elzaher, R. A. Abdelsamaia, A. A. Labib., Appl.
Organomet. Chem., 21 (2007) 613.
30]N. Chavain, E. Davioud-Charvet, X. Trivelli, L. Mbeki, M. Rottmann, R. Brun, C. Biot.
Bioorg. Med. Chem. 17 (2009) 8048.
31]F. Dubar, T. J. Egan, B. Pradines, D. Kuter, K, K. Ncokazi, D. Forge, J-F. Paul, C.
[
[
Pierrot, H. Kalamou, J. K. E. Buisine, C. Rogier, H. E. Vezin, I. Forfar, C. Slomianny, O. X.
Trivelli, S. Kapishnikov, L. Leiserowitz, D. Dive, C. Biot. ACS Chem. Biol. 6 (2011) 275.
[
32]C. Reiter, T. Frohlich, M. Zeino, M. Marschall, H. Bahsi, M. Leidenberger, O.
Friedrich, B. Kappes, F. Hampel, T. Efferth, S. B. Tsogoeva, Eur. J. Med. Chem. 97
(
[
[
2015) 164.
33]Y. Li, C. DeKock, P.J. Smith, K. Chibale, G. S. Smith, Organometallics, 33 (2014) 4345.
34]N. K. Sahu, S. S. Balbhadra, J. Choudhary, D.V. Kohli, Curr. Med. Chem., 19 (2012)
2
09.
[
35]D.I. Batovska, I.T. Todorova, Curr. Clin. Pharmacol., 5 (2010) 1.

ACCEPTED MANUSCRIPT
[
36]M. Chen, T.G. Theander, S.B. Christensen, L. Hviid, L. Zhai, A. Kharazmi, Antimicrob.
Agents Chemother., 38 (1994) 1470.
37]R. Li; G.L. Kenyon, F.E. Cohen, X. Chen, B. Gong, J.N. Dominguez, E. Davidson, G.
Kurzban, R.E. Miller, E.O. Nuzum, P.J. Rosenthal, J.H. McKerrow, J. Med. Chem.,
8(1995) 5031.
38]J. A. Geyer, S. M. Keenan, C. L. Woodard, P. A. Thompson, L. Gerena, D. A. Nichols,
C. E. Gutteridge, N. C. Waters, Bioorg. Med. Chem. Lett., 19(2009) 1982.
39]N. Sriwilaijaroen, M. Liu, M.-L. Go, P. Wilairat, Southeast Asian J. Trop. Med. Public
Health., 37 (2006) 607.
40]G. Wanare, R. Aher, N. Kawathekar, R. Ranjan, N.K. Kaushik, D. Sahal, Bioorg. Med.
Chem. Lett., 420 (2010) 4675.
41]J.A. Geyer, S.M. Keenan, C.L. Woodard, P. A. Thompson, L. Gerena, D.A. Nichols, C.E.
Gutteridge, N.C. Waters, Bioorg. Med. Chem. Lett., 19 (2009) 1982.
42]M.-L. Go, M. Liu, P. Wilairat, P. J. Rosenthal, K.J. Saliba, K. Kirk, Antimicrob. Agents
Chemother., 48 (2004) 3241.
43](a) K. Kumar, S.C. Kremer, L. Kremer, Y. Guérardel, C. Biot, V. Kumar,
[
3
[
[
[
[
[
[
Organometallics, 32 (2013) 5713. (b) K. Kumar, C. Biot, S.C. Kremer, L. Kremer, Y.
Guérardel, P. Roussel, V. Kumar, Organometallics, 32 (2013) 7386. (c) K. Kumar, P.
Singh, L. Kremer, Y. Guérardel, C. Biot, V. Kumar, Dalton Trans.
, 41 (2012) 5778 (d) K.
Kumar, S. C. Kremer, L. Kremer, Y. Guérardel, C. Biot, V. Kumar, Dalton Trans.,42
(
2013) 1492. (e) R. Raj, A. Saini, J. Gut, P. J. Rosenthal, V. Kumar, Eur. J. Med. Chem., 95
2015) 230. (f) R. Raj, P. Singh, N.T. Haberkern, R.M. Faucher, N. Patel, K. M. Land, V.
(
Kumar, Eur. J. Med. Chem., 63 (2013) 897.
[
[
(
[
44] H.C. Kolb, K.B. Sharpless, Drug Discovery Today, 8 (2003) 1128.
45]M. G. Bhovi. P. Tanwar, G.C. Yadav, Indian Journal of Heterocyclic Chemistry, 19
2010) 215.
46]X. Wang,Y. Zhang, T. Haibo, Y. Wang, P. Han, Z. D. Wang, J. Org. Chem., 75 (2010)
2
403.
[
47]J. B. Jensen, D.L. Doolan (Eds), Humana, Totowa, NJ, 2002, 477.
[
48]A. Singh, P. J. Rosenthal, Antimicrob. Agents Chemother., 45(2001) 949.

ACCEPTED MANUSCRIPT
[
49]C. Biot, W. Daher, C. M. Ndiaye, P. Melnyk, B. Pradines, N. Chavain, A. Pellet, L. Fraisse,
L. Pelinski, C. Jarry, J. Brocard, J. Khalife, I. Forfar-Bares, D. Dive; J. Med. Chem., 49 (2006)
707
4
Supporting information
H and 13C NMR spectra of representative compounds viz. 8a, 8c, 13a, 17e are
1
provided in the supporting information.
Acknowledgements
Financial assistance from University Grants Commission (UGC), New Delhi, India, under
UGC-JRF Fellowship with Ref. No. 23/12/2012(ii)EU-V is gratefully acknowledged (AS). VK
acknowledges the financial assistance provided by Science and Engineering Board (SERB),
New Delhi under grant no. EMR/2015/001687.
Captions
:
Figure 1. 1H-1,2,3-triazole linked 4-aminoquinoline-ferrocenyl chalcone conjugates
Scheme 1: Synthesis of O-alkyl azide ferrocenyl-chalcones
Scheme 2: Synthesis of piperazine-linked 7-chloroquinoline-ferrocenylchalcone conjugates
Scheme 3: Synthesis of phenyl linked 7-chloroquinoline-ferrocenylchalcone conjugates
Scheme 4: Synthesis of amino alcohol linked 7-chloroquinoline-ferrocenylchalcone
conjugates
Table 1:In vitro anti-malarial activity of compounds(8a-f, 13a-f, 17a-l) against W2 strain of
P.falciparum
Table 2: Cytotoxicity and selectivity index of the conjugates 17g-17k

ACCEPTED MANUSCRIPT
Figure 1. 1H-1,2,3-triazole linked 4-aminoquinoline-ferrocenyl chalcone conjugates
Scheme 1: Synthesis of O-alkyl azide ferrocenyl-chalcones

ACCEPTED MANUSCRIPT
Scheme 2: Synthesis of piperazine-linked 7-chloroquinoline-ferrocenylchalcone conjugates
Scheme 3: Synthesis of phenyl linked 7-chloroquinoline-ferrocenylchalcone conjugates
Scheme 4: Synthesis of amino alcohol linked 7-chloroquinoline-ferrocenylchalcone
conjugates

ACCEPTED MANUSCRIPT
Table 1: In vitro anti-malarial activity of compounds(8a-f, 13a-f, 17a-l) against W2 strain of
P.falciparum
Compounds IC (µM)
Compounds
IC50 (µM)
Compounds
IC (µM)
50
5
0
8
8
8
8
8
8
1
1
a
2.55±0.25
4.98±0.33
5.08±0.45
3.33±0.20
3.29±0.36
3.73±0.09
4.27±0.87
13c
13d
13e
13f
4.25±0.81
3.72±0.19
2.40±0.42
1.16±0.04
0.95±0.03
0.91±0.10
1.34±0.14
2.92±0.37
17e
17f
17g
17h
17i
0.66±0.02
0.69±0.17
0.42±0.02
0.41±0.17
0.53±0.04
0.37±0.03
0.55±0.05
1.78±0.07
b
c
d
e
17a
17b
17c
17d
f
17j
3a
3b
17k
17l
4.98±0.11
0.060
CQ
4
9
FQ
0.0081
Table 2: Cytotoxicity on HeLa cells and selectivity index of the conjugates 17g-17k
Compound
IC (µM)
Cytotoxicity (µM)
Selectivity Index (SI)
5
0
1
7g
0.42
0.41
0.53
0.37
0.55
17.45
20.12
23.34
18.20
16.12
8.30
41.54
49.07
43.84
49.18
29.30
1
7h
1
7i
7j
1
1
7k
Doxorubicin

ACCEPTED MANUSCRIPT
ꢀ
Synthesis and antiplasmodial evaluation of 4-amino-quinoline-ferrocenylchalcone
conjugates
ꢀ
ꢀ
Conjugates with aliphatic substituents exhibited better activities than cyclic counterparts
Most potent and non-cytotoxic conjugate displayed an IC value of 0.37 µM W2 strain
50