Design and synthesis of 3-[(7-chloro-1-oxidoquinolin-4-ylamino)alkyl]-1,3- thiazolidin-4-ones as antimalarial agents

Article abstract of DOI:10.3109/14756366.2012.710848

A new series of quinoline analogs have been synthesized and found active against P. falciparum in vitro and P. yoelli in vivo. Compounds 8, 10 and 11 exhibited superior in vitro activity compared to chloroquine. Selected compounds 8, 10 and 11 exhibited significant suppression of parasitaemia in vivo assay. These analogs form a complex with hematin and inhibit the β-hematin formation, suggesting that this class of compounds act on a heme polymerization target. Further this study confirms that quinoline ring nitrogen is essential for both transportation of the molecule across the membrane as well as for tight binding to hematin.

Full text of DOI:10.3109/14756366.2012.710848

Journal of Enzyme Inhibition and Medicinal Chemistry, 2013; 28(5): 1048–1053
2013 Informa UK, Ltd.
©
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2012.710848
RESEARCH ARTICLE
Design and synthesis of 3-[(7-chloro-1-oxidoquinolin-4-
ylamino)alkyl]-1,3-thiazolidin-4-ones as antimalarial agents
1
1
2
2
1
V. Raja Solomon , W. Haq , Kumkum Srivastava , Sunil K. Puri , and S. B. Katti
1
2
Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow, India and Division of
Parasitology, Central Drug Research Institute, Lucknow, India
Abstract
A new series of quinoline analogs have been synthesized and found active against P. falciparum in vitro and P. yoelli
in vivo. Compounds 8, 10 and 11 exhibited superior in vitro activity compared to chloroquine. Selected compounds
8
, 10 and 11 exhibited significant suppression of parasitaemia in vivo assay. These analogs form a complex with
hematin and inhibit the β-hematin formation, suggesting that this class of compounds act on a heme polymerization
target. Further this study confirms that quinoline ring nitrogen is essential for both transportation of the molecule
across the membrane as well as for tight binding to hematin.
Keywords: Quinoline-N-oxide, antimalarial agents, heme polymerization, P. falciparum
Introduction
formation. e hematin exerts a toxic effect on the para-
5
–7
Malaria remains one of the greatest global health chal-
lenges despite intensive efforts to control the disease. It
is endemic in many developing countries and leads to
the death of 1–2 million people yearly. e rapid spread
of multidrug resistance, especially toward chloroquine
site . In this continuation several research groups have
developed numerous 4-aminoquinoline derivatives,
which are significantly more potent than CQ against P.
8
–11
falciparum in in vitro studies
.
In our ongoing drug discovery program for
malaria chemotherapeutic agent, we have carried
out modification on 4-aminoquinoline lateral side
chain with guanyl and tetramethyl guanyl moieties
(Figure 1a) leads to increase the pKa2 value and the
resulting analogs showed in vitro and in vivo antimalarial
activity against NF-54 strain P. falciparum and N-67 strain
(CQ), the main drug in use for many years, is a cause
for major concern. It clearly highlights the urgent need
of novel chemotherapeutic agents for the treatment
of malaria. Intensive drug discovery efforts have been
aimed at developing new antimalarial drugs or modify-
1,2
ing existing agents .
1
2
Recent literature evidences show that alteration of
chain length (shortening) of CQ and its derivatives is
active against CQ-resistant parasite strains, it clearly
indicates that the resistance mechanism does not involve
any change in the target of this class of drugs but involves
a compound specific resistance . e molecular biology
studies suggested that the CQ and closely related 4-ami-
noquinoline compounds enter the food vacuole and
inhibit the parasite growth by forming a complex with
hematin (Fe(III)FPIX), thereby inhibiting the hemozoin
ofP.yoelii,respectively .Continuationofoureffortsforthe
identification of new molecules by selectively modifying
the pendant amino group of 4-aminoquinoline terminal
side chain with amide bond of (-CONH-) cationic amino
acid of lysine and ornithine conjugates (Figure 1b)
3,4
13
showedthatpromisinginvitroantimalarialactivity . Also
we have demonstrated that 4-aminoquinoline analogues
with altered chain length having thiazolidin-4-ones
(Figure 1c) and thiazolidine exhibit potential activity
against P. falciparum NF-54 strain in vitro and N-67 strain
Address for Correspondence: S. B. Katti, Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001,
India. Tel.: +91 0522 2620586; Fax: +91 0522 2623405. E-mail: setu_katti@yahoo.com, sb_katti@cdri.res.in
(
Received 26 April 2012; revised 30 June 2012; accepted 02 July 2012)
1
048

Design and synthesis of novel antimalarial agents 1049
of P. yoelii in vivo and some of these compounds were
through metal-oxygen type interaction. ese results are
described in this communication.
14,15
indeed more effective than CQ
.
As an obvious extension of this work we turned our
attention on the role of quinoline nitrogen atom (pKa1)
with doppelganger objective in mind namely, whether
basicity of this nitrogen is important for the transporta-
tion of 4-aminoquinoline scaffold across the membrane
or to form association complex with hematin or both.
Apart from these in literature very few studies have
Experimental
Meting points (mp) were determined on a Complab
melting point apparatus and are uncorrected. IR spectra
−1
(cm ) were recorded on Perkin-Elmer 621 spectrom-
1
eter using the KBr disc technique. e H-NMR spectra
were recorded on a DPX-200 MHz Bruker FT-NMR
spectrometer using CDCl and DMSO-d as solvent.
Tetramethylsilane (δ 0.0 ppm) was used as an inter-
nal standard. Fast Atom Bombardment Mass Spectra
(FAB-MS) were obtained on Jeol (Japan)/SX-102 spec-
trometer using glycerol or m-nitrobenzyl alcohol as
matrix. Elemental analysis was performed on a Perkin-
Elmer 2400 C, H, N analyzer and values were within the
acceptable limits of the calculated values. e progress
1
6
shown modification on quinoline ring nitrogen . To
3
6
ω
address this issue a new series of compounds having N -
oxide in the quinoline ring (Scheme 1) were synthesized.

e modification carried out in the present study may
affect the basicity and lipophilic nature of molecules,
which could have a cascading effect on the antimalarial
activity. Such a modification drastically decreases the
basicity (pKa1) yet allows complexation with hematin
Figure 1. Some lead molecules of 4-aminoquinoline derived antimalarials developed from this laboratory.
ω
Scheme 1. Synthesis of quinoline N oxide derived thiazolidin-4-ones. Reagents and conditions: (a) Glacial Acetic acid/ H O , 70–80ºC for
2
2
1
2 h (b) Diamino alkane, ethanol reflux for 6–8 h; (c) RCHO, Mercapto acetic acid, Toluene reflux 18–24 h.
©
2013 Informa UK, Ltd.

1
050 V. R. Solomon et al.
of the reaction was monitored on readymade silica gel
plates (Merck) using chloroform-methanol (9:1) as a sol-
vent system. Iodine was used as developing agent or by
spraying with Dragendorff’s reagent. Chromatographic
purification was performed over silica gel (100–200
mesh). All chemicals and reagents were obtained from
Aldrich (USA), Lancaster (UK) or Spectrochem Pvt. Ltd
schizonts in presence of different concentrations. e
test concentrations, which inhibited the complete matu-
ration into schizonts, were recorded as the minimum
inhibitory concentration (MIC). CQ was used as the stan-
dard reference drug.
In vivo antimalarial efficacy test
(
India) and were used without further purification.
e in vivo drug response was evaluated in Swiss mice
2
0,21
infected with P. yoelii (N-67 strain) . e mice (22 ± 2 g)
1
6
General synthetic procedure for N -(7-chloro-1-
were inoculated with 1 × 10 parasitised RBC on day 0 and
oxidoquinolin-4-yl)diaminoalkane (3–5)
treatment was administered to a group of five mice from
day 0 to 3, once daily. e aqueous suspension of com-
pounds was prepared with a few drops of Tween 80. e
efficacy of test compounds was evaluated at 30.0 mg/kg/
day and required daily dose was administered in 0.2mL
volume via intraperitoneal route. Parasitaemia levels
were recorded from thin blood smears between days 4
and 28 . e mean value determined for a group of five
mice was used to calculate the percent suppression of
parasitaemia with respect to the untreated control group.
Mice treated with CQ served as positive controls.
A mixture of 4,7-dichloroquinoline-1-oxide 2 (2.5 g, 12.5
mmol) and appropriate diaminoalkane (25 mmol) was
refluxed in absolute ethanol for 6–8 h with continues stir-
ring. e reaction mixture was cooled to room tempera-
ture and concentrated under vacuum; the residue was
taken up in dichloromethane. e organic layer was suc-
2
0,21
cessively washed with 5% aq. NaHCO followed by water
3
wash and then finally with brine. e organic layer was
dried over anhydrous Na SO and solvent was removed
2
4
under reduced pressure and the residue was precipitated
by addition of 80:20 hexane: chloroform.
Determination of haematin-4 aminoquinoline
derivatives association constant
General synthetic procedure for 3-[(7-chloro-1-
oxidoquinolin-4-ylamino)alkyl]-2-(unsubstituted/
substituted)-1,3-thiazolidin-4-one (6–14)
Association constant for haematin-4-aminoquinoline
derivatives complex formation were determined by
spectrometric titration procedure in aqueous dimethyl

e appropriate amine (1.0 mmol), aldehyde (2.0 mmol)
2
2
and mercaptoacetic acid (3.0 mmol) in 20mL dry toluene
was heated to reflux for 20–22 h. e reaction mixture was
cooled to room temperature and concentrated to dryness
under reduced pressure and the residue was taken up
in chloroform and washed with 5% aq. sodium hydro-
gen carbonate and then finally with brine solution. e
organic phase was then dried over sodium sulfate, the
filtrate was concentrated to dryness under reduced pres-
sure and the crude product was purified by column chro-
matography on silica gel using chloroform-methanol.
sulfoxide (DMSO) at pH 7.5 . In this assay condition,
haematin is strictly in monomeric state and interpreta-
tion of results is not complicated by the need to consider
haematin disaggregation process. Association constant
calculated in this technique is a good reflection of the
interaction would occur in the acidic food vacuole. e
pH 7.5 improves the stability of haematin solutions and
quality of data.
In vitro inhibition of β-haematin polymerization
e ability of the 4-aminoquinoline derivatives to inhibit
Biological and biophysical studies
Measurement of in vitro antimalarial activity
β-haematin polymerization was induced by 1-oleoyl-
rac-glycerol using UV spectrophotometer and mea-
2
3

e in vitro antimalarial assay was carried out in 96-well
surements were carried out at 405 nm . e triplicate
values obtained from the assay are expressed as percent
inhibition relative to haemozoin formation in a drug free
control. e 50% inhibitory concentration (IC ) values
1
7–19
microtitre plates . e cultures of P. falciparum NF 54
strain are routinely maintained in medium RPMI 1640
supplemented with 25 mM HEPES, 1% D-glucose, 0.23%
sodium bicarbonate and 10% heat inactivated human
50
for the compounds were obtained from the sigmoi-
dal dose–response curves using non-linear regression
curve fitting analyses with GraphPad Prism version 3.00
2
0
serum . e asynchronous parasites of P. falciparum
were synchronized after 5% D-sorbitol treatment to
obtain only the ring stage parasitized cells. For carrying
out the assay, the initial ring stage parasitaemia of 0.8
to 1.5% at 3% haematocrit in a total volume of 200 µL
of medium RPMI-1640 was uniformly maintained. e
test compound in 20 µL volume concentrations ranging
between 0.5 and 50 µg/mL in duplicate well were incu-
bated with parasitized cell preparation at 37ºC in a can-
dle jar. After 36–40-h incubation, the blood smears from
2
4
software . Each IC value is the result of at least three
5
0
separate experiments performed in duplicate.
Results and discussion
Chemistry
e desired target compounds (6–14) were synthesized
ω
as outlined in Scheme 1. 4,7-Dichloroquinoline N oxide
1
9,20
each well prepared and stained with giemsa stain
e slides were microscopically observed to record
maturation of ring stage parasites into trophozoites and
.
(2) was synthesized by the reported procedure in which
4,7-dichloroquinoline (1) was refluxed at 70–80°C with
glacial acetic acid/hydrogen peroxide (H O ) solution

2
2
Journal of Enzyme Inhibition and Medicinal Chemistry

Design and synthesis of novel antimalarial agents 1051
1
6
for 18 h . e amino components (3–5) used in the
present study were prepared by aromatic nucleophilic
substitution on 4,7-dichloroquinoline Nω oxide with
excess of diaminoalkane in ethanol reflux. e desired
thiazolidin-4-one compounds (6–14) were obtained from
appropriate amines, substituted aldehyde and mercapto
acetic acid in toluene reflux protocol. Both analytical and
spectral data of the synthesized compounds are in agree-
ment with the structures of the synthesized compounds.
Table 1. Biological and biophysical data of the compounds (3–14).
Comp.
No
a
b
c
d
d
MIC (μM) Log K
IC50 (μM)
Log P
0.23
0.58
1.09
0.25
3.18
3.82
0.61
3.54
4.18
1.12
4.05
4.69
4.27
pKa1
3
4
5
6
7
8
9
10
11
12
13
14
4.21
3.97
3.76
3.18
2.30
0.27
2.96
0.28
0.52
2.84
4.04
4.32
0.39
4.75 ± 0.02 0.57 ± 0.11
4.79 ± 0.02 0.59 ± 0.09
5.00 ± 0.02 0.56 ± 0.09
4.29 ± 0.03 0.65 ± 0.09
5.14 ± 0.01 0.56 ± 0.06
5.12 ± 0.02 0.35 ± 0.04
4.32 ± 0.04 0.52 ± 0.13
5.19 ± 0.05 0.36 ± 0.07
5.22 ± 0.01 0.43 ± 0.05
4.38 ± 0.06 0.57 ± 0.13
5.24 ± 0.04 0.62 ± 0.21
5.35 ± 0.01 0.65 ± 0.19
5.52 ± 0.02 0.40 ± 0.10
2.41
2.54
2.93
2.63
2.63
2.63
2.63
2.63
2.63
2.93
2.93
2.93
8.41
Pharmacology
All the compounds were evaluated for their antima-
larial activity against the NF-54 strain of P. falciparum in
in vitro for the determination of minimum inhibitory
concentration (MIC) values according to reported proto-
col, and the data is presented in Table 1. Among all the
CQ
a
1
2 compounds tested, 3 compounds showed MIC range
MIC = Minimum inhibiting concentration for the development
of the ring stage parasite into the schizont stage during 40-h
between 0.27 and 0.52 μM, 9 compounds showed MIC
range between 2.30 and 4.34 μM. e difference in the
MIC values can be attributed to the number of carbon
atoms in the side chain and C-2 substitutions on the
thiazolidin-4-one ring system. is result suggests that
the modification at quinoline nitrogen atom is tolerated
for antimalarial activity in vitro. Among the amino com-
ponent (3–5), compounds having two carbon atoms (3)
in the side chain are less active compared to which have
three (4) or four carbon atoms (5) in the side chain. ese
findings are in consonance with the earlier data from this
b
incubation. 1:1 (compound: Haematin) complex formation
in 40% aqueous DMSO, 20 mM HEPES buffer, pH 7.5 at 25°C
(
data are expressed as means ± SD from at least three different
c
experiments in duplicate). e IC represents the micromolar
5
0
equivalents of test compounds, relative to hemin, required to
inhibit β-haematin formation by 50% (data are expressed as means
d
±
SD from at least three different experiments in duplicate). Log P
and pKa values are calculated by Pallas software.
Table 2. In vivo antimalarial activity data of the compounds (8,
10, 11) against N-67 strain of P. yoelii in Swice mice.
1
2,14
b
laboratory . In amino component (3–5) introduction
of thiazolidin-4-one ring system resulted molecules hav-
ing interesting antimalarial activity.
% Suppression on
Mean survival time
(MST in days) ± SE
a
C. No
day 4
8
56.76
59.49
48.23
99.99
—
14.42 ± 0.59
1
1
0
1
14.22 ± 1.11

e compounds having thiazolidin-4-ones ring sys-
13.43 ± 0.24
tem (6, 9, 12) on lateral side chain leads to increases the
antimalarial activity. e compound having substitution
of 4-chlorophenyl (7, MIC = 2.30 μM) on C-2 position of
thiazolidin-4-one ring system leads to increased antima-
larial activity in comparison to unsubstituted compound
CQ
Control
18.00 ± 1.53
10.11 ± 0.71
a
Percent suppression = [(C–T)/C] × 100; where C = parasitaemia
b
in control group, and T = parasitaemia in treated group. MST
calculated for the mice which died during 28 day observation
period and the mice which survived beyond 28 day are excluded.
(
6, MIC = 3.18 μM). e compound having 4-chlorophe-
nyl substitution on C-2 position of thiazolidin-4-one ring
system (10, MIC = 0.28 μM) leads to substantial increase
in the antimalarial activity in comparison to the CQ (MIC
time and parasitaemia on day four were compared with
those of control mice receiving saline (Table 2). ese
compounds showed significant activity against P. yoelli
infections in mice. e compounds 8, 10, 11 suppressed
56.76, 59.49, 48.23% parasitaemia on day 4 compared to
100% suppression displayed by CQ. e mean survival
time (MST) is also in accordance with inhibition data. e
compounds (8, 10, 11) have shown lesser Log P value than
CQ (Table 1). e Log P values of these compounds are
=
0.39 μM). However introduction of 2,6-dichlorophenyl
substitution on thiazolidin-4-one ring system (11) (MIC
0.52 μM) leads to reduced the antimalarial activity
=
twofold in comparison to 4-chlorophenyl substituted
compound (10). Conversely, introduction of 2,6-dichlo-
rophenyl substitution of C-2 position of thiazolidin-4-one
ring system (8) (MIC = 0.27 μM) leads to substantial
increase in activity as compared to CQ. e compounds
having substitution of 4-chlorophenyl (13) (MIC = 4.04
μM) and 2,6-dichlorophenyl (14) (MIC = 4.32 μM) on
C-2 position of thiazolidin-4-one ring system leads to
decreased antimalarial activity.
ω
decreased due to N oxide modification in quinoline ring
system. If lipophilic nature of molecules affects (decrease),
it may decrease the cell permeability. It clearly highlights
the importance of lipophilicity in the antimalarial activity
of the synthesized compounds.
Compounds with most significant activity in vitro
8, 10 and 11) were selected for in vivo activity against
P. yoelli (N-67 strain) in Swiss mice (Table 2). e mice
were treated with compounds (30mg/kg) intraperitone-
ally, once daily for four consecutive days, and their survival
To understand mode of action of these derivatives,
all the compounds were evaluated for the association
complex formation with haematin (Log K) and ability
to inhibit β-haematin formation (IC ). e ability of the
(
5
0
compounds synthesized in the present study to form
©
2013 Informa UK, Ltd.

1
052 V. R. Solomon et al.
association complex with hematin was investigated by
UV spectrophotometer and it may be inferred from the
data shown in Table 1. All the compounds bind with an
association constant in the range 4.29–5.25 with hematin
and form a complex. It is appropriate to mention that
higher Log K value (i.e. >5.0) indicate tight binding of
theses analogs to haematin. e results suggest that the
principle interaction might be involving metal type inter-
with haematin and thereby inhibit β-haematin formation.
Further this study suggests that 4-aminoquinoline scaf-
fold is essential for activity and modification on quinoline
ring nitrogen atom leads to affect in vivo antimalarial
activity of this class of compounds.
Acknowledgements
ω
action of the quinoline ring N oxide with the porphyrin

e authors thank the Director, CDRI for the support
and the SAIF for the spectral data. One of the authors
V.R.S.) thanks the CSIR, New Delhi for Senior Research
25–27
ring system of haematin . Furthermore the most active
compounds 8, 10, 11 have shown lesser Log K values in
comparison to CQ (Log K = 5.52). e leeser Log K value
(
Fellowship. CDRI communication no. 93/2012/SBK.
ω
is due to N oxide modification in quinoline ring system.

e ability of these compounds to inhibit hemo-
Declaration of interest
zoin formation was studied to shed some light on the
mode of action. In addition to that all the compounds
inhibited the β-hematin formation in a concentration-
dependent manner. e most active compounds 8, 10,
e authors report no conflicts of interest. e authors
alone are responsible for the content and writing of the
paper.
1
1 have shown the inhibitory concentration values of
β-haematin formation are in the range of 0.35–0.43 μM.
ω
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Further biophysical study results suggest that this class
of compounds act on haem polymerization target. It may
be inferred from the above data that these compounds
binds to haematin monomer or haematin µ-oxo dimers
and inhibit the β-haematin formation by blocking the
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ω
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2
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