Synthesis and antimalarial activity of new heterocyclic hybrids based on chloroquine and thiazolidinone scaffolds

Article abstract of DOI:10.1016/j.bmc.2011.06.025

A series of new 21 chloroquine heterocyclic hybrids containing either benzylamino fragment or N-(aminoalkyl)thiazolidin-4-one moiety were synthesized and screened for their antimalarial activity against chloroquine (CQ)-sensitive 3D7 and multidrug-resistance Dd2 strains of Plasmodium falciparum. Although no compounds more active than CQ against 3D7 was found; against Dd2 strain, six compounds, four of them with benzylamino fragment, showed an excellent activity, up to 3-fold more active than CQ. Non specific cytotoxicity on J774 macrophages was observed in some compounds whereas only two of them showed liver toxicity on HepG2 cells. In addition, all active compounds inhibited the ferriprotoporphyrin IX biocrystalization process in concentrations around to CQ. In vivo preliminary results have shown that at least two compounds are as active as CQ against Plasmodium berghei ANKA.

Full text of DOI:10.1016/j.bmc.2011.06.025

Bioorganic & Medicinal Chemistry 19 (2011) 4562–4573
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and antimalarial activity of new heterocyclic hybrids based
on chloroquine and thiazolidinone scaffolds
Fernando A. Rojas Ruiz a, Rory N. García-Sánchez b,c, Santiago Villabona Estupiñan a, Alicia Gómez-Barrio b,
Diego F. Torres Amado a, Berta Martín Pérez-Solórzano b, Juan J. Nogal-Ruiz b,
Antonio R. Martínez-Fernández b, Vladimir V. Kouznetsov a,
⇑
a Laboratorio de Química Orgánica y Biomolecular, Escuela de Química, Universidad Industrial de Santander, A. A. 678, Bucaramanga, Colombia
b Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, España, Spain
c Laboratorio de Investigación de Productos Naturales Antiparasitarios de la Amazonía, Universidad Nacional de la Amazonía Peruana, Iquitos, Perú
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new 21 chloroquine heterocyclic hybrids containing either benzylamino fragment or
N-(aminoalkyl)thiazolidin-4-one moiety were synthesized and screened for their antimalarial activity
against chloroquine (CQ)-sensitive 3D7 and multidrug-resistance Dd2 strains of Plasmodium falciparum.
Although no compounds more active than CQ against 3D7 was found; against Dd2 strain, six compounds,
four of them with benzylamino fragment, showed an excellent activity, up to 3-fold more active than CQ.
Non specific cytotoxicity on J774 macrophages was observed in some compounds whereas only two of
them showed liver toxicity on HepG2 cells. In addition, all active compounds inhibited the ferriprotopor-
phyrin IX biocrystalization process in concentrations around to CQ. In vivo preliminary results have
shown that at least two compounds are as active as CQ against Plasmodium berghei ANKA.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 17 March 2011
Revised 31 May 2011
Accepted 5 June 2011
Available online 15 June 2011
Keywords:
Chloroquine
Thiazolidin-4-ones
Heterocyclic hybrids
Synthesis
Antimalarial activity
1. Introduction
for target-based antimalarial drug discovery. The structure–activ-
ity relationship studies on 4-aminoquinoline antimalarial
Despite decades of fighting malaria, the disease is gaining ground
as the parasite’s resistance to drugs and the parasite-carrying mos-
quito’s resistance to insecticides expands. The increasing spread of
malaria together with the emergence of resistance against conven-
tional drugs has put enormous pressure on public health systems
to introduce new malaria treatments.1 Quinoline containing com-
pounds are still attractive models for treatment of malaria (Fig. 1).
The success of the antimalarial aminoquinoline drug, chloroquine
(CQ), has been based on its excellent clinical efficacy, limited host
toxicity, ease to use and simple cost-effective synthesis. However,
the use of this drug has been seriously eroded in recent years, mainly
as a result of the development of parasite resistance to CQ.
Amodiaquine (AQ), another drug based on 7-chloro-4-aminoquino-
line nucleus, is effective against many CQ-resistant strains of
Plasmodium falciparum.
compounds suggest that 7-chloro-4-aminoquinoline skeleton is
obligatory for antimalarial activity, particularly, inhibition of
b-hematin formation and accumulation of the drug at the target
site.3 New potent leads such as AQ-13 and GSK369796 were devel-
oped by modifying aminoalkyl side chain or amino function of CQ
and IsoQ, respectively.4,5
Nowadays, double drug development and/or multi-therapeutic
strategies, which utilize new chemical entities with two (or more
than two) different N-heterocyclic skeletons, are also valid and
perspective to create new antimalarial drugs.2 These strategies
have the potential to overcome the drug resistant parasites prob-
lem. So, the design and synthesis of aminoquinoline-containing
dual inhibitors or ‘double drugs’ that would potentially inhibit hae-
mozoin formation and another target within P. falciparum, and will
not be recognized by the proteins involved in drug efflux, are very
productive in the generation of new chemical entities that are
effective against drug resistant parasites in the long term. The suc-
cess of this hybridization approach has wonderful examples as tri-
oxaquines6 or artemisinin–quinine hybrid.7
However, its clinical use has been restricted because of associ-
ations with hepatotoxicity and agranulocytosis due to the toxic
quinone–imine metabolite. Its isomeric analogue, isoquine (IsoQ)
showed excellent oral in vivo ED50 activity and did not undergo
in vivo bioactivation.2 These drugs are also important templates
Among these nitrogen containing heterocyclic skeletons, thiaz-
olidin-4-ones, rigid molecules, are considered as a biologically
privileged scaffold well-tolerated in human subjets8 and could be
perspective models for the designing of new antimalarial
CQ-hybrids.9
⇑
Corresponding author.
E-mail address: kouznet@uis.edu.co (V.V. Kouznetsov).
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.06.025

F. A. Rojas Ruiz et al. / Bioorg. Med. Chem. 19 (2011) 4562–4573
4563
OMe
Cl
Cl
Me
Me
H
N
OH
N
H
N
N
N
Me
N
N
Me
N
OH Me
AQ
CQ
Quinine
H
R2
Cl
Cl
Cl
Ar
H
N
H
Cl
N
N
( )n
S
N
N
R1
N
A
B
DCQ
O
Figure 1. Aminoquinoline drugs and structures of the investigated compounds.
Keeping in view the above facts and continuing our program on
the development of efficient methods to generate drug-like nitro-
gen-containing molecules, we were interested in a simple synthesis
of CQ or AQ analogues containing the N-(aminoalkyl)thiazolidin-4-
one moiety or the benzylamino fragment and their evaluation as
potentially active compounds against Plasmodium malaria parasite.
Now, we report the biological results of a new series of chloro-
quine heterocyclic hybrids that contain benzylamino fragment and
N-(aminoalkyl)thiazolidin-4-one moiety at C-4 position (molecules
A and B) (Fig. 1). We expected at the outset that these chemical
functions at C-4 will alter the biological activity of new quinoline
compounds and may help in developing structure–activity
relationships.
and a-mercaptoacetic acid with ratios 1:2.5:2.5 respectively, in
refluxing dry toluene for 4–5 h to get solid products, which can
be filtered and recrystallized in ethanol from the reaction mixture
(Scheme 1).
Almost all target compounds were obtained in good yields
(56–98%); conversely synthesis of aminoquinolines 3,4 was less
effective (37%), probably due to steric hindrance of methyl group
in
a-methylbenzylamines. All aminoquinoline derivatives were
purified by column chromatography and obtained as powdered
stable substances with well-defined melting points.
Calculated log P values, using commercially available ACD LAB
6.0 program, for all 21 aminoquinolines 1–4, 8–24 ranged from
3.25 (compd 9) to 4.64 (compd 3, 4). Since this estimation is con-
sidered to be a well established lipophilicity parameter, these data
allow predicting the good absorption and transport properties
across cell membranes for the obtained molecules.
2. Results and discussion
2.1. Chemistry
2.2. Biological activity
The target compounds 1–4 and key intermediate molecules 5–7
were synthesized employing straightforward and efficient proce-
dures.13 Benzylamino fragments were attached to the 4,7-chloro-
quinoline ring (DCQ) by nucleophilic substitution SNAr using
commercial benzylamines to give compd 1–4. This reaction was
carried out in the presence of DMF at elevated temperature
140 °C. Amino side functions were introduced in compd 5–7 by
Initially, all 21 compounds were tested for their activity against
CQ-sensitive 3D7 strain of P. falciparum, under in vitro conditions
described in Experimental. Subsequently, compounds that showed
an IC50 value less than 2 lM (Table 1) were evaluated against mul-
tidrug-resistance Dd2 strain.
No compound more active than CQ against 3D7 strain was
found. In fact, the activity shown by the most active compounds
was 9- to 15-fold minor than CQ. Nonetheless, against Dd2 strain,
4-benzylamino-7-chloroquinolines 1, 2, 3, and 4-amino-7-chloro-
quinoline-thiazolidinone hybrid 19, were more active than CQ
interaction of DCQ and
a,x-diaminoalkane excess refluxing with-
out any solvent.
Finally, target compounds 8–24 were prepared by one-pot three
component reaction of diamines 5–7, furfuraldehyde (2-FuCHO),
thiophencarboxyaldehyde (2-ThieCHO) or benzaldehydes (ArCHO)
(IC50 = 0.50
lM), with IC50 values between 0.30 and 0.44 lM. Other
Cl
R2
H
N
a
1
R1 = R2 = H;
Cl
N
R1
Ar
2 R1 = H, R2 = OMe;
37-93%
Cl
H
3
R
1 = Me (R), R2 = H;
N
N
( )n
S
4 R1 = Me (S), R2 = H
Cl
N
Cl
8-24
O
N
H
N
c
b
n = 1-3;
NH2
DCQ
( )n
Ar = 2-Thie, 2-Fu, Ph;
3,4-(MeO)2Ph; 3,4,5-(MeO)3Ph;
4-HO-3-MeOPh; 4-MeO-3-HOPh
56-98%
70-86%
N
5 n = 1;
6 n = 2;
7
n = 3
Scheme 1. Reagents and conditions: (a) 4,7-dichloroquinoline (2.5 mmol), N-benzylamine (5.10 mmol), and K2CO3 (5.01 mmol), DMF, 140 °C, 10 h; (b) 4,7-dichloroquinoline
(20.2 mmol), -diaminoalkane (101 mmol), 80 °C for 1 h, 140–150 °C for 6–7 h; (c) amine 5–7, ArCHO, HSCH2COOH, PhMe, 4–5 h reflux.
a,x

4564
F. A. Rojas Ruiz et al. / Bioorg. Med. Chem. 19 (2011) 4562–4573
Table 1
Structure and antimalarial activity of quinolines 1–4, 8–24 against P. falciparum 3D7 and Dd2 strains and cytotoxicity data
Compd
Structure
Log Pc
P. falciparum (
l
M)
FBIT(
lM)
Cytotoxicity
MØJ774
3D7
Dd2
l
M
HepG2
a
a
b
IC50
SD
IC50
SD
IC50
SD
%
SD
%
SD
Cl
H
N
1
2
3
4
4.08
4.14
4.64
4.64
0.30
0.25
0.30
0.35
0.04
0.33
0.05
46.52
39.32
44.20
44.20
2.98
37
33
35
35
0.00
0.0
46.58
10.13
10.94
45.51
2.5
N
O
Cl
H
N
0.03
0.03
0.05
0.30
0.35
0.58
0.02
0.02
0.04
1.84
1.15
1.41
28.31
34.02
53.77
0.9
2.0
2.4
0.8
0.4
2.1
N
Cl
H
N
N
Cl
H
N
N
S
Cl
H
N
8
3.58
2.94
3.85
3.21
4.12
3.48
10.54
1.82
14.16
0.53
0.23
0.09
0.36
0.03
0.16
0.19
ntd
ntd
ntd
ntd
ntd
N
S
S
N
O
O
Cl
H
N
9
1.59
0.07
200.59
3.08
27
56.6
4.5
16.96
1.1
N
N
O
S
Cl
S
10
11
12
13
ntd
ntd
ntd
ntd
ntd
H
N
N
O
N
Cl
O
S
H
N
0.80
0.05
83.78
4.19
26
43.65
3.3
8.14
0.6
N
O
N
Cl
S
H
N
5.93
8.16
ntd
ntd
ntd
ntd
ntd
N
S
N
O
Cl
O
H
N
ntd
ntd
ntd
ntd
ntd
N
O
S
N
O
O
N
Cl
14
3.64
3.91
0.92
0.06
1.76
1.77
0.10
0.07
91.80
2.93
3.33
23
22
28.38
34.61
1.8
2.2
2.21
0.1
H
N
S
N
O
O
O
15
Cl
1.18
0.12
158.33
0.03
0
S
H
N
N
O
N

F. A. Rojas Ruiz et al. / Bioorg. Med. Chem. 19 (2011) 4562–4573
4565
Table 1 (continued)
Compd
Structure
Log Pc
P. falciparum (
l
M)
FBIT(
lM)
Cytotoxicity
MØJ774
3D7
Dd2
l
M
HepG2
a
a
b
IC50
SD
IC50
SD
IC50
SD
%
SD
%
SD
O
S
O
Cl
Cl
16
4.18
0.39
0.05
0.75
0.04
79.45
2.33
21
45.22
1.7
13.26
1.2
H
N
N
O
N
N
O
O
O
17
18
3.62
3.88
1.56
0.51
0.09
0.04
1.87
0.75
0.07
121.33
2.95
21
23
9.16
1.1
1.64
0.1
H
N
N
S
O
O
O
N
Cl
Cl
0.05
0.02
58.42
1.93
2.21
47.93
3.2
0.1
25.53
1.7
H
N
S
S
N
N
O
O
H
N
19
20
4.46
4.56
0.36
2.19
0.02
0.14
0.44
54.70
26
2.01
0
0
N
Cl
Cl
S
ntd
ntd
ntd
ntd
ntd
H
N
N
O
N
N
OH
O
21
22
3.33
3.60
0.72
0.06
0.93
0.06
52.92
2.38
23
3.1
0.2
1.65
0.1
H
N
N
S
O
O
HO
> 22.00
ntd
ntd
ntd
ntd
ntd
Cl
Cl
S
H
N
N
O
O
N
N
HO
23
24
3.33
3.87
0.40
0.03
0.17
0.54
0.03
52.34
1.51
23
1.8
0.0
14.71
1.3
H
N
N
O
S
OH
S
O
Cl
10.94
ntd
ntd
ntd
ntd
ntd
H
N
N
N
O
(continued on next page)

4566
F. A. Rojas Ruiz et al. / Bioorg. Med. Chem. 19 (2011) 4562–4573
Table 1 (continued)
Compd
Structure
Log Pc
P. falciparum (
l
M)
FBIT(
lM)
Cytotoxicity
MØJ774
3D7
Dd2
l
M
HepG2
a
a
b
IC50
SD
IC50
SD
IC50
SD
%
SD
%
SD
Cl
Me
Me
H
N
N
CQ
3.27
0.027
0.004
0.50
0.03
22.29
0.58
19
0.0
0.0
0.0
0
N
Me
IC50 values, concentration inhibiting 50% of the parasite growtha or b-hematine formationb, are expressed as means SD from two different experiments in triplicate.
a
in vitro IC50 values for P. falciparum strains 3D7 and Dd2.
in vitro IC50 values for inhibition of b-hematine.
Theoretical values log P were calculated using commercially available ACD LAB 6.0 program.
Not tested, because compounds showed an IC50 value more than 2 lM.
b
c
d
two compounds, 4 and 23, showed IC50 values comparable than CQ,
0.58 and 0.54 M respectively.
allowing the compounds to reach its target in the food vacuole
inhibiting the crystallization process of FPIX.
l
In general, the activity showed by 4-benzylamino-7-chloro-
quinolines 1–4 was greater than 4-amino-7-chloroquinoline-thia-
zolidinone hybrids 8–24. Previously reported results have shown
that benzylamino chloroquinolines5,10,11 are better than the
4-amino-7-chloroquinoline-thiazolidinone hybrids with 4-chloro-
phenyl or 2,6-dichlorophenyl substituents at C-2 of thiazolidinone9
as potential antimalarial agents.
Another important fact to highlight is that the activity showed
by compounds against both P. falciparum strains, 3D7 and Dd2,
was in most cases not significantly different or slightly lower
against Dd2.
Ferriprotoporphyrin IX (FPIX) biocrystallization is a Plasmo-
dium-specific process in which the toxic FPIX derived from the
digestion of ingested hemoglobin is converted into an insoluble
non-toxic crystalline species called hemozoin. The inhibition of
this process is the main mechanism of action associated to chloro-
quine and other 4-amino-7-chloroquinolines; consequently it was
essential to verify if the prepared compounds also act by this
mechanism of action.
A nonspecific cytotoxicity assay on J774 murine macrophages at
concentrations between 19 and 37 lM was performed in order to
knowtheselectivitydegreeoftheactivecompounds. Inaddition,un-
der similar conditions, the effect of the aminoquinoline derivatives
on HepG2 cells (human hepatocellular carcinoma cell line), which
is widely used as a liver toxicity marker, was measured. Cytotoxicity
on J774 murine macrophages was observed in seven compounds,
whereas only two showed to be cytotoxic for HepG2 cells.
Given that the concentrations tested on both cytotoxicity assays
are far enough from the limit accepted as active against the para-
site, we could consider that four of the more active compounds,
compd 1,2, 19 and 23, showing no more that 30% of cytotoxicity,
have a selective activity against the parasite, and therefore good
candidates for the in vivo test.
The structure-activity relationship studies for the series 1–4
suggest that the presence of methyl (compd 3,4) or methoxy
(compd 2) functional groups on the benzylamino fragment did
not improve their activity and increased the cytotoxicity of these
compounds.
As expected, all in vitro active compounds showed the capabil-
ity to block the b-hematine formation process on FPIX biocrystalli-
zation inhibition assay (FBIT) at concentrations lower than
Regarding to thiazolidinone-based CQ hybrids 8–24, it was ob-
served a critical decrease in activity when a
tached to the thiazolidinone skeleton at position C-2 (compd
8,10 and 12). On the other hand, if a -furanyl group is present
a-thienyl ring is at-
500
1, 2, 3, and 4 were the most active on FBIT as well, showing IC50
values between 39.32 and 46.52 M, which are only 1.76- to
2.1-fold lower than CQ (IC50 = 22.29 M). Moreover, a direct rela-
lM. In fact, the most in vitro active benzylaminoquinolines
a
at same position (compd 9,11 and 13); the activity is increased,
provided that the length of the aminoalkyl side chain was 2 or 3
carbons. Nevertheless, these compounds showed high cytotoxicity
levels on J774 macrophages.
l
l
tionship between the activity against the parasite and the capabil-
ity to inhibit b-hematine formation was observed (Fig. 2).
Another modification performed on hybrids 8–24 structures
was the introduction of an aryl ring in the same position of thiazo-
lidinone skeleton, with and without substituents. The presence of a
phenyl group in this skeleton with two carbons length of aminoal-
kyl side chain (compd 19) increased considerably the activity, but
when the length of aminoalkyl side chain was increased in three
carbons (compd 20), the activity decreased.
Based on the in vitro and FBIT results, the association with
thiazolidin-4-one moiety and the addition of a benzylamino frag-
ment to the 4-amino-7-cloroquinoline skeleton prevent the action
of the mechanisms of resistance associated to CQ derivatives,
1000
100
10
Although the presence of 4-hydroxy-3-methoxyphenyl (compd
21,22 and 24) or 3-hydroxy-4-methoxyphenyl (compd 23) radicals
did not modify significantly the activity in comparison with unsub-
stituted aryl ring, the effect of the length of aminoalkyl side chain in
these compounds was evident, as the activity decreased notoriously
or even disappeared with 3 or 4 carbons length. According to our re-
sults, an optimal length of two carbons in aminoalkyl side chain is
also necessary in order to maintain the antimalarial activity of thia-
zolidinone-based hybrids.
Several research groups have studied the appropriate length and
size of the aminoalkyl side chain. Solomon et al. synthesized and
evaluated the antimalarial activity of 4-amino-7-chloroquinoline-
thiazolidinone hybrids with 4-chlorophenyl and 4,6-dichloro-
phenyl substitutions at C-2 of thiazolidinone and 2, 3 and 4 carbons
chain length, showing that 4,6-dichlorophenyl substitution and 2
1
CQ
1
2
3
4
9
11 14 15 16 17 18 19 20 21 23
Compounds
Figure 2. Relationship between the activity against P. falciparum and FBIT. IC50
values against 3D7 (–N–) and Dd2 (–d–) in M and FBIT in M (–j–).
l
l

F. A. Rojas Ruiz et al. / Bioorg. Med. Chem. 19 (2011) 4562–4573
4567
Table 2
In vivo assay (4-day suppressive test) against P. berghei ANKA using compd 1, 19 and 23 at a dose of 10 mg/kg/daya
c
c
Tested compd
% Inhibition
Log Pb
Log D5.2
Log D7.4
Cl
H
N
25
4.08
2.44
4.27
3.59
N
1
S
Cl
O
N
H
N
80
4.46
3.81
3.33
1.72
0.21
1.28
N
19
Cl
ntd
0.23
3.13
H
N
N
S
COOH
OCH3
H
N
19M
S
Cl
O
N
H
N
100
OH
N
23
OMe
OH
Cl
ntd
3.15
5.25
0.04
3.86
0.05
4.95
H
N
N
H
S
COOH
N
23M
Cl
Cl
H
N
Cl
76e
N
S
S
N
O
25
Cl
Cl
Cl
ntd
5.07
3.27
1.56
1.36
1.92
H
N
N
H
COOH
N
25M
Cl
Me
Me
H
N
N
100
ꢀ1.42
N
Me
CQ
a
b
c
Each group of mice was treated intraperitoneally ip.
Theoretical values log P were calculated using commercially available ACD LAB 6.0 program.
Theoretical values log D were calculated using the on line available SPARC V4.5 program.
Not tested in vivo assay.
d
e
In vivo assay (4-day suppressive test) against Plasmodium yoelli (N-67 strain), data from the Ref.9.
carbons chain length (compd 25) is the best and more active than
CQ combination against NF-54 strain of P. falciparum.9 However,
their nonspecific cytotoxicity has not been reported and discussed.
De et al. suggested that both shortening and lengthening pro-
duce compounds that retain the activity.12 Stocks et al. synthesized
novel short chain chloroquine analogues which retained the activ-
ity against CQ resistant K1 P. falciparum and Natarajan et al. have
shown that the most active 4-aminoquinoline derivatives were
those having two carbons in the aminoalkyl side chain.13,14
Finally, the presence of two methoxy groups (compd 14–16) on
phenyl ring reduced the activity and increased cytotoxicity.
A preliminary in vivo assay (4-day suppressive test) against
P. berghei ANKA using benzylaminoquinoline 1, and the 7-
chloroquinoline-thiazolidinone hybrids 19 and 23 at a dose of
10 mg/kg/day was carried out (Table 2). These compounds were
selected because they were three of the most active compounds
and, at the same time, did not showed nonspecific cytotoxicity.
Compounds 19 and 23 inhibited 80% and 100% respectively the
parasite growth in infected mice, whereas compound 1 only 25%.
CQ used as positive control showed 100% of inhibition at the same
dose. As the variation of log P for tested compd 1, 19 and 23 did not
appear to play a role in the in vivo antimalarial activity, we ad-
dressed to another quantitative parameter. Log D can predict gas-
tro intestinal (GI) track absorption and lipophilic properties as it
is a pH dependent function. Calculated values demonstrated the
high GI track absorption (pH 3–7) and lipophilic properties. It
was observed a good correlation between the calculated distribu-
tion coefficients at pH 7.4 and pH 5.2 (log D5.2 and log D7.4 param-
eters), and the found inhibition percentages for the tested compds
Moreover, conversely to the compd 259, these ADME properties are
enhanced by replacing the two chlorine atoms on the aryl moiety.
In addition, metabolic opening of the thiazolidinone ring of hybrids
19, 23, and 25 could provide the more active metabolites 19M,
23M, and 25M (Table 2). Comparing their calculated parameters,

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F. A. Rojas Ruiz et al. / Bioorg. Med. Chem. 19 (2011) 4562–4573
it can be confirmed that possible metabolite 23M has better lipo-
philic properties. In contrast to this, compd 1 cannot be metabo-
lized in this way which explains its low in vivo activity.
(2C), 127.5, 125.5, 121.2, 117.2, 99.7, 47.5; GC–MS: tR = 25.3 min, m/
z (%): 268 (M+ꢀ, 50), 91 (100), 232 (15). Anal. Calcd. for C16H13N2Cl:
C, 71.51; H, 4.88; N, 10.42. Found: C 71.43; H 4.56; N 10.26.
According to these theoretical values, our most active and lipo-
philic compound 23 may have an improved absorption and distri-
bution comparable to CQ, observed on its in vivo antimalarial
activity, in addition to the in vitro activity against the Dd2 strain.
4.1.1.2.
amine (2).
7-Chloro-N-[(4-methoxyphenyl)methyl]quinolin-4-
White crystals; yield 93% from DCQ and
p-methoxybenzylamine; Rf = 0.3 (P.E/E.A 1:1), mp 165–168 °C; IR
(KBr): 3220 (N–H), 2928–3018 (CH2), 1573 (C@N), 1510 (N–H) cm
ꢀ1
;
1H NMR (400 MHz, CDCl3, Me4Si), d (ppm): 5.62 (1H, s,
3. Conclusion
-NH), 4.51 (2H, d, J = 4.7 Hz, –CH2), 3.82 (3H, s, –OCH3), 8.51 (1H, d,
J = 5.3 Hz, 2-H), 6.45 (1H, d, J = 5.3 Hz, 3-H), 7.69 (1H, d, J = 8.9 Hz,
6-H), 7.34 (1H, d, J = 8.3 Hz, 7-H), 7.95 (1H, d, J = 1.7 Hz, 9-H), 7.31
(2H, d, J = 8.6 Hz, 2-HAr–6-HAr), 6.91 (2H, d, J = 8.5 Hz, 3-HAr–5HAr);
13C NMR (100 MHz, CDCl3, Me4Si), d (ppm): 160.9, 159.4, 152.1,
149.5, 149.1, 134.9, 129.2, 128.9, 128.8, 125.4, 121.1, 117.2, 114.4,
114.2, 99.6, 55.4, 47.1; GC–MS: tR = 28.4 min, m/z (%): 298 (M+ꢀ,
15), 121 (100), 191 (8). Anal. Calcd. for C17H15N2OCl: C, 68.34; H,
5.06; N, 9.38. Found: C 68.13; H 5.28; N 9.11.
Designing compounds based on 4-amino-7-chloroquinoline
scaffolds is an alternative pathway in order to obtain new and
promising antimalarial entities. Especially, some heterocyclic
hybrids containing benzylamino fragments or N-(aminoal-
kyl)thiazolidin-4-one moiety, as compounds 1, 19 or 23 described
in this study, showed excellent in vitro and in vivo antimalarial
activity and low cytotoxicity levels to be considered as potential
antimalarial agents.
4.1.1.3.
(3).
(R)-7-Chloro-N-(1-phenylethyl)quinolin-4-amine
White crystals; yield 37% from DCQ and (R)- -methylben-
4. Experimental
4.1. Chemistry
a
zylamine; Rf = 0.6 (P.E/E.A 1:1), mp 115–118 °C; IR (KBr): 3327
(N–H), 2918 (CH2), 1573 (C@N), 1445 (N–H) cmꢀ1 1H NMR
;
(400 MHz, CDCl3, Me4Si), d (ppm): 5.34 (1H, s, -NH), 4.71 (1H, t,
J = 5.8 Hz, –CH), 1.68 (3H, d, J = 6.4 Hz, –CH3) 8.39 (1H, d, J = 4.9 Hz,
2-H), 6.22 (1H, d, J = 4.9 Hz, 3-H), 7.39 (1H, d, J = 9.0 Hz, 6-H),
7.91 (1H, d, J = 8.8 Hz, 5-H), 7.96 (1H, s, 8-H), 7.26–7.35 (5H, m,
2-HAr–6-HAr); 13C NMR (100 MHz, CDCl3, Me4Si), d (ppm): 154.5,
152.7, 149.3, 143.5, 134.9, 129.4, 128.5, 126.9, 126.7 (2C), 124.8
(2C), 121.6, 117.5, 99.2, 60.6, 21.6. GC–MS: tR = 24.8 min, m/z (%):
282 (M+ꢀ, 48), 178 (40), 267 (35), 105 (100). Anal. Calcd. for
The melting points (uncorrected) were determined on a Fisher-
Johns melting point apparatus. The IR spectra were recorded on a
Lumex Infralum FT-02 spectrophotometer in KBR. 1H MNR spectra
were recorded on Bruker AM-400 spectrometer. Chemical shifts
are reported in ppm (d relative to the solvent peak (CHCl3 in CDCl3
at 7.24 ppm for protons). Signals are designated as follows: s, sin-
glet; d, doublet; dd, doublet of doublets; ddd, doublet of doublets
of doublets; t, triplet; dt, doublet of triplets; td, triplet of doublets;
q, quartet; quint., quintet; m, multiplet; br, broad. On DEPT-135
spectra, the signals of CH3, CH2, and CH carbons are shown as po-
sitive (+), negative (ꢀ), and positive (+), respectively, and quater-
nary carbons are not shown. A Hewlett Packard 5890a series II
Gas Chromatograph interfaced to an HP 5972 Mass Selective
Detector (MSD) with an HP MS Chemstation Data system was used
for ms identification at 70 ev using a 60 m capillary column coated
with HP-5 [5%-phenyl-poly(dimethyl-siloxane)]. Elemental analy-
ses were performed on a Perkin Elmer 2400 Series II analyzer
and were within 0.4 of theoretical values. The reaction progress
was monitored using thin layer chromatography on a silufol
UV254 TLC aluminum sheet.
C17H15N2Cl: C, 72.21; H, 5.35; N, 9.91. Found: C 72.45; H 5.19; N 9.76.
4.1.1.4.
(4).
(S)-7-Chloro-N-(1-phenylethyl)quinolin-4-amine
White crystals; yield 37% from DCQ and (S)- -methylben-
a
zylamine; Rf = 0.6 (P.E: E.A 1:1), mp 115–118 °C; IR (KBr): 3327
(N–H), 2918–2973 (CH2), 1573 (C@N), 1445 (N–H) cmꢀ1 1H NMR
;
(400 MHz, CDCl3, Me4Si), d (ppm): 5.34 (1H, s, -NH), 4.71 (1H, t,
J = 5.8 Hz, –CH), 1.68 (3H, d, J = 6.4 Hz, –CH3) 8.39 (1H, d, J = 4.9 Hz,
2-H), 6.22 (1H, d, J = 4.9 Hz, 3-H), 7.39 (1H, d, J = 9.0 Hz, 6-H),
7.91 (1H, d, J = 8.8 Hz, 5-H), 7.96 (1H, s, 8-H), 7.26–7.35 (5H, m,
2-HAr–6-HAr); 13C NMR (100 MHz, CDCl3, Me4Si), d (ppm): 154.5,
152.7, 149.3, 143.5, 134.9, 129.4, 128.5, 126.9, 126.7 (2C), 124.8
(2C), 121.6, 117.5, 99.2, 60.6, 21.6. GC–MS: tR = 24.8 min, m/z (%):
282 (M+ꢀ, 48), 178 (40), 267 (35), 105 (100). Anal. Calcd. for
4.1.1. Group A. General procedure for synthesis of 4-N-benzyl-
aminoquinolines 1–4
C17H15N2Cl: C, 72.21; H, 5.35; N, 9.91. Found: C 72.35; H 5.21; N 9.76.
Under nitrogen atmosphere 0.50 g of DCQ (2.5 mmol), benzyl-
amine 0.70 g (5.10 mmol), and K2CO3 0.70 g (5.01 mmol) were dis-
solved in 8 mL de DMF. The mixture was stirred under reflux
during 10 h (TLC) and cooled to ambient temp. After, the reaction
mass was diluted with water and extracted with dichloromethane
(2 ꢁ 30 mL). The organic layer was dried over Na2SO4, concen-
trated under vacuum and purified by flash column chromatogra-
phy using petroleum ether (P.E) and ethyl acetate (E.A) mixes,
obtaining the 4-N-benzylamino substituted quinolines 1–4.
4.1.2. General procedure for synthesis of 4-amino7-chloro-
quinoline precursors 5–7
A mixture of DCQ (4.0 g, 20.2 mmol) and
a,x-diaminoalkane
(101 mmol) was heated at 80 °C for 1 h with stirring and subse-
quently at 140–150 °C for 6–7 h with continued stirring. The reac-
tion mixture was cooled to room temp and basified with 10% NaOH
(70 mL). The resultant mixture was extracted with chloroform-
methanol (20:1, 4 ꢁ 50 mL). The combined extracts were washed
with brine, dried over anhydrous Na2SO4, concentrated under re-
duced pressure and the residue (10 mL) was precipitated by the
addition of 70 mL n-heptane. The solid was purified by washing
with 40 mL ethyl ether.
4.1.1.1.
N-Benzyl-7-chloroquinolin-4-amine (1)15
.
White
crystals; yield 80% from DCQ and benzylamine; Rf = 0.5 (P.E/E.A
1:1), mp 175–178 °C; IR (KBr): 3220 (N–H), 2928–3013 (CH2), 1575
(C@N), 1448 (N–H) cmꢀ1 1H NMR (400 MHz, CDCl3, Me4Si), d
;
4.1.2.1.
(5).
N1-(7-Chloroquinolin-4-yl)-ethane-1,2-diamine
Yellowish white solid, yield 75% from DCQ and 1,2-diami-
(ppm): 5.62 (1H, s, –NH), 4.51 (2H, d, J = 4.7 Hz, –CH2), 8.51 (1H, d,
J = 5.0 Hz, 2-H), 6.40 (1H, d, J = 5.1 Hz, 3-H), 7.72 (1H, d, J = 8.9 Hz,
6-H), 7.33 (1H, d, J = 8.5 Hz, 7-H), 7.93 (1H, s, 9-H), 7.32–7.38 (5H,
dd, J = 8.9, 2.0 Hz, 2-HAr–6-HAr); 13C NMR (100 MHz, CDCl3, Me4Si), d
(ppm): 152.1, 149.6, 149.2, 137.3, 134.9, 129.4, 128.9 (2C), 127.9
noethane; mp 143–145 °C; IR (KBr): 3248 (N–H), 2893 (CH2), 1589
(N–H), 1142 (C–N) cmꢀ1; 1H NMR (400 MHz, CDCl3, Me4Si) d (ppm):
8.51 (1H, d,, J = 5.4 Hz, 2-H), 7.94 (1H, d, J = 2.0 Hz, 5-H), 7.75 (1H, d,
J = 8.9 Hz, 8-H), 7.34 (1H, dd, J = 8.8, 1.8 Hz, 6-H), 6.39 (1H, d,

F. A. Rojas Ruiz et al. / Bioorg. Med. Chem. 19 (2011) 4562–4573
4569
J = 5.4 Hz, 3-H), 5.82(1H, brs, NH), 3.27 (2H, br s, NH2), 3.11–3.18 (4H,
m, 10-Hab, 20-Hab); 13C NMR (100 MHz, CDCl3, Me4Si) d (ppm): 156.1,
144.7, 140.5, 138.4, 127.4, 126.6, 120.7, 117.1, 99.4, 42.9, 38.1. GC–
MS: tR = 22.13 min, m/z (%): 221 (M+ꢀ, 29),192 (55), 191 (100), 179
(17), 163 (25), 156 (87), 155 (44), 128 (18). Anal. Calcd. for
2-HThiaz), 3.81 (1H, dd, J = 15.6 Hz, J = 1.3 Hz, 5-HaThiaz), 3.72 (1H, d,
J = 15.5 Hz, 5-HbThiaz), 3.65–3.58 (1H, m, 20-Ha), 3.50–3.42 (1H, m,
10-Ha), 3.27–3.19 (1H, m, 10-Hb), 3.10–3.03 (1H, m, 20-Hb). 13C NMR
(100 MHz, DMSO-d6, Me4Si), d (ppm): 170.4, 151.5 (+), 149.7, 148.7,
143.9, 133.5 (+), 128.3 (+, 2C), 127.3 (+), 126.7 (+), 124.3 (+), 123.7
(+), 117.3, 98.4 (+), 58.2 (+) 40.6 (ꢀ), 39.3 (ꢀ), 32.0 (ꢀ). GC–MS:
tR = 23.71 min, m/z (%): 389 (M+ꢀ, 10), 356 (9), 205 (62), 204 (51),
203 (49), 192 (15), 178 (11), 156 (51), 155 (35). Anal. Calcd. for
C11H12ClN3: C, 59.60; H, 5.46; N, 18.95. Found: C 59.83; H 5.25; N
18.74.
N1-(7-Chloroquinolin-4-yl)-propane-1,3-diamine
Yellowish white solid, yield 86% from DCQ and 1,3-diami-
C
18H16ClN3OS2: C, 55.45; H, 4.14; N, 16.45. Found: C 55.67; H 4.01;
4.1.2.2.
(6).
N 16.33.
nopropane; mp 130–132 °C; IR (KBr): 3278 (N–H), 2871 (CH2),
1589 (N–H), 1141 (C–N) cmꢀ1 1H NMR (400 MHz, CDCl3, Me4Si) d
;
4.1.3.2.
yl)thiazolidin-4-one (9).
3-(2-(7-Chloroquinolin-4-ylamino)ethyl)-2-(furan-2-
This compound was obtained as a
yellowish white solid in 60% yield, from N1-(7-chloroquinolin-4-yl)-
ethane-1,2-diamine 5, 2-furancarboxaldenyde and -mercaptocetic
acid; mp 158–160 °C; IR (KBr): 3379, 2908, 1666, 1612, 1581,
640 cmꢀ1 1H NMR (400 MHz, DMSO-d6, Me4Si), d (ppm): 8.40 (1H,
(ppm): 8.47 (1H, d,, J = 5.3 Hz, 2-H), 7.92 (1H, d, J = 1.9 Hz, 5-H),
7.71 (1H, d, J = 8.9 Hz, 8-H), 7.37 (1H, br s, NH), 7.28 (1H, dd,
J = 8.8, 1.9 Hz, 6-H), 6.34 (1H, d, J = 5.4 Hz, 3-H), 3.47–3.28 (2H, m,
10-Hab), 3.11–3.02 (2H, m, 30-Hab), 2.74 (2H, br s, NH2), 1.97–1.93
(2H, m, 20-Hab); 13C NMR (100 MHz, CDCl3, Me4Si) d (ppm): 155.9,
144.4, 140.3, 138.2, 127.2, 126.4, 120.4, 117.3, 98.7, 42.2, 40.6,
30.6. GC–MS: tR = 23.23 min, m/z (%): 235 (M+ꢀ, 93), 219 (21), 218
(44), 217 (52), 205 (35), 203 (36), 192 (95), 191 (100), 179 (92),
163 (25), 156 (87), 155 (67), 128 (26). Anal. Calcd. for C12H14ClN3:
C, 61.15; H, 5.99; N, 17.83. Found: C 61.23; H 5.76; N 17.65.
a
.
d, J = 5.5 Hz, 2-H), 8.16 (1H, d, J = 9.0 Hz, 5-H), 7.80 (1H, d, J = 2.0 Hz,
8-H), 7.71 (1H, s, 5-HFu), 7.56 (1H, t, J = 5.0 Hz, NH), 7.46 (1H, dd,
J = 9.0, 2.1 Hz, 6-H), 6.54 (1H, d, J = 3.2 Hz, 3-HFu), 6.46 (1H, d,
J = 5.0 Hz, 4-HFu), 6.46 (1H, s, 3-H), 6.10 (1H, s, 2-HThiaz), 3.80 (1H, d,
J = 15.6 Hz, 5-HaThiaz), 3.66 (1H, d, J = 15.6 Hz, 5-HbThiaz), 3.65–3.61
(1H, m, 20-Ha), 3.50–3.41 (1H, m, 10-Ha), 3.23–3.15 (1H, m, 10-Hb),
3.11–3.05 (1H, m, 20-Hb). 13C NMR (100 MHz, DMSO-d6, Me4Si), d
(ppm): 170.8, 151.1 (+), 150.9, 150.0, 148.2, 144.1 (+), 133.7 (+),
126.9 (+), 124.4 (+), 123.8 (+), 117.2, 110.7 (+), 109.7 (+), 98.4 (+),
55.7 (+), 41.0 (ꢀ), 39.3 (ꢀ), 31.6 (ꢀ). GC–MS: tR = 48.88 min, m/z (%):
373 (M+ꢀ, 10), 344 (2), 205 (51), 204 (52), 203 (51), 192 (12), 191
(100), 178 (7), 156 (53), 155 (34). Anal. Calcd. for C18H16ClN3O2S: C,
57.83; H, 4.31; N, 11.24. Found: C 57.74 H 4.54; N 11.02.
4.1.2.3.
(7).
N1-(7-Chloroquinolin-4-yl)-butane-1,4-diamine
Yellowish white solid, yield 70% from DCQ and 1,4-diamin-
obutane; mp 115–117 °C; IR (KBr): 3278 (N–H), 2871 (CH2), 1589
(N–H), 1141 (C–N) cmꢀ1 1H NMR (400 MHz, CDCl3, Me4Si) d
;
(ppm): 8.47 (1H, d,, J = 5.3 Hz, 2-H), 7.92 (1H, d, J = 1.9 Hz, 5-H),
7.71 (1H, d, J = 8.9 Hz, 8-H), 7.37 (1H, br s, NH), 7.28 (1H, dd,
J = 8.8, 1.9 Hz, 6-H), 6.34 (1H, d, J = 5.4 Hz, 3-H), 3.47–3.28 (2H, m,
10-Hab), 3.11–3.02 (2H, m, 30-Hab), 2.74 (2H, br s, NH2),
1.97–1.93 (2H, m, 20-Hab), 1.83–1.78 (2H, m, 40-Hab); 13C NMR
(100 MHz, CDCl3, Me4Si) d (ppm): 155.6, 144.3, 140.3, 138.1, 127.2,
126.3, 120.4, 117.1, 98.8, 42.2, 40.6, 38.8, 30.5. GC–MS:
tR = 24.27 min, m/z (%): 249 (M+ꢀ, 34), 219 (5), 205 (99), 203 (36),
192 (25), 191 (100), 179 (91), 163 (18), 156 (80), 155 (62), 128
(21). Anal. Calcd. for C13H16ClN3: C, 62.52; H, 6.46; N, 16.83. Found:
C 62.48; H 6.57; N 16.69.
4.1.3.3. 3-(3-(7-Chloroquinolin-4-ylamino)propyl)-2-(thien-2-
yl)thiazolidin-4-one (10).
This compound was obtained as a
yellowish white solid in 64% yield, from N1-(7-chloroquinolin-4-yl)-
propane-1,3-diamine
(5.09 mmol) and
6
(4.24 mmol), 2-thiophencarboxaldenyde
a-mercaptoacetic acid (5.09 mmol); mp
160–162 °C; IR (KBr): 3332, 3032, 2846, 1666, 1612, 1574, 648 cm
ꢀ1
.
1H NMR (400 MHz, DMSO-d6, Me4Si), d (ppm): 8.39 (1H, d,
J = 5.4 Hz, 2-H), 8.19 (1H, d, J = 9.1 Hz, 5-H), 7.79 (1H, d, J = 2.2 Hz, 8-
H), 7.57 (1H, d, J = 5.0 Hz, 5-HThie), 7.46 (1H, dd, J = 9.0 Hz, J = 2.2 Hz,
6-H), 7.29 (1H, t, J = 5.3 Hz, NH), 7.19 (1H, dd, J = 3.4, 0.8 Hz, 3-HThie),
6.88 (1H, dd, J = 5.0, 3.5 Hz, 40-HThie), 6.39 (1H, d, J = 5.5 Hz, 3-H), 6.20
(1H, s, 2-HThiaz), 3.80 (1H, dd, J = 15.7, 1.2 Hz, 5-HaThiaz), 3.70 (1H, d,
J = 15.6 Hz, 5-HbThiaz), 3.58–3.51 (1H, m, 30-Ha), 3.20 (2H, q,
J = 6.1 Hz, 10-Ha, 10-Hb), 2.93–2.86 (1H, m, 30-Hb), 1.86–1.76 (1H, m,
20-Ha), 1.74–1.64 (1H, m, 20-Hb). 13C NMR (100 MHz, DMSO-d6,
Me4Si), d (ppm): 170.0, 151.6 (+), 149.9, 148.7, 144.3, 133.4 (+),
127.8 (+), 127.7 (+), 127.2 (+), 126. 7 (+), 124.1 (+), 123.8 (+), 117.3,
98.6 (+), 57.9 (+), 40.4 (ꢀ), 39.7 (ꢀ), 31.9 (ꢀ), 25.2 (ꢀ). GC–MS:
tR = 112.18 min, m/z (%): 403 (M+ꢀ, 7), 370 (13), 219 (48), 218 (5),
217 (20), 192 (100), 191 (78), 178 (12), 156 (35), 155 (29). Anal. Calcd
for C19H18ClN3OS2: C, 56.49; H, 4.49; N, 10.40. Found: C 56.32; H 4.61;
N 10.45.
4.1.3. Group B. General procedure for synthesis of 4-amino-7-
chloroquinoline-thiazolidin-4-ones 8–24
A mixture of the amine 5 (6 or 7) (4.51 mmol), aldehyde
(5.41 mmol) and
a-mercaptoacetic acid (5.41 mmol) was stirred
and heated to boiling and refluxed for 4–5 h while collecting water
distilled as an azeotropic mixture of toluene/water in a Dean-Stark
trap. The reaction mixture was cooled to room temp and the tolu-
ene was removed by vacuum distillation. The obtained mass was
dissolved in a mixture of ethyl acetate-methanol (10:1, 150 mL),
successively basified with 10% NaHCO3 (50 mL) and then washed
with brine. The organic layer was dried over anhydrous Na2SO4,
and the solvent was removed under reduced pressure to get a
crude product that was purified by column chromatography on sil-
ica gel using petroleum ether and ethyl acetate. The products 8–24
were obtained as viscous oils then solidified by adding n-heptane.
4.1.3.4.
yl)thiazolidin-4-one (11).
yellowish white solid in 62% yield, from N1-(7-chloroquinolin-4-yl)-
3-(3-(7-Chloroquinolin-4-ylamino)propyl)-2-(furan-2-
This compound was obtained as a
4.1.3.1. 3-(2-(7-Chloroquinolin-4-ylamino)ethyl)-2-(thiophen-2-
yl)thiazolidin-4-one (8).
beige solid in 85% yield, from 1,2-diamine 5, 2-thi-
ophencarboxaldenyde and -mercaptoacetic acid; mp178–180 °C;
IR (KBr): 3379, 2924, 1682, 1605, 1574, 656 cmꢀ1 1H NMR
(400 MHz, DMSO-d6, Me4Si), d (ppm): 8.37 (1H, d, J = 5.4 Hz, 2-H),
8.14 (1H, d, J = 9.1 Hz, 5-H), 7.79 (1H, d, J = 2.2 Hz, 8-H), 7.64 (1H, d,
J = 5.1 Hz, 5-HThie), 7.46 (1H, s, N-H), 7.46 (1H, dd, J = 9.0 Hz,
J = 2.2 Hz, 6-H), 7.22 (1H, dd, J = 3.4, 0.9 Hz, 3-HThie), 7.00 (1H, dd,
J = 5.1, 3.5 Hz, 4-HThie), 6.38 (1H, d, J = 5.5 Hz, 3-H), 6.28 (1H, s,
This compound was obtained as a
propane-1,3-diamine
(5.09 mmol) and
6
(4.24 mmol), 2-furancarboxaldenyde
-mercaptocetic acid (5.09 mmol); mp
1H
a
125–127 °C; IR (KBr): 3356, 2885, 1666, 1612, 1589, 633 cmꢀ1
.
a
.
NMR (400 MHz, DMSO-d6, Me4Si), d (ppm): 8.39 (1H, d, J = 5.4 Hz,
2-H), 8.20 (1H, d, J = 9.1 Hz, 5-H), 7.79 (1H, d, J = 2.1 Hz, 8-H), 7.67
(1H, s, 5-HFu), 7.46 (1H, dd, J = 9.0, 2.2 Hz, 6-H), 7.28 (1H, t,
J = 5.2 Hz, NH), 6.48 (1H, dd, J = 3.2, 0.6 Hz, 3-HFu), 6.43–6.38 (2H, m,
4-HFu, 3-H), 6.00 (1H, s, 2-HThiaz), 3.78 (1H, d, J = 15.4 Hz,
5-HaThiaz), 3.64 (1H, d, J = 15.4 Hz, 5-HbThiaz), 3.59–3.50 (1H, m,

4570
F. A. Rojas Ruiz et al. / Bioorg. Med. Chem. 19 (2011) 4562–4573
30-Ha), 3.20 (2H, q, Hz, J = 6.4 Hz, 10-Ha, 10-Hb), 2.94–2.87 (1H, m, 30-
Hb), 1.87–1.74 (1H, m, 20-Ha), 1.74–1.61 (1H, m, 20-Hb). 13C NMR
(100 MHz, DMSO-d6, Me4Si), d (ppm): 171.2, 154.5 (+), 152.7, 151.5,
149.3, 142.1 (+), 134.9, 129.4, 124.8 (+), 121.6 (+), 117.5, 110.6 (+),
107.0 (+), 99.2 (+), 62.6 (+), 41.2 (ꢀ), 40.3 (ꢀ), 31.5 (ꢀ), 25.6 (ꢀ).
GC–MS: tR = 60.29 min, m/z (%): 387 (M+ꢀ, 15), 354 (9), 219 (44), 217
(23), 205 (50), 192 (100), 191 (91), 178 (15), 156 (42), 155 (31). Anal.
Calcd for C19H18ClN3O2S:C, 58.83; H, 4.68;N, 10.83. Found: C 58.95;H
4.53; N 10.65.
(+), 149.6, 149.3, 148.9, 148.9 (+), 133.4, 131.3, 127.5 (+), 124.2
(+), 123.7 (+), 120.1 (+), 117.3, 111.5 (+), 110.7 (+), 98.3 (+), 62.9
(+), 55.5 (+), 55.4 (+), 40.6 (ꢀ), 32.1 (ꢀ), 24.8 (ꢀ). Anal. Calcd for
C
22H22ClN3O3S: C, 59.52; H, 4.99; Cl, 7.99; N, 9.47. Found: C
59.43; H 5.06; N 9.35.
4.1.3.8. 3-(3-(7-Chloroquinolin-4-ylamino)propyl)-2-(3,4-dime-
thoxyphenyl) thiazolidin-4-one (15).
This compound was
obtained as a beige solid in 88% yield, from N1-(7-chloroquinolin-
4-yl)-propane-1,3-diamine 6 (4.24 mmol), 3,4-dimetoxybenzalde-
4.1.3.5.
yl)thiazolidin-4-one (12).
3-(4-(7-Chloroquinolin-4-ylamino)butyl)-2-(thien-2-
hyde (5.09 mmol) and
145–147 °C; IR (KBr): 3232, 2839, 1606, 1612, 1581, 1265,
640 cmꢀ1 1H NMR (400 MHz, DMSO-d6, Me4Si), d (ppm): 8.37
a-mercaptoacetic acid (5.09 mmol); mp
This compound was obtained as a
yellowish white solid in 80% yield, from N1-(7-chloroquinolin-4-
yl)-butane-1,4-diamine 7 (4.00 mmol), 2-thiophencarboxaldenyde
.
(1H, d, J = 5.3 Hz, 2-H), 8.16 (1H, d, J = 9.0 Hz, 5-H), 7.79 (1H, s,
8-H), 7.44 (1H, dd, J = 8.9, 1.7 Hz, 6-H), 7.22 (1H, t, J = 4.6 Hz,
NH), 6.93 (1H, s, 2-HAr), 6.86 (1H, d, J = 8.3 Hz, 6-HAr), 6.81 (1H,
d, J = 8.3 Hz, 5-HAr), 6.37 (1H, d, J = 5.4 Hz, 3-H), 5.78 (1H, s, 2-HThi-
az), 3.87 (1H, d, J = 15.5 Hz, 5-HaThiaz), 3.71 (1H, s, 3-HAr), 3.70 (1H,
s, 4-HAr), 3.67 (1H, d, J = 15.5 Hz, 5-Hbthiaz), 3.59–3.52 (1H, m, 30-
Ha), 3.23–3.14 (2H, m, 10-Ha, 10-Hb), 2.82–2.76 (1H, m, 30-Hb),
1.83–1.67 (2H, m, 20-Ha, 20-Hb). 13C NMR (100 MHz, DMSO-d6,
Me4Si), d (ppm): 170.6, 151.7 (+), 149.7, 149.1, 148.9, 148.9 (+),
133.3, 131.8, 127.4 (+), 123.9 (+), 123.7 (+), 119.6 (+), 117.3,
111.4 (+), 110.3 (+), 98.5 (+), 62.3 (+), 55.4 (+), 55.4 (+), 40.3 (ꢀ),
34.7 (ꢀ), 32.0 (ꢀ), 25.1 (ꢀ). Anal. Calcd for C23H24ClN3O3S: C,
60.29; H, 5.30; N, 9.21. Found: C 60.42; H 5.18; N 9.35.
(4.80 mmol) and
a-mercaptoacetic acid (4.80 mmol); mp
173–175 °C; IR (KBr): 3363, 2862, 1666, 1605, 1574, 656 cmꢀ1
.
1H NMR (400 MHz, DMSO-d6, Me4Si), d (ppm): 8.38 (1H, d,
J = 5.4 Hz, 2-H), 8.25 (1H, d, J = 9.1 Hz, 5-H), 7.78 (1H, d,
J = 2.2 Hz, 8-H), 7.57 (1H, d, J = 5.1 Hz, 5-HThie), 7.45 (1H, dd,
J = 9.0, 2.2 Hz, 6-H), 7.32 (1H, br s, NH), 7.24 (1H, dd, J = 3.4,
0.8 Hz, 3-HThie), 6.95 (1H, dd, J = 5.0, 3.5 Hz, 4-HThie), 6.43 (1H, d,
J = 5.5 Hz, 3-H), 6.19 (1H, s, 2-HThiaz), 3.79 (1H, dd, J = 15.7,
1.1 Hz, 5-HaThiaz), 3.69 (1H, d, J = 15.6 Hz, 5-HbThiaz), 3.55–3.48
(1H, m, 40-Ha), 3.21 (2H, c, J = 5.8 Hz, 10-Ha, 10-Hb), 2.82–2.75
(1H, m, 40-Hb), 1.59–1.42 (4H, m, 20-Ha, 20-Hb, 30-Ha, 30-Hb). 13C
NMR (100 MHz, DMSO-d6, Me4Si), d (ppm): 169.8, 151.5 (+),
150.1, 148.6, 144.5, 133.4 (+), 127.7 (+), 127.5 (+), 127.1 (+),
126.7 (+), 124.0 (+), 124.0 (+), 117.3, 98.5 (+), 57.6 (+), 41.9 (ꢀ),
41.8 (ꢀ), 31.9 (ꢀ), 24.9 (ꢀ), 24.0 (ꢀ). Anal. Calcd for C20H20ClN3OS2:
C, 57.47; H, 4.82; N, 10.05. Found: C 57.32; H 4.67; N 10.23.
4.1.3.9. 3-(4-(7-Chloroquinolin-4-ylamino)butyl)-2-(3,4-dime-
thoxyphenyl) thiazolidin-4-one (16).
This compound was
obtained as a beige solid in 70% yield, from N1-(7-chloroquinolin-
4-yl)-butane-1,4-diamine 7 (4.00 mmol), 3,4-dimetoxybenzalde-
4.1.3.6.
yl)thiazolidin-4-one (13).
yellowish white solid in 56% yield, from N1-(7-chloroquinolin-4-
yl)-butane-1,4-diamine (4.00 mmol), 2-furancarboxaldenyde
(4.80 mmol) and -mercaptocetic acid (4.80 mmol); mp
179–181 °C; IR (KBr): 3356, 2862, 1666, 1605, 1574, 656 cmꢀ1
3-(4-(7-Chloroquinolin-4-ylamino)butyl)-2-(furan-2-
hyde (4.80 mmol) and
185–187 °C; IR (KBr): 3371, 2870, 1666, 1612, 1574, 1257,
648 cmꢀ1 1H NMR (400 MHz, DMSO-d6, Me4Si), d (ppm): 8.38
(1H, d, J = 5.4 Hz, 2-H), 8.25 (1H, d, J = 9.1 Hz, 5-H), 7.78 (1H, d,
J = 2.1 Hz, 8-H), 7.44 (1H, dd, J = 9.0, 2.1 Hz, 6-H), 7.27 (1H, t,
a-mercaptoacetic acid (4.80 mmol); mp
This compound was obtained as a
.
7
a
.
J = 5.0 Hz, NH), 6.93 (1H, s, 2-HAr), 6.91–6.86 (2H, m, 5-HAr,
1H NMR (400 MHz, DMSO-d6, Me4Si), d (ppm): 8.38 (1H, d,
J = 5.4 Hz, 2-H), 8.25 (1H, d, J = 9.1 Hz, 5-H), 7.78 (1H, d,
J = 2.2 Hz, 8-H), 7.58 (1H, d, J = 5.1 Hz, 5-HFu), 7.44 (1H, dd, J = 9.0,
2.2 Hz, 6-H), 7.29 (1H, t, J = 5.0 Hz, NH), 7.24 (1H, dd, J = 3.4,
0.9 Hz, 3-HFu), 6.95 (1H, dd, J = 5.1, 3.5 Hz, 4-HFu), 6.43 (1H, d,
J = 5.5 Hz, 3-H), 6.19 (1H, s, 2-HThiaz), 3.79 (1H, d, J = 15.7 Hz,
5-HaThiaz), 3.69 (1H, d, J = 15.6 Hz, 5-HbThiaz), 3.55–3.48 (1H, m,
40-Ha), 3.21 (2H, q, J = 5.7 Hz, 10-Ha, 10-Hb), 2.82–2.75 (1H, m, 40-
Hb), 1.61–1.41 (4H, m, 20-Ha, 20-Hb, 30-Ha, 30-Hb). 13C NMR
(100 MHz, DMSO-d6, Me4Si), d (ppm): 170.0, 151.7 (+), 150.0,
148.9, 144.5, 133.3 (+), 127.7 (+), 127.5 (+), 127.2 (+), 126.7 (+),
124.0 (+), 123.9 (+), 117.3, 98.5 (+), 57.6 (+), 41.8 (ꢀ), 41.8 (+),
31.9 (ꢀ), 24.9 (ꢀ), 24.0 (ꢀ). Anal. Calcd for C20H20ClN3O2S: C,
59.77; H, 5.02; N, 10.46. Found: C 59.59 H 5.17; N 10.55.
6-HAr), 6.41 (1H, d, J = 5.5 Hz, 3-H), 5.77 (1H, s, 2-HThiaz), 3.86
(1H, dd, J = 15.6, 0.9 Hz, 5-HaThiaz), 3.73 (1H, s, 3-HAr), 3.72 (1H, s,
4-HAr), 3.66 (1H, d, J = 15.4 Hz, 5-Hbthiaz), 3.59–3.52 (1H, m,
40-Ha), 3.23–3.18 (2H, m, 10-Ha, 10-Hb), 2.69–2.62 (1H, m, 40-Hb),
1.61–1.50 (4H, m, 20-Ha, 20-Hb, 30-Ha, 30-Hb). 13C NMR (100 MHz,
DMSO-d6, Me4Si), d (ppm): 170.4, 151.7 (+), 149.9, 149.1, 149.0,
149.0 (+), 133.3, 131.9, 127.3 (+), 124.0 (+), 123.9 (+), 119.4 (+),
117.3, 111.5 (+), 110.3 (+), 98.5 (+), 62.0 (+), 55.5 (+), 55.4 (+),
41.9 (ꢀ), 41.7 (ꢀ), 32.0 (ꢀ), 24.8 (ꢀ), 23.8 (ꢀ). Anal. Calcd for
C
24H26ClN3O3S: C, 61.07; H, 5.55; N, 8.90. Found: C 61.23; H
5.67; N 8.97.
4.1.3.10. 3-(2-(7-Chloroquinolin-4-ylamino)ethyl)-2-(3,4,5-tri-
methoxyphenyl) thiazolidin-4-one (17).
This compound
was obtained as a withe solid in 71% yield, from N1-(7-chloroquin-
olin-4-yl)-ethane-1,2-diamine 5 (4.00 mmol), 3,4,5-trimethoxy-
4.1.3.7. 3-(2-(7-Chloroquinolin-4-ylamino)ethyl)-2-(3,4-dime-
thoxyphenyl) thiazolidin-4-one (14).
This compound was
benzaldehyde
(4.80 mmol); mp 182–184 °C; IR (KBr): 3356, 2862, 1670, 1605,
1574, 656 cmꢀ1 1H NMR (400 MHz, DMSO-d6, Me4Si), d (ppm):
(4.80 mmol)
and
a
-mercaptoacetic
acid
obtained as a beige solid in 81% yield, from N1-(7-chloroquinolin-
4-yl)-ethane-1,2-diamine 5 (4.24 mmol), 3,4-dimetoxybenzalde-
.
hyde (5.09 mmol) and
210–212 °C; IR (KBr): 3348, 2831, 1651, 1605, 1574, 1265,
648 cmꢀ1 1H NMR (400 MHz, DMSO-d6, Me4Si), d (ppm): 8.30
(1H, d, J = 5.4 Hz, 2-H), 8.12 (1H, d, J = 8.3 Hz, 5-H), 7.78 (1H, s, 8-
H), 7.46–7.44 (1H, m, 6-H), 7.46–7.44 (1H, m, NH), 6.93 (1H, s, 2-
a
-mercaptocetic acid (5.09 mmol); mp
8.31 (1H, d, J = 5.4 Hz, 2-H), 8.14 (1H, d, J = 9.1 Hz, 5-H), 7.78 (1H,
d, J = 2.2 Hz, 8-H), 7.45 (1H, dd, J = 9.0, 2.2 Hz, 6-H), 7.42 (1H, s,
NH), 6.66 (2H, s, 2-HAr, 6-HAr), 6.30 (1H, d, J = 5.5 Hz, 3-H), 5.85
(1H, s, 2-HThiaz), 3.90 (1H, dd, J = 15.3, 1.6 Hz, 5-HaThiaz), 3.71 (6H,
s, –OCH3), 3.70 (1H, d, J = 15.1, 5-HbThiaz), 3.65 (3H, s, –OCH3),
3.63–3.56 (1H, m, 20-Ha), 3.53–3.42 (1H, m, 10-Ha), 3.28–3.20
(1H, m, 10-Hb), 3.06–2.99 (1H, m, 20-Hb). 13C NMR (100 MHz,
DMSO-d6, Me4Si), d (ppm): 171.2, 153.5 (+), 152.8, 152.8, 152.7,
149.3 (+), 137.6, 134.9, 133.4 (+), 129.4, 124.6 (+), 127.6 (+),
117.5, 106.1 (+), 106.0 (+), 99.2 (+), 71.1 (+), 60.8 (+), 56.5 (+),
.
HAr), 6.93 (2H, s, 6-HAr, 5-HAr), 6.26 (1H, d, J = 3.5 Hz, 3-H), 5.85
(1H, s, 2-HThiaz), 3.88–3.71 (2H, m, 5-HaThiaz, 5-HbThiaz), 3.75 (1H,
s, 3-HAr), 3.69 (1H, s, 4-HAr), 3.55–3.53 (1H, m, 20-Ha), 3.45–3.44
(1H, m, 10-Ha), 3.20–3.19 (1H, m, 10-Hb), 3.01–2.97 (1H, m, 20-
Hb). 13C NMR (100 MHz, DMSO-d6, Me4Si), d (ppm): 171.0, 151.6

F. A. Rojas Ruiz et al. / Bioorg. Med. Chem. 19 (2011) 4562–4573
4571
56.3 (+), 52.1 (ꢀ), 46.9 (ꢀ), 33.9 (ꢀ). Anal. Calcd for C23H24ClN3O4S:
4.1.3.14.
3-(2-((7-Chloroquinolin-4-yl)amino)ethyl)-2-(4-
(21). This
C, 58.28; H, 5.10; N, 8.87. Found: C 58.12; H 5.23; N 8.63.
hydroxy-3-methoxyphenyl)thiazolidin-4-one
compound was obtained as a withe solid in 92% yield, from
N1-(7-chloroquinolin-4-yl)-ethane-1,2-diamine 5 (4.00 mmol), 4-
4.1.3.11. 2-(3,4-(Methylendioxy)phenyl)-3-(2-((7-chloroquino-
hydroxy-3-methoxybenzaldehyde (4.80 mmol) and
cetic acid (4.80 mmol); mp 233–236 °C; IR (KBr): 3400, 3382,
3020, 1665, 1614, 1581, 665 cmꢀ1 1H NMR (400 MHz, DMSO-d6,
Me4Si), (ppm): 8.29 (1H, d, J = 5.4 Hz, 2-H), 8.12 (1H, d,
a-mercaptoa-
lin-4-yl)amino)ethyl)thiazolidin-4-one (18).
was obtained as a withe solid in 82% yield, from N1-(7-chloroquin-
olin-4-yl)-ethane-1,2-diamine (4.00 mmol), 3,4-(methylendi-
oxy)-benzaldehyde (4.80 mmol) and -mercaptoacetic acid
(4.80 mmol); mp 238–240 °C; IR (KBr): 3390, 2862, 1659, 1615,
1569, 656 cmꢀ1 1H NMR (400 MHz, DMSO-d6, Me4Si), d (ppm):
This compound
.
5
d
a
J = 9.2 Hz, 5-H), 7.78 (1H, d, J = 2.2 Hz, 8-H), 7.45 (1H, dd, J = 9.0,
2.2 Hz, 6-H), 7.44–7.41(1H, m, NH), 6.90 (1H, s, 2-HAr), 6.84–6.73
(2H, m, 5-HAr, 6-HAr), 6.22 (1H, d, J = 5.5 Hz, 3-H), 5.81 (1H, s, 2-
.
8.33 (1H, d, J = 5.4 Hz, 2-H), 8.12 (1H, d, J = 9.0 Hz, 5-H), 7.78 (1H,
d, J = 1.9 Hz, 8-H), 7.45 (1H, dd, J = 9.0, 2.0 Hz, 6-H), 7.41 (1H, t,
J = 5.7 Hz, NH), 6.98 (1H, s, 2-HAr), 6.86 (2H, s, 5-HAr,6-HAr), 6.34
(1H, d, J = 5.4 Hz, 3-H), 6.02 (2H, d, J = 4.9 Hz, –OCH2O–), 5.84
(1H, s, 2-HThiaz), 3.88 (1H, dd, J = 15.1, 1.0 Hz, 5-HaThiaz), 3.66 (1H,
d, J = 15.3 Hz, 5-HbThiaz), 3.57–355 (1H, m, 20-Ha), 3.52–3.47 (1H,
m, 1H, m, 10-Ha), 3.27–3.18 (1H, m, 10-Hb), 3.01- 2.92 (1H, m,
20-Hb). 13C NMR (100 MHz, DMSO-d6, Me4Si), d (ppm): 171.2,
154.5 (+), 152.7, 149.3, 148.7, 147.2 (+), 134.9, 132.5, 129.4 (+),
124.8 (+), 122.0 (+), 121.6 (+), 117.5, 113.8 (+), 112.3 (+), 101.2
(+), 99.2 (+), 70.8 (ꢀ), 52.0 (ꢀ), 46.5 (ꢀ), 33.9 (ꢀ). Anal. Calcd for
H
Thiaz), 3.83 (1H, d, J = 15.3, 5-HaThiaz), 3.69 (3H, s, –OCH3), 3.68
(1H, d, J = 15.0, 5-HbThiaz), 3.55–3.43 (2H, m, 20-Ha,10-Ha), 3.39
(1H, s, –OH), 3.21–3.13 (1H, m, 10-Hb), 3.03–2.96 (1H, m, 20-Hb).
13C NMR (100 MHz, DMSO-d6, Me4Si), d (ppm): 170.4, 154.7 (+),
152.9, 149.3, 149.4, 149.1 (+), 133.3, 131.9, 129.3 (+), 122.0 (+),
123.9 (+), 121.4 (+), 117.3, 115.5 (+), 114.3 (+), 98.5 (+), 62.0 (+),
56.5 (+), 55.4 (ꢀ), 46.9 (ꢀ), 41.7 (ꢀ). Anal. Calcd for C21H20ClN3O3S:
C, 58.67; H, 4.69; N, 9.77. Found: C 58.55; H 4.86; N 9.64.
4.1.3.15.
hydroxy-3-methoxyphenyl)thiazolidin-4-one
compound was obtained as a withe solid in 98% yield, from
N1-(7-chloroquinolin-4-yl)-propane-1,3-diamine
(4.00 mmol),
4-hydroxy-3-methoxybenzaldehyde (4.80 mmol) and -mercapto-
acetic acid (4.80 mmol); mp 180–183 °C; IR (KBr): 3420, 2862,
3356, 2934, 1664, 1612, 1541, 1150, 656 cmꢀ1 1H NMR
(400 MHz, DMSO-d6, Me4Si), d (ppm): 8.38 (1H, d, J = 5.3 Hz,
2-H), 8.17 (1H, d, J = 9.0 Hz, 5-H), 7.78 (1H, d, J = 2.1 Hz, 8-H),
7.44 (1H, dd, J = 9.0, 2.2 Hz, 6-H), 7.21(1H, t, NH), 6.91 (1H, d,
J = 1.7 Hz, 2-HAr), 6.78 (1H, dd, J = 8.2, 1.7 Hz, 6-HAr), 6.73 (1H, d,
J = 8.1 Hz, 5-HAr), 6.37 (1H, d, J = 5.4 Hz, 3-H), 5.74 (1H, s, 2-HThiaz),
3.84 (1H, d, J = 15.3 Hz, 5-HaThiaz), 3.71 (3H, s, –OCH3), 3.66 (1H, d,
J = 15.5 Hz, 5-HbThiaz), 3.57–3.50 (1H, m, 30-Ha), 3.40 (1H, s, –OH),
3.22–3.13 (2H, m, 10-Ha, 10-Hb), 2.84–2.77 (1H, m, 30-Hb),
1.81–1.67 (2H, m, 20-Ha, 20-Hb). 13C NMR (100 MHz, DMSO-d6,
Me4Si), d (ppm): 171.4, 154.7 (+), 150.9, 149.3, 147.1, 147.4 (+),
134.3, 131.9, 128.3 (+), 124.8 (+), 123.9 (+), 121.4 (+), 117.5,
115.5 (+), 113.9 (+), 98.5 (+), 72.0 (+), 55.5 (+), 42.9 (ꢀ), 41.7 (ꢀ),
32.0 (ꢀ), 26.8 (ꢀ). Anal. Calcd for C22H22ClN3O3S: C, 59.52; H,
4.99; N, 9.47 Found: C 59.43; H 5.06; N 9.17.
3-(3-((7-Chloroquinolin-4-yl)amino)propyl)-2-(4-
(22). This
C21H18ClN3O3S: C, 58.94; H, 4.24; N, 9.82. Found: C 58.90; H
4.28; N 9.73.
6
a
4.1.3.12. 3-(2-((7-Chloroquinolin-4-yl)amino)ethyl)-2-phenyl-
thiazolidin-4-one (19).
solid in 93% yield, from N1-(7-chloroquinolin-4-yl)-ethane-1,2-dia-
mine 5 (4.00 mmol), benzaldehyde (4.80 mmol) and -mercaptoa-
cetic acid (4.80 mmol); mp 120–122 °C; IR (KBr): 3356, 2862, 1666,
1605, 1574, 656 cmꢀ1 1H NMR (400 MHz, DMSO-d6, Me4Si), d
This compound was obtained as a withe
.
a
.
(ppm): 8.31 (1H, d, J = 5.4 Hz, 2-H), 8.12 (1H, d, J = 9.1 Hz, 5-H),
7.79 (1H, d, J = 2.2 Hz, 8-H), 7.44 (1H, dd, J = 9.0, 2.3 Hz, 6-H),
7.41–7.38 (6H, m, 2-HPh-6-HPh, NH), 6.26 (1H, d, J = 5.5 Hz, 3-H),
5.92 (1H, J = 1.5 Hz, 2-HThiaz), 3.88 (1H, dd, J = 15.5, 1.8 Hz, 5-HaThi-
az), 3.71 (1H, d, J = 15.5 Hz, 5-Hb), 3.65–3.58 (1H, m, 20-Ha),
3.50–3.41 (1H, m, 10-Ha), 3.25–3.17 (1H, m, 10-Hb), 2.98–2.91
(1H, m, 20-Hb). 13C NMR (100 MHz, DMSO-d6, Me4Si), d (ppm):
171.2, 154.5 (+), 152.7, 149.3, 143.8, 134.9 (+), 129.4 (+), 128.6
(+), 128.6 (+), 127.1 (+), 126.9 (+), 124.8 (+), 121.6 (+), 117.5 (+),
99.3 (+), 70.5 (+), 52.0 (+), 46.5 (ꢀ), 34.8 (ꢀ), 33.9 (ꢀ). Anal. Calcd
for C20H18ClN3OS: C, 62.57; H, 4.73; N, 10.95; Found: C 62.44; H
4.89; N 10.76.
4.1.3.16.
hydroxy-4-methoxyphenyl)thiazolidin-4-one (23).
pound was obtained as bagie solid in 56% yield, from
N1-(7-chloroquinolin-4-yl)-ethane-1,2-diamine
(4.00 mmol),
3-hydroxy-4-methoxybenzaldehyde (4.80 mmol) and -mercapto-
acetic acid (4.80 mmol); mp 250–253 °C; IR (KBr): 3371, 2870,
1666, 1612, 1574, 1257, 648 cmꢀ1 1H NMR (400 MHz, DMSO-d6,
Me4Si), (ppm): 8.33 (1H, d, J = 5.5 Hz, 2-H), 8.14 (1H, d,
3-(2-((7-Chloroquinolin-4-yl)amino)ethyl)-2-(3-
This com-
a
4.1.3.13. 3-(3-((7-Chloroquinolin-4-yl)amino)propyl)-2-phenyl-
5
thiazolidin-4-one (20).
solid in 65% yield, from N1-(7-chloroquinolin-4-yl)-propane-1,3-
diamine 6 (4.24 mmol), benzaldehyde (5.09 mmol) and -mercap-
toacetic acid (5.09 mmol); mp 128–130 °C; IR (KBr): 3348, 2846,
1666, 1612, 1581, 640 cmꢀ1 1H NMR (400 MHz, DMSO-d6, Me4Si),
This compound was obtained as a beige
a
a
.
d
.
J = 9.0 Hz, 5-H), 7.80 (1H, d, J = 2.1 Hz, 8-H), 7.55(1H, t, NH), 7.46
(1H, dd, J = 9.0, 2.0 Hz, 6-H), 6.88 (1H, d, J = 8.3 Hz 5-HAr), 6.84
(1H, d, J = 2.0, 2-HAr), 6.77 (1H, dd, J = 8.2, 1.8 Hz, 5-HAr) 6.29 (1H,
d, J = 5.6 Hz, 3-H), 5.79 (1H, s, 2-HThiaz), 3.76 (3H, s, –OCH3)
3.82–3.62 (2H, m, 5-HaThiaz, 5-HbThiaz), 3.59–3.52 (1H, m, 20-Ha),
3.50–3.42 (1H, m, 10-Ha), 3.25–3.18 (1H, m, 10-Hb), 3.39 (1H, s,
–OH), 3.01–2.94 (1H, m, 20-Hb). 13C NMR (100 MHz, DMSO-d6,
Me4Si), d (ppm): 171.0, 151.6 (+), 149.6, 149.3, 147.9, 148.9 (+),
133.4, 131.3, 127.5 (+), 124.2 (+), 123.7 (+), 120.1 (+), 117.3,
111.5 (+), 110.7 (+), 98.3 (+), 62.9 (+), 55.5 (+), 55.4 (ꢀ), 40.6
(ꢀ), = 32.1 (ꢀ). Anal. Calcd for C21H20ClN3O3S: C, 58.67; H, 4.69;
N, 9.77; Found: C 58.58; H 4.79; N 9.54.
d (ppm): 8.38 (1H, d, J = 5.4 Hz, 2-H), 8.17 (1H, d, J = 9.1 Hz, 5-H),
7.79 (1H, d, J = 1.9 Hz, 8-H), 7.45 (1H, dd, J = 8.9, 1.7 Hz, 6-H),
7.37–7.27 (5H, m, 2-HPh-6-HPh), 7.25 (1H, t, J = 4.8 Hz, NH), 6.37
(1H, d, J = 5.4 Hz, 3-H), 5.84 (1H, s, 2-HThiaz), 3.88 (1H, d,
J = 15.4 Hz, 5-HaThiaz), 3.69 (1H, d, J = 15.4 Hz, 5-HbThiaz),
3.63–3.56 (1H, m, 30-Ha), 3.19 (2H, d, J = 5.8 Hz, 10-Ha, 10-Hb),
2.77–2.70 (1H, m, 30-Hb), 1.84–1.67 (2H, m, 20-Ha, 20-Hb). 13C
NMR (100 MHz, DMSO-d6, Me4Si), d (ppm): 171.2, 149.3 (+),
154.5, 152.7, 143.8, 134.9, 129.4 (+), 128.6 (2C, +), 127.1 (+),
126.9 (2C, +), 124.8 (+), 121.6 (+), 117.5, 99.2 (+), 70.8 (+), 42.7
(ꢀ), 41.2 (ꢀ), 33.9 (ꢀ), 26.2 (ꢀ). GC–MS: tR = 109.55 min, m/z (%):
397 (M+ꢀ, 4), 324 (6), 219 (48), 218 (6), 217 (15), 205 (54), 192
(100), 191 (80), 178 (21), 156 (37), 155 (24). Anal. Calcd for
4.1.3.17.
3-(4-((7-Chloroquinolin-4-yl)amino)butyl)-2-(4-
(24). This
C
21H20ClN3OS: C, 63.39; H, 5.07; N, 10.56. Found: C 63.21; H
hydroxy-3-methoxyphenyl)thiazolidin-4-one
5.19; N 10.43.

4572
F. A. Rojas Ruiz et al. / Bioorg. Med. Chem. 19 (2011) 4562–4573
compound was obtained as a bagie solid in 98% yield, from
N1-(7-chloroquinolin-4-yl)-butane-1,4-diamine
(4.00 mmol),
4-hydroxy-3-methoxybenzaldehyde (4.80 mmol) and -mercapto-
the selected concentration, or DMSO at the same concentration
of the control. The cells were exposed to compound solutions for
another 24 h. Afterwards, the medium was eliminated and
7
a
acetic acid (4.80 mmol); mp 180–183 °C; IR (KBr): 3333, 3224,
100 lL/well of 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazoli-
2947, 1658, 1612, 1581, 1137, 602. 1H NMR (400 MHz, DMSO-d6,
um bromide (MTT) solution, 0.4 mg/mL in PBS, was added and
the plates were returned to incubator for 1 h. The suspension
was removed and the toxic effect of the compounds was assessed
by the reduction of MTT to formazan crystals (as a cell viability
Me4Si),
J = 9.2 Hz, 5-H), 7.77 (1H, d, J = 2.2 Hz, 8-H), 7.43 (1H, dd, J = 8.9,
1.9 Hz, 6-H), 7.27 (1H, t, J = 5.2 Hz, NH), 6.97–6.91 (3H, m, 2-HAr
d (ppm): 8.38 (1H, d, J = 5.5 Hz, 2-H), 8.25 (1H, d,
,
5-HAr, 6-HAr), 6.42 (1H, d, J = 5.5 Hz, 3-H), 5.75 (1H, s, 2-HThiaz),
3.83 (1H, d, J = 15.7 Hz, 5-HaThiaz), 3.73 (3H, s, –OCH3), 3.64 (1H,
d, J = 15.4 Hz, 5-HbThiaz), 3.58–3.49 (1H, m, 40-Ha), 3.23–3.18 (2H,
m, 10-Ha, 10-Hb), 3.40 (1H, s, –OH), 2.69–2.64 (1H, m, 40-Hb),
1.62–1.42 (4H, m, 20-Ha, 20-Hb, 30-Ha, 30-Hb). 13C NMR (100 MHz,
DMSO-d6, Me4Si), d (ppm): 172.4, 151.7 (+), 149.9, 149.5, 149.1,
149.0 (+), 133.3, 131.9, 127.3 (+), 124.0 (+), 123.9 (+), 119.4 (+),
117.3, 111.5 (+), 110.3 (+), 98.5 (+), 62.0 (+), 55.5 (+), 55.4 (+),
41.9 (ꢀ), 41.7 (ꢀ), 32.0 (ꢀ), 23.8 (ꢀ). Anal. Calcd for C23H24ClN3O3S:
C, 60.32; H, 5.28; N, 9.18. Found: C 60.43; H 5.35; N 9.02.
indicator). Crystals were solubilized by adding 100 lL of DMSO
after discarding the supernatant and the optical density of the final
solution (O.D.) was measured at 595 nm. The cytotoxicity percent-
ages were calculated as follows:
%toxicity ¼ ½ðO:D:control ꢀ O:D:compÞ=ðO:D:controlÞꢂ ꢁ 100
4.2.3. Ferriprotoporphyrin IX biomineralization inhibition test
(FBIT)
The procedure for testing FP biomineralization was performed
according to the method described by Deharo et al.19 A mixture
containing: 50
solvent (for control), 50
H 5533) freshly dissolved in dimethylsulphoxide (DMSO) and
100 L of 0.5 M sodium acetate buffer pH 4.4, was incubated in a
l
L of a 10 mg/mL compound solution or 50
lL of
4.2. Biology
l
L of 0.5 mg/ml of haemin chloride (Sigma
4.2.1. In vitro antimalarial activity screening against
Plasmodium falciparum
l
non-sterile flat bottom 96-well plate at 37 °C for 18–24 hrs. After
incubation, the plate was centrifuged at 1600 g for 5 min and the
supernatant was discarded. The remaining pellet was resuspended
The SYBRÓGreenI-based micromethod described by Smilkstein
et al16 was followed for testing antimalarial activity. Erythrocytic
stages of P. falciparum 3D7 chloroquine-sensitive and Dd2
multidrug-resistance strains were maintained according to meth-
od of Trager and Jensen,17 with minor modifications. RPMI 1640
culture medium supplemented with 0.5% Albumax II at 37 °C in
an atmosphere with 5% CO2. An erythrocyte suspension, with ini-
tial 1% parasitemia and 4% hematocrit, was prepared using the
aforementioned culture and then distributed in a 96-well plate
with 200
was then centrifuged once again and the supernatant discarded.
The pellet (precipitate of ß-haematin), was dissolved in 150 L of
lL of DMSO in order to remove unreacted FP. The plate
l
0.1 M NaOH and the absorbance quantified at 405 nm with a
microplate reader. The data were expressed as the percentage of
inhibition of FP biomineralization calculated using the following
equation:
(50
pared in DMSO and diluted in RPMI medium in order to obtain con-
centrations from 10 to 0.01 g/mL. The final DMSO concentration
was never higher than 0.1%. 50 L of each prepared concentration
lL per well). Next, stock solutions of each compound were pre-
%inhibition ¼ 100 ꢁ ½ðO:D:control ꢀ O:D:drugÞ=ðO:D:controlÞꢂ
l
l
4.2.4. In vivo antimalarial activity assessment
were added per well. DMSO, chloroquine and mefloquine were in-
The in vivo antimalarial activity of the compounds was mea-
sured by the classical 4-day suppressive test.20 Briefly, on day 0,
groups of five NMRI male mice, with weight of 20 2 g, were inoc-
ulated with 2 ꢁ 107 red blood cells RBCs infected by erythrocytic
stages of rodent malaria parasite P. berghei ANKA strain. Two hours
later, each group of mice was treated intraperitoneally i.p. with a
dose of 10 mg/kg/day of the selected compound, which were pre-
viously prepared in DMSO. Treatment was continued from day 1
to 3, always at similar times. On the day 4, Giemsa-stained thin
blood smears from the tail of the mice were made and microscop-
ically examined with 1000ꢁ magnification. The mean of the para-
sitemia (Par.) of each group was calculated in a total of 1000 RBCs,
and the growth inhibition percentage of parasite was estimated in
relation to the control group, which received only the solvent of
the compounds.
cluded as a negative and positive control, respectively.
All compounds and controls were placed in triplicate. The plate
was incubated under the same conditions. After 48 h, the plate was
removed from the incubator and frozen for at least 1 h at -70 °C
and then thawed. Finally, 100
l
L of SYBRÓGreenI in lysis buffer
(0.2 L/mL) was added per well and shaken for 5 minutes or until
l
no erythrocyte precipitated was observed. The plate was left to
stand in the dark for 1 h at room temperature. The fluorescence
intensity (F.I.) for each well was measured at 485 nm of excitation
and 530 nm of emission. The background fluorescence for the no
parasitized erythrocytes was subtracted to each well tested. Per-
centage inhibition of the parasite growth for each concentration
was calculated by using the following formula:
%inhibition ¼ 100 ꢁ ½ðF:I:control ꢀ F:I:compÞ=ðF:I:controlÞꢂ
%inhibition ¼ ½ðPar: control ꢀ Par: compÞ=ðPar: controlÞꢂ ꢁ 100
IC50 values were estimated by plotting drug concentration ver-
sus percentage inhibition.
Acknowledgments
4.2.2. Hepatotoxicity and nonspecific cytotoxicity assays
Murine J774 macrophages and human hepatocarcinoma cells
(HepG2) were maintained on RPMI 1640 medium supplemented
with 10% FBS at 37 °C in a 5% CO2 atmosphere. The same
MTT-based method, according to Hattori and Nakanishi18, was
used to measure the cytotoxicity level on both cell lines. In a flat
The authors are grateful to the Research Center of Excellence,
CENIVAM (contract no 432–2004) and Ministerio de Ciencia e
Innovación (Project SAF 2009–10399), and Ministerio de Asuntos
Exteriores y Cooperación (A/024093/09) of Spain.
References and notes
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medium, containing 5 ꢁ 104 cells, were distributed per well. The
cells were allowed to attach for 24 h at 37 °C. Then, the medium
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