Synthesis of oxalamide and triazine derivatives as a novel class of hybrid 4-aminoquinoline with potent antiplasmodial activity

Article abstract of DOI:10.1016/j.bmc.2009.05.075

Frequency of malaria and its resistance to chemotherapeutic options are emerging rapidly. To counter this problem, a series of 4-aminoquinolines having oxalamide and triazine functionalities in the side chain were synthesized and screened for their antimalarial activities. Triazine derivative 48 found to be the most active against CQ sensitive strain 3D7 of Plasmodium falciparum in an in vitro assay with an IC₅₀ of 5.23 ng/mL and oxalamide derivative 13 showed an in vivo suppression of 70.45% on day 4 against CQ resistant strain N-67 of Plasmodium yoelii.

Full text of DOI:10.1016/j.bmc.2009.05.075

Bioorganic & Medicinal Chemistry 17 (2009) 6451–6462
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis of oxalamide and triazine derivatives as a novel class of hybrid
4-aminoquinoline with potent antiplasmodial activity
Naresh Sunduru a, Moni Sharma a, Kumkum Srivastava b, S. Rajakumar b, S. K. Puri b,
J. K. Saxena c, Prem M. S. Chauhan a,
*
a Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226001, India
b Division of Parasitology, Central Drug Research Institute, Lucknow 226001, India
c Division of Biochemistry, Central Drug Research Institute, Lucknow 226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Frequency of malaria and its resistance to chemotherapeutic options are emerging rapidly. To counter
this problem, a series of 4-aminoquinolines having oxalamide and triazine functionalities in the side
chain were synthesized and screened for their antimalarial activities. Triazine derivative 48 found to
be the most active against CQ sensitive strain 3D7 of Plasmodium falciparum in an in vitro assay with
an IC50 of 5.23 ng/mL and oxalamide derivative 13 showed an in vivo suppression of 70.45% on day 4
against CQ resistant strain N-67 of Plasmodium yoelii.
Received 20 April 2009
Revised 28 May 2009
Accepted 29 May 2009
Available online 6 June 2009
Keywords:
Ó 2009 Published by Elsevier Ltd.
Antimalarial
4-Aminoquinoline
Triazine
Oxalamide
1. Introduction
fully understood. However, it is clear that the resistance is a conse-
quence of decreased accumulation of the drug in the parasite, due
Among more than 100 species of Plasmodium; falciparum is the
most severe and main causative agent of malaria worldwide.1 De-
spite decades of research and the successful development of com-
bination therapy, malaria remains one of the most serious health
problem to the developing world specially the countries where it
is endemic.2 It is estimated that approximately 500 million people
are infected in subtropical countries with a mortal rate of 2.5 mil-
lion death annually and about a million of these being children un-
der the age of five.3 Chloroquine (CQ), a frontline antimalarial
developed as substitute for quinine during World war II was ap-
proved as a safe, effective, easily available, affordable and eco-
nomic treatment against malaria.1 For understanding the action
of chloroquine, it is relevant that the actual disease malaria is
caused by multiplication of the parasites in human red blood cells.
During digestion of host cell hemoglobin by the parasite, large
amounts of free heme are produced in the food vacuole. Most of
this is polymerized to inert hemozoin, while the residual heme dif-
fuses into the parasite’s cytosol where it is detoxified by interac-
tion with glutathione (GSH). The CQ-induced heme accumulation
in cytosol and membranes of the parasite causes or at least contrib-
utes to cell death.4 The molecular basis for CQ resistance is not
to enhanced efflux, reduced uptake or a combination of the both.
Several studies indicate that point mutations in the multidrug
resistance 1 (pfmdR1), candidate (cg2) and CQ resistance trans-
porter (pfcrt) gene are involved in the mechanism of resistance.5
The other antimalarial drugs cycloguanil and pyrimethamine are
specific inhibitor of plasmodial DHFR which is one of the important
target for drugs against malaria, are also become resistant.6 There-
fore, the metabolic functions related to hemoglobin digestion,
heme detoxification and DHFR inhibitor pathways still represent
a valid target for the discovery of new antimalarial drugs.
In chemotherapeutic point of view, the search for a molecule
having multiple targets has always been a very attractive strategy
for medicinal chemists. In search of such molecules, trioxaneami-
noquinoline chimeras (‘trioxaquines’),7 artemisinin-quinine,8 4-
aminoquinoline based isatin derivatives,9 ferrocene-chloroquine
analogues10 and the 4-aminoquinoline based inhibitors of neutral
zinc aminopeptidase,11 possess improved antimalarial activity in
comparison to parent drugs are reported to counter the problem
of drug resistance. Additionally, a new hybrid chloroquine reversal
agents have also been developed through coupling of imipramine
(reversal agent) with 4-aminoquinoline.12 Our group has synthe-
sized the novel heterocylces as antimalarial agents such as substi-
tuted triazines, pyrimidines13 and also established the synthesis
of hybrid molecules by the introduction of diverse functionalities
in the lateral side chain of 4-aminoquinoline, which led to the
* Corresponding author. Tel.: +91 522 2262411x4470; fax: +91 522 2623405.
E-mail addresses: Prem_chauhan_2000@yahoo.mail.com, premsc58@hotmail.
com (P.M.S. Chauhan).
0968-0896/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.bmc.2009.05.075

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N. Sunduru et al. / Bioorg. Med. Chem. 17 (2009) 6451–6462
identification of new 4-aminoquinoline based antimalarials, effec-
tive against both chloroquine sensitive and chloroquine resistant
strains of P. falciparum.14 The role of carbon chain length in amino-
alkyl side chain is also investigated by many research groups,
introducing the side chain modified derivatives with potent anti-
malarial activity.15-17 A wealth of information accumulated during
the past decade, introduced urea derivatives with potent antima-
larial activity targeting DHFR18 and b-hematin formation inhibi-
tion.19 Urea derivatives interact with aspartic/glutamic acid
corresponding to D54 in PfDHFR via hydrogen bonding ability of
these derivatives through urea linkage.18 More recently it was ob-
served that the urea derivatives also accumulate in the food vacu-
ole and inhibit the plasmepsin of the parasite.20
The advantages of the chloroquine are seems to be simply too
strong to abandon, therefore identification of hybrid 4-aminoquin-
olines having multiple targets is a hope of generating effective
antimalarial chemotherapy. In this perception we introduced the
oxalamide functionality in the side chain of 4-aminoquinoline
which is based on; its greater stability towards enzyme degrada-
tion21 and retained H-bonding ability22 (Fig 2). Our another
approach is to synthesise the hybrid of 4-aminoquinoline 1,3,5-tri-
azines to enhance the antimalarial activity by inducing DHFR
inhibitor on the side chain of 4-aminoquinoline(Fig. 1).
carbon to which Cl is directly attached. These compounds further
undergo the nucleophilic substitution reaction with different
amines (Table 1) at acetate group to furnish the final product 4–
26 in good to moderate yield. In another route compounds 2c
and 2d were reacted with 2-(indol-3-yl)-2-oxoacetyl chloride
(28), which was prepared by the reaction of indole with oxalylchlo-
ride to yield the hybrid of quinoline and indole (29, 30). In these
hybrid molecules, NH of indole was protected with alkyl or aryl
halides to yield the compounds (31–34).
The synthesis of monosubstituted [1,3,5]-triazines (36, 37) were
accomplished by the ipso nucleophilic substitution of the Cl atom
of the cynauric chloride (35). The sequence of addition of amines
to cyanuric chloride depends upon the strength and structure of
nucleophile. Subsequently the monosubstituted triazines were
reacted initially with compounds 2a and 2b, followed by the
treatment with more nucleophilic amines (Table 2) to obtain the
respective targeted compounds (38–57). All the synthesized
compounds were well characterized by IR, Mass, NMR and the
purity was established with elemental analysis.
3. Results and discussion
All the compounds having modification at the lateral side chain
of 4-aminoquinoline with oxalamide linker (4–26),
a-ketoamide
2. Chemistry
linker coupled with indole (29–34) and hybrid derivatives of ami-
noquinoline–triazine (38–57) were evaluated for their in vitro
antimalarial activities against CQ sensitive 3D7 strain of P. falcipa-
rum. The in vitro antimalarial activity, inhibition of b-hematin for-
mation and selectivity index (SI) of above synthesised compounds
are given in Tables 1 and 2. Compounds with potent in vitro
antimalarial activity and good SI values were also evaluated for
their in vivo potency against the CQ resistant N-67 strain of
Plasmodium yoelii in swiss mice at 50 mg/kg/day for 4 days by
intraperitoneal route (ip).
The desired compounds 4–26, 29–34 and 38–57 were synthes-
ised by the synthetic protocols as outlined in Schemes 1 and 2,
respectively. Synthesis of compounds 2a–2d was achieved by the
ipso nucleophilic substitution of the 4-Cl atom of 4,7-dichloroquin-
oline (1) with various cyclic and acyclic amines. The so formed
compounds then reacted with ethylchlorooxoacetate to afford
the corresponding oxaloacetates 3a–3d. Chemoselectivity of these
compounds arises due to the greater electrophilicity of carbonyl
Among all the synthesised side chain modified derivatives,
compounds having oxalamide linker joining two alkyl amine side
chains with high degree of flexibility and H-bonding capability,
showed moderate antimalarial activity with IC50 in the range of
15.58–233.38 ng/mL. Compound 12 consisting of aminopropyl
chain linked to the 7-chloroquinoline and N,N-diethylethylenedi-
amine as R1 showed potent antimalarial activity of IC50 15.58 ng/
Cl
N
NH2
N
HN
N
H2N
N
Cl
N
mL with inhibitory activity of b-hematin formation IC50 7.99 lg/
Chloroquine
Cycloguanil
mL. On replacing R1 with N,N-dimethylethylenediamine (13) the
activity decreases to 26.41 ng/mL, though its b-hematin inhibitory
activity remains same. Compound 10 having aminopropylmorpho-
line as R1 have shown IC50 of 25.42 ng/mL with b-hematin forma-
X = CH2, O
N
N
R
O
N
N
R
H
HN
HN
linker
NH
tion inhibition of IC50 8.74 l
g/mL, while replacing R1 with
N
O
n = 0,1
aminoethylmorpholine (9) the activity reduced to 82.21 ng/mL
due to its decreased inhibition of b-hematin formation of IC50
Cl
N
38-57
Cl
N
4-26, 29-34
10.67
as R1 showed decrease in activity with IC50 233.38 ng/mL due to re-
duced b-hematin formation inhibitory activity of 15.66 g/mL.
lg/mL. Similarly, compound 11 consisting of n-butyl chain
Figure 1. Structure of chloroquine, cycloguanil and synthesised compounds.
l
Reducing the methylene group at the lateral side chain signifi-
cantly increased the b-hematin inhibitory activity but reduced
the antimalarial activity of the compounds (4–8). Compound 5
having aminopropylmorpholine as R1 showed IC50 of 31.32 ng/
Hydrogen bonding ability
Donor property
mL with b-hematin formation inhibition of IC50 7.18 lg/mL and
compound 8 having N,N-dimethylethylenediamine as R1 showed
equal potency of IC50 31.59 ng/mL even though b-hematin forma-
tion inhibition decreased to 11.09 lg/mL. Contrarily compounds
H
N
H
N
H
N
H
N
R
R
R
R
4, 6 and 7 showed decrease in antimalarial activity, though the
O
O
O
b-hematin formation inhibition is increased to 6.87, 6.76 and
7.01 lg/mL, respectively. Compounds with cyclic diamine that is,
aminoethylpiperazine (14–20), piprazine (21–26) were found to
be less active compared to their acyclic analogues which may be
Acceptor sites
Figure 2. Hydrogen bonding ability of oxalamide group.

N. Sunduru et al. / Bioorg. Med. Chem. 17 (2009) 6451–6462
6453
O
O
Z
OC2H5
NHR1
Z
O
O
(II)
(III)
Cl
N
Cl
N
3a: (4-8)
(3a-3d)
Z
3b: (9-13)
3c: (14-20)
3d: (21-26)
Cl
N
Z
(Ix,Iy)
Cl
N
Cl
O
Z
O
(2a-2d)
(1)
NH2
NH2
NH
(V)
HN
HN
2a: Z=
2b: Z=
2c: Z=
N
H
O
O
Cl
N
Cl
N
2c: (29)
2d: (30)
HN
N
N
H
NH
2d: Z=
(VI)
(28)
O
Z
O
(IV)
N
R2
N
Cl
N
H
2c: (31,32)
2d: (33,34)
(27)
Scheme 1. Reagents and conditions: (I) (x)
a,c-diamines, reflux, 7 h; (y) N-aminoethylpiperazine/piperazine, MeOH, reflux, 5 h; (II) ClCOCO2Et, DCM, rt, 1 h; (III) primary
amines, n-BuOH, reflux under pressure, 8 h; (IV) (COCl)2, dry Et2O, 0 °C, 1 h; (V) 2c/2d, Et3N, n-BuOH, reflux, 9 h; (VI) MeI/ PTSC, NaOH, TBAB, DCM, 0 °C—rt, 2 h.
CQ. These compounds have piperidine ring as R3 and N,N-dialkyle-
R3
thylenediamines as R4 and showed moderate b-hematin inhibitory
N
N
Cl
N
Cl
activity in the range of IC50 8.19–13.34 lg/mL compared to previ-
Cl
N
Cl
R4
(VIII)
(IX)
ous ones. The compounds having morpholine substitution as R3
on the triazine ring system (47, 53–56) or aminoalkylmorpholines
as R4 (38, 47, 53) have shown a great fall in the antiplasmodial
activity, however the compounds 43, 44 showed better activity
compared to above molecules with an IC50 of 22.20 and 29.74 ng/
mL, respectively. As discussed above, we find that the morpholine
substitution on the triazine ring system reduces the activity of the
compounds while piperidine substitution enhances the antimalarial
potency. It has also been conjectured that to further increase the
antiplasmodial activity the N-methylpiperazine, N,N-dimethyleth-
ylenediamine and N,N-diethylethylenediamine plays a critical role
due to the basic nature of terminal nitrogen atom of these molecules.
These compounds were also tested for their cytotoxicity against
VERO cells. Among all, aminoquinoline–triazine derivatives have
good selectivity index (Table 2) in comparison with oxalamide
derivatives (Table 1). Compound 46 having an IC50 of 10.02 ng/
mL showed highest selectivity index of 4692.08, while most potent
compound 48 having an IC50 of 5.23 ng/mL showed selectivity in-
dex of 860.41. Similarly compound 41 having an IC50 of 7.88 ng/
mL showed SI of 958.12, thus illustrating the good activity profile.
On the other hand oxalamide derivatives (5, 10 and 13) having an
IC50 of 31.32, 25.42 and 26.41 ng/mL showed selectivity index of
1567.05, 1625.52 and 2527.65, respectively. Considering the
in vitro antimalarial activity and selectivity index, compounds (5,
10, 13, 41, 46 and 48) were also screened in an in vivo model
against chloroquine resistant N-67 strain of P. yoelii in swiss mice
at 50 mg/kg/day for 4 days by intraperitoneal route (ip) (Table 1)
and (Table 2). Out of six evaluated compounds, oxalamide deriva-
tive 13 found to be the most active against chloroquine resistant
strain with 70.45% suppression on day 4. Where as hybrid deriva-
tives of aminoquinoline–triazine found to be toxic against this
Z
N
(VII)
N
N
N
N
Cl
R3
(36, 37)
Cl
N
(35)
2a (36, 37): 38-47
2b (36, 37): 48-57
Scheme 2. Reagents and conditions: (VII) piperidine/morpholine, 0 °C, THF, 1 h;
(VIII) 2a/2b, K2CO3, THF, 4 h; (IX) different amines, K2CO3, 80 °C, reflux, 6 h.
due to the inflexible nature of the side chain and the loss of
secondary amide character. Compounds 15, 24 having amin-
opropylmorpholine and N,N-diethylethylenediamine as R1 showed
better antimalarial activity of IC50 40.84, 41.98 ng/mL, respectively,
compared to the other substituents of R1. Hybridization of the
aminoquinoline with indole derivatives by
a-ketoamide linkage
(29–34) diminishes the antimalarial activity and b-hematin forma-
tion inhibition of these compounds. All these foregoing results
suggest that the oxalamide derivatives having secondary amide
and acyclic lateral side chain on 4-aminoquinoline were most
active. So, the retaining of secondary amide character of the oxala-
mide entity is the necessary criteria for antimalarial activity.
On the other hand, incorporation of 1,3,5-triazine on the lateral
side chain of 4-aminoquinoline led to the significant increase of
antimalarial potency which is comparable to the chloroquine.
Among all the hybrid derivatives (38–57), compounds 41, 46, 48,
49, 51 showed potent antimalarial activity in the range of IC50
5.23–10.02 ng/mL and the b-hematin inhibition of these com-
pounds is also in good agreement with their antimalarial activity
having IC50 in the range of 6.19–9.10 lg/mL. Compounds 39, 40
and 50 also showed the moderate antiplasmodial activity with
IC50 of 14.70, 15.89 and 15.63 ng/mL, respectively compared to

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N. Sunduru et al. / Bioorg. Med. Chem. 17 (2009) 6451–6462
Table 1
Biological activity of Scheme 1 compounds
Compound
Z
R1/R2
In vitro antimalarial
activity
IC50 (ng/mL)
SIb
Inhibition of b-hematin
In vivo % suppression
on day 4d
formation
a
c
IC50 (ng/mL)
4
5
6
7
8
9
1,2-Ethylenediamine
1,2-Ethylenediamine
1,2-Ethylenediamine
1,2-Ethylenediamine
1,2-Ethylenediamine
1,3-Propanediamine
1,3-Propanediamine
1,3-Propanediamine
1,3-Propanediamine
1,3-Propanediamine
Aminoethylpiperazine
Aminoethylpiperazine
Aminoethylpiperazine
Aminoethylpiperazine
Aminoethylpiperazine
Aminoethylpiperazine
Aminoethylpiperazine
Piperazine
Piperazine
Piperazine
Piperazine
Piperazine
Piperazine
Aminoethylpiperazine
Piperazine
Aminoethylpiperazine
Aminoethylpiperazine
Piperazine
2-Aminoethylmorpholine
3-Aminopropylmorpholine
n-Butylamine
N,N-Diethylethylenediamine
N,N-Dimethylethylenediamine
2-Aminoethylmorpholine
3-Aminopropylmorpholine
n-Butylamine
N,N-Diethylethylenediamine
N,N-Dimethylethylenediamine
2-Aminoethylmorpholine
3-Aminopropylmorpholine
n-Butylamine
N,N-Diethylethylenediamine
N,N-Dimethylethylenediamine
t-Butylamine
1-Aminopropylimidazole
2-Aminoethylmorpholine
3-Aminopropylmorpholine
n-Butylamine
N,N-Diethylethylenediamine
N,N-Dimethylethylenediamine
t-Butylamine
90.83
31.32
233.07
50.28
31.59
82.21
25.42
233.38
15.58
26.41
261.84
40.84
NA
79.78
84.45
NA
135.01
NA
NA
NA
41.98
NA
NA
567.43
1567.05
18.88
605.61
383.03
191.82
1625.52
38.13
232.99
2527.65
183.05
1221.84
ND
194.0
65.0
ND
233.09
ND
ND
ND
1183.41
ND
ND
ND
ND
ND
ND
ND
6.87 (5.71–8.26)
7.18 (6.01–8.58)
6.76 (5.60–8.16)
7.01 (5.80–8.47)
11.09 (8.70–14.14)
10.67 (8.38–13.59)
8.74 (6.91–11.08)
15.66 (9.99–24.55)
7.99 (6.84–9.33)
7.98 (6.80–9.39)
14.17 (10.86–16.13)
NI
ND
NI
<20
ND
<20
ND
ND
ND
<20
ND
ND
ND
ND
ND
ND
ND
ND
43.64
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
29
30
31
32
33
34
21.36
70.45
Hydrogen
Hydrogen
Methyl
p-Tolylsulphonyl
Methyl
p-Tolylsulphonyl
NA
NA
NA
NA
NA
NA
Piperazine
ND
Table 2
Biological activity of the Scheme 2 compounds
Compound
Z
R3
R4
In vitro antimalarial
SIb
Inhibition of b-hematin
In vivo % suppression
on day 4d
activity
formation
a
c
IC50 (ng/mL)
IC50
(lg/mL)
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
CQe
1,2-Ethylenediamine
1,2-Ethylenediamine
1,2-Ethylenediamine
1,2-Ethylenediamine
1,2-Ethylenediamine
1,2-Ethylenediamine
1,2-Ethylenediamine
1,2-Ethylenediamine
1,2-Ethylenediamine
1,2-Ethylenediamine
1,3-Propanediamine
1,3-Propanediamine
1,3-Propanediamine
1,3-Propanediamine
1,3-Propanediamine
1,3-Propanediamine
1,3-Propanediamine
1,3-Propanediamine
1,3-Propanediamine
1,3-Propanediamine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
3-Aminopropylmorpholine
65.63
65.21
7.79 (6.71–9.04)
10.15 (8.86–11.62)
13.34 (11.15–15.96)
9.10 (7.34–11.28)
ND
8.58 (6.93–10.61)
9.42 (7.33–12.11)
8.10 (6.59–9.96)
6.19 (5.13–7.46)
17.16 (11.05–26.63)
7.54 (6.50–8.76)
7.45 (6.44–8.63)
8.19 (7.07–9.49)
7.45 (6.19–8.97)
ND
N,N-Diethylethylenediamine
N,N-Dimethylethylenediamine
N-Methylpiperazine
2-Aminoethylmorpholine
3-Aminopropylmorpholine
N,N-Diethylethylenediamine
N,N-Dimethylethylenediamine
N-Methylpiperazine
2-Aminoethylmorpholine
3-Aminopropylmorpholine
N,N-Diethylethylenediamine
N,N-Dimethylethylenediamine
N-Methylpiperazine
2-Aminoethylmorpholine
3-Aminopropylmorpholine
N,N-Diethylethylenediamine
N,N-Dimethylethylenediamine
N-Methylpiperazine
14.70
15.89
7.88
223.13
1062.30
958.12
ND
Toxic
NA
22.20
29.74
39.39
10.02
48.18
5.23
8.97
15.63
9.13
2405.86
1663.75
1291.71
4692.08
1176.40
860.41
1011.15
330.11
530.20
ND
706.15
1068.32
219.77
704.25
1017.32
8983
Toxic
Toxic
NA
52.06
40.27
163.99
40.08
17.87
5.2
8.60 (7.52–9.84)
10.64 (8.01–14.14)
7.94 (6.85–9.19)
8.55 (7.46–9.81)
8.72 (7.39–10.72)
4.87
2-Aminoethylmorpholine
99.05
a
IC50: concentration corresponding to 50% growth inhibition of chloroquine sensitive strain 3D7 of P. falciparum.
SI = IC50 values of toxicity against VERO cell line/IC50 values of antimlarial activity.
The 50% inhibitory concentration (IC50) was determined using non-linear regression analysis dose–response curves, confidence interval is of 95%.
In vivo antimalarial activity against chloroquine resistant strain N-67 of P. yoelii in swiss mice at dose 50 mg/kg/day by intraperitoneal route.
Chloroquine at a dose of 10 mg/kg, oral for 4 days; NA: not active; ND: not done; NI: no inhibition; Toxic: mice died.
b
C
d
e
strain, but their in vitro results prove these new hybrids as prom-
ising model for further optimization.
tance in malaria, it appears wise to concentrate on drug discovery
efforts towards new structural classes. In this connection we de-
signed, synthesised the hybrid of 4-aminoquinolines having oxala-
mide and triazine functionalities in the side chain and studied their
structure activity relationship. In oxalamide derivatives the pres-
ence of secondary amide functionality increases the antimalarial
4. Conclusion
Malaria is progressively increasing worldwide and developing
its virulent forms. In order to overcome the problem of drug resis-
activity, while the presence of tertiary amide and
a-ketoamide

N. Sunduru et al. / Bioorg. Med. Chem. 17 (2009) 6451–6462
6455
decreases the activity due to less binding ability sites for H-bond-
5.2.1. 7-Chloro-N-(2-(piperazin-1-yl)ethyl)quinolin-4-amine
(2c)
Yield: 85%; mp 140–142 °C; ESMS: 291 (M+1); IR (KBr) 3450,
3022, 2950, 1652, 1217, 762 cmÀ1 1H NMR (300 MHz, CDCl3): d
ing. On the other hand triazine derivatives substituted with amines
which have terminal basic nitrogen like chloroquine increases the
antiplasmodial potency.
;
(ppm) 8.67 (d, 1H, J = 5.05 Hz), 8.15–7.94 (m, 3H), 7.51 (dd, 1H,
J = 2.11, 8.65 Hz), 6.86 (d, 1H, J = 5.12 Hz), 3.52–3.39 (m, 4H),
2.99 (t, 2H, J = 6.02 Hz), 2.91–2.83 (m, 4H), 2.72 (t, 2H,
J = 5.71 Hz), 2.16 (br s, 1H); 13C NMR (75 MHz, CDCl3): 161.41,
155.22, 153.13, 139.32, 131.42, 130.21, 129.32, 125.61, 112.81,
61.32, 56.71, 55.70, 40.91; Anal. Calcd for C15H19ClN4: C, 61.96;
H, 6.59; N, 19.27. Found: C, 61.94; H, 6.65; N, 19.28.
5. Experimental
IR spectra were recorded on Beckman Aculab-10, Perkin Elmer
881 and FTIR 8210 PC, Schimadzu spectrophotometers either on
KBr discs or in neat. Nuclear magnetic resonance spectra were re-
corded on either Bruker Avance DRX-300 MHz or Bruker DPX 200
FT spectrometers using TMS as an internal reference. FAB mass
spectra were recorded on JEOL SX 102/DA 6000 mass spectrometer
using argon/xenon (6 Kv, 10 mA) as the FAB gas. Chemical analysis
was carried out on carlo-Erba-1108 instrument. The melting points
were recorded on an electrically heated melting point apparatus
and are uncorrected.
5.2.2. 7-Chloro-4-(piperazin-1-yl)quinoline (2d)
Yield: 80%; mp 160–162 °C; ESMS: 248 (M+1); IR (KBr) 3433,
3026, 2967, 1642, 1216, 760; 1H NMR (300 MHz, CDCl3): d (ppm)
8.71 (d, 1H, J = 5.12 Hz), 8.07–7.97 (m, 2H), 7.59 (dd, 1H, J = 2.08,
8.73 Hz), 6.89 (d, 1H, J = 5.07 Hz), 4.01 (t, 2H, J = 6.62 Hz), 3.96 (t,
2H, J = 6.58 Hz), 2.94–2.87 (m, 4H), 2.42 (br s, 1H); 13C NMR
(75 MHz, CDCl3): 158.01, 151.62, 149.50, 135.62, 127.81, 126.62,
125.52, 122.01, 109.21, 53.01, 45.52; Anal. Calcd for C13H14ClN3:
C, 63.03; H, 5.70; N, 16.96. Found: C, 63.07; H, 5.75; N, 16.92.
5.1. General procedure for the synthesis of compounds 2a, 2b
A mixture of 4,7-dichloroquinoline (1 equiv) and 1,2-diami-
noethane/1,3-diaminopropane (5 equiv) was heated slowly from
room temperature to 80 °C over 1 h with stirring and subse-
quently at 120–130 °C for 6 h with continued stirring to drive
the reaction to completion. The reaction mixture was cooled to
room temp and taken up in dichloromethane. The organic layer
was successively washed with 5% aq NaHCO3 followed by water
wash and then finally with brine. The organic layer was dried
over anhydrous Na2SO4 and solvent was removed under reduced
pressure and the residue was precipitated by the addition of
80:20 hexane–chloroform to obtain compounds 2a, 2b,
respectively.
5.3. General procedure for the synthesis of compounds (3a–3d)
A mixture of 2a–2d (1.0 equiv) and ethylchlorooxoacetate
(1.5 equiv) in DCM were stirred for 1 h at room temperature. The
solvent was evaporated under vacuum and the solid was purified
directly with column chromatography to obtain the respective
compounds 3a–3d.
5.3.1. Ethyl 2-(2-(7-chloroquinolin-4-ylamino) ethylamino)-2-
oxoacetate (3a)
Yield: 71%; mp 194–196 °C; ESMS: 322 (M+1); IR (KBr) 3296,
3019, 1754, 1615, 1450, 1215, 749 cmÀ1 1H NMR (200 MHz,
;
5.1.1. N1-(7-Chloroquinolin-4-yl)ethane-1,2-diamine (2a)
Yield: 87%; mp 131–132 °C; ESMS: 222 (M+1); IR (KBr) 3356,
DMSO-d6): d (ppm) 9.16–9.11 (m, 2H), 8.56 (d, 1H, J = 4.58 Hz),
8.49 (d, 1H, J = 6.06 Hz), 8.01 (d, 1H, J = 1.34 Hz), 7.74 (dd, 1H,
J = 1.32, 6.08 Hz), 6.91 (d, 1H, J = 4.62 Hz), 4.22 (q, 2H,
J = 4.72 Hz), 3.65–3.61 (m, 2H), 3.47–3.45 (m, 2H), 1.27 (t, 3H,
J = 4.47); 13C NMR (50 MHz, DMSO-d6): 161.19, 158.20, 156.04,
144.67, 140.51, 138.38, 127.45, 126.51, 120.81, 116.65, 99.47,
62.95, 42.78, 38.33, 14.70; Anal. Calcd for C15H16ClN3O3: C,
55.99; H, 5.01; N, 13.06. Found: C, 56.03; H, 4.98; N, 13.11.
2973, 1585, 1216, 763 cmÀ1 1H NMR (200 MHz, CDCl3): d (ppm)
;
8.51 (d, 1H, J = 5.37 Hz), 7.94 (d, 1H, J = 2.02 Hz), 7.75 (d, 1H,
J = 8.92 Hz), 7.34 (dd, 1H, J = 1.86, 8.89 Hz), 6.39 (d, 1H,
J = 5.35 Hz), 5.82 (br s, 1H), 3.27 (br s, 2H), 3.11–3.18 (m, 4H);
13C NMR (50 MHz, DMSO-d6): 156.13, 144.71, 140.52, 138.43,
127.41, 126.55, 120.74, 117.06, 99.39, 42.94, 38.12; Anal. Calcd
for C11H12ClN3: C, 59.60; H, 5.46; N, 18.95. Found: C, 59.62; H,
5.51; N, 18.91.
5.3.2. Ethyl 2-(3-(7-chloroquinolin-4-ylamino)propylamino)-2-
oxoacetate (3b)
5.1.2. N1-(7-Chloroquinolin-4-yl)propane-1,3-diamine (2b)
Yield: 88%; mp 96–98 °C; ESMS: 236 (M+1); IR (KBr) 3379,
Yield: 72%; mp 140–142 °C; ESMS: 336 (M+1); IR (KBr) 3402,
;
3020,1751, 1615, 1447, 1216, 762 cmÀ1 1H NMR (200 MHz,
3019, 1587, 1216, 762 cmÀ1
; d
1H NMR (200 MHz, CDCl3):
DMSO-d6): d (ppm) 9.31–9.27 (m, 1H), 9.17–9.02 (m, 1H), 8.59–
8.51 (m, 2H), 8.02 (d, 1H, J = 2.03 Hz), 7.73 (dd, 1H, J = 1.94,
8.98 Hz), 6.82 (d, 1H, J = 6.98 Hz), 4.19 (q, 2H, J = 7.09 Hz), 3.49–
3.37 (m, 2H), 3.31–3.21 (m, 2H), 1.91–1.84 (m, 2H), 1.27 (t, 3H,
J = 4.82); 13C NMR (50 MHz, DMSO-d6): 161.11, 158.17, 156.02,
144.65, 140.52, 138.33, 127.46, 126.47, 120.84, 116.59, 99.43,
62.87, 42.83, 39.13, 28.14, 14.91; Anal. Calcd for C16H18ClN3O3: C,
57.23; H, 5.40; N, 12.51. Found: C, 57.27; H, 5.37; N, 12.53.
(ppm) 8.47 (d, 1H, J = 5.32 Hz), 7.92 (d, 1H, J = 1.98 Hz), 7.71
(d, 1H, J = 8.89 Hz), 7.37 (br s, 1H), 7.28 (dd, 1H, J = 1.92,
8.84 Hz), 6.34 (d, 1H, J = 5.37 Hz), 3.47–3.28 (m, 2H), 3.11–3.02
(m, 2H), 2.74 (br s, 2H), 1.97–1.93 (m, 2H); 13C NMR (50 MHz,
DMSO-d6): 155.96, 144.38, 140.26, 138.17, 127.21, 126.37,
120.43, 117.13, 98.87, 42.19, 40.63. 30.65; Anal. Calcd for
C12H14ClN3: C, 61.15; H, 5.99; N, 17.83. Found: C, 61.19; H,
5.94; N, 17.89.
5.3.3. Ethyl 2-(4-(2-(7-chloroquinolin-4-
5.2. General procedure for the synthesis of compounds 2c, 2d
ylamino)ethyl)piperazin-1-yl)-2-oxoacetate (3c)
Yield: 75%; mp 178–180 °C; ESMS: 391 (M+1); IR (KBr) 3450,
3022, 2950, 1754, 1652, 1562, 1423, 1216, 762 cmÀ1 1H NMR
;
A mixture of 4,7-dichloroquinoline (1 equiv) and N-aminoethyl
piperazine/piperazine (5 equiv) in MeOH were refluxed for 5 h.
After completion of reaction the solvent was evaporated under
vacuum and solid mass was extracted with water and ethylacetate.
The organic layer was evaporated under vacuum and the solid was
purified with column chromatography to obtain compounds 2c,
2d, respectively.
(300 MHz, CDCl3): d (ppm) 8.69 (d, 1H, J = 5.13 Hz), 8.09 (d, 1H,
J = 2.11 Hz), 7.86–7.79 (m, 2H), 7.53 (dd, 1H, J = 2.06, 8.83 Hz),
6.87 (d, 1H, J = 5.09 Hz), 4.08 (q, 2H, J = 8.11 Hz), 3.48 (t, 2H,
J = 6.02 Hz), 3.51–3.39 (m, 4H), 2.93–2.81 (m, 4H), 2.71 (t, 2H,
J = 6.59 Hz), 1.13 (t, 3H, J = 6.71 Hz); 13C NMR (75 MHz, CDCl3):
161.02, 160.72, 156.33, 151.22, 149.91, 135.02, 128.91, 125.91,

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N. Sunduru et al. / Bioorg. Med. Chem. 17 (2009) 6451–6462
124.72, 123.32, 110.12, 63.72, 61.31, 56.72, 55.73, 40.93, 16.72;
Anal. Calcd for C19H23ClN4O3: C, 58.38, H, 5.93; N, 14.33. Found:
C, 58.34; H, 5.98; N, 14.31.
5.4.4. N1-(2-(7-Chloroquinolin-4-ylamino)ethyl)-N2-(2-
(diethylamino)ethyl)oxalamide (7)
Yield: 68%; mp 92–94 °C; ESMS: 392 (M+1); IR (KBr) 3340,
2970, 1672, 1585, 1506, 1207, 766 cmÀ1 1H NMR (200 MHz,
;
5.3.4. Ethyl 2-(4-(7-chloroquinolin-4-yl)piperazin-1-yl)-2-
oxoacetate (3d)
CDCl3): d (ppm) 8.51 (d, 1H, J = 5.36 Hz), 8.08 (br s, 2H), 7.93 (d,
1H, J = 2.08 Hz), 7.74 (d, 1H, J = 8.96 Hz), 7.33 (dd, 1H, J = 2.12,
8.93 Hz), 6.33 (d, 1H, J = 5.42 Hz), 6.26 (br s, 1H), 3.81–3.72 (m,
2H), 3.52–3.44 (m, 2H), 3.39–3.30 (m, 2H), 2.64–2.52 (m, 6H)
1.04 (t, 6H, J = 7.12 Hz); 13C NMR (50 MHz, CDCl3): 161.26,
160.06, 151.84, 150.37, 149.12, 135.62, 128.42, 125.86, 121.96,
118.03, 99.04, 51.61, 47.52, 44.68, 39.76, 37.92, 13.83; Anal. Calcd
for C19H26ClN5O2: C, 58.23; H, 6.69; N, 17.87. Found: C, 58.19; H,
6.72; N, 17.91.
Yield: 73%; mp 190–192 °C; ESMS: 348 (M+1); IR (KBr) 3432,
3019, 2962, 1754, 1652, 1570, 1438, 1216, 762 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d (ppm) 8.72 (d, 1H, J = 5.05 Hz), 8.07 (d, 1H,
J = 1.79 Hz), 7.86 (d, 1H, J = 9.01 Hz), 7.57 (dd, 1H, J = 2.11,
8.65 Hz), 6.83 (d, 1H, J = 5.05 Hz), 4.11 (q, 2H, J = 8.11 Hz), 4.03 (t,
2H, J = 6.78 Hz), 3.99 (t, 2H, J = 6.71 Hz), 3.47–3.31 (m, 4H), 1.19
(t, 3H, J = 6.58 Hz); 13C NMR (75 MHz, CDCl3): 161.31, 160.42,
156.73, 152.01, 150.53, 135.42, 129.32, 126.64, 125.14, 123.72,
111.14, 63.92, 53.73, 45.82, 17.33; Anal. Calcd for C17H18ClN3O3:
C, 58.71; H, 5.22; N, 12.08. Found: C, 58.76; H, 5.26; N, 12.13.
5.4.5. N1-(2-(7-Chloroquinolin-4-ylamino)ethyl)-N2-(2-
(dimethylamino)ethyl)oxalamide (8)
Yield: 71%; mp 112–114 °C; ESMS: 364 (M+1); IR (KBr) 3306,
2943, 1656, 1582, 1525, 1222, 769 cmÀ1 1H NMR (200 MHz,
;
5.4. General procedure for the synthesis of compounds (4–26)
DMSO-d6): d (ppm) 9.01 (br s, 1H), 8.58 (t, 1H, J = 5.82 Hz), 8.39
(d, 1H, J = 5.41 Hz), 8.19 (d, 1H, J = 9.14 Hz), 7.77 (d, 1H,
J = 2.18 Hz), 7.45 (dd, 1H, J = 2.18, 8.86 Hz), 7.42 (br s, 1H), 6.61
(d, 1H, J = 5.48 Hz), 3.39–3.33 (m, 4H), 3.27–3.17 (m, 2H), 2.36 (t,
2H, J = 6.47 Hz), 2.15 (s, 6H); 13C NMR (50 MHz, DMSO-d6):
161.28, 160.58, 152.67, 151.01, 149.74, 134.40, 128.23, 125.10,
124.81, 118.28, 99.62, 58.22, 45.73, 42.47, 38.31, 37.54; Anal. Calcd
for C17H22ClN5O2: C, 56.12; H, 6.09; N, 19.25. Found: C, 58.15; H,
6.11; N, 19.23.
A mixture of 3a–3d and different amines (1.5 equiv) listed in
Table 1 were refluxed in n-BuOH at 120 °C in the steal bomb for
8 h. The solvent was removed under reduced pressure and the solid
mass was purified by column chromatography over silica gel using
CHCl3/MeOH as the eluent to yield the compounds 4–26.
5.4.1. N1-(2-(7-Chloroquinolin-4-ylamino)ethyl)-N2-(2-
morpholinoethyl)oxalamide (4)
Yield: 76%; mp 173–175 °C; ESMS: 406 (M+1); IR (KBr) 3297,
5.4.6. N1-(3-(7-Chloroquinolin-4-ylamino)propyl)-N2-(2-
morpholinoethyl)oxalamide (9)
2924, 1657, 1584, 1529, 1226, 773 cmÀ1 1H NMR (200 MHz,
;
CDCl3): d (ppm) 8.52 (d, 1H, J = 5.36 Hz), 8.03 (br s, 1H), 7.94 (d,
1H, J = 2.12 Hz), 7.86 (br s, 1H), 7.73 (d, 1H, J = 8.96 Hz), 7.36 (dd,
1H, J = 2.14, 8.94 Hz), 6.35 (d, 1H, J = 5.42 Hz), 6.18 (br s, 1H),
3.82–3.71 (m, 6H), 3.53–3.37 (m, 4H), 2.56–2.44 (m, 6H); 13C
NMR (50 MHz, CDCl3): 161.18, 160.86, 152.51, 151.12, 149.65,
134.57, 128.17, 125.09, 124.96, 118.41, 99.63, 67.15, 57.71, 53.89,
41.02, 37.76, 36.91; Anal. Calcd for C19H24ClN5O3: C, 56.22; H,
5.96; N, 17.25. Found: C, 56.25; H, 6.01; N, 17.22.
Yield: 74%; mp 166–168 °C; ESMS: 420 (M+1); IR (KBr) 3422,
3020, 1658, 1583, 1519, 1216, 762 cmÀ1 1H NMR (200 MHz,
;
DMSO-d6):
d (ppm) 8.91 (t, 1H, J = 6.02 Hz), 8.58 (t, 1H,
J = 5.99 Hz), 8.37 (d, 1H, J = 5.44 Hz), 8.22 (d, 1H, J = 9.02 Hz), 7.77
(d, 1H, J = 2.21 Hz), 7.45 (dd, 1H, J = 2.24, 8.98 Hz), 7.37 (t, 1H,
J = 5.07 Hz), 6.46 (d, 1H, J = 5.54 Hz), 3.53 (t, 4H, J = 4.63 Hz),
3.32–3.19 (m, 6H), 2.50–2.46 (m, 2H), 2.41–2.33 (m, 4H), 1.89–
1.78 (m, 2H); 13C NMR (50 MHz, DMSO-d6): 161.01, 160.73,
152.42, 151.02, 149.55, 134.44, 128.06, 125.04, 124.91, 118.28,
99.49, 67.05, 57.62, 53.99, 40.72, 37.62, 36.79, 28.15; Anal. Calcd
for C20H26ClN5O3: C, 57.21; H, 6.24; N, 16.68. Found: C, 57.18; H,
6.21; N, 16.71.
5.4.2. N1-(2-(7-Chloroquinolin-4-ylamino)ethyl)-N2-(3-
morpholinopropyl)oxalamide (5)
Yield: 73%; mp 158–160 °C; ESMS: 420 (M+1); IR (KBr) 3344,
2924, 1668, 1580, 1495, 1205, 767 cmÀ1 1H NMR (200 MHz,
;
5.4.7. N1-(3-(7-Chloroquinolin-4-ylamino)propyl)-N2-(3-
morpholinopropyl)oxalamide (10)
CDCl3): d (ppm) 9.21 (br s, 1H), 8.51 (d, 1H, J = 5.36 Hz), 8.09 (br
s, 1H), 7.94 (d, 1H, J = 2.06 Hz), 7.75 (d, 1H, J = 8.96 Hz), 7.37 (dd,
1H, J = 2.12, 8.93 Hz), 6.42 (br s, 1H), 6.32 (d, 1H, J = 5.41 Hz),
3.88–3.72 (m, 6H), 3.51–3.39 (m, 4H), 2.55–2.48 (m, 6H) 1.76–
1.67 (m, 2H); 13C NMR (50 MHz, CDCl3): 161.19, 158.20, 156.04,
144.67, 140.50, 138.38, 127.45, 126.51, 120.80, 116.65, 99.47,
67.18, 62.95, 60.64, 42.78, 39.17, 38.33, 29.87; Anal. Calcd for
C20H26ClN5O3: C, 57.21; H, 6.24; N, 16.68. Found: C, 57.19; H,
6.21; N, 16.71.
Yield: 72%; mp 195–197 °C; ESMS: 434 (M+1); IR (KBr) 3392,
3020, 1664, 1582, 1516, 1216, 764 cmÀ1 1H NMR (200 MHz,
;
CDCl3): d (ppm) 9.31 (br s, 1H), 8.51 (d, 1H, J = 5.41 Hz), 7.95–
7.86 (m, 2H), 7.74 (br s, 1H), 7.42 (dd, 1H, J = 2.17, 8.94 Hz), 6.41
(d, 1H, J = 5.46 Hz), 6.34 (br s, 1H), 3.87 (t, 4H, J = 4.62 Hz), 3.52–
3.36 (m, 6H), 2.58–2.52 (m, 6H), 1.92–1.86 (m, 2H), 1.81–1.72
(m, 2H); 13C NMR (50 MHz, CDCl3+DMSO-d6): 165.90, 165.06,
157.03, 155.48, 154.42, 139.45, 133.06, 129.63, 128.60, 122.97,
103.74, 71.80, 62.67, 58.90, 44.75, 44.31, 41.85, 32.40, 30.10; Anal.
Calcd for C21H28ClN5O3: C, 58.13; H, 6.50; N, 16.14. Found: C,
58.09; H, 6.48; N, 16.21.
5.4.3. N1-Butyl-N2-(2-(7-chloroquinolin-4-
ylamino)ethyl)oxalamide (6)
Yield: 71%; mp 178–180 °C; ESMS: 349 (M+1); IR (KBr) 3312,
3020, 1666, 1578, 1518, 1216, 762 cmÀ1 1H NMR (200 MHz,
;
5.4.8. N1-Butyl-N2-(3-(7-chloroquinolin-4-
ylamino)propyl)oxalamide (11)
CDCl3): d (ppm) 8.51 (d, 1H, J = 5.34 Hz), 8.08 (br s, 1H), 7.94 (d,
1H, J = 2.06 Hz), 7.71 (d, 1H, J = 8.96 Hz), 7.49 (br s, 1H), 7.36 (dd,
1H, J = 2.08, 8.92 Hz), 6.33 (d, 1H, J = 5.41 Hz), 6.18 (br s, 1H),
3.80–3.72 (m, 2H), 3.52–3.44 (m, 2H), 3.37–3.27 (m, 2H), 1.60–
1.49 (m, 2H) 1.33–1.28 (m, 2H), 0.92 (t, 3H, J = 7.17 Hz); 13C NMR
(50 MHz, CDCl3): 161.17, 160.74, 152.56, 151.08, 149.62, 134.53,
128.09, 125.17, 124.86, 118.52, 96.78, 46.26, 42.13, 39.91, 33.14,
21.76, 14.07; Anal. Calcd for C17H21ClN4O2: C, 58.53; H, 6.07; N,
16.06. Found: C, 58.56; H, 6.11; N, 16.03.
Yield: 71%; mp 146–148 °C; ESMS: 363 (M+1); IR (KBr) 3384,
3016, 1668, 1582, 1520, 1222, 762 cmÀ1 1H NMR (200 MHz,
;
CDCl3): d (ppm) 9.26 (br s, 1H), 8.52 (d, 1H, J = 5.36 Hz), 7.94 (d,
1H, J = 2.14 Hz), 7.89 (d, 1H, J = 8.97 Hz), 7.51 (br s, 1H), 7.39 (dd,
1H, J = 2.14, 8.86 Hz), 6.39–6.29 (m, 2H), 3.51–3.44 (m, 2H),
3.38–3.19 (m, 6H), 1.89–1.77 (m, 2H), 1.35–1.28 (m, 2H), 0.93 (t,
3H, J = 7.13 Hz); 13C NMR (50 MHz, CDCl3): 161.21, 160.82,

N. Sunduru et al. / Bioorg. Med. Chem. 17 (2009) 6451–6462
6457
152.61, 151.03, 149.63, 135.02, 128.16, 125.27, 124.88, 117.76,
99.43, 43.19, 40.86, 39.13, 35.28, 28.16, 22.03, 14.11; Anal. Calcd
for C18H23ClN4O2: C, 59.58; H, 6.39; N, 15.44. Found: C, 59.62; H,
6.37; N, 15.47.
NMR (300 MHz, CDCl3): d (ppm) 8.73 (d, 1H, J = 5.18 Hz), 8.11 (d,
1H, J = 2.09 Hz), 7.95–7.90 (m, 2H), 7.52–7.42 (m, 2H), 6.87 (d,
1H, J = 5.06 Hz), 3.53–3.47 (m, 2H), 3.37–3.30 (m, 6H), 2.93–2.81
(m, 4H,), 2.72 (t, 2H, J = 6.01 Hz), 1.81–1.74 (m, 2H), 1.51–1.26
(m, 2H), 0.91 (t, 3H, J = 7.26 Hz); 13C NMR (75 MHz, CDCl3):
159.92, 159.71, 156.91, 151.72, 149.93, 135.02, 128.73, 126.13,
125.12, 121.82, 108.92, 56.24, 52.72, 52.01, 39.43, 36.24, 31.23,
19.91, 13.62; Anal. Calcd for C21H28ClN5O2: C, 60.35; H, 6.75; N,
16.76. Found: C, 60.38; H, 6.72; N, 16.79.
5.4.9. N1-(3-(7-Chloroquinolin-4-ylamino)propyl)-N2-(2-
(diethylamino)ethyl)oxalamide (12)
Yield: 70%; mp 127–129 °C; ESMS: 406 (M+1); IR (KBr) 3298,
3060, 1652, 1580, 1516, 1213, 769 cmÀ1 1H NMR (200 MHz,
;
CDCl3): d (ppm) 8.51 (d, 1H, J = 5.44 Hz), 7.98 (br s, 1H), 7.95 (d,
1H, J = 2.12 Hz), 7.88 (d, 1H, J = 8.98 Hz), 7.76 (br s, 1H), 7.38 (dd,
1H, J = 2.15, 8.95 Hz), 6.39 (d, 1H, J = 5.51 Hz), 6.21 (br s, 1H),
3.53–3.33 (m, 6H), 2.70–2.53 (m, 6H), 1.99–1.89 (m, 2H), 1.04 (t,
6H, J = 7.12 Hz), 1.89–1.78 (m, 2H); 13C NMR (50 MHz, CDCl3):
161.38, 159.89, 151.81, 150.46, 149.09, 135.54, 128.47, 125.82,
122.19, 117.79, 98.97, 51.54, 47.30, 39.78, 37.89, 37.13, 28.25,
12.16; Anal. Calcd for C20H28ClN5O2: C, 59.18; H, 6.95; N, 17.25.
Found: C, 59.14; H, 6.93; N, 17.31.
5.4.14. 2-(4-(2-(7-Chloroquinolin-4-ylamino)ethyl)piperazin-1-
yl)-N-(2-(diethylamino)ethyl)-2-oxoacetamide (17)
Yield: 71%; mp 150–152 °C; ESMS: 461 (M+1); IR (KBr) 3392,
3019, 2966, 1673, 1572, 1509, 1457, 1216, 756 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d (ppm) 8.74 (d, 1H, J = 5.09 Hz), 8.56 (br s,
1H), 8.06 (d, 1H, J = 1.82 Hz), 7.96 (d, 1H, J = 9.01 Hz), 7.85 (br s,
1H), 7.45 (dd, 1H, J = 1.97, 8.85 Hz), 6.86 (d, 1H, J = 5.14 Hz),
3.51–3.41 (m, 4H), 3.38–3.27 (m, 4H), 2.86–2.79 (m, 4H), 2.28–
1.97 (m, 8H), 1.10 (t, 6H, J = 6.89 Hz); 13C NMR (75 MHz, CDCl3):
159.82, 159.33, 156.52, 151.92, 149.81, 134.94, 128.82, 126.14,
125.13, 121.72, 109.02, 56.33, 52.81, 52.03, 51.13, 46.92, 37.12,
36.24, 29.63, 11.52, 11.42; Anal. Calcd for C23H33ClN6O2: C,
59.92; H, 7.22; N, 18.23. Found: C, 59.87; H, 7.27; N,18.19.
5.4.10. N1-(3-(7-Chloroquinolin-4-ylamino)propyl)-N2-(2-
(dimethylamino)ethyl)oxalamide (13)
Yield: 72%; mp 167–169 °C; ESMS: 478 (M+1); IR (KBr) 3400,
3020, 1664, 1582, 1518, 1216, 762 cmÀ1 1H NMR (200 MHz,
;
DMSO-d6):
d (ppm) 8.91 (t, 1H, J = 5.74 Hz), 8.54 (t, 1H,
J = 5.79 Hz), 8.37 (d, 1H, J = 5.41 Hz), 8.22 (d, 1H, J = 9.04 Hz), 7.76
(d, 1H, J = 2.16 Hz), 7.44 (dd, 1H, J = 2.17, 8.97 Hz), 7.35 (br s, 1H),
6.45 (d, 1H, J = 5.48 Hz), 3.31–3.18 (m, 6H), 2.38 (t, 2H,
J = 6.47 Hz), 2.17 (s, 6H), 1.81–1.79 (m, 2H); 13C NMR (50 MHz,
CDCl3+DMSO-d6): 160.98, 160.73, 152.62, 150.91, 149.79, 134.32,
128.24, 124.97, 124.92, 118.33, 99.49, 58.22, 45.72, 40.09, 37.89,
37.62, 37.48, 28.15; Anal. Calcd for C18H24ClN5O2: C, 57.21; H,
6.40; N, 18.53. Found: C, 57.24; H, 6.39; N, 18.59.
5.4.15. 2-(4-(2-(7-Chloroquinolin-4-ylamino)ethyl)piperazin-1-
yl)-N-(2-(dimethylamino)ethyl)-2-oxoacetamide (18)
Yield: 68%; mp 130–134 °C ESMS: 433 (M+1); IR (KBr) 3415,
3020, 2971, 1674, 1572, 1511, 1459, 1216, 763 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d (ppm) 8.83 (d, 1H, J = 5.17 Hz), 8.61 (br s,
1H), 8.15 (d, 1H, J = 1.81 Hz), 8.05 (d, 1H, J = 8.69 Hz), 7.96 (br s,
1H), 7.54 (dd, 1H, J = 1.81, 8.68 Hz), 6.95 (d, 1H, J = 4.68 Hz),
3.60–3.50 (m, 4H), 3.42–3.35 (m, 4H), 2.91–2.84 (m, 4H), 2.79 (t,
2H, J = 6.11 Hz), 2.61 (t, 2H, J = 6.02 Hz), 2.36 (s, 6H,); 13C NMR
(75 MHz, CDCl3): 159.81, 159.32, 156.81, 151.94, 150.12, 134.93,
128.82, 126.14, 125.13, 121.92, 109.04, 57.54, 56.31, 52.83, 52.04,
45.14, 37.12, 36.22, 29.61; Anal. Calcd for C21H29ClN6O2: C,
58.26; H, 6.75; N, 19.41. Found: C, 58.29; H, 6.76; N, 19.43.
5.4.11. 2-(4-(2-(7-Chloroquinolin-4-ylamino)ethyl)piperazin-1-
yl)-N-(2-morpholinoethyl)-2-oxoacetamide (14)
Yield: 72%; mp 84–88 °C; ESMS: 475 (M+1); IR (KBr) 3421, 3019,
2959, 1669, 1576, 1510, 1454, 1216, 1116, 762 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d (ppm) 8.74 (d, 1H, J = 5.05 Hz), 8.66 (br s, 1H),
8.07 (d, 1H, J = 2.11 Hz), 7.96 (d, 1H, J = 9.24 Hz), 7.86 (br s, 1H),
7.45 (dd, 1H, J = 1.83, 8.68 Hz), 6.86 (d, 1H, J = 5.05 Hz), 3.84–3.81
(m, 4H), 3.53–3.42 (m, 4H), 3.37–3.29 (m, 4H), 2.87–2.79 (m, 4H),
2.72 (t, 2H, J = 5.71 Hz), 2.63–2.48 (m, 6H); 13C NMR (75 MHz,
CDCl3): 160.32, 160.21, 157.33, 152.21, 150.42, 135.32, 129.22,
126.62, 125.53, 122.32, 109.41, 58.12, 56.73, 53.22, 52.42, 39.91,
36.64, 30.12, 25.12; Anal. Calcd for C23H31ClN6O3: C, 58.16; H,
6.58; N, 17.69. Found: C, 58.21; H, 6.57; N, 17.73.
5.4.16. N-tert-Butyl-2-(4-(2-(7-chloroquinolin-4-
ylamino)ethyl)piperazin-1-yl)-2 oxoacetamide (19)
Yield: 74%; mp 98–100 °C ESMS: 418 (M+1); IR (KBr) 3424,
3021, 2970, 1641, 1521, 1430, 1216, 760 cmÀ1
;
1H NMR
(300 MHz, CDCl3+CD3OD): d (ppm) 8.74 (d, 1H, J = 5.12 Hz), 8.08
(d, 1H, J = 2.11 Hz), 8.02 (d, 1H, J = 9.01 Hz), 7.60 (dd, 1H, J = 1.81,
9.02 Hz), 7.04 (d, 1H, J = 5.06 Hz), 3.76–3.63 (m, 8H), 3.47–3.41
(m, 4H), 1.39 (s, 9H); 13C NMR (75 MHz, CDCl3): 168.12, 167.43,
159.34, 154.53, 152.32, 139.34, 131.22, 130.50, 127.91, 124.62,
112.93, 59.62, 55.21, 53.15, 51.42, 36.93, 32.90; Anal. Calcd for
C21H28ClN5O2: C, 60.35; H, 6.75; N, 16.76. Found: C, 60.32, H,
6.81, N, 16.79.
5.4.12. 2-(4-(2-(7-Chloroquinolin-4-ylamino)ethyl)piperazin-1-
yl)-N-(3-morpholinopropyl)-2-oxoacetamide (15)
Yield: 74%; mp 180–182 °C; ESMS: 489 (M+1); IR (KBr) 3402,
3019, 2968, 1669, 1509, 1454, 1216, 1116, 761 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d (ppm) 8.72 (d, 1H, J = 5.05 Hz), 8.63 (br s,
1H), 8.07 (d, 1H, J = 2.11 Hz), 7.95 (d, 1H, J = 9.12 Hz), 7.84 (br s,
1H), 7.42 (dd, 1H, J = 1.82, 8.69 Hz), 6.85 (d, 1H, J = 5.11 Hz),
3.81–3.78 (m, 4H) 3.51–3.39 (m, 4H), 3.38–3.29 (m, 4H), 2.83–
2.77 (m, 4H), 2.69 (t, 2H, J = 5.69 Hz), 2.62–2.54 (m, 6H), 1.81–
1.77 (m, 2H); 13C NMR (75 MHz, CDCl3): 160.32, 160.23, 157.32,
152.24, 150.43, 135.32, 129.21, 126.63, 125.52, 122.32, 109.42,
58.13, 56.72, 53.23, 52.43, 39.91, 36.62, 30.11, 25.12, 25.01; Anal.
Calcd for C24H33ClN6O3: C, 58.95; H, 6.80; N, 17.19. Found: C,
58.91; H, 6.77; N, 17.22.
5.4.17. N-(3-(1H-Imidazol-2-yl)propyl)-2-(4-(2-(7-
chloroquinolin-4-ylamino)ethyl)piperazin-1-yl)-2-
oxoacetamide (20)
Yield: 72%; mp 142–144 °C ESMS: 470 (M+1); IR (KBr): 3437,
3020, 2980, 1635, 1520, 1437, 1216, 1124, 768 cmÀ1 1H NMR
;
(300 MHz, CDCl3+CD3OD): d (ppm) 8.62 (d, 1H, J = 5.16 Hz), 8.01–
7.97 (m, 1H), 7.91 (d, 1H, J = 9.02 Hz), 7.61–7.53 (m, 1H), 7.42
(dd, 1H, J = 2.11, 9.01 Hz), 7.03–6.99 (m, 1H), 6.98–6.94 (m, 1H),
6.84 (d, 1H, J = 5.19 Hz), 3.98 (t, 4H, J = 5.98 Hz), 3.47 (t, 2H,
J = 5.62 Hz), 3.34–3.24 (m, 6H), 2.83–2.74 (m, 2H), 2.68 (m, 2H,
J = 5.91 Hz), 2.07–1.95 (m, 2H); 13C NMR (75 MHz, CDCl3):
157.02, 151.61, 149.81, 136.92, 135.13, 128.33, 126.32, 126.25,
125.13, 121.81, 119.54, 119.23, 109.02, 56.21, 52.74, 51.91, 44.34,
36.71, 30.61, 29.62; Anal. Calcd for C23H28ClN7O2: C, 58.78; H,
6.01; N, 20.86. Found: C, 58.81; H, 6.04; N, 20.83.
5.4.13. N-Butyl-2-(4-(2-(7-chloroquinolin-4-
ylamino)ethyl)piperazin-1-yl)-2-oxoacetamide (16)
Yield: 71%; mp 100–104 °C; ESMS: 418 (M+1); IR (KBr) 3394,
3293, 2955, 1663, 1575, 1513, 1429, 1218, 1143, 762 cmÀ1 1H
;

6458
N. Sunduru et al. / Bioorg. Med. Chem. 17 (2009) 6451–6462
5.4.18. 2-(4-(7-Chloroquinolin-4-yl)piperazin-1-yl)-N-(2-
morpholinoethyl)-2-oxoacetamide (21)
121.82, 109.32, 57.32, 52.52, 52.02, 46.22, 45.13, 42.91, 36.81;
Anal. Calcd for C19H24ClN5O2: C, 58.53; H, 6.20; N, 17.96. Found:
C, 58.57; H, 6.21; N, 17.93.
Yield: 68%; mp 118–120 °C; ESMS: 432 (M+1); IR (KBr) 3430,
3020, 2972, 1637, 1523, 1430, 1216, 1118, 761 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d (ppm) 8.67 (d, 1H, J = 5.23 Hz), 8.01–7.94 (m,
3H), 7.51 (dd, 1H, J = 1.81, 9.02 Hz), 6.94 (d, 1H, J = 5.17 Hz),
4.21–4.09 (m, 8H), 3.68–333 (m, 4H), 2.99 (t, 2H, J = 6.01 Hz),
2.89–2.81 (m, 4H), 2.59 (t, 2H, J = 6.34 Hz); 13C NMR (75 MHz,
CDCl3): 161.42, 161.12, 155.23, 153.12, 150.61, 139.32, 131.43,
130.21, 129.32, 125.62, 112.83, 61.32, 57.31, 56.74, 55.72, 40.92;
Anal. Calcd for C21H26ClN5O3: C, 58.40; H, 6.07; N, 16.21. Found:
C, 58.45; H, 6.09; N, 16.24.
5.4.23. N-tert-Butyl-2-(4-(7-chloroquinolin-4-yl)piperazin-1-
yl)-2-oxoacetamide (26)
Yield: 74%; mp 100–104 °C; ESMS: 375 (M+1); IR (KBr) 3441,
3020, 2968, 1659, 1579, 1426, 1215, 1035, 761 cmÀ1 1H NMR
;
(300 MHz, CDCl3+CD3OD): d (ppm) 8.74 (d, 1H, J = 5.05 Hz), 8.08
(d, 1H, J = 2.11 Hz), 8.02 (d, 1H, J = 9.01 Hz), 7.60 (dd, 1H, J = 1.81,
9.02 Hz), 7.04 (d, 1H, J = 5.05 Hz), 4.14–3.92 (m, 2H), 3.94–3.87
(m, 2H), 3.50 (m, 4H), 1.37 (s, 9H); 13C NMR (75 MHz, CDCl3):
168.11, 167.42, 159.32, 154.52, 152.31, 139.32, 131.24, 130.52,
127.91, 124.63, 112.91, 59.61, 55.21, 53.13, 51.41, 36.91, 32.91;
Anal. Calcd for C19H23ClN4O2: C, 60.88; H, 6.18; N, 14.95. Found:
C, 60.84; H, 6.22, N, 14.98.
5.4.19. 2-(4-(7-Chloroquinolin-4-yl)piperazin-1-yl)-N-(3-
morpholinopropyl)-2-oxoacetamide (22)
Yield: 73%; mp 194–196 °C; ESMS: 446 (M+1); IR (KBr) 3454,
3067, 2980, 1643, 1529, 1427, 1206, 1115, 761 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d (ppm) 8.75 (d, 1H, J = 5.16 Hz), 8.49 (br s,
1H), 8.07 (d, 1H, J = 2.11 Hz), 7.97 (d, 1H, J = 9.01 Hz), 7.48 (dd,
1H, J = 2.11, 9.02 Hz), 6.85 (d, 1H, J = 5.05 Hz), 4.45 (t, 2H,
J = 4.82 Hz), 3.96 (t, 2H, J = 4.81 Hz), 3.78 (t, 4H, J = 4.52 Hz),
3.44–3.37 (m, 2H), 3.31–3.26 (m, 4H), 2.52–2.48 (m, 6H), 1.84–
1.71 (m, 2H); 13C NMR (75 MHz, CDCl3):160.99, 160.96, 156.32,
151.82, 150.02, 135.23, 128.90, 126.71, 124.72, 121.71, 109.32,
66.82, 56.71, 53.32, 52.52, 52.01, 46.22, 43.03, 35.71; Anal. Calcd
for C22H28ClN5O3: C, 59.25; H, 6.33; N, 15.70. Found: C, 59.21; H,
6.34; N, 15.67.
5.5. General procedure for the synthesis of compounds (29–30)
A mixture of 2-(1H-indol-3-yl)-2-oxoacetyl chloride 28 (pre-
pared by the reaction of indole with oxalylchloride in dry ether
at 0 °C for 1 h, a yellow color precipitate formed is filtered and
immediately used for further reaction), 2c/2d and Et3N were reflux
at 120 °C in steal bomb for 9 h. The Solvent was removed under re-
duced pressure to yield a residue. The solid mass was purified by
column chromatography over silica gel using CHCl3/MeOH as the
eluent to yield compounds 29 and 30.
5.4.20. N-Butyl-2-(4-(7-chloroquinolin-4-yl)piperazin-1-yl)-2-
oxoacetamide (23)
5.5.1. 1-(4-(2-(7-Chloroquinolin-4-ylamino)ethyl)piperazin-1-
yl)-2-(1H-indol-3-yl)ethane-1,2-dione (29)
Yield: 70%; mp 110–112 °C; ESMS: 375 (M+1); IR (KBr) 3338,
Yield: 75%; mp 182–184 °C; ESMS: 462 (M+1); IR (KBr) 3371,
3075, 2955, 1673, 1642, 1570, 1427, 1381, 1210, 1160, 771 cmÀ1
;
3061, 2943, 1681, 1620, 1573, 1492, 1239, 786 cmÀ1 1H NMR
;
1H NMR (300 MHz, CDCl3): d (ppm) 8.75 (d, 1H, J = 5.05 Hz), 8.09
(d, 1H, J = 1.82 Hz), 7.96 (d, 1H, J = 9.01 Hz), 7.49 (dd, 1H, J = 2.11,
9.02 Hz), 7.32 (br s, 1H), 6.85 (d, 1H, J = 5.16 Hz), 4.50 (t, 2H,
J = 4.82 Hz), 3.96 (t, 2H, J = 4.81 Hz), 3.35–3.26 (m, 6H), 1.61–1.51
(m, 2H), 1.45–1.32 (m, 2H), 0.97 (t, 3H, J = 6.92 Hz); 13C NMR
(75 MHz, CDCl3): 160.91, 160.72, 156.32, 151.72, 150.01, 135.21,
128.90, 126.61, 124.72, 121.71, 109.32, 57.32, 52.62, 52.01, 46.32,
43.12, 39.21, 31.22, 20.02, 13.61; Anal. Calcd for C19H23ClN4O2: C,
60.88; H, 6.18; N, 14.95. Found: C, 60.86; H, 6.21; N, 14.98.
(300 MHz, CDCl3+CD3OD): d (ppm) 8.97 (s, 1H), 8.66 (d, 1H,
J = 5.12 Hz), 8.41–8.38 (m, 1H), 8.01–7.95 (m, 2H), 7.49–7.44 (m,
2H), 7.36–7.28 (m, 3H), 6.91 (d, 1H, J = 5.09 Hz), 3.59 (t, 2H,
J = 6.01 Hz), 3.38–3.33 (m, 4H), 2.85–2.75 (m, 6H); 13C NMR
(75 MHz, CDCl3): 184.52, 167.41, 161.53, 155.11, 153.03, 142.90,
140.32, 139.32, 131.32, 130.61, 130.23, 129.43, 127.72, 126.93,
125.81, 125.62, 116.71, 116.02, 112.81, 60.32, 56.62, 55.71,
39.82; Anal. Calcd for C25H24ClN5O2: C, 65.00; H, 5.24; N, 15.16.
Found: C, 65.04; H, 5.29; N, 15.13.
5.4.21. 2-(4-(7-Chloroquinolin-4-yl)piperazin-1-yl)-N-(2-
(diethylamino)ethyl)-2-oxoacetamide (24)
5.5.2. 1-(4-(7-Chloroquinolin-4-yl)piperazin-1-yl)-2-(1H-indol-
3-yl)ethane-1,2-dione (30)
Yield: 73%; mp 168–170 °C ESMS: 418 (M+1); IR (KBr) 3452,
Yield: 77% mp 190–194 °C; ESMS: 419 (M+1); IR (KBr): 3420,
3020, 2973, 1629, 1500, 1426, 1216, 1046, 761 cmÀ1
;
1H NMR
3020, 2926, 1643, 1577, 1530, 1442, 1216, 762 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d (ppm) 8.75 (d, 1H, J = 4.81 Hz), 8.07 (d, 1H,
J = 1.81 Hz), 7.97 (d, 1H, J = 9.02 Hz), 7.83 (br s, 1H) 7.48 (dd, 1H,
J = 1.81, 8.69 Hz), 6.85 (d, 1H, J = 4.81 Hz), 4.38 (m, 2H), 3.94 (m,
2H), 3.41–3.39 (m, 2H), 3.25 (m, 4H), 2.69–2.59 (m, 6H), 1.13 (t,
6H, J = 6.89 Hz); 13C NMR (75 MHz, CDCl3): 161.22, 161.12,
156.32, 151.91, 150.02, 135.23, 128.90, 126.61, 124.72, 121.71,
109.32, 52.52, 52.02, 51.13, 46.24, 42.92, 36.91, 11.51; Anal. Calcd
for C21H28ClN5O2: C, 60.35; H, 6.75; N, 16.76. Found: C, 60.31; H,
6.78; N, 16.73.
(300 MHz, CDCl3+CD3OD): d (ppm) 8.97 (s, 1H), 8.66 (d, 1H,
J = 5.18 Hz), 8.41–8.38 (m, 1H), 8.01–7.95 (m, 2H), 7.49–7.44 (m,
2H), 7.36–7.28 (m, 2H), 6.91 (d, 1H, J = 5.12 Hz), 3.97 (t, 2H,
J = 4.81 Hz), 3.79 (t, 2H, J = 5.05 Hz), 3.39 (t, 2H, J = 4.82 Hz) 3.22
(t, 2H, J = 4.82 Hz); 13C NMR (75 MHz, CDCl3): 188.11, 169.32,
159.52, 154.01, 151.72, 140.02, 138.32, 130.11, 129.41, 127.62,
127.22, 126.32, 125.42, 124.11, 124.05, 116.31, 114.72, 112.01,
54.91, 54.41, 48.72, 44.22; Anal. Calcd for C23H19ClN4O2: C,
65.95; H, 4.57; N, 13.38. Found: C, 65.97; H, 4.53; N, 13.41.
5.4.22. 2-(4-(7-Chloroquinolin-4-yl)piperazin-1-yl)-N-(2-
(dimethylamino)ethyl)-2-oxoacetamide (25)
5.6. General procedure for the synthesis of compounds (31–34)
Yield: 72%; mp158–160 °C; ESMS: 390 (M+1); IR (KBr) 3236,
The solution of methyl iodide/p-toluenesulphonyl chloride
(1.5 equiv) in DCM was added dropwise to an ice-cold mixture of
hybrid quinoline–indoles (29, 30), NaOH and phasetransfer cata-
lyst in DCM during 30 min. The reaction mixture was stirred at
0 °C for 1 h and consequently at room temperature for 1 h. Solvent
was removed under reduced pressure and solid was extracted with
water and DCM. Organic layer was separated and dried over anhy-
drous Na2SO4, concentrated. The residue was purified by column
3195, 2988, 1676, 1574, 1426, 1379, 1230, 1189, 775 cmÀ1 1H
;
NMR (300 MHz, CDCl3): d (ppm) 8.75 (d, 1H, J = 5.21 Hz), 8.07 (d,
1H, J = 2.11 Hz), 7.97 (d, 1H, J = 9.01 Hz), 7.68 (br s, 1H) 7.49 (dd,
1H, J = 2.02, 9.02 Hz), 6.86 (d, 1H, J = 5.19 Hz), 4.41 (t, 2H,
J = 4.81 Hz), 3.46–3.40 (m, 2H), 3.37–3.29 (m, 6H), 2.56 (t, 2H,
J = 6.02 Hz), 2.31 (s, 6H); 13C NMR (75 MHz, CDCl3): 161.19,
161.02, 156.31, 151.92, 150.12, 135.12, 129.02, 126.62, 124.73,

N. Sunduru et al. / Bioorg. Med. Chem. 17 (2009) 6451–6462
6459
chromatography over silica gel using CHCl3/MeOH as the eluent to
yield the desired compounds 31–34.
mixture was filtered and solvent was evaporated under vacuum to
dryness. The solid mass was dissolved in CHCl3, washed with water
and dried over anhydrous Na2SO4, concentrated, and purified with
column chromatography to afford respective compounds 36 and 37.
5.6.1. 1-(4-(2-(7-Chloroquinolin-4-ylamino) ethyl)piperazin-1-
yl)-2-(1-methyl-1H-indol-3-yl)ethane-1,2-dione (31)
Yield: 73%; mp 164–166 °C; ESMS: 476 (M+1); IR (KBr): 3397,
5.7.1. 2,4-Dichloro-6-(piperidin-1-yl)-1,3,5-triazine (36)
3020, 2974, 1672, 1623, 1504, 1466, 1426, 1216, 761 cmÀ1
;
1H
Yield: 84%; mp 176–178 °C; ESMS: 233 (M+1); IR (KBr) 2945,
NMR (300 MHz, CDCl3): d (ppm) 8.98 (s, 1H), 8.73 (d, 1H,
J = 4.82 Hz), 8.44–8.41 (m, 1H), 8.06 (d, 1H, J = 2.11 Hz), 7.96–
7.93 (m, 2H), 7.44–7.33 (m, 4H), 6.87 (d, 1H, J = 5.02 Hz), 3.92 (s,
3H), 3.60–3.54 (m, 2H), 3.31–3.29 (m, 4H), 2.84–2.73 (m, 6H);
13C NMR (75 MHz, CDCl3): 179.81, 162.62, 156.81, 151.72, 50.02,
141.91, 137.02, 134.91, 128.90, 127.61, 126.12, 125.02, 123.81,
123.42, 122.61, 121.81, 112.02, 109.73, 109.02, 56.53, 52.81,
52.12, 35.92, 33.71; Anal. Calcd for C26H26ClN5O2: C, 65.61; H,
5.51; N, 14.71. Found: C, 65.65; H, 5.54; N, 14.67.
1574, 1472, 1217, 765 cmÀ1 1H NMR (200 MHz, CDCl3): d (ppm)
;
3.81 (t, 4H, J = 5.18 Hz), 1.68–1.59 (m, 6H); 13C NMR (50 MHz,
CDCl3): 170.54, 164.43, 45.74, 26.06, 24.63; Anal. Calcd for
C8H10Cl2N4: C, 41.22; H, 4.32; N, 24.04. Found: C, 41.26; H, 4.29;
N, 24.11.
5.7.2. 4-(4,6-Dichloro-1,3,5-triazin-2-yl)morpholine (37)
Yield: 82%; mp 154–156 °C; ESMS: 235 (M+1); IR (KBr) 2968,
1576, 1477, 1219, 763 cmÀ1 1H NMR (200 MHz, CDCl3): d (ppm)
;
3.91 (t, 4H, J = 3.21 Hz), 3.76(t, 4H, J = 3.18 Hz); 13C NMR
(50 MHz, CDCl3): 170.83, 164.50, 66.77, 44.88; Anal. Calcd for
C7H8Cl2N4O: C, 35.77; H, 3.43; N, 23.83. Found: C, 35.69; H, 3.37;
N, 23.85.
5.6.2. 1-(4-(2-(7-Chloroquinolin-4-ylamino)ethyl)piperazin-1-
yl)-2-(1-tosyl-1H-indol-3-yl)ethane-1,2-dione (32)
Yield: 71%; mp 144–148 °C ESMS: 616 (M+1); IR (KBr): 3380,
3022, 2978, 1675, 1620, 1500, 1465, 1420, 1216, 765 cmÀ1 1H
;
NMR (300 MHz, CDCl3): d (ppm), 9.35 (s, 1H), 8.65 (d, 1H,
J = 4.52 Hz), 8.31 (d, 1H, J = 6.91 Hz), 8.01–7.85 (m, 6H), 7.43–
7.25 (m, 5H), 6.85 (d, 1H, J = 4.81), 3.93–3.89 (m, 2H), 3.54–3.30
(m, 4H), 2.77–2.62 (m, 6H), 2.24 (s, 3H); 13C NMR (75 MHz, CDCl3):
179.72, 162.22, 157.02, 151.51, 150.02, 141.32, 139.03, 136.51,
134.42, 134.01, 131.92, 128.41, 127.12, 126.52, 125.32, 124.31,
123.3, 123.0, 122.12, 121.51, 112.02, 109.71, 109.12, 56.23, 52.63,
51.71, 35.24, 23.71; Anal. Calcd for C32H30ClN5O4S: C, 62.38; H,
4.91; N, 11.37. Found: C, 62.34; H, 4.97; N, 11.35.
5.8. General procedure for the synthesis of compounds 38–57
The mixture of compounds 36/37 (1 equiv) and 2a/2b (1 equiv)
and K2CO3 (1 equiv) in dry THF was stirred at room temperature
for 4 h. Subsequently the different amines (1.5 equiv) listed in
and K2CO3 (1 equiv) were added to the reaction and stirred at
80 °C for 6 h additionally. The reaction mixture was filtered and
the solvent was evaporated under vacuum. The solid residue was
purified with column chromatography using silica gel as adsorbent
to obtain respective compounds 38–57.
5.6.3. 1-(4-(7-Chloroquinolin-4-yl)piperazin-1-yl)-2-(1-methyl-
1H-indol-3-yl)ethane-1,2-dione (33)
5.8.1. N2-(2-(7-Chloroquinolin-4-ylamino)ethyl)-N4-(3-
morpholinopropyl)-6-(piperidin-1-yl)-1,3,5-triazine-2,4-
diamine (38)
Yield: 71%; mp 178–180 °C; ESMS: 433 (M+1); IR (KBr) 3432,
3027, 2928, 1650, 1579, 1543, 1445, 1216, 765 cmÀ1 1H NMR
;
(300 MHz, CDCl3+CD3OD): d (ppm) 8.67 (d, 1H, J = 5.12 Hz), 8.29–
8.26 (m, 1H), 8.02–7.99 (m, 3H), 7.52–7.48 (m, 2H), 7.34–7.31
(m, 2H), 6.96 (d, 1H, J = 5.05 Hz), 4.08–4.05 (m, 2H), 3.84–3.81
(m, 2H), 3.41 (t, 2H, J = 4.79 Hz), 3.35 (s, 3H) 3.29 (t, 2H,
J = 4.81 Hz); 13C NMR (75 MHz, CDCl3): 188.51, 169.91, 160.02,
154.31, 152.21, 140.21, 138.72, 130.71, 129.82, 128.21, 127.90,
127.12, 126.14, 124.62, 124.52, 116.92, 115.21, 112.43, 55.11,
54.82, 49.12, 44.34, 33.61; Anal. Calcd for C24H21ClN4O2: C,
66.59; H, 4.89; N, 12.94. Found: C, 66.57; H, 4.93; N, 12.91.
Yield: 70%; mp 163–165 °C; ESMS: 526 (M+1); IR (KBr) 3366,
2927, 1611, 1562, 1455, 1370, 1214, 1109, 808, 762 cmÀ1 1H
;
NMR (200 MHz, CDCl3): d (ppm) 8.44 (d, 1H, J = 5.48 Hz), 7.92 (d,
1H, J = 2.01 Hz), 7.58–7.56 (m, 1H), 7.34–7.21 (m, 2H), 6.26 (d,
1H, J = 5.42 Hz), 5.42 (br s, 1H), 5.34 (br s, 1H), 3.93–3.69 (m,
10H), 3.52–3.29 (m, 4H), 2.59–2.42 (m, 6H), 1.93–1.71 (m, 8H);
13C NMR (50 MHz, CDCl3): 167.81, 165.05, 151.67, 151.17,
149.14, 135.34, 128.34, 125.37, 122.88, 117.49, 98.50, 67.38,
63.07, 57.76, 54.11, 51.33, 44.71, 39.47, 34.67, 26.23, 25.21; Anal.
Calcd for C26H36ClN9O: C, 59.36; H, 6.90; N, 23.96. Found: C,
59.33; H, 6.94; N, 23.91.
5.6.4. 1-(4-(7-Chloroquinolin-4-yl)piperazin-1-yl)-2-(1-tosyl-
1H-indol-3-yl)ethane-1,2-dione (34)
Yield: 69%; mp 150–152 °C; ESMS: 573 (M+1); IR (KBr) 3423,
5.8.2. N2-(2-(7-Chloroquinolin-4-ylamino)ethyl)-N4-(2-
(diethylamino)ethyl)-6-(piperidin-1-yl)-1,3,5-triazine-2,4-
diamine (39)
3020, 2926, 1643, 1577, 1530, 1442, 1216, 762 cmÀ1 1H NMR
;
(200 MHz, CDCl3): d (ppm), 8.74 (d, 1H, J = 4.94 Hz), 8.41 (s, 1H),
8.38–8.27 (m, 1H), 8.06 (d, 1H, J = 2.02 Hz), 7.94–7.85 (m, 4H),
7.47–7.25 (m, 5H), 6.86 (d, 1H, J = 4.95 Hz), 4.08–4.04 (m, 2H),
3.84–3.79 (m, 2H), 3.36–3.24 (m, 4H), 2.38 (s, 3H); 13C NMR
(50 MHz, CDCl3): 179.72, 162.21, 157.03, 151.53, 150.01, 141.32,
139.04, 136.52, 134.41, 134.04, 131.92, 128.40, 127.12, 126.52,
125.33, 124.31, 123.33, 123.01, 122.13, 121.52, 112.01, 109.71,
109.10, 54.91, 54.31, 48.64, 44.03, 33.25; Anal. Calcd for
C30H25ClN4O4S: C, 62.88; H, 4.40; N, 9.78. Found: C, 62.84; H,
4.43; N, 9.76.
Yield: 68%; mp 81–83 °C; ESMS: 498 (M+1); IR (KBr) 3424, 3020,
1582, 1540, 1445, 1367, 1216, 1141, 806, 768 cmÀ1 1H NMR
;
(200 MHz, CDCl3): d (ppm) 8.45 (d, 1H, J = 5.34 Hz), 7.91 (d, 1H,
J = 1.84 Hz), 7.63–7.59 (m, 1H), 7.25–7.21 (m, 2H), 6.27 (d, 1H,
J = 5.41 Hz), 5.59 (br s, 2H), 3.83–3.77 (m, 6H), 3.51–3.42 (m, 4H),
2.66–2.49 (m, 6H), 1.69–1.52 (m, 6H), 1.05 (t, 6H, J = 7.11 Hz); 13C
NMR (50 MHz, CDCl3): 167.92, 164.97, 151.47, 151.26, 148.83,
135.41, 127.95, 125.44, 122.94, 117.51, 98.52, 52.25, 47.31, 44.84,
39.41, 38.52, 30.09, 26.23, 25.19, 11.48; Anal. Calcd for C25H36ClN9:
C, 60.29; H, 7.29; N, 25.31. Found: C, 60.26; H, 7.34; N, 25.27.
5.7. General procedure for the synthesis of compounds 36, 37
5.8.3. N2-(2-(7-Chloroquinolin-4-ylamino)ethyl)-N4-(2-
(dimethylamino)ethyl)-6-(piperidin-1-yl)-1,3,5-triazine-2,4-
diamine (40)
The solution of piperidine/morpholine (1 equiv) in dry THF was
added dropwise to an ice-cold mixture of cyanuric chloride
(1.5 equiv) and K2CO3 (1 equiv) in dry THF during 30 min. The reac-
tion mixture was stirred at room temperature for 1 h. The reaction
Yield: 71%; mp 127–129 °C; ESMS: 470 (M+1); IR (KBr) 3417,
3020, 1580, 1535, 1450, 1216, 1112, 806, 762 cmÀ1 1H NMR
;

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N. Sunduru et al. / Bioorg. Med. Chem. 17 (2009) 6451–6462
(200 MHz, CDCl3): d (ppm) 8.46 (d, 1H, J = 5.46 Hz), 7.92 (d, 1H,
J = 2.11 Hz), 7.57–7.51 (m, 1H), 7.35–7.22 (m, 2H), 6.28 (d, 1H,
J = 5.52 Hz), 5.49 (br s, 2H), 3.77–3.68 (m, 6H), 3.48–3.41 (m, 4H),
2.51–2.42 (m, 2H), 2.28 (s, 6H), 1.71–1.59 (m, 6H); 13C NMR
(50 MHz, CDCl3+CD3OD): 172.44, 164.73, 151.56, 151.02, 147.96,
135.75, 127.14, 125.57, 122.85, 117.37, 98.51, 58.77, 45.34, 44.84,
39.14, 38.28, 30.01, 26.12, 25.05; Anal. Calcd for C23H32ClN9: C,
58.77; H, 6.86; N, 26.82. Found: C, 58.75; H, 6.91; N, 26.85.
5.8.8. N2-(2-(7-Chloroquinolin-4-ylamino)ethyl)-N4-(2-
(dimethylamino)ethyl)-6-morpholino-1,3,5-triazine-2,4-
diamine (45)
Yield: 74%; mp 137–139 °C; ESMS: 472 (M+1); IR (KBr) 3423,
3020, 1580, 1545, 1445, 1363, 1216, 1113, 809, 763 cmÀ1 1H
;
NMR (200 MHz, CDCl3): d (ppm) 8.47 (d, 1H, J = 5.42 Hz), 7.91 (d,
1H, J = 2.08 Hz), 7.57–7.54 (m, 1H), 7.26 (dd, 1H, J = 1.86,
8.76 Hz), 6.93 (br s, 1H), 6.29 (d, 1H, J = 5.46 Hz), 5.55 (br s, 1H),
5.31 (br s, 1H), 3.79–3.71 (m, 10H), 3.49–3.42 (m, 4H), 2.62–2.54
(m, 2H), 2.27 (s, 6H); 13C NMR (50 MHz, CDCl3): 167.76, 165.87,
152.52, 150.85, 149.06, 135.51, 128.82, 126.15, 122.15, 117.81,
99.12, 67.75, 59.07, 47.93, 46.72, 44.38, 40.05, 38.38; Anal. Calcd
for C22H30ClN9O: C, 55.98; H, 6.41; N, 26.71. Found: C, 56.03; H,
6.39; N, 26.75.
5.8.4. N1-(7-Chloroquinolin-4-yl)-N2-(4-(4-methylpiperazin-1-
yl)-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)ethane-1,2-diamine (41)
Yield: 74%; mp 139–141 °C; ESMS: 482 (M+1); IR (KBr) 3265,
2931, 2850, 1585, 1528, 1443, 1364, 1279, 1141, 806, 771 cmÀ1
;
1H NMR (200 MHz, CDCl3): d (ppm) 8.47 (d, 1H, J = 5.41 Hz), 7.91
(d, 1H, J = 2.04 Hz), 7.47 (d, 1H, J = 8.92 Hz), 7.26–7.21 (m, 1H),
7.09 (br s, 1H), 6.28 (d, 1H, J = 5.44 Hz), 5.21 (t, 1H, J = 6.65 Hz),
3.87–3.72 (m, 10H), 3.43–3.38 (m, 2H), 2.49–2.36 (m, 4H), 2.31
(s, 3H), 1.71–1.53 (m, 6H); 13C NMR (50 MHz, CDCl3): 167.91,
165.48, 152.07, 150.96, 149.08, 135.22, 128.55, 125.51, 122.58,
117.56, 98.55, 55.33, 47.09, 46.62, 44.81, 43.58, 39.42, 26.22,
25.22; Anal. Calcd for C24H32ClN9: C, 59.80; H, 6.69; N, 26.15.
Found: C, 59.84; H, 6.72; N, 26.11.
5.8.9. N1-(7-Chloroquinolin-4-yl)-N2-(4-(4-methylpiperazin-1-
yl)-6-morpholino-1,3,5-triazin-2-yl)ethane-1,2-diamine (46)
Yield: 72%; mp 161–163 °C; ESMS: 484 (M+1); IR (KBr) 3399,
3020, 2852, 1586, 1525, 1442, 1363, 1216, 1039, 812, 762 cmÀ1
;
1H NMR (200 MHz, CDCl3): d (ppm) 8.49 (d, 1H, J = 5.38 Hz), 7.92
(d, 1H, J = 2.04 Hz), 7.46 (d, 1H, J = 8.91 Hz), 7.25 (dd, 1H, J = 2.14,
8.86 Hz), 6.87 (br s, 1H), 6.31 (d, 1H, J = 5.46 Hz), 5.19 (br s, 1H),
3.88–3.73 (m, 14H), 3.45–3.41 (m, 2H), 2.52–2.42 (m, 4H), 2.32
(s, 3H); 13C NMR (50 MHz, CDCl3): 167.84, 165.48, 152.26,
150.74, 149.21, 135.18, 128.85, 125.60, 122.24, 117.57, 98.68,
67.22, 55.31, 46.85, 46.62, 44.19, 42.78, 39.47; Anal. Calcd for
C23H30ClN9O: C, 57.08; H, 6.25; N, 26.05. Found: C, 57.05; H,
6.22; N, 26.09.
5.8.5. N2-(2-(7-Chloroquinolin-4-ylamino)ethyl)-N4-(2-
morpholinoethyl)-6-(piperidin-1-yl)-1,3,5-triazine-2,4-diamine
(42)
Yield: 70%; mp 147–149 °C; ESMS: 512 (M+1); IR (KBr) 3375,
2937, 1588, 1537, 1357, 1218, 1115, 806, 767 cmÀ1 1H NMR
;
(200 MHz, CDCl3): d (ppm) 8.47 (d, 1H, J = 5.42 Hz), 7.91 (d, 1H,
J = 2.06 Hz), 7.54–7.51 (m, 1H), 7.21 (dd, 1H, J = 1.91, 8.91 Hz),
7.12 (br s, 1H), 6.28 (d, 1H, J = 5.51 Hz), 5.41 (br s, 1H), 5.27 (br s,
1H), 3.84–3.68 (m, 10H), 3.51–3.39 (m, 4H), 2.58–2.47 (m, 6H),
1.67–1.54 (m, 6H); 13C NMR (50 MHz, CDCl3): 167.89, 165.08,
151.91, 151.02, 149.68, 135.24, 128.39, 125.32, 122.59, 117.53,
98.56, 57.91, 53.85, 46.87, 44.83, 39.47, 37.53, 26.25, 25.19; Anal.
Calcd for C25H34ClN9O: C, 58.64; H, 6.69; N, 24.62. Found: C,
58.62; H, 6.73; N, 24.59.
5.8.10. N2-(2-(7-Chloroquinolin-4-ylamino)ethyl)-6-
morpholino-N4-(2-morpholinoethyl)-1,3,5-triazine-2,4-
diamine (47)
Yield: 71%; mp 148–150 °C; ESMS: 513 (M+1); IR (KBr) 3292,
2970, 1583, 1543, 1438, 1356, 1212, 1114, 809, 768 cmÀ1 1H
;
NMR (200 MHz, CDCl3): d (ppm) 8.48 (d, 1H, J = 5.38 Hz), 7.92 (d,
1H, J = 2.08 Hz), 7.53–7.51 (m, 1H), 7.26–7.21 (m, 2H), 6.31 (d,
1H, J = 5.44 Hz), 5.48 (br s, 1H), 5.32 (br s, 1H), 3.81–3.68 (m,
16H), 3.42–3.32 (m, 2H), 2.51–2.37 (m, 6H); 13C NMR (50 MHz,
CDCl3): 167.73, 165.38, 152.15, 151.27, 149.69, 135.21, 128.82,
125.49, 122.48, 117.57, 98.68, 67.31, 67.22, 53.83, 47.05, 44.38,
41.27, 39.51, 37.04; Anal. Calcd for C24H32ClN9O2: C, 56.08; H,
6.27; N, 24.52. Found: C, 56.11; H, 6.32; N, 24.49.
5.8.6. N2-(2-(7-Chloroquinolin-4-ylamino)ethyl)-6-
morpholino-N4-(3-morpholinopropyl)-1,3,5-triazine-2,4-
diamine (43)
Yield: 73%; mp 165–167 °C; ESMS: 528 (M+1); IR (KBr) 3379,
3020, 1589, 1546, 1444, 1361, 1216, 1115, 811, 763 cmÀ1; 1H NMR
(200 MHz, CDCl3): d (ppm) 8.47 (d, 1H, J = 5.36 Hz), 7.91 (d, 1H,
J = 2.11 Hz), 7.54–7.49 (m, 1H), 7.26–7.21 (m, 2H), 6.28 (d, 1H,
J = 5.28 Hz), 5.37 (br s, 1H), 5.31 (br s, 1H), 3.72–3.66 (m, 16H),
3.41–3.32 (m, 2H), 2.45–2.36 (m, 6H), 1.86–1.67 (m, 2H); 13C NMR
(50 MHz, CDCl3): 167.81, 165.54, 152.25, 150.76, 149.27, 135.06,
128.72, 125.25, 123.15, 117.59, 98.62, 67.37, 67.19, 58.03, 54.09,
46.58, 44.07, 40.67, 39.51, 30.08; Anal. Calcd for C25H34ClN9O2: C,
56.86; H, 6.49; N, 23.87. Found: C, 56.83; H, 6.51; N, 23.84.
5.8.11. N2-(3-(7-Chloroquinolin-4-ylamino)propyl)-N4-(3-
morpholinopropyl)-6-(piperidin-1-yl)-1,3,5-triazine-2,4-
diamine (48)
Yield: 71%; mp 127–129 °C; ESMS: 540 (M+1); IR (KBr) 3445,
3020, 1579, 1540, 1446, 1364, 1216, 1117, 810, 762 cmÀ1; 1H NMR
(200 MHz, CDCl3): d (ppm) 8.49 (d, 1H, J = 5.38 Hz), 7.93 (d, 1H,
J = 2.09 Hz), 7.66 (d, 1H, J = 7.36 Hz), 7.29 (dd, 1H, J = 2.12,
9.04 Hz), 7.25 (br s, 1H), 6.39 (d, 1H, J = 5.46 Hz), 5.51 (br s, 1H),
5.11 (br s, 1H), 3.69–3.52 (m, 10H), 3.48–3.36 (m, 4H), 2.43–2.36
(m, 6H), 2.08–1.94 (m, 2H), 1.76–1.51 (m, 8H); 13C NMR (50 MHz,
CDCl3): 167.13, 164.95, 151.99, 150.51, 149.14, 135.31, 128.65,
125.54, 121.95, 117.73, 99.29, 67.37, 57.52, 54.11, 44.52, 41.14,
40.12, 38.61, 29.13, 26.51, 26.20, 25.26; Anal. Calcd for C27H38ClN9O:
C, 60.04; H, 7.09; N, 23.34. Found: C, 59.97; H, 7.06; N, 23.31.
5.8.7. N2-(2-(7-Chloroquinolin-4-ylamino)ethyl)-N4-(2-
(diethylamino)ethyl)-6-morpholino-1,3,5-triazine-2,4-diamine
(44)
Yield: 71%; mp 119–121 °C; ESMS: 500 (M+1); IR (KBr) 3280,
2971, 1587, 1544, 1434, 1276, 1113, 810, 767 cmÀ1 1H NMR
;
(200 MHz, CDCl3): d (ppm) 8.48 (d, 1H, J = 5.41 Hz), 7.91 (d, 1H,
J = 2.02 Hz), 7.54–7.51 (m, 1H), 7.25 (dd, 1H, J = 2.09, 8.41 Hz),
7.09 (br s, 1H), 6.29 (d, 1H, J = 5.39 Hz), 5.56 (br s, 1H), 5.29 (br s,
1H), 3.79–3.72 (m, 10H), 3.62–3.41 (m, 4H), 2.64–2.54 (m, 6H),
1.02 (t, 6H, J = 7.11 Hz); 13C NMR (50 MHz, CDCl3): 167.61,
165.53, 152.09, 150.81, 149.12, 135.16, 128.56, 125.39, 122.42,
117.57, 98.61, 67.20, 52.20, 47.14, 46.48, 44.13, 39.47, 38.85,
11.85; Anal. Calcd for C24H34ClN9O: C, 57.65; H, 6.85; N, 25.21.
Found: C, 57.63; H, 6.79; N, 25.18.
5.8.12. N2-(3-(7-Chloroquinolin-4-ylamino)propyl)-N4-(2-
(diethylamino)ethyl)-6-(piperidin-1-yl)-1,3,5-triazine-2,4-
diamine (49)
Yield: 68%; mp 80–82 °C; ESMS: 512 (M+1); IR (KBr) 3418,
3019, 1580, 1540, 1446, 1366, 1216, 1114, 813, 768 cmÀ1 1H
;
NMR (200 MHz, CDCl3): d (ppm) 8.48 (d, 1H, J = 5.41 Hz), 7.92 (d,
1H, J = 2.01 Hz), 7.71–7.63 (m, 1H), 7.38–7.27 (m, 2H), 6.41 (d,
1H, J = 5.43 Hz), 5.53 (br s, 2H), 3.76–3.67 (m, 4H), 3.58–3.47 (m,

N. Sunduru et al. / Bioorg. Med. Chem. 17 (2009) 6451–6462
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6H), 2.68–2.54 (m, 6H), 2.05–1.98 (m, 2H), 1.61–1.51 (m, 6H), 1.08
(t, 6H, J = 7.09 Hz); 13C NMR (50 MHz, CDCl3+CD3OD): 169.33,
168.39, 157.57, 151.01, 147.97, 141.57, 130.51, 128.48, 127.52,
120.93, 102.93, 64.49, 52.15, 48.51, 44.93, 42.16, 33.93, 31.97,
30.02, 29.01, 13.54; Anal. Calcd for C26H38ClN9: C, 60.98; H, 7.48;
N, 24.62. Found: C, 60.97; H, 7.44; N, 24.59.
5.8.17. N2-(3-(7-Chloroquinolin-4-ylamino)propyl)-N4-(2-
(diethylamino)ethyl)-6-morpholino-1,3,5-triazine-2,4-diamine
(54)
Yield: 71%; mp 134–136 °C; ESMS: 514 (M+1); IR (KBr) 3423,
3020, 1580, 1543, 1438, 1362, 1216, 1045, 806, 763 cmÀ1 1H
;
NMR (200 MHz, CDCl3): d (ppm) 8.43 (d, 1H, J = 5.37 Hz), 7.89 (d,
1H, J = 2.03 Hz), 7.74 (d, 1H, J = 8.41 Hz), 7.42–7.26 (m, 2H), 6.32
(d, 1H, J = 5.43 Hz), 5.51 (br s, 1H), 4.92 (br s, 1H), 3.79–3.64 (m,
8H), 3.51–3.39 (m, 6H), 2.61–2.55 (m, 6H), 2.02–1.94 (m, 2H),
1.02 (d, 6H, J = 7.03 Hz); 13C NMR (50 MHz, CDCl3): 167.53,
165.47, 151.83, 150.69, 149.23, 135.39, 128.44, 125.32, 122.63,
118.03, 99.08, 67.32, 53.19, 47.18, 46.57, 43.92, 40.06, 38.19,
28.34, 12.15; Anal. Calcd for C25H36ClN9O: C, 58.41; H, 7.06; N,
24.52. Found: C, 58.39; H, 7.11; N, 24.54.
5.8.13. N2-(3-(7-Chloroquinolin-4-ylamino)propyl)-N4-(2-
(dimethylamino)ethyl)-6-(piperidin-1-yl)-1,3,5-triazine-2,4-
diamine (50)
Yield: 70%; mp 87–89 °C; ESMS: 484 (M+1); IR (KBr) 3432,
3021, 1583, 1542, 1446, 1365, 1216, 1084, 808, 762 cmÀ1 1H
;
NMR (200 MHz, CDCl3): d (ppm) 8.49 (d, 1H, J = 5.37 Hz), 7.92 (d,
1H, J = 2.06 Hz), 7.59–7.51 (m, 1H), 7.36–7.28 (m, 2H), 6.39 (d,
1H, J = 5.39 Hz), 5.52 (br s, 2H), 3.81–3.52 (m, 10H), 2.75–2.59
(m, 2H), 2.29 (s, 6H), 2.07–1.92 (m, 2H), 1.69–1.56 (m, 6H); 13C
NMR (50 MHz, CDCl3+CD3OD): 169.34, 168.23, 158.28, 149.77,
146.67, 142.21, 130.86, 128.76, 126.44, 120.67, 102.52, 62.66,
48.54, 48.26, 42.09, 41.33, 33.92, 31.87, 30.01, 28.99; Anal. Calcd
for C24H34ClN9: C, 59.55; H, 7.08; N, 26.04. Found: C, 59.57; H,
7.11; N, 26.09.
5.8.18. N2-(3-(7-Chloroquinolin-4-ylamino)propyl)-N4-(2-
(dimethylamino)ethyl)-6-morpholino-1,3,5-triazine-2,4-
diamine (55)
Yield: 74%; mp 123–125 °C; ESMS: 486 (M+1); IR (KBr) 3383,
3020, 1586, 1541, 1444, 1356, 1216, 1117, 806, 764 cmÀ1; 1H NMR
(200 MHz, CDCl3): d (ppm) 8.28 (d, 1H, J = 5.44 Hz), 7.84 (d, 1H,
J = 2.12 Hz), 7.74 (d, 1H, J = 8.73 Hz), 7.35–7.26 (m, 2H), 6.39 (d,
1H, J = 5.39 Hz), 5.56 (br s, 2H), 3.82–3.62 (m, 8H), 3.54–3.32 (m,
6H), 2.71 (t, 2H, J = 5.61 Hz), 2.44 (s, 6H), 1.95–1.87 (m, 2H); 13C
NMR (50 MHz, CDCl3): 167.19, 165.03, 151.52, 150.36, 148.97,
135.42, 128.15, 125.26, 121.91, 117.78, 98.73, 67.43, 58.97, 47.69,
46.53, 44.27, 41.49, 40.07, 30.14; Anal. Calcd for C23H32ClN9O: C,
56.84; H, 6.64; N, 25.94. Found: C, 56.81; H, 6.67; N, 25.92.
5.8.14. N1-(7-Chloroquinolin-4-yl)-N3-(4-(4-methylpiperazin-1-
yl)-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)propane-1,3-diamine
(51)
Yield: 74%; mp 217–219 °C; ESMS: 484 (M+1); IR (KBr) 3440,
3067, 2850, 1579, 1546, 1443, 1365, 1218, 1138, 808, 765 cmÀ1
;
1H NMR (200 MHz, CDCl3): d (ppm) 8.51 (d, 1H, J = 5.06 Hz), 7.93
(d, 1H, J = 1.89 Hz), 7.53 (d, 1H, J = 8.86 Hz), 7.31–7.26 (m, 2H),
6.39 (d, 1H, J = 5.34 Hz), 5.42 (br s, 1H), 3.75–3.53 (m, 10H),
3.49–3.42 (m, 2H), 2.59–2.35 (m, 4H), 2.31 (s, 3H), 2.03–1.96 (m,
2H), 1.67–1.53 (m, 6H); 13C NMR (50 MHz, CDCl3+CD3OD):
168.37, 167.98, 154.46, 154.14, 151.42, 138.73, 130.08, 128.57,
125.66, 120.43, 101.93, 58.01, 49.05, 47.54, 45.93, 44.07, 41.63,
31.66, 29.04, 28.11; Anal. Calcd for C25H34ClN9: C, 60.53; H, 6.91;
N, 25.41. Found: C, 60.49; H, 6.87; N, 25.47.
5.8.19. N1-(7-Chloroquinolin-4-yl)-N3-(4-(4-methylpiperazin-1-
yl)-6-morpholino-1,3,5-triazin-2-yl)propane-1,3-diamine (56)
Yield: 74%; mp 119–121 °C; ESMS: 498 (M+1); IR (KBr) 3442,
3020, 2855, 1613, 1536, 1441, 1364, 1216, 1093, 815, 763 cmÀ1
;
1H NMR (200 MHz, CDCl3): d (ppm) 8.53 (d, 1H, J = 5.39 Hz),
8.35–8.19 (m, 2H), 7.29–7.26 (m, 1H), 7.04 (br s, 1H), 6.38 (d, 1H,
J = 5.36 Hz), 5.41 (br s, 1H), 3.94–3.55 (m, 16H), 2.47–2.39 (m,
4H), 2.32 (s, 3H), 2.04–1.92 (m, 2H); 13C NMR (50 MHz, CDCl3):
167.37, 165.24, 152.03, 150.84, 149.51, 135.42, 128.63, 125.31,
121.78, 117.82, 98.76, 67.15, 55.46, 46.81, 46.59, 44.26, 42.07,
40.11, 29.72; Anal. Calcd for C24H32ClN9O: C, 57.88; H, 6.48; N,
25.31. Found: C, 57.91; H, 6.47; N, 25.36.
5.8.15. N2-(3-(7-Chloroquinolin-4-ylamino)propyl)-N4-(2-
morpholinoethyl)-6-(piperidin-1-yl)-1,3,5-triazine-2,4-diamine
(52)
Yield: 70%; mp 102–104 °C; ESMS: 526 (M+1); IR (KBr) 3317,
2931, 1581, 1505, 1443, 1361, 1282, 1115, 806, 771 cmÀ1; 1H NMR
(200 MHz, CDCl3): d (ppm) 8.49 (d, 1H, J = 5.42 Hz), 7.95 (d, 1H,
J = 1.92 Hz), 7.73–7.69 (m, 1H), 7.31 (dd, 1H, J = 2.14, 8.91 Hz), 7.28
(br s, 1H), 6.41 (d, 1H, J = 5.48 Hz), 5.47 (br s, 1H), 5.37 (br s, 1H),
3.68–3.52 (m, 10H), 3.47–3.31 (m, 4H), 2.53–2.45 (m, 6H), 2.01–
1.95 (m, 2H), 1.62–1.42 (m, 6H); 13C NMR (50 MHz, CDCl3): 166.37,
164.71, 151.01, 150.12, 148.21, 135.71, 127.83, 125.73, 122.38,
117.57, 99.13, 67.31, 57.82, 53.82, 44.59, 41.13, 38.58, 37.45,
28.96, 26.21, 25.22; Anal. Calcd for C26H36ClN9O: C, 59.36; H, 6.90;
N, 23.96. Found: C, 59.39; H, 6.87; N, 23.92.
5.8.20. N2-(3-(7-Chloroquinolin-4-ylamino)propyl)-6-
morpholino-N4-(2-morpholinoethyl)-1,3,5-triazine-2,4-
diamine (57)
Yield: 71%; mp 124–126 °C; ESMS: 528 (M+1); IR (KBr) 3422,
3020, 1615, 1545, 1442, 1362, 1216, 1114, 817, 763 cmÀ1 1H
;
NMR (200 MHz, CDCl3): d (ppm) 8.48 (d, 1H, J = 5.38 Hz), 7.91 (d,
1H, J = 2.11 Hz), 7.58–7.52 (m, 1H), 7.37–7.28 (m, 2H), 6.38 (d,
1H, J = 5.34 Hz), 5.3 (br s, 2H), 3.81–3.53 (m, 12H), 3.47–3.41 (m,
6H), 2.54–2.38 (m, 6H), 2.03–1.85 (m, 2H); 13C NMR (50 MHz,
CDCl3): 167.21, 165.74, 151.87, 150.47, 149.72, 135.32, 128.63,
125.44, 121.29, 117.56, 99.31, 67.54, 67.39, 54.02, 47.46, 44.27,
41.83, 40.27, 28.92; Anal. Calcd for C25H34ClN9O2: C, 56.86; H,
6.49; N, 23.87. Found: C, 56.83; H, 6.47; N, 23.91.
5.8.16. N2-(3-(7-Chloroquinolin-4-ylamino)propyl)-6-
morpholino-N4-(3-morpholinopropyl)-1,3,5-triazine-2,4-
diamine (53)
Yield: 73%; mp 109–111 °C; ESMS: 542 (M+1); IR (KBr) 3379,
3020, 1589, 1547, 1439, 1356, 1216, 1112, 809, 762 cmÀ1 1H
;
6. Biological materials and methods
6.1. In vitro antimalarial assay
NMR (200 MHz, CDCl3): d (ppm) 8.51 (d, 1H, J = 5.42 Hz), 7.89 (d,
1H, J = 1.93 Hz), 7.52 (d, 1H, J = 8.76 Hz), 7.39–7.28 (m, 2H), 6.41
(d, 1H, J = 5.39 Hz), 5.37 (br s, 2H), 3.82–3.57 (m, 12H), 3.47–3.39
(m, 6H), 2.57–2.41 (m, 6H), 2.03–1.89 (m, 2H), 1.73–1.54 (m,
2H); 13C NMR (50 MHz, CDCl3): 166.97, 165.23, 151.54, 150.27,
149.16, 135.57, 128.46, 125.13, 122.36, 117.41, 98.89, 67.43,
67.19, 59.13, 54.72, 47.51, 44.03, 40.92, 38.97, 30.03, 26.76; Anal.
Calcd for C26H36ClN9O2: C, 57.61; H, 6.69; N, 23.26. Found: C,
57.64; H, 6.73; N, 23.21.
The compounds were dissolved in DMSO at 5 mg/mL. For the
assays, fresh dilutions of all compounds in screening medium were
prepared and 50 lL of highest starting concentration (500 ng/mL)
was dispensed in duplicate wells in row B of 96 well tissue culture
plate. The highest concentration for chloroquine was 25 ng/mL.
Subsequently two fold serial dilutions were prepared up to row

6462
N. Sunduru et al. / Bioorg. Med. Chem. 17 (2009) 6451–6462
H (seven concentrations). Finally 50 lL of 2.5% parasitized cell sus-
Acknowledgements
pension containing 0.5% parasitaemia was added to each well ex-
cept four wells in row A which received non infected cell
suspension. These wells containing non infected erythrocytes in
the absence of drugs served as negative controls, while parasitized
erythrocytes in the presence of CQ served as positive control. After
N.S. thanks the Council of Scientific and Industrial Research, In-
dia, for the award of Senior Research Fellowship and M.S. thanks
the Indian Council of Medical Research (ICMR) for providing finan-
cial support. We are also thankful to S.A.I.F. Division, CDRI, Luc-
know, for providing spectroscopic data. Thanks are also due to
Mr. M. P. S. Negi, Division of Biometry & Statistics, CDRI for data
analysis. CDRI Communication No. 7760.
72 h of incubation, 100 lL of lysis buffer [20 mM tris (Ph 7.5),
5 mM EDTA, 0.008% (wt/vol) saponin, and 0.08% (vol/vol) Triton
X-100] containing 1 Â concentration of SYBER Green I (Invitrogen)
was added to each cell.23 The plates were re-incubated for 1 h at
room temperature and examined for the relative fluorescence units
(RFUs) per well using the FLUOstar, BMG lab technologies. The 50%
inhibitory concentration (IC50) was determined using non-linear
regression analysis dose–response curves.
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Male swiss mice, weighing 15–20 g were inoculated with
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6.3. Cytotoxicity assay
Cytotoxicityof the compounds was determined against VERO cell
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cells/well were incubated with varying concentrations of compound
for 72 h. The highest concentration of compound was 100 lg/mL.
MTT was used as reagent for the detection of cytotoxicity.25 50%
cytotoxic concentration (CC50) values represented the concentration
of compound required to kill 50% of the fibroblast cells.
Selectivity Index (SI): CC50/IC50
.
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the untreated control group. Mice treated with CQ served as
reference controls.26
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