Synthesis of new 4-aminoquinolines and quinoline-acridine hybrids as antimalarial agents

Article abstract of DOI:10.1016/j.bmcl.2010.09.107

Despite emergence of resistance to CQ and other 4-aminoquinoline drugs in most of the endemic regions, research findings provide considerable support that there is still significant potential to discover new affordable, safe, and efficacious 4-aminoquinol

Full text of DOI:10.1016/j.bmcl.2010.09.107

Bioorganic & Medicinal Chemistry Letters 20 (2010) 7059–7063
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of new 4-aminoquinolines and quinoline–acridine hybrids
as antimalarial agents
Ashok Kumar a, Kumkum Srivastava b, S. Raja Kumar b, S. K. Puri b, Prem M. S. Chauhan a,
⇑
a Division of Medicinal & Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India
b Division of Parasitology, Central Drug Research Institute, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2010
Revised 17 September 2010
Accepted 21 September 2010
Available online 27 September 2010
Despite emergence of resistance to CQ and other 4-aminoquinoline drugs in most of the endemic regions,
research findings provide considerable support that there is still significant potential to discover new
affordable, safe, and efficacious 4-aminoquinoline antimalarials. In present study, new side chain modi-
fied 4-aminoquinoline derivatives and quinoline–acridine hybrids were synthesized and evaluated
in vitro against NF 54 strain of Plasmodium falciparum. Among the evaluated compounds, compound
17 (MIC = 0.125
lg/mL) was equipotent to standard drug CQ (MIC = 0.125 lg/mL) and compound 21
Keywords:
Antimalarial
4-Aminoquinoline
Quinoline–acridine
Plasmodium falciparum
Plasmodium yoelii
(MIC = 0.031 g/mL) was four times more potent than CQ. Compound 17 showed the curative response
l
to all the treated swiss mice infected with CQ-resistant N-67 strain of Plasmodium yoelii at the doses
50 mg/kg and 25 mg/kg for four days by intraperitoneal route and was found to be orally active at the
dose of 100 mg/kg for four days. The promising antimalarial potency of compound 17 highlights the sig-
nificance of exploring the privileged 4-aminoquinoline class for new antimalarials.
Ó 2010 Published by Elsevier Ltd.
Despite the extensive research efforts, malaria continues to ex-
ert the tremendous burden on the health and economies of devel-
oping countries. It is estimated that 40% population of the world is
exposed to the malaria, killing more than 2 million people every
year.1 Malaria caused by Plasmodium falciparum is the most fatal
and accounts for 95% mortality.2 Since the discovery of natural
product quinine, structural modifications of its quinoline pharma-
cophore led to the development of most effective antimalarial
agents namely chloroquine (CQ, 1), amodiaquine (AQ, 2), and mef-
loquine (3) (Fig. 1).3,4 The wide-spread resistance to 4-aminoquin-
olines and antifolates has seriously limited the therapeutic options.
Therefore, there is urgency to develop new affordable, safe, and
efficacious antimalarilas.5 Although the resistance to CQ and re-
lated 4-aminoquinoline antimalarial drugs has emerged; designing
new antimalarial based on the quinoline pharmacophore has dis-
tinct advantages due to unique pharmacological effect of 4-amino-
quinoline drugs.6
process, thus substantial build up of heme lead to the parasite
death.9 Despite the persistent heavy drug pressure of CQ for several
decades, the delayed emergence of resistance to CQ is considered
due to the complexity of digestive vacuole environment and the
immutable nature of heme target. Multiple point mutations in
P. falciparum chloroquine resistance transporter protein (pfcrt) con-
ferred resistance to CQ characterized by the substantially reduced
accumulation of CQ level in food vacuole. Interaction of CQ with pfcrt
induces resistance very slowly to P. falciparum owing to the com-
plexity in amino acid substitutions in pfcrt.10
OH
N
N
HN
HN
Cl
N
Cl
N
During the erythrocyte stage, malaria parasite invade the red
blood cell of human host, digest and degrade a huge amount of
hemoglobin as a source of amino acids, consequently releasing toxic
heme as a by product.7 Heme detoxification crucial for parasite sur-
vival is a unique non-enzymatic efficient process characterized by
conversion of free heme into non-toxic crystalline pigment hemo-
zoin.8 CQ and other related drugs block the heme detoxification
CQ, 1
AQ, 2
HO
HN
N
N
N
H
N
N
Cl
N
CF3
CF3
⇑
Corresponding author. Tel.: +91 522 221 2411x4332; fax: +91 522 262 3405.
E-mail addresses: prem_chauhan_2000@yahoo.com, premsc58@hotmail.com
Mefloquine, 3
Compound 17
(P.M.S. Chauhan).
Figure 1. Structures of CQ (1), AQ (2), mefloquine (3), and target compound 17.
0960-894X/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2010.09.107

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A. Kumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7059–7063
The structure–activity relationship studies on CQ–Heme bind-
not allow drug efflux by the proteinaceous transporter.19,20 Though
bisquinolines such as Ro 47-773720 and other piperaquine, hydrox-
ypiperaquine and dichloroquinazine21 exhibited promising anti-
malarial efficacy but toxic liabilities ruled out their development
as drug candidate. In addition, bisacridine derivatives with di-,
tri-, and tetramine linker have been investigated for their effect
on the antimalarial activity.22 Hybridization of the 4-aminoquino-
line and 9-amino acridine with 1,2,4-trioxanes produced the anti-
malarials exhibiting the low nM potency.23
As part of research program devoted to the synthesis of nitrogen
heterocycles as antimalarials, our group has identified potential
quinoline-based antimalarials.24 In view of this background, we
have synthesized the side chain modified 4-aminoquinolines and
quinoline–acridine hybrids and screened in vitro against NF 54
strain of P. falciparum. Selected compounds were also subjected
to in vivo study against CQ-resistant strain of Plasmodium yoelii.
New side chain modified 4-aminoquinoline derivatives (12–23)
were synthesized by a synthetic route as described in Scheme 1.
Starting compounds, substituted aryl/heteroaryl piperazines
(4–7) were synthesized by aromatic nucleophilic substitution reac-
tion of aryl/heteroaryl substrates with piperazine under appropri-
ate reaction conditions, depending upon the nature of substrates.
ing have been explored in order to identify the key structural
requirement for designing the new antimalarial agents. It was well
established that the 7-chloro-4-aminoquinoline nucleus is quintes-
sential for the inhibition of heme polymerization and parasite
growth.11 Moreover, the basic nature of the side chain is crucial
for accumulation of drug within the acidic food vacuole of the par-
asite.12 Several studies demonstrated that various structurally di-
verse modifications in the side chain of CQ were well tolerated
for the antimalarial activity. Systematic variation of the branching
and basicity of the side chain of CQ yielded the new 4-aminoquin-
oline derivatives exhibiting excellent potency against CQ-sensitive
and CQ-resistant strains.13 Replacement of diethylamino function
of CQ with tert-butyl or cyclic amines such as piperidine, morpho-
line furnished the metabolically stable potent antimalarials.14,15
Incorporation of guanidines,16 and intramolecular hydrogen-
bonding motif like
a
-aminocresols17 in the side chain produced
the new potential antimalarials. More recently, the 4-aminoquino-
line carrying dimethylaminomethyl substituted phenyl ring, phen-
ylequine (PQ) has been identified as potent antimalarial.18
To overcome the resistance, the bulky bisquinolines were
designed embodying the hypothesis that steric hindrance would
R1
NH
R1
Y
N
i
4, X = CH; R1 = NO2; R2 = H
X
5, X = CH; R1 = NO2; R2 = CH3
X
6, X = N; R1 = H, R2 = H
R2
R2
7, X = N; R1 = NO2, R2 = H
X = N, CH; Y = Cl, F
R1 = H, NO2; R2 = H, CH3
OH
Cl
( )n
NH
ii
8, n = 1
Cl
N
Cl
Cl
N
iii
9, n = 2
O
O
S
O
( )n
NH
N
10, n = 1
11, n = 2
iv
CN
R1
N
N
N
R2
( )n
NH
N
X
( )n
NH
N
N
( )n
NH
N
Cl
Cl
20, n = 1
22, n = 1
Cl
21, n = 2
23, n = 2
12, n = 1; X = CH; R1 = NO2; R2 = H
13, n = 2; X = CH; R1 = NO2; R2 = H
14, n = 1; X = CH; R1 = NO2; R2 = CH3
15, n = 2; X = CH; R1 = NO2; R2 = CH3
16, n = 1; X = N; R1 = H, R2 = H
17, n = 2; X = N;
R
1 = H, R2 = H
18, n = 1; X = N; R1 = NO2, R2 = H
19, n = 2; X = N; R1 = NO2, R2 = H
Scheme 1. Reagents and conditions: (i) piperazine, THF, 0 °C to rt, 3 h; (ii) 2-amino ethanol or 3-amino-propan-1-ol, n-butanol, 100 °C, 8 h; (iii) methanesulfonyl chloride, dry
pyridine, 0 °C, 3 h; (iv) amines, NMP, MW, 30 s.

A. Kumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7059–7063
7061
Condensation of 4,7-dichloroquinoline with 2-amino-ethanol and
3-amino-propan-1-ol in presence of Et3N afforded the 2-(7-
chloro-quinolin-4-ylamino)-ethanol 8 and 3-(7-chloro-quinolin-
4-ylamino)-propan-1-ol 9.25 The chemoselective o-mesylation of
8 and 9 was done in pyridine at 0 °C for 5 h to achieve the
methanesulfonic acid 2-(7-chloro-quinolin-4-ylamino)-ethyl ester
10 and methanesulfonic acid 3-(7-chloro-quinolin-4-ylamino)-
propyl ester 11, respectively.26 Compounds 10 and 11 were sub-
jected to nucleophilic substitution with substituted aryl/heteroaryl
piperazines, tetrahydroisoquinoline and 4-cyano-4-aryl-piperidine
under microwave condition to yield the targeted new 4-amino-
quinolines (12–23).
The synthetic strategy for the synthesis of hybrid quinoline–
acridine derivatives (29, 30, 33, 34) is outlined in Scheme 2.
Amination of 4,7-dichloroquinoline with piperazine (6 equiv) in
n-butanol at 100 °C for 10 h furnished the 7-chloro-4-piperazin-
1-yl-quinoline 24. Condensation of 6,9-dichloro-2-methoxy-acri-
dine with 2-amino-ethanol and 3-amino-propan-1-ol (10 equiv)
was carried out in n-butanol to afford the 2-(6-chloro-2-meth-
oxy-acridin-9-ylamino)-ethanol 25 and 3-(6-chloro-2-methoxy-
acridin-9-ylamino)-propan-1-ol 26, respectively.25 Compounds 25
and 26 were further underwent chemoselective o-mesylation at
0 °C in THF to obtain the corresponding methanesulfonic acid
2-(6-chloro-2-methoxy-acridin-9-ylamino)-ethyl ester 27 and
methanesulfonic acid 3-(6-chloro-2-methoxy-acridin-9-ylamino)-
propyl ester 28. Compounds 27 and 28 were subjected to nucleo-
philic substitution with the 7-chloro-4-piperazin-1-yl-quinoline
24 to yield the hybrid quinoline–acridine (6-chloro-2-methoxy-
acridin-9-yl)-{2-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-ethyl}-
amine 29 and (6-chloro-2-methoxy-acridin-9-yl)-{2-[4-(7-chloro-
quinolin-4-yl)-piperazin-1-yl]-propyl}-amine 30, respectively.
Coupling of 4,7-dichloroquinoline with p-phenylenediamine and
m-phenylenediamine in presence of catalyst p-TSA in absolute eth-
anol furnished the N-(7-chloro-quinolin-4-yl)-benzene-1,4-dia-
mine 31 and N-(7-chloro-quinolin-4-yl)-benzene-1,3-diamine 32,
respectively.27 Compounds 31 and 32 were further subjected to
nucleophilic substitution with 6,9-dichloro-2-methoxy-acridine
in absolute ethanol using catalyst p-TSA to yield the hybrids
H
N
Cl
N
N
i
Cl
N
Cl
24
O
O
S
O
OMe
OH
( )n
Cl
N
( )n
HN
N
HN
N
OMe
OMe
ii
iii
Cl
Cl
Cl
27, n = 1
28, n = 2
25, n = 1
26, n = 2
N
N
N
( )n
HN
N
Cl
OMe
iv
Cl
MeO
29, n = 1
30, n = 2
H
N
N
HN
NH2
HN
v
vii
Cl
Cl
N
31
Cl
N
33
Cl
MeO
Cl
N
HN
NH2
HN
N
H
N
vi
viii
Cl
N
Cl
N
Cl
32
34
Scheme 2. Reagents and conditions: (i) piperazine, n-butanol, 100 °C, 10 h; (ii) 2-amino-ethanol or 3-amino-propan-1-ol, n-butanol, 100 °C, 8 h; (iii) methanesulfonyl
chloride, dry THF, 0 °C, 3 h; (iv) 7-chloro-4-piperazin-1-yl-quinoline, NMP, MW, 30 s; (v) p-phenylenediamine, EtOH, p-TSA, 3 h; (vi) m-phenylenediamine, EtOH, p-TSA, 3 h;
(vii) 6,9-dichloro-2-methoxy-acridine, EtOH, p-TSA, 4 h.

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A. Kumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7059–7063
quinoline–acridine
N-(6-chloro-2-methoxy-acridin-9-yl)-N0-(7-
Table 2
In vivo antimalarial activities of representative compounds against CQ-resistant N-67
strain of P. yoelii in swiss mice
chloro-quinolin-4-yl)-benzene-1,4-diamine 33 and N-(6-chloro-2-
methoxy-acridin-9-yl)-N0-(7-chloro-quinolin-4-yl)-benzene-1,3-
diamine 34, respectively. All the synthesized compounds were well
characterized by IR, mass, NMR, and elemental analysis.28
Compound
Dose
(mg/kg ꢀ 4 days)
% Suppression
on day 4a
Mice alive
on day 28
17
50 (ip)
25 (ip)
100 (oral)
50 (ip)
50 (ip)
100
100
100
100
100
5/5
5/5
5/5
0/5
0/5
The in vitro antimalarial assay was carried out in 96 well micro-
titer plates according to the micro assay of Rieckmann.29 The cul-
ture of P. falciparum NF-54 strain is routinely being maintained
in medium RPMI-1640 supplemented with 25 mM HEPES, 1%
21
34
D
-glucose, 0.23% sodium bicarbonate and 10% heat inactivated
a
Percent suppression = [(C ꢁ T)/C] ꢀ 100; where C = parasitemia in control group
human serum.30 The asynchronous parasite of P. falciparum was
and T = parasitemia in treated group.
synchronized after 5% D-Sorbitol treatment to obtain parasitized
cells harboring only the ring stage.31 For carrying out the assay,
an initial ring stage parasitemia of 1% at 3% hematocrit in total vol-
ume of 200
The test compound in 20
(ranging between 0.25 g and 50
l
L of medium RPMI-1640 was uniformly maintained.
L volume at the required concentration
g/mL) in duplicate wells, were
activity. Interestingly, substitution of nitro group at the 3-position
(19) of the pyridine ring of compound 17 significantly reduced the
l
l
l
antimalarial activity from 0.125 to 10
taining ethyl linker attached to the tetrahydroisoquinoline exhib-
ited MIC value of 2 g/mL while replacement of ethyl linker (20)
with propyl linker (21) led the excellent improvement in the
antimalarial potency with MIC value of 0.031 g/mL. Compound
22 having ethyl linker attached to the 4-phenyl-piperidine-4-
carbonitrile displayed MIC value of 10 g/mL. Introduction of addi-
tional methylene unit (23) into the side chain of compound 22
improved the potency five times (20, MIC = 2 g/mL). Comparison
lg/mL. Compound 20 con-
incubated with parasitized cell preparation at 37 °C in candle jar.
After 36–40 h incubation, the blood smears from each well were
prepared and stained with giemsa stain. The slides were micro-
scopically observed to record maturation of ring stage parasites
into trophozoites and schizonts in presence of different concentra-
tions of compounds. The tested concentration, which inhibits the
complete maturation into schizonts, was recorded as the minimum
inhibitory concentration (MIC). Chloroquine was used as the stan-
dard reference drug. Activity of all the tested compounds is shown
in Table 1.
All the synthesized compounds were evaluated in vitro for their
antimalarial activity against NF 54 strain of P. falciparum. 4-Amino-
quinoline derivatives 12 and 13 containing ethyl and propyl chain
attached to the 2-nitrophenyl substituted piperazine exhibited MIC
value of 10 lg/mL. Further, substitution of methyl at the 4-position
of phenyl ring of the side chain of compound 12 and 13 resulting in
l
l
l
l
of antimalarial effects of compounds 16, 17, 20, 21, 22, and 23
clearly demonstrated that propyl linker was favorable for the anti-
malarial activity.
Quinoline–acridine hybrids 29 and 30 attached with ethylene
and propylene functionalized piperazine had MIC values of 10
mL. Compound 33 exhibiting quinoline linked to acridine with
p-phenylenediamine expressed MIC value of 0.5 g/mL while
lg/
l
replacing the p-phenyenediamine (33) with m-phenylenediamine
(34) resulted in two times improvement in the antimalarial activity.
Representative compounds (17, 21, 34) characterized by good
in vitro antimalarial activity were tested in vivo in swiss mice in-
fected with CQ-resistant N-67 strain of P. yoelii parasite (Table
2).32 Compound 17 provided 100% protection to the treated mice
at the doses of 50 and 25 mg/kg ꢀ 4 days once daily by intraperito-
neal route (ip). Further, compound 17 exhibited the curative
response to all the treated mice (5/5) when administered by oral
route at the dose of 100 mg/kg ꢀ 4 days. Compounds 21 and 34
displayed the complete clearance of parasitemia on day 4 at the
dose of 50 mg/kg ꢀ 4 days by ip route but none of mice survived
beyond day 28. The promising in vivo activity of compound 17
highlights the importance of investigating the privileged 4-amino-
quinoline class to deliver the new antimalarials. Modification
around the pyridine nucleus of compound 17 might lead to the
more potent molecules.
In conclusion, while the most of quinoline-based drugs target-
ing heme have lost their efficacy due to emergence of resistance,
modification in the side chain of CQ still can provide new afford-
able, safe, efficacious antimalarials. In present study, the side
chain modified 4-aminoquinolines and quinoline–acridine hy-
brids were synthesized and screened in vitro against NF 54 strain
of P. falciparum. Compounds 17 and 21 exhibited the good anti-
corresponding compounds 14 and 15 had no effect on the antima-
larial activity ( 14, 15, MIC = 10
derivative 16 carrying ethyl linker attached to the 1-pyridin-2-yl-
piperazine group showed MIC value of 10 g/mL while replace-
lg/mL). 4-Aminoquinoline
l
ment of ethyl linker (16) with propyl linker (17) produced the
remarkable improvement in the antimalarial potency with MIC
value of 0.125 lg/mL. Introduction of nitro group at the 3-position
(18) of the pyridine ring of compound 16 showed no effect on the
Table 1
In vitro antimalarial activity of compounds
against NF 54 strain of P. falciparum
Compound
MICa
(lg/mL)
12
13
14
15
16
17
18
19
20
21
22
23
29
30
33
34
CQ
10
10
10
10
10
0.125
10
10
2
0.031
10
2
1
1
0.5
0.25
0.125
malarial potency with MIC values of 0.125 and 0.031 lg/mL,
respectively. Compound 17 containing pyridine nucleus in the
side chain showed the curative response in swiss mice infected
with CQ-resistant strain of P. yoelii at the doses of 50 mg/kg
and 25 mg/kg for four days by ip route as well as orally active
at the dose of 100 mg/kg for four days. Considering the promising
antimalarial activity of compound 17, modifications around the
pyridine nucleus can guide to the development of more potent
compounds.
a
MIC = Minimum inhibiting concen-
tration for the development of ring stage
parasite into the schizont stage during
40 h incubation.

A. Kumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7059–7063
7063
23. Araujo, N. C. P.; Barton, V.; Jones, M.; Stocks, P. A.; Ward, S. A.; Davies, J.; Bray,
P. G.; Shone, A. E.; Cristiano, M. L. S.; O’Neill, P. M. Bioorg. Med. Chem. Lett. 2009,
19, 2038.
Acknowledgments
A.K. thanks the Council of Scientific and Industrial Research, In-
dia, for the award of Senior Research Fellowship. We are also
thankful to S.A.I.F. Division, CDRI, Lucknow, for providing spectro-
scopic data. C.D.R.I. communication No. 7969.
24. (a) Kumar, A.; Srivastava, K.; Rajakumar, S.; Puri, S. K.; Chauhan, P. M. S. Bioorg.
Med. Chem. Lett. 2008, 18, 6530; (b) Kumar, A.; Srivastava, K.; Rajakumar, S.;
Puri, S. K.; Chauhan, P. M. S. Bioorg. Med. Chem. Lett. 2009, 19, 6996; (c) Naresh,
S.; Sharma, M.; Srivastava, K.; Rajakumar, S.; Puri, S. K.; Saxena, J. K.; Chauhan,
P. M. S. Bioorg. Med. Chem. 2009, 17, 6451; (d) Naresh, S.; Srivastava, K.;
Rajakumar, S.; Puri, S. K.; Saxena, J. K.; Chauhan, P. M. S. Biorg. Med. Chem. Lett.
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28. Spectroscopic data for 17: MS: 382 (M+1); 1H NMR (300 MHz, CDCl3): d 8.54 (d,
1H, J = 5.34 Hz, Ar-H), 8.26 (dd, 1H, J = 1.77, 5.22 Hz, Ar-H), 7.95 (d, 1H,
J = 1.98 Hz, Ar-H), 7.83 (d, 1H, J = 8.97 Hz, Ar-H), 7.56 (dt, 1H, J = 1.8, 8.67 Hz,
Ar-H), 7.38 (br s, 1H, NH), 7.27 (dd, 1H, J = 1.98, 8.67 Hz, Ar-H), 6.73–6.69 (m, 2H,
Ar-H), 6.38 (d, 1H, J = 5.34 Hz, Ar-H), 3.69 (t, 4H, J = 5.07 Hz, NCH2), 3.44 (t, 2H,
J = 5.67 Hz, CH2), 2.73–2.68 (m, 6H, NCH2), 2.02 (quint, 2H, J = 5.43 Hz, CH2); 13
C
NMR (75 MHz, DMSO-d6): d 164.28, 157.11, 155.38, 154.25, 152.76, 142.86,
138.60, 132.69, 129.23, 122.67, 118.17, 112.25, 103.85, 60.87, 57.87, 49.90,
46.04, 30.23. Anal. Calcd for C21H24ClN5: C, 66.04; H, 6.33; N, 18.34. Found: C,
65.81; H: 6.46, N: 18.53. Compound 21: MS: 352 (M+1); 1H NMR (300 MHz,
CDCl3): d 8.47 (d, 1H, J = 5.37 Hz, Ar-H), 8.35 (br s, 1H, NH), 7.83 (d, 1H,
J = 2.07 Hz, Ar-H), 7.33–7.23 (m, 4H, Ar-H), 7.10 (d, 1H, J = 8.76 Hz, Ar-H), 6.47
(dd, 1H, J = 2.07, 8.91 Hz, Ar-H), 6.29 (d, 1H, J = 5.37 Hz, Ar-H), 3.79 (s, 2H, CH2),
3.46 (t, 2H, J = 4.44 Hz, CH2), 3.07 (t, 2H, J = 5.79 Hz, CH2), 2.92–2.86 (m, 4H, CH2),
2.07 (quint, 2H, J = 5.31 Hz, CH2); 13C NMR (75 MHz, CDCl3): d 154.25, 151.52,
148.73, 141.28, 136.21, 134.68, 129.17, 128.36, 127.13, 126.65, 125.72, 125.24,
122.04, 117.26, 101.07, 58.52, 55.98, 51.28, 49.98, 32.82, 28.46. Anal. Calcd for
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