Novel 4-aminoquinolines through microwave-assisted SNAr reactions: A practical route to antimalarial agents

Article abstract of DOI:10.1002/ejoc.200700612

4-Aminoquinolines have recently been indicated to be an important class of chemotherapeutic agents for artemisinin-based antimalarial combination therapy. A rapid, cheap, possibly clean and scalable route to 4-aminoquinolines endowed with multiple diversi

Full text of DOI:10.1002/ejoc.200700612

FULL PAPER
DOI: 10.1002/ejoc.200700612
Novel 4-Aminoquinolines through Microwave-Assisted SNAr Reactions: a
Practical Route to Antimalarial Agents
Sergio Melato,[a] Paolo Coghi,[a] Nicoletta Basilico,[b] Davide Prosperi,[a] and
Diego Monti*[a]
Keywords: Heterocycles / Aromatic substitution / Antimalarial agents / Microwave irradiation / Aminoquinolines
4-Aminoquinolines have recently been indicated to be an im-
portant class of chemotherapeutic agents for artemisinin-
based antimalarial combination therapy. A rapid, cheap,
possibly clean and scalable route to 4-aminoquinolines en-
dowed with multiple diversity is therefore badly needed.
conversion of the available 4,7-dichloroquinoline into a li-
brary of aminoquinolines in high yields and purities, with no
need for further purification steps and requiring very short
reaction times. Some of the compounds in this library were
active against chloroquine-sensitive and chloroquine-resist-
Classically, they have been prepared by means of SNAr reac- ant parasite strains.
tions, requiring hazardous or costly reagents and conditions
and complex purification procedures. In this paper, micro-
wave flash-heating chemistry is shown to allow the efficient
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
Malaria nowadays remains one of the world’s greatest
public health problems, especially in the developing coun-
tries. Despite numerous efforts expended to reduce its mor-
tality and morbidity,[1] malaria still threatens approximately
2 billion people worldwide, being responsible for almost two
million deaths per year, mostly among young children in
sub-Saharan Africa.[2] P. falciparum, the causative agent of
the most invasive, malignant form of malaria, is a particu-
larly resistant parasite, which is known to have high adapt-
ability by mutation.[3] This mutability makes the develop-
ment of resistance to chemotherapies quite likely. In this
context, quinoline compounds such as chloroquine (CQ, 1),
quinine (2), piperaquine (3), amodiaquine (4) and prima-
quine (5) (Figure 1) were developed and used clinically for
the treatment of malaria.[4] In particular, several 4-amino-
7-chloroquinolines have been found to possess strong anti-
malarial activity.[5] Nevertheless, the emergence of resis-
tance towards this class of compounds in several P. falcipa-
rum strains makes it urgent to develop simple, efficient (and
Figure 1. Quinoline-based antimalarial drugs.
One of the key issues in the attainment of a persistent
if possible cheap) new routes to novel substituted 4-amino- antiplasmodial response is the careful identification of a
quinolines with improved effectiveness against resistant suitable combination of antimalarial drugs.[6] Indeed, it is
strains.
well documented that in many cases this approach results
in a twofold effect: on one side, further development of re-
sistance may be prevented, while on the other, the efficacy
of the therapy could also be considerably improved. As a
result, in order to prevent recrudescence, artemisinin deriva-
tives, the most widely used antimalarial drugs since the dis-
covery of the antiparasite properties of Artemisia annua, are
frequently administered clinically in combination with
[a] Institute of Molecular Science and Technology, CNR,
Via G. Venezian 21, 20133 Milano, Italy
Fax: +39-0250313927
E-mail: diego.monti@istm.cnr.it
[b] Department of Public Health, Microbiology, Virology, Univer-
sity of Milan,
Via Pascal 36, 20133 Milano, Italy
6118
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Practical Route to Antimalarial Agents
longer-acting drugs.[7] Among these, 4-amino-7-chloroquin- the amine (1.3 to 4.5 equiv.) were injected into an open mi-
olines are considered promising partners of artemisinin de- crowave vial and, when appropriate, the solvent was added.
rivatives for malaria combination therapy: examples include The vessel was then hermetically sealed with a removable
artesunate/amodiaquine and dihydroartemisinin/pipera- fitted cap and placed in the cavity of a microwave reactor
quine (artekin) pairs.[8] As a consequence, there is an acute fitted with a thermostat for temperature control. Heating
need for rapid and efficient synthetic routes to this impor- was maintained for an appropriate period. In most cases,
tant class of antimalarial compounds.
depending on the nucleophile reactivity, 1 equiv. base (N-
The 4-amino-7-chloroquinoline family may be directly methylmorpholine or solid NaOH) was also added before
accessed by selective displacement of the corresponding 4- heating. To optimize temperature and reaction time, the
halogen atom in the original heteroaryl halide backbone. course of the reaction was monitored by HPLC-MS analy-
Common methods thus involve SNAr reactions, which gen- sis carried out on samples periodically taken from the reac-
erally need elevated temperatures or catalysis by costly rea- tion mixture. Isolation and purification of the products
gents, and the isolation of the products often requires com- were accomplished by simple precipitation induced by ad-
plex, low-yielding purification steps.[9]
dition of diethyl ether or 2  NaOH (depending on the
As an alternative to conventional heating, microwave ir- product solubility), followed by centrifugation and repeated
radiation has been demonstrated to be a clever strategy in washings of the solid matter with ethanolic ether or etha-
various transformations, resulting in drastic increases in re- nolic aqueous solutions. In this way, laborious purification
action rates and in substantial improvements of yields.[10] by multiphase extractions and time-consuming silica
The growing interest in microwave-assisted reactions in or- chromatography was unnecessary.
ganic synthesis resides in the fact that high yields and clean
Our main goal was to design a general strategy to synthe-
reactions may be obtained with the use of only small size small 4-aminoquinolines as building blocks for novel
amounts of energy. Microwave heating of closed reaction antimalarial drugs. An inspection of the characteristics of
vessels is a very energy efficient heating technique because the aminoquinoline library reported in Table 1 highlights
only the reaction mixture is directly heated, thus minimizing the fact that three kinds of compounds were synthesized by
wall effects and allowing superheating. Heating control is use of three different classes of amines as nucleophiles. All
also highly reliable, since the energy input starts and stops the substituents used in our investigation are commercially
as the power is turned on or off.[11] For this reason, much available and cheap. To test our method, we first examined
attention has been devoted to microwave-assisted organic the reaction with known primary alkylamines (Entries 1–3
synthesis in combinatorial medicinal chemistry.[12] How- in Table 1).[15–17] In particular, we chose N-(3-aminopropyl)-
ever, there are only a few examples in the literature in which imidazole (Entry 1) for three reasons: 1) the propyl chain is
this methodology has been applied to antimalarial drug dis- reminiscent of the recently discovered antiplasmodial com-
covery. Microwave irradiation was exploited for the isola- pound AQ13,[18] 2) we used this amine to obtain a quinoline
tion of artemisinin,[13] and for the synthesis of quinoline with a basic and buffering group at the end of the chain,
derivatives by a Friedländer two-component condensa- useful for the proton trapping within the food vacuole, and
tion.[14] However, direct access to substituted 4-aminoquin- 3) the imidazole group should stimulate interactions with
olines from haloquinolines through SNAr reactions remains the sulfate groups of the plasmodium membrane, thus in-
unexplored. Here we report the successful preparation of creasing the cell uptake of the aminoquinoline compound.
a small library of 4-amino-7-chloroquinolines obtained by Since the heterocyclic compound piperaquine has recently
aromatic nucleophilic substitution on the corresponding 4- been indicated to be a bis-quinoline antimalarial drug use-
chloro precursors under microwave irradiation conditions. ful for combination therapy, in a second set of reactions we
This approach proved very valuable, allowing us to obtain considered different piperazines in order to prepare quino-
the desired products in high yields, concomitantly decreas- line-based piperaquine analogues (Entries 4–8). Finally, we
ing the reaction times and the amounts of solvent required, evaluated five aromatic amines for the synthesis of hetero-
and involving quick workups. Overall, this procedure ap- aromatic functionalized quinolines as amodiaquine ana-
pears to be a general strategy for the rapid, clean synthesis logues (Entries 9–13).
of libraries of aminoquinoline derivatives, and thus particu-
In general, the reactions were completed in 15–20 min,
larly suitable for combinatorial chemistry and high- thus generating a library of thirteen different 4-amino-7-
throughput screening, and immediately adaptable to chloroquinolines in good to excellent yields. After various
“green” scale-up.
solvents, dichloroquinoline/nucleophile ratios, bases and
thermal parameters had been surveyed, the best reaction
conditions were set up depending on the use of primary,
secondary or aromatic amines. Results and conditions are
summarized in Table 1. Except in the cases of Entries 1–3,
Results and Discussion
We examined the substitution reactions of 4,7-dichlo- in which we found that solvent-free conditions were opti-
roquinoline with different amines by heating mixtures in a mal, in all other cases dimethyl sulfoxide proved to be the
microwave reactor at 6 bar pressure. Reaction parameters best choice. Alternative organic solvents, including dimethyl
were adjusted depending on the characteristics of the nucle- formamide, acetonitrile, ethanol, tetrahydrofuran and
ophilic amine. In general, dichloroquinoline (1 equiv.) and water, were unsatisfactory, due to the formation of by-prod-
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S. Melato, P. Coghi, N. Basilico, D. Prosperi, D. Monti
FULL PAPER
Table 1. Synthesis of 4-aminoquinoline library by microwave irradiation.
[a] 4,7-Dichloroquinoline/amine ratio. [b] 1 equiv. of base, when applicable. [c] NMM = N-methylmorpholine.
ucts deriving from solvent decomposition. Illustrative ex-
Most of the chloroquinoline conversions required ca.
amples for each class of aminoquinoline derivatives are 2 equiv. of amine to achieve optimal yields. By comparing
given in Table 2. As expected, only the chlorine substituent our results under microwave-assisted conditions with the
in the pyridine ring (4-position) is subject to nucleophilic same transformations carried out with conventional heat-
displacement, while the chlorine in the phenyl ring is sub- ing, we found that in the first case the efficiency of the con-
stantially inert.
version was convincingly improved. Indeed, conventional
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Practical Route to Antimalarial Agents
Table 2. Illustrative results for microwave-assisted SNAr reactions ingly, these compounds show improved activities, relative to
in different solvents.[a,b]
CQ, on the W2 (CQ-R) strain. The other synthesized prod-
ucts were inactive (IC50 Ͼ1000 n) against both strains,
Compound
Solvent
% Yield
Time [min] T [°C]
and are not reported in Table 4.
6a
EtOH
acetonitrile
DMF
DMSO
EtOH
acetonitrile
DMF
DMSO
EtOH
acetonitrile
DMF
61
72
62
78
57
60
66
92
41
32
39
89
20
20
20
20
18
18
18
18
15
15
15
12
140
140
140
140
140
140
180
180
130
130
130
130
Table 4. Antimalarial activities of newly synthesized 4-amino-7-
chloroquinolines.[a,b]
7e
8a
Compound
D10 CQ-S Strain
IC50 [n]
W2 CQ-R Strain
IC50 [n]
6a
92Ϯ20
257Ϯ83
219Ϯ43
30Ϯ5
290Ϯ27
238Ϯ53
242Ϯ77
744Ϯ28
7d
7e
CQ[c]
DMSO
[a] All synthesized compounds were screened. Those compounds
not included in this Table showed IC50 values Ͼ1000 n against
both D10 and W2 P. falciparum strains. [b] Data are the
meansϮSDs of three different experiments in duplicate. [c] CQ =
chloroquine.
[a] One example was chosen from each class of aminoquinoline
derivatives. [b] The use of THF and water as solvents led to decom-
position of the starting material.
reaction environments always gave lower yields of the de-
sired products. In particular, we observed good reactivities
of substituted aromatic amines, which were completely un-
reactive under conventional heating conditions. In Table 3,
the comparison between SNAr reactions carried out by mi-
crowave irradiation conditions and with conventional heat-
ing testifies to the considerable difference in terms of yields
and reaction times.
Conclusions
In summary, a library of thirteen 4-aminoquinolines was
synthesized as chloroquine analogues from commercially
available 4,7-dichloroquinoline by means of microwave-as-
sisted SNAr reactions. Of these products, three compounds
showed significant antimalarial activities against plasmodia
CQ-sensitive and CQ-resistant strains. All the compounds
were obtained by a mild, clean and straightforward pro-
cedure, without formation of by-products. The use of mi-
crowave irradiation appears to be a promising, environmen-
tally friendly and immediately scalable methodology
through which to access novel, more effective antimalarial
compounds for combination therapies.
Table 3. Comparison between SNAr reactions carried out under mi-
crowave irradiation conditions or with conventional heating.
Microwave irradiation
% Yield Time
Conventional heating
% Yield Time
[min]
T
T
[°C]
[min]
[°C]
6a
6b
6c
7a
7b
7c
7d
7e
8a
8b
8c
8d
8e
84
92
94
83
80
87
95
92
89
85
88
85
83
20
22
22
18
18
18
18
18
12
16
16
16
18
140
140
130
180
180
180
180
180
130
200
200
200
200
80
92
90
78
69
66
80
70
20
0
300
240
240
360
360
360
420
360
480
480
480
480
480
110
140
118
130
140
135
118
120
150
189
189
189
189
Experimental Section
General Remarks: All chemicals were of analytical grade and were
used without further purification. Microwave-assisted reactions
were performed with a Biotage Initiator (Uppsala, Sweden) high-
frequency microwave synthesizer working at 2.45 GHz, fitted with
magnetic stirrer and sample processor (30 vials capacity, 5 mL
each); reaction vessels were Biotage microwave glass vials sealed
with applicable cap; temperature was controlled through the in-
ternal IR sensor of the microwave apparatus. 1H NMR and 13C
NMR spectra were recorded on a Bruker AVANCE 400 instru-
ment. Mass spectra were acquired on a Bruker Esquire 3000 instru-
ment (ionic trap), fitted with an Agilent 1100 analytical HPLC with
a Waters Xterra column (4.6ϫ50 mm, 3.5 µm granulometry) as
stationary phase and an acetonitrile/water gradient as elution sol-
vent (10 to 100% acetonitrile in 6 min, 10 µL injection). Elemental
analyses were performed with a Perkin–Elmer Series II CHNS/O
2400 analyser.
0
0
0
In order to assess the potential of this approach for high-
throughput screening, all the compounds from the amino-
quinoline library were screened to determine their in vitro
antimalarial activity, by the pLDH assay, against D10 (CQ-
sensitive) and W2 (CQ-resistant) strains of P. falciparum.[19]
Some of the newly synthesized compounds, namely 6a, 7d
and
7e,
exhibited
good
antimalarial
activities
(IC50 Ͻ1000 n) on both P. falciparum strains. The IC50
values of these compounds and of CQ are reported in
Table 4. According to WHO indications, any compound
with an IC50 value below a 300 n threshold should be con-
sidered an active molecule for each corresponding strain
test. Compound 6a is more active against the CQ-sensitive
strain than the CQ-resistant strain, while compounds 7d
Typical Procedure (Entry 7): 1-Isopropylpiperazine (795 µL,
5.54 mmol) and DMSO (2 mL) were placed in a 5 mL microwave
reaction vessel equipped with a magnetic stirrer. After 10 min, 4,7-
dichloroquinoline (500 mg, 2.52 mmol) and N-methylmorpholine
(275 µL, 2.52 mmol) were added at room temperature. The reaction
vessel was then placed in the cavity of the microwave reactor. The
and 7e present similar activities on both stains. Interest- temperature was raised to 180 °C and the vessel was irradiated for
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S. Melato, P. Coghi, N. Basilico, D. Prosperi, D. Monti
FULL PAPER
18 min at 6 bar pressure at the same temperature (the reaction tem-
perature was modulated through the power switch and measured
through the internal infrared sensor of the microwave apparatus).
Samples of the reaction mixture were taken by syringe every 2 min,
and were directly injected into the HPLC-MS analyzer. After com-
plete disappearance of the MS signal corresponding to 4,7-dichlo-
roquinoline, the reaction environment was cooled to room tempera-
ture, after which diethyl ether (5 mL) was added at 0 °C. Immedi-
ately after ether addition, a brown precipitate formed. The solid
residue was isolated by centrifugation and the above liquid was
discarded. The product was purified by washing several times with
a diethyl ether/ethanol (9:1) mixture, to provide 7-chloro-4-(4-iso-
propylpiperazin-1-yl)quinoline (7d) as a light brown solid (692 mg,
95% yield). The identity and purity of compound 7d were checked
by NMR spectroscopy and HPLC-MS. M.p. 155–157 °C. 1H NMR
(400 MHz, [D6]DMSO, TMS): δ = 1.05 (d, J = 6.5 Hz, 6 H), 2.72
(m, 5 H), 3.16 (t, J = 6.2 Hz, 2 H), 6.74 (d, J = 5.3 Hz, 1 H), 7.32
(dd, J = 8.8 and 2.0 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.94 (d, J
= 2.0 Hz, 1 H), 8.61 (d, J = 5.3 Hz, 1 H) ppm. 13C NMR
(100.6 MHz, [D6]DMSO, TMS): δ = 17.88, 48.80, 52.93, 53.67,
106.42, 121.24, 125.05, 125.65, 126.04, 133.57, 149.39, 152.07,
156.37 ppm. HPLC-MS: m/z = 289.9 [M + 1]. C16H20ClN3
(289.13): calcd. C 66.31, H 6.96, N 14.50; found C 66.22, H 7.01,
N 14.58. HPLC purity Ͼ 99% (254 nm).
121.96, 125.06, 126.41, 128.93, 135.06, 150.15, 151.90, 156.97,
157.80, 161.71 ppm. HPLC-MS: m/z = 326.1 [M + 1]. C17H16ClN5
(325.11): calcd. C 62.67, H 4.95, N 21.50; found C 62.85, H 4.96,
N 21.43. HPLC purity Ͼ 99% (254 nm).
7-Chloro-4-{4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl}quinoline
(7b): Light brown solid, isolated yield 901 mg, 80%. M.p. 65–66 °C.
1H NMR (400 MHz, CDCl3, TMS): δ = 3.49 (m, 4 H), 4.15 (m, 4
H), 5.49 (s, 1 H), 7.28 (d, J = 5.8 Hz, 1 H), 7.40 (m, 5 H), 7.67 (d,
J = 8.8 Hz, 1 H), 7.75 (m, 4 H), 8.05 (s, 1 H), 8.16 (d, J = 8.8 Hz,
1 H), 8.64 (d, J = 5.8 Hz, 1 H) ppm. HPLC-MS: m/z = 447.9 [M
+ 1]. C26H23Cl2N3 (447.13): calcd. C 69.64, H 5.17, N 9.37; found
C 69.44, H 5.16, N 9.39. HPLC purity Ͼ 99% (254 nm).
2-[4-(7-Chloroquinolin-4-yl)piperazin-1-yl]benzonitrile (7c): Light
brown solid, isolated yield 763 mg, 87%. M.p. 74–75 °C. 1H NMR
(400 MHz, CDCl3, TMS): δ = 3.38 (m, 4 H), 3.42 (m, 4 H), 6.83
(d, J = 6.1 Hz, 1 H), 7.03 (m, 2 H) 7.36 (d, J = 8.9 Hz, 1 H), 7.46
(m, 1 H), 7.53 (d, J = 8.2 Hz, 1 H), 7.90 (d, J = 8.9 Hz, 1 H), 7.99
(s, 1 H), 8.67 (s, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3, TMS):
δ = 51.01, 52.30, 106.55, 109.35, 118.25, 118.97, 121.86, 122.50,
125.02, 126.40, 128.87, 133.96, 134.44, 135.12, 149.98, 151.82,
155.26, 156.78 ppm. HPLC-MS: m/z = 349.1 [M + 1]. C20H17ClN4
(348.11): calcd. C 68.52, H 4.72, N 16.39; found C 68.38, H 4.71,
N 16.45. HPLC purity Ͼ 99% (254 nm).
7-Chloro-4-{4-[3-(dimethylamino)propyl]piperazin-1-yl}quinoline
(7e): Light brown solid, isolated yield 770 mg, 92 %. M.p. 149–
151 °C. 1H NMR (400 MHz, [D6]DMSO, TMS): δ = 2.13 (m, 2
H), 2.84 (s, 6 H), 3.19 (m, 2 H), 3.23 (m, 2 H), 3.53 (m, 4 H), 3.88
(m, 4 H), 7.30 (d, J = 6.2 Hz, 1 H), 7.70 (dd, J = 9.0 and 2.0 Hz,
1 H), 8.13 (d, J = 2.0 Hz, 1 H), 8.19 (d, J = 9.0 Hz, 1 H), 8.82 (d,
J = 6.2 Hz, 1 H) ppm. 13C NMR (100.6 MHz, [D6]DMSO, TMS):
δ = 19.22, 42.61, 51.02, 52.12, 54.10, 108.56, 119.47, 122.07, 122.81,
127.29, 128.14, 137.30, 143.51, 146.68, 158.65, 159.11, 159.41 ppm.
HPLC-MS: m/z = 333.1 [M + 1]. C18H25ClN4 (332.18): calcd. C
64.95, H 7.57, N 16.83; found C 65.11, H 7.55, N 16.78. HPLC
purity Ͼ 99% (254 nm).
7-Chloro-4-[3-(1H-imidazol-1-yl)propylamino]quinoline
(6a):
1
Colourless solid, isolated yield 605 mg, 84%. M.p. 174–176 °C. H
NMR (400 MHz, CD3OD, TMS): δ = 2.23 (m, 2 H), 3.33 (t, J =
6.9 Hz, 2 H), 4.19 (t, J = 6.6 Hz, 2 H), 6.41 (d, J = 4.9 Hz, 1 H),
7.00 (s, 1 H), 7.18 (s, 1 H), 7.37 (d, J = 8.9 Hz, 1 H), 7.69 (s, 1 H),
7.77 (s, 1 H), 8.05 (d, J = 8.9 Hz, 1 H), 8.33 (d, J = 4.9 Hz, 1
H) ppm. 13C NMR (100.6 MHz, CD3OD, TMS): δ = 29.17, 39.83,
44.53, 98.79, 117.61, 119.17, 122.62, 124.51, 126.07, 127.64, 134.85,
137.05, 148.34, 151.76, 151.79 ppm. HPLC-MS: m/z = 287.0 [M +
1]. C15H15ClN4 (286.10): calcd. C 62.83, H 5.27, N 19.54; found C
62.71, H 5.26, N 19.52. HPLC purity Ͼ 99% (254 nm).
2-(7-Chloroquinolin-4-ylamino)ethanol (6b): Colourless solid, iso-
lated yield 515 mg, 92%. M.p. 213–215 °C. 1H NMR (400 MHz,
[D6]DMSO, TMS): δ = 3.33 (t, J = 6.7 Hz, 2 H), 3.66 (t, J = 6.7 Hz,
2 H), 4.86 (brs, 1 H), 6.48 (d, J = 4.9 Hz, 1 H), 7.24 (m, 1 H), 7.42
(d, J = 8.8 Hz, 1 H), 7.87 (s, 1 H), 8.25 (d, J = 8.8 Hz, 1 H), 8.38
(d, J = 6.7 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CD3OD, TMS):
δ = 45.47, 59.59, 98.79, 118.23, 124.51, 127.96, 133.60, 149.28,
4-[(4-Amino-6-phenyl-1,3,5-triazin-2-yl)amino]-7-chloroquinoline
(8a): Pale yellow solid, isolated yield 780 mg, 89 %. M.p. 202–
204 °C. 1H NMR (400 MHz, [D6]DMSO, TMS): δ = 7.50 (m, 4
H), 8.03 (s, 1 H), 8.31 (m, 3 H), 8.43 (d, J = 8.9 Hz, 1 H), 8.83 (d,
J = 6.0 Hz, 1 H) ppm. 13C NMR (100.6 MHz, [D6]DMSO, TMS):
δ = 112.90, 120.19, 125.55, 125.99, 127.60, 127.95, 128.55, 131.74,
133.98, 136.25, 143.10, 149.12, 151.70, 165.39, 167.28, 170.72 ppm.
HPLC-MS: m/z = 349.0 [M + 1]. C18H13ClN6 (348.09): calcd. C
61.98, H 3.76, N 20.09; found C 61.76, H 3.80, N 20.15. HPLC
purity Ͼ 99% (254 nm).
150.85, 152.73 ppm. HPLC-MS: m/z
= 222.8 [M + 1].
C11H11ClN2O (222.06): calcd. C 59.33, H 4.98, N 12.58; found C
59.28, H 4.96, N 12.62. HPLC purity Ͼ 99% (254 nm).
4-[(2-Aminoethyl)amino]-7-chloroquinoline (6c): Colourless solid,
isolated yield 525 mg, 94%. M.p. 131–132 °C. 1H NMR (400 MHz,
[D6]DMSO, TMS): δ = 2.82 (t, J = 6.7 Hz, 2 H), 3.25 (t, J = 6.7 Hz,
2 H), 6.46 (d, J = 5.0 Hz, 1 H), 7.24 (brs, 1 H), 7.42 (d, J = 8.8 Hz,
1 H), 7.78 (s, 1 H), 8.27 (d, J = 8.8 Hz, 1 H), 8.37 (d, J = 5.0 Hz,
1 H) ppm. 13C NMR (100.6 MHz, [D6]DMSO, TMS): δ = 40.76,
46.76, 98.91, 117.80, 124.39, 127.99, 133.68, 149.57, 150.77,
152.87 ppm. HPLC-MS: m/z = 221.6 [M + 1]. C11H12ClN3
(221.07): calcd. C 59.60, H 5.46, N 18.95; found C 59.78, H 5.52,
N 18.86. HPLC purity Ͼ 99% (254 nm).
4Ј-[(7-Chloroquinolin-4-yl)amino]-1,1Ј-biphenyl-4-carboxylic Acid
(8b): Pale yellow solid, isolated yield 801 mg, 85 %. M.p. 256–
259 °C. H NMR (400 MHz, [D6]DMSO, TMS): δ = 6.95 (d, J =
5.7 Hz, 1 H), 7.41 (brs, 1 H) 7.58 (d, J = 8.0 Hz, 1 H), 7.82 (d, J
= 8.0 Hz, 1 H), 7.89 (d, J = 8.5 Hz, 1 H), 7.94 (d, J = 7.9 Hz, 2
H), 7.99 (d, J = 7.9 Hz, 2 H), 8.05 (s, 2 H), 8.57 (d, J = 5.7 Hz,
1 H), 8.72 (d, J = 8.5 Hz, 1 H) ppm. HPLC-MS: m/z = 373.9.
C22H15ClN2O2 (374.08): calcd. C 70.50, H 4.03, N 7.47; found C
70.38, H 4.04, N 7.52. HPLC purity Ͼ 99% (254 nm).
1
7-Chloro-4-[4-(pyrimidin-2-yl)piperazin-1-yl]quinoline (7a): Light
brown solid, isolated yield 680 mg, 83%. M.p. 161–163 °C. 1H
7-Chloro-4-[(3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]quinoline
(8c): Yellow solid, isolated yield 741 mg, 88%. M.p. 206–208 °C.
NMR (400 MHz, CDCl3, TMS): δ = 3.19 (t, J = 7.0 Hz, 4 H), 4.09 1H NMR (400 MHz, [D6]DMSO, TMS): δ = 2.28 (s, 3 H), 6.23 (s,
(t, J = 7.0 Hz, 4 H), 6.47 (t, J = 4.8 Hz, 1 H), 6.79 (d, J = 5.2 Hz,
1 H), 7.38 (d, J = 8.8 Hz, 1 H), 7.93 (d, J = 8.8 Hz, 1 H), 8.07 (s,
1 H), 8.23 (d, J = 4.8 Hz, 2 H), 8.64 (d, J = 5.2 Hz, 1 H) ppm. 13C
1 H), 6.38 (d, J = 6.0 Hz, 1 H), 7.21 (m, 1 H), 7.33 (d, J = 8.2 Hz,
2 H), 7.48 (d, J = 8.7 Hz, 1 H), 7.58 (m, 2 H), 7.78 (s, 1 H), 8.21
(d, J = 6.0 Hz, 1 H), 8.32 (d, J = 8.2 Hz, 1 H) ppm. 13C NMR
NMR (100.6 MHz, CDCl3, TMS): δ = 43.75, 51.43, 109.16, 110.47, (100.6 MHz, [D6]DMSO, TMS): δ = 13.99, 101.66, 118.57, 122.48,
6122
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Eur. J. Org. Chem. 2007, 6118–6123

Practical Route to Antimalarial Agents
123.37, 124.61, 124.85, 125.44, 126.33, 128.80, 134.27, 139.07, Antimal-LSHP-CT-2005-18834. S. M. is grateful to the University
140.69, 147.25, 148.28, 150.29 ppm. HPLC-MS: m/z = 335.1 [M +
1]. C19H15ClN4 (334.10): calcd. C 68.16, H 4.52, N 16.73; found C
68.26, H 4.56, N 16.68. HPLC purity Ͼ 99% (254 nm).
of Milan for a Ph.D. fellowship. We thank the Italian National
Research Council (CNR) for financial support.
[1] World Health Organization 2006: http://www.rollbackmalar-
ia.org/malariaFAQ.html.
7-Chloro-4-[(3-methyl-1-methylphenyl-1H-pyrazol-5-yl)amino]quino-
line (8d): Yellow solid, isolated yield 716 mg, 85 %. M.p. 254–
255 °C. 1H NMR (400 MHz, [D6]DMSO, TMS): δ = 2.25 (s, 3 H),
6.31 (brs, 1 H), 6.44 (brs, 1 H), 7.17 (m, 1 H), 7.46 (m, 3 H), 7.77
(m, 2 H), 8.26 (d, J = 6.2 Hz, 1 H), 8.32 (d, J = 8.8 Hz, 1 H) ppm.
13C NMR (100.6 MHz, [D6]DMSO, TMS): δ = 20.42, 89.68,
101.58, 122.07, 122.82, 124.40, 125.09, 125.87, 128.13, 128.18,
128.75, 129.34, 129.46, 134.37, 136.48, 139.46, 139.99, 151.90 ppm.
HPLC-MS: m/z = 335.0 [M + 1]. C19H15ClN4 (334.10): calcd. C
68.16, H 4.52, N 16.73; found C 68.03, H 4.51, N 16.79. HPLC
purity Ͼ 99% (254 nm).
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7-Chloro-4-[5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)amino]quino-
line (8e): Yellow solid, isolated yield 770 mg, 83 %. M.p. 203–
205 °C. 1H NMR (400 MHz, CD3OD, TMS): δ = 3.89 (s, 3 H),
7.08 (m, 2 H), 7.85 (m, 3 H), 8.05 (s, 1 H), 8.65 (d, J = 8.7 Hz, 2
H), 8.80 (d, J = 6.3 Hz, 1 H) ppm. HPLC-MS: m/z = 369.0 [M +
1]. C18H13ClN4OS (368.05): calcd. C 58.61, H 3.55, N 15.19; found
C 58.67, H 3.56, N 15.16. HPLC purity Ͼ 99% (254 nm).
Parasite Growth: P. falciparum cultures were carried out in vitro by
Trager and Jensen’s method with slight modifications.[20] The CQ-
sensitive strain D10 and the CQ-resistant strain W2 were main-
tained at 5% hematocrit (human type A-positive red blood cells)
in RPMI 1640 (EuroClone, Celbio) (NaHCO3 24 m) medium
with the addition of heat-inactivated A-positive human plasma
(10%), Hepes (20 m) and glutamine (2 m). All the cultures were
maintained at 37 °C in a standard gas mixture consisting of 1%
(O2), CO2 (5%), N2 (94%).
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Acknowledgments
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Received: July 4, 2007
We acknowledge D. Taramelli for helpful discussion. Financial sup-
port for this work has been provided by European Community,
Published Online: October 23, 2007
Eur. J. Org. Chem. 2007, 6118–6123
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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