Design and synthesis of new antimalarial agents from 4-aminoquinoline

Article abstract of DOI:10.1016/j.bmc.2004.12.051

This study describes the synthesis of new 4-aminoquinoline derivatives and evaluation of their activity against a chloroquine sensitive strain of P. falciparum in vitro and chloroquine resistant N-67 strain of P. yoelii in vivo. All the analogues were found to form strong complex with hematin and inhibit the β-hematin formation in vitro. These results suggest that these compounds act on heme polymerization target.

Full text of DOI:10.1016/j.bmc.2004.12.051

Bioorganic & Medicinal Chemistry 13 (2005) 2157–2165
Design and synthesis of new antimalarial agents from
4-aminoquinoline
V. Raja Solomon,a Sunil K. Puri,b Kumkum Srivastavab and S. B. Kattia,*
aDivision of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India
bDivision of Parasitology, Central Drug Research Institute, Lucknow 226 001, India
Received 8 December 2004; revised 28 December 2004; accepted 29 December 2004
Available online 21 January 2005
Abstract—This study describes the synthesis of new 4-aminoquinoline derivatives and evaluation of their activity against a chloro-
quine sensitive strain of P. falciparum in vitro and chloroquine resistant N-67 strain of P. yoelii in vivo. All the analogues were found
to form strong complex with hematin and inhibit the b-hematin formation in vitro. These results suggest that these compounds act
on heme polymerization target.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
by inhibiting the haemozoin formation.5 Accumulation
of hematin is detrimental to the parasite survival.
Malaria remains one of the most widespread diseases in
the world, affecting mainly the population living in tropi-
cal and subtropical areas. Approximately 40% of the
world population lives in malaria endemic areas. Every
year, 300–500 million people suffer from acute malaria
and 0.5–2.5 million die from this disease.1 Over the years
chloroquine (CQ) has remained the drug of choice for
malaria chemotherapy because it is highly effective, less
toxic and cheap drug.2 During the past two decades
emergence of drug resistance has severely limited the
choice of available antimalarial drugs. The biochemical
studies on CQ and closely related 4-aminoquinoline
antimalarial compounds suggested that accumulation
of the chemotherapeutic agents in the parasite vacuole
is critical for their antimalarial activity.3 However, there
are conflicting reports in the literature on the signifi-
cance of vacuolar accumulation ratio (VAR) and cellu-
lar accumulation ratio (CAR) in terms of antimalarial
activity.3d Studies on the mechanism underlying the
drug resistance have indicated that the resistance is con-
sequence of decreased accumulation of the drug as a
result of enhanced efflux, reduced uptake or a combina-
tion of both.4 This class of compounds enter the food
vacuole and inhibit the parasite growth by forming com-
plex with hematin (Fe(III)FPIX) (p–p interaction) there-
Recent reports have shown that close analogues of CQ
and its derivatives are active against CQ-resistant para-
site strains,6 strongly suggesting that the resistance
mechanism does not involve any change to the target
of this class of drug but involves a compound specific
resistance. Based on this premise a number of groups
have developed short-chain analogues of quinoline
derivatives, which are significantly more potent than
CQ against a CQ-resistant strain of P. falciparum in in
vitro studies.7 These findings have given impetus to the
antimalarial drug discovery programme further aug-
menting the realization that rational choice of inputs
based on known antimalarial scaffold could lead to mole-
cules with desirable activity profile. Encouraged by these
results we designed new compounds by selectively modi-
fying the pendant amino group (Scheme 1) with a view
to facilitate, (i) their accumulation in the food vacuole,
and (ii) achieve better interaction with hematin leading
to improved antimalarial activity. The results are
described in this communication.
N
HN
Keywords: 4-Aminoquinoline; Antimalarial; Heam binding.
*
Cl
N
Corresponding author. Tel.: +91 0522 2220586; fax: +91 0522
223405; e-mail: setu_katti@yahoo.com
Chloroquine (CQ)
0968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.12.051

2158
V. R. Solomon et al. / Bioorg. Med. Chem. 13 (2005) 2157–2165
R
R
NCO C(CH )
2
3 3
NH
2
Cl
N
NH
n
C
NHCO C(CH )
HN
N
2
3 3
n
HN
R
b
a
NH
2
+
H N
2
n
Cl
Cl
Cl
N
1
2a R= H
2b R= CH n=2
2C R= H
2d R= H
n=2
3a R= H
3b R= CH n=2
3C R= H
3d R= H
n=2
4a R= H
4b R= CH n=2
4C R= H
4d R= H
n=2
+
R
3
3
3
NHBoc
n=3
n=4
n=3
n=4
n=3
n=4
H N
2
n
c
d
e
R
R
NH
C
R
N(CH )
3 2
NHBoc
NH
NH
2
.HCl
.PF
C N(CH )
3 2
NH
n
6
HN
HN
N
n
HN
N
n
Cl
N
Cl
Cl
5a R= H
5b R= CH n=2
5C R= H
5d R= H
n=2
6a R= H
6b R= CH
6C R= H
6d R= H
n=2
7a R= H
7b R= CH n=2
7C R= H
7d R= H
n=2
3
n=2
n=3
n=4
3
3
n=3
n=4
n=3
n=4
Scheme 1. Reagents and conditions: (a) 80 ꢁC for 1 h, 120–130 ꢁC for 6–8 h; (b) 1,3-bis-(tert-butoxycarbonyl)-2-methyl-2-thiopseudurea, THF,
60 ꢁC; (c) 20% dioxane/HCl, rt, 1 h; (d) HBTU, dry CH3CN, rt, 8 h; (e) 80 ꢁC for 1 h, 120–130 ꢁC for 6–8 h.
2. Chemistry
P. falciparum. Despite improved in vitro activity these
compounds were less active than CQ in the in vivo model.
This was attributed to rapid N-dealkylation in the bio-
logical milieu. On the basis of these results we surmised
that appropriate modification of the side chain amino
group could give compounds with improved antimalar-
ial activity. Accordingly, tert-butoxycarboxyl (Boc),
guanyl and tetramethylguanyl moieties were introduced
at the side chain amino group of the 4-aminoquinoline.
All compounds (Table 1) were tested for in vitro antima-
larial activity against the CQ sensitive NF-54 strain of
P. falciparum. The activity data (Table 1) clearly suggest
that compounds with four carbon chain in the side chain
(4d, 5d, 6d, 7d) are more active than the compounds with
three (4c, 5c, 6c, 7c) or two (4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b)
carbon chain. Furthermore the data also suggest that
the compounds having Boc protecting group (7a–d)
were more active than corresponding amino compounds
(3a–d). This is because under assay conditions Boc
derivatives of 4-aminoquinoline (7a–d) and 4-amino-
quinoline guanidine (4a–d) do not undergo protonation
and this protecting group is hydrophobic. As a result
they have proclivity to diffuse freely and rapidly across
the biological membrane and are transformed to mono
or diprotonated derivatives within the parasite food vac-
uole. Once they are protonated they are less permeable,
and are trapped in the food vacuole resulting in in-
creased drug accumulation at the target site. It has been
shown previously that accumulation of the compound at
the target site viz parasite food vacuole has a direct bear-
ing on the antimalarial activity.3d The level of accumu-
lation depends on the pKa of side chain nitrogen.5d
Therefore, we hypothesized that a systematic change in
the pKa of the side chain amino group could provide in-
sight into the role of amino nitrogen with respect to pKa,
4-Aminoquinoline (3a–d) were prepared by aromatic
nucleophilic substitution on 4,7-dichloroquinoline 1
with excess of diaminoalkane in neat conditions with
simple standard workup procedure in excellent yields.
Here we performed nucleophilic substitution in neat
amine to avoid the use of phenol as a solvent, which is
prone to polymerization.8 The guanidine derivatives
(5a–d) were prepared by refluxing 4-aminoquinoline
with guanylating reagents like 1,3-bis-(tert-butoxycar-
bonyl)-2-methyl-2-thiopseudurea in 2% aqueous THF.
The Boc-protected derivatives (4a–d) thus obtained were
deblocked with 20% HCl/dioxane. Tetramethylguan-
idine derivatives (6a–d) were synthesized in a single step,
by the reaction of 4-aminoquinoline with HBTU (2-1H-
benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluoro-
phosphate in dry acetonitrile solvent at room tempera-
ture stirring. These compounds were obtained as PF6
salt. This was confirmed by 31P NMR studies wherein,
a septet at ꢀ159.73 to ꢀ194.70 (J = 704) corresponding
to the PF6 was observed in all these compounds (6a–d).
Mono Boc-protected 4-aminoquinoline were synthesized
by aromatic nucleophilic substitution of 4,7-dichloro-
quinoline with excess of mono Boc-protected diaminoal-
kane. The compounds reported in this study have been
thoroughly characterized by elemental analysis and
spectral data.
3. Result and discussion
A recent study by Ridley et al.6a has shown that 4-ami-
noquinoline analogues with altered chain length exhibit
antimalarial activity against CQ-resistant strains of

V. R. Solomon et al. / Bioorg. Med. Chem. 13 (2005) 2157–2165
Table 1. Biological and biophysical data of the compounds
2159
LogKa
IC50
b
C. No.
MIC (lM)
LogP
pKa1
pKa2
VAR
CAR
3a
4a
5a
6a
7a
9.02
1.08
1.63
3.59
1.33
2.15
3.18
7.85
c
—
10.00
c
62882.12
c
2012.23
c
5.99 0.01
c
0.23 0.08
c
—
13.83
16.28
—
63095.70
63095.73
—
2019.06
2019.06
—
5.56 0.02
5.70 0.04
—
0.35 0.02
1.00 0.05
6.66
21.50
6.21
8.00
8.53
c
—
c
—
c
—
c
—
c
—
c
—
3b
4b
5b
6b
7b
4.24
1.05
2.17
4.12
1.86
2.69
3.72
8.03
c
—
10.00
c
62900.20
c
2012.81
c
6.02 0.05
c
0.46 0.15
c
—
13.83
16.32
—
63095.71
63095.73
—
2019.06
2019.06
—
6.32 0.01
7.26 0.02
—
0.49 0.03
1.23 0.02
31.83
20.84
2.98
8.18
8.71
c
—
c
—
c
—
c
—
c
—
c
—
3c
4c
5c
6c
7c
8.49
1.05
1.99
3.94
1.68
2.52
3.54
8.08
c
—
10.15
c
62984.20
c
2015.49
c
6.24 0.03
c
0.50 0.06
c
—
14.00
16.10
—
63095.72
63095.73
—
2019.06
2019.06
—
6.04 0.01
6.48 0.02
—
0.69 0.05
0.86 0.06
6.36
104.20
5.96
8.23
8.23
c
—
c
—
c
—
c
—
c
—
c
—
3d
4d
5d
6d
7d
8.00
1.02
2.50
4.45
2.19
3.02
4.05
8.76
c
—
10.15
c
62979.32
c
2015.34
c
6.45 0.02
c
0.51 0.11
c
—
14.00
16.42
—
63095.72
63095.73
—
2019.06
2019.06
—
7.14 0.03
7.65 0.04
—
0.62 0.02
1.19 0.07
6.09
20.25
1.42
8.76
8.76
c
—
c
—
c
—
c
—
c
—
c
—
CQ
0.39
4.72
8.41
10.27
63002.78
2016.08
5.52 0.02
0.17 0.02
a 1:1 complex formation in 40% aqueous DMSO, 20 mM HEPES buffer, pH 7.5 at 25 ꢁC (data are expressed as means SD from at least three
different experiments in duplicate).
b The IC50 represents the millimolar equivalents of test compounds, relative to hemin, required to inhibit b-hematin formation by 50% (data are
expressed as means SD from at least three different experiments in duplicate).
c The values not determined.
drug accumulation viz-a-viz antimalarial activity. To-
wards this objective compounds having guanyl (5a–d)
and tetramethylguanyl (6a–d) derivatives were synthe-
sized. It may be appropriate to mention here that guani-
dine group is a privileged pharmacophore found in
many biologically active compounds.9 Guanidine itself,
the imine of urea has strongly basic character (pKa of
guanidinium ion approximately 13.5). Due to their
strongly basic character, guanidines are fully protonated
under physiological conditions. The positive charge thus
imposed on the molecules forms the basis for specific
interaction between ligand and receptor or enzyme and
substrate, mediated by hydrogen bonds or electrostatic
interactions.10 In this particular case it was expected that
compounds with guanyl (5a–d) and tetramethylguanyl
(6a–d) moieties would form tighter association complex
with hematin leading to improved antimalarial activity.
Since such a modification would alter pKa of the side
chain nitrogen in turn effecting the accumulation of
the compound at the target site. Therefore we have cal-
culated the logP, pKa1 and pKa2 values of these com-
pounds using Pallas.11 The data presented in Table 1
clearly showed that introduction of guanyl (5a–d) and
tetramethylguanyl (6a–d) moieties increased the pKa
values. Although in some cases there is no direct corre-
lation between drug accumulation and antimalarial
activity, VAR and CAR could be considered while
designing the compounds. Accordingly with the help
of pKa values we have calculated the VAR and CAR.
As expected introduction of guanyl moiety has increased
the pKa values as compared to CQ while there is mar-
ginal increase in the VAR and CAR values. Therefore
it was expected that guanylated compounds to accumu-
late at higher concentration within the parasite food
vacuole. However the antimalarial activity of these com-
pounds (5a–d, 6a–d) is much lower than CQ suggesting
that the pKa values must be in the range of 8.41 (pKa1)
and 10.27 (pKa2) in order to exhibit maximum activity.
The ability of the 4-aminoquinoline guanidine (5a–d)
and tetramethylguanidine (6a–d) derivatives to form
association complex with Fe(III)FPIX was investigated
by UV spectrophotometer. The results are shown in
Table 1. Boc-protected derivatives of 4-aminoquinoline
guanidine (4a–d) and 4-aminoaquinoline (7a–d) will
transform (according to weak base effect) to correspond-
ing free amino compounds. Therefore, no attempt was
made for the determination of association constant
and inhibition of b-hematin formation for these com-
pounds. The data shows that all the compounds bind
or interact with Fe(III)FPIX and form a complex, in
the range of 5.56–7.65. Because of marginally higher
accumulations and strongly basic character of these
compounds there is a tight binding to Fe(III)FPIX.
These results explain that the principle interaction might
be involving p–p stacking interaction of the quinoline
ring with the porphyrin ring system. The second weak
electrostatic interaction is of the positively charged cen-
tre of guanidine and tetramethylguanidine derivatives
with carboxyl groups of hematin. All the 4-aminoquino-
line guanidine (5a–d) and tetramethylguanidine (6a–d)
derivatives inhibited b-hematin formation (Table 1) in
a concentration-dependent manner. Data suggest that
this class of compound binds to hematin monomer
or hematin l-oxo dimers. This binding inhibits hema-
tin polymerization by shifting hematin dimerization

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V. R. Solomon et al. / Bioorg. Med. Chem. 13 (2005) 2157–2165
Table 2. In vivo antimalarial activity against CQ resistant N-67 strain
of Plasmodium yoelii in Swice mice
cal shifts were reported as parts per million (d ppm) tetra-
methylsilane (TMS) as an internal standard. Mass
spectra were obtained on a JEOL-SX-102 instrument
using fast atom bombardment (FAB positive). The pro-
gress of the reaction was monitored on readymade silica
gel plates (Merck) using chloroform–methanol (9:1) as a
solvent system. Iodine was used as developing agent or by
spraying with DragendorffÕs reagent. Chromatographic
purification was performed over silica gel (100–200
mesh). All chemicals and reagents were obtained from
Aldrich (USA), Lancaster (UK) or Spectrochem Pvt.
Ltd (India) and were used without further purification.
C. No.
% Suppression on
day 4a
Mean survival time
(MST in days) SEb
4d
5d
6d
5c
76.08
88.98
73.92
56.72
100.00
15.80 1.24
14.80 1.77
14.67 1.76
16.00 1.92
All animals survived
CQ
Control
—
13.20 1.07
a Percent suppression = [(CꢀT)/C] · 100; where C = parasitaemia in
control group, and T = parasitaemia in treated group.
b MST calculated for the mice which died during 28-day observation
period and the mice which survived beyond 28 days are excluded.
6. Biological and physicochemical studies
6.1. In vitro antimalarial efficacy test
equilibrium to the l-oxo dimer, thus reducing the avail-
ability of monomeric hematin for incorporation into
hemozoin. Although none of the new derivatives were
more potent than CQ the study has provided substantial
evidence to highlight the importance of pKa, drug accu-
mulation and formation of association complex with b-
hematin on the overall antimalarial activity of this class
of compounds.
The in vitro antimalarial assay was carried out in 96
well-microtitre plates. The cultures of P. falciparum
NF 54 strain are routinely maintained in medium RPMI
1640 supplemented with 25 mM HEPES, 1% D-glucose,
0.23% sodium bicarbonate and 10% heat inactivated
human serum. The asynchronous parasites of P. falcipa-
rum were synchronized after 5% D-sorbitol treatment to
obtain only the ring stage parasitized cells. For carrying
out the assay, the initial ring stage parasitaemia of 0.8–
1.5% at 3% haematocrit in a total volume of 200 lL of
medium RPMI-1640 was uniformly maintained. The
test compound in 20 lL volume concentrations ranging
between 0.5 and 50 lg/mL in duplicate well were incu-
bated with parasitized cell preparation at 37 ꢁC in a can-
dle jar. After 36–40 h incubation, the blood smears from
each well prepared and stained with giemsa stain. The
slides were microscopically observed to record matura-
tion of ring stage parasites into trophozoites and schizo-
nts in the presence of different concentrations. The test
concentrations which inhibited the complete maturation
into schizonts were recorded as the minimum inhibitory
concentration (MIC). CQ was used as the standard ref-
erence drug.
The most effective analogues (4d, 5d, 6d, 5c) were
selected for in vivo bio evaluation against CQ-resistant
N-67 strain of P. yoelii in Swiss mice at 30.0 mg/kg by
intraperitoneal route (Table 2). The in vivo activity
exhibited by these compounds is much less than CQ.
It is possible to improve the in vivo activity by fine tun-
ing the modifications at the side chain amino group of
the 4-aminoquinoline moiety.
4. Conclusion
In summary, the synthesis of a new series of 4-amino-
quinoline derivatives has been described. These deriva-
tives have exhibited promising antimalarial activity
against CQ sensitive strain of NF-54 in in vitro and
CQ resistant N-67 strain of P. yoelii in vivo. The order
of activity appears to be Boc-protected (4a–d) com-
pounds are more active than the guanylated com-
pounds. The present biophysical studies have
suggested that this class of compounds form association
complex with hematin and thereby inhibit the hemozoin
formation. The pKa of second nitrogen in the range of
10.27 is critical for activity. Either increase or decrease
in the pKa beyond this limit has adverse effect on the
antimalarial activity.
6.2. In vivo antimalarial efficacy test
The in vivo efficacy of test compounds was evaluated
against CQ resistant N-67 strain of P. yoelii in Swiss
mice model at 30.0 mg/kg/day. The mice (22 2 g) were
inoculated with 1 · 106 parasitized RBC on day 0 and
treatment was administered to a group of five mice from
day 0 to 3, once daily. The aqueous suspension of com-
pounds were prepared with a few drops of Tween 80.
The required drug dose was administered in 0.2 mL vol-
ume via intraperitoneal route. Parasitaemia level were
recorded from thin blood smears between days 4 and
28.12 The mean value determined for a group of 5 mice
was used to calculate the percent suppression of para-
sitaemia with respect to the untreated control group.
Mice treated with CQ served as positive controls.
5. Experimental
Melting points (mp) were taken in open capillaries on
Complab melting point apparatus and are uncorrected.
Elemental analysis was performed on a Perkin–Elmer
2400 C,H,N analyzer and values were within the accept-
able limits of the calculated values. Infrared (IR) spectra
were recorded on an FT-IR Perkin–Elmer spectrometer.
The 1H spectra were recorded on a DPX-200/DRX-
300 MHz Bruker FT-NMR spectrometer using CDCl3,
CD3OD, CD3CN and DMSO-d6 as solvent. The chemi-
6.3. Determination of logP and pKa values
The logP and pKa values of 4-aminoquinoline guanidine
(5a–d) and tetramethylguanidine (6a–d) derivatives were

V. R. Solomon et al. / Bioorg. Med. Chem. 13 (2005) 2157–2165
2161
calculated by Pallas.11 In the case of pKa two values
were obtained. These data presented in Table 1 show
pKa of quinoline N (the acid dissociation constant of
the quinolinuim cation and referred to below as pKa1)
and pKa of tertiary amino group in the lateral chain
(the acid dissociation constant of the tertiary ammo-
nium group in the lateral side chain is referred to
pKa2). With the help of these values we predicted theo-
retical vacuolar accumulation ratio (VAR) by the fol-
lowing equation.3d
6.6. General synthetic procedure for N1-(7-chloroquinolin-
4-yl)diaminoalkane (3a–d)
A mixture of 4,7-dichloroquinoline 1 (2.5 g, 12.5 mmol)
and 1,2-diaminoalkane (25 mmol) was heated slowly
from room temp to 80 ꢁC over 1 h with stirring and sub-
sequently at 120–130 ꢁC for 6–8 h with continued stir-
ring 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.
a1þpKa2ꢀ2pHvÞ
1 þ 10ðpK ꢀpHvÞ þ 10ðpK
a1
VAR ¼
a1þpKa2ꢀ2pHoÞ
1 þ 10ðpK ꢀpHoÞ þ 10ðpK
a1
This equation proceeds from a derivation of the Hender-
son–Hasselbach equation, where pHv = pH inside the
vacuole (assumed to be pH 5.0) pHo = pH externally
(assumed to be pH 7.4).
6.6.1. N1-(7-Chloroquinolin-4-yl)ethane-1,2-diamine (3a).
This compound was obtained as a yellowish white solid
in 85% yield. Mp 131–132 ꢁC; IR (KBr) 3327.2 cmꢀ1
;
1583.2 cmꢀ1; H NMR (200 MHz, CDCl3): d 3.09–3.15
(m, 4H, CH2), 3.27 (br s, 2H, NH2), 5.82 (br s, 1H,
NH), 6.38–6.41 (d, J = 5.34 Hz, 1H, 3H quinoline),
7.32–7.37 (dd, J = 8.96, 1.72 Hz, 1H, 6H quinoline),
7.73–7.77 (d, J = 8.92 Hz, 1H, 5H quinoline), 7.94–
7.95 (d, J = 1.92 Hz, 1H, 8H quinoline), 8.49–8.52 (d,
J = 5.34 Hz, 1H, 2H quinoline); FAB-MS m/z 222
[M+H]+; Anal. Calcd for C11H12ClN3: C, 59.60; H,
5.46; N, 18.95; found: C, 60.01; H, 5.56; N, 19.00.
1
Making the assumptions that the parasites acid vacuole
occupies 3.2% of its total cell volume, corresponding cel-
lular drug accumulation ratioÕs (CARs) for each cell
type were then calculated using the following
equation.3d
CAR ¼ VAR ꢁ Fractional cell volume occupied
by acid vacuoles
6.6.2.
N2-(7-Chloroquinolin-4-yl)-propane-1,2-diamine
(3b). This compound was obtained as a yellowish
white solid in 82% yield. mp 126–127 ꢁC; IR (KBr)
6.4. Determination of hematin-4-aminoquinoline guan-
idine and tetramethylguanidine derivatives association
constant
3342.3 cmꢀ1
;
1581.9 cmꢀ1
;
1H NMR (200 MHz,
CDCl3): d 1.23–1.26 (d, J = 6.31 Hz, 3H, CH3), 1.59
(br s, 2H, NH2), 2.94–3.04 (m, 2H, CH2), 3.25–3.36
(m, 1H, CH3–CH–), 5.62 (br s, 1H, NH), 6.36–6.39 (d,
J = 5.38 Hz, 1H, 3H quinoline), 7.32–7.38 (dd, J =
8.92, 2.02 Hz, 1H, 6H quinoline), 7.71–7.76 (d, J =
8.94 Hz, 1H, 5H quinoline), 7.94–7.95 (d, J = 2.1 Hz,
1H, 8H quinoline), 8.49–8.52 (d, J = 5.36 Hz, 1H, 2H
quinoline); FAB-MS m/z 236 [M+H]+; Anal. Calcd for
C12H14ClN3: C, 61.15; H, 5.99; N, 17.83; found: C,
61.20; H, 5.98; N, 17.80.
Association constant for hematin-4-aminoquinoline
guanidine (5a–b) and tetramethylguanidine (6a–d) deriv-
atives complex formation were determined by spectro-
metric titration procedure in aqueous dimeth-
ylsulfoxide (DMSO) at pH 7.5.13 The major advantage
of this titration method is that, in this condition
Fe(III)PPIX is strictly in monomeric state and interpre-
tation of results is not complicated by the need to con-
sider Fe(III)PPIX disaggregation process. Association
constant measured in this method is a good reflection
of the interaction would occur in the acidic food vacu-
ole. Utilizing a pH of 7.5, rather than more acidic con-
ditions, improves the stability of Fe(III)PPIX solutions
and quality of data.
6.6.3.
(3c). This compound was obtained as a yellowish white
solid in 88% yield. mp 96–98 ꢁC; IR (KBr) 3328.7 cmꢀ1
2236.7 cmꢀ1 1587.5 cmꢀ1 1216.4 cmꢀ1 1H NMR
N1-(7-Chloroquinolin-4-yl)-propane-1,3-diamine
;
;
;
;
(200 MHz, CDCl3): d 1.90–1.93 (m, 2H, CH2), 2.76 (br
s, 2H, NH2), 2.99–3.05 (m, 2H, CH2), 3.32–3.40 (m,
2H, CH2), 6.29–6.32 (d, J = 5.30 Hz, 1H, 3H quinoline),
7.26–7.30 (dd, J = 8.78, 1.96 Hz, 1H, 6H quinoline), 7.38
(br s, 1H, NH), 7.68–7.73 (d, J = 8.88 Hz, 1H, 5H quino-
line), 7.91–7.92 (d, J = 2.02 Hz, 1H, 8H quinoline),
8.46–8.48 (d, J = 5.29 Hz, 1H, 2H quinoline); FAB-MS
m/z 236 [M+H]+; Anal. Calcd for C12H14ClN3: C,
61.15; H, 5.99; N, 17.83; found: C, 61.15; H, 6.00; N,
17.91.
6.5. In vitro inhibition of b-hematin polymerization
The ability of the 4-aminoquinoline guanidine (5a–d)
and tetramethylguanidine (6a–d) derivatives to inhibit
b-hematin polymerization was induced by parasite
lysate using UV spectrophotometer and measurements
were carried out at 405 nm.14 The values obtained
from the assay were expressed as percent inhibition
relative to hemozoin formation in a drug-free control.
The values of triplicate assays were plotted semi-loga-
rithmically on GraphPad Prism 3.5 and the IC50 val-
6.6.4.
N1-(7-Chloroquinolin-4-yl)-butane-1,4-diamine
(3d). This compound was obtained as a yellowish white
solid in 76% yield. mp 122–124 ꢁC; IR (KBr)
ues (mM) calculated graphically
deviation).
SD (standard
3329.2 cmꢀ1; 2235.9 cmꢀ1; 1587.4 cmꢀ1; 1218.4 cmꢀ1
;

2162
V. R. Solomon et al. / Bioorg. Med. Chem. 13 (2005) 2157–2165
1H NMR (200 MHz, CDCl3): d 1.57–1.61 (m, 2H, CH2),
1.64–1.68 (m, 2H, CH2), 2.73 (br s, 2H, NH2), 2.78–2.85
(m, 2H, CH2–NH2), 3.25–3.34 (m, 2H, –NH–CH2), 6.00
(br s, 1H, NH), 6.35–6.38 (d, J = 5.42 Hz, 1H, 3H quino-
line), 7.30–7.35 (dd, J = 8.95, 2.12 Hz, 1H, 6H quino-
line), 7.72–7.76 (d, J = 8.96 Hz, 1H, 5H quinoline),
7.93–7.94 (d, J = 2.08 Hz, 1H, 8H quinoline), 8.48–
8.51 (d, J = 5.39 Hz, 1H, 2H quinoline); FAB-MS m/z
250 [M+H]+; Anal. Calcd for C13H16ClN3: C, 65.52;
H, 6.46; N, 16.83; found: C, 65.95; H, 6.38; N, 16.72.
(200 MHz, CDCl3): d 1.52 (s, 9H, –C–NH–COO–
C(CH3)3), 1.54 (s, 9H, –C@N–COO–C(CH3)3), 1.69–
1.73 (m, 2H, CH2), 1.81 (br s, 1H, NH), 3.41–3.46 (m,
4H, CH2), 6.40–6.42 (d, J = 5.54 Hz, 1H, 3H quinoline),
6.94 (br s, 1H, NH), 7.31–7.36 (dd, J = 8.90, 2.10 Hz,
1H, 6H quinoline), 7.77–7.82 (d, J = 9.02 Hz, 1H, 5H
quinoline), 7.93–7.94 (d, J = 2.12 Hz, 1H, 8H quino-
line), 8.47–8.50 (d, J = 5.41 Hz, 1H, 2H quinoline),
8.60 (br s, 1H, NH); FAB-MS m/z 478 [M+H]+; Anal.
Calcd for C23H32ClN5O4: C, 57.79; H, 6.75; N, 14.65;
found: C, 57.82; H, 6.78; N, 14.68.
6.7. General synthetic procedure for N,N1-bis-(tert-
butoxycarbonyl)-N11-[(7-chloroquinolin-4-ylamino)-
alkyl]-guanidine (4a-d)
6.7.4. N,N1-Bis-(tert-butoxycarbonyl)-N11-[4-(7-chloro-
quinolin-4-ylamino)-butyl]-guanidine (4d). This com-
pound was obtained as white solid in 60% yield. Mp
1,3-Bis-(tert-butoxycarbonyl)-2-methyl-2-thiopseudurea
(4.6 mmol) and 4-aminoquinoline (3 mmol) (3a–d) were
heated at 60 ꢁC for 6 h in 2% aq. THF. Solvent was re-
moved, and the residue was treated with 5% aq. NaH-
CO3, followed by extraction with dichloromethane
(2·). After brine wash, the crude product was chroma-
tography over silica gel using chloroform-methanol.
121–122 ꢁC; Rf 0.72; IR (KBr) 3328.3 cmꢀ1
;
2981.7 cmꢀ1
; ; ;
1721.1 cmꢀ1 1417.6 cmꢀ1 1H NMR
(200 MHz, CDCl3): d 1.43 (s, 9H, –C–NH–COO–
C(CH3)3), 1.50 (s, 9H, –C@N–COO–C(CH3)3), 1.52–
1.64 (m, 4H, CH2), 1.83 (br s, 1H, NH), 3.38–3.41 (m,
2H, CH2), 3.49–3.52 (m, 2H, CH2), 5.73 (br s, 1H,
NH), 6.39–6.41 (d, J = 5.36 Hz, 1H, 3H quinoline),
7.28–7.35 (dd, J = 8.98, 1.92 Hz, 1H, 6H quinoline),
7.79–7.84 (d, J = 8.95 Hz, 1H, 5H quinoline), 7.94–
7.95 (d, J = 1.89 Hz, 1H, 8H quinoline), 8.50–8.53 (d,
J = 5.28 Hz, 1H, 2H quinoline), 8.60 (br s, 1H, NH);
FAB-MS m/z 478 [M+H]+; Anal. Calcd for
C24H34ClN5O4: C, 58.59; H, 6.97; N, 14.23; found: C,
58.62; H, 7.02; N, 14.34.
6.7.1. N,N1-Bis-(tert-butoxycarbonyl)-N11-[2-(7-chloro-
quinolin-4-ylamino)-ethyl]-guanidine
compound was obtained as white solid in 65% yield.
mp 143–145 ꢁC; Rf 0.62; IR (KBr) 3324.4 cmꢀ1
2980.2 cmꢀ1 1723.7 cmꢀ1 1582.6 cmꢀ1 1H NMR
(4a).
This
;
;
;
;
(200 MHz, CDCl3): d 1.49 (s, 9H, –C–NH–COO–
C(CH3)3), 1.61 (s, 9H, –C=N–COO–C(CH3)3), 1.89 (br
s, 1H, NH), 3.42–3.58 (m, 2H, CH2), 3.81–4.01 (m,
2H, CH2), 6.29–6.31 (d, J = 5.34 Hz, 1H, 3H quinoline),
7.16 (br s, 1H, NH), 7.32–7.37 (dd, J = 8.96, 2.01 Hz,
1H, 6H quinoline), 7.84–7.88 (d, J = 8.94 Hz, 1H, 5H
quinoline), 7.93–7.94 (d, J = 2.08 Hz, 1H, 8H quino-
line), 8.48–8.51 (d, J = 5.38 Hz, 1H, 2H quinoline),
8.91 (br s, 1H, NH); FAB-MS m/z 464 [M+H]+; Anal.
Calcd for C22H30ClN5O4: C, 56.95; H, 6.52; N, 15.09;
found: C, 57.02; H, 6.48; N, 15.12.
6.8. General synthetic procedure for N-[(7-chloroquinolin-
4-ylamino)-alkyl]-guanidine hydrochloride (5a–d)
N,N1-Bis-(tert-butoxycarbonyl)-N11-[(7-chloro-quinolin-
4-ylamino)-alkyl]-guanidine (4a–d) were treated with
20% HCl/dioxane solution and kept for 1 h. The solvent
was evaporated under reduced pressure and the residue
was scraped with ether. Finally the ethereal layer was
evaporated to get the product.
6.7.2. N,N1-Bis-(tert-butoxycarbonyl)-N11-[2-(7-chloro-
6.8.1. N-[2-(7-Chloroquinolin-4-ylamino)-ethyl]-guanidine
hydrochloride (5a). This compound was obtained as
white solid in 55% yield. Mp 143–144 ꢁC; Rf 0.32; H
quinolin-4-ylamino)-propyl]-guanidine
compound was obtained as white solid in 65% yield.
Mp 116–117 ꢁC; Rf 0.72; IR (KBr) 3325.3 cmꢀ1
2980.5 cmꢀ1 1724.5 cmꢀ1 1615.3 cmꢀ1 1H NMR
(4b).
This
1
;
NMR (200 MHz, CDCl3+CD3OD): d 2.36 (br s, 2H,
NH2), 2.51 (br s, 1H, NH), 3.36–3.42 (m, 2H, CH2),
3.75–3.96 (m, 2H, CH2), 4.26 (br s, 1H, NH), 6.59–
6.61 (d, J = 5.32 Hz, 1H, 3H quinoline), 7.02 (br s,
1H, NH), 7.27–7.32 (dd, J = 8.98, 2.02 Hz, 1H, 6H
quinoline), 7.74–7.78 (d, J = 9.02 Hz, 1H, 5H quino-
line), 7.83–7.84 (d, J = 2.04 Hz, 1H, 8H quinoline),
8.38–8.41 (d, J = 5.34 Hz, 1H, 2H quinoline); FAB-MS
m/z 264 [M+H]+; Anal. Calcd for C12H15Cl2N5: C,
48.01; H, 5.04; N, 23.33; found: C, 48.06; H, 5.41; N,
23.45.
;
;
;
(200 MHz, CDCl3): d 1.32–1.35 (d, J = 6.2 Hz, 3H,
CH3), 1.50 (s, 9H, –C–NH–COO–C(CH3)3), 1.51 (s,
9H, –C@N–COO–C(CH3)3), 1.74 (br s, 1H, NH),
2.62–2.64 (m, 2H, CH2), 3.43–3.46 (m, 1H, CH3–CH–),
6.43–6.45 (d, J = 5.34 Hz, 1H, 3H quinoline), 6.66 (br
s, 1H, NH), 7.27–7.32 (dd, J = 8.96, 1.98 Hz, 1H, 6H
quinoline), 7.77–7.82 (d, J = 9.02 Hz, 1H, 5H quino-
line), 7.92–7.93 (d, J = 1.92 Hz, 1H, 8H quinoline),
8.62–8.65 (d, J = 5.40 Hz, 1H, 2H quinoline), 8.93 (br
s, 1H, NH); FAB-MS m/z 478 [M+H]+; Anal. Calcd
for C23H32ClN5O4: C, 57.79; H, 6.75; N, 14.65; found:
C, 57.82; H, 6.78; N, 14.56.
6.8.2. N-[2-(7-Chloroquinolin-4-ylamino)-propyl]-guan-
idine hydrochloride (5b). This compound was obtained
as white solid in 58% yield. Mp 222–223 ꢁC; Rf 0.28;
6.7.3. N,N1-Bis-(tert-butoxycarbonyl)-N11-[3-(7-chloro-
quinolin-4-ylamino)-propyl]-guanidine (4c). This com-
pound was obtained as white solid in 63% yield. Mp
IR (KBr) 3426.3 cmꢀ1
;
2928.3 cmꢀ1
;
2372.5 cmꢀ1
1H NMR
1.30–133 (d,
;
1809.6 cmꢀ1; 1662.0 cmꢀ1; 1589.6. cmꢀ1
(200 MHz, CDCl3+CD3OD):
;
d
115–116 ꢁC; Rf 0.70; IR (KBr) 3324.3 cmꢀ1
;
J = 6.38 Hz, 3H, CH3), 2.38 (br s, 2H, NH2), 2.49 (br
s, 1H, NH), 2.58–2.59 (m, 2H, CH2), 3.63–3.66 (m,
2979.8 cmꢀ1
; ; ;
1722.5 cmꢀ1 1578.9 cmꢀ1 1H NMR

V. R. Solomon et al. / Bioorg. Med. Chem. 13 (2005) 2157–2165
2163
1H, –CH–CH3), 4.25 (br s, 1H, NH), 6.89–6.91 (d,
J = 5.64 Hz, 1H, 3H quinoline), 7.73–7.80 (dd,
J = 9.16, 2.02 Hz, 1H, 6H quinoline), 7.89 (br s, 1H,
NH), 8.05–8.55 (d, J = 9.02 Hz, 1H, 5H quinoline),
8.56–8.57 (d, J = 1.98 Hz, 1H, 8H quinoline), 9.29–
9.31 (d, J = 5.64 Hz, 1H, 2H quinoline); FAB-MS m/z
278 [M+H]+; Anal. Calcd for C13H17Cl2N5: C, 49.69;
H, 5.45; N, 22.29; found: C, 49.72; H, 5.48; N, 22.45.
1H, 3H quinoline), 7.45–7.49 (dd, J = 9.0, 2.1 Hz, 1H,
6H quinoline), 7.89–7.90 (d, J = 2.1 Hz, 1H, 8H quino-
line), 7.95–7.98 (d, J = 9.00 Hz, 1H, 5H quinoline),
8.49–8.51 (d, J = 5.40 Hz, 1H, 2H quinoline); 32P
NMR (120 MHz, CD3CN) ꢀ159.7 to ꢀ194.7 (sept,
J = 704.0 Hz, 1P, PF6); FAB-MS m/z 320 [M+H]+;
Anal. Calcd for C16H23ClF6N5P: C, 41.26; H, 4.98; N,
15.04 Found: C, 41.60; H, 5.02; N, 15.20.
6.8.3. N-[3-(7-Chloroquinolin-4-ylamino)-propyl]-guan-
idine hydrochloride (5c). This compound was obtained
as white solid in 58% yield. mp 242–244 ꢁC; Rf 0.28;
6.9.2. N-[2-(7-Chloroquinolin-4-ylamino)-propyl]-N0,N0,
N00,N00-tetramethylguanidine hexafluorophosphate (6b).
This compound was obtained as gummy matter in
1
IR (KBr) 3429.5 cmꢀ1
;
3022.5 cmꢀ1
;
2118.4 cmꢀ1
;
58% yield. H NMR (200 MHz, CD3CN) d 1.27–1.30
1637.5 cmꢀ1
;
1217.1 cmꢀ1
;
1H NMR (200 MHz,
(d, J = 6.34 Hz, 3H, CH3), 2.24 (s, 6H, N(CH3)2), 2.89
(s, 6H, N(CH3)2), 2.96–2.99 (m, 2H, CH2), 3.03–3.10
(m, 1H, –CH–CH3), 5.98 (br s, H, NH), 6.06 (br s,
1H, NH), 6.78–6.81 (d, J = 5.34 Hz, 1H, 3H quinoline),
7.30–7.35 (dd, J = 9.02, 2.12 Hz, 1H, 6H quinoline),
7.89–7.90 (d, J = 2.02 Hz, 1H, 8H quinoline), 7.96–
7.99 (d, J = 9.00 Hz, 1H, 5H quinoline), 8.61–8.64 (d,
J = 5.36 Hz, 1H, 2H quinoline); FAB-MS m/z 334
[M+H]+; Anal. Calcd for C17H25ClF6N5P: C, 42.55;
H, 5.25; N, 14.60; found: C, 42.86; H, 5.29; N, 14.98.
CDCl3+CD3OD): d 1.68–1.74 (m, 2H, CH2), 2.39 (br
s, 2H, NH2), 2.52 (br s, 1H, NH), 3.21–3.44 (m, 4H,
CH2), 4.33 (br s, 1H, NH), 5.68 (br s, 1H, NH), 6.38–
6.41 (d, J = 5.36 Hz, 1H, 3H quinoline), 7.32–7.36 (dd,
J = 8.98, 1.96 Hz, 1H, 6H quinoline), 7.79–7.80 (d,
J = 1.98 Hz, 1H, 5H quinoline), 8.12–8.16 (d, J =
8.96 Hz, 1H, 8H quinoline), 8.38–8.41 (d, J = 5.38 Hz,
1H, 2H quinoline); FAB-MS m/z 288 [M+H]+; Anal.
Calcd for C13H17Cl2N5: C, 46.69; H, 5.45; N, 22.29;
found: C, 47.04; H, 5.57; N, 22.35.
6.9.3. N-[3-(7-Chloroquinolin-4-ylamino)-propyl]-N0,N0,
N00,N00-tetramethylguanidine hexafluorophosphate (6c).
This compound was obtained as gummy matter in
6.8.4. N-[4-(7-Chloroquinolin-4-ylamino)-butyl]-guanidine
hydrochloride (5d). This compound was obtained as
white solid in 54% yield. Mp 109–110 ꢁC; Rf 0.29; IR
1
55% yield. H NMR (200 MHz, CD3CN) d 1.90–1.93
(KBr)
3428.5 cmꢀ1
;
3024.5 cmꢀ1
;
;
2116.4 cmꢀ1
;
(m, 2H, CH2), 2.31 (s, 6H, N(CH3)2), 2.64–2.67 (m,
2H, CH2), 2.91 (s, 6H, N(CH3)2), 2.96–2.99 (m, 2H,
CH2), 5.92 (br s, 1H, NH), 6.15 (br s, 1H, NH), 6.27–
1635.5 cmꢀ1
;
1214.1 cmꢀ1
1H NMR (200 MHz,
CDCl3+CD3OD): d 1.69–1.85 (m, 4H, CH2), 1.91 (br
s, 2H, NH2), 2.76 (br s, 1H, NH), 3.17–3.29 (m, 4H,
CH2), 4.53 (br s, 1H, C@NH), 5.65 (br s, 1H, NH),
6.38–6.41 (d, J = 5.12 Hz, 1H, 3H quinoline), 7.30–
7.35 (dd, J = 9.02, 2.02 Hz, 1H, 6H quinoline), 7.69–
7.74 (d, J = 8.98 Hz, 1H, 5H quinoline), 7.93–7.94 (d,
J = 1.98 Hz, 1H, 8H quinoline), 8.44–8.47 (d,
J = 5.16 Hz, 1H, 2H quinoline); FAB-MS m/z 292
[M+H]+; Anal. Calcd for C14H19Cl2N5: C, 51.23; H,
5.83; N, 21.34; found: C, 51.33; H, 5.97; N, 21.35.
6.29
(d,
J = 5.60 Hz,
1H,
3H
quinoline),
7.32–7.36 (dd, J = 9.0, 1.98 Hz, 1H, 6H quinoline),
7.92–7.93 (d, J = 1.96 Hz, 1H, 8H quinoline), 8.00–
8.40 (d, J = 8.96 Hz, 1H, 5H quinoline), 8.48–8.51 (d,
J = 5.58 Hz, 1H, 2H quinoline); FAB-MS m/z
334 [M+H]+; Anal. Calcd for C17H25ClF6N5P: C,
42.55; H, 5.25; N, 14.60; found: C, 42.75; H, 5.32; N,
14.56.
6.9.4.
N-[4-(7-Chloroquinolin-4-ylamino)-butyl]-N0,N0,
6.9. General synthetic procedure for N-[(7-chloroquinolin-
4-ylamino)-alkyl]-tertramethylguanidine hexafluorophos-
phate (6a–d)
N00,N00-tetramethylguanidine hexafluorophosphate (6d).
This compound was obtained as gummy matter in
1
55% yield. H NMR (200 MHz, CD3CN) d 1.41–1.60
(m, 4H, CH2), 2.46 (s, 6H, N(CH3)2), 2.94 (s, 6H,
N(CH3)2), 3.14–3.36 (m, 4H, CH2), 5.66 (br s, 1H,
NH), 6.10 (br s, 1H, NH), 6.34–6.37 (d, J = 5.52 Hz,
1H, 3H quinoline), 7.36–7.42 (dd, J = 8.96, 2.02 Hz,
1H, 6H quinoline), 7.92–7.93 (d, J = 1.96 Hz, 1H, 8H
quinoline), 8.00–8.40 (d, J = 8.96 Hz, 1H, 5H quino-
line), 8.46–8.48 (d, J = 5.37 Hz, 1H, 2H quinoline);
FAB-MS m/z 350 [M+H]+; Anal. Calcd for
C18H27ClF6N5P: C, 43.78; H, 5.51; N, 14.18; found: C,
43.96; H, 5.84; N, 14.22.
HBTU (2-1H-benzotriazol-1-yl)-1,1,3,3-tertamethyluro-
nium hexaflurophosphate (4.6 mmol) and 4-aminoquino-
line derivatives (3a–d) (3 mmol) were stirred at room
temp for 8 h in dry acetonitrile. Solvent was removed,
and the residue was treated with 5% aq NaHCO3, fol-
lowed by extraction with dichloromethane (2·). After
brine wash, the crude product was chromatography over
LH-20 using chloroform–methanol.
6.9.1.
N-[2-(7-Chloroquinolin-4-ylamino)-ethyl]-N0,N0,
N00,N00-tetramethylguanidine hexafluorophosphate (6a).
This compound was obtained as gummy matter in
6.10. General synthetic procedure for [(7-chloroquinolin-
4-ylamino)-alkyl]-carbamic acid tert-butyl ester (7a–d)
52% yield. IR (neat) 3391.1 cmꢀ1
;
2926.8 cmꢀ1
;
;
2370.9 cmꢀ1; 2144.1 cmꢀ1; 1580.3 cmꢀ1; 1425.1 cmꢀ1
1221.4 cmꢀ1 1137.3 cmꢀ1 1080.7 cmꢀ1
A mixture of 4,7-dichloroquinoline 1 (2.5 g, 12.5 mmol)
and monoprotected 1,2-diaminoalkane (25 mmol) were
heated slowly from room temp to 80 ꢁC over 1 h with
stirring and subsequently at 120–130 ꢁC for 6–8 h with
continued stirring to drive the reaction to completion.
;
;
;
1H NMR
(300 MHz, CD3CN) d 2.24 (s, 6H, N(CH3)2), 2.86 (s,
6H, N(CH3)2), 3.49–3.57 (m, 4H, CH2), 5.95 (br s, 1H,
NH), 6.06 (br s, 1H, NH), 6.56–6.58 (d, J = 5.40 Hz,

2164
V. R. Solomon et al. / Bioorg. Med. Chem. 13 (2005) 2157–2165
The reaction mixture was cooled to room temp and
taken up in dichloromethane. The organic layer was suc-
cessively washed with 5% aq NaHCO3 followed by
water and then finally with brine. The organic layer
was dried over anhydrous Na2SO4 and solvent was
removed under reduced pressure to get a final product.
7.32–7.37 (dd, J = 8.91, 1.84 Hz, 1H, 6H quinoline),
7.71–7.75 (d, J = 8.94 Hz, 1H, 5H quinoline), 7.95–
7.96 (d, J = 1.86 Hz, 1H, 8H quinoline), 8.45–8.48 (d,
J = 5.37 Hz, 1H, 2H quinoline); FAB-MS m/z 350
[M+H]+; Anal. Calcd for C18H24ClN3O2: C, 61.79; H,
6.91; N, 12.01; found: C, 61.84; H, 7.02; N, 12.31.
6.10.1. [2-(7-Chloroquinolin-4-ylamino)-ethyl]-carbamic
acid tert-butyl ester (7a). This compound was obtained
as white solid in 75% yield. Mp 98–100 ꢁC; Rf 0.57; IR
Acknowledgements
1
(KBr) 3313.2 cmꢀ1; 1582.6 cmꢀ1; H NMR (200 MHz,
CDCl3): d 1.44 (s, 9H, –NH–COO–C(CH3)3), 3.29–
3.39 (m, 2H, CH2), 3.62–3.74 (m, 2H, CH2), 4.95 (br s,
1H, NH), 5.61 (br s, 1H, NH), 6.38–6.41 (d,
J = 5.34 Hz, 1H, 3H quinoline), 7.32–7.37 (dd,
J = 8.96, 1.94 Hz, 1H, 6H quinoline), 7.73–7.77
(d, J = 8.92 Hz, 1H, 5H quinoline), 7.94–7.95 (d, J =
1.96 Hz, 1H, 8H quinoline), 8.59–8.62 (d, J = 5.34 Hz,
1H, 2H quinoline); FAB-MS m/z 322 [M+H]+; Anal.
Calcd for C16H20ClN3O2: C, 59.72; H, 6.26; N, 13.06;
found: C, 60.04; H, 6.41; N, 13.45.
The authors thank the Director, CDRI for the support
and the SAIF for the spectral data. One of the authors
V.R.S. thanks the CSIR, New Delhi for Senior Research
Fellowship. CDRI communication no. 6691.
References and notes
1. Wiesner, J.; Ortmann, R.; Schlitzer, M. Angew. Chem., Int.
Ed. 2003, 42, 5274.
2. Winstanely, P. A.; Breckenridge, A. M. Ann. Trop. Med.
Parasitol. 1987, 81, 619.
6.10.2. [2-(7-Chloroquinolin-4-ylamino)-propyl]-carbamic
acid tert-butyl ester (7b). This compound was obtained
as white solid in 68% yield. Mp 209–210 ꢁC; Rf 0.54;
3. (a) Homewood, C. A.; Warhurst, D. C.; Peters, W.;
Baggaley, V. C. Nature 1972, 235, 50; (b) Krogstad, D. J.;
Schlesinger, P. H. Biochem. Pharmacol. 1986, 35, 547; (c)
Schlesinger, P. H.; Krogstad, D. J.; Herwaldt, B. L.
Antimicrob. Agents Chemother. 1988, 32, 793; (d) Hawley,
S. R.; Bray, P. G.; OÕNeill, P. M.; Park, B. K.; Ward, S. A.
Biochem. Pharmacol. 1996, 52, 723; (e) Hawley, S. R.;
Bray, P. G.; Mungthin, M.; Atkinson, J. D.; OÕNeill, P.
M.; Ward, S. A. Antimicrob. Agents Chemother. 1998, 42,
682.
IR (KBr) 3320.9 cmꢀ1
; ; ;
2981.3 cmꢀ1 1705.8 cmꢀ1
1
1579.3 cmꢀ1; H NMR (200 MHz, CDCl3): d 1.32–1.35
(d, J = 6.64 Hz, 3H, CH3), 1.44 (s, 9H, –NH–COO–C
(CH3)3), 2.43–2.72 (m, 2H, CH2), 3.42–3.47 (m, 1H,
CH3–CH–), 5.42 (br s, 1H, NH), 6.36–6.39 (d,
J = 5.42 Hz, 1H, 3H quinoline), 7.32–7.38 (dd, J =
8.94, 1.86 Hz, 1H, 6H quinoline), 7.72–7.77 (d, J =
9.02 Hz, 1H, 5H quinoline), 7.97–7.98 (d, J = 1.92 Hz,
1H, 8H quinoline), 8.22–8.25 (d, J = 5.46 Hz, 1H, 2H
quinoline), 8.42 (br s, 1H, NH); FAB-MS m/z 336
[M+H]+; Anal. Calcd for C17H22ClN3O2: C, 60.80; H,
6.60; N, 12.51; found: C, 60.96; H, 7.02; N, 12.75.
4. (a) Bray, P. G.; Howells, R. E.; Ward, S. A. Biochem.
Pharmacol. 1992, 43, 1219; (b) Bray, P. G.; Howells, R. E.;
Ritchie, G. Y.; Ward, S. A. Biochem. Pharmacol. 1992, 44,
1317.
5. (a) Warhurst, D. C. Biochem. Pharmacol. 1981, 30, 3323;
(b) Goldberg, D. E.; Slater, A. F. G.; Cerami, A.;
Henderson, G. B. Proc. Natl. Acad. Sci. U.S.A. 1990, 87,
2931; (c) Ridley, R. G. J. Pharm. Pharmacol. 1997, 49(2),
43; (d) Egan, T. J.; Hunter, R.; Kaschula, C. H.; Marques,
H. M.; Misplon, A.; Waldon, J. C. J. Med. Chem. 2000,
43, 283; (e) Kaschula, C. H.; Egan, T. J.; Hunter, R.;
Basilico, N.; Parapani, S.; Tarameli, D.; Pasini, E.; Monti,
D. J. Med. Chem. 2002, 45, 3531; (f) Ridley, R. G. Nature
2002, 415, 686.
6. (a) Ridley, R. G.; Hofheinz, Z.; Matile, H.; Jaquet, C.;
Dorn, A.; Masciadri, R.; Jolidon, S.; Richter, W. F.;
Guenzi, A.; Girometta, M. A.; Urwyler, H.; Thaithong, S.;
Peters, W. Antimicrob. Agents Chemother. 1996, 40, 1846;
(b) De, D.; Krogstad, F. M.; Byers, L. D.; Krogstad, D. J.
J. Med. Chem. 1998, 41, 4918; (c) Biot, C.; Glorian, G.;
Maciejewski, L. A.; Brocard, J. S. J. Med. Chem. 1997, 40,
3715.
7. Stocks, P. A.; Raynes, K. J.; Bray, P. G.; Park, B. K.;
OÕNeill, P. M.; Ward, S. A. J. Med. Chem. 2002, 45,
4975.
8. Surrey, A. R.; Cutler, R. A. J. Am. Chem. Soc. 1951, 73,
2623.
9. Greenhill, J. V.; Lue, P. Amidines and Guanidines in
Medicinal Chemistry. In Progress in Medicinal Chemistry;
Ellis, G. P., Luscombe, D. K., Eds.; Elsevier Sciences:
Amsterdam, The Netherlands, 1993; Vol. 30, pp 203.
10. Guanidines: Historical, Biological, Biochemical and Clinical
Aspects of the Naturally Occurring Guanido Compounds;
6.10.3. [3-(7-Chloroquinolin-4-ylamino)-propyl]-carbamic
acid tert-butyl ester (7c). This compound was obtained
as white solid in 70% yield. Mp 137–138 ꢁC; Rf 0.52;
IR (KBr) 3378.9 cmꢀ1
; ; ;
2236.7 cmꢀ1 1705.4 cmꢀ1
1216.4 cmꢀ1; H NMR (200 MHz, CDCl3): d 1.44 (s,
9H, –NH–COO–C(CH3)3), 1.61–1.64 (m, 2H, CH2),
3.16–3.21 (m, 4H, CH2), 3.26 (br s, 1H, NH), 4.91 (br
s, 1H, NH), 6.30–6.33 (d, J = 5.64 Hz, 1H, 3H quino-
line), 7.34–7.39 (dd, J = 8.94, 1.86 Hz, 1H, 6H quino-
line), 7.63–7.68 (d, J = 9.00 Hz, 1H, 5H quinoline),
7.99–8.00 (d, J = 2.02 Hz, 1H, 8H quinoline),
8.21–8.24 (d, J = 5.62 Hz, 1H, 2H quinoline); FAB-MS
m/z 336 [M+H]+; Anal. Calcd for C17H22ClN3O2: C,
60.80; H, 6.60; N, 12.51; found: C, 60.92; H, 6.72; N,
12.55.
1
6.10.4. [4-(7-Chloroquinolin-4-ylamino)-butyl]-carbamic
acid tert-butyl ester (7d). This compound was obtained
as white solid in 68% yield. Mp 144–146 ꢁC; Rf 0.55;
IR (KBr) 3313.2 cmꢀ1
;
1582.6 cmꢀ1
;
1H NMR
(200 MHz, CDCl3):
d 1.44 (s, 9H, –NH–COO–
C(CH3)3), 1.51–1.53 (m, 2H, CH2), 1.54–1.56 (m, 2H,
CH2), 3.12–3.17 (m, 2H, CH2–NH–), 3.31–3.35 (m,
2H, –NH–CH2–), 4.65 (br s, 1H, NH), 5.64 (br s, 1H,
NH), 6.38–6.41 (d, J = 5.09 Hz, 1H, 3H quinoline),

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12. Puri, S. K.; Singh, N. Expl. Parasit. 2000, 94, 8.
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M. J. Inorg. Biochem. 1997, 68, 137; (b) Egan, T. J.;
Marques, H. M. Coord. Chem. Rev. 1999, 190, 493.
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Anal. Chem. 2004, 325, 85.