Pharmacologically relevant bifunctional compounds containing chloroquinoline and dihydropyrimidone moieties: Syntheses and crystal structures of a target molecule and selected intermediates

Article abstract of DOI:10.1007/s10870-009-9568-2

We report the regioselective synthesis and X-ray structure of the pharmacologically relevant 3-[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-4- (4-methoxy-phenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5- carboxylic acid methyl ester (3) (tri

Full text of DOI:10.1007/s10870-009-9568-2

J Chem Crystallogr (2009) 39:753–760
DOI 10.1007/s10870-009-9568-2
ORIGINAL PAPER
Pharmacologically Relevant Bifunctional Compounds Containing
Chloroquinoline and Dihydropyrimidone Moieties: Syntheses
and Crystal Structures of a Target Molecule and Selected
Intermediates
Nicholas D. Watermeyer Æ Kelly Chibale Æ
Mino R. Caira
Received: 11 July 2008 / Accepted: 23 March 2009 / Published online: 3 April 2009
Ó Springer Science+Business Media, LLC 2009
Abstract We report the regioselective synthesis and
X-ray structure of the pharmacologically relevant 3-[2-(7-
chloro-quinolin-4-ylamino)-ethylcarbamoyl]-4-(4-methoxy-
phenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-
Keywords Dihydropyrimidone ꢀ Chloroquinoline ꢀ
Bifunctional compounds ꢀ Crystal structure
ꢀ
5-carboxylic acid methyl ester (3) (triclinic, space group P1,
Introduction
˚
a = 11.1775 (3), b = 13.6470 (4), c = 16.3680 (6) A, a =
82.645 (1), b = 86.423 (1), c = 88.415 (2)°, V = 2470.9 (1)
The synthesis of 4-aryl-3,4-dihydropyrimidin-2(1H)-ones
(DHPMs) was first reported in 1893 by Biginelli [1] who
developed a multi-component reaction to produce these
highly functionalised heterocyclic compounds in a one-pot
process [2]. Recent pharmacological interest in DHPMs (1,
Fig. 1) arises from their structural similarity to the well-
known Hantzsch dihydropyridine (DHP) 2 calcium channel
modulators [2, 3]. Since the discovery that DHPMs exhibit
a similar pharmacological profile to nifedipine-type DHP
calcium channel modulators, much activity has been
reported in this area [4–7]. Since the 1990s, DHPM
derivatives have shown activity in a range of other phar-
macological areas, including a1a adrenoceptor-selective
antagonism (for the treatment of benign prostatic hyper-
plasia) [8, 9], anti-tuberculosis [10], and anti-cancer
treatment (as inhibitors of the mitotic kinesin protein, Eg5)
[11–13].
3
A , Z = 4). Further support for the regioselectivity is pro-
˚
vided by the X-ray structures of two intermediates, namely 4-
(4-methoxy-phenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylic acid methyl ester, 8 (monoclinic,
space group P21/c, a = 11.7710 (2), b = 5.5290 (1),
3
˚
˚
c = 22.9500 (5) A, b = 104.342 (1)°, V = 1447.08 (5) A ,
Z = 4), and 4-(4-methoxy-phenyl)-1,3,6-trimethyl-2-oxo-
1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl
ester, 9 (monoclinic, space group P21/c, a = 16.6529 (7),
˚
b = 10.9426 (4), c = 8.2819 (3) A, b = 91.395 (2)°,
3
V = 1508.7 (1) A , Z = 4), which are also reported. The
˚
three compounds display significant differences in the con-
formations of their DHPM rings as well as a variety of
hydrogen bonding arrangements in their crystals.
Within the context of malaria treatment, various calcium
channel modulators have been shown to exhibit synergistic
properties with quinoline-containing antimalarials against
drug-resistant Plasmodium parasite strains [14]. Similarly,
Peyton and co-workers have shown that covalently linking
a resistance reversing agent to a quinoline-containing
functionality is a viable means of overcoming parasite drug
resistance [15]. In the search for novel antimalarial agents,
we set out to design a bifunctional compound containing a
DHPM resistance reversing agent covalently linked to a 4-
amino-7-chloroquinoline antimalarial pharmacophore. The
target molecule 3 (Fig. 2) was designed to combine two
N. D. Watermeyer ꢀ K. Chibale (&) ꢀ M. R. Caira (&)
Department of Chemistry, University of Cape Town,
Rondebosch 7701, South Africa
e-mail: Kelly.Chibale@uct.ac.za
M. R. Caira
e-mail: Mino.Caira@uct.ac.za
K. Chibale
Institute of Infectious Disease and Molecular Medicine,
University of Cape Town, Rondebosch 7701, South Africa
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J Chem Crystallogr (2009) 39:753–760
Synthesis and Characterization of 4-(4-Methoxy-Phenyl)-
1,6-Dimethyl-2-Oxo-1,2,3,4-Tetrahydro-Pyrimidine-5-
Carboxylic Acid Methyl Ester, 8, and 4-(4-Methoxy-
Phenyl)-1,3,6-Trimethyl-2-Oxo-1,2,3,4-Tetrahydro-
Pyrimidine-5-Carboxylic Acid Methyl Ester, 9
To a suspension of a 60% oil dispersion of NaH (0.478 g
(60%), 11.99 mmol) in DMF (10 mL) at 0 °C was added a
solution of 7 (3.0 g, 10.90 mmol) in DMF (5 mL) at 0 °C.
After the mixture was stirred for 30 min at 0 °C, a solution
of methyl iodide (1.70 g, 11.99 mmol) in DMF (1 mL) was
added to the reaction mixture which was stirred at 25 °C
for 45 min. TLC analysis indicated complete conversion of
starting material to product. The reaction mixture was
diluted with water (50 mL) and extracted with EtOAc
(3 9 50 mL). The organic extracts were combined, washed
with brine (50 mL), water (5 9 50 mL), dried over
MgSO4, filtered and concentrated in vacuo to yield a white
residue. The desired pure product, 8 and a byproduct, 9
were separated by column chromatography on SiO2 gel
using Et2O/CH2Cl2 (1:9) as eluent.
Fig. 1 Structural differences between Biginelli DHPMs and Han-
tzsch DHPs
Fig. 2 Structure of the target DHPM derivative, 3
Spectroscopic characterization of 8: White solid (0.40 g,
76%), m.p. 149–151 °C; Rf (Et2O:CH2Cl2, 1:9) 0.56; IR
mmax (CH2Cl2)/cm-1 3,300 (N–H), 3,052 (C–H), 1,696
(C=O) and 1,628 (C=O); dH(400 MHz, CDCl3) 7.18 (2H,
d, J 8.8, H-20 and H-60), 6.82 (2H, d, J 8.8, H-30 and H-50),
5.60 (1H, s, NH), 5.38 (1H, s, H-4), 3.77 (3H, s, CO2Me),
3.64 (3H, s, ArOCH3), 3.21 (3H, s NCH3-1), and 2.50 (3H,
s, CH3-6); dC(100 MHz, CDCl3) 167.0 (C=O), 159.0, 154.0
(C=O), 149.5, 135.0, 127.5 (2C), 114.3 (2C), 110.0, 55.5,
53.5, 51.5, 30.5 and 16.8; LRMS (EI) m/z 290 (60%, M?);
Found: C, 62.15; H, 6.16; N, 9.57%; Anal. Calc.: C, 62.06;
H, 6.25; N, 9.65% for C15H18N2O4.
functionalities into a single compound capable of inducing
chemosensitisation, as well as parasite termination medi-
ated by the chloroquinoline. Here, we report the synthesis
and X-ray structure of both the target molecule 3 as well as
those of two of its intermediates.
Experimental
Synthesis
Spectroscopic characterization of 9: White solid (0.19 g,
6%), m.p. 86–87 °C; Rf (Et2O:CH2Cl2, 1:9) 0.18; IR mmax
(CH2Cl2)/cm-1 3,398 (N–H), 3,052 (C–H), 1,778 (C=O)
and 1,638 (C=O); dH(400 MHz, CDCl3) 7.18 (2H, d, J 8.8,
H-20 and H-60), 6.82 (2H, d, J 8.8, H-30 and H-50), 5.20 (1H,
s, H-4), 3.78 (3H, s, CO2Me), 3.67 (3H, s, ArOCH3), 3.26
(3H, s NCH3-1), 2.90 (3H, s, NCH3-3) and 2.73 (3H, s,
CH3-6); dC(100 MHz, CDCl3) 167.0 (C=O), 159.0, 154.0
(C=O), 149.5, 135.0, 127.9 (2C), 114.2 (2C), 110.0, 55.5,
53.5, 51.5, 32.0, 30.0 and 16.8; LRMS (EI) m/z 304 (75%,
M?); Found: C, 63.25; H, 6.58; N, 9.15%; Anal. Calc.: C,
63.14; H, 6.62; N, 9.20% for C16H20N2O4.
The target compound 3 was synthesised in five steps, as
outlined in Scheme 1. The first step involved the formation
of the Biginelli dihydropyrimidinone 7, in a one-pot reac-
tion catalysed by CeCl3 ꢀ 7H2O. This was followed by N-
methylation resulting in 8 and a dimethylated by-product,
9. The regioselectivity of this step was confirmed by X-ray
analysis of 8, identifying the site of methylation as N1. The
X-ray structure of 9 was determined to confirm double
methylation. Reaction of 8 with phenyl chloroformate in
the presence of NaH gave carbamate 10. This functionality
provided a chemoselectively superior point of attachment
over the methyl ester at the 5-position.
Synthesis and Characterization of 3-[2-(7-Chloro-
Quinolin-4-Ylamino)-Ethylcarbamoyl]-4-(4-Methoxy-
Phenyl)-1,6-Dimethyl-2-Oxo-1,2,3,4-Tetrahydro-
Pyrimidine-5-Carboxylic Acid Methyl Ester, 3
The N-(7-chloroquinolin-4-yl)ethylenediamine 11 was
synthesised in a simple one-step reaction from 4,7-
dichloroquinoline and ethylene diamine, according to a
reported procedure [16] and reacted with 10 to give target
molecule 3. Synthetic procedures for 8, 9 and 3 follow with
details of their characterization.
To a stirred mixture of 10 (0.20 g, 0.50 mmol) and K2CO3
in THF (10 mL) at 25 °C under an argon atmosphere was
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755
Scheme 1 Reagents and
Conditions: (i) CeCl3ꢀ7H2O,
ethanol, reflux, 3 h, 94%; (ii)
1.1 eq. NaH, anhydrous DMF,
0 °C, 30 min; 1.0 eq. MeI, rt.,
45 min, 61% (iii) 11.0 eq. NaH,
0 °C; 10.0 eq. phenyl
chloroformate, THF, 60 °C,
86%, (iv) K2CO3, THF,
ethylene diamine, nitrogen
atmosphere, 25 °C, 15 h, 97%
˚
added a solution of diamine 11 (0.50 mmol) in THF
(15 mL) and stirring was continued for 2 h. TLC analysis
indicated complete conversion of starting material to
product. The solvent was removed under reduced pressure
and the residue obtained was redissolved in CH2Cl2
(50 mL). The solution was washed with 5% NaHCO3
(3 9 25 mL), brine (50 mL), dried over MgSO4 and fil-
tered. The solvent was reduced in vacuo and the residue
obtained was purified by column chromatography using
MeOH/CH2Cl2 (1:9) as eluent to give the desired product.
Spectroscopic characterization of 3: White solid (0.25 g,
97%), m.p. 98–100 °C; Rf (MeOH:CH2Cl2, 1:19) 0.35; IR
mmax (CH2Cl2)/cm-1 3,320 (N–H), 2,987 (C–H), 1,765
(C=O), 1,693 (C=O) and 1,638 (C=O); dH(400 MHz,
CDCl3) 9.20 (1H, bt, J 6.4, NH-1200), 8.40 (1H, d, J 5.6, H-
200), 7.88 (1H, d, J 2.0, H-800), 7.67 (1H, d, J 9.2, H-500),
7.22 (1H, dd, J 2.0 and 9.2, H-600), 7.19 (1H, bs, NH-900),
7.02 (2H, d, J 9.2, H-20 and H-60), 6.76 (1H, s, H-4), 6.54
(2H, d, J 9.2, H-30 and H-50), 6.24 (1H, d, J 5.6, H-300), 3.80
(2H, q, J 5.2, CH2-1100), 3.77 (3H, s, CO2Me), 3.66 (3H, s,
ArOCH3), 3.38 (2H, q, J 5.2, CH2-1000), 3.14 (3H, s,
NCH3), 2.51 (3H, s, CH3-6); dC(100 MHz, CDCl3) 165.8
(C=O), 159.0 (C=O), 156.8, 154.4 (C=O), 151.4, 150.7,
148.6, 148.5, 135.4, 131.6, 128.0, 127.8, 127.7, 125.7,
122.2, 117.3, 114.2 (2C), 108.2, 98.4, 55.3, 52.1, 51.5,
46.0, 39.7, 31.6 and 16.2; HRMS (FAB) Found m/z
537.17355 [M ? 1]? C27H28ClN5O5 requires 537.17790;
Found: C, 60.08; H, 5.20; N, 12.98%; Anal. Calc.: C,
60.28; H, 5.25; N, 13.02% for C27H28ClN5O5.
monochromated Mo–Ka radiation (k = 0.71073 A) on a
Nonius Kappa CCD diffractometer with the crystal speci-
mens cooled to 113(2) K. Data-reduction, including unit
cell refinements and corrections for Lorentz and polariza-
tion effects, were performed with DENZO-SMN [17]. The
structures were solved using program SHELXS-97 [18]
and refined by full-matrix least-squares on F2 with
SHELXL-97 [19]. All H atoms were located unequivocally
in difference electron-density maps and were included in
idealized positions in a riding model with Uiso 1.2–1.5
times those of the parent atoms. All non-H atoms refined
anisotropically. Table 1 lists crystal parameters and details
of the data-collections and refinements.
Results and Discussion
The molecular structures of the intermediates 8 and 9 are
shown in Fig. 3 and selected molecular parameters are
listed in Table 2. In the context of the synthetic pathway
(Scheme 1), the X-ray structure of 8 indicates that the
resonance-stabilised nitrogen atom N1 (corresponding to
N4 in Fig. 3) of the DHPM ring of 7 was regioselectively
methylated. In 8, the heterocyclic ring is slightly puckered
˚
(Q = 0.151(2) A, h = 74.2(6)°, / = 46.0(7)°) [20] with
the endocyclic torsion angles listed in Table 2 (magnitude
range *1–17) defining the precise conformation. The
mean plane of the p-methoxyphenyl substituent bisects the
heterocyclic ring symmetrically (dihedral angle N4ꢀꢀꢀC1–
C14–C15 = 4.3(2)°). The bond lengths in the heterocyclic
ring correspond to those observed in the closely related
molecule, methyl-1,6-dimethyl-4(-3-nitrophenyl)-2-oxo-
1,2,3,4-terahydropyrimidine-5-carboxylate [21], which
differs from 8 only by substitution of the p-methoxyphenyl
X-Ray Crystallography
Intensity data for the intermediate compounds 8 and 9, and
the target compound 3 were collected with graphite-
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757
˚
Table 2 Selected bond distances (A), angles (°) and torsion angles
(°) in 8 and 9
Compound 8
Cl–N2
1.455(2)
1.334(2)
1.391(2)
127.5(2)
117.1(2)
121.6(1)
9.2(3)
N4–C5
1.395(2)
1.361(2)
1.514(2)
120.4(1)
121.5(1)
109.5(1)
12.3(2)
N2–C3
C5–C6
C3–N4
C6–C1
C1–N2–C3
N2–C3–N4
C3–N4–C5
C1–N2–C3–N4
N2–C3–N4–C5
C3–N4–C5–C6
N4–C5–C6–C1
Compound 9
Cl–N2
N4–C5–C6
C5–C6–C1
C6–C1–N2
C5–C6–C1–N2
C6–C1–N2–C3
C5–C6–C10–O11
N2–C1–C14–C15
5.1(2)
-17.1(2)
19.5(3)
-8.8(2)
-1.0(3)
-55.4(2)
1.476(2)
1.353(2)
1.405(3)
122.6(2)
116.1(2)
122.4(1)
23.3(2)
N4–C5
1.393(2)
1.360(2)
1.505(3)
119.7(2)
120.4(2)
109.5(1)
24.3(2)
N2–C3
C5–C6
C3–N4
C6–C1
C1–N2–C3
N2–C3–N4
C3–N4–C5
C1–N2–C3–N4
N2–C3–N4–C5
C3–N4–C5–C6
N4–C5–C6–C1
N4–C5–C6
C5–C6–C1
C6–C1–N2
C5–C6–C1–N2
C6–C1–N2–C3
C5–C6–C11–O12
N2–C1–C15–C16
3.3(2)
-35.9(2)
2.8(3)
-13.4(2)
-2.3(3)
-55.6(2)
Molecular stabilisation occurs via an intramolecular C–
HꢀꢀꢀO bond (Fig. 4) involving a methyl H atom. The figure
also shows a second, centrosymmetric dimeric hydrogen-
bonded motif in the crystal of 8, with the graph-set R22 (8),
based on weaker intermolecular C–HꢀꢀꢀO hydrogen bond-
ing. One remaining C–HꢀꢀꢀO intermolecular hydrogen
˚
bond, with CꢀꢀꢀO 3.472(2) A, contributes to crystal
cohesion.
X-ray analysis of compound 9 (the by-product of 8 in
Scheme 1) proved that it is the dimethylated DHPM spe-
cies. A result of the second methylation is that the distances
N2–C1 and N2–C3 in 9 are significantly longer than their
counterparts in 8 and the heterocyclic ring becomes more
˚
puckered (Q = 0.295(2) A, h = 67.9(3)°, / = 37.9(4)°),
the endocyclic torsion angles spanning the wider magni-
tude range 2.3(2)–35.9(2)° (Table 2). The orientation of the
p-methoxyphenyl residue is virtually unchanged (N2ꢀꢀꢀC1–
C15–C16 = 5.5(2)°) relative to that in the molecule of 8. A
further consequence of N-methylation in 9 is that the type
of dimerisation based on N–HꢀꢀꢀO=C H-bonding displayed
by 8 in its crystal structure is now precluded. However, the
dimeric R22 (8) motif based on C–HꢀꢀꢀO hydrogen bonding
is retained in the crystal structure of 9 (Fig. 4), as is the
intramolecular C–HꢀꢀꢀO hydrogen bond.
Fig. 3 ORTEP diagrams of 8 and 9 showing the crystallographic
numbering (thermal ellipsoids are drawn at the 50% probability level)
moiety by a m-nitrophenyl substituent. Figure 4 shows the
principal motif in the crystal structure of 8, namely a dimer
formed by complementary N–HꢀꢀꢀO=C hydrogen bonding
of type R22 (8) [22] between two molecules related by a
centre of symmetry. H-bond data are listed in Table 3.
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Table 3 Hydrogen bond data
˚
˚
˚
D–HꢀꢀꢀA
D–H/A HꢀꢀꢀA/A DꢀꢀꢀA/A D–HꢀꢀꢀA/°
Compound 8
N2–H2ꢀꢀꢀO7a
0.88
0.95
0.98
1.96
2.52
2.16
2.835(2) 172
3.364(2) 149
2.912(2) 133
C16–H16ꢀꢀꢀO20b
C9–H9CꢀꢀꢀO11
Compound 9
C17–H17ꢀꢀꢀO21c
C9–H9CꢀꢀꢀO12
Compound 3
0.95
0.98
2.51
2.13
3.444(2) 168
2.899(2) 134
N24a–H24aꢀꢀꢀO7a
0.88
1.94
2.30
1.93
2.18
2.15
2.11
2.55
2.57
2.54
2.617(3) 132
3.060(3) 144
2.604(3) 132
2.952(3) 146
2.888(3) 131
2.819(3) 127
3.431(3) 149
3.355(3) 137
3.310(3) 138
N27a–H27aꢀꢀꢀO23a 0.88
N24b–H24bꢀꢀꢀO7b
N27b–H27bꢀꢀꢀO23b 0.88
C9a–H9aꢀꢀꢀO12a
C9b–H9bꢀꢀꢀO12b
C8a–H8bꢀꢀꢀO11bd
C8b–H8eꢀꢀꢀO11ae
C19a–H19aꢀꢀꢀN31af
0.88
0.98
0.98
0.98
0.98
0.95
Symmetry code: (a) = 1 - x, 2 - y, -z; (b) = 2 - x, 1 - y, -z;
(c) = 1 - x, 1 - y, 2 - z; (d) = 1 - x, 1 - y, - z; (e) = 1 - x,
1 - y, 1 - z; (f) = x, - 1 ? y, z
(weighted RMS-fit of inverted molecule a on molecule
˚
b = 0.495 A for all 38 fitted non-hydrogen atoms). Similar
magnitudes, but opposite signs, of corresponding torsion
angles for molecules a and b confirm the symmetry rela-
tionship described above (Table 4). Bond lengths and
angles for the two independent molecules are in close
agreement. For the DHPM unit, these parameters are in
good agreement with those found in compound 9 but the
heterocyclic ring becomes more puckered in 3 following
replacement of the methyl group on N2 in 9 by the
extended linker chain with its pendant chloroquinoline
˚
residue (Q = 0.431(2) A, h = 72.7(3)°, / = 44.5(3)° in
˚
molecule a, Q = 0.409(2) A, h = 106.3(3)°, / = 219.9(4)
in molecule b). Other notable differences in proceeding
from 9 to 3 are the changes in the orientation of the p-
methoxyphenyl substituent (whose plane is now parallel to
the C1–C6 bond) and that of the carbomethoxy group
(rotated *180° around the C6–C10 bond). The chloro-
quinoline rings are planar (max. deviations from their least-
Fig. 4 Hydrogen bonds occurring in the crystal structures of 8 and 9
˚
˚
squares planes are 0.018(2) A for C35a and 0.026(2) A for
C29b).
The overall conformation of molecule 3 is largely
determined by the presence of two intramolecular N–HꢀꢀꢀO
hydrogen bonds (Fig. 5; Table 3) that yield rings with
graph sets R11 (6) and R11 (7). A weaker intramolecular
hydrogen bond C9–H9ꢀꢀꢀO12 (not shown) occurs in each of
the independent molecules of 3, stabilising the orientation
of the carbomethoxy group. Intermolecular interactions in
the crystal of 3 include two C–HꢀꢀꢀO hydrogen bonds and a
X-ray analysis finally confirmed the expected structure
of the bifunctional target molecule 3 which was obtained
by the reaction between N-(7-chloroquinolin-4-yl)ethy-
lenediamine 11 and compound 10 (Scheme 1). The
asymmetric unit in the crystal of compound 3 contains two
molecules (a, b), drawn separately for clarity in Fig. 5. In
the crystal, these are related by a pseudo-inversion centre
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759
˚
Table 4 Selected bond distances (A), angles (°) and torsion angles
(°) in 3
Molecule a
Molecule b
Cl–N2
1.488(3)
1.389(3)
1.380(3)
1.412(3)
1.351(3)
1.507(3)
1.414(3)
1.337(3)
1.456(3)
1.507(3)
1.461(3)
1.361(3)
1.319(3)
1.378(3)
1.740(2)
118.3(2)
114.8(2)
123.3(2)
118.0(2)
118.2(2)
109.0(2)
117.9(2)
120.6(2)
114.5(2)
112.2(2)
121.2(2)
23.9(3)
1.489(3)
1.396(3)
1.375(3)
1.414(3)
1.346(3)
1.503(3)
1.411(3)
1.344(3)
1.461(3)
1.512(3)
1.454(3)
1.359(3)
1.317(3)
1.376(3)
1.740(3)
118.6(2)
115.5(2)
122.6(2)
118.4(2)
119.3(2)
109.1(2)
117.1(2)
120.6(2)
114.2(2)
112.4(2)
123.2(2)
-24.7(3)
-11.4(3)
24.5(3)
N2–C3
C3–N4
N4–C5
C5–C6
C6–C1
N2–C22
C22–N24
N24–C25
C25–C26
C26–N27
N27–C28
C30–N31
N31–C32
C34–Cl1
C1–N2–C3
N2–C3–N4
C3–N4–C5
N4–C5–C6
C5–C6–C1
C6–C1–N2
N2–C22–N24
C22–N24–C25
N24–C25–C26
C25–C26–N27
C26–N27–C28
C1–N2–C3–N4
N2–C3–N4–C5
C3–N4–C5–C6
N4–C5–C6–C1
C5–C6–C1–N2
C6–C1–N2–C3
C1–N2–C22–N24
N2–C22–N24–C25
C22–N24–C25–C26
N24–C25–C26–N27
C25–C26–N27–C28
C26–N27–C28–C29
13.4(3)
-24.3(3)
-3.4(3)
35.7(3)
-0.2(3)
-31.3(3)
44.6(3)
-47.0(3)
163.6(2)
-172.7(2)
-94.2(3)
65.4(3)
-165.6(2)
171.2(2)
90.5(3)
-65.9(3)
-163.6(2)
2.2(4)
173.4(2)
0.2(4)
(Fig. 6). For the a–a0 interaction, the centroid–centroid
0
˚
distance is 3.756(1) A while for that labelled b–b the
˚
distance is 3.823(1) A. This p-stacking pattern propagates
parallel to the crystal c-axis.
Fig. 5 ORTEP diagram of the two independent molecules in the
asymmetric unit of 3 (thermal ellipsoids are drawn at the 40%
probability level)
Regarding biological activity, compound 3 and several
of its analogues have been evaluated for antimalarial, b-
haematin inhibition and cytotoxic activity in in vitro assays
with promising results. These data will be published
elsewhere.
C–HꢀꢀꢀN hydrogen bond (Table 3). Further stabilisation in
the crystal of 3 is effected by p-stacking that involves pairs
of chloroquinoline rings related by inversion centres
123

760
J Chem Crystallogr (2009) 39:753–760
Fig. 6 Stereoview illustrating
p-stacking between
chloroquinoline residues across
inversion centres in the crystal
of 3. The c-axis is horizontal
8. Barrow JC, Nantermet PG, Selnick HG, Glass KL, Rittle KE,
Gilbert KF, Steele TG, Homnick CF, Freidinger RM, Ransom
RW, Kling P, Reiss D, Broten TP, Schorn TW, Chang RSL,
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Mitchison TJ (1999) Science 286:971–974
Supplementary Material
CCDC 689848-689850 contain the supplementary crystal-
lographic data for this paper. These data can be obtained
free of charge at http://www.ccdc.ac.uk/conts/retrieving.
html [or from the Cambridge Crystallographic Data Centre
(CCDC), 12 Union Road, Cambridge CV2 1EZ, UK;
fax: ?44(0)1223-336033; e-mail: deposit@ccdc.cam.uk].
Additional data describing the synthesis and characteriza-
tion of other compounds in Scheme 1 have been included
in the Supplementary Material.
12. Kapoor TM, Mayer TU, Coughlin ML, Mitchison TJ (2000) J
Cell Biol 150:975–988
Acknowledgment We thank the University of Cape Town and the
NRF (Pretoria) for research support.
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