Journal of Chemical Crystallography, Vol. 36, No.

6, June 2006 (
C 2006)

DOI: 10.1007/s10870-006-9082-8

Structures of two N-methylated tricyclic quinolones

with antimalarial activity
Mario V. Capparelli,(1) Jaime E. Charris,(2) and Jose N. Domnguez(2)
Received July 8, 2005; accepted February 13, 2006
Published Online May 13, 2006

The crystal structures of two N-methylated tricyclic quinolones were determined. 3amino-6-methoxy-9-methyl-(1H)pyrazolo[3,4-b]-4-quinolone hydrate, C12 H12 N4 O2 H2 O
b = 13.0614(19) A,
c = 9.0860(15) A,

(1) crystallizes in P-1 with a = 11.5078(18) A,

= 106.229(4) , = 108.378(3) , = 71.118(3) and Z = 4, while 2,4-diamino-10methyl-9-methoxypyrimido[4,5-b]-5-quinolone, C13 H13 N5 O2 (2) crystallizes in P21 /n with
b = 10.1114(17) A,
c = 11.3185(18) A,
= 99.351(4) and Z = 4. Both
a = 10.6643(17) A,
molecules are essentially planar, including the exocyclic groups. 1 and 2 have moderate antimalarial activity which seems to be related to the formation of intramolecular
N H O=C hydrogen bonds; 1 does not form these bonds and has approximately twice
the activity of 2. In both crystal structures there are extensive networks of NH O and
NH N hydrogen bonds, and in 1 the water molecules of solvation form NH Ow,
OwH O=C and OwH Ow bonds.
KEY WORDS: Quinolone; crystal structure; hydrogen bond; antimalarial drug; Plasmodium falciparum.

of quinolone, pyrimidone, pyridopyrimidone,

thiocromone and pyrazole derivatives were synthesized, characterized and tested for antimalarial
activity.519 The title compounds, viz. 3-amino6-methoxy-9-methyl-(1H)pyrazolo[3,4-b]-4-quinolone hydrate, C12 H12 N4 O2 H2 O (1) and
2,4-diamino-10-methyl-9-methoxypyrimido[4,5b]-5-quinolone, C13 H13 N5 O2 (2), were prepared
within that project and were found to have a
moderate in vitro activity against a chloroquineresistant strain of Plasmodium falciparum.20

Introduction
Malaria is believed to affect some 300 to 500
million people worldwide, and to cause one to
three million deaths each year.1 The disease is on
the rise, as Plasmodium falciparum, responsible
for the most malignant forms of malaria, have
developed resistance to chloroquine, the most
widely used anti-malarial drug, through gene mutation.2 Therefore, there is an urgent need for the
development of new antimalarial drugs.3,4
As a part of a general project aimed at finding
new, more effective, antimalarial drugs, a number

Experimental
(1)

Escuela de Qumica, Facultad de Ciencias, Universidad Central

de Venezuela, Apartado 47074, Caracas 1041-A, Venezuela.
(2) Facultad de Farmacia, Universidad Central, de Venezuela, Caracas 1051, Venezuela.
To whom correspondence should be addressed; e-mail: mariocapparelli@cantv.net

Syntheses
Compounds 1 and 2 were synthesized as reported elsewhere.21 Crystals suitable for X-ray
389
C 2006 Springer Science+Business Media, Inc.
1074-1542/06/0600-0389/0

390

Capparelli et al.

Fig. 1. Molecular structure of compound 1 (molecule 1a) showing the atomic numbering. The
displacement parameters are drawn at 50% probability.

Fig. 2. Molecular structure of compound 2 showing the atomic numbering. The displacement parameters are drawn at 50% probability.

Two N-methylated tricyclic quinolones

391

Table 1. Crystal data, intensity data collection parameters and final refinement results
Compound

CCDC deposit No.

(a) Crystal Data:
Formula
Formula weight
Color
Morphology
Specimen size, mm
T (K)

a (A)

b (A)

c (A)
( )
( )
( )
V (A 3 )
Crystal system
Space group
Z
Dc (g/cm3 )
F(000)
Radiation

Wavelength (A)
(mm1 )
No. refls. for cell
Range for cell ( )
(b) Data collection:
range ( )
h range
k range
l range
No. refls. unique
No. refls. with I > 2 (I)
Mean I/I for checks (%)
(c) Refinement (last cycle):
No. params. refined
No. of restrains
R1 [I > 2 (I), all data]
wR2 [I > 2 (I), all data]
S (gof) (all data)
/ max
/ mean
 max ,  min (e A 3 )

CCDC 277123

CCDC 277124

C12 H14 N4 O3
262.27
light yellow
irregular
0.48 0.35 0.30
298(2)
9.0860(15)
11.5078(18)
13.0614(19)
71.118(3)
73.771(4)
71.622(3)
1202.1(3)
triclinic
P-1
4
1.449
552
Cu-K
1.54178
0.896
25
16.822.1

C13 H13 N5 O2
271.28
light yellow
prism
0.45 0.35 0.26
298(2)
10.6643(17)
10.1114(17)
11.3185(18)

3.6557.50
9, 9
12, 0
14, 13
3293
2488
0.12

2.4330.01
0, 15
0, 14
15, 15
3467
2131
0.55

377
0
0.0463, 0.0685
0.1083, 0.1213
1.039
<0.0005
<0.0005
0.173, 0.201

198
0
0.0549, 0.1018
0.1427, 0.1605
1.080
<0.0005
<0.0005
0.308, 0.199

diffraction were obtained by the slow evaporation

of solutions in EtOH/TFA(1) and EtOH (2).
Spectroscopy
The IR spectra were measured with a
Shimadzu IR 470 spectrophotometer. IR data

99.351(4)
1204.3(3)
monoclinic
P21 /n
4
1.496
568
Mo-K
0.71069
0.106
25
9.812.6

[KBr pellet, , cm1 ]. 1: 3440 (m, NH2 ), 3244

(m, NH2 ), 1622 (s, CO); 2: 3408 (m, NH2 ), 3104
(m, NH2 ), 1660 (s, CO).
The NMR spectra were recorded on Jeol
EX 270 MHz and Bruker 500 FT (500 MHz)
spectrometers.1 H NMR data (DMSO-d6 /TMS, ,
ppm) 1: 3.61(s, 3H, NCH3 ), 3.81 (s, 3H, OCH3 ),
6.33 (s, 2H, NH2 ), 7.27 (dd, 1H, H3 , J: 9.1 Hz),

392

Capparelli et al.

) for compound 1
Table 2. Geometric parameters (A,
Molec. a

Molec. b

(a) Bond lengths

C1C2
C1C6
C2C3
C2O14
C3C4
C4C5
C5C6
C5N10
C6C7
C7C8
C7O16
C8C9
C8C11
C9N10
C9N13
N10C17
C11N12
C11N18
N12N13
O14C15

1.371(4)
1.392(4)
1.390(4)
1.378(3)
1.375(4)
1.400(4)
1.407(3)
1.396(3)
1.474(3)
1.406(3)
1.253(3)
1.397(3)
1.428(4)
1.351(3)
1.334(3)
1.463(3)
1.324(3)
1.362(3)
1.398(3)
1.427(3)

1.370(4)
1.383(4)
1.388(4)
1.371(3)
1.368(4)
1.393(4)
1.417(4)
1.398(3)
1.474(3)
1.400(4)
1.259(3)
1.396(3)
1.429(4)
1.348(3)
1.335(3)
1.469(3)
1.315(3)
1.365(3)
1.399(3)
1.423(3)

(b) Bond angles

C2C1C6
C1C2C3
C1C2O14
C3C2O14
C2C3C4
C3C4C5
C4C5C6
C4C5N10
C6C5N10
C1C6C5
C1C6C7
C5C6C7
C6C7C8
C6C7O16
C8C7O16
C7C8C9
C7C8C11
C9C8C11
C8C9N10
C8C9N13
N10C9N13
C5N10C9
C5N10C17
C9N10C17
C8C11N12
C8C11N18
N12C11N18
C11N12N13
C9N13N12
C2O14C15

121.2(2)
119.5(3)
116.3(2)
124.1(2)
120.2(3)
121.2(2)
118.2(2)
121.0(2)
120.9(2)
119.7(2)
118.7(2)
121.6(2)
113.7(2)
122.1(2)
124.1(2)
121.9(2)
133.8(2)
104.2(2)
124.1(2)
108.0(2)
127.9(2)
117.6(2)
122.8(2)
119.6(2)
111.3(2)
126.1(2)
122.7(3)
105.2(2)
111.3(2)
118.8(2)

122.0(3)
118.6(3)
116.9(2)
124.5(3)
120.9(3)
121.2(3)
118.0(3)
120.8(2)
121.2(2)
119.3(2)
119.6(2)
121.0(2)
114.1(2)
121.9(2)
123.9(2)
121.9(2)
134.4(2)
103.6(2)
124.6(2)
108.1(2)
127.2(2)
117.0(2)
122.2(2)
120.7(2)
112.1(2)
124.8(3)
123.0(3)
104.8(2)
111.3(2)
118.1(2)

Two N-methylated tricyclic quinolones

393

Table 2. (Continued)

(c) Possible hydrogen bonds

DH A
N13aH13a O1w i
N13bH13b N12aii
N18aH181a O16aiii
N18aH182a N12bii
N18bH181b O2wiv
N18bH182b O14av
O1wH11w O2w
O1wH12w O16avi
O2wH21w O16bvii
O2wH22w O16bviii

Molec. a

Molec. b

DH
0.86
0.86
0.90(3)
0.98(3)
0.92(4)
0.84(3)
0.77(4)
0.92(4)
1.04(4)
0.86(5)

H A
2.01
2.01
2.14(3)
2.14(4)
2.60(4)
2.24(4)
2.12(4)
1.93(4)
1.77(4)
2.04(5)

D A
2.864(3)
2.804(3)
2.967(3)
3.076(4)
3.398(4)
2.997(3)
2.884(4)
2.842(3)
2.794(3)
2.873(3)

DHA
169
154
152(3)
160(3)
146(3)
150(3)
174(4)
170(4)
166(3)
163(5)

Note. Symmetry codes: i. x + 1, y + 1, z + 2; ii. x, y + 2, z + 2; iii. x + 2, y + 2, z + 2; iv. x 1,y, z; v. x 2, y, z;

vi. x + 2, y + 1, z + 2; vii. x + 1, y + 1, z + 1; viii. x + 1, y, z.

Fig. 3. Possible hydrogen bonds in crystal structure of 1. The organic molecules are approximately coplanar and the
of the Ow atoms to the mean plane through the four tricyclic systems are shown within brackets. For clarity,
distances (in A)
the O1wH12w O16a bond (see Table 1) is not depicted.

394

Capparelli et al.
) for compound 2
Table 3. Geometric parameters (A,

(a) Bond lengths

C1C2
C2C3
C4C5
C5C6
C6C7
C7O17
C8C11
C9N14
C11N12
N12C13
C13N20

1.371(3)
1.385(2)
1.426(2)
1.408(2)
1.470(2)
1.264(2)
1.438(2)
1.339(2)
1.330(2)
1.357(2)
1.340(2)

C1C6
C3C4
C4O15
C5N10
C7C8
C8C9
C9N10
N10C18
C11N19
C13N14
O15C16

1.403(2)
1.381(2)
1.369(2)
1.402(2)
1.421(2)
1.417(2)
1.375(2)
1.477(2)
1.339(2)
1.336(2)
1.419(2)

(b) Bond angles

C2C1C6
C2C3C4
C3C4O15
C4C5C6
C6C5N10
C1C6C7
C6C7C8
C8C7O17
C7C8C11
C8C9N10
N10C9N14
C5N10C18
C8C11N12
N12C11N19
N12C13N14
N14C13N20
C4O15C16

120.5(2)
121.7(2)
122.6(2)
117.5(2)
119.6(1)
118.2(1)
116.1(1)
123.6(1)
124.1(1)
121.1(1)
115.7(1)
123.1(1)
122.3(1)
117.4(2)
127.0(2)
116.8(1)
118.8(2)

C1C2C3
C3C4C5
C5C4O15
C4C5N10
C1C6C5
C5C6-C7
C6C7O17
C7C8C9
C9C8C11
C8C9N14
C5N10C9
C9N10C18
C8C11N19
C11N12C13
N12C13N20
C9N14C13

119.5(2)
119.8(2)
117.5(2)
122.9(1)
120.7(2)
121.1(1)
120.3(1)
121.1(1)
114.7(1)
123.3(1)
120.6(1)
115.9(1)
120.3(2)
116.6(1)
116.2(2)
116.1(1)

(c) Possible hydrogen bonds

DH A
N19H191 O17
N19H192 O17i
N20H201 N12ii
N20H202 O17iii

DH
0.86(2)
0.94(2)
0.93(2)
0.91(3)

H A
2.03(2)
2.29(2)
2.05(2)
2.25(3)

D A
2.707(2)
3.203(2)
2.975(2)
3.019(2)

DHA
135(2)
166(2)
175(2)
142(2)

Note. Symmetry codes: i. x + 1.5, y + 0.5, z + 1.5; ii. x + 1, y + 1, z + 1; iii. x 0.5, y + 0.5, z 0.5.

7.41 (d, 1H, H4 , J: 9.1 Hz), 7.61 (d, 1H, H1 ,

J: 2.9 Hz), 11.73 (brb, 1H, N[13]H); 2: 3.90
(s, 3H, OCH3 ), 3.92 (s, 3H, NCH3 ), 6.80 (brb, 2H,
N[20]H2 ), 7.22 (dd, 1H, H2 , J: 7.9 Hz), 7.41
(d, 1H, H3 , J: 7.9 Hz), 7.60 (d, 1H, N[19]H N19,
J: 4.5 Hz), 7.85(d, 1H, H1 , J: 7.8 Hz), 9.55
(d, 1H, N[19]H, J: 4.5 Hz).13 C NMR data
(DMSO-d6 /TMS, , ppm). 1: 152.07 (C11), 95.55
(C8), 173.56 (C7), 123.74 (C6), 106.73 (C1),
153.18 (C2), 121.98 (C3), 115.32 (C4), 137.64
(C5), 148.91 (C9), 31.97 (NCH3 ), 55.93 (OCH3 );
2: 166.19 (C13), 158.16 (C11), 94.16 (C8), 175.65

(C7), 123.39 (C6), 125.16 (C1), 117.72 (C2),

109.03 (C3), 157.37 (C4), 104.37 (C5), 162.75
(C9), 31.39 (NCH3 ), 56.73 (OCH3 ). Atoms are
numbered as in Figs. 1 and 2.

X-ray crystallography
Unit cell and intensity measurements were
carried out on a Huber A-8901 diffractometer.
Unit-cell parameters were obtained from
least-squares fit of the setting angles of 25

Two N-methylated tricyclic quinolones

395

Fig. 4. Possible hydrogen bonds in crystal structure of 2.

automatically centered reflections. Intensity data

were recorded using a -2 scan mode, with fixed
speed. Three check reflections were monitored
every 97 intensity measurements. The data were
scaled using the check reflections and corrected
by Lorentz and polarization effects. No absorption
corrections were applied. Low diffracting power
(even using Cu-K radiation) limited the value of
max for the data collection of 1.
The structures were solved by direct methods
and refined on F2 using all reflections with I > 0.
The C and N(ring)-bonded H atoms were placed
in calculated positions, and refined using a riding
atom model with fixed CH [0.93 A for C(sp2 ),
distances,
0.96 A for C(sp3 )] and NH [0.86 A]

and Uiso = p Ueq (parent atom) [p = 1.2 for C(sp2 )

and N, 1.5 for C(sp3 )]. Three methyl groups were
found to be disordered; in each of these groups
two (staggered) sets of H atoms with complementary occupancies were assigned [final occupancies: 1: C17a, 0.63(3); C17b, 0.77(3); 2: C18,
0.54(3)]. The H atoms of the water molecules and
amino groups were located in difference Fourier
syntheses and refined isotropically. Limited data
and Z = 2 resulted in a somewhat poor final
data/parameters ratio (8.73) for 1.
The following computer programs were
used: data reduction, REDUCE UCLA22 ; cell
refinement, LEAST UCLA22 ; structure solution, SHELXS-9723 ; structure refinement,

396

Capparelli et al.

Fig. 5. Crystal structure of 1 showing the layered structure and the interlayer H-bonds (for clarity,
H atoms were omitted).

SHELXL-9724 ; molecular graphics, ORTEP 3.25

The structure solution, the refinement and the
drawings were carried out with the aid of the
WinGX26 suite of programs.

Results and discussion

Crystal data, intensity data collection parameters and final refinement results are summarized
in Table 1.
The X-ray structure determinations (Figs. 1
and 2) showed that the crystals of compound 1
contain two organic molecules (1a and 1b) and
two water molecules of solvation per asymmetric
unit, while those of 2 contain only one organic
molecule per asymmetric unit. In both compounds
the bond lengths are in good agreement with the
tabulated standard values26 (Tables 2 and 3).
Within experimental error (i.e. 3 e.s.d.s)
most bond lengths and angles are equal in 1a
and 1b. The larger difference, in the exocyclic
angle C8C11N18, is of marginal statistical significance, and probably due to packing effects.
As a result of hydrogen bonding to the carbonyl

oxygens (see below), in both compounds the C=O

distances are somewhat longer than the tabulated
27 indicating weakstandard value [1.222(13) A],
ened double bonds.
The molecules are essentially planar, including the exocyclic groups. The r.m.s. deviations
of the atoms in the tricyclic systems are 0.020,
0.032 and 0.054 A for 1a, 1b and 2 respectively;
the largest deviations from these mean planes are:
0.130(3) A for O16a (1a), 0.180(4) A for C15b
(1b) and 0.449(3) A for C18 (2). The two independent molecules in 1 are approximately parallel
[dihedral angle between mean panes: 3.1(1) ].
The molecules of 2 form intramolecular hydrogen bonds, NH O=C (Fig. 2), which are
observed in the1 H NMR spectrum (resonances
at 7.60 and 9.55 ppm). Due to the geometry
of the tricyclic system, similar interactions do
not exist in 1 because the N O distances are
longer [3.154(3) and 3.139(4) A in 1a and 1b]
and the NH O angles too small [116(2) and
120(3) in 1a and 1b]. It was found that the antimalarial activity of tricyclic quinolones can be
correlated with some molecular features, among
which is the H O distance in these hydrogen

Two N-methylated tricyclic quinolones

397

Fig. 6. Crystal structure of 2 (for clarity, H atoms were omitted).

bonds,20 which usually fall in the range 1.58

28 Longer distances favor the inhibition
2.05 A.
of P. falciparum, probably because weaker or no
intramolecular hydrogen bonds increase the availability of the NH2 and CO groups to bind the
receptor. Accordingly, the in vitro antimalarial activity of 1 was found to be approximately twice
that of 2.20
In both crystal structures the organic
molecules are linked to their neighbors by intermolecular bonds of the types NH O and
NH N. In addition, in the crystal structure of
1 the water molecules of solvation are involved in
bonds of the types NH Ow, OwH O=C
and OwH Ow (Figs. 3 and 4).
In the crystal structure of 1 both independent organic molecules are approximately coplanar, so that the crystal packing consists in layers
containing the organic molecules and the O1w
water molecules, while the O2w molecules are
located within the interplanar spaces and form
hydrogen bonds connecting the layers (Fig. 5).
The distance between the mean planes of adja-

In the crystal structure of

cent layers is 3.38 A.
2 the molecules are packed in a herringbone-like
arrangement (Fig. 6). The distance between the
mean planes of (partially) stacked molecules is

3.48 A.
Supplementary material
Comprehensive crystallographic data (CIF
files) for the structural analyses have been
deposited with the Cambridge Crystallographic
Data Centre; and can be obtained free of charge
from http://www.ccdc.cam.ac.uk/products/csd/
request/.
Acknowledgements
We thank Dr. Saeed Khan (Dept. of Chemistry and Biochemistry, UCLA, USA) and
Dr. Duilio Cascio (Molecular Biology Institute,
UCLA, USA) for the X-ray diffraction data
collections.

398
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