Solid state structural analysis of new pentamidine analogs designed as chemotherapeutics that target DNA by X-ray diffraction and 13C, 15N CP/MAS NMR methods

Article abstract of DOI:10.1016/j.molstruc.2010.09.008

The paper presents the solid-state analysis of the crystalline form of 1,5-bis[(4-cyanophenyl)-N-methylamino]pentane (1) and polycrystalline powder sample of 1,5-bis[(4-amidinophenyl)-N-methylamino]pentane dihydrochloride (2). The methods used are X-ray d

Full text of DOI:10.1016/j.molstruc.2010.09.008

Journal of Molecular Structure 984 (2010) 68–74
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Solid state structural analysis of new pentamidine analogs designed as
chemotherapeutics that target DNA by X-ray diffraction and 13C, 15N CP/MAS
NMR methods
a
b,
b
⇑
_
´
Jerzy Zabinski , Dorota Maciejewska , Irena Wolska
a Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02 097 Warsaw, Poland
b Department of Crystallography, Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60 780 Poznan´, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 July 2010
Received in revised form 7 September 2010
Accepted 7 September 2010
Available online 7 October 2010
The paper presents the solid-state analysis of the crystalline form of 1,5-bis[(4-cyanophenyl)-N-methyl-
amino]pentane (1) and polycrystalline powder sample of 1,5-bis[(4-amidinophenyl)-N-methyl-
amino]pentane dihydrochloride (2). The methods used are X-ray diffraction technique and 13C, 15N CP/
MAS NMR spectroscopy in an attempt to detect the effects of possible polymorphism. Both methods indi-
cate that only single conformers exist in the solid-state for 1 and 2. 1,5-Bis[(4-cyanophenyl)-N-methyl-
amino]pentane 1, crystallizes in the orthorhombic space group P21212. The asymmetric unit contains
one half of the ordered molecule. Only weak intermolecular interactions were found in solid-state, in
which methyl groups are engaged.
Keywords:
Pentamidine analogs
X-ray diffraction data
13C and 15N CP/MAS NMR analysis
Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction
(1), and 1,5-bis[(4-amidinophenyl)-N-methylamino]pentane dihy-
drochloride (2) (N-methylamino analog of pentamidine). In struc-
Pneumocystis is an opportunistic fungus that is the cause of
lethal pneumonia (PCP) in immunocompromised persons [1,2].
Pentamidine isethionate is a drug used clinically against PCP, and
also against leishmaniasis and trypanosomiasis but a number of
toxic side effects have been observed during treatment including
abscesses at the injection site, nephrotoxicity, cardiotoxicity and
hypoglycemia [3,4]. Chemically pentamidine belongs to diami-
dines that have a broad range of activities against eukaryotic par-
asites, bacteria, viruses and tumors. Diamidines have been found to
bind specifically to adenine–thymine minor groove sequences of
DNA. There are strong evidences that DNA binding is involved in
the mechanism of action of these compounds [5–9]. Among bis-
nitriles, which are intermediates while preparing bis-amidines,
many investigators have also found active substances against
tumor [10,11]. Given this knowledge, bis-amidines and bis-nitriles
represent the promising templates for design and development of
new drugs.
tural analysis we have applied X-ray diffraction technique,
together with 13C and 15N CP/MAS NMR spectroscopy combined
with molecular modeling.
2. Experimental
2.1. Syntheses
All chemicals were obtained from major chemicals suppliers as
high or highest purity and were used without further purification.
Melting points were determined with an Electrothermal 9001 Dig-
ital Melting Point Apparatus and are uncorrected. Elemental anal-
yses were performed on C, H, N, S Elementar GmbH Vario EL III
analyzer. IR spectra were recorded on Schimadzu FTIR-8300 in
KBr tablets. Notation used in NMR assignments is given in Fig. 1.
2.1.1. 1,5-Bis[(4-cyanophenyl)-N-methylamino]pentane (1)
The solid-state analysis of biologically active substances is of
special interest [12,13] and the CP/MAS NMR spectroscopy in the
solid state or XRD technique are the most frequently methods used
in those investigations [12,13]. In the paper we report the synthe-
ses (Scheme 1) and structural features in solid-state of two new
1,5-Dibromopentane (1.15 g, 0.005 mol), N-methyl-4-amino-
benzonitrile (1.32 g, 0.01 mol), sodium hydroxide (0.8 g, 0.02 mol)
and tetr-butylammonium bromide (0.32 g, 0.001 mol) in toluene
(20 ml) were refluxed together for 3 h while stirring. Then, the
hot mixture was poured into ice water to obtain a white precipitate
that was recrystallized from ethanol with hot filtering to give 0.9 g
(54%) of white crystals of 1. M.p. 141–142.5 °C. AC21H24N4 (332.45)
calcd C 75.87, H 7.28, N 16.85, found C 75.82, H 6.95, N 16.52. A1H
NMR (400.13 MHz, CDCl3): 1.33–1.37 (m, 2H, H-11), 1.63
compounds:
1,5-bis[(4-cyanophenyl)-N-methylamino]pentane
⇑
Corresponding author. Tel./fax: +48 22 5720643.
E-mail address: dorota.maciejewska@wum.edu.pl (D. Maciejewska).
0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2010.09.008

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J. Zabinski et al. / Journal of Molecular Structure 984 (2010) 68–74
CH
CN
8A
3
2
6A
5A
4A
NaOH /
Br
CH3
9
11
9A
7
C
1
4
N
N
N
C
7A
N
+
Br
10
10A
1A
2A 3A
CH3
8
5
6
1
NH
1. HCl / C2H5OH
CH3
2. NH3 / C2H5OH
8A
6A
3
2
5A
CH3
N
9
11
H2N
H2N
9A
10A
NH2
1
4A
4
Cl
C
7
N
C
7A
Cl
10
1A
NH2
CH3
8
5
6
2A 3A
2
Scheme 1. Details of synthetic procedures of 1 and 2 with atom numbering.
Fig. 1. A perspective view of the molecular conformation of 1.
(q, J = 7.6 Hz, 4H, H-10, H-10A), 2.98 (s, 6H, H-8, H-8A), 3.37 (t,
J = 7.6 Hz, 4H, H-9, H-9A), 6.60–6.62 (m, 4H, H-2, H-6, H-2A, H-
6A), 7.43–7.45 (m, 4H, H-3, H-5, H-3A, H-5A) ppm. A13C NMR
(100.61 MHz, CDCl3): 24.67 (C-11), 26.90 (C-10, C-10A), 38.54 (C-
8, C-8A), 52.29 (C-9, C-9A), 97.26 (C-4, C-4A), 111.36 (C-2, C-6, C-
2A,C-6A), 120.82 (C-7, C-7A), 133.67 (C-3, C-5, C-3A, C-5A),
H-10, H-10A), 2.99 (s, 6H, H-8, H-8A), 3.43 (t, J = 7.2 Hz, 4H, H-9,
H-9A), 6.77–6.80 (m, 4H, H-2, H-6, H-2A, H-6A), 7.73–7.76 (m,
4H, H-3, H-5, H-3A, H-5A), 8.63 (s broad, 4H, 2 ꢁ 2NH), 8.91 (s
broad, 4H, 2 ꢁ 2NH) ppm. A13C NMR (100.61 MHz, DMSO-d6):
23.66 (C-11), 26.14 (C-10, C-10A), 38.06 (C-8, C-8A), 51.24 (C-9,
C-9A), 110.82 (C-2, C-6, C-2A, C-6A), 111.74 (C-4, C-4A), 129.67
(C-3, C-5, C-3A, C-5A), 152.78 (C-1, C-1A), 164.10 (C-7, C-7A)
151.58 (C-1, C-1A) ppm. -IR: 3100–3090 (
2920 ( CH2as), 2862 (mCH3sym CH2sym), 2206 (
C@C), 1458 (dCHalif), 1373 ( CN), 1257 ( COas), 1003 (
HC) cmꢀ1
m
CHarom), 2950 (
C„N), 1589,1512
COsym), 818
mCH3as),
m
;
m
m
ppm. -IR: 3550–2780 (mNH
1612 ( C@C), 1570 (dNH), 1510–1420 (
HC) cmꢀ1
;
mCHarom
;
mCH3
;
mCH2
;
m
CH2), 1682 (
m@NH),
(
(
m
c
m
m
m
m
m
C@C; dCH2), 1396 ( CN), 852
m
.
(c
.
2.1.2. 1,5-Bis[(4-amidinophenyl)N-methylamino]pentane
2.2. Crystallography
dihydrochloride (2)
1,5-Bis[(4-cyanophenyl)-N-methylamino]pentane (1) (0.66 g,
0.002 mol) and ethanol (25 ml) saturated with dry hydrochloride
were stirred in a round-bottomed flask at room temperature for
20 h, then dry diethyl ether (60 ml) was added. The precipitate
was washed with ether and dried in vacuum under CaCl2 for 4 h.
Crude iminoester was stirred together with ethanol (25 ml) satu-
rated with dry ammonia at room temperature for 48 h, then the
solvent was evaporated off and the remaining solid was washed
with aqueous sodium hydroxide and water, dried, and converted
into dihydrochloride by solution of hydrochloride in ethanol.
0.76 g (74%) of white solid of 2 was obtained. M.p. 315.0–
Crystals of 1 suitable for X-ray analysis were grown by slow
evaporation from ethanol solution. Diffraction data were collected
on an Oxford Diffraction KM4CCD diffractometer [14] at 293 K,
using graphite-monochromated Mo K
a radiation. The unit cell
parameters were determined by least-squares treatment of setting
angles of highest-intensity reflections chosen from the whole
experiment. Intensity data were corrected for the Lorentz and
polarization effects [15]. The structure was solved by direct meth-
ods by use of the SHELXS97 program [16] and refined by the full-
matrix least-squares method with the SHELXL97 program [17].
One reflection was excluded from the reflection file due to its large
318.0 °C (decomp).
C
21H30N6 ꢁ 2HCl ꢁ 4H2O (511.51) calcd.
C
(|Fo|2 ꢀ |Fc|2) difference. The function
R
w(|Fo|2 ꢀ |Fc|2)2 was mini-
49.31, H 7.88, N 16.43, found C 49.67, H 7.87, N 16.07. A1H NMR
mized with wꢀ1 = [
r
2(Fo)2 + (0.0327P)2], where P ¼ ðF2 þ 2F2c Þ=3.
o
(400.13 MHz, DMSO-d6): 1.32 (m, 2H, H-11), 1.52–1.57 (m, 4H,
All non-hydrogen atoms were refined with anisotropic thermal

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J. Zabinski et al. / Journal of Molecular Structure 984 (2010) 68–74
Table 1
Table 2
Crystal data, data collection and structure refinement for 1.
Selected bond lengths (Å) and angles (°) and
selected torsional angles (°) for 1.
Compound
(1)
C21H24N4
332.44
293(2)
C1AN8
1.357(3)
1.453(3)
1.531(3)
1.149(4)
121.8(3)
110.7(4)
ꢀ83.1(4)
ꢀ175.0(2)
180.0(3)
Empirical formula
Formula weight
T (K)
N8AC9
C9AC10
C7AN7
Wavelength (Å)
Crystal system, space group
Unit cell dimensions
a (Å)
0.71073
Orthorhombic, P21212
C1AN8AC9
C10AC11AC10A
C1AN8AC9AC10
N8AC9AC10AC11
C9AC10AC11AC10A
10.624(1)
19.855(3)
4.4848(7)
946.0(2)
2, 1.167
0.071
b (Å)
c (Å)
Volume (Å3)
Z, Dx (Mg/m3)
l
(mmꢀ1
)
Table 3
Hydrogen bonding geometry (Å and °) for compound 1.
F(0 0 0)
h range for data collection (°)
hkl range
356
4.11–25.68
ꢀ12 6 h 6 12
ꢀ24 6 k 6 14
ꢀ4 6 l 6 5
DAHꢃ ꢃ ꢃA
C8AH8Cꢃ ꢃ ꢃN7i
d(DAH)
d(Hꢃ ꢃ ꢃA)
2.64
d(Dꢃ ꢃ ꢃA)
3.602(4)
<(DHA)
177
0.96
Reflections
Collected
Symmetry code: (i) 1.5ꢀx, 0.5 + y, ꢀz.
3637
Unique (Rint
Observed (I > 2
)
1737 (0.06)
573
r(I))
Data/restraints/parameters
Absorption correction
Goodness-of-fit on F2
1737/0/118
Multi-scan
0.786
0.0384
0.0892
cient
v was equal to 0.0025(3). The deposition number CCDC
791244 for 1 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif,
data_request@ccdc.cam.ac.uk.
R(F) (I > 2
wR(F2) (all data)
Max/min.
(e/Å3)
r(I))
or
by
emailing
D
q
0.134/ꢀ0.127
parameters. The coordinates of the hydrogen atoms were calcu-
lated in idealized positions and refined as a riding model with their
thermal parameters calculated as 1.2 (1.5 for methyl group) times
Ueq of the respective carrier carbon atom. An empirical extinction
correction was also applieꢀd1=4 according to the formula
2.3. NMR spectra and molecular modeling
The 1H NMR and 13C NMR 1D and 2D spectra in solution were
recorded with a Bruker Avance DMX 400, as well as the solid state
13C and 15N CP/MAS NMR spectra. Typical acquisition conditions
F0 ¼ kFc½1 þ ð0:001
v
F2c k3=sin2hÞꢂ
[17], and the extinction coeffi-
for 13C CP/MAS NMR at 100.62 MHz were: pulse duration, 4.5
ls;
c
Fig. 2. Interconnections within a layer of 1.

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J. Zabinski et al. / Journal of Molecular Structure 984 (2010) 68–74
contact time, 2 ms; repetition time, 10 s; spectral width, 24 kHz;
number of transients, 1000. Spinning speeds ranged from 8 to
10 kHz. Nonprotonated carbons and methyl groups were selec-
tively observed by dipolar-dephasing experiment with delay time
pentamidine [20]. They could be responsible for the efficient inter-
action with the biological target.
3.1.1. 13C and 15N CP/MAS NMR spectra of 1 and 2
50 l
s. Chemical shifts d (ppm) for 13C were references to TMS.
The values of chemical shifts from 13C and 15N CP/MAS NMR
spectra together with shielding constants obtained from DFT com-
putations provided complementary information on the solid-state
structure of 1 and 2. We could expect single, twofold or even four-
fold resonances for each carbon, dependent on the symmetry and/
or the number of conformations present. The 13C CP/MAS NMR
spectra of 1 and 2 are shown in Fig. 4. In the spectrum of 1 multi-
plets are not observed, meaning that only a single structure is
detected in solid-state, which is consistent with the single-crystal
structure described in Section 3.1. Small high frequency shifts of
C7 (C7A) and C8 (C8A) atoms (as compared with the solution res-
onances) can be correlated with the existence of weak intermolec-
ular CAHꢃ ꢃ ꢃN hydrogen bonds. DFT computations of the isotropic
Spectral conditions for 15N CP/MAS NMR at 40.55 MHz and high-
power proton decoupling field were: spectral width, 55 kHz; pulse
duration, 3.8 ls; contact time, 5 ms; repetition time, 10 s; number
of transients, 6800. Chemical shifts for 15N were calibrated indi-
rectly on glycine resonance (ꢀ345 ppm), and referenced to CH3NO2
signal (see Fig. 4).
Crystallographic atom coordinates for 1 and the optimized ones
for 1 and 2 were used for computation of shielding constants
r
(ppm) of 13C atoms as the help in assignment of resonances in
the solid-state NMR spectra. We employed the DFT method with
B3LYP/6-311(d,p) hybrid functional for structure optimization,
and the CPHF–GIAO approach for the NMR shielding constants
computations using Gaussian 03 program [18].
shielding constants
r(ppm) using B3LYP/6-311G (d,p) hybrid func-
tional applied to the crystallographic and optimized coordinates of
compound 1 were related to the experimental chemical shifts d
(ppm). We observed two linear (almost parallel) correlations (cor-
relation coefficients r2 were close to 0.98) for both functions
3. Results and discussion
3.1. X-ray structure of 1,5-bis[(4-cyanophenyl)-N-methylamino]-
rcryst = f(d) and roptimized = f(d). This finding could be proof that
pentane (1)
these simple computations give quite satisfactory results and can
be used in the powder sample analysis of compound 2, for which
a single-crystal form was not obtained. In the NMR spectrum of
2 the single pattern of resonances was also observed, and only
one structure for compound 2 was detected. In theoretical analysis
we have considered two conformations of 2 shown in Fig. 5: first in
which NCH3 groups have the alignment as in the crystal structure
of 1 i.e. they are pointed out in opposite directions, and the second
in which NCH3 groups are oriented in the same direction. DFT cal-
culation showed small energy differences of the conformers (about
5 kJ/mol), but the experimental resonances d are consistent only
The crystal and molecular structures of 1 were analyzed by
X-ray diffraction. All details of the measurement, crystal data and
structure refinement are given in Table 1. Selected bond lengths,
bond angles and torsion angles are listed in Table 2, and hydrogen
bonding parameters in Table 3. A perspective view of the molecular
conformation, together with the atom numbering scheme, is
shown in Fig. 1 (the drawings were performed with Mercury pro-
gram [19]).
1,5-Bis[(4-cyanophenyl)-N-methylamino]pentane (1), new ana-
log of pentamidine synthesized by us, crystallizes in the ortho-
rhombic space group P21212. The central C11 atom is located at a
twofold crystallographic axis (according to symmetry 1 ꢀ x,
1 ꢀ y, z) and the asymmetric unit contains one half of the ordered
molecule. At the angle between the best planes of the two planar
aromatic rings being 73.52(7)°, the nitrile groups and methyl-car-
bons are nearly coplanar with these rings. The conformation of the
central linkage is trans for C9AC10AC11AC10A and N8AC9A
C10AC11 but gauche for C1AN8AC9AC10 (the appropriate torsion
angles are listed in Table 2), and the distance from C1 to C1A atom
is equal to 8.85 Å. This symmetry is very similar to that described
in our earlier paper for 4,40-[1,5-(3-oxapentanediylbis(amino))]-
bisbenzonitrile [15]. The crystal structure of 1 is stabilized by an
intermolecular CAHꢃ ꢃ ꢃN hydrogen bond between the methyl and
nitrile groups (see Table 3). The molecules are linked by C8A
H8Cꢃ ꢃ ꢃN7 interactions forming folded layers parallel to the (0 0 1)
plane (Figs. 2 and 3). Such participation of the nitrile substituents
in the hydrogen bonds were also found for other analogs of
with the calculated shielding constants
r obtained for the former
conformation. The experimental d values in solid-state are very
close to the solution ones, indicating that only a very weak hydro-
gen bond could exist in solid-state. The conformation of the ali-
phatic linker of bis-amidine 2 is much more extended than this
of bis-nitrile 1, and the distance from C1 to C10 is equal to 9.42 Å.
The molecule of 2 is flattened as compared to 1, and the angle be-
tween two planar aromatic rings is equal to 134.0°. The resonances
of each pair of ortho carbons to NCH3 groups are inequivalent
(108.9 for C2, C2A and 112.2 ppm for C6, C6A). The assignment is
based on the dipolar diphased spectra revealing quaternary atom
resonances. The observed splitting between C2 and C6 signals are
mainly due to the shielding effects of the nitrogen lone pairs and
pointed out the lack of phenyl ring rotation. Amidine C7, C7A
atoms give one broad resonance at 164.0 ppm, proving an equiva-
lency of these groups.
It was thought that natural abundance 15N CP/MAS NMR spec-
troscopy would be a useful probe in complementary structural
Fig. 3. Packing arrangement of 1 indicating folded layers parallel to (0 0 1) plane.

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J. Zabinski et al. / Journal of Molecular Structure 984 (2010) 68–74
Fig. 4. 13C CP/MAS spectra of 1 and 2. Sidebands are marked with an asterisk.
analysis of 1 and 2, because it possesses a large chemical shift
range resulting in good dispersion of signals. The 15N NMR spectra
in solid state of 1 and 2 are shown in Fig. 6. In the spectrum of 1
sharp signals are observed for C„N and NCH3 groups at ꢀ125.3
and ꢀ301.0 ppm, respectively, indicating absence of any exchange
broadening. The spectrum of 2 is not so good, but we can clearly
identify the NCH3 signal at ꢀ298.5 ppm, and doublet of amidine
nitrogens at 278.3 and ꢀ281.5 ppm. The two signals arise from

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J. Zabinski et al. / Journal of Molecular Structure 984 (2010) 68–74
Fig. 5. Two analyzed conformations of 2 in solid-state: upper – NCH3 groups oriented in opposite directions; bottom – NCH3 groups oriented in the same direction.
Fig. 6. 15N CP/MAS spectra of 1 and 2.

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J. Zabinski et al. / Journal of Molecular Structure 984 (2010) 68–74
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New 1,5-bis[(4-cyanophenyl)-N-methylamino]pentane (1) and
1,5-bis[(4-amidinophenyl)-N-methylamino]pentane dihydrochlo-
ride (2) have been characterized in solid-state, showing lack of
polymorphism. Single-crystal X-ray analysis showed that 1 crystal-
lizes in the orthorhombic space group P21212 and the asymmetric
unit contains one half of the ordered molecule. The crystal structure
of 1 is stabilized by intermolecular CAHꢃ ꢃ ꢃN hydrogen bond be-
tween the methyl and nitrile groups. Conformational analysis of 2
using NMR solid-state spectroscopy combined with DFT theoretical
computations has confirmed that NCH3 groups in aliphatic linker
has the alignment as in the crystal structure of 1, but its conforma-
tion is much more extended than that of bis-nitrile 1, and the dis-
tance from C1 to C10 is equal to 9.42 Å. In the present case, we
can suppose that the intermolecular hydrogen bonds are very weak.
New compounds 1 and 2 were synthesized with good yields by
an optimized procedure.
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