Comparative study of the 3-phenylcoumarin scaffold: Synthesis, X-ray structural analysis and semiempirical calculations of a selected series of compounds

Article abstract of DOI:10.1016/j.molstruc.2013.07.037

Compounds 1 (6-methyl-3-phenylcoumarin), 2 (3-(o-methoxyphenyl)-6- methylcoumarin) and 3 (3-(m-methoxyphenyl)-6-methylcoumarin) were synthesized by a Perkin reaction between the 2-hydroxy-5-methylbenzaldehyde and the corresponding phenyl acetic acid.

Full text of DOI:10.1016/j.molstruc.2013.07.037

Journal of Molecular Structure 1050 (2013) 185–191
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Comparative study of the 3-phenylcoumarin scaffold: Synthesis, X-ray
structural analysis and semiempirical calculations of a selected series of
compounds
Maria J. Matos a, , Santiago Vilar a,b, Nicholas P. Tatonetti b, Lourdes Santana a, Eugenio Uriarte a
⇑
a Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
b Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA
h i g h l i g h t s
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Compound 1 6-methyl-3-phenylcoumarin was synthetized.
Compound 2 (3-(o-methoxyphenyl)-6-methylcoumarin) was synthetized.
Compound 3 (3-(m-methoxyphenyl)-6-methylcoumarin) was synthetized.
1H and 13C NMR and X-ray diffractometry determined the molecular structures.
AM1 and PM3 yielded results reproducing the whole 3D structure of the three molecules.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 May 2013
Received in revised form 23 July 2013
Accepted 23 July 2013
Available online 27 July 2013
Compounds 1 (6-methyl-3-phenylcoumarin), 2 (3-(o-methoxyphenyl)-6-methylcoumarin) and 3 (3-(m-
methoxyphenyl)-6-methylcoumarin) were synthesized by a Perkin reaction between the 2-hydroxy-5-
methylbenzaldehyde and the corresponding phenyl acetic acid. 1H and 13C NMR and X-ray diffractometry
determined the molecular structures of the derivatives. A comparative study between compounds 1, 2
and 3, based on the structural results, was carried out. In addition, the X-ray structures were compared
to those obtained combining conformational analysis with semiempirical methodologies (AM1 and PM3).
The results provided by the semiempirical calculations in gas phase are in strong agreement with the X-
ray method for the three molecules under study, meaning that the determination of the 3D structure for
this type of compounds could be extrapolated from semiempirical studies.
Keywords:
Coumarin derivatives
Synthesis
X-ray structural analysis
Conformational analysis
Semiempirical calculations
Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction
these compounds may be potential drug leads to treat neurodegen-
erative diseases [11–17]. The prevalence of these diseases com-
Coumarins are natural compounds that can be found in several
sources [1–3]. Naturally occurring or synthetic produced deriva-
tives of the benzopyrone moiety are of pharmaceutical interest
due to the important biological activities that they display [1–3].
Coumarins have been previously described as anti-inflammatory,
antimicrobial, anticancer, vasorelaxant, cardioprotective, and anti-
oxidant agents [1–10]. Furthermore, in previous work we have re-
ported inhibitory effects of several coumarins on monoamine
oxidase B (MAO-B) activity, and in some cases this is accompanied
by acetylcholinesterase (AChE) inhibitory activity [13]. Some of
bined with their complex etiology has led to an intensive search
for compounds that interact with some specific receptors. Due to
the biological importance of the coumarins, the synthesis and char-
acterization of these derivatives is a topic of interest. The interac-
tion between a specific molecule – a drug candidate – and a
receptor is mediated through recognition between the small mol-
ecule compound and the protein structure. An important step in
the study of molecular interactions is the correct determination
of the structure of the potential drugs. This requires an analysis
of the spatial arrangement of the different atomic groups and their
chemical properties. The first step, in this analysis, is to obtain
information about the intramolecular features responsible for the
3D structure of the molecule under study. The X-ray structure is
an important tool for examining the chemical structure of the mol-
ecules and to better understands the interaction of the compound
⇑
Corresponding author. Tel.: +34 881 814 936.
E-mail addresses: mariacmatos@gmail.com (M.J. Matos), qosanti@yahoo.es
(S. Vilar), npt@dbmi.columbia.edu (N.P. Tatonetti), lourdes.santana@usc.es
(L. Santana), eugenio.uriarte@usc.es (E. Uriarte).
0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2013.07.037

186
M.J. Matos et al. / Journal of Molecular Structure 1050 (2013) 185–191
O
R
H3C
H3C
H
R
HOOC
OH
O
O
1: R = H
2: R = o-OCH3
3: R = m-OCH3
Scheme 1. Synthesis of the compounds 1–3. Reagents and conditions: N,N0-dicyclohexylcarbodiimide (DCC), 110 °C, 24 h.
with the enzyme’s active site. However, semiempirical methods of-
fer an efficient alternative to investigate the molecular structure of
novel 3-arylcoumarins, especially when no X-ray data are avail-
able. Molecular mechanics methods [18] are appropriate in the
study of complex systems, such as proteins. Higher-level ap-
proaches, such as ab initio methods [19] are only applicable in
small molecules due to the complexity of the quantum mechanical
calculations. Nevertheless, an intermediary level of complexity is
provided through semiempirical calculations [20], such as AM1
or PM3. These methods combine quantum chemical calculations
with the use of some parameters from empirical data and accu-
rately reproduce experimental molecular geometries [21–23].
Therefore, structural characteristics of coumarins make unneces-
sary to complement the semiempirical conformational analysis at
higher computational levels [24].
In this work, we described experimental and semiempirical
structural analysis of three synthesized 3-arylcoumarins without
substituents in the aromatic ring (compound 1), an ortho-methoxy
group substitution (compound 2), and a meta-methoxy substitu-
tion (compound 3). Their structures were characterized by experi-
mental methods such as NMR spectrometry (validated by X-ray
diffractometry) and semiempirical calculations combining confor-
mational analysis with the AM1 and PM3 methods. The compari-
son between the semiempirical and the crystal structure for all
the compounds showed a high level of similarity. This demon-
strates the capability of the semiempirical methods to reproduce
experimental molecular geometry and establishes these methods
as an alternative to obtain three-dimensional information when
the crystal structure is not available.
Table 1
Crystal data and structure refinement parameters for compound 1–3.
Compound 1
16H12O2
236.26
Monoclinic
P21
Compound 2
Compound 3
Empirical formula
Formula weight
Crystal system
Space group
C
C17H14O3
266.28
Monoclinic
P21/n
13.7688(15)
6.7855(10)
14.6983(18)
1276.4(3)
4
C17H14O3
266.28
Triclinic
P-1
6.5861(3)
9.3113(5)
11.0593(5)
658.63(6)
2
Unit cell
a = 6.2360(4)
dimensions (Å) b = 7.3111(3)
c = 12.4092(7)
Volume (Å3)
Z
Density
561.26(5)
2
1.398
1.386
1.343
(calculated)
(Mg/m3)
Absorption
coefficient
0.091
0.095
0.092
(mmꢂ1
F(000)
)
248
560
280
Crystal size (mm3) 0.95 ꢁ 0.17 ꢁ 0.13 0.37 ꢁ 0.33 ꢁ 0.13 0.35 ꢁ 0.19 ꢁ 0.10
Theta range for
data collection
(°)
1.65–26.02
1.73–25.68
1.89–28.28
Index ranges
ꢂ7 6 h 6 7,
0 6 k 6 9,
0 6 l 6 15
8634
ꢂ16 6 h 6 15,
0 6 k 6 8,
0 6 l 6 17
10,480
ꢂ8 6 h 6 8,
ꢂ12 6 k 6 12,
0 6 l 6 14
20,409
Reflections
collected
Independent
reflections
Completeness to
theta = 26.02°,
25.68° or 28.28°
(%)
Max. and min.
transmission
Data/restraints/
parameters
1196
[R(int) = 0.0880]
100.0
2424 [0.0420]
99.8
3240 [0.0277]
98.9
2. Experimental section
1.0000 and 0.9124 1.0000 and 0.9361 0.9806 and
0.9241
1196/1/164
2.1. Synthesis of compounds 1–3
2424/0/183
3240/0/183
Goodness-of-fit on 0.968
1.057
1.104
Compounds 1–3 (Scheme 1) were prepared according to the
protocol described by us [11,12].
F2
Final R índices
[I > 2sigma(I)]
R1 = 0.0366,
wR2 = 0.0764
0.0431, 0.1015
0.0571, 0.1093
0.0456, 0.1197
0.0612, 0.1290
A solution of 2-hydroxy-5-methylbenzaldehyde (7.34 mmol)
and the corresponding phenylacetic acid (9.18 mmol) in dimethyl
sulfoxide (15 mL) was prepared. N,N’-Dicyclohexylcarbodiimide
(11.46 mmol) was added, and the mixture was heated in an oil
bath at 110 °C for 24 h. Ice (100 mL) and acetic acid (10 mL) were
added to the reaction mixture. After keeping it at room tempera-
ture for 2 h, the mixture was extracted with ether (3 ꢁ 25 mL).
The organic layer was extracted with sodium bicarbonate solution
(50 mL, 5%) and then water (20 mL). The solvent was evaporated
under vacuum, and the dry residue was purified by flash chroma-
tography (hexane/ethyl acetate 9:1). Colorless solids were ob-
tained in a yield of 68%, 59% and 53%, respectively. Suitable
crystals for X-ray studies were grown from slow evaporation from
acetone/ethanol.
R indices (all data) R1 = 0.0449,
wR2 = 0.0792
Largest diff. peak
and hole (e Åꢂ3
0.164 and ꢂ0.243 0.213 and ꢂ0.232 0.337 and ꢂ0.372
)
Common parameters for all the molecules: temperature – 100(2) K; wavelength –
0.71073 Å; absorption correction – semi-empirical from equivalents; refinement
method – full-matrix least-squares on F2.
uncorrected. 1H and 13C NMR spectra were recorded on a Bruker
AMX spectrometer at 300 and 75.47 MHz, respectively, using
TMS as internal standard (chemical shifts in d values, J in Hz) and
CDCl3 as solvent. Mass spectra were obtained using a Hewlett
Packard 5972-MSD spectrometer. Elemental analyses were per-
formed using a Perkin-Elmer 240B microanalyser and were within
0.4% of calculated values in all cases. Silica gel (Merck 60, 230–00
mesh) was used for flash chromatography (FC). Analytical thin
layer chromatography (TLC) was performed on plates precoated
2.1.1. Material and measurements
Melting points were determined using a Reichert Kofler ther-
mopan or in capillary tubes on a Büchi 510 apparatus and are

M.J. Matos et al. / Journal of Molecular Structure 1050 (2013) 185–191
187
119.24 (C-10), 120.57 (C-50), 124.20 (C-4a), 126.36 (C-3), 127.58
(C-5), 130.14 (C-40), 130.80 (C-60), 132.21 (C-7), 133.89 (C-6),
141.84 (C-4), 151.82 (C-8a), 157.22 (C-20), 160.55 (C-2). DEPT:
20.80 (CH3), 55.81 (OCH3), 111.31 (C-30), 116.21 (C-8), 120.57 (C-
50), 127.58 (C-5), 130.14 (C-40), 130.81 (C-60), 132.21 (C-7),
141.84 (C-4). EI MS m/z (%): 267 (22), 266 (M+, 100), 265 (10),
249 (29), 237 (22), 235 (14), 223 (22), 220 (12), 195 (29), 173
(26), 165 (25), 152 (17), 145 (19), 118 (19). Anal. Calcd for
C17
C16
C18
C4
C6
C12
C15
C5
C13
C14
C3
C7
C17H14O3: C, 76.68; H, 5.30. Found: C, 76.76; H, 5.22. [12].
6-Methyl-3-(m-methoxyphenyl)coumarin (3). It was obtained a
colorless solid with a yield of 53%. Mp 84–85 °C. 1H NMR: 2.44 (s,
3H, CH3), 3.88 (s, 1H, OCH3), 6.97 (m, 1H, H-40), 7.26–7.42 (m, 6H,
H-5, H-7, H-8, H-20, H-50 and H-60), 7.78 (s, 1H, H-4). 13C NMR:
20.77 (CH3), 55.37 (OCH3), 114.15 (C-20), 114.38 (C-40), 116.10 (C-
8), 119.28 (C-4a), 120.86 (C-60), 127.70 (C-5), 129.43 (C-50),
132.48 (C-7), 134.12 (C-3), 136.12 (C-10), 139.91 (C-4), 140.10 (C-
6), 151.60 (C-8a), 159.45 (C-30), 160.66 (C-2). DEPT: 20.77 (CH3),
55.37 (OCH3), 114.15 (C-20), 114.38 (C-40), 116.10 (C-8), 120.86
(C-60), 127.70 (C-35), 129.44 (C-50), 132.48 (C-7), 139.91 (C-4). EI
MS m/z (%): 267 (48), 266 (M+, 100), 239 (16), 238 (70), 237 (20),
195 (48), 194 (16), 166 (10), 165 (29), 152 (23). Anal. Calcd for
O11
C10
C2
C8
O1
C9
C17
C16
C18
C4
C15
C6
C3
C13
C12
C5
C
17H14O3: C, 76.68; H, 5.30. Found: C, 76.76; H, 5.21. [12].
C14
C7
2.2. X-ray data collection and reduction
O19
C2
C20
C10
C8
Colorless prismatic crystals of compounds 1 (C16H12O2), 2
(C17H14O3) and 3 (C17H14O3) were mounted on a glass fiber for data
collection. Cell constants and orientation matrix were obtained by
least-squares refinement of the diffraction data for 1196, 2424 and
3240 reflections in the range of 1.7–26.0°, 1.7–25.7° and 1.9–28.3°,
respectively, measured on a Bruker APEX2 [25]. Data were col-
O11
O1
C9
C16
C17
lected by the
x scan technique at 100 K using radiation
C15
C14
(k = 0.71073 Å), and were corrected for Lorentz and polarization ef-
fects. The crystal data and structure refinement were detailed in
C19
C12
Table 1.
A semiempirical absorption correction was also
C4
performed.
C6
C5
O18
C13
C3
C20
2.3. Structure solution and refinement
C7
C2
The structures were solved by direct methods [26], which re-
vealed the positions of all non-hydrogen atoms, and were refined
on F2 by a full-matrix least-squares procedure using anisotropic
displacement parameters. The program used to refine the struc-
tures was SHELXL97 [27]. All hydrogen atoms were located from
difference Fourier maps and were refined isotropically. Atomic
scattering factors were taken from International Tables for X-ray
Crystallography [28]. Molecular graphics were generated with Pla-
ton [29]. Finally, the software used to prepare material for publica-
tion was WinGX publication routines [30]. A summary of the
crystals data, experimental details, and refinements results is given
in Table 1.
C10
O11
C8
O1
C9
Fig. 1. Molecular structures of compounds 1, 2 and 3, with the atom-numbering
scheme. Displacement ellipsoids are drawn at the 50% probability level.
with silica gel (Merck 60 F254, 0.25 mm). The purity of compounds
was assessed by HPLC and was found to be higher than 95%.
6-Methyl-3-phenylcoumarin (1). It was obtained a colorless so-
lid with a yield of 68%. Mp 148–149 °C. 1H NMR: 2.42 (s, 3H, CH3),
7.27 (m, 1H, H-7), 7.34 (m, 2H, H-40 and H-8), 7.43 (m, 3H, H-20, H-
40 and H-5), 7.70 (dd, 2H, H-10 and H-50, J = 7.7 and 1.8), 7.77 (s, 1H,
H-4). 13C NMR: 21.29 (CH3), 116.67 (C-8), 119.57 (C-4a), 128.17 (C-
5), 128.70 (C-3), 128.95 (C-40), 129.02 (C-20, C-30), 129.26 (C-50, C-
60), 132.95 (C-7), 134.65 (C-6), 135.35 (C-10), 140.39 (C-4), 152.16
(C-8a), 161.31 (C-2). DEPT: 21.29 (CH3), 116.67 (C-8), 128.17 (C-
5), 128.95 (C-40), 129.02 (C-20, C-30), 129.26 (C-50, C-60), 132.95
(C-7), 140.39 (C-4). EI MS m/z (%): 236 (M+, 100), 208 (50), 178
(8), 165 (8) 76 (6), 51 (69). Anal. Calcd for C16H12O2: C, 81.34; H,
5.12; O, 13.54. Found: C, 81.44; H, 4.84. [11].
2.4. Theoretical calculations: conformational analysis and
semiempirical methods
A stochastic conformational search was performed using MOE
software [31]. MMFF94x force field was used to implement the
partial charges. Calculation parameters were established with a
RMS gradient of 0.005 and an interaction limit of 500. Although dif-
ferent conformations were retained using a RMSD limit of 0.25 and
energy window of 7 kcal/mol regarding the global minimum en-
ergy, the conformations with the lowest energy were representa-
tive of the calculation and were optimized using AM1 and PM3
semiempirical methods implemented in the Schrödinger package
[32,33]. All the calculations were performed in gas phase.
6-Methyl-3-(o-methoxyphenyl)coumarin (2). It was obtained a
colorless solid with a yield of 59%. Mp 177–178 °C. 1H NMR: 2.41
(s, 3H, CH3), 3.82 (s, 1H, OCH3), 7.02 (m, 2H, H-30, H-40), 7.24–
7.41 (m, 5H, H-5, H-7, H-8, H-50 and H-60) 7.69 (s, 1H, H-4). 13C
NMR: 20.80 (CH3), 55.81 (OCH3), 111.31 (C-30), 116.21 (C-8),

188
M.J. Matos et al. / Journal of Molecular Structure 1050 (2013) 185–191
Fig. 2. (a) Electrostatic potential surfaces for compounds 1–3. Color-coded: blue (positive), white (neutral) and red (negative). (b) Partial charge distribution for compounds
1–3. Atoms are coloured according to the charge range.
compound 3 has a dihedral angle (33°) between planes similar to
compound 1. This compound proved to be the best one of the series
(IC50 MAO-B = 0.802 nM) [12]. Therefore, the relative position be-
tween the main planes of the molecule could be important to mod-
ulate the accommodation of the derivatives in the active site of the
receptor, regardless of the same nature of the substituent group.
The described compounds are structurally similar to the com-
pound previously described by us [34]. The previously described
compound is the 3-phenylcoumarin. In that crystal, the dihedral
angle between the coumarin core and the 3-phenyl ring is 47.6°.
The activity against MAO-B of this compound is higher than com-
3. Results and discussion
Compound 1 was prepared in 68% yield, by Perkin reaction be-
tween the 2-hydroxy-5-methylbenzaldahyde and the phenyl acetic
acid (Scheme 1) [11]. Compound 2 was prepared in 59% yield, by
Perkin reaction between the 2-hydroxy-5-methylbenzaldahyde
and the o-methoxyphenyl acetic acid (Scheme 1) [12]. Finally,
compound 3 was prepared in 53% yield, by Perkin reaction be-
tween the 2-hydroxy-5-methylbenzaldahyde and the m-methoxy-
phenyl acetic acid (Scheme 1) [12]. Through examination of the
NMR spectra we identified the chemical shifts of the different pro-
tons and carbons for all the compounds. Also, the molecular struc-
tures of the three compounds were resolved by X-ray
diffractometry and are shown in Fig. 1, together with the atomic
numbering scheme used.
As it can be observed in Fig. 1, the molecules adopted some sim-
ilar aspects in the conformation of the crystal. In all cases the cou-
marin nucleuses and the aromatic rings attached to them are
planar, as expected. The main difference between the molecular
structures of the compounds is the dihedral angle formed between
those planes. These relative positions depend on the substituent
presented in aromatic ring attached to the coumarin. The greatest
conformational freedom of the molecules resides, therefore, in the
link between the coumarin scaffold and the 3-aryl ring. The dihe-
dral angle between the main planes is higher in compound 2
(56.48°), compound that presents an ortho-methoxy group. This
compound proved to be the less active of these series against
pound 2 (IC50 MAO-B = 11.81 lM) [14], but is less than compound
1 and 3. In all cases the activity is related to the angle formed be-
tween the main planes of the 3-arylcoumarin scaffold.
The compounds have also shown different charge distribution
patterns due to the diverse substituents that can further explain
the described changes in the activity. The structures for the com-
pounds 1–3 extracted from the AM1 calculation showed differ-
ences in the electrostatic potential surfaces (see Fig. 2a). An area
of negative charge is placed in ortho position of the 3-aryl ring
for the compound 2, whereas a similar area is placed in meta posi-
tion for compound 3. Moreover, substitution in ortho or meta posi-
tion causes a redistribution of the charges in the different carbon
atoms in the aryl ring (see different colors in the aryl carbon atoms
in Fig. 2b) that can also influence the complementarity with the
receptor. Nevertheless, the fact that the methoxy group in meta po-
sition rather than ortho could fit better in the hydrophobic en-
trance cavity of the MAO-B receptor could also be important for
the MAO-B activity.
MAO-B isoenzyme (inactive at 100 lM, highest concentration
tested; at higher concentrations the compounds precipitate) [11],
proving that the accommodation of this derivative in the active site
of this enzyme is the less efficient. In the case of compound 1, the
non-substituted derivative, the dihedral angle between the main
planes is 38.69°. This compound is more active (IC50 MAO-
B = 283 nM) than compound 2 [12]. The relative position between
planes is better tolerated to the active site than the first one. Finally,
Tables 2–4 (Supplementary information) list the bond lengths,
bond angles and dihedral angles obtained for the three described
compounds (1, 2 and 3 respectively), according to the X-ray anal-
ysis. The results for the semiempirical calculations (conformational
analysis combined with AM1 and PM3 methods) are also shown in
the tables.

M.J. Matos et al. / Journal of Molecular Structure 1050 (2013) 185–191
189
Fig. 3. Superposition of the crystal structure (pink carbons) and the semiempirical conformations calculated through AM1 (grey carbons) and PM3 (green carbons) for
compounds 1 (panels a and d), 2 (panels b and e) and 3 (panels c and f).
The 3D structures determined through semiempirical methods
are highly coincident with the information provided by X-ray.
Table 5
The calculations yielded for all the compounds two possible con-
formational states that differentiate in the orientation of the aryl
fragment regarding the plane of the coumarin nucleus. As an
example, the dihedral angles C(2)–C(3)–C(13)–C(14) calculated
with AM1 method for compounds 1, 2 and the equivalent dihedral
C(2)–C(3)–C(12)–C(13) for compound 3 could present values of
36.7, 73.2 and 36.5 or ꢂ35.8, ꢂ73.2 and ꢂ36.4 degrees respec-
tively. In Fig. 3 we superimposed the coumarin ring of the crystal
structure and the conformations extracted from AM1 and PM3
for the three compounds (semiempirical conformations with val-
ues for the dihedral angle connecting the coumarin ring and the
aryl fragment of 36.7°, 73.2° and 36.5° for compounds 1, 2 and 3,
using AM1 method). The comparison between experimental and
semiempirical 3D structures showed a high level of coincidence.
The RMSD (root mean square deviation) values for distances (Å),
bond angles (°), dihedral angles (°) and the heavy atoms coordi-
nates are shown in Table 5. PM3 performed slightly better to repro-
duce the bond lengths. However, AM1 method yielded better
results in the reproduction of angles and dihedral angles (see Ta-
ble 5). It is worth noting that the RMSD value for the dihedral an-
gles is higher in compound 3 using both semiempirical methods.
This is due to the different methoxy orientation found between
the crystal and the calculated conformers. However, a similar
methoxy conformation can be found through these methods with
a slightly higher semiempirical energy and showing a possible con-
formational state equilibrium for the methoxy orientation. Never-
theless, the RMSD dihedral angle value drastically decreases if we
exclude the methoxy group of the aryl fragment in the calculation
(see Table 5). The RMSD of the heavy atoms coordinates also
showed that AM1 is more coincident with the crystal structures.
However, our intention is not to justify the selection of one method
since both AM1 and PM3 performed with high degree of accuracy.
The results are in agreement with previous publications [23–25].
RMSD between the 3D structures determined through X-ray and semiempirical
methods for compounds 1, 2 and 3. The values are shown for distances (Å), bond
angles (°), dihedral angles (°) and the heavy atoms coordinates (no hydrogens were
considered).
Compound 1
AM1 PM3
Compound 2
AM1 PM3
Compound 3
AM1 PM3
RMSD
Distance
Angles
Dihedral angles
Heavy atoms
coordinates
0.013 0.009 0.014 0.012 0.013
1.848 2.431 1.717 2.223 3.009
0.010
3.505
2.971 5.057 7.039 9.809 37.749a 37.812a
0.115 0.137 0.168 0.302 0.502
0.569
a
The RMSD values excluding the methoxy group in the aryl fragment are 2.523
and 6.128 respectively.
Packing diagram of the three structures allows the interpreta-
tion of the spatial orientation of the molecules and are shown in
Fig. 4.
4. Conclusion
In summary, we have determined and analyzed the entire struc-
tural parameters in the crystalline state of three coumarin deriva-
tives, and demonstrated that the results are well reproduced using
conformational analysis in combination with semiempirical AM1
and PM3 methods. Therefore, when X-ray data is not available,
semiempirical approaches could be an alternative method to deter-
mine the 3D structure for this type of compounds. We can also
conclude that it is possible to modulate the relative position of
the coumarin scaffold and the aromatic ring at position 3 by
modifying the position of the chemical substituent in the aromatic
ring. These modifications are correlated with the affinity for the

190
M.J. Matos et al. / Journal of Molecular Structure 1050 (2013) 185–191
a
c
ORIG
a
c
ORIG
a
c
ORIG
Fig. 4. Packing diagram of both structures viewed along the b axis.
active site of the target and with the compounds activity. With
simple semiempirical calculations it can be easily reproduced the
3D structure of the studied compounds, which allows establish
important structure–activity relationship studies.
Ciência e Tecnologia (SFRH/BD/61262/2009) grant. S.V. thanks
the Angeles Alvariño program from Xunta de Galicia (Spain).
Appendix A. Supplementary material
Acknowledgements
CCDC 929059, CCDC 929168 and CCDC 929169 contain the sup-
plementary crystallographic data for this paper. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data
Partial financial support from the Spanish researchers personal
funds is gratefully acknowledged. M.J.M. thanks Fundação para a

M.J. Matos et al. / Journal of Molecular Structure 1050 (2013) 185–191
191
[14] M.J. Matos, C. Terán, Y. Pérez-Castillo, E. Uriarte, L. Santana, D. Viña, J. Med.
Chem. 54 (2011) 7127.
[15] M.J. Matos, S. Vázquez-Rodriguez, E. Uriarte, L. Santana, D. Viña, Bioorg. Med.
Chem. Lett. 21 (2011) 4224.
[16] E. Molina, E. Sobarzo-Sánchez, A. Speck-Planche, M.J. Matos, E. Uriarte, L.
Santana, M. Yáñez, F. Orallo, Med. Chem. 12 (2012) 947.
[17] D. Viña, M.J. Matos, G. Ferino, E. Cadoni, R. Laguna, F. Borges, E. Uriarte, L.
Santana, Chem. Med. Chem. 7 (2012) 464.
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.2013.07.
037.
[18] J.C.A. Boeyens, P. Comba, Coord. Chem. Rev. 212 (2001) 3.
[19] T. Helgaker, S. Coriani, P. Jorgensen, K. Kristensen, J. Olsen, K. Ruud, Chem. Rev.
112 (2012) 543.
[20] C.B. Barnett, K.J. Neidoo, J. Phys. Chem. B 114 (2010) 17142.
[21] E. Estrada, J. Gonzalez, L. Santana, E. Uriarte, A. Castiñeiras, Struct. Chem. 11
(2000) 249.
[22] E. Quezada, S. Vilar, L. Valencia, L. Santana, R.A. Mosquera, E. Uriarte, Struct.
Chem. 17 (2006) 459.
[23] M.J. Matos, E. Uriarte, L. Santana, S. Vilar, J. Mol. Struct. 1041 (2013) 144.
[24] C.M. Estévez, A.M. Graña, M.A. Ríos, J. Rodríguez, THEOCHEM 231 (1991) 163.
[25] Bruker, APEX2, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA,
2012.
[26] G.M. Sheldrick, Program for the Refinement of Crystal Structures, University of
Göttingen, Germany, 1997.
[27] G.M. Sheldrick, Acta Cryst. A 64 (2008) 112.
[28] A.J.C. Wilson, International Tables for X-ray Crystallography, vol. C, Kluwer
Academic Publishers, Dordrecht, The Netherlands, 1992.
[29] A.L. Spek, Acta Cryst. D 65 (2009) 148.
References
[1] F. Borges, F. Roleira, N. Milhazes, L. Santana, E. Uriarte, Curr. Med. Chem. 12
(2005) 887.
[2] F. Borges, F. Roleira, N. Milhazes, E. Uriarte, L. Santana, Med. Chem. 4 (2009) 23.
[3] M.E. Riveiro, N. De Kimpe, A. Moglioni, R. Vazquez, F. Monczor, C. Shayo, C.
Davio, Curr. Med. Chem. 17 (2010) 1325.
[4] S. Vilar, E. Quezada, L. Santana, E. Uriarte, M. Yanez, N. Fraiz, C. Alcaide, E. Cano,
F. Orallo, Bioorg. Med. Chem. Lett. 16 (2006) 257.
[5] I. Kostova, S. Bhatia, P. Grigorov, S. Balkansky, V.S. Parmar, A.K. Prasad, L. Saso,
Curr. Med. Chem. 18 (2011) 3929.
[6] J.R. Hwu, S.-Y. Lin, S.-C. Tsay, E. De Clercq, P. Leyssen, J. Neyts, J. Med. Chem. 54
(2011) 2114.
[7] A. Chilin, R. Battistutta, A. Bortolato, G. Cozza, S. Zanatta, G. Poletto, M.
Mazzorana, G. Zagotto, E. Uriarte, A. Guiotto, F. Meggio, S. Moro, J. Med. Chem.
51 (2008) 752.
[8] M.J. Matos, L. Santana, E. Uriarte, S. Serra, M. Corda, M.B. Fadda, B. Era, A. Fais, J.
Pharm. Pharmacol. 64 (2012) 742.
[9] M.J. Matos, S. Vazquez-Rodriguez, L. Santana, E. Uriarte, C. Fuentes-Edfuf, Y.
Santos, A. Muñoz-Crego, Med. Chem. 8 (2012) 1140.
[30] L.J. Farrugia, J. Appl. Cryst. 45 (2012) 849.
[31] MOE software, version 2011.10; Chemical Computing Group, Inc., 2011.
www.chemcomp.com/.
[32] MOPAC, James J.P. Stewart, Stewart Computational Chemistry, Colorado
Springs, CO, USA, http://OpenMOPAC.net (accessed October 2012).
[33] Maestro, version 9.2, Schrödinger, LLC., New York, NY, 2011.
[34] M.J. Matos, L. Santana, E. Uriarte, Acta Cryst. E 68 (2012) 2645.
[10] P. Anand, B. Singh, N. Singh, Bioorg. Med. Chem. 20 (2012) 1175.
[11] M.J. Matos, D. Viña, E. Quezada, C. Picciau, G. Delogu, F. Orallo, L. Santana, E.
Uriarte, Bioorg. Med. Chem. Lett. 19 (2009) 3268.
[12] M.J. Matos, D. Viña, C. Picciau, F. Orallo, L. Santana, E. Uriarte, Bioorg. Med.
Chem. Lett. 19 (2009) 5053.
[13] D. Viña, M.J. Matos, M. Yáñez, L. Santana, E. Uriarte, MedChemComm 3 (2012)
213.