Biological and structure-activity evaluation of chalcone derivatives against bacteria and fungi

Article abstract of DOI:10.1590/S0103-50532013000100018

The present work describes the antibacterial and antifungal activities of several chalcones obtained by a straight Claisen-Schmidt aldol condensation determined by the minimal inhibitory concentration against different microorganisms (Gram-positive and Gram-negative bacteria and fungi). Solid state crystal structures of seven chalcones were determined by X-ray diffraction (XRD) analysis. Chemometric studies were carried out in order to identify a potential structureactivity relationship.

Full text of DOI:10.1590/S0103-50532013000100018

J. Braz. Chem. Soc., Vol. 24, No. 1, 133-144, 2013.
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Article
A
Biological and Structure-Activity Evaluation of Chalcone Derivatives against
Bacteria and Fungi
Wender A. Silva,*,a Carlos Kleber Z. Andrade,*,a Hamilton B. Napolitano,a,b Ivo
Vencato,b,c Carlito Lariucci,c Miriam. R. C. de Castrob and Ademir J. Camargob
aLaQMOS, Instituto de Química, Universidade de Brasília, CP 4478, 70910-970 Brasília-DF, Brazil
bCiências Exatas e Tecnológicas, Universidade Estadual de Goiás,
BR 153, km 98, 75133-050 Anápolis-GO, Brazil
cInstituto de Física, Universidade Federal de Goiás, CP 131, 74001-970 Goiânia-GO, Brazil
O presente trabalho descreve as atividades antibacterianas e antifúngicas de diversas chalconas
obtidas diretamente através da condensação aldólica tipo Claisen-Schmidt das quais se determinou
a concentração inibitória mínima frente a diferentes microrganismos (bactérias Gram-positivas
e Gram-negativas e fungos). Estruturas no estado sólido cristalino de sete chalconas foram
determinadas por análise de difração de raios X (XRD). Estudos quimiométricos foram realizados
com intuito de identificar uma potencial relação entre estrutura e atividade.
The present work describes the antibacterial and antifungal activities of several chalcones
obtained by a straight Claisen-Schmidt aldol condensation determined by the minimal inhibitory
concentration against different microorganisms (Gram-positive and Gram-negative bacteria and
fungi). Solid state crystal structures of seven chalcones were determined by X-ray diffraction
(XRD) analysis. Chemometric studies were carried out in order to identify a potential structure-
activity relationship.
Keywords: chalcones, biological activities, X-ray structures, theoretical calculations
Introduction
Chalcone (1,3-diaryl-2-propen-1-ones) derivatives are
found widespread in natural products from pteridophytes
to highly organized multicellular organisms. This class of
compounds is considered as key precursors for flavonoid and
isoflavonoid syntheses1 and can be directly obtained by aldol
reactions under basic catalytic conditions. Chemically, they
consist of open-chain flavonoids in which the two aromatic
rings are joined by a three-carbon α,β-unsaturated carbonyl
system (Figure 1). Studies on their multiple biological
activities including anti-inflammatory,2 anti-leishmania,3
antimitotic4 and antiviral are some few examples of their
broad range of action.5 In particular, chalcone systems
usually show different levels of inhibition during proliferative
processes of a plethora of cancer cell lines.6
Figure 1. General structure of a chalcone.
For instance, the inclusion of two hydroxyl groups
(dihydroxychalcones) enhanced both the antitumor and
lipidic antiperoxidation activities.8 Other activities have
already been reported9-11 and Figure 2 shows some examples
of biologically active chalcones.
Toxicity against several tumoral human cells12 renders
this class an attractive alternative to commonly used taxoid
compounds, which are very complex structures of low
The presence of hydroxyl, allyl and prenyl groups in
their structures commonly potentiates their activities.7
*e-mail: wender@unb.br; ckleber@unb.br

134
Biological and Structure-Activity Evaluation of Chalcone Derivatives against Bacteria and Fungi
J. Braz. Chem. Soc.
Figure 2. Some biologically active chalcone derivatives.
availability. Hence, the preparation and identification of
simpler low-cost compounds such as chalcone derivatives
for cytotoxic tests are still inexhaustible tasks aiming
at the development of new and promising biologically
active readily available molecules. As part of our ongoing
studies on the synthesis, characterization and in silico
studies of chalcone derivatives,13 it is described herein
the preparation of 21 different chalcone derivatives,
three of them (3c, 3f, 3u) are novel compounds, and their
evaluation as antibacterial and antifungal agents upon
determination of the minimal inhibitory concentration
(MIC) against different microorganisms (Gram-positive and
Gram-negative bacteria and fungi). Moreover, solid state
crystal structures of seven chalcones were determined by
X-ray diffraction (XRD) analysis. Theoretical calculation
studies (structure modeling) were equally carried out in
order to identify a potential structure-activity relationship.
olefins whereas the carbonyl carbons appear in the range
of 187.7 to 193.7 ppm in the 13C NMR spectra.
Due to the wide spectrum of action of this class of
compounds and to their good cytotoxicity, our group began
to investigate some structural modifications based on related
studies in order to obtain molecules with potential biological
activity.Allyl chalcones in particular were reported to exhibit
widespread biological activities, with improved activities
in some cases, probably due to their structural similarity to
licochalcone E.7 In our group, studies were carried out in this
way, and the allyl group was introduced into the structures
of chalcones 3b, 3n and 3t. Nevertheless, the insertions were
not efficient, not reaching the expected activity.
Biological activity
Sevenbacterialstrainswereusedfortestingantimicrobial
activities, including Gram-positives: Sthaphylococcus
aureus ATCC 6538, Bacillus subtilis ATCC 6833,
Streptococcus mutans ATCC 25175, Micrococcus
luteus ATCC 10240, and Gram-negatives: Escherichia
coli ATCC 94863, Pseudomonas aeruginosa and
Salmonella choleraesuis ATCC 14028. Three fungi were
used: Aspergillus niger ATCC 16404, Cladosporium
cladosporioides IMI 178517 and Candida albicans ATCC
18804. The results are summarized in Table 2 and indicate,
in some cases, considerable activity against bacteria in
comparison with the standard, especially for chalcones
3m, 3n and 3o, which showed a good profile towards
some microorganisms (e.g., chalcone 3n on S. mutans).
No activity at all was observed against the following
microorganisms: S. choleraesuis ATCC 14028, E. Coli
ATCC 94863 and P. aeruginosa.
Results and Discussion
Synthesis of chalcones
The chalcones were easily obtained from the aldol
condensation of aromatic aldehydes and aromatic ketones14
(Table 1), in yields ranging from 70 to 100%. Chalcones
3a-g are derived from 3,4-methylenedioxybenzaldehyde;
chalcones 3h-i from 4-nitrobenzaldeyde; chalcone 3J from
4-(N,N)-dimethylbenzaldehyde; chalcones 3k-l from
cinnamaldehyde; chalcones 3m-r from benzaldehyde and
finally chalcones 3s-u from furfural. The chalcones were
1
13
characterized by H and C nuclear magnetic resonance
(NMR) spectroscopy, X-ray diffractometry and elemental
1
analyses (for the novel compounds). The H NMR
spectra showed two doublets between 7.0 and 8.0 ppm
(Jtrans 15-16 Hz) confirming the trans configuration of the
In some cases, the activity is dependent on the
substituents on the aromatic ring. For instance, chalcones

Vol. 24, No. 1, 2013
Silva et al.
135
3m-q, obtained from benzaldehyde, showed distinct
activities against S. mutans (Table 2). The best activity was
achieved when the hydroxyl group resides on the ortho
position (as in 3n). In contrast, the activity is diminished in
3o (OH in meta position) and in the absence of a substituent
there was no activity. The protection of the hydroxyl group in
3n as an allyl ether decreased the activity by two dilutions.
Chalcones derived from furaldehyde (3s-u) were somewhat
active but those derived from piperonal (3a-g) were inactive
irrespective of the substituents on the aromatic ring.
When the fungi are concerned, C. cladosporioides was
the most sensitive to the chalcones. The greatest activities
were achieved by compounds 3a, 3e and 3k. In the last two
cases, the activities were at the same level of dilution as
compared to Loprox®, the standard drug used in the assay.
characterization. Figure 3 shows the ORTEP drawings of
chalcones 3a, 3f, 3i, 3n, 3o, 3q and 3t and the refinement
data are shown in the Supplementary Information section.
Principal component analysis (PCA) of chalcones
The aim of this section is to get a relationship between
geometric and electronic properties of the 21 synthesized
chalcones and the biological activities against S. aureus
ATCC 6538 and C. cladosporioides IMI 178517. For
this purpose, quantum chemical calculations were carried
out on chalcones and analogues, as listed in Table 1. The
chalcones were tested against 10 microorganisms, but only
two microorganisms were selected for this study, because
the number of active and inactive chalcones for these two
organisms is roughly equally distributed and this is very
important for the statistical analysis of the calculated data
to be meaningful, as shown in Table 3.
Crystallographic analysis
In order to get a better insight on the relationship
between biological activity and structures, the crystal
structure of seven chalcones were obtained for better
As can be seen in Figure 3, chalcones are chemical
compounds with several rotational degrees of freedom
and, in turn, they present many geometric conformations
Figure 3. ORTEP drawings of chalcones 3a, 3f, 3i, 3n, 3o, 3q and 3t, with the atom-numbering schemes. The displacement ellipsoids are drawn at the
30% probability levels.

136
Biological and Structure-Activity Evaluation of Chalcone Derivatives against Bacteria and Fungi
J. Braz. Chem. Soc.
Table 1. Synthesis of chalcones and analogues 3a-3u
Compound
Chalcone
R1
H
H
H
H
H
Br
H
−
R2
H
R3
H
H
H
H
H
H
H
−
R4
H
Yield / %
92
3a
3b
3c
3d
3e
3f
OH
O(allyl)
H
H
81
H
100
90
OMe
NO2
H
H
84
OH
H
80
3g
3h
Ph
85
−
NO2
70
3i
−
−
−
−
H
85
90
3j
−
−
NO2
3k
3l
−
−
−
−
−
−
H
90
85
NO2
3m
3n
3o
3p
3q
3r
3s
−
−
−
−
−
−
−
−
−
H
H
H
H
H
80
84
OH
H
OH
H
H
83
H
OMe
NO2
H
80
H
H
82
O(allyl)
H
100
96
−
−
−
H
−
3t
OH
O(allyl)
−
88
3u
−
100
that are energetically stable. For this reason, it is
mandatory to carry out a conformational search to find
the molecular conformation with the lowest energy. In
this work, the conformational searches were carried
out using HyperChemTM 7.5 suite of programs15 with
semiempirical quantum method PM316,17 and random
walk algorithm. Initially, the most active chalcone was
analyzed and the most stable conformation was selected.
Afterwards, the remaining chalcones were investigated and
the energetically most stable conformation that was similar
to the conformation selected before was chosen for the
calculation of the molecular properties. Before calculating
the properties, the molecular geometries were optimized
again, but now using the density functional theory
(DFT)18,19 with the hybrid exchange-correlation functional
B3LYP20-22 and the basis set 6-31G(d) as implemented
in the software package G0923, which was also used to
calculate the molecular properties (descriptors or variables).
In this work, the following molecular descriptors were
calculated: HOMO-1 (second highest occupied molecular
orbital energy), HOMO (highest occupied molecular
orbital energy), LUMO (lowest unoccupied molecular
orbital energy), LUMO+1 (second lowest unoccupied
molecular orbital energy), partition coefficient (logP) (this
property was obtained from the hydrophobic parameters
of the substituents using HyperChemTM 7.5), Mulliken

Vol. 24, No. 1, 2013
Silva et al.
137
Table 2. Activities (MICs) of the chalcones against bacteria and fungi
Microrganisms
S. mutans S. choleraesuís E. coli
ATCC 6633 ATCC 6538 ATCC 10240 ATCC 25175 ATCC 14028 ATCC 94863
Samples /
(µg mL-1)
B. subtilis
S. aureus
M. luteus
P. aeruginosa C. albicans
A. niger
C. cladosporioides
ATCC 18804 ATCC 16404
IMI 178517
3a
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
100
100
>100
50
100
>100
100
>100
>100
100
100
>100
>100
>100
100
>100
>100
>100
>100
100
12,5
25
>100
>100
>100
>100
>100
>100
>100
>100
> 100
>100
>100
> 100
>100
>100
>100
>100
>100
>100
>100
>100
>100
6.3
>100
>100
>100
>100
>100
>100
>100
>100
> 100
>100
>100
> 100
>100
>100
>100
>100
>100
>100
>100
>100
>100
3.1
>100
>100
>100
>100
>100
>100
>100
>100
> 100
>100
>100
> 100
>100
>100
>100
>100
>100
>100
>100
>100
>100
100
>100
>100
100
>100
50
12.5
> 100
> 100
100
3b
3c
>100
100
3d
100
> 100
>100
>100
>100
>100
>100
>100
>100
25
>100
>100
>100
>100
>100
>100
>100
>100
100
>100
>100
>100
>100
>100
> 100
>100
100
3e
>100
100
6,3
3f
> 100
> 100
> 100
>100
> 100
6.3
3g
>100
>100
> 100
>100
>100
> 100
>100
>100
100
3h
3i
3j
3k
3l
> 100
50
> 100
25
3m
100
3n
25
25
100
25
3o
50
25
25
50
100
3p
>100
>100
>100
>100
50
100
>100
100
100
100
50
100
>100
>100
50
>100
>100
>100
>100
>100
50
>100
>100
>100
>100
>100
>100
> 100
> 100
> 100
50
3q
>100
100
3r
3s
100
100
50
3t
50
100
3u
> 100
6.3
100
50
> 100
Chloramphenicol
Loprox®
6.3
0.78
−
6.3
−
6.3
−
12.5
−
6.3
−
−
−
−
−
−
Table 3. Theoretical values for the selected descriptors used in the PCA analysis for the activities against C. cladosporioides and S. aureus. The activities
are also included
C. cladosporioides
S. aureus
Chalcone
AD1,2,3,4
–174.90
173.37
174.92
–175.08
176.37
174.09
174.07
175.27
178.39
174.69
–174.43
174.43
–175.58
177.96
–179.18
178.83
–174.68
–173.97
–175.92
–179.97
–175.92
PsiH-13
Ref
Activity
active
b7,14
PsiL-2
11.76
9.075
6.371
11.187
10.078
14.336
20.293
4.842
18.849
11.011
9.531
9.908
2.275
15.108
2.532
3.368
2.286
5.034
3.542
10.289
20.97
A12,2,3
Activity
active
3a
3b
3c
3d
3e
3f
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.02
0.00
0.00
0.00
0.00
0.06
0.24
0.22
0.00
0.05
0.00
0.00
0.00
72.64
68.50
74.32
88.27
74.34
68.57
73.34
74.20
82.50
58.69
79.11
60.39
79.97
81.89
97.78
82.89
81.53
74.20
88.56
75.56
66.88
0.9023
1.1184
0.8945
0.9063
0.9053
0.8950
0.9005
0.8982
1.0147
0.9024
0.9005
0.9015
0.8984
1.1188
0.8974
0.8916
0.8974
0.9014
0.8990
0.8967
0.9022
118.126
118.338
119.975
118.131
117.849
118.198
118.183
118.25
inactive
inactive
active
inactive
active
active
active
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
active
inactive
inactive
inactive
inactive
inactive
active
3g
3h
3i
117.72
3j
120.045
118.135
120.039
118.204
116.365
116.038
117.105
118.482
118.433
117.913
117.424
117.913
3k
3l
inactive
active
3m
3n
3o
3p
3q
3r
3s
active
active
active
active
inactive
inactive
inactive
active
active
inactive
active
active
3t
active
active
3u
inactive
active

138
Biological and Structure-Activity Evaluation of Chalcone Derivatives against Bacteria and Fungi
J. Braz. Chem. Soc.
electronegativity (χ = (EHOMO − ELUMO)/2), dipole moment,
molecular polarizability, total electronic energy, heat of
formation, electron affinity (obtained as −EHOMO), band
gap energy (ELUMO − EHOMO), hardness, softness, molar
refractivity index, ionization potential energy, net atomic
charge on atom derived from electrostatic potential,
molecular area, molecular volume, bond order, bond length
between adjacent atoms, angles between three consecutive
atoms, dihedral angles between four consecutive atoms,
molecular length, hydration energy, Psi – x = Si|ci|2HOMO
and Psi – x = Si|ci|2LUMO, where x stands for atom number
as shown in Figure 4.
compounds between active and inactive, allowing, in this
way, a reduction in the number of variables to be used in
PCA.
The major aim in the PCA technique is to reduce the
dimensionality of the data set to lower dimensional space
for analysis.27 This is achieved through an orthogonal linear
transformation of the original data set of descriptors into a
smaller set of uncorrelated significant principal components
(PCs). This transformation can be seen as a rotation of
the original coordinate system in such a way that the first
principal component (PC1) axis describes the maximum
variance of the data set. The second principal component
(PC2), which is orthogonal to the first one, describes the
second maximum variance and so on. In general, the
great majority of the variance of the data set is described
by the first components and can be utilized to represent
the entire data set in a simplified way. For this reason,
principal component analysis is a useful tool for helping in
the visualization of hidden patterns, providing descriptive
models. A priori, all descriptors are likewise important to
explain the biological activity. So, before applying PCA
technique, the data were auto-scaled, i.e., each variable
was mean centered and divided by standard deviation, so
each variable in the matrix data can be compared to each
other on the same scale. The auto-scaling procedure was
calculated according to equation 2,
Figure 4. Atomic numbering used in the calculations of the molecular
descriptors.
The frontier electron reactivity theory, which explains
many organic reactions, states that the reaction between
two reactants takes place where the overlap of HOMO and
LUMO is maximized.24 The HOMO density (PsiH-x) is
closely related to the charge transfer (nucleophilic reactant),
while for an acceptor compound the LUMO density
(PsiL-x) is important (electrophilic reactant). A total of
118 geometrical and electronic molecular descriptors was
obtained from ab initio calculations in such a way that they
can represent electronic, steric and hydrophobic features of
the chalcones. These features are supposed to be important
to elucidate the biological activity of the chalcones against
S. aureusATCC 6538 and C. cladosporioides IMI 178517.
In order to find a relationship between the calculated
descriptors and the biological activities, an analysis using
the multivariate statistical was carried out using the Einsight
program.25 At the outset, the Fisher weight26 for each
descriptor was calculated in order to discriminate those
variables that are the most important to separate the active
from the inactive chalcones. The Fisher weight (wk) for
the variable k was obtained from the following equation 1:
(2)
where xik represents the auto-scaled variable i for the sample
–
k,
stands for standard deviation and xi is the mean value
of the variable i.
Activity against C. cladosporioides IMI 178517
The atomic numbering used in the calculation of the
molecular descriptors is shown in Figure 4. After several
attempts to separate the active from the inactive chalcones
against C. cladosporioides IMI 178517, the best result
was finally obtained with three descriptors: dihedral angle
between atoms 1, 2, 3, and 4 (DA1,2,3,4), (PsiH-13), and
refractive index (Ref) (the names in parenthesis represent
the names of the respective descriptors plotted in
Figure 5). Figure 6 shows the score plots. Observe that two
components (PC1 and PC2) are necessary to discriminate
the chalcones into active and inactive. These two principal
components together explain 89.33% of the total variance in
the data set as follows: PC1 = 56.32% and PC2 = 33.01%.
The amount of total variance explained in the data set by
these two components represents very well the higher
order space. The score plot in Figure 6 shows that the
(1)
–
–
In this equation, xactive and xinactive are the mean
values for the active and inactive molecules and
–
–
2
(1/Nactive)S(xactive – xactive)2 and (1/Ninactive)S(xinactive – xinactive
)
are the respective variances. Those descriptors with high
Fisher weights are more significant to discriminate the

Vol. 24, No. 1, 2013
Silva et al.
139
both components. For a chalcone to be classified as active
against C. cladosporioides, it must stand below the solid
line drawn in Figure 6. This means that the scores for both
components should be small and, in turn, for the scores
to be small, the variables Ref and PsiH-13 should present
lower values. However, as shown in equations 3 and 4,
the situation for the variable DA1,2,3,4 is a little delicate
because it should present higher value in the first component
(the loading is negative for this variable in PC1) and lower
value in the second one (the loading is positive) in order
to help in the discrimination of the compounds. As shown
in Table 3, the value of this dihedral angle is almost 180º,
which means that the chalcones are almost planar in this
molecular region. PsiH-13 describes the HOMO density
on atom 13 and, according to equations 1 and 2, it should
have lower values in order to help in the discrimination of
the compounds. From these observations, it is possible to
hypothesize the three major characteristics for a chalcone to
be active: (i) lower values of refractive index (Ref), (ii) lower
values of the HOMO density on atom 13 (PsiH-13) (see
Figure 4 for the numbering), and (iii) intermediate values of
dihedral angle between the atoms 1, 2, 3 and 4 (DA1,2,3,4).
These molecular characteristics can help us to design new
chalcones with activity against C. cladosporioides.
Figure 5. Plot showing the descriptor loadings, which explain the activity
of the compounds against C. cladosporioides. DA1,2,3,4 stands for
dihedral angle among the atoms 1, 2, 3 and 4, PsiH-13 represents the
HOMO density on atom 13 and Ref stands for molecular refractive index.
Activity against S. aureus ATCC 6538
The active chalcones against S. aureusATCC 6538 stand
above the solid line drawn in Figure 7. As can be noted in
this figure, only one component (PC2) is needed to separate
the active chalcones from the inactive ones. The component
PC2 accounts for 33.02% of the total variance of the
original data, while the first component (PC1) accounts for
46.62%. Both components added up to 79.64% of the total
variance in the original data. A close look in equation 5 and
in Figure 8 shows that the descriptors responsible for the
discrimination are the angle between atoms 12, 2 and 3
(A12-2-3), PsiL-2, and bond order between atoms 7 and 14
(b7,14). Equation 5 also shows that for a compound to fall in
the active group, it should present higher values of PsiL-2 and
A12-2-3 variables. The bond order b7-14 is not important
in this component, but to run the Einsight program,25 it was
necessary to include it in the calculation.
Figure 6. Plot showing the scores for the activity of the chalcone
derivatives against C. cladosporioides. It is worth noting that all the active
compounds (3a, 3d, 3e, 3k, 3m, 3n, 3o, 3s and 3t) stand below the solid
line drawn in figure.
active chalcones against C. cladosporioides are gathered
below the solid line drawn in the figure. The mathematic
representations for these two components are expressed
through equations 3 and 4.
PC1 = 0.7046 Ref + 0.5552 PsiH – 13 – 0.4419DA1,2,3,4 (3)
PC2 = 0.0033 Ref + 0.6202 PsiH – 13 – 0.7845DA1,2,3,4 (4)
PC1 + 0.001b7.14 + 0.694PsiL2 + 0.720A12,2,3
(5)
From analysis of equations 3 and 4, it is possible to
see that the variable Ref is not meaningful in the second
component but is very important in the first component.
The other descriptors, namely PsiH-13 and dihedral angle
between atoms 1, 2, 3, and 4 (DA1,2,3,4) are important in
As pointed out before, the variable PsiL-2 is closely
related to the importance of the atom 2 in the lowest
unoccupied molecular orbital (LUMO). Equation 5 shows
that this descriptor should be higher for the molecule to be
active. That may mean that the atom 2 (Figure 4) could be

140
Biological and Structure-Activity Evaluation of Chalcone Derivatives against Bacteria and Fungi
J. Braz. Chem. Soc.
promising activity against C. cladosporioides, with
low inhibitory values, in some cases in the same order
of magnitude as the standard (Loprox®). Chemometric
studies were employed to find a possible structure-activity
relationship and allowed to establish some important
features for the chalcones to be active. For instance, the
best activity against C. cladosporioides IMI 178517 was
obtained with three descriptors: dihedral angle between
atoms, HOMO density on atom 13 (PsiH-13) and
refractivity index (Ref) and two components (PC1 and
PC2) were necessary to discriminate the chalcones into
active and inactive. In the case of S. aureus ATCC 6538,
only one component (PC2) was needed and the descriptors
responsible for the discrimination were the bond angle
(A12-2-3), PsiL-2, and bond order between atoms (b7,14).
Future efforts to optimize the structures of this class of
compounds may involve design, as well as the study of the
effect of some groups strategically placed in positions in the
structure of chalcones that may influence some properties
such as solubility.
Figure 7. Plot showing the scores for the activity of the compound
derivatives against S. aureus. Note that all the active compounds stand
above the solid line drawn in figure.
Experimental
General
All reagents were obtained from Sigma-Aldrich and
used without purification. 1H NMR spectra were recorded at
300 MHz on aVarian Mercury Plus 7.04 T spectrometer and
chemical shifts were reported relative to internal Me4Si.
13C NMR spectra were recorded at 75 MHz on a Varian
Mercury Plus 7.04 T spectrometer and chemical shifts
were reported relative to internal CDCl3. The infrared
spectra were obtained on a Bomem MB-100 spectrometer.
Elemental analyses were obtained on a Perkin Elmer series
II CHNS/O Analyzer 2400.
Figure 8. Graphic representation of variable loadings (A12,2,3, PsiL-2,
b7,14) that discriminate the active from the inactive chalcones against
S. aureus.
involved in the formation of some kind of chemical bond in
the structure of S. aureusATCC 6538. From that discussion,
it is possible to postulate that the chalcones studied need
to present two main characteristics to express activity
against S. aureus ATCC 6538: (i) they must have a large
angle between atoms 12, 2 and 3 (A12,2,3), and (ii) they
need to increase the value of LUMO density, which is
probably related to some kind of reaction in expressing their
activities. This characteristic can be useful in designing
compounds with activity against S. aureus ATCC 6538.
General synthetic procedure for chalcones
The ketone (1 mmol) was added to a solution of
NaOH (10% m/v) and ethanol (3 mL) and the mixture
was stirred for 20 min under ice bath cooling. Then, the
aldehyde (1 mmol) was added and the resulting mixture
was stirred overnight at room temperature. The reaction
mixture was acidified with 10% HCl. The precipitate was
collected, washed with cold water, dried and purified by
recrystallization from EtOH or in appropriate solvents
(generally chloroform and methylene chloride). The
chalcones that did not crystallize were washed with
chloroform and purified by column chromatography (20%
ethyl acetate/hexane).
Conclusions
A series of chalcones was prepared and evaluated
against bacteria and fungi. Some compounds showed

Vol. 24, No. 1, 2013
Silva et al.
141
MIC assays
stereochemical predictions. They were refined with fixed
individual displacement parameters 20% greater than
the equivalent isotropic displacement parameter of the
corresponding carbon atom. Aromatic C-H bond distances
were fixed according to the riding model (0.93Å). The (x, y,
z) fractional coordinates and the isotropic thermal parameter
of these H atoms were not constrained during refinements.
The Mercury33 and ORTEP-334 programs were used within
the WinGX35 software package to deal with the processed
crystallographic data and artwork representations. The
conformational and geometric features of this molecule
were checked comparing with other similar structures.
The crystallographic data for compounds 3f, 3i, 3a, 3n
and 3t were deposited at the Cambridge Crystallographic
Data Center under the numbers 819655, 819656, 819657,
819681 and 823762, respectively.
The determinations of MIC were performed essentially
according to the National Committee for Clinical Laboratory
Standards (NCCLS)28 as described by Ellof29 and
Kusucu et al.30 The microorganisms were obtained from
the Fundação Tropical de Pesquisa e Tecnologia André
Tosello, Campinas-SP, Brazil, with exception of E. coli and
P. aeruginosa, obtained from Departamento de Farmácia of
Universidade Federal da Bahia, Salvador-BA, Brazil. The
bacteria were grown for 24 h at 35 ºC on nutrient agar. The
fungi and yeast were cultivated for 72 h at 26 ºC on malt
extract agar and yeast malt agar, respectively. The inocula
for the assays were prepared by cell suspensions according
to McFarland scale 0.5 (108 CFU mL-1).
To determine MIC of the compounds against the
microorganisms, the following modified micro dilution
method was carried out: the compounds were dissolved
in sterile dimethyl sulfoxide (2000 mg mL-1) and 20 µL
of the stock solutions were transferred into 96 well sterile
microtiter plates. Then, serial dilutions with nutrient broth
to bacteria and malt extract broth to fungi were performed,
so that the concentrations of the tested compounds ranged
from 100 to 0.78 mg mL-1. Finally, an aliquot (100 µL) of
culture medium containing the microorganism suspension
was added to the wells. Chloramphenicol and Loprox®
were used as the reference drugs against bacteria and
fungi, respectively, and DMSO was used as negative
control. The plates were incubated at 35 ºC for 24 h to
bacteria and fungi and yeast were maintained at 26 ºC for
72 h. After incubation, an aliquot of 50 µL of aqueous
[3-(4,5-dimethyl-2-tiazolyl)-2,5 diphenyl-2H-tetrazolium
bromide] (MTT at 0.05%) was added on the wells and the
reduction of tetrazolium salt (yellow) from (blue) indicated
the presence of viable cells. MIC is defined as the lowest
concentration of the substances which inhibited the growth
of the microorganisms.
The respective solutions, anisotropic refinements,
geometrical calculations, molecular packing and drawings
were performed using the program package WINGX. (3a):
C16H12O3, a = 7.809(2), b = 11.1764(9), c = 28.601(2) Å,
orthorhombic system, space group Pcab, R = 0.0557; (3f):
C16H11O4Br, a = 4.160(3), b = 11.757(2), c = 27.598(7) Å,
β = 92.87(4)o , monoclinic system, space group P21/c,
R = 0.0809; (3i): C15H11NO3, a = 4.7580(9), b = 6.096(1),
c = 10.658(2) Å, α = 95.807(2)o, β = 90.482(2)o,
γ = 96.397(2)o, triclinic system, space group P1,
R = 0.0492; (3t): C13H10O3, a = 3.9530(9), b = 14.583(2),
c = 17.893(5) Å, monoclinic, space group P21/n,
R = 0.0527; (3o): C15H12O2: a = 12.641(1), b = 12.066(2),
c = 7.813(1)Å, β = 101.278(9)o, monoclinic system, space
group P21/c, R = 0.0820; (3n): C15H12O2, a = 6.822(2),
b = 10.474(4), c = 17.097(2)Å, α = 73.88(2), β = 84.29(2),
γ = 87.66(3)o. Triclinic, space group P-1, R = 0.0701; (3q):
C15H11NO3, a = 6.299(3), b = 13.226(3), c = 14.809 Å,
β = 99.73(9)o , monoclinic system, space group P21/c,
R = 0.0660.
Spectroscopic data for the chalcones
Crystallographic structure determinations of compounds
3a, 3f, 3i, 3n, 3o, 3q and 3t
(2E)-3-(1,3-Benzodioxol-5-yl)-1-phenylprop-2-en-1-one
(3a):36 IR (KBr) νmax/cm-1 3021, 2928, 1660, 1598, 1503,
1310, 1104, 770, 686; 1H NMR (300 MHz, CDCl3) 8.02-
7.98 (m, 2H), 7.73 (d, 1H, J 15.7 Hz), 7.61-7.46 (m, 3H),
7.36 (d, 1H, J 15.7 Hz), 7.16 (d, 1H, J 1.4 Hz), 7.11 (dd,
1H, J 8.1 and 1.9 Hz), 6.84 (d, 1H, J 8.1 Hz), 6.02 (s, 2H);
13C NMR (75 MHz, CDCl3) 190.4, 149.9, 148.4, 144.7,
138.3, 132.6, 129.3, 128.5, 128.4, 125.2, 120.0, 108.6,
106.6, 101.6.
Single crystal X-ray diffraction data were collected at
room temperature using a Nonius CAD-4 diffratometer31 and
using Cu Kα radiation (λ = 1.54180Å). The structures were
solved by direct methods and anisotropically refined with
full-matrix least-squares on F2 using SHELXL97.32 The
hydrogen atoms were placed at calculated position except
those involved in H-bonds and weak interactions found on
difference maps and refined with riding constraints. With
regard to the hydrogen atoms, those bonded to carbon
atoms were placed in expected positions according to the
(E)-3-(Benzo[d][1,3]dioxol-6-yl)-1-(2-hydroxyphenyl)
prop-2-en-1-one (3b):36 1H NMR (300 MHz, CDCl3) 12.90

142
Biological and Structure-Activity Evaluation of Chalcone Derivatives against Bacteria and Fungi
J. Braz. Chem. Soc.
(s, 1H), 7.90 (dd, 1H, J 6.6 and 1.4 Hz), 7.85 (d, 1H,
J 15.3 Hz), 7.50 (d, 1H, J 15.3 Hz), 7.52-7.47 (m, 1H), 7.18
(dd, 1H, J 6.9 and 1.7 Hz), 7.14 (d, 1H, J 1.45 Hz), 7.03
(dd, 1H, J 8.4 and 0.9 Hz), 6.97-6.91 (m, 1H), 6.82 (d, 1H,
J 8.1 Hz), 6.05 (s, 2H); 13C NMR (75 MHz, CDCl3) 193.5,
163.5, 150.3, 148.5, 145.3, 136.2, 129.5, 129.0, 125.7,
120.0, 118.8, 118.6, 117.9, 108.7, 106.7, 101.7.
7.15 (dd, 1H, J 8.0 and 1.4 Hz), 6.85 (d, 1H, J 8.0 Hz), 6,03
(s, 2H); 13C NMR (75 MHz, CDCl3) 189.7, 149.9, 148.4,
145.4, 144.6, 139.9, 137.0, 129.4, 129.0, 128.9, 128.1,
127.3, 127.2, 125,3, 119.9, 108.7, 106.7, 101.6.
(E)-1,3-bis(4-nitrophenyl)prop-2-en-1-one (3h):38
1H NMR (300 MHz, CDCl3) 8.41-8.37 (m, 1H), 8.34-8.28
(m, 3H), 8.21-8.16 (m, 2H), 7.91-7.81 (m, 3H), 7.61 (d,
1H, J 15.5 Hz); 13C NMR (75 MHz, CDCl3) 188.2, 143.4,
142.2, 140.3, 129.5, 129.4, 129.2, 124.7, 124.3, 124.2,
124.0, 123.8.
(E)-1-(2-(allyloxy)phenyl)-3-(benzo[d][1,3]dioxol-6-yl)
1
prop-2-en-1-one (3c): H NMR (300 MHz, CDCl3) 7.64
(dd, 1H, J 7.4 and 1.8 Hz), 7.56 (d, 1H, J 15.7 Hz), 7.47-
7.41 (m, 1H), 7.30 (d, 1H, J 15.7 Hz), 7.09-6.96 (m, 4H),
6.81 (d, 1H, J 7.8 Hz), 6.10-5.97 (m, 3H), 5.42 (dq, 1H,
J 3.0 and 1.5 Hz), 5.26 (dq, 1H, J 3.0 and 1.5 Hz); 13C NMR
(75 MHz, CDCl3) 192.5, 157.0, 149.5, 148.2, 142.6, 132.7,
132.5, 130.4, 129.7, 129.5, 125.2, 124. 9, 120.9, 117.6,
112.8, 108.5, 106.5, 101.5, 69.2 anal. calcd. for C16H14O3: C,
75.57; H, 5.55; O,18.88; found: C, 75.48; H, 5.51; O, 19.01.
(2E)-3-(4-Nitrophenyl)-1-phenylprop-2-en-1-one (3i):39
1H NMR (300 MHz, CDCl3) 8.30-8.25 (m, 2H), 8.06-
8.02 (m, 2H), 7.85-7.75 (m, 3H), 7.82 (d, 1H, J 15.6 Hz);
13C NMR (75 MHz, CDCl3) 189.6, 148.5, 141.4, 141.0,
137.4, 133.3, 128.9, 128.8, 128.5, 125.6, 124.1.
(E)-3-(4-(Dimethylamino)phenyl)-1-(4-nitrophenyl)prop-
2-en-1-one (3j):40 1H NMR (300 MHz, CDCl3) 8.38-8.31
(m, 2H), 8.15-8.09 (m, 2H), 7.82 (d, 1H, J 15.3 Hz), 7.58-
7.54 (m, 2H), 7.27 (d, 1H, J 15.3 Hz), 6.73-6.69 (m, 2H);
13C NMR (75 MHz, CDCl3) 188.9, 152.3, 149.6, 147.8,
144.2, 130.9, 129.1, 123.7, 122.2, 116.0, 111.9, 40.2.
(E)-3-(Benzo[d][1,3]dioxol-6-yl)-1-(4-methoxyphenyl)
prop-2-en-1-one (3d):36 1H NMR (300 MHz, CDCl3)
7.99-8.05 (m, 2H), 7.73 (d, 1H, J 15.6 Hz), 7.38 (d, 1H,
J 15.9 Hz), 7.17 (d, 1H, J 1.9 Hz), 7.11 (dd, 1H, J 8.4 and
1.9 Hz), 6.95-7.00 (m, 1H), 6.83 (d, 2H, J 7.8 Hz), 6.02
13
(s, 2H), 3.88 (s, 3H); C NMR (75 MHz, CDCl3) 188.5,
163.3, 149.7, 148.3, 143.8, 131.2, 130.7, 129.5, 125.0,
119.9, 113.8, 108.6, 106.6, 101.6, 55.5.
(2E,4E)-1,5-Diphenylpenta-2,4-dien-1-one (3k):41 IR
(film) νmax/cm-1 3059, 3027, 1676, 1594, 1448, 1034, 776,
700; 1H NMR (300 MHz, CDCl3) 8.03-7.93 (m, 2H), 7.63-
7.22 (m, 10H), 7.13-6.92 (m, 2H); 13C NMR (75 MHz,
CDCl3) 190.3, 144.7, 141.8, 138.1, 135.9, 132.5, 129.1,
129.0, 128.8, 128.7, 128.5, 128.4, 128.3, 127.2, 126.8, 125.2.
(E)-3-(Benzo[d][1,3]dioxol-6-yl)-1-(4-nitrophenyl)prop-
2-en-1-one (3e):36 1H NMR (300 MHz, CDCl3) 8.37-8.32
(m, 2H), 8.15-8.11 (m, 2H), 7.78 (d, 1H, J 15.4 Hz), 7.31 (d,
1H, J 15.4 Hz), 7.18-7.13 (m, 2H), 6.88 (d, 1H, J 8.1 Hz),
6.06 (s, 2H); 13C NMR (75 MHz, CDCl3) 188.8, 150.7,
150.6, 148.6, 146.7, 143.3, 129.3, 128.8, 126.0, 123.9,
119.2, 108.8, 106.7, 101.8.
(2E,4E)-1-(4-Nitrophenyl)-5-phenylpenta-2,4-dien-
1-one (3l):41 1H NMR (300 MHz, CDCl3) 8.36-8.32 (m,
2H), 8.12-8.08 (m, 2H), 7.66 (dd, 1H, J 8.8 and 1.5 Hz),
7.54-7.50 (m, 2H), 7.43-7.35 (m, 3H), 7.07-7.02 (m, 3H);
13C NMR (75 MHz, CDCl3) 188.9, 149.9, 146.7, 143.6,
143.1, 135.7, 129.7, 129.3, 128.9, 128.6, 127.5, 126.5,
124.5, 123.8, 123.5.
(E)-3-(4-Bromobenzo[d][1,3]dioxol-5-yl)-1-(2-hydroxy-
phenyl) prop-2-en-1-one (3f): 1H NMR (300 MHz, CDCl3)
12.80 (s, 1H), 8.23 (d, 1H, J 15.6 Hz), 7.88 (dd, 1H,
J 8.1 and 1.7 Hz), 7.53-7.47 (m, 1H), 7.44 (d, J 15.6 Hz),
7.23 (s, 1H), 7.10 (s, 1H), 7.03 (dd, 1H, J 8.1 and 1.7 Hz),
6.97-6.91 (m, 1H), 6.06 (s, 2H); 13C NMR (75 MHz,
CDCl3) 193.3, 163.6, 150.6, 148.0, 143.7, 136.4, 129.6,
127.9, 120.7, 119.9, 118.9, 118.7, 113.4, 106.5, 102.4.
Anal. Calcd. for C16H11BrO4: C, 55.36; H, 3.19. Found:
C, 55,25; H, 3.16.
(2E)-1,3-Diphenylprop-2-en-1-one (3m):42 IR (KBr)
1
3056, 1661, 1605, 1576, 1448, 746, 689 cm–1. H NMR
(300 MHz, CDCl3) 8.01-7.97 (m, 2H), 7.77 (d, 1H,
J 15.9 Hz), 7.55-7.24 (m, 9H); 13C NMR (75 MHz, CDCl3)
189.5, 144.1, 137.6, 134.3, 132.3, 130.0, 128.4, 128.1,
128.0, 128.0, 121.4.
(E)-3-(Benzo[d][1,3]dioxol-6-yl)-1-(4-phenyl)prop-2-en-
1-one (3g):37 1H NMR (300 MHz, CDCl3) 8.11-8.08 (m,
2H), 7.78 (d, 1H, J 15.7 Hz), 7.74-7.64 (m, 4H), 7.51-7.38
(m, 3H), 7.43 (d, J 15.7 Hz, 1H), 7.20 (d, 1H, J 1.8 Hz),
(E)-1-(2-Hydroxyphenyl)-3-phenylprop-2-en-1-one
(3n):43 1H NMR (300 MHz, CDCl3) 12.82 (s, 1H), 7.95-7.91
(m, 2H), 7.69-7.64 (m, 3H), 7.54-7.43 (m, 3H), 7.05-6.93
(m, 2H); 13C NMR (75 MHz, CDCl3) 193.7, 163.6, 145.5,

Vol. 24, No. 1, 2013
Silva et al.
143
136.4, 134.6, 130.9, 129.6, 129.0, 128.7, 120.1, 118.8,
118.6.
150.81, 145.34, 142.31, 139.59, 135.94, 129.58, 129.28,
128.82, 128.48, 127.29, 126.74, 124.97, 121,55. 125.86,
125.68, 21.06
(E)-1-(3-Hydroxyphenyl)-3-phenylprop-2-en-1-one
(3o):43 1H NMR (300 MHz, DMSO-d6): 9.89 (s, 1H),
7.92-7.85 (m, 3H), 7.75 (d, 1H, J 15.6 Hz), 7.65 (dd, 1H,
J 1.5 and 1.1 Hz), 7.50-7.38 (m, 5H), 7.09 (dd, 1H, J 2.6 and
0.9 Hz); 13C NMR (75 MHz, CDCl3) 189.5, 169.3, 150.9,
145.5, 139.6, 134.7, 130.7, 129.7, 129.0, 128.5, 126.1,
125.9, 121.7, 121.7.
(E)-1-(3-(Allyloxy)phenyl)-3-(furan-2-yl)prop-2-en-1-one
(3u): 1H NMR (300 MHz, CDCl3) 7.63-7.52 (m, 4H), 7.45-
7.36 (m, 2H), 7.12 (dd, 1H, J 2.6 and 0.7 Hz), 6.71 (d, 1H,
J 3.4 Hz), 6.50 (dd, 1H, J 3.4 and 1.9 Hz), 6.14-6.01 (m,
1H), 5.44 (dq, 1H, J 3.1 and 1.5 Hz), 5.31 (dq, 1H, J 3.1 and
1.5 Hz), 4.61 (dt, 2H, J 3.1 and 1.5 Hz); 13C NMR (75 MHz,
CDCl3) 189.2, 158.7, 151.5, 144.8, 139.3, 132.7, 130.5,
129.4, 120.9, 119.7, 119.1, 117.8, 116.2, 113.5, 112.6,
68.7; anal. calcd. for C19H16O4: C, 74.01; H, 5.23; O, 20.76;
found: C, 73.93; H, 5.19; O, 20.88.
(E)-1-(4-Methoxyphenyl)-3-phenylprop-2-en-1-one
(3p):39 1H NMR (300 MHz, CDCl3) 8.07-8.02 (m, 2H),
7.80 (d, 1H, J 15.7 Hz), 7.66-7.63 (m, 2H), 7.55 (d, 1H,
J 15.7 Hz), 7.43-7.39 (m, 3H), 7.00-6.96 (m, 2H), 3.88
(s, 3H); 13C NMR (75 MHz, CDCl3) 188.7, 163.4, 143.9,
135.0, 131.0, 130.8, 130.3, 128.9, 128.3, 121.8, 113.8,
55.4.
Supplementary Information
Data spectra and spectra of synthesized compounds are
available free of charge at http://jbcs.sbq.org.br as PDF file.
(E)-1-(4-Nitrophenyl)-3-phenylprop-2-en-1-one (3q):39
1H NMR (300 MHz, CDCl3) 8.37-8.32 (m, 2H), 8.17-8.12
(m, 2H), 7.85 (d, 1H, J 15.6 Hz), 7.69-7.63 (m, 2H), 7.49
(d, 1H, J 15.6 Hz), 7.47-7.43 (m, 3H); 13C NMR (75 MHz,
CDCl3) 189.0, 150.0, 146.8, 143.0, 134.2, 131.2, 129.4,
129.1, 128.7, 123.8, 121.2.
Acknowledgments
We thank the Instituto de Química, Universidade
de Brasília, FINEP-CT INFRA No. 970/01, Conselho
Nacional de Desenvolvimento Científico e Tecnológico
(CNPq), PrP/UEG and FUNAPE/UFG for financial
support.
(E)-1-(2-(Allyloxy)phenyl)-3-phenylprop-2-en-1-one
(3r):44 1H NMR (300 MHz, CDCl3) 7.68-7.64 (m, 1H), 7.63-
7.56 (m, 2H), 7.49-7.43 (m, 2H), 7.41-7.36 (m, 3H), 7.05
(td, 1H, J 7.5 and 1.4 Hz), 6.98 (dd, 1H, J 8.2 and 0.7 Hz),
6.10-5.97 (m, 1H), 5.42 (dq, 1H, J 2.8 and 1.4 Hz), 5.24
(dq, 1H, J 2.8 and 1.4 Hz), 4.64 (dt, 3H, J 3.2 and 1.4 Hz);
13C NMR (75 MHz, CDCl3) 192.7, 157.1, 142.7, 135.0,
132.9, 132.5, 130.5, 130.1, 129.5, 128.8, 128.3, 127.1,
120.9, 117.7, 112.8, 69.2.
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Published online: February 19, 2013