Antileishmaniai chalcones: Statistical design, synthesis, and three- dimensional quantitative structure-activity relationship analysis

Article abstract of DOI:10.1021/jm980410m

A large number of substituted chalcones have been synthesized and tested for antileishmanial and lymphocyte-suppressing activities. A subset of the chalcones was designed by using statistical methods. 3D-QSAR analyses using 67 (antileishmanial activity) and 63 (lymphocyte-suppressing activity) of the compounds for the training sets and 9 compounds as an external validation set were performed by using the GRID/GOLPE methodology. The Smart Region Definition procedure with subsequent region selection as implemented in GOLPE reduced the number of variables to approximately 1300 yielding 3D-QSAR models of high quality (lymphocyte-suppressing model, R² = 0.90, Q² = 0.80; antileishmanial model, R² = 0.73, Q² = 0.63). The coefficient plots indicate that steric interactions between the chalcones and the target are of major importance for the potencies of the compounds. A comparison of the coefficient plots for the antileishmanial effect and the lymphocyte- suppressing activity discloses significant differences which should make it possible to design chalcones having a high antileishmanial activity without suppressing the proliferation of lymphocytes.

Full text of DOI:10.1021/jm980410m

J . Med. Chem. 1998, 41, 4819-4832
4819
An tileish m a n ia l Ch a lcon es: Sta tistica l Design , Syn th esis, a n d
Th r ee-Dim en sion a l Qu a n tita tive Str u ctu r e-Activity Rela tion sh ip An a lysis
Simon Feldbæk Nielsen,†,‡ Søren Brøgger Christensen,† Gabriele Cruciani,§ Arsalan Kharazmi,∇ and
Tommy Liljefors*,†
Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark,
State Serum Institute, Copenhagen, Denmark, Department of Chemistry, Laboratory for Chemometrics, University of Perugia,
Italy, and Department of Clinical Microbiology, University Hospital, Copenhagen, Denmark
Received J uly 10, 1998
A large number of substituted chalcones have been synthesized and tested for antileishmanial
and lymphocyte-suppressing activities. A subset of the chalcones was designed by using
statistical methods. 3D-QSAR analyses using 67 (antileishmanial activity) and 63 (lymphocyte-
suppressing activity) of the compounds for the training sets and 9 compounds as an external
validation set were performed by using the GRID/GOLPE methodology. The Smart Region
Definition procedure with subsequent region selection as implemented in GOLPE reduced the
number of variables to approximately 1300 yielding 3D-QSAR models of high quality
(lymphocyte-suppressing model, R2 ) 0.90, Q2 ) 0.80; antileishmanial model, R2 ) 0.73, Q2 )
0.63). The coefficient plots indicate that steric interactions between the chalcones and the
target are of major importance for the potencies of the compounds. A comparison of the
coefficient plots for the antileishmanial effect and the lymphocyte-suppressing activity discloses
significant differences which should make it possible to design chalcones having a high
antileishmanial activity without suppressing the proliferation of lymphocytes.
Ch a r t 1
In tr od u ction
Various species of the protozoan parasite Leishmania
cause a broad spectrum of diseases ranging from the
cutaneous healing skin lesions caused by L. major to a
fatal visceral form called kala azar caused by L. dono-
vani.1,2 Leishmaniases are widespread in many parts
of the world with the highest prevalence in Africa, Asia,
and Latin America. It is estimated that 12 million
people suffer from the disease, with 400 000 new cases
and 100 000 deaths each year.3 Not less than 350
million individuals in 88 countries, including some
southern European countries, are at risk of infection.4
Therapy of patients with leishmaniasis still poses a
serious problem. The drugs of first choice are pentava-
lent antimonial compounds, which require long-term
treatment and have severe side effects.4 The reported
large-scale clinical resistance to antimonial agents in
India and Sudan5 has created an urgent need for the
development of new, efficient, and safe drugs for the
treatment of the diseases.6
Licochalcone A (1; Chart 1), isolated from Chinese
licorice, efficiently inhibits proliferation of L. donovani
and L. major promastigotes and amastigotes in vitro by
interfering with the function of the parasite mitochon-
dria. In vitro tests have revealed that licochalcone A
at lower concentrations inhibits phytohemmagglutinin
A-induced proliferation of human lymphocytes.7 Thus,
the use of chalcones for the treatment of leishmania
infections may result in a suppression of the immune
system as an undesirable side effect. Preliminary
studies reveal that changes of the substitution pattern
of the chalcones appear to affect the activities against
leishmania promastigotes and lymphocytes differently,
indicating that it should be possible to prepare chalcones
with a high selectivity. Since the binding sites of the
chalcones at the targets are unknown, the design of
optimal ligands based on the topographies of the binding
sites is excluded.
In the present work, the synthesis of a large number
of chalcones, partly designed by statistical methods, was
undertaken and 3D-QSAR analyses of the data were
performed in order to reveal structure-activity rela-
tionships for antileishmanial activity and for the inhibi-
tion of proliferation of lymphocytes. The aim of this
study is to elucidate how selectivity might be optimized
by appropriate substitution of the chalcone skeleton.
The 3D-QSAR analyses were performed by using the
GRID program8,9 to generate molecular descriptors
(variables) and the GOLPE program10-12 for the mul-
tivariate data (PLS) analyses. To obtain a comprehen-
sive data material for the multivariate 3D-QSAR analy-
sis, 30 substituted chalcones were designed by statistical
methods.13-15
† Royal Danish School of Pharmacy.
‡ State Serum Institute.
§ University of Perugia.
∇ University Hospital.
10.1021/jm980410m CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/04/1998

4820 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 24
Nielsen et al.
Ta ble 1. Properties of the Principal Components: Weights (w)
and Loadings (p)
Ta ble 3. Substituents in Ring A According to Three 22
Factorial Designsa
IC50 ( SD (µM)
leish lymph
3,5-OCH3 7.2 ( 1.2 13 ( 1
variable
mean
w
p1
p2
compd PC1 PC2
ring A
ring B
MR
π
σm
σp
15.4
0.53
0.13
0.01
0.13
0.95
4.46
2.84
0.42
0.47
-0.57
-0.52
0.59
0.49
0.38
0.51
15
16
17
18
19
20
21
22
23
24
25
26
+
+
-
-
+
+
-
-
+
+
-
-
+
-
+
-
+
-
+
-
+
-
+
-
2′-OC4H9
2′-N(CH3)2 3,5-OCH3 7.3 ( 1.0 5.7 ( 0.3
2′-NO2
2′-F
3,5-OCH3 3.4 ( 0.5 3.7 ( 0.2
3,5-OCH3 3.5 ( 0.8 6.0 ( 0.4
3′-OC4H9
2,4-OCH3 20 ( 3
65 ( 4
3′-N(CH3)2 3,5-OCH3 5.8 ( 0.7 5.0 ( 0.2
3′-NO2
3′-F
4′-C6H11
2,4-OCH3 8.6 ( 1.1 18 ( 2
3,5-OCH3 5.5 ( 0.3 9.2 ( 0.5
3,5-OCH3 31 ( 2
4′-N(CH3)2 3,5-OCH3 NS
39 ( 2
NS
4′-NO2
4′-F
3,5-OCH3 16 ( 1
20 ( 1
23 ( 21
H
15 ( 1
a
A plus (+) represents a high value and a minus (-) a low value
of the parameters. NS indicates that the compound could not be
tested due to low solubility in the test medium. The substituents
and test data of the compounds in the validation set are in bold
type.
employed. Substituents with high and low values of the
two principal components were placed in each of the
three positions of one of the rings according to a 22 factor
design. At the same time a substitution pattern known
to afford chalcones with high activity was kept in the
other ring (Tables 3 and 4). The advantage of selecting
chalcones with medium to high activities is that the poor
solubility in the test medium will be sufficient for
determination of the IC50 values. In ring B, the 3,5- or
2,4-dimethoxy substitution (Table 3) and in ring A, the
2′,3′,4′-trimethoxy pattern (Table 4) were chosen.
Ch em istr y. The chalcones 7-71 were synthesized
by a Claisen-Schmidt condensation19 of the appropriate
benzaldehyde with the appropriate acetophenone. The
chalcones 8, 12, 17, and 29 were prepared using
hydrochloric acid as a catalyst, whereas the remaining
chalcones 7-71 were prepared by a sodium hydroxide-
catalyzed condensation. To increase the yield, the
hydroxy groups in the starting materials for the hy-
droxychalcones 72-82 were masked as tetrahydropy-
ranyl ethers before condensation. The hydroxy group
was demasked by acid hydrolysis.
The procedure developed for the syntheses of the
naturally occurring licorice chalcones 1 and 27 were
followed for the preparation of the alkylated chalcones
3-6 (Scheme 1). The alkylated 2,4-dihydroxybenz-
aldehydes 3b-6b were prepared by a Vilsmeier formy-
lation20 of the resorcinols 3a -6a . In all cases a rapid
regioselective acylation was obtained. Reaction with
dihydropyran selectively afforded the 4-O-tetrahydro-
pyranyl ethers 3c-6c, which were methylated at O-2
to give the starting materials 3d -6d .
F igu r e 1. Substituents in the space of the principal compo-
nents.
Ta ble 2. 24-1 Design in the 4- and 4′-Positiona
4-position 4′-position
IC50 ( SD (µM)
4-
4′-
compd PC1 PC2 PC1 PC2 position position leish
lymph
7
8
9
10
11
12
13
14
+
-
+
-
+
-
+
-
+
+
-
-
+
+
-
-
+
+
+
+
-
-
-
-
+
-
-
+
-
+
+
-
OC6H5
NMe2
NMe2
OC6H5
F
NO2
NO2
F
C6H11 NS
NO2 NS
NS
NS
NMe2 30 ( 4 NS
42 ( 6 33 ( 2
C6H11 27 ( 2 74 ( 2
NO2 26 ( 4 51 ( 3
NMe2 NS NS
15 ( 2 22 ( 1
F
F
a
A plus (+) represents a high value and a minus (-) a low value
of the parameters. NS indicates that the compound could not be
tested due to low solubility in the test medium.
Resu lts a n d Discu ssion
Sta tistica l Design . The chalcones studied contain
a common skeleton, and the description of the molecules
can therefore be based on substituent parameters.16,17
The substituents were described by four parameters
which may be related to the biological activity of the
compounds, the molar refractivity (MR) describing steric
effects, the lipophilicity constant π, and the Hammett
constants σp and σm describing electronic effects. Sixty-
two substituents, which can be introduced on the
chalcone skeleton, were selected for the analysis, and a
principal components analysis (PCA)18 was performed
on the 62 × 4 matrix. Parameter values for the
substituents were taken from ref 18. The two first
principal components, which explain 89% of the vari-
ance in the four original parameters (Table 1), were used
for the statistical design. Figure 1 displays the sub-
stituents in the space of the principal components (PCs).
Since a preliminary 2D-QSAR analysis (data not
shown) reveals that positions 4 and 4′ are the most
important ones for the biological activity, a 24-1 frac-
tional factorial design14 (FFD) in these positions was
first performed (Table 2). However, poor solubility of
some of the compounds (e.g., 7-9 and 13) prevented this
approach, and instead a more simple approach was
3D-QSAR An a lyses. The 30 chalcones designed by
statistical methods (7-36, Tables 2-4) supplemented
with 52 chalcones (1-6 and 38-82) prepared for open-
ing studies were used for the 3D-QSAR analyses.
Conformational analysis of the compounds and the
molecular alignments employed were performed as
described in the Experimental Section. The interaction
energies between the compounds and three different
probes (water, methyl, and ammonium ion) were cal-
culated by using the GRID program employing a grid
spacing of 1 Å. The probes were selected to reflect
possible interactions with the target. The GRID calcu-
lations give 57 200 variables for each compound.
A

Antileishmanial Chalcones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 24 4821
Ta ble 4. Substituents in Ring B According to Three 22 Factorial Designsa
IC50 ( SD (µM)
compd
PC1
PC2
ring B
ring A
leish
lymph
27
28
29
30
31
32
33
34
+
+
-
-
+
+
-
-
+
+
-
-
+
-
+
-
+
-
+
-
+
-
+
-
2-OC4H9
2-N(CH3)2
2-NO2
2′,3′,4′-OCH3
2′,3′,4′-OCH3
2′,3′,4′-OCH3
2′,3′,4′-OCH3
2′,3′,4′-OCH3
2′,3′,4′-OCH3
2′,3′,4′-OCH3
2′,3′,4′-OCH3
26 ( 1
52 ( 3
5.9 ( 0.4
15 ( 1
7.0 ( 0.6
11 ( 1
2-F
3-OC6H5
3-N(CH3)2
3-NO2
8.7 ( 0.5
20 ( 3
17 ( 1
26 ( 1
17 ( 2
36 ( 2
3-F
9.7 ( 0.9
6.4 ( 0.4
10, Table 2
35
36
4-N(CH3)3
4-CN
2′,3′,4′-OCH3
2′,3′,4′-OCH3
21 ( 2
8.6( 0.9
35 ( 2
5.4 ( 0.3
11 and 14, Table 2
a
A plus (+) represents a high value and a minus (-) a low value of the parameters. Substituents and test data of the compounds in
the validation set are in bold type.
Sch em e 1a
Ta ble 5. Properties of the 3D-QSAR Models for
Antileishmanial Activity
number of number of
variables components R2
Q2
initial model
after SRD pretreatment
after FFD region selection
39 950
4 077
1 365
2
2
2
0.68 0.48
0.68 0.49
0.73 0.63
a
3: R2 ) C3H7, R1 ) R3 ) H. 4: R2 ) C6H13, R1 ) R3 ) H. 5:
R3 ) CH3, R1 ) R2 ) H. 6: R1 ) CH3, R2 ) R3 ) H. Reagents: (a)
POCl3, DMF; (b) H2O; (c) 3,4-dihydro-2H-pyran, pyridinium p-
toluenesulfonate, CH2Cl2; (d) CH3I, NaOH, DMSO; (e) 4-[(tetrahy-
dropyranyl)oxy]acetophenone, NaOH, ethanol; (f) 4 M HCl.
major part of these variables is not important for
describing the interaction between the chalcone and the
target and is only introducing noise in the PLS model.21
These variables are eliminated using the GOLPE algo-
rithm, and the resulting models are of higher quality
than models calculated without variable selection.
F igu r e 2. Observed and predicted antileishmanial activi-
ties: O, training set; 1, validation set.
The QSAR was calculated using GOLPE on 67 (an-
tileishmanial activity) and 63 (lymphocyte-suppressing
activity) of the chalcones, using the Smart Region
Definition (SRD) procedure for variable preselection,22
followed by a FFD variable selection11 (see Experimental
Section). The data pretreatment reduces the number
of variables to approximately 10%, and region selection
was then applied to eliminate regions which are not
significantly contributing to the predictivity. This is
done by building a large number (twice the number of
variables) of reduced models according to a FFD pro-
cedure in which some regions are left out and the
predictivity of the reduced models is calculated. This
makes it possible to evaluate the effect of each indi-
vidual region, and only the regions that contribute in a
positive way to the predictivity of the model are in-
cluded. Scaling did not improve the quality of the
models and was not used.
set. These compounds are shown in bold in Tables 3,
4, and 7. The compounds were chosen to cover the
entire activity interval as well as to represent different
substituent types and patterns.
3D-QSAR Mod el for An t ileish m a n ia l Act ivit y.
Using the SRD preselection procedure, the number of
variables was reduced from 39 950 variables (after
rejection of variables having a total sum of squares (SS)
lower than 10-7; see Experimental Section) to 4 077
variables without any significant change in the quality
of the model (Table 5). Region selection based on the
FFD procedure further reduced the number of variables
to 1365 with a major improvement in the quality of the
model (Table 5). The correlation between observed and
predicted activities is shown in Figure 2. The prediction
of the activity of the external validation set is good
(SDEP ) 22.2), and the model is able to predict the
activity of both high- and low-potency compounds.
Nine chalcones, compounds 2, 25, 35, 44, 55, 56, 67,
68, and 73, were chosen to form an external validation

4822 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 24
Nielsen et al.
Ta ble 6. Properties of the 3D-QSAR Models for the
Suppression of Proliferation of Lymphocytes
number of number of
variables components R2
Q2
initial model
after SRD pretreatment
after FFD region selection
46 062
4 021
1 454
3
3
3
0.85 0.52
0.86 0.57
0.90 0.80
regions around the 2′- and 3′-positions (Figure 4, top)
indicate that substituents which in these regions give
unfavorable interactions with the methyl probe, i.e.,
bulky substituents, are predicted to increase the activity
of the compound. The positive coefficients (Figure 4,
bottom) illustrate regions around the molecule in which
introduction of substituents is predicted to reduce the
activity of the compounds. Thus, a bulky substituent
in the 4′-position is predicted to reduce the antileish-
manial activity of the compound.
3D-QSAR Mod el for Lym p h ocyt e-Su p p r essin g
Activity. The SRD preselection method applied to the
lymphocyte data reduces the number of variables from
46 062 (after rejection of variables having SS lower than
10-7) to 4 021 with preserved quality of the model, and
subsequent FFD region selection results in a model of
very high quality (R2 ) 0.90, Q2 ) 0.80) using 1 454
variables (Table 6). Examination of the plot in Figure
3 indicates that the prediction of the external validation
set is good (SDEP ) 25.0) and that the model is able to
predict the activities of high- as well as low-potency
compounds.
The coefficient plots for the three different probes are
also in this case very similar indicating that the interac-
tion with the lymphocyte target is determined mainly
by steric factors. The coefficient plots for the methyl
probe are displayed in Figure 5. In contrast to the
coefficient plots for antileishmanial activity (Figure 4),
examination of the plots in Figure 5 indicates that the
antilymphocytic activity of the chalcones is influenced
by substituents on the A- as well as the B-ring. Nega-
tive coefficient regions around the 2′-position (ring A)
as well as the 5- and 6-positions (ring B) indicate that
F igu r e 3. Observed and predicted antilymphocytic activi-
ties: O, training set; 1, validation set.
The coefficient plots for the three probes used in the
GRID calculations are almost identical indicating that
the difference in activity between the chalcones is
mainly due to steric interactions with the target. The
interpretation of the model is thereby simplified since
the coefficient plot for the methyl probe contains almost
all relevant information. This is confirmed by calculat-
ing a model using only the methyl probe. The coefficent
regions are essentially identical to those obtained by
using the more complex model based on three probes.
The quality of the model using only the methyl probe is
only slightly lower (R2 ) 0.68, Q2 ) 0.53 compared to
R2 ) 0.73, Q2 ) 0.63) indicating that electrostatic
interactions with the target play a minor role in the
activity.
The regions with the highest positive and negative
coefficients are located around the A-ring (Figure 4)
indicating that substituents on the A-ring are mainly
responsible for the differences in the antileishmanial
activity of the chalcones. The negative coefficient
F igu r e 4. Contour maps (stereoview) for antileishmanial activity. The negative (top) and positive (bottom) coefficients at the
0.0005 level for the methyl probe are shown. An unfavorable interaction (positive interaction energy) between a substituent and
the probe in regions with negative coefficients will reduce the IC50, i.e., increase the activity of the compound, and vice versa for
positive coefficients. The chalcone 27 is drawn to illustrate the size of the regions.

Antileishmanial Chalcones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 24 4823
F igu r e 5. Contour maps (stereoview) for lymphocyte suppression activity. The negative (top) and positive (bottom) coefficients
at the 0.0005 level for the methyl probe are shown. An unfavorable interaction (positive interaction energy) between a substituent
and the probe in regions with positive coefficients will increase the IC50, i.e., reduce the activity of the compound, and vice versa
for the negative coefficients. The chalcone 27 is drawn to illustrate the size of the regions.
quartet (q), multiplet (m), and broad (b); NMR values are given
in δ units. An asterisk indicates that signals with similar
shifts may be interchanged. The uncorrected melting points
are determined on an Electrothermal melting point apparatus.
Column chromatography was performed on silica gel (Merck,
0.040-0.063 mm) using a mixture of toluene and ethyl acetate
as an eluent. All moisture-sensitive reactions were performed
under nitrogen using oven-dried glassware. Tetrahydrofuran
(THF) was freshly distilled from sodium/benzophenone.
bulky groups giving unfavorable interactions with the
methyl probe will cause an (undesirable) increase in the
antilymphocytic activity of the compound (Figure 5, top).
The presence of positive coefficient regions around the
4′-, 2-, 3-, and 4-positions (Figure 5, bottom) indicates
that bulky groups in these positions will lead to less
active and thereby less toxic compounds.
Con clu sion s
The following chalcones were prepared as previously de-
scribed: licochalcone A (1),23 echinatin (2),23 licochalcone C
(37),23 2,4-dimethoxy-2′,4′-difluorochalcone (48),24 2,4-difluoro-
2′,4′-dimethoxychalcone (49),24 2,4-dichloro-2′,3′,4′-trimethoxy-
chalcone (50),24 3,4-difluoro-2′,4′-dimethoxychalcone (51),24 2,4-
dichloro-2′,5′-dimethoxychalcone (52),24 4,4′-dimethoxychalcone
(54),25 2,4-dimethoxy-4′-butoxychalcone (62),26 2,4-dimethoxy-
chalcone (64),27 2,4-dimethoxy-2′-hydroxychalcone (69),28 4,4′-
dihydroxychalcone (72),29 4′-hydroxychalcone (77),30 2,5-
dimethoxy-4′-hydroxychalcone (78),31 and 2,3-dimethoxy-4′-
hydroxychalcone (74).32 Chalcone (57) was purchased from
Aldrich; butein (53) and homobutein (55) were from Roth.
The 3D-QSAR models developed for the antileishma-
nial activity and the lymphocyte-suppressing activity of
substituted chalcones show high predictability, indicat-
ing that the models can be expected to give reliable
predictions of the activities of new chalcones. The
coefficient plots for the three probes employed indicate
that steric interactions between the chalcones and the
target are of major importance for the potencies of the
compounds. A comparison of the coefficient plots for the
antileishmanial effect (Figure 4) and the lymphocyte-
suppressing activity (Figure 5) discloses that large
substituents in positions 4′, 2, 3, and 4 are predicted to
decrease the activity toward lymphocytes, whereas the
antileishmanial activity should not be affected. These
observations make it possible to separate the antileish-
manial activity and the antilymphocyte properties of the
chalcones. The coefficient plots in Figures 4 and 5 may
then be employed to design chalcones with high selec-
tivity against the parasites.
2,4-Dih yd r oxy-5-p r op ylben za ld eh yd e (3b). Gen er a l
P r oced u r e A. Phosphorus oxychloride (0.800 mL, 8.6 mmol)
was added dropwise with stirring to dimethylformamide (2.6
mL, 33.6 mmol), the temperature being kept at 10-20 °C. This
reagent was slowly added to a solution of 2,4-dihydroxy-5-
propylbenzene33 (0.59 g, 3.9 mmol) in dimethylformamide (2.6
mL), the temperature being kept at 20-30 °C. After 30 min
the mixture was poured in 2 M NaOH (20 mL). The organic
phase was extracted with 2 M NaOH (210 mL). The combined
aqueous phases were neutralized with hydrochloric acid 4 M
and extracted with ethyl acetate (320 mL). The combined
organic phases were concentrated in vacuo, and the residue
was purified by column chromatography to give 3b (0.44 g,
63%) as gray crystals: mp 92.8-93.6 °C (water-ethanol),33
mp 71-76 °C; 1H NMR (CD3OD) 9.65 (s, -CHO), 7.28 (s, H6),
6.28 (s, H3), 4.94 (b, OH), 2.48 (t, J ) 7.3 Hz, H1′), 1.56 (sext,
Exp er im en ta l Section
Ch em istr y. 1H NMR, 13C NMR, and DEPT (135) spectra
were recorded on a Bruker AC-200F spectrometer. Splitting
patterns are described as singlet (s), doublet (d), triplet (t),

4824 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 24
Nielsen et al.
Ta ble 7. Structure and Activity of Chalcones for Opening
3c (1.25 g), sodium hydroxide (0.4 g), and iodomethane (0.31
mL, 5 mmol) were suspended in DMSO (5 mL), stirred for 60
min at room temperature, and added to water (20 mL). The
mixture was extracted with methylene chloride (420 mL), and
the combined organic phases were washed with water (320
mL) and concentrated in vacuo to give 1.26 g of a brown oil,
Studiesa
IC50 ( SD (µM)
structure: substituents
compd
on chalone
leish
lymph
1
2
3
4
5
licochalcone A
13 ( 1
68 ( 4
26 ( 2
9.7 ( 0.9
22 ( 3
39 ( 5
55 ( 3
27 ( 2
90 ( 14
19 ( 4
3.8 ( 0.9
3.7 ( 0.6
9.3 ( 1.0
8.3 ( 0.9
18 ( 3
14 ( 2
16 ( 1
26 ( 2
27 ( 4
6.3 ( 0.6
16 ( 1
7.8 ( 0.7
66 ( 2
106 ( 9
16 ( 2
41 ( 4
20 ( 1
73 ( 4
60 ( 5
16 ( 1
136 (15
95 ( 10
62 ( 5
15 ( 0
104 ( 9
81 ( 7
49 ( 3
35 ( 3
35 ( 2
5.0 ( 0.7
38 ( 2
83 ( 5
82 ( 8
89 ( 9
12 ( 1
106 ( 8
16 ( 1
23 ( 2
16 ( 2
48 ( 3
49 ( 4
79 ( 6
48 ( 5
94 (4
1
2-OCH3-4,4′-OH
2-OCH3-4,4′-OH-5-propyl
2-OCH3-4,4′-OH-5-hexyl
2-OCH3-3-methyl-4,4′-OH
2-OCH3-4,4′-OH-6-methyl
licochalcone C
3,5-OCH3-4′-allyloxy
4-C4H9-3,5-OCH3-4′-allyloxy
4-C6H13-3,5-OCH3-4′-allyloxy
2′-OH-3,5-OCH3
3′-OH-3,5-OCH3
2-OH-2′,3′,4′-OCH3
2′,3′,4′,3,5-OCH3
3′,2,4-OCH3
which according to the H NMR spectrum consisted of 3d : 1H
41 ( 3
46 ( 3
27 ( 4
53 ( 6
53 ( 2
25 ( 2
NS
NMR (CDCl3) 10.28 (s, CHO), 7.58 (s, H6), 6.73 (s, H3), 5.55
(b, H2′), 3.81 (s, OCH3), 3.8 (b, H6a′), 3.6 (b, H6e′), 2.55 (t, J
) 7 Hz, H1′′), 1.61 (m, H2′′), 2.1-1.4 (m, H3′-5′), 0.91 (t, J )
7 Hz, H3′′).
6
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
2-Meth oxy-4,4′-d ih yd r oxy-5-p r op ylch a lcon e (3). P r o-
ced u r e D. A solution of the crude product 3d (1.26 g), 4-[(2-
tetrahydropyranyl)oxy]acetophenone (0.48 g, 2.2 mmol), and
sodium hydroxide (50 mg) in anhydrous ethanol (10 mL) was
stirred for 18 h at room temperature. The solution was added
to 4 M hydrochloric acid (2 mL), stirred for an additional 15
min, and added to water (40 mL). The mixture was extracted
with ethyl acetate (450 mL), and the combined organic phases
were concentrated in vacuo to give 3 (0.32 g, 41% overall yield
based on 3b): orange-brown crystals; mp 126.5-128.0 °C
(ethanol-water); 1H NMR ((CD3)2CO) 8.11 (d, J ) 15.5 Hz,
Hâ), 8.06 (m, H2′ and H6′), 7.73 (d, J ) 15.5 Hz, HR), 7.63 (s,
H6), 6.97 (m, H3′ and H5′), 6.59 (s, H3), 3.85 (s, OCH3), 2.58
(t, J ) 7.3 Hz, H1′′), 1.64 (sext, J ) 7.3 Hz, H2′′), 0.95 (t, J )
7.3 Hz, H3′′); 13C NMR ((CD3)2CO) 188.4 (CHO), 162.3*(C4′),
159.7*(C2), 159.5*(C4), 139.5 (Câ), 131.7 (C1′), 131.6 (C2′, C6′),
131.3 (C6), 122.4 (C5), 119.1 (CR), 116.3 (C1), 116.0 (C3′, C5′),
99.7 (C3), 55.9 (OCH3), 32.2 (C1′′), 23.9 (C2′′), 14.3 (C3′′). Anal.
(C19H20O4‚0.5H2O) C, H, N.
2,4-Dih yd r oxy-5-h exylben za ld eh yd e (4b) was synthe-
sized according to procedure A using 2,4-dihydroxy-5-hexyl-
benzene (1.39 g, 7.2 mmol) as starting material: yellow-white
crystals (0.74 g, 46%); mp 108.2-109.5 °C (ethanol-water),34
mp 109 °C; 1H NMR (CD3OD) 9.65 (s, OH, CHO), 7.30 (s, H6),
6.29 (s, H3), 4.94 (b, OH), 2.50 (t, J ) 7.3 Hz, H1′), 1.56 (m,
H2′), 1.30 (m, H3′-H5′), 0.91 (t, J ) 7.3 Hz, H6′); 13C NMR
(CD3OD) 193.5 (CdO), 163.3*(C4), 161.8*(C2), 133.8 (C6),
122.0 (C5), 113.7 (C1), 100.7 (C3), 30.9 (C1′), 28.8 (C2′), 28.2
(C3′, C4′), 21.7 (C5′), 12.5 (C6′).
2-Hyd r oxy-4-[(2-tetr a h yd r op yr a n yl)oxy]-5-h exylben z-
a ld eh yd e (4c) was synthesized according to procedure B using
4b (0.23 g, 1 mmol) as starting material: yellow oil (0.62 g);
1H NMR (CDCl3) 11.28 (s, -OH), 9.69 (s, -CHO), 7.23 (s, H6),
6.66 (s, H3), 5.50 (bt, H2′), 3.9 (b, H6a′), 3.6 (b, H6e′), 2.55 (t,
J ) 7 Hz, H1′′), 2.1-1.4 (m, H3′-5′, H2′′-H5′′), 0.90 (t, J ) 7
Hz, H6′′).
2-Meth oxy-4-[(2-tetr a h yd r op yr a n yl)oxy]-5-h exylben z-
a ld eh yd e (4d ) was synthesized according to procedure C
using crude 4c (0.62 g) as starting material: brown oil (0.61
g); 1H NMR (CDCl3) 10.28 (s, CHO), 7.58 (s, H6), 6.75 (s, H3),
5.58 (b, H2′), 3.88 (s, OCH3), 3.80 (b, H6a′), 3.61 (b, H6e′), 2.60
(m, H1′′), 2.1-1.4 (m, H3′-H5′, H2′′-H5′′), 0.90 (bt, J ) 7.1
Hz, H6′′).
2-Meth oxy-4,4′-d ih yd r oxy-5-h exylch a lcon e (4) was syn-
thesized according to procedure D using crude 4d (0.61 g) and
4-[(2-tetrahydropyranyl)oxy]acetophenone23 (0.10 g, 0.45 mmol)
as starting materials: an orange amorphous powder (0.19 g,
51% overall yield based on 4b); 1H NMR ((CD3)2CO) 8.10 (d, J
) 15.6 Hz, Hâ), 8.05 (m, H2′ and H6′), 7.73 (d, J ) 15.6 Hz,
HR), 7.64 (s, H6), 6.96 (m, H3′ and H5′), 6.58 (s, H3), 3.85 (s,
OCH3), 2.60 (t, J ) 7 Hz, H1′′), 1.33 (m, H2′′), 1.1 (m, H3′′-
H5′′), 0.88 (bt, J ) 7 Hz, H6′′); 13C NMR ((CD3)2CO) 188.5
(CHO), 162.3*(C4′), 159.6*(C2), 159.4*(C4), 139.6 (Câ), 131.7
(C1′), 131.6 (C2′, C6′), 131.3 (C6), 122.6 (C5), 119.0 (CR), 116.2
(C1), 116.0 (C3′, C5′), 99.7 (C3), 55.9 (OCH3), 32.5 (C1′′), 30.9
(C2′′), 30.1 (C3′′), 29.9 (C4′′), 23.3 (C5′′), 14.4 (C6′′). Anal.
(C22H26O4) C, H.
3-Meth yl-2,4-d ih yd r oxyben za ld eh yd e (5b) was synthe-
sized according to procedure A using 3-methyl-2,4-dihydroxy-
benzene (1.48 g, 11.9 mmol) as starting material: white
crystals (1.46 g, 80%); mp 149.6-150.3 °C (ethanol-water),35
mp 150 °C; 1H NMR (CD3OD) 9.61 (s, OH, CHO), 7.30 (d J )
8.6 Hz, H6), 6.47 (d J ) 8.6 Hz, H5), 4.94 (b, OH), 2.04 (s,
15 ( 1
8.1 ( 0.8
3.2 ( 0.4
9.0 ( 0.7
8.7 ( 0.5
42 ( 2
35 ( 3
37 ( 2
74 ( 4
12 ( 0
7.8 ( 0.9
5.3 ( 0.6
5.7 ( 0.5
16 ( 1
112 ( 8
31 ( 2
30 ( 1
21 ( 2
55 ( 2
51 ( 6
26 ( 2
NS
2′-Br-2,4-OCH3
3′-Br-2,4-OCH3
2′,4′-F-2,4-OCH3
2′,4′-OCH3-2,4-F
2′,3′,4′-OCH3-2,4-Cl
2′,4′-OCH3-3,4-F
2′,5′-OCH3-2,4-Cl
2′,4′,3,4-OH
4′,4-OCH3
2′,4′,4-OH-3-OCH3
3,4,5-OCH3-4′-a llyloxy
chalcon
2,5-OCH3-4′-allyloxy
3,4-OCH3-4′-allyloxy
2,4,2′-OCH3
2,4-OCH3-4′-OC6H13
2,4-OCH3-4′-OC4H9
4′-OC6H13
NS
99 ( 7
48 ( 2
127 ( 10
96 ( 8
96 ( 6
52 ( 3
144 ( 9
NS
61 ( 3
59 ( 3
60 ( 2
70 ( 4
14 ( 1
44 ( 2
28 ( 1
22 ( 1
28 ( 2
71 ( 5
111 ( 7
130 ( 13
2,4-OCH3
2,6-OCH3-4′-OC4H9
2,6-OCH3-4′-allyloxy
2,3-OCH3-4′-a llyloxy
3,5-OCH3-4′-OC4H9
2,4-OCH3-2′-OH
2,4-OCH3-2′-allyloxy
2,5,4′-allyloxy
4′,4-OH
2,6-OCH3-4′OH
2,3-OCH3-4′OH
3,5-OCH3-4′OH
2,4,6-OCH3-4′-OH
4′-OH
2,5-OCH3-4′-OH
2,4,5-OCH3-4′OH
2,4-OCH3-4′-OH
2-OCH3-4-OH-4′-N(CH3)2
4-N(CH3)2-4′OH
a
NS indicates that the compound could not be tested due to
low solubility in the test medium. The substituents and test data
of the compounds in the validation set are in bold type.
J ) 7.3 Hz, H2′), 0.91 (t, J ) 7.3 Hz, H3′); 13C NMR (CD3OD)
193.5 (CdO), 163.4*(C4), 161.8*(C2), 134.0 (C6), 121.8 (C5),
113.7 (C1), 100.7 (C3), 30.4 (C1′), 21.9 (C2′), 12.3 (C3′).
2-Hydr oxy-4-[(2-tetr ah ydr opyr an yl)oxy]-5-pr opylben z-
a ld eh yd e (3c). Gen er a l P r oced u r e B. A solution of 3b
(0.45 g, 2.5 mmol), pyridinium p-toluenesulfonate (20 mg, 0.1
mmol), and 3,4-dihydro-2H-pyran (0.34 mL, 4.0 mmol) in
methylene chloride (5 mL) was stirred for 4 h at room
temperature. The solution was washed with 1 M sodium
carbonate (5 mL) and concentrated in vacuo to give 1.25 g of
a
yellow oil, which according to the 1H NMR spectrum
consisted of 3c: 1H NMR (CDCl3) 11.30 (s, -OH), 9.68 (s,
-CHO), 7.21 (s, H6), 6.68 (s, H3), 5.49 (bt, H2′), 3.85 (b, H6a′),
3.60 (b, H6e′), 2.55 (t, J ) 7 Hz, H1′′), 1.58 (hext, J ) 7 Hz,
H2′′), 2.1-1,4 (m, H3′-5′), 0.91 (t, J ) 7 Hz, H3′′).
2-Meth oxy-4-[(2-tetr ah ydr opyr an yl)oxy]-5-pr opylben z-
a ld eh yd e (3d ). Gen er a l P r oced u r e C. The crude product

Antileishmanial Chalcones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 24 4825
CH3); 13C NMR (CD3OD) 196.1 (CdO), 164.9*(C4), 163.2*(C2),
134.2 (C6), 115.7 (C1), 112.1 (C3), 108.9 (C5), 7.3 (CH3).
2-Hydr oxy-3-m eth yl-4-[(2-tetr ah ydr opyr an yl)oxy]ben z-
a ld eh yd e (5c) was synthesized according to procedure B using
5b (0.38 g, 2.5 mmol) as starting material: yellow oil (0.60 g);
1H NMR (CDCl3) 9.68 (s, OH, CHO), 7.31 (d, J ) 9.1 Hz, H6),
6.78 (d, J ) 9.1 Hz, H5), 5.58 (bt, H2′), 3.9 (b, H6a′), 3.6 (b,
H6e′), 2.18 (s, CH3), 2.1-1.4 (m, H3′-5′).
4-(Dim eth yla m in o)-4′-n itr och a lcon e (8). P r oced u r e F .
A solution of 4-nitroacetophenone (0.50 g, 3.0 mmol) and
4-(dimethylamino)benzaldehyde (0.45 g, 3.0 mmol) in ethanol
(3 mL) was saturated with hydrochloric acid. After 24 h, 8
(0.28 g, 32%) was isolated by filtration as brown crystals: mp
214.0-214.7 °C (acetonitrile-water); 1H NMR (CDCl3) 8.34
(m, H3′ and H5′), 8.12 (m, H2′ and H6′), 7.82 (d, J ) 15.3 Hz,
Hâ), 7.60 (m, H2 and H6), 7.28 (d, J ) 15.3 Hz, HR), 6.71 (m,
H3 and H5), 3.09 (s, NCH3). Anal. (C17H16N2O3) C, H, N.
4,4′-Bis(d im eth yla m in o)ch a lcon e (9) was synthesized
according to procedure E using 4-(dimethylamino)benzalde-
hyde (0.12 g, 0.8 mmol) and 4-(dimethylamino)acetophenone
(0.13 g, 0.8 mmol)37 as starting materials: orange crystals (0.18
g, 76%); mp 149.8-150.7 °C (ethanol-water); 1H NMR (CDCl3)
8.00 (m, H2′ and H6′), 7.77 (d, J ) 15.4 Hz, Hâ), 7.54 (m, H2
and H6), 7.40 (d, J ) 15.4 Hz, HR), 6.70 (m, H3 and H5, H3′
and H5′), 3.06 (s, NCH3), 3.02 (s, NCH3); 13C NMR (CDCl3)
188.9 (CdO), 152.3*(C4′), 148.4*(C4), 143.4 (Câ), 130.5*(C3′,
C5′), 130.0*(C3, C5), 127.1 (C1′), 123.0 (C1), 117.0 (CR), 111.9*-
(C2, C6), 110.8*(C2′, C6′), 40.5 (NCH3), 40.1 (NCH3). Anal.
(C19H22N2O) C, H, N.
4-P h en oxy-4′-flu or och a lcon e (10) was synthesized ac-
cording to procedure E using 4-phenoxybenzaldehyde (0.29 mL,
1.5 mmol) and 4-fluoroacetophenone (0.18 mL, 1.5 mmol) as
starting materials: white crystals (0.42 g, 90%); mp 115.7-
116.0 °C (ethanol-water); 1H NMR (CDCl3) 8.26 (m, H2′ and
H6′), 7.90 (m, H2 and H6), 7.84 (d, J ) 15.4 Hz, Hâ), 7.3-7.0
(remaining H). Anal. (C21H15O2F) C, H.
4-F lu or o-4′-cycloh exylch a lcon e (11) was synthesized
according to procedure E using 4-fluorobenzaldehyde (0.53 mL,
4.9 mmol) and 4-cyclohexylacetophenone (1.0 g, 4.9 mmol) as
starting materials: white crystals (1.3 g, 86%); mp 166.8-
167.9 °C (ethanol-water); 1H NMR (CDCl3) 7.95 (m, H2′ and
H6′), 7.78 (d, J ) 15.7 Hz, Hâ), 7.60 (m, H3′ and H5′), 7.45 (d,
J ) 15.7 Hz, HR), 7.38 (dd, J ) 8.3, 6.5 Hz, H2, H6), 7.05 (dd,
J ) 9.9, 8.3 Hz), 2.55 (b, H1c), 1.87 (m, H2c, H6c), 1.41 (m,
H3c-H5c); 13C NMR (CDCl3) 189.9 (CdO), 160.4 (C4), 153.4
(C4′), 143.7 (Câ), 136.1 (C1′), 129.8 (C1), 128.7 (C2′, C6′), 127.0
(C2, C6), 124.1 (CR), 119.7 (C3′, C5′), 118.4 (C3, C5), 44.7 (C1c),
34.1 (C2c, C6c), 26.7 (C3c, C5c), 26.0 (C4c). Anal. (C21H21OF)
C, H.
2-Meth oxy-3-m eth yl-4-[(2-tetr ah ydr opyr an yl)oxy]ben z-
a ld eh yd e (5d ) was synthesized according to procedure C
using crude 5c (0.60 g) as starting material: brown oil (0.69
1
g); H NMR (CDCl3) 10.2 (s, CHO), 7.70 (d, J ) 8.9 Hz, H6),
6.98 (d, J ) 8.9 Hz, H5), 5.55 (bt, H2′), 3.85 (s, OCH3), 3.82 (b,
H6a′), 3.64 (b, H6e′), 2.20 (s, CH3), 2.1-1.4 (m, H3′-5′).
2-Meth oxy-3-m eth yl-4,4′-d ih yd r oxych a lcon e (5) was
synthesized according to procedure D using crude 5d (0.69 g)
and 4-[(2-tetrahydropyranyl)oxy]acetophenone23 (0.38 g, 1.7
mmol) as starting materials: yellow crystals (0.38 g, 54%
overall yield based on 5b); mp 185.4-186.7 °C (ethanol-
1
water); H NMR ((CD3)2CO) 8.07 (m, H2′ and H6′), 8.03 (d, J
) 15.6 Hz, Hâ), 7.71 (d, J ) 15.6 Hz, HR), 7.67 (d, J ) 8.5 Hz,
H6), 6.98 (m, H3′ and H5′), 6.76 (d, J ) 8.5 Hz, H5), 3.77 (s,
OCH3), 2.18 (s, -CH3); 13C NMR ((CD3)2CO) 188.6 (CdO),
162.3*(C4), 160.6*(C4′), 159.4*(C2), 139.3 (Câ), 131.7 (C2′, C6′),
131.6 (C1′), 127.0 (C6), 120.9 (C1), 120.3 (CR), 118.9 (C3), 116.1
(C3′, C5′), 112.4 (C5), 61.8 (OCH3), 9.1 (CH3). Anal. (C17H16O4)
C, H.
2,4-Dih yd r oxy-6-m eth ylben za ld eh yd e (6b) was synthe-
sized according to procedure A using 2,4-dihydroxy-6-methyl-
benzene (2.9 g, 20.8 mmol) as starting material: orange
crystals (65%); mp 173.7C -177.3 °C (water-ethanol),36 mp
1
178-180 °C; H NMR (CD3OD) 10.2 (s, OH, CHO), 6.18 (d J
) 2 Hz, H5), 6.08 (d J ) 2 Hz, H3), 4.95 (s, OH) 2.47 (s, CH3);
13C NMR (CD3OD) 192.3 (CdO), 165.8*(C4), 165.2*(C2), 144.3
(C6), 112.0 (C1), 109.9 (C5), 99.5 (C3), 16.4 (CH3).
2-Hydr oxy-4-[(2-tetr ah ydr opyr an yl)oxy]-6-m eth ylben z-
a ld eh yd e (6c) was synthesized according to procedure B using
6b (0.76 g, 5.0 mmol) as starting material: yellow oil (1.80 g);
1H NMR (CDCl3) 10.09 (s, OH, CHO), 6.45 (d, J ) 2 Hz, H5),
6.37 (d, J ) 2 Hz, H3), 5.49 (bt, H2′), 3.9 (b, H6a′), 3.6 (b, H6e′),
2.52 (s, CH3), 2.1-1.4 (m, H3′-5′).
4,4′-Din it r och a lcon e (12) was synthesized according to
procedure F using 4-nitrobenzaldehyde (0.46 g, 3.0 mmol) and
4-nitroacetophenone (0.50 g, 3.0 mmol) as starting materials:
yellow crystals (0.35 g, 40%); mp 175-178 °C dec; 1H NMR
(CDCl3) 8.39 (m, H3′ and H5′), 8.31 (m, H3 and H5), 8.16 (m,
H2′ and H6′), 7.84 (d, J ) 15.8 Hz, Hâ), 7.80 (m, H2 and H6),
7.62 (d, J ) 15.8 Hz, HR). Anal. (C15H10N2O5) C, H, N.
4-Nitr o-4′-(d im eth yla m in o)ch a lcon e (13) was synthe-
sized according to procedure E using 4-nitrobenzaldehyde (0.17
g, 1.1 mmol) and 4-(dimethylamino)acetophenone (0.20 g, 1.1
mmol)37 as starting materials: orange crystals (0.29 g, 80%);
mp 198.5-199.5 °C (acetonitrile-water); 1H NMR (CDCl3) 8.40
(d, J ) 15.5 Hz, Hâ), 8.30 (m, H3 and H5), 8.1 (m, H2, H6,
H2′, H6′), 7.74 (d, J ) 15.5 Hz, HR), 6.81 (m, H3′ and H5′),
3.11 (s, NCH3). Anal. (C17H16N2O3) C, H, N.
2-Meth oxy-4-[(2-tetr ah ydr opyr an yl)oxy]-6-m eth ylben z-
a ld eh yd e (6d ) was synthesized according to procedure C
using crude 6c (1.80 g) as starting material: brown oil (1.74
g); H NMR (CDCl3) 10.5 (s, CHO), 6.48 (b, H3, H5), 5.55 (bt,
H2′), 3.85 (s, OCH3), 3.8 (b, H6a′), 3.6 (b, H6e′), 2.55 (s, CH3),
2.1-1.4 (m, H3′-5′).
1
2-Meth oxy-4,4′-d ih yd r oxy-6-m eth ylch a lcon e (6) was
synthesized according to procedure D using crude 6d (1.74 g)
and 4-[(2-tetrahydropyranyl)oxy]acetophenone23 (0.80 g, 3.6
mmol) as starting materials: yellow crystals (0.73 g, 51%
overall yield based on 6b); mp 197.0-197.9 °C (ethanol-
water); 1H NMR ((CD3)2CO) 8.02 (d, J ) 15.7 Hz, Hâ), 8.00
(m, H2′ and H6′), 7.83 (d, J ) 15.7 Hz, HR), 6.97 (m, H3′ and
H5′), 6.46 (d, J ) 2 Hz, H5), 6.40 (d, J ) 2 Hz, H3), 3.93 (s,
OCH3), 2.43 (s, CH3); 13C NMR ((CD3)2CO) 188.8 (CHO),
162.7*(C4), 162.1*(C4′), 160.5*(C2), 142.8 (C6), 138.0 (Câ),
131.8 (C1′), 131.5 (C2′, C6′), 122.9 (CR), 116.1 (C3′, C5′), 115.5
(C1), 111.2 (C5), 98.1 (C3), 55.9 (OCH3), 21.5 (-CH3). Anal.
(C17H16O4‚0.5H2O) C, H.
4-P h en oxy-4′-cycloh exylch a lcon e (7). P r oced u r e E. To
a solution of 4-phenoxybenzaldehyde (0.86 mL, 4.9 mmol) and
4-cyclohexylacetophenone (1.0 g, 4.9 mmol) in anhydrous
ethanol (5 mL) was added sodium hydroxide (30 mg). The
solution was stirred for 16 h, neutralized with 4 M hydrochloric
acid, added to water (10 mL), and extracted four times with
ethyl acetate (20 mL). The combined organic phases were
concentrated in vacuo, and the residue was purified by column
chromatography to give 7 (1.47 g, 79%) as white crystals: mp
160.9-161.1 °C (ethanol-water); 1H NMR (CDCl3) 8.11 (m,
H2′ and H6′), 7.96 (d, J ) 15.5 Hz, Hâ), 7.9 (m, H2, H6, H3′,
H5′), 7.79 (m, H3 and H5), 7.70 (d, J ) 15.5 Hz, HR), 7.41 (m,
H3′′, H5′′), 7.26 (m, H2′′, H4′′, H6′′), 2.61 (b, H1c), 1.9 (m, H2c,
H6c), 1.5 (H3c-H5c). Anal. (C27H26O2) C, H.
4,4′-Diflu or och a lcon e (14) was synthesized according to
procedure E using 4-fluoro-benzaldehyde (0.78 mL, 7.2 mmol)
and 4-fluoroacetophenone (0.89 mL, 7.2 mmol) as starting
materials: white crystals (1.2 g, 68%); mp 112.0-112.9 °C
1
(ethanol-water); H NMR (CDCl3) 8.05 (dd, J ) 8.7, 5.6 Hz,
H2′, H6′), 7.78 (d, J ) 15.7 Hz, Hâ), 7.63 (dd, J ) 8.7, 5.6 Hz,
H2, H6), 7.43 (d, J ) 15.7 Hz, HR), 7.1 (m, H3, H5, H3′, H5′).
Anal. (C15H10OF2) C, H.
3,5-Dim eth oxy-2′-bu toxych a lcon e (15) was synthesized
according to procedure E using 3,5-dimethoxybenzaldehyde
(2.0 g, 12.0 mmol) and 2′-butoxyacetophenone (2.3 g, 12.0
mmol) as starting materials: yellow crystals (3.8 g, 92%); mp
1
69.5-70.1 °C (ethanol-water); H NMR (CDCl3) 7.66 (dd, J
) 7.6, 1.8 Hz, H6′), 7.57 (d, J ) 15.9 Hz, Hâ), 7.44 (d, J ) 15.9
Hz, HR), 7.43 (t, J ) 7.7 Hz, H4′), 7.00 (bt, J ) 7.7 Hz, H5′),
6.95 (bd, J ) 7.7 Hz, H3′), 6.73 (d, J ) 2.2 Hz, H2, H6), 6.49
(t, J ) 2.2 Hz, H4), 4.03 (t, J ) 6.3 Hz, H1′′), 3.79 (s, OCH3),
1.77 (pent, J ) 7.3 Hz, H2′′), 1.45 (hext, J ) 7.3 Hz, H3′′),

4826 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 24
Nielsen et al.
0.87 (t, J ) 7.3 Hz, H4′′); 13C NMR (CDCl3) 192.4 (CdO), 160.7
(C3, C5), 157.7 (C2′), 142.1 (Câ), 136.9 (C1), 132.9 (C4′), 130.4
(C6′), 128.9 (C1′), 127.4 (CR), 120.4 (C5′), 112.1 (C3′), 105.9
(C2, C6), 102.2 (C4), 68.0 (C1′′), 55.1 (OCH3), 31.1 (C2′′), 19.1
(C3′′), 13.5 (C4′′). Anal. (C21H24O4) C, H.
(0.5 g, 3.0 mmol) and 3′-nitroacetophenone (0.5 g, 3.0 mmol)
as starting materials: gray crystals (0.61 g, 64%); mp 88.1-
88.7 °C (ethanol-water); 1H NMR (CDCl3) 8.82 (t, J ) 2.0 Hz,
H2′), 8.52 (dt, J ) 8.0, 1.4 Hz, H4′), 8.46 (ddd, J ) 8.0, 2.0, 1.4
Hz, H6′), 8.17 (d, J ) 15.6 Hz, Hâ), 7.87 (d, J ) 8.0 Hz, H6),
7.86 (t, J ) 8.0 Hz, H5), 7.80 (d, J ) 15.6 Hz, HR), 6.64 (bs,
H3), 6.62 (dd, J ) 8.0, 2.1 Hz, H5′), 3.97 (s, OCH3), 3.89 (s,
OCH3); 13C NMR (CDCl3) 186.0 (CdO), 162.9*(C4), 159.6*(C2),
143.3 (C3′), 139.9 (Câ), 139.2 (C1′), 133.2 (C6′), 129.6 (C5′),
129.3 (C6), 125.7 (C4′), 121.8 (CR), 117.3 (C2′), 115.3 (C1),
3,5-Dim eth oxy-2′-(d im eth yla m in o)ch a lcon e (16) was
synthesized according to procedure E using 3,5-dimethoxy-
benzaldehyde (1.5 g, 8.9 mmol) and 2′-(dimethylamino)ac-
etophenone38 (1.45 g, 8.9 mmol) as starting materials: yellow
crystals (1.9 g, 66%); mp 159.8-160.5 °C (ethanol-water); 1H
NMR (CDCl3) 7.63 (d, J ) 15.9 Hz, Hâ), 7.53 (dd, J ) 7.6, 1.6
Hz, H6′), 7.37 (dt, J ) 7.6, 1.7 Hz, H4′), 7.33 (d, J ) 15.9 Hz,
HR), 6.98 (bt, J ) 7.6 Hz, H5′), 6.75 (bd, J ) 7.6 Hz, H3′), 6.72
(d, J ) 2.2 Hz, H2, H6), 6.48 (t, J ) 2.2 Hz, H4), 3.78 (s, OCH3),
2.80 (s, NCH3); 13C NMR (CDCl3) 194.8 (CdO), 160.9 (C3, C5),
152.2 (C2′), 142.4 (Câ), 137.1 (C1), 132.0 (C4′), 131.3 (C1′),
130.4 (C6′), 126.6 (CR), 120.0 (C5′), 116.9 (C3′), 106.1 (C2, C6),
102.1 (C4), 55.3 (OCH3), 44.3 (NCH3). Anal. (C19H21NO3) C,
H.
105.3 (C5), 97.2 (C3), 54.4 (OCH3), 54.2 (OCH3). Anal. (C17H15
NO5) C, H, N.
-
3,5-Dim eth oxy-3′-flu or och a lcon e (22) was synthesized
according to procedure E using 3,5-dimethoxybenzaldehyde
(2.4 g, 14.4 mmol) and 3′-fluoroacetophenone (1.78 mL, 14.4
mmol) as starting materials: white crystals (2.3 g, 56%); mp
89.5-90.3 °C (ethanol-water); 1H NMR (CDCl3) 7.79 (bd, J ∼
8 Hz, H6′), 7.73 (d, J ) 15.7 Hz, Hâ), 7.69 (dt, J ∼ 9, 3 Hz,
H2′), 7.49 (m, H4′), 7.48 (d, J ) 15.7 Hz, HR), 7.28 (td, J ∼ 8,
∼2 Hz, H5′), 6.78 (d, J ) 2.2 Hz, H2, H6), 6.51 (t, J ) 2.2 Hz,
H4), 3.84 (s, OCH3); 13C NMR (CDCl3) 189.0 (CdO), 165.1 (C3′),
160.9 (C3, C5), 145.5 (Câ), 139.9 (C1′), 136.4 (C1), 130.3 (C5′),
124.1 (CR), 121.8 (C6′), 119.9 (C4′), 115.4 (C2′), 106.3 (C2, C6),
102.9 (C4), 55.4 (OCH3). Anal. (C17H15O3F) C, H.
3,5-Dim eth oxy-2′-n itr och a lcon e (17) was synthesized
according to procedure F using 3,5-dimethoxybenzaldehyde
(1.0 g, 6.1 mmol) and 2′-nitroacetophenone (1.0 g, 6.1 mmol)
as starting materials: yellow crystals (0.45 g, 23%); mp 98.4-
1
98.9 °C (ethanol-water); H NMR (CDCl3) 8.18 (dd, J ) 8.0,
1.2 Hz, H3′), 7.78 (td, J ) 7.4, 1.2 Hz, H5′), 7.66 (td, J ) 8.0,
1.5 Hz, H4′), 7.50 (dd, J ) 7.4, 1.5 Hz, H6′), 7.11 (d, J ) 15.9
Hz, Hâ), 6.92 (d, J ) 15.9 Hz, HR), 6.61 (d, J ) 2.2 Hz, H2,
H6), 6.49 (t, J ) 2.2 Hz, H4), 3.79 (s, OCH3); 13C NMR (CDCl3)
192.9 (CdO), 160.9 (C3, C5), 146.4 (C2′), 146.2 (Câ), 136.1 (C1),
135.6 (C1′), 134.0 (C5′), 130.5 (C4′), 128.7 (C6′), 126.6 (CR),
124.4 (C3′), 106.2 (C2, C6), 103.2 (C4), 55.3 (OCH3). Anal.
(C17H15NO5) C, H.
3,5-Dim eth oxy-4′-cycloh exylch a lcon e (23) was synthe-
sized according to procedure E using 3,5-dimethoxybenzalde-
hyde (0.82 g, 4.9 mmol) and 4-cyclohexylacetophenone (1.0 g,
4.9 mmol) as starting materials: brown crystals (1.6 g, 92%);
1
mp 75.5-76.2 °C (ethanol-water); H NMR (CDCl3) 7.95 (m,
H2′ and H6′), 7.64 (d, J ) 15.9 Hz, Hâ), 7.48 (d, J ) 15.9 Hz,
HR), 7.33 (m, H3′ and H5′), 6.78 (d, J ) 2.2 Hz, H2, H6), 6.52
(t, J ) 2.2 Hz, H4), 3.84 (s, OCH3), 2.58 (b, H1′), 1.8 (m, H2′′,
H6′′), 1.4 (m, H3′′-H5′′); 13C NMR (CDCl3) 189.9 (CdO), 161.0
(C3, C5), 153.7 (C4′), 144.3 (Câ), 137.0 (C1), 136.0 (C1′), 128.8
(C2′, C6′), 127.1 (C3′, C5′), 122.6 (CR), 106.3 (C2, C6), 102.6
(C4), 55.5 (OCH3), 44.7 (C1′′), 34.1 (C2′′, C6′′), 26.7 (C3′′, C5′),
26.0 (C4′′). Anal. (C23H26O3) C, H.
3,5-Dim eth oxy-2′-flu or och a lcon e (18) was synthesized
according to procedure E using 3,5-dimethoxybenzaldehyde
(2.4 g, 14.4 mmol) and 2′-fluoroacetophenone (2.0 g, 14.4 mmol)
as starting materials: yellow crystals (2.9 g, 71%); mp 71.6-
1
72.5 °C (ethanol-water); H NMR (CDCl3) 7.81 (dt, J ) 7.6,
1.8 Hz, H6′), 7.64 (d, J ) 15.7 Hz, Hâ), 7.57 (m, H4′), 7.34 (d,
J ) 15.7 Hz, HR), 7.3-7.1 (m, H3′, H5′), 6.76 (d, J ) 2.2 Hz,
H2, H6), 6.53 (t, J ) 2.2 Hz, H4), 3.83 (s, OCH3); 13C NMR
(CDCl3) 189.0 (CdO), 161.0 (C3, C5), 158.6 (C2′), 144.8 (Câ),
136.5 (C1), 134.1 (C4′), 131.0 (C6′), 126.9 (C1′), 125.9 (CR),
124.5 (C5′), 116.3 (C3′), 106.4 (C2, C6), 102.9 (C4), 55.4 (OCH3).
Anal. (C17H15O3F) C, H.
3,5-Dim eth oxy-4′-(d im eth yla m in o)ch a lcon e (24) was
synthesized according to procedure E using 3,5-dimethoxy-
benzaldehyde (0.67 g, 4.0 mmol) and 4-(dimethylamino)-
acetophenone37 (0.66 g, 4.0 mmol) as starting materials:
orange crystals (0.91 g, 73%); mp 155.1-156.2 °C (ethanol-
1
water); H NMR ((CD3)2CO) 8.10 (m, H2′ and H6′), 7.92 (d, J
) 15.6 Hz, Hâ), 7.63 (d, J ) 15.6 Hz, HR), 7.15 (d, J ) 2.1 Hz,
H2, H6), 6.79 (m, H3′ and H5′), 6.56 (t, J ) 2.1 Hz, H4), 3.85
(s, OCH3), 3.10 (s, -N(CH3)2); 13C NMR ((CD3)2CO) 186.8 (Cd
O), 161.8 (C3, C5), 154.2 (C4′), 142.4 (Câ), 138.1 (C1), 131.4
(C2′, C6′), 126.4 (C1′), 123.5 (CR), 111.5 (C3′, C5′), 106.9 (C2,
2,4-Dim eth oxy-3′-bu toxych a lcon e (19) was synthesized
according to procedure E using 2,4-dimethoxybenzaldehyde
(1.62 g, 9.7 mmol) and 3′-butoxyacetophenone (1.87 g, 9.7
mmol) as starting materials: yellow crystals (3.0 g, 92%); mp
1
C6), 102.8 (C4), 55.7 (OCH3), 39.9 (-N(CH3)2). Anal. (C19H21
NO3) C, H, N.
-
80.4-81.3 °C (ethanol-water); H NMR (CDCl3) 8.07 (d, J )
15.8 Hz, Hâ), 7.56 (m, H2′, H6′, H6), 7.51 (d, J ) 15.8 Hz,
HR), 7.36 (t, J ) 7.8 Hz, H5′), 7.07 (ddd, J ) 8.2, 2.6, 0.9 Hz,
H4′), 6.50 (dd, J ) 2.2 Hz, H5), 6.43 (d, J ) 2.2 Hz, H3), 4.00
(t, J ) 6.4 Hz, H1′), 3.85 (s, OCH3), 1.78 (pent, J ) 7.2 Hz,
H2′′), 1.47 (hext, J ) 7.2 Hz, H3′′), 0.97 (t, J ) 7.2 Hz, H4′′);
13C NMR (CDCl3) 190.5 (CdO), 162.8*(C4), 160.1*(C2), 159.1
(C3′), 140.1 (Câ), 139.9 (C1′), 130.5 (C5′), 129.1 (C6), 120.5 (CR),
119.9 (C6′), 118.9 (C4′), 116.7 (C1), 113.2 (C2′), 105.2 (C5), 98.1
(C3), 67.6 (C1′′), 55.2 (OCH3), 55.1 (OCH3), 31.0 (C2′′), 19.0
(C3′′), 13.6 (C4′). Anal. (C21H24O4) C, H.
3,5-Dim eth oxy-4′-n itr och a lcon e (25) was synthesized
according to procedure E using 3,5-dimethoxybenzaldehyde
(1.0 g, 6.1 mmol) and 4-nitroacetophenone (1.0 g, 6.1 mmol)
as starting materials: yellow crystals (1.5 g, 77%); mp 165.5-
166.3 °C (ethanol-water); 1H NMR (CDCl3) 8.36 (m, H3′ and
H5′), 8.14 (m, H2′ and H6′), 7.75 (d, J ) 15.3 Hz, Hâ), 7.42 (d,
J ) 15.3 Hz, HR), 6.78 (d, J ) 2.2 Hz, H2, H6), 6.56 (t, J ) 2.2
Hz, H4), 3.84 (s, OCH3); 13C NMR (CDCl3) 189.4 (CdO), 161.4
(C3, C5), 150.4 (C4′), 143.2 (C1′), 140.7 (Câ), 136.4 (C1), 132.5
(C2′, C6′), 129.7 (CR), 127.9 (C3′, C5′), 106.8 (C2, C6), 103.7
(C4), 55.6 (OCH3). Anal. (C17H15NO5) C, H, N.
3,5-Dim eth oxy-3′-(d im eth yla m in o)ch a lcon e (20) was
synthesized according to procedure E using 3,5-dimethoxy-
benzaldehyde (2.0 g, 12.3 mmol) and 3′-(dimethylamino)-
acetophenone39 (2.0 g, 12.3 mmol) as starting materials: yellow
crystals (2.6 g, 49%); mp 81.8-82.6 °C (ethanol-water); 1H
NMR (CDCl3) 7.70 (d, J ) 15.7 Hz, Hâ), 7.45 (d, J ) 15.7 Hz,
HR), 7.33 (m, H2′, H4′, H5′), 6.76 (d, J ) 2.2 Hz, H2, H6), 6.51
(t, J ) 2.2 Hz, H4), 6.93 (m, H6′), 3.82 (s, OCH3), 3.00 (s,
-N(CH3)2); 13C NMR (CDCl3) 191.1 (CdO), 160.8 (C3, C5),
150.5 (C3′), 144.1 (Câ), 138.7 (C1′), 136.8 (C1), 128.9 (C5′),
123.0 (CR), 116.7 (C6′, C4′), 111.5 (C2′), 106.1 (C2, C6), 102.4
(C4), 55.3 (OCH3), 40.4 (-N(CH3)2). Anal. (C19H21NO3) C, H,
N.
4′-F lu or och a lcon e (26) was synthesized according to
procedure E using benzaldehyde (0.10 mL, 1.0 mmol) and
4-fluoroacetophenone (0.14 g, 1.0 mmol) as starting materi-
als: yellow crystals (0.20 g, 90%); mp 102.1-103.2 °C (etha-
1
nol-water); H NMR (CDCl3) 8.04 (m, H2′, H6′), 7.80 (d, J )
15.5 Hz, Hâ), 7.62 (m, H3′, H5′), 7.49 (d, J ) 15.5 Hz, HR),
7.40 (m, H2, H4, H6), 7.15 (m, H3, H5); 13C NMR 188.1 (Cd
O), 168.1 (C4′), 145.0 (Câ), 134.7 (C1), 134.4 (C1′), 131.0 (C2′,
C6′), 130.6 (C3, C5), 129.0 (C2, C6), 128.5 (C4), 121.4 (CR),
115.9 (C3′, C5′). Anal. (C15H11OF) C, H.
2-Bu toxy-2′,3′,4′-tr im eth oxych a lcon e (27) was synthe-
sized according to procedure E using 2-butoxybenzaldehyde40
(1.7 g, 9.5 mmol) and 2,3,4-trimethoxyacetophenone (1.7 mL,
2,4-Dim eth oxy-3′-n itr och a lcon e (21) was synthesized
according to procedure E using 2,4-dimethoxybenzaldehyde

Antileishmanial Chalcones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 24 4827
9.5 mmol) as starting materials: yellow crystals (3.0 g, 86%);
mp 129.4-130.2 °C (ethanol-water); 1H NMR (CDCl3) 8.04
(d, J ) 16.0 Hz, Hâ), 7.62 (dd, J ) 7.7, 1.5 Hz, H6), 7.55 (d, J
) 16.0 Hz, HR), 7.46 (d, J ) 8.8 Hz, H6′), 7.31 (td, J ) 7.7, 1.5
Hz, H4), 6.94 (bt, J ) 7.7 Hz, H5), 6.89 (bd, J ) 7.7 Hz, H3),
6.74 (d, J ) 8.8 Hz, H5′), 4.00 (t, J ) 6.4 Hz, H1′′), 3.97 (s,
OCH3), 1.80 (pent, J ) 7.4 Hz, H2′′), 1.48 (hext, J ) 7.4 Hz,
H3′′), 0.96 (t, J ) 7.3 Hz, H4′′); 13C NMR (CDCl3) 191.4 (Cd
O), 157.8 (C2), 156.3 (C4′), 153.1 (C2′), 141.6 (C3′), 138.7 (Câ),
131.2 (C4), 128.4 (C6), 126.6 (C1), 126.5 (CR), 125.2 (C6′), 123.6
(C1′), 120.1 (C5), 111.7 (C3), 106.8 (C5′), 67.7 (C1′′), 61.7
(OCH3), 60.6 (OCH3), 55.7 (OCH3), 30.8 (C2′′), 19.0 (C3′′), 13.5
(C4′′). Anal. (C22H26O5) C, H.
2-(Dim eth ylam in o)-2′,3′,4′-tr im eth oxych alcon e (28) was
synthesized according to procedure E using 2-(dimethylamino)-
benzaldehyde (0.15 g, 1.0 mmol) and 2,3,4-trimethoxy-
acetophenone (0.18 mL, 1.0 mmol) as starting materials:
yellow crystals (0.26 g, 76%); mp 143.2-145.7 °C (ethanol-
water); 1H NMR (CO(CD3)2) 8.00 (d, J ) 16.0 Hz, Hâ), 7.60
(dd, J ) 7.7, 1.4 Hz, H6), 7.51 (d, J ) 16.0 Hz, HR), 7.43 (d, J
) 8.8 Hz, H6′), 7.33 (td, J ) 7.7, 1.4 Hz, H4), 6.91 (bt, J ) 8
Hz, H5), 6.76 (d, J ) 8.8 Hz, H5′), 6.71 (bd, J ) 8 Hz, H3),
4.01 (s, OCH3), 2.91 (s, NCH3); 13C NMR 193.2 (CdO), 156.5
(C4′), 153.2 (C2′), 149.8 (C2), 142.0 (C3′), 139.3 (Câ), 133.2 (C4),
128.9 (C6), 129.0 (C1), 126.9 (CR), 125.3 (C6′), 123.6 (C1′),
122.2 (C5), 110.5 (C3), 106.9 (C5′), 61.8 (OCH3), 60.9 (OCH3),
55.7 (OCH3), 44.9 (NCH3). Anal. (C20H23NO4) C, H, N.
(bd, J ) 7.9 Hz, H6), 6.92 (b, H2), 6.78 (bd, J ) 7.9 Hz, H4),
6.75 (d, J ) 8.8 Hz, H5′), 3.93 (s, OCH3), 3.92 (s, OCH3), 2.99
(s, -(N(CH3)2); 13C NMR (CDCl3) 191.1 (CdO), 156.8 (C4′),
153.6 (C2′), 144.4 (Câ), 141.9 (C3), 135.7 (C1), 136.8 (C3′) 129.4
(C5), 126.8 (C1′), 126.6 (C6′), 126.1 (CR), 116.2 (C6), 114.4 (C4),
112.3 (C2), 107.1 (C5′), 62.0 (OCH3), 61.0 (OCH3), 56.0 (OCH3),
40.5 (-N(CH3)2). Anal. (C20H23NO4) C, H, N.
3-Nitr o-2′,3′,4′-tr im eth oxych a lcon e (33) was synthesized
according to procedure E using 3-nitrobenzaldehyde (0.72 g,
4.8 mmol) and 2,3,4-trimethoxyacetophenone (0.87 mL, 4.8
mmol) as starting materials: yellow crystals (1.0 g, 64%); mp
130.1-130.7 °C (ethanol-water); 1H NMR (CDCl3) 8.46 (bt, J
) 1.7 Hz, H2), 8.22 (dt, J ) 8.1, 1.2 Hz, H6), 7.92 (bd, J ) 7.8
Hz, H4), 7.72 (d, J ) 15.8 Hz, Hâ), 7.66 (d, J ) 15.8 Hz, HR),
7.61 (t, J ) 8.0 Hz, H5), 7.55 (d, J ) 8.8 Hz, H6′), 6.80 (d, J )
8.8 Hz, H5′), 3.96 (s, OCH3), 3.95 (s, OCH3); 13C NMR (CDCl3)
189.6 (CdO), 157.4 (C4′), 153.8 (C2′), 141.9 (C3), 139.2 (Câ),
136.8 (C1), 135.1 (C3′) 133.8 (C6), 129.8 (C5), 129.0 (CR), 125.9
(C6), 125.8 (C4), 124.1 (C1′), 122.3 (C2), 107.3 (C5′), 61.9
(OCH3), 60.9 (OCH3), 56.0 (OCH3). Anal. (C18H17NO6) C, H,
N.
3-F lu or o-2′,3′,4′-tr im eth oxych a lcon e (34) was synthe-
sized according to procedure E using 3-fluorobenzaldehyde (1.7
mL, 16.1 mmol) and 2,3,4-trimethoxyacetophenone (2.9 mL,
16.1 mmol) as starting materials: yellow crystals (1.7 g, 34%);
1
mp 79.3-80.2 °C (ethanol-water); H NMR (CDCl3) 7.65 (d,
J ) 15.8 Hz, Hâ), 7.52 (d, J ) 8.8 Hz, H6′), 7.50 (d, J ) 15.8
Hz, HR), 7.42-7.28 (m, H4-H6), 7.1 (m, H2), 6.77 (d, J ) 8.8
Hz, H5′), 3.94 (s, OCH3), 3.93 (s, OCH3); 13C NMR (CDCl3)
190.5 (CdO), 165.3 (C4′), 157.9 (C3), 153.8 (C2′), 141.3 (Câ),
138.0 (C1), 136.1 (C3′) 130.5 (C5), 127.7 (CR), 126.3 (C1′), 126.0
(C6′), 124.5 (C6), 117.2 (C4), 114.6 (C2), 107.4 (C5′), 62.1
(OCH3), 61.1 (OCH3), 56.2 (OCH3). Anal. (C18H17O4F) C, H.
2-Nitr o-2′,3′,4′-tr im eth oxych a lcon e (29) was synthesized
according to procedure F using 2-nitrobenzaldehyde (0.72 g,
4.8 mmol) and 2,3,4-trimethoxyacetophenone (0.8 mL, 4.8
mmol) as starting materials: red-brown crystals (0.22 g, 13%);
mp 107.1-108.0 °C (ethanol-water); 1H NMR (CDCl3) 8.04
(d, J ) 15.7 Hz, Hâ), 8.03 (dd, J ) 8.0, 1.2 Hz, H3), 7.76 (dd,
J ) 7.8, 1.7 Hz, H6), 7.67 (td, J ) 7.8, 1.2 Hz, H5), 7.55 (td, J
) 8.0, 1.8 Hz, H4), 7.53 (d, J ) 8.8 Hz, H6′), 7.37 (d, J ) 15.7
Hz, HR), 6.79 (d, J ) 8.8 Hz, H5′), 3.94 (s, OCH3), 3.92 (s,
OCH3), 3.91 (s, OCH3); 13C NMR (CDCl3) 190.0 (CdO), 157.3
(C4′), 153.9 (C2′), 142.1 (C2), 137.7 (Câ), 136.0 (C3′), 133.3 (C5),
131.3 (C1), 131.2 (C4), 129.9 (C6), 129.0 (CR), 126.0 (C3), 125.8
(C1′), 124.8 (C6′), 107.3 (C5′), 62.1 (OCH3), 61.0 (OCH3), 56.0
(OCH3). Anal. (C18H17NO6) C, H, N.
4-(Dim eth ylam in o)-2′,3′,4′-tr im eth oxych alcon e (35) was
synthesized according to procedure E using 4-(dimethylamino)-
benzaldehyde (0.71 g, 4.8 mmol) and 2,3,4-trimethoxy-
acetophenone (0.87 mL, 4.8 mmol) as starting materials:
yellow crystals (0.86 g, 53%); mp 168.1-169.3 °C (ethanol-
1
water); H NMR (CDCl3) 7.64 (d, J ) 15.9 Hz, Hâ), 7.51 (m,
H2 and H6), 7.43 (d, J ) 8.8 Hz, H6′), 7.28 (d, 15.9 Hz, HR),
6.75 (d, J ) 8.8 Hz, H5′), 6.68 (m, H3 and H5), 3.92 (s, OCH3),
3.90 (s, OCH3), 3.03 (s, -N(CH3)2); 13C NMR (CDCl3) 190.9 (Cd
O), 156.2* (C4′), 152.1* (C2′), 144.7 (Câ), 143.8 (C4), 130.3 (C2,
C6), 130.2 (C3′), 127.1 (C1), 126.1 (C1′), 125.5 (CR), 121.6 (C6′),
111.8 (C3, C5), 107.1 (C5′), 62.1* (OCH3), 61.1* (OCH3), 56.1*
(OCH3), 40.2 (NCH3). Anal. (C20H23NO4) C, H, N.
2-F lu or o-2′,3′,4′-tr im eth oxych a lcon e (30) was synthe-
sized according to procedure E using 2-fluorobenzaldehyde (1.7
mL, 16.1 mmol) and 2,3,4-trimethoxyacetophenone (2.9 mL,
16.1 mmol) as starting materials: white crystals (3.6 g, 81%);
1
mp 75.0-75.8 °C (ethanol-water); H NMR (CDCl3) 7.82 (d,
J ) 16.0 Hz, Hâ), 7.64 (td, J ) 7.6, 1.4 Hz, H4), 7.62 (d, J )
16.0 Hz, HR), 7.52 (d, J ) 8.8 Hz, H6′), 7.35 (m, H6), 7.17 (bt,
J ) ∼8 Hz, H5), 7.10 (bt, J ) ∼8 Hz, H3), 6.77 (d, J ) 8.8 Hz,
H5′), 3.96 (s, OCH3), 3.94 (s, OCH3), 3.91 (s, OCH3); 13C NMR
(CDCl3) 190.4 (CdO), 164.8 (C4′), 157.0 (C2), 154.1 (C2′), 136.0
(C3′), 135.1 (Câ), 131.4 (C4), 129.1 (C6), 128.5 (CR), 126.2 (C1),
125.8 (C6′), 124.3 (C5), 123.8 (C1′), 116.2 (C3), 107.1 (C5′), 61.8
(OCH3), 60.8 (OCH3), 55.9 (OCH3). Anal. (C18H17O4F) C, H.
4-Cya n o-2′,3′,4′-tr im eth oxych a lcon e (36) was synthe-
sized according to procedure E using 4-cyanobenzaldehyde (1.3
g, 9.5 mmol) and 2,3,4-trimethoxyacetophenone (1.7 mL, 9.5
mmol) as starting materials: yellow crystals (2.4 g, 81%); mp
131.7-133.0 °C (ethanol-water); 1H NMR (CDCl3) 7.7-7.6 (m,
Hâ, HR, H2, H3, H5, H6), 7.55 (d, J ) 8.8 Hz, H6′), 6.78 (d, J
) 8.8 Hz, H5′), 3.95 (s, OCH3), 3.92 (s, OCH3); 13C NMR
(CDCl3) 189.6 (CdO), 157.3 (C4′), 154.2 (C2′), 139.6 (Câ), 139.5
(C1), 136.7 (C3′), 132.4 (C2, C6), 129.4 (CR), 128.4 (C3, C5),
126.0 (C6′), 125.9 (C1′), 118.9 (CN), 112.8 (C4), 107.3 (C5′),
62.0* (OCH3), 60.9* (OCH3), 56.0* (OCH3). Anal. (C19H17NO4)
C, H, N.
3-P h en oxy-2′,3′,4′-tr im eth oxych a lcon e (31) was synthe-
sized according to procedure E using 3-phenoxybenzaldehyde
(0.82 mL, 4.8 mmol) and 2,3,4-trimethoxyacetophenone (0.87
mL, 4.8 mmol) as starting materials: yellow crystals (1.1 g,
58%); mp 63.3-64.0 °C (ethanol-water); 1H NMR (CDCl3) 7.63
(d, J ) 15.8 Hz, Hâ), 7.48 (d, J ) 8.8 Hz, H6′), 7.45 (d, J )
15.8 Hz, HR), 7.4-7.0 (m, H2, H3, H6, H5′, H3′′-H5′′), 7.12
(t, J ) 7.8 Hz, H5), 7.02 (m, H2′, H6′′), 3.91 (s, OCH3), 3.87 (s,
OCH3); 13C NMR (CDCl3) 190.2 (CdO), 157.6 (C3, C1′′), 157.0
(C4′), 156.4 (C2′), 141.8 (Câ), 137.6 (C3′) 136.7 (C1), 130.0 (C5),
129.6 (C3′′), 126.9 (CR), 126.2 (C1′), 125.7 (C6′), 123.4 (C4′′),
123.1 (C6), 120.1 (C4), 118.9 (C2′′), 117.6 (C2), 107.1 (C5′), 61.7
(OCH3), 60.8 (OCH3), 55.9 (OCH3). Anal. (C24H22O5) C, H.
3-(Dim eth ylam in o)-2′,3′,4′-tr im eth oxych alcon e (32) was
synthesized according to procedure E using 3-(dimethylamino)-
benzaldehyde39 (1.0 g, 6.9 mmol) and 2,3,4-trimethoxy-
acetophenone (1.3 mL, 6.9 mmol) as starting materials: orange
crystals (2.1 g, 90%); mp 87.2-87.9 °C (ethanol-water); 1H
NMR (CDCl3) 7.66 (d, J ) 15.8 Hz, Hâ), 7.48 (d, J ) 8.8 Hz,
H6′), 7.46 (d, J ) 15.8 Hz, HR), 7.27 (t, J ) 7.9 Hz, H5), 7.02
3,5-Dim eth oxy-4′-(2-pr open yloxy)ch alcon e (38) was syn-
thesized according to procedure E using 3,5-dimethoxybenz-
aldehyde (16.6 g, 10 mmol) and 4-(2-propenyloxy)acetophenone
(17.1 g, 10 mmol) as starting materials: yellow crystals (28.2
g, 91%); mp 89-90 °C (ethanol-water); 1H NMR (CDCl3) 8.07
(m, H2′ and H6′), 7.72 (d, J ) 15.9 Hz, Hâ), 7.62 (d, J ) 15.9
Hz, HR), 7.03 (m, H3′ and H5′), 6.90 (d, J ) 1.9 Hz, H2 and
H6), 6.52 (t, J ) 1.9 Hz, H4), 6.03 (ddq, J ) 17.3, 10.5, 5.2 Hz,
H2′′), 5.42 (dd, J ) 17.3, 1.3 Hz, H3′'trans), 5.32 (dd, J ) 10.5,
1.3 Hz, H3′′cis); 13C NMR (CDCl3) 187.4 (CdO), 163.5 (C4′),
162.1 (C3, C5), 144.1 (Câ), 138.0 (C1), 134.1 (C2′′), 131.9 (C1′),
131.8 (C2′, C6′), 103.4 (C4), 123.1 (CR), 118.3 (C3′′), 115.5 (C3′,
C5′), 107.3 (C2, C6), 69.7 (C1′′), 56.2 (OCH3). Anal. (C20H20O4)
C, H.

4828 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 24
Nielsen et al.
4-Bu t yl-3,5-m et h oxy-4′-(2-p r op en yloxy)ch a lcon e (39)
was synthesized according to procedure E using 4-butyl-3,5-
dimethoxybenzaldehyde41 (40 mg, 0.18 mmol) and 4-(2-propen-
yloxy)acetophenone42 (32 mg, 0.18 mmol) as starting materi-
als: yellow crystals (44 mg, 64%); mp 74-75 °C (ethanol-
(0.79 g, 4.8 mmol) and 2,3,4-trimethoxyacetophenone (0.87 mL,
4.8 mmol) as starting materials: yellow crystals (1.4 g, 83%);
mp 111.6-112.5 °C (ethanol-water); 1H NMR (CDCl3) 7.60
(d, J ) 15.8 Hz, Hâ), 7.49 (d, J ) 8.8 Hz, H6′), 7.46 (d, J )
15.8 Hz, HR), 6.76 (d, J ) 8.8 Hz, H5′), 6.75 (d, J ) 2.2 Hz,
H2, H6), 6.50 (t, J ) 2.2 Hz, H4), 3.92 (s, OCH3), 3.79 (s,
OCH3); 13C NMR (CDCl3) 190.5 (CdO), 160.7 (C3, C5), 156.8
(C4′), 153.5 (C2′), 142.7 (Câ), 141.8 (C1), 136.8 (C3′), 126.8 (CR),
126.4 (C1), 125.6 (C6′), 107.1 (C5′), 106.0 (C6), 102.1 (C4),
61.8*(OCH3), 60.8*(OCH3), 55.8*(OCH3), 55.1 (C3/5-OCH3).
Anal. (C20H22O6) C, H.
1
water); H NMR (CDCl3) 8.03 (m, H2′ and H6′), 7.75 (d, J )
15.9 Hz, Hâ), 7.45 (d, J ) 15.9 Hz, HR), 6.99 (m, H3′ and H5′),
6.80 (s, H2, H6), 6.03 (ddq, J ) 17.3, 10.5, 5.2 Hz, H2′′), 5.42
(dd, J ) 17.3, 1.3 Hz, H3′'trans), 5.32 (dd, J ) 10.5, 1.3 Hz,
H3′′cis), 4.58 (bd, J ) 5.2, H1′′), 3.87 (s, OCH3), 2.65 (t, J )
7.4 Hz, Hbu1), 1.40 (m, Hbu2, Hbu3), 0.92 (t, J ) 7.4 Hz, Hbu4);
13C NMR (CDCl3) 188.9 (CdO), 162.3 (C4′), 158.4 (C3, C5),
144.9 (Câ), 133.4 (C1), 132.5 (C2′′), 131.4 (C1′), 130.8 (C2′, C6′),
123.0 (C4), 121.0 (CR), 118.2 (C3′′), 114.5 (C3′, C5′), 103.8 (C2,
C6), 68.9 (C1′′), 55.8 (OCH3), 31.3 (Cbu1), 23.0 (Cbu2), 22.9
(Cbu3), 14.1 (Cbu4). Anal. (C24H28O4) C, H.
4-Hexyl-3,5-dim eth oxy-4′-(2-pr open yloxy)ch alcon e (40)
was synthesized according to procedure E using 4-hexyl-3,5-
dimethoxybenzaldehyde (0.10 g, 0.4 mmol) and 4-(2-propenyl-
oxy)acetophenone42 (0.07 g, 0.4 mmol) as starting materials:
white crystals (0.16 g, 90%); mp 77.9-78.2 °C; 1H NMR
(CDCl3) 8.03 (m, H2′ and H6′), 7.77 (d, J ) 15.4 Hz, Hâ), 7.47
(d, J ) 15.4 Hz, HR), 7.00 (m, H3′ and H5′), 6.80 (s, H2, H6),
6.03 (ddq, J ) 17.3, 10.5, 5.2 Hz, H2′′), 5.42 (dd, J ) 17.3, 1.3
Hz, H3′'trans), 5.32 (dd, J ) 10.5, 1.3 Hz, H3′′cis), 4.58 (bd, J
) 5.2, H1′′), 3.87 (s, OCH3), 2.65 (t, J ) 7.4 Hz, Hhex1), 1.40
(m, Hhex2-Hhex5), 0.89 (t, J ) 7 Hz, Hhex6); 13C NMR (CDCl3)
188.9 (CdO), 162.3 (C4′), 158.4 (C3, C5), 144.9 (Câ), 133.4 (C1),
132.5 (C2′′), 131.3 (C1′), 130.8 (C2′, C6′), 121.0 (CR), 118.2
(C3′′), 117.3 (C4), 114.5 (C3′, C5′), 103.8 (C2, C6), 68.9 (C1′′),
55.8 (OCH3), 31.8 (Chex1), 29.5 (Chex2), 29.0 (Chex3), 23.2 (Chex4),
22.7 (Chex5), 14.2 (Chex6). Anal. (C26H32O4) C, H.
3,5-Dim eth oxy-2′-h yd r oxych a lcon e (41) was synthesized
according to procedure E using 3,5-dimethoxybenzaldehyde
(0.47 g, 2.8 mmol) and 2-hydroxyacetophenone (0.34 mL, 2.8
mmol) as starting materials: orange crystals (0.27 g, 34%);
mp 110.2-110.9 °C (ethanol-water); 1H NMR (CDCl3) 7.91
(dd, J ) 8.4, 1.0 Hz, H6′), 7.82 (d, J ) 15.6 Hz, Hâ), 7.59 (d, J
) 15.6 Hz, HR), 7.50 (td, J ) 8.4, 1.0 Hz, H4′), 7.03 (d, J ) 8.4
Hz, H3′), 6.95 (t, J ) 8.4 Hz, H5′), 6.79 (d, J ) 2.2 Hz, H2,
H6), 6.55 (t, J ) 2.2 Hz, H4), 3.85 (s, OCH3); 13C NMR (CDCl3)
193.4 (CdO), 163.4 (C2′), 161.1 (C3, C5), 145.5 (Câ), 136.4 (C1),
136.5 (C4′), 129.7 (C6′), 120.5 (CR), 120.0 (C1′), 118.9 (C5′),
118.6 (C3′), 106.5 (C2, C6), 103.0 (C4), 55.5 (OCH3). Anal.
(C17H16O4) C, H.
3,5-Dim eth oxy-3′-h yd r oxych a lcon e (42) was synthesized
according to procedure E using 3,5-dimethoxybenzaldehyde
(0.47 g, 2.8 mmol) and 3-hydroxyacetophenone (0.38 g, 2.8
mmol) as starting materials: yellow crystals (0.25 g, 32%); mp
126.2-126.8 °C (ethanol-water); 1H NMR (CDCl3) 9.66 (s,
OH), 7.74 (d, J ) 16.0 Hz, Hâ), 7.66 (d, J ) 16.0 Hz, HR), 7.59
(bd, J ∼ 8 Hz, H4′), 7.52 (bt, J ) 2 Hz, H2′), 7.36 (t, J ) 7.8
Hz, H5′), 7.10 (dd, J ) 7.8, 2.4 Hz, H6′), 6.95 (d, J ) 2.2 Hz,
H2, H6), 6.58 (t, J ) 2.2 Hz, H4), 3.82 (s, OCH3); 13C NMR
(CDCl3) 188.8 (CdO), 160.3 (C3, C5), 157.3 (C3′), 143.2 (Câ),
138.6 (C1′), 136.1 (C1), 129.1 (C5′), 122.0 (CR), 119.5 (C6′),
118.9 (C4′), 114.1 (C2′), 105.8 (C2, C6), 101.9 (C4), 54.5 (OCH3).
Anal. (C17H16O4) C, H.
2,4,3′-Tr im eth oxych a lcon e (45) was synthesized accord-
ing to procedure E using 2,4-dimethoxybenzaldehyde (0.84 g,
5.0 mmol) and 3-methoxyacetophenone (0.67 mL, 5.0 mL) as
starting materials: yellow crystals (1.6 g, 91%); mp 75.6-78.9
°C (ethanol-water); 1H NMR (CDCl3) 8.06 (d, J ) 15.8 Hz,
Hâ), 7.7-7.6 (m, H6, H6′, H2′), 7.55 (d, J ) 15.8 Hz, HR), 7.43
(t, J ) 8.0 Hz, H5′), 7.07 (dt, J ) 8.0, 1.0 Hz, H4′), 6.55 (dd, J
) 8.4, 2.4 Hz, H5), 6.49 (d, J ) 2.4 Hz, H3), 3.90 (s, OCH3),
3.88 (s, OCH3), 3.86 (s, OCH3); 13C NMR (CDCl3) 191.1 (Cd
O), 163.2*(C3′), 160.4*(C4), 159.8*(C2), 140.6 (Câ), 140.3 (C1′),
131.0 (C5′), 129.4 (C6), 121.1 (CR), 120.4 (C6′), 118.8 (C4′),
112.8 (C2′), 112.2 (C1), 105.4 (C5), 98.4 (C3), 55.5 (OCH3), 55.4
(OCH3). Anal. (C18H18O4) C, H.
2,4-Dim eth oxy-2′-br om och a lcon e (46) was synthesized
according to procedure E using 2,4-dimethoxybenzaldehyde
(0.42 g, 2.5 mmol) and 2-bromoacetophenone (0.33 mL, 2.5
mmol) as starting materials: yellow crystals (0.65 g, 71%); mp
1
91.3-91.8 °C (ethanol-water); H NMR (CDCl3) 7.67 (d, J )
16.2 Hz, Hâ), 7.61 (dd, J ) 7.0, 1.0 Hz, H6′), 7.48 (d, J ) 8.6
Hz, H6), 7.5-7.25 (m, H3′-H5′), 7.10 (d, J ) 16.2 Hz, HR),
6.51 (dd, J ) 8.6, 2.3 Hz, H5), 6.43 (d, J ) 2.3 Hz, H3), 3.83
(s, OCH3), 3.82 (s, OCH3); 13C NMR (CDCl3) 195.2 (CdO),
163.4*(C4), 160.3*(C2), 142.6 (Câ), 141.6 (C1′), 133.3 (C4′),
131.0 (C3′), 130.9 (C6′), 129.1 (C6), 127.2 (CR), 124.3 (C5′),
119.5 (C2′), 116.5 (C1), 105.5 (C5), 98.3 (C3), 55.5 (OCH3). Anal.
(C17H15O3Br) C, H, Br.
2,4-Dim eth oxy-3′-br om och a lcon e (47) was synthesized
according to procedure E using 2,4-dimethoxybenzaldehyde
(0.84 g, 5.0 mmol) and 3-bromoacetophenone (0.65 mL, 5.0
mmol) as starting materials: yellow crystals (1.6 g, 87%); mp
1
74-75 °C (ethanol-water); H NMR (CDCl3) 8.12 (t, J ) 1.7
Hz, H2′), 8.06 (d, J ) 16.5 Hz, Hâ), 7.90 (bd, J ) 8 Hz, H4′),
7.68 (bd, J ) 8 Hz, H6′), 7.57 (d, J ) 8.6 Hz, H6), 7.46 (d, J )
16.5 Hz, HR), 7.36 (t, J ) 8.0 Hz, H5′), 6.56 (dd, J ) 8.6, 2.3
Hz, H5), 6.48 (d, J ) 2.3 Hz, H3), 3.90 (s, OCH3), 3.87 (s,
OCH3). Anal. (C17H15O3Br) C, H, Br.
3,4,5-Tr im eth oxy-4′-(p r op -2-en yloxy)ch a lcon e (56) was
prepared according to procedure E using 4-(allyloxy)acetophe-
none42 (1.76 g, 10 mmol) and 3,4,5-trimethoxybenzaldehyde
(1.96 g, 10 mmol) as starting materials: yellow crystals (3.41
1
g, 96%); mp 92-93 °C (methanol); H NMR (CDCl3) 8.03 (m,
H-2′ and H-6′), 7.71 (d, J ) 15 Hz, H-â), 7.42 (d, J ) 15 Hz,
H-R), 7.13 (s, H-6), 6.99 (m, H-3′ and H-5′), 6.52 (s, H-3), 6.05
(m, dCH-), 5.42 (m, dCHH), 5.32 (m, dCHH), 4.60 (m,
-CH2-), 3.92 (s, CH3O) 3.90 (s, CH3-O); 13C NMR (CDCl3)
188.6 (CdO), 162.4 (C-4′), 153.4 (C-5), 144.1 (C-â), 132.5 (d
CH-), 131.2 (C-1′), 130.8 (C-2′ and C-6′), 130.6 (C-1), 121.2
(C-R), 118.2 (dCH2), 114.5 (C-3′ and C-5′), 105.6 (C-6), 68.9
(-CH2-), 61.0 and 56.2 (CH3O). Anal. (C21H22O5) C, H.
2-Hyd r oxy-2′,3′,4′-tr im eth oxych a lcon e (43) was synthe-
sized according to procedure E using 2-hydroxybenzaldehyde
(0.25 mL, 2.4 mmol) and 2,3,4-trimethoxyacetophenone (0.43
mL, 2.4 mmol) as starting materials: brown crystals (0.29 g,
39%); mp 122.6-123.0 °C (ethanol-water); 1H NMR (CD3CN/
DMSO) 7.84 (d, J ) 16.0 Hz, Hâ), 7.61 (bd, J ) 7.7 Hz, H6),
7.47 (d, J ) 16.0 Hz, HR), 7.35 (d, J ) 8.7 Hz, H6′), 7.25 (bt,
J ∼ 8, 7.7 Hz, H4), 6.94 (bd, J ) 8.2 Hz, H3), 6.85 (m, H5′,
H5), 3.88 (OCH3), 3.87 (OCH3), 3.82 (OCH3); 13C NMR (CD3-
CN/DMSO) 190.6 (CdO), 156.6 (C2), 156.5 (C4′), 156.0 (C2′),
141.6 (Câ), 138.1 (C4), 136.4 (C3′), 131.0 (C6), 128.1 (CR), 126.2
(C1), 125.6 (C6′), 124.4 (C5), 118.9 (C1′), 115.7 (C3), 106.9 (C5′),
60.9 (OCH3), 59.7 (OCH3), 55.2 (OCH3). Anal. (C18H18O5) C,
H.
2,5-Dim et h oxy-4′-(p r op -2-en yloxy)ch a lcon e (58) was
prepared according to procedure E using 4-(allyloxy)acetophe-
none39 (1.66 g, 10 mmol) and 2,5-dimethoxybenzaldehyde (1.67
g, 10 mmol) as starting materials: yellow crystals (2.50 g,
83%); mp 86-87 °C (methanol); 1H NMR (CDCl3) 8.06 (d, J )
15 Hz, H-â), 8.02 (m, H-2′ and H-6′), 7.59 (d, J ) 15 Hz, H-R),
7.16 (d, J ) 2 Hz, H-6), 6.97 (m, H-3′ and H-5′), 6.93 (dd, J )
2, 7 Hz, H-4), 6.84 (d, J ) 7 Hz, H-3), 6.05 (m, dCH-), 5.42
(m, dCHH), 5.32 (m, dCHH), 4.60 (m, -CH2-), 3.85 (s, CH3-
O), 3.80 (s, CH3-O); 13C NMR (CDCl3) 122.9 (C-R), 139.3 (C-
â), 189.1 (CdO), 124.6 (C-1), 152.2 (C-2), 112.4 (C-3), 113.8
(C-4), 153.5 (C-5), 116.9 (C-6), 131.4 (C-1′), 130.7 (C-2′ and
3,5,2′,3′,4′-P en ta m eth oxych a lcon e (44) was synthesized
according to procedure E using 3,5-dimethoxybenzaldehyde

Antileishmanial Chalcones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 24 4829
C-6′), 114.5 (C-3′ and C-5′), 162.3 (C-4′), 68.9 (CH2), 118.1 (d
CH2), 132.7 (dCH-CH2), 56.1 and 55.8 (CH3). Anal. (C20H20O4)
C, H.
4′), 67.7 (CH2O), 55.6 (OCH3), 31.0 and 19.0 (CH2), 13.7 (CH3).
Anal. (C21H24O4) C, H.
2,6-Dim et h oxy-4′-(p r op -2-en yloxy)ch a lcon e (66) was
synthesized according to procedure E using 4-(allyloxy)-
acetophenone42 (0.59 g, 3.3 mmol) and 2,6-dimethoxybenzal-
dehyde (0.56 g, 3.3 mmol) as starting materials: yellow
crystals (0.56 g, 52%); mp 102-103 °C; 1H NMR (CDCl3) 8.26
(d, J ) 15 Hz, H-â), 8.03 (m, H-2′ and H-6′), 7.99 (d, J ) 15
Hz, H-R), 7.27 (t, J ) 7 Hz, H-4), 6.98 (m, H-3′ and H-5′), 6.57
(d, J ) 7 Hz, H-3 and H-5), 6.05 (m, dCH), 5.42 (m, dCHH),
5.32 (m, dCHH), 4.60 (m, -CH2-), 3.90 (s, CH3-O); 13C NMR
(CDCl3) 132.6 (C-R), 134.9 (C-â), 190.3 (CdO), 112.9 (C-1),
160.3 (C-2 and C-6), 103.7 (C-3 and C-5), 124.7 (C-4), 132.0
(C-1′), 130.7 (C-2′ and C-6′), 114.3 (C-3′ and C-5′), 161.6 (C-
4′), 68.8 (CH2), 118.1 (dCH2), 132.0 (dCH-CH2), 55.8 (CH3).
Anal. (C20H20O4) C, H.
2,3-Dim et h oxy-4′-(p r op -2-en yloxy)ch a lcon e (67) was
synthesized according to procedure E using 4-(allyloxy)-
acetophenone42 (1.76 g, 10 mmol) and 2,3-dimethoxybenzal-
dehyde (1.66 g, 10 mmol) as starting materials: yellow crystals
(2.92 g, 90%); mp 98-99 °C (methanol-water); 1H NMR
(CDCl3) 8.09 (d, J ) 15 Hz, H-â), 8.03 (H-2′ and H-6′), 7.59 (d,
J ) 15 Hz, H-R), 7.27 (dd, J ) 7, 2 Hz, H-6), 7.09 (t, J ) 7 Hz,
H-5), 6.96 (m, H-3′ and H-5′), 6.95 (dd, J ) 2, 7 Hz, H-4), 6.05
(m, dCH-), 5.42 (m, dCHH), 5.32 (m, dCHH), 4.60 (m,
-CH2-), 3.88 and 3.46 (s, CH3); 13C NMR (CDCl3) 124.2 (C-
R), 138.9 (C-â), 189.1 (CdO), 129.2 (C-1), 153.2 (C-2), 148.8
(C-3), 114.1 (C-4), 119.6 (C-5), 123.4 (C-6), 131.2 (C-1′), 130.8
(C-2′ and C-6′), 114.5 (C-3′ and C-5′), 162.4 (C-4′), 68.9 (CH2),
118.2 (dCH2), 132.5 (dCH-CH2), 61.3 and 55.8 (CH3). Anal.
(C20H20O4) C, H.
3,5-Dim eth oxy-4′-bu toxych a lcon e (68) was synthesized
according to procedure E using 4-butoxyacetophenone (5.00
g, 26 mmol) and 3,5-dimethoxybenzaldehyde (4.32 g, 26 mmol)
as starting materials: yellow crystals (7.89 g, 91%); mp 100-
101 °C; 1H NMR (CDCl3) 8.00 (H-2′ and H-6′), 7.58 (d, J ) 15
Hz, H-â), 7.48 (d, J ) 15 Hz, H-R), 6.92 (m, H-3′ and H-5′),
6.49 (d, J ) 2 Hz, H-2 and H-5), 6.48 (t, J ) 2 Hz), 3.97 (t J )
7 Hz, -OCH2-), 3.79 (s, OCH3) 1.58 and 1.48 (m, CH2), 0.96
(t, J ) 8 Hz, CH2); 13C NMR (CDCl3) 122.0 (C-R), 143.5 (C-â),
188.2 (CdO), 136.7 (C-1), 106.0 (C-2, C-6), 160.8 (C-3, C-5),
102.2 (C-4), 130.4 (C-1′), 130.6 (C-2′ and C-6′), 114.0 (C-3′ and
C-5′), 162.9 (C-4′), 67.7 (OCH2), 55.2 (OCH3), 30.9 and 19.0
(CH2), 13.7 (CH3). Anal. (C21H24O4) C, H.
2,4-Dim eth oxy-2′-(2-pr open yloxy)ch alcon e (70) was syn-
thesized according to procedure E using 2-(2-propenyloxy)-
acetophenone43 (1.7 g, 10 mmol) and 2,4-dimethoxybenzalde-
hyde (1.66 g, 10 mmol) as starting materials. The reaction
mixture was concentrated and the residue partitioned between
1 M hydrochloric acid and ethyl acetate. The residue of the
organic phase was purified over silica gel using toluene-ethyl
acetate as an eluent to give a yellow oil (3.0 g, 95%): 1H NMR
(CDCl3) 7.91 (d, J ) 16 Hz, Hâ), 7.60 (dd, J ) 8.4, 1.8 Hz,
H-6′), 7.52 (d, J ) 8.4 Hz, H-5), 7.42 (dt, J ) 7.5, 1.8 Hz, H-5′),
7.39 (d, J ) 15 Hz, HR), 7.02 (dt, J ) 7.5, 1.8 Hz, H-4′), 6.96
(d, J ) 8.7 Hz, H-3′), 6.50 (dd, J ) 8.4, 2.4 Hz, H-4), 6.44 (d,
J ) 2.4 Hz, H-3), 6.03 (m, CHdC), 5.41 and 5.22 (m, CH2dC);
13C NMR (CDCl3) 121.1 (CR), 139.0 (Câ), 193.9 (CdO), 117.6
(C-1), 160.4 (C-2), 98.5 (C-3), 163.1 (C-4), 105.5 (C-5), 130.6
(C-6), 125.6 (C-1′), 157.2 (C-2′), 113.1 (C-3′), 132.4 (C-4′), 117.5
(C-5′), 130.6 (C-6′), 69.4 (OCH2), 133.0 (CH)CH2), 117.4 (CHd
CH2), 55.5 (OCH3). Anal. (C20H20O4) C, H.
3,4-Dim et h oxy-4′-(p r op -2-en yloxy)ch a lcon e (59) was
prepared according to procedure E using 4-(allyloxy)acetophe-
none42 (1.76 g, 10 mmol) and 3,4-dimethoxybenzaldehyde (1.66
g, 10 mmol) as starting materials: yellow crystals (3.0 g, 99%);
mp 74.5-75 °C (ethanol); 1H NMR (CDCl3) 8.06 (H-2′ and
H-6′), 7.70 (d, J ) 15 Hz, H-â), 7.58 (d, J ) 15 Hz, H-R), 7.33
(d, J ) 2 Hz, H-2), 7.25 (dd, J ) 2, 8 Hz, H-6), 7.00 (m, H-3′
and H-5′), 6.91 (d, J ) 8 Hz, H-5), 6.04 (m, dCH-), 5.42 (m,
dCHH), 5.28 (m, dCHH), 4.60 (m, -CH2-), 3.87 and 3.83 (s,
CH3); 13C NMR (CDCl3) 119.2 (C-R), 143.0 (C-â), 187.9 (CdO),
130.9 (C-1), 109.9 (C-2), 151.0 (C-3), 148.8 (C-4), 110.9 (C-5),
122.7 (C-6), 127.4 (C-1′), 130.1 (C-2′ and C-6′), 113.9 (C-3′ and
C-5′), 161.7 (C-4′), 68.2 (CH2), 116.9 (dCH2), 132.6 (dCH-CH2),
54.9 and 54.8 (CH3). Anal. (C20H20O4) C, H.
2,4,2′-Tr im eth oxych a lcon e (60) was prepared according
to procedure E using 2-methoxyacetophenone (0.46 mL, 3.3
mmol) and 2,4-dimethoxybenzaldehyde (0.55 g, 3.3 mmol) as
starting materials: yellow crystals (0.76 g, 73%); mp 84.5-85
1
°C (ethanol); H NMR (CDCl3) 7.87 (d, J ) 16 Hz, H-â), 7.57
(dd, J ) 8, 2 Hz, H-6′), 7.51 (d, J ) 8 Hz, H-6), 7.44 (td, J )
6, 2 Hz, H-4′), 7.31 (d, J ) 16 Hz, H-R), 7.05-6.95 (m, H-3′
and H-5′), 6.50 (dd, J ) 8, 2 Hz, H-5), 6.43 (d, J ) 2 Hz, H-3),
3.84 and 3.79 (s, CH3O). Anal. (C18H18O4) C, H.
4-(Hexyloxy)a cetop h en on e. To a solution of 2.76 g (20
mmol) 4-hydroxyacetophenone and 1.46 g (10 mmol) of sodium
iodide in 30 mL of acetone was added 8.37 g (60 mmol) of
potassium carbonate and 9.77 g (80 mmol) of hexyl chloride.
The mixture was stirred at 70 °C for 72 h in a sealed glass
vessel. The mixture was then filtered and the precipitate
washed twice with 5 mL of acetone. The combined filtrates
were concentrated in a vacuum. The residue was dissolved
in 30 mL of ether and the solution washed twice with a molar
aqueous solution of sodium hydroxide. The ether phase was
dried (MgSO4) and concentrated in a vacuum. The residue
was distilled in a Kugelrohr to give 2.56 g (72%) of 4-(hexyl-
oxy)acetophenone as a colorless oil.
2,4-Dim eth oxy-4′-(h exyloxy)ch a lcon e (61) was prepared
according to procedure E using 4-(hexyloxy)acetophenone (0.73
g, 4 mmol) and 2,4-dimethoxybenzaldehyde (0.68 g, 4 mmol)
as starting materials: yellow crystals (0.93 g, 63%); mp 67.5-
68 °C (ethanol-water); 1H NMR (CDCl3) 8.04 (d, J ) 15.8 Hz,
H-â), 8.02 (m, H-2′ and H-6′), 7.57 (d, J ) 8.5 Hz, H-6), 7.56
(d, J ) 15.8 Hz, H-R), 6.95 (m, H-3′ and H-5′), 6.52 (dd, J )
8.5, 2.3 Hz, H-5), 6.47 (d, J ) 2.3 Hz, H-3) 4.02 (t, J ) 7 Hz,
CH2O), 3.89 and 3.85 (s, CH3O) 1.81 (pentet, OCCH2) 1.6-1.3
[m, (CH2)3], 0.91 (t, J ) 7 Hz, CCH3); 13C NMR (CDCl3) 117.3
(C-1), 162.8 (C-2), 98.4 (C-3), 160.3 (C-4), 105.3 (C-5), 130.8
(C-6), 131.4 (C-1′), 130.7 (C-2′, C-6′), 114.1 (C-3′, C-5′), 162.7
(C-4′), 68.2 (OCH2), 31.6, 29.1, 25.7, 22.6 (CH2), 14.1 (CCH3),
189.4 (CO), 120.2 (C-R), 139.5 (C-â), 55.5, 55.5 (CH3O). Anal.
(C23H28O4) C, H.
4′-(Hexyloxy)ch a lcon e (63) was synthesized according to
procedure E using 4-(hexyloxy)acetophenone (1.00 g, 4 mmol)
and benzaldehyde (0.46 mL, 4 mmol) as starting materials:
yellow crystals (0.69 g, 51.7%); mp 64.5-65 °C (ethanol-
water); 1H NMR (CDCl3) 8.02 (m, H-2′ and H-6′), 7.80 (d, J )
15 Hz, H-â), 7.7-7.6 (m, H-3, H-4, and H-5), 7.50 (d, J ) 15
Hz, H-R), 7.45-7.35 (m, H-2 and H-6), 6.97 (m, H-3′ and H-5′).
Anal. (C21H24O2) C, H.
2,6-Dim eth oxy-4′-bu toxych a lcon e (65) was synthesized
according to procedure E using 4-butoxyacetophenone (11.6
g, 60 mmol) and 2,6-dimethoxybenzaldehyde (10.0 g, 60 mmol)
as starting materials: yellow crystals (18.77 g, 91%); mp 101-
2,5,4′-Tr is(2-p r op en yloxy)ch a lcon e (71) was synthesized
according to procedure E using 2,5-bis(2-propenyloxy)benzal-
dehyde (2.18 g, 10 mmol) and 4-(2-propenyloxy)acetophenone42
(1.76 g, 10 mmol) as starting materials. The reaction mixture
was concentrated and the residue partitioned between hydro-
chloric acid and ethyl acetate. The residue of the organic phase
was purified over silica gel using toluene-ethyl acetate as
eluent to give a yellow oil (3.5 g, 90%): 1H NMR (CDCl3) 8.04
(d, J ) 15 Hz, Hâ), 8.00 (m, H-2′ and H-6′), 7.59 (d, J ) 15 Hz,
HR), 7.55 (d, J ) 6.4 Hz, H-6), 6.96 (m, H-3′ and H-5′), 6.53
(dd, J ) 2, 7 Hz, H-4), 6.48 (d, J ) 2 Hz, H-3), 6.0-6.2 (m,
dCH-), 5.2-5.4 (m, dCH2), 4.3-4.5 (m, -CH2); 13C NMR
1
102 °C; H NMR (CDCl3) 8.26 (d, J ) 15 Hz, H-â), 8.03 (m,
H-2′ and H-6′), 7.99 (d, J ) 15 Hz, H-R), 7.25 (t, J ) 7 Hz,
H-4), 6.98 (m, H-3′ and H-5′), 6.57 (d, J ) 7 Hz, H-3 and H-5),
6.05 (m, dCH), 4.00 (t, J ) 4 Hz, OCH2-), 3.90 (s, CH3-O),
1.75 and 1.49 (m, -CH2-), 0.97 (t, J ) 4 Hz, -CH3); 13C NMR
(CDCl3) 131.2 (C-R), 134.6 (C-â), 190.1 (CdO), 112.9 (C-1),
160.1 (C-2 and C-6), 103.5 (C-3 and C-5), 124.4 (C-4), 131.3
(C-1′), 130.6 (C-2′ and C-6′), 113.9 (C-3′ and C-5′), 160.1 (C-

4830 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 24
Nielsen et al.
(CDCl3) 120.6 (CR), 139.9 (Câ), 189.6 (CdO), 117.8 (C-1), 159.0
(C-2), 100.4 (C-3), 162.4 (C-4), 106.6 (C-5), 130.8 (C-6), 131.2
(C-1′), 130.8 (C-2′ and C-6′), 114.5 (C-3′ and C-5′), 161.9 (C-
4′), 69.0, 69.1, 69.3 (CH2), 118.3 (dCH2), 133.0, 132.9, 132.9
(dCH-CH2). Anal. (C24H24O4) C, H.
2,6-Dim eth oxy-4′-h yd r oxych a lcon e (73) was synthesized
according to procedure D using 1 g of 4-[(2-tetrahydropyranyl)-
oxy]acetophenone (1.00 g, 4.5 mmol) and 2,6-dimethoxybenz-
aldehyde (754 mg, 4.5 mmol) as starting materials: yellow
crystals (733 mg, 57%); mp 172-176 °C; 1H NMR (CDCl3) 8.21
(d, J ) 15 Hz, H-â), 7.92 (d, J ) 15 Hz, H-R), 7.92 (m, H-2′
and H-6′), 7.30 (t, J ) 7 Hz, H-4), 6.91 (m, H-3′ and H-5′),
6.58 (d, J ) 7 Hz, H-3 and H-5), 3.90 (s, CH3-O). Anal.
(C17H16O4) C, H.
3,5-Dim et h oxy-4′-h yd r oxych a lcon e (75). 2-Methoxy-
ethoxymethyl chloride (13.6 g, 11 mmol) and 4-hydroxy-
acetophenone (13.6 g, 10 mmol) were dissolved in dry acetone.
After addition of potasium carbonate (40 g), the mixture was
refluxed for 1 h. The mixture was filtered and the filtrate
concentrated. The residue was dissolved in ether (50 mL). The
ether solution was washed with aqueous sodium hydroxide (50
mL, 1 M) and concentrated to give 4-(methoxyethoxymethoxy)-
acetophenone. Compound 75 was synthesized according to
procedure D using 4-(methoxyethoxymethoxy)acetophenone
(2.24 g, 10 mmol) and 3,5-dimethoxybenzaldehyde (1.6 g, 10
mmol) as starting materials: yellow crystals (1.5 g, 50%); mp
123-127 °C (ethanol-water); 1H NMR (DMSO-d6) 8.03 (m,
H-2′ and H-6′), 7.74 (d, J ) 15 Hz, H-â), 7.63 (d, J ) 15 Hz,
H-R), 7.0-6.9 (m, H-3′, H-5′, H-2, and H-6), 6.55 (t, J ) 2 Hz,
H-4), 3.84 (s, CH3); 13C NMR (DMSO-d6) 122.1 (C-R), 142.1
(C-â), 187.4 (CdO), 138.0 (C-1), 105.7 (C-2 and C-6), 160.6 (C-3
and C-5), 101.7 (C-4), 129.0 (C-1′), 130.5 (C-2′ and C-6′), 114.8
(C-3′ and C-5′), 161.9 (C-4′). Anal. (C17H16O4) C, H.
as starting material: yellow crystals (70 mg, 25%); mp 165-
166 °C (methanol); 1H NMR (CD3CN-DMSO-d6) 7.98 (m, H-2′
and H-6′), 7.96 (d, J ) 15.8 Hz, H-â), 7.72 (d, J ) 7 Hz, H-6),
7.65 (d, J ) 15 Hz, H-R), 6.91 (m, H-3′ and H-5′), 6.59 (dd, J
) 7, 2 Hz, H-5), 6.57 (d, J ) 2 Hz, H-3), 3.90 and 3.84 (s,
CH3O); 13C NMR (CDCl3) 122.0 (C-R), 137.3 (C-â), 187.5 (CO),
116.0 (C-1), 159.6 (C-2), 97.7 (C-3), 161.4 (C-4), 105.3 (C-5),
129.5 (C-6), 119.0 (C-1′), 130.2 (C-2′, C-6′), 114.7 (C-3′, C-5′),
162.5 (C-4′). Anal. (C17H16O4) C, H.
2-Meth oxy-4-h yd r oxy-4′-(d im eth yla m in o)ch a lcon e (81)
was prepared according to procedure D using 2-methoxy-4-
[(tetrahydropyranyl)oxy]benzaldehyde23 (0.342 g, 1.0 mmol)
and 4-(dimethylamino)acetophenone (0.163 g, 1.0 mmol) as
starting materials: yellow crystals (0.16 g, 41%); mp 198-
199 °C (ethanol); 1H NMR [(CD3)2CO] 8.03 (m, H-2′ and H-6′),
8.04 (d, J ) 15.8 Hz, H-â), 7.70 (d, J ) 7 Hz, H-6), 7.72 (d, J
) 15 Hz, H-R), 6.78 (m, H-3′ and H-5′), 6.52 (dd, J ) 8, 2 Hz,
H-5), 6.56 (d, J ) 2 Hz, H-3), 3.91 (s, CH3O), 3.09 (s, NCH3);
13C NMR [(CD3)2CO] 118.1 (C-R), 136.5 (C-â), 187.1 (CO), 114.6
(C-1), 160.9 (C-2), 98.5 (C-3), 153.1 (C-4), 107.5 (C-5), 129.3
(C-6), 125.8 (C-1′), 129.7 (C-2′, C-6′), 110.2 (C-3′, C-5′), 159.8
(C-4′) 38.7 (CH3N), 58.7 (CH3O). Anal. (C18H19NO3) C, H, N.
4-(Dim eth yla m in o)-4′-h yd r oxych a lcon e (82) was pre-
pared according to procedure D using 4-[(tetrahydropyranyl)-
oxy]acetophenone (0.22 g, 1.0 mmol) and 4-(dimethylamino)-
benzaldehyde (0.15 g, 1.0 mmol) as starting materials: yellow
crystals (67 mg, 25%); mp 206-208 °C (ethanol); 1H NMR
[(CD3)2CO] 8.05 (m, H-2′ and H-6′), 7.72 (d, J ) 15.8 Hz, H-â),
7.67 (m, H-2 and H-6), 7.60 (d, J ) 15 Hz, H-R), 6.77 (m, H-3′
and H-5′), 6.93 (m, H-3 and H-5), 3.03 (s, NCH3); 13C NMR
[(CD3)2CO] 117.2 (C-R), 152.9 (C-â), 187.6 (CO), 123.7 (C-1),
131.0 (C-2 and C-6), 112.7 (C-3 and C-5), 157.6 (C-4), 144.6
(C-1′), 131.4 (C-2′ and C-6′), 116.0 (C-3′ and C-5′), 162.4 (C-4′)
38.7 (CH3N). Anal. (C17H17NO2) C, H, N.
2,4,6-Tr im eth oxy-4′-h yd r oxych a lcon e (76). P r oced u r e
G. 2,4,6-Trimethoxy-4′-(prop-2-enyloxy)chalcone (0.89 g, 2.5
mmol), prepared according to procedure D, was dissolved in
10 mL of methanol, and to the solution were added 2 mL of
water, 0.12 g of 10% of palladium on carbon, and 0.2 g of
p-toluenesulfonic acid. The mixture was refluxed for 4.5 h and
filtered and the filtrate poured into 10 mL of water. The
solution was concentrated in vacuo to one-half volume and
poured into 25 mL of ethyl acetate. The organic phase was
washed with 10 mL of a saturated aqueous solution of sodium
hydrogen carbonate and subsequently with 10 mL of a
saturated aqueous solution of sodium chloride and concen-
trated in vacuo to give 106 mg of a yellow gum. The gum was
chromatographed over silica gel 60 (Merck 0.063-0.200, 110
g) using petroleum ether-ethyl acetate (2:1, 500 mL; 1:1, 200
mL; 1:2, 700 mL) with 0.5% acetic acid as eluents to give 76
(54.7 mg, 6.6%), which was recrystallized from methanol to
give 28 mg of yellow crystals: mp 200-201 °C; 1H NMR
(CDCl3-DMSO-d6) 8.15 (d, J ) 15 Hz, H-â), 7.92 (m, H-2′ and
H-6′), 7.90 (d, J ) 15 Hz, H-R), 6.91 (m, H-3′ and H-5′), 6.16
(s, H-3 and H-5), 3.92 (s, CH3-O), 3.86 (s, CH3-O); 13C NMR
(CDCl3-DMSO-d6) 189.0 (CdO), 162.1 (C-4′), 160.8 (C-2),
160.7 (C-4), 133.7 (C-â), 129.8 (C-2′ and C-6′), 120.7 (C-R), 114.5
(C-3′ and C-5′), 105.5 (C-1), 89.8 (C-3), 55.0 and 54.6 (CH3O).
Anal. (C18H18O5) C, H.
Biologica l Testin g. The antileishmanial activities were
determined in vitro by incubating L. donovani promastigotes
with increasing concentrations of the chalcones as previously
described.7 The inhibitory effect on proliferation of human
lymphocytes was determined as previously described7 by
incubating phytohemmagglutinin A-stimulated lymphocytes
with increasing concentrations of the chalcones. In both cases
the IC50 values were estimated by fitting the data to the
equation:
E ) a/(1 + bSc) + d
(1)
in which S is the concentration of the analogues, E is the
percent inhibition compared to control, and a, b, c, and d are
constants.44
Sta tistica l Design . Principal component analysis was
performed by using SIMCA P 2.1.45 The variables were
autoscaled to unit variance.
Molecu la r Align m en ts. Low-energy conformations of the
chalcones were generated by using the MM3* force field in
MacroModel version 4.5.46 The chalcones adopt four low-
energy conformations reflecting rotations about C1′-CdO and
C1-Câ bonds. The energy differences between the four
conformations are calculated to be low (less than 1.5 kcal/mol)
for all chalcones. To get consistent molecular alignments for
the 3D-QSAR analyses, the conformation in which the lowest-
numbered substituent points in the same direction as the
carbonyl group was employed. The compounds were aligned
using the carbonyl oxygen and the carbon atoms of the R,â-
unsaturated carbonyl system as fitting points.
2,4,5-Tr im eth oxy-4′-h yd r oxych a lcon e (79) was prepared
according to procedure G using 0.89 g (2.5 mmol) of 2,4,5-
trimethoxy-4′-(prop-2-enyloxy)chalcone (0.89 g, 2.5 mmol)
synthesized from 4-(allyloxy)acetophenone and 2,4,5-trimethoxy-
benzaldehyde as starting materials: yellow crystals (130 mg,
1
17%); mp 184-186 °C; H NMR (CDCl3-DMSO-d6) 7.88 (d, J
) 15 Hz, H-â), 7.78 (m, H-2′ and H-6′), 7.32 (d, J ) 15 Hz,
H-R), 6.99 (s, H-6), 6.75 (m, H-3′ and H-5′), 6.38 (s, H-3), 3.78,
3.74, and 3.74 (3 s, CH3-O), 3.86 (s, CH3-O); 13C NMR (CDCl3-
DMSO-d6) 188.7 (CdO), 153.9 (C-5), 151.8 (C-2), 142.7 (C-4),
138.3 (C-â), 130.4 (C-2′ and C-6′), 129.8 (C-1′), 119.4 (C-R),
114.9 (C-1, C-3′, and C-5′), 110.8 (C-6), 96.4 (C-3), 56.1, 55.9
and 55.5 (CH3O). Anal. (C18H18O5) C, H.
2,4-Dim eth oxy-4′-h yd r oxych a lcon e (80) was prepared
according to procedure G using 2,4-dimethoxy-4′-(allyloxy)-
chalcone (326 mg, 1 mmol) prepared according to procedure E
GRID Ca lcu la tion s. The interaction energies were cal-
culated by using GRID (version 15)9 with a grid spacing of 1
Å and the grid dimensions (Å): Xmin/Xmax, -17.5/13.5; Ymin
/
Y
max, -13.5/15.0; and Zmin/Zmax, -8.5/10.5. Interaction energies
were calculated for three probes (OH2, C3, and N4) giving
57 600 variables for each chalcone.
GOLP E An a lyses. Partial least squares (PLS) models
were calculated by using GOLPE 3.02.12
Va r ia ble P r eselection . GOLPE rejects variables having
a total sum of squares (SS) lower than 10-7. The number of

Antileishmanial Chalcones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 24 4831
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region selection before applying variable selection. Variables
were selected according to their position in the weight space,
using a D-optimal design criterion. The variables containing
the most information and having the least correlation were
selected. The number of variables was reduced by no more
than 50% each time, until the R2 value starts to decrease.
Sm a r t Region Defin ition (SRD). A number of seeds
(1920) were selected using a D-optimal design criterion in the
weight space. Structural difference between different mol-
ecules in the series will be reflected in groups of variables,
and therefore groups were generated around each seed in the
3D-space. Variables with a distance of no more than 1 Å to
the seeds were included in the groups. If two neighboring
groups (with a distance smaller than 2 Å) contained the same
information, the groups were collapsed. The groups were used
in the variable selection procedure replacing the original
variables. The effect of the groups on the predictivity was
evaluated, and groups instead of individual variables were
removed from the data file.
Region Selection . The effect of the grouped variables on
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design (FFD) procedure. A number of reduced models (twice
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variables according to the FFD design. The effect of dummy
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the effect of the average dummy variable was the variable
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Ack n ow led gm en t. This work was partially funded
by the Danish Medical Research Council and the
European Commissions INCO-DC program. We are
grateful to Puk Holst, Anna Asanovski, and Sascha
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