Modifications of the α,β-double bond in chalcones only marginally affect the antiprotozoal activities

Article abstract of DOI:10.1016/S0968-0896(98)00051-0

Methods for selective alkylation of chalcones in the α- or β-position and for selective reduction of the α,β-double bond have been developed. The antiparasitic potencies of the α,β-double bond modified chalcones only differ marginally from the potencies of the parent chalcones indicating that the propenone residue only functions as a spacer between the two benzene rings, which are the true pharmacophore. Copyright (C) 1998 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(98)00051-0

BIOORGANIC &
MEDICINAL
CHEMISTRY
Bioorganic & Medicinal Chemistry 6 (1998) 937±945
Modi®cations of the ꢀ,ꢁ-Double Bond in Chalcones only
Marginally A€ect the Antiprotozoal Activities
Simon Feldbñk Nielsen,a,b Arsalan Kharazmic and S. Brùgger Christensena,*
aDepartment of Medicinal Chemistry, Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark
bState Serum Institute, Copenhagen, Denmark
cDepartment of Clinical Microbiology, University Hospital 7806, Tagensvej 20, DK-2200 Copenhagen, Denmark
Received 5 December 1997; accepted 21 January 1998
AbstractÐMethods for selective alkylation of chalcones in the a- or b-position and for selective reduction of the a,b-
double bond have been developed. The antiparasitic potencies of the a,b-double bond modi®ed chalcones only di€er
marginally from the potencies of the parent chalcones indicating that the propenone residue only functions as a spacer
between the two benzene rings, which are the true pharmacophore. # 1998 Elsevier Science Ltd. All rights reserved.
Introduction
a€ord compounds eciently inhibiting the growth of
parasites in concentrations that has little e€ect on
the proliferation of phytohaemagglutinin A stimulated
lymphocytes.23 A later medicinal chemical study based
on the hypothesis that chalcones are plasmodium pro-
tease inhibitors revealed that appropriate substitution of
the chalcone skeleton results in derivatives with nano-
molar IC50 values.24 This study, however, did not
encompass the selectivity of the prepared chalcones.
Together the performed studies have created a major
interest for chalcones as potential drugs against the dis-
eases malaria and leishmaniasis. A spreading resistance
against the drugs of ®rst choice have created an alarm-
ing need for new drugs against both of these diseases.25
Chalcones are a group of natural products characterised
by the presence of a 1,3-diphenylprop-2-en-1-one skele-
ton.1 The radical quenching properties of the phenolic
groups present in many of the naturally occurring chal-
cones have raised interest for using the compounds or
chalcone rich plant extracts as drugs or food pre-
servatives.2,3 In addition chalcones possess a broad
spectrum of biological activities including anti-
bacterial,4±6 anthelmintic,7 amoebicidal,8 antiulcer,9±11
antimitotic e€ects,12 and immunosuppressive activity,13,14
including inhibition of lipoxygenase,15±17 cyclooxygen-
ase,15 and interleukin biosynthesis.16 The bactericidal
e€ects have been related to the ability of the a,b-
unsaturated ketone to undergo a conjugated addition to
a nucleophilic group like a thiolo group in an essential
protein.5 We have shown that a number of naturally
occurring licorice chalcones in vitro inhibits the growth
of parasites belonging the species Leishmania18±20 and
Plasmodium,20,21 causing the diseases leishmaniasis and
malaria, respectively. In vivo licochalcone A (1, Scheme 1)
eciently clears leishmania infections in mice and
hamsters22 and plasmodium infections in mice21 without
showing any toxic side e€ects, indicating that the broad
spectrum of activities of the chalcones is not a general
cytotoxic e€ect. Additional in vitro studies have
revealed that structural modi®cations of chalcones
In spite of the increased interest for chalcones only very
few studies have been performed on the importance of
the double bond. Some dihydrochalcone glycosides have
been found to possess antimalarial activity, most likely
by blocking pores induced by the parasite in the host
cell membrane.26 Substitution on the a- or b-carbon
also a€ords less interesting compound.12,24 In contrast,
conversion of the double bond into a triple bond has
given interesting structures,1,27 some of which can be
used for inhibition of calcium uptake into lympho-
cytes27 or as antimitotic agents.12
A limiting factor for studying the consequences of
alkylating chalcones in the a- or b-position is that only
few methods for their preparation are known and all of
*Corresponding author.
0968-0896/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved
PII: S0968-0896(98)00051-0

938
S. F. Nielsen et al./Bioorg. Med. Chem. 6 (1998) 937±945
The present paper describes an ecient method for
introducing alkyl groups in the a- and b-positions of
chalcones. The activities of double bond modi®ed chal-
cones, including the dihydrochalcones and the acetyl-
enic analogues, are compared with the activities of the
parent compounds.
Scheme 1. (a) CF3COOH, (CH3CH2)3SiH, CH2Cl2, rt.
Chemistry
these have a limited scope. Published methods for
preparing b-methylchalcones include cycloaddition of
diazomethane to chalcones followed by pyrolysis,28 self
condensation of acetophenones catalysed by various
catalyst to give b-methylchalcones with identical
substitution pattern at the two aromatic rings,29±32
palladium assisted condensation of substituted a-1,2-
propadienylbenzenemethanols to halogenated benzenes,33
and conjugate addition of lithium dimethylcuprate to
give a dihydrochalcone, which is selenylated with
phenylselenyl bromide followed by oxidation and elimi-
nation of phenylselenoxide.34 In principle the last men-
tioned method can be used for introduction of alkyl
groups larger than methyl. In our hands, however,
this method failed because of limited solubility of the
starting material. a-Alkylated chalcones are generally
obtained by condensation of an arylketones with a
benzaldehyde. In general, however, the yields are poor
especially when larger arylketones are used as starting
material. A number of catalysts including alkali hydrox-
ides,35 piperidinium acetate36 and hydrochloric acid,37
have not increased the yields. A further drawback is the
dicult availability of the starting arylketones.
Reduction of the chalcone double bond in 1 was per-
formed by ionic hydrogenation using tri¯uoroacetic acid
as a proton donor and triethylsilane as a hydride donor
(Scheme 1).38 The poor polarisation of the side chain
double bond makes it inert towards this reagent. The
use of equimolar amounts of silane and chalcone pre-
vents reduction of the carbonyl group. The dihydro-
chalcone 2 is obtained in high yield and is easily isolated
from the reaction mixture.
The previous described methods for a- or b-substitution
of chalcones were found to be of limited value for
modifying 1 and 3. Instead 4, which is obtained in high
yield by conjugated addition of hydrogen cyanide to 3,
is found to be an excellent precursor for the a- as well as
b-chalcone anion (Scheme 2). Compound 4 has two
sets of activated protons, the protons a to the carbonyl
group and the protons a to the cyano group. Since the
a-protons of b-cyanoketones in general are more acti-
vated than the b-protons addition of two equivalents of
LDA followed by an alkyl halide a€ords b-alkylation.39
In the case of 4, however, addition of one equivalent of
Scheme 2. (a) NaCN, NH4Cl, DMF, 100 ꢀC; (b) LDA, THF, 78 ꢀC; (c) R-I; (d) NaH, toluene, re¯ux; (e) TBDMS-Cl, NaH, THF,
rt; (f) R-I, DMF, rt; (g) CsF, rt; (h) NaH, toluene, re¯ux; (i) NaH, toluene, re¯ux.

S. F. Nielsen et al./Bioorg. Med. Chem. 6 (1998) 937±945
939
LDA followed by addition of alkyl halide selectively
a€orded b-alkylation, indicating that the b-proton is
more activated. Attempts to a-alkylate the diainion of
4 by adding surplus of LDA followed by an alkyl
halide failed. Sodium hydride in boiling toluene
cleanly eliminated hydrogen cyanide from 5 or 6 to
give the b-alkylated chalcone 7 or 8.
Attempts to synthesise a-alkylated chalcones from 4 via
the dianion obtained by treatment with excess of sodium
hydride failed since elimination of hydrogen cyanide
a€ording the starting chalcone 3 was the dominating
reaction. This elimination, however, proved that the
a-protons were a€ected by sodium hydride. The a-alkyl-
ated chalcones were prepared in excellent yield via the
silylenol ether 9 formed by treatment of the mono anion
of b-cyanoketone 4 with t-butyldimethylsilyl chloride.40
In contrast to the trimethylsilylenol ether the t-butyl-
dimethylsilylenol ether can be isolated by column
chromatography. Under absolutely anhydrous condi-
tions the silylenol ether reacted with ¯uoride ions to
create a partial negative charge on the a-carbon which
was alkylated with iodomethane or iodopropane to give
the a-alkylated-b-cyano ketone 10 and 11, respectively.
Even though poor solubility of cesium ¯uoride in the
reaction medium only a€orded a low ¯uoride con-
centration and consequently a poor reaction rate, this
reagent was preferred for tetrabutylammonium ¯uoride,
since the latter reagent could not be obtained in a su-
cient dry state.41,42 The a-alkylated chalcones 12 and 13
are formed by sodium hydride provoked elimination of
hydrogen cyanide from 10 and 11, respectively.
Scheme 3. (a) PPh3, CBr4, CH2Cl2, 5 ꢀC; (b) 2 equiv. n-BuLi,
THF, 78 ꢀC; (c) H2O; (d) 4-allyloxybenzoylchloride, (PPh3)2
PdCl2-CuI, Et3N, toluene, rt.
benzoyl chloride44 in the presence of a bistriphenylphos-
phinpalladium(II)chloride copper(I) iodide complex
according to a previously described procedure for simi-
lar compounds.45 The alkynylbenzene 16 is obtained by
elimination of hydrogen bromide from the dibromo-
ethenylbenzene 15, followed by halogen-metal exchange
with n-butyllithium. Compound 15 is obtained by
reacting the ylide formed from tetrabromomethane and
triphenylphosphine with 14, as has been described for
analogous compounds.46
Biological Results
The antiparasitic activities were determined in vitro by
incubating Leishmania major promastigotes or erythro-
cytes infected with Plasmodium falciparum schizonts
with increasing concentrations of the double bond
modi®ed chalcones. The IC50 values were estimated by
®tting the data to eq (1):
As evidenced by NOESY experiments the a-alkylchal-
cones 12 and 13 and the b-methylchalcone 7 was only
obtained as the E-isomers, whereas the b-propyl-
chalcone 8 was obtained as the E- as well as the Z-iso-
mer. a,b-Unsubstituted chalcones are crystallising as the
E-isomers but under the in¯uence of daylight a solution
of the E-isomer is converted into a mixture of the two
geometric isomers, except when a hydroxy group is pre-
sent in the 2- or 4-position.43 The ease of light induced
isomerization of chalcones is of importance, because it
makes it dicult to distinguish between the biological
activities of the two geometric isomers. The stabilities of
the two b-propylchalcones, however, gives a possibility
for answering the question in this case.
Inh ˆ Max=ꢀ1 ‡ ꢀIC50†n=Concnn†
ꢀ1†
in which Concn is the concentration of the analogues,
Inh is the percent inhibition compared to control (Max)
and n is the Hill slope.47 The estimated IC50 values are
given in Table 1.
Discussion
Comparison of the IC50 values for the double bond
modi®ed chalcones with the values of the parent chal-
cones reveals that modi®cations of the double bond do
not signi®cantly a€ect the antiparasitic activities. The
only two compounds that show activities slightly di€er-
ent from those of the unmodi®ed chalcone are the (Z)-8
and the acetylenic analogue 17. Comparison of the IC50
values of licA (1) with the dihydro derivative 2 reveals
that saturation of the double bond causes some but no
Whereas it was possible to follow the concept that the
chalcone modi®ed at the double bond should be pre-
pared from the parent chalcone when the a- or b-alkyl-
ated chalcones and the dihydrochalcones were
synthesised we had to abandon from this principle when
preparing the acetylenic chalcone analogue 17
(Scheme 3). This compound was prepared by acylating
the appropriate alkynylbenzene with an appropriate

940
S. F. Nielsen et al./Bioorg. Med. Chem. 6 (1998) 937±945
Table 1. IC50 values against Leishmania major and Plasmo-
dium falciparum for double bond modi®ed and parent chalcones
a minor extent, indicating that the major part of the
di€erences in biological activity observed in series of
chalcones is caused by the di€erent substitution patterns
at the two benzene rings. At the present we are per-
forming a study on the biological activity of a series of
chalcones in order to develop 2D- and 3D-QSAR model,
which will reveal the substitution patterns a€ording
increased antiparasitic activities.
IC50‹SD (mM)
Compd
Leishmania
Plasmodium
1
13‹0
23‹2
56‹3
72‹4
84‹8
35‹3
54‹5
86‹9
13‹1
5.6‹0.6
7.3‹0.2
24‹2
36‹4
39‹4
10‹1
26‹1
37‹1
12‹1
2
3
7
(E)-8
(Z)-8
12
13
17
Experimental
The NMR spectra were recorded on a Bruker AC-200F
spectrometer. Splitting pattern are described as singlet
(s), doublet (d), triplet (t), quartet (q) and broad (b). An
asterisk indicates that signals with similar shifts might
be interchanged. Mass spectra were recorded on a JEOL
AX505W mass spectrometer. Melting points were deter-
mined on a Electrothermal melting point apparatus, and
were not corrected. Elemental analyses are within 0.4%
of the calculated values, unless otherwise stated. All
moisture sensitive reactions were performed under
nitrogen using oven dried glassware. Solvents were dried
before use: tetrahydrofurane (THF) was freshly distilled
from sodium/benzophenone, toluene was distilled and
stored over sodium. HPLC grade dimethylformamide
(DMF) was dried and stored over 4 A molecular sieves.
1-Iodopropane was distilled from CaH2 before use.
Cesium ¯ouride was dried at 150 ꢀC under oil pump
vacuum for 2 h and stored in a desiccator. Samples of
E-8, Z-8 and 13 for biological testing were puri®ed by
HPLC using a Waters 6000 A pump, a prepacked
Knauer column (16Â250 mm, LiChrosorp RP18, eluent:
acetonitrile±water) and a Shimadzu SPD 6A UV detec-
tor at 254 mn. Column chromatography was performed
on silica gel (Merck, 0.040±0.063 mm) using mixtures of
toluene and ethyl acetate as eluents.
drastic reduction of activity. Especially the remaining
activity of 2 and the high activity of 17 but also the
activities of the a- and b-alkylated analogues of 3 justify
the conclusion that the alkylating properties of the a,b-
unsaturated ketone is of minor importance for the anti-
parasitic activities of the chalcones. This conclusion
concerning antiparasitic e€ects is di€erent from pre-
vious suggestions, that the antibacterial e€ect is caused
by an inactivation of essential enzymes by a conjugated
addition of the chalcones to thiolo groups or other
nucleophilic centres.5
Based on modelling studies of the active site of Plasmo-
dium proteases a number of inhibitors, including chal-
cones, for these enzymes have been designed.24,48
According to this model, the pharmacophore of chal-
cones is the two aromatic rings and the a,b-unsaturated
ketone only functions as a spacer. The optimum length
of the spacer is calculated to be approximately the
length of four connected atoms. Leishmania mutants
lacking cysteine proteases were as sensitive to some of
the present chalcones as wild type parasites indicating
that cysteine proteases are not the target for these chal-
cones (data not shown). Even though, the data given in
Table 1 do con®rm that the pharmacophore is the two
aromatic rings and that the propanone chain just func-
tions as a spacer. Substituents on the spacer only have a
minor in¯uence of the antiparasitic activity. The descri-
bed antiparasitic activities of neolignans49 can also be
explained by this model, if it is assumed that the lignans
have the same target molecule as the chalcones.
1-(4-Hydroxyphenyl)-3-(5-(1,1-dimethylpropenyl)-4-hyd-
roxy-2-methoxyphenyl)propanone (2). Tri¯uoroacetic
acid (770 mL, 10.0 mmol) was slowly added to a stirred
suspension of licochalcone A50 (0.507 g, 1.5 mmol) in
dichloromethane (5 mL) and triethylsilane (240 mL,
1.5 mmol). Water was added after stirring for 2 h. The
aqueous phase was extracted with dichloromethane
(2Â10 mL) and the combined organic phases were con-
centrated in vacuo and the residue puri®ed by column
chromatography to give 2 (0.359 g, 70.4%) as colourless
crystals, mp 153.5±154.4 ꢀC (ethanol±water). 1H NMR
(CDCl3) d 7.91 (AA0 part of an AA0MM0 system, H20,
H60), 7.00 (s, H6), 6.90 (MM0 part of an AA0MM0 sys-
tem, H30, H50), 6.40 (s, H3), 6.24 (dd J=10.5, 17.7 Hz,
H200), 5.33 (dd, J=17.7, 1.0 Hz, H300trans), 5.28 (dd,
J=10.5, 1.0 Hz, H300cis), 3.76 (s, OCH3), 3.18 (bt,
J=7.0 Hz, Ha), 2.96 (bt, J=7.0 Hz, Hb), 1.38 (s, CH3).
13C NMR (CDCl3) d 200.6 (C=O), 160.8* (C40), 157.2*
The limited ¯exibility of the spacer in the E- and Z-
chalcones and in the acetylene analogue 17 causes a
di€erent spacial orientation of the two benzene rings,
whereas the ¯exibility of the propanone-spacer in 2
allows the two benzene rings to be located as in the E- as
well as in the Z-isomer. Apparently these confor-
mational di€erences only a€ect the biological activity to

S. F. Nielsen et al./Bioorg. Med. Chem. 6 (1998) 937±945
941
(C2), 154.0* (C4), 148.3 (C200), 130.9 (C20, C60), 129.8
(C10), 127.7 (C6), 123.4 (C5), 121.0 (C1), 115.4 (C30,
C50), 113.3 (C300), 100.7 (C3), 55.3 (OCH3), 39.7 (C100),
39.2 (Ca), 27.0 (CH3), 26.1 (Cb). Anal. (C21H24O4)
C, H.
(C3), 68.8 (C100), 55.5 (OCH3), 55.3 (OCH3), 45.2 (Ca),
37.1 (Cb), 25.2 (b-CH3). Anal. (C22H23NO4) C, H, N.
2-(2,4-Dimethoxyphenyl)-2-propyl-4-(4-(2-propenyloxy)
phenyl)-4-oxobutanenitrile (6). To a cold ( 78 ꢀC) solu-
tion of 4 (3.52 g, 10 mmol) in anhydrous THF (40 mL)
was slowly added LDA (11 mL of a 2 M soln in diethyl
ether, 22 mmol). After 5 min 1-iodopropane (4.8 mL,
50 mmol) was added and the reaction was stirred for
additional 10 min. The reaction was heated to rt
(30 min) and water (50 mL) was added. The mixture was
extracted with ethyl acetate (3Â50 mL) and the com-
bined organic phases were concentrated in vacuo and
the residue puri®ed by column chromatography, to give
6 (3.21 g, 81.6%) as colourless crystals, mp 86.1±87.1 ꢀC
2-(2,4-Dimethoxyphenyl)-4-(4-(2-propenyloxy)phenyl)-4-
oxobutanenitrile (4). A stirred solution of 2,4-dimeth-
oxy-40-allyloxychalcon, 3 (19.44 g, 60.0 mmol), sodium
cyanide (29.4 g, 600 mmol) and ammonium chloride
(3.24 g, 60 mmol) in DMF (240 mL) was heated to
100 ꢀC for 20 min. The reaction was allowed to cool to
rt, ®ltered, slowly added 4 M HCl (240 mL) and extrac-
ted with ethyl acetate (3Â200 mL). The combined
organic phase were concentrated in vacuo and the resi-
due freeze-dried to give 4 (17.8 g, 84.4%) as colourless
crystals, mp 112.2±112.7 ꢀC (ethanol±water). 1H NMR
(CDCl3) d 7.90 (AA0 part of an AA0MM0 system, H20,
H60), 7.37 (d, J=8.4 Hz, H6), 6.91 (MM0 part of an
AA0MM0 system, H30, H50), 6.50 (dd, J=8.4, 2.0 Hz,
H5), 6.47 (bs, H3), 6.03 (ddq, J=17.3, 10.5, 5.2 Hz,
H200), 5.42 (dd, J=17.3, 1.3 Hz, H300trans), 5.32 (dd,
J=10.5, 1.3 Hz, H300cis), 4.67 (dd, J=8.4, 5.0 Hz, Hb),
4.58 (bd, J=5.2 Hz, H100), 3.82 (s, OCH3), 3.79 (s,
OCH3), 3.58 (dd, J=17.4, 8.4 Hz, Ha), 3.40 (dd,
J=17.4, 5.0 Hz, Ha0); 13C NMR (CDCl3) d 193.6
(C=O), 162.4* (C40), 160.6* (C2), 156.8* (C4), 132.0
(C200), 129.9 (C20, C60), 129.0 (C6), 128.6 (C10), 120.6
(CꢁN), 117.7 (C300), 115.0 (C1), 114.1 (C30, C50), 104.2
(C5), 98.5 (C3), 68.4 (C100), 55.2 (OCH3), 55.0 (OCH3),
41.4 (Ca), 26.5 (Cb). Anal. (C21H21NO4) C, H, N.
(ethanol±water). H NMR (CDCl3) d 7.86 (AA0 part of
1
an AA0MM0 system, H20, H60), 7.61 (d, J=8.6 Hz, H6),
6.90 (MM0 part of an AA0MM0 system, H30, H50), 6.50
(dd, J=8.6, 1.5 Hz, H5), 6.40 (d, J=1.5 Hz, H3), 6.03
(ddq, J=17.3, 10.5, 5.2 Hz, H200), 5.41 (dd, J=17.3,
1.3 Hz, H300trans), 5.32 (dd, J=10.5, 1.3 Hz, H300cis),
4.59 (bd, J=5.2 Hz, H100), 4.10 (d, J=17.1 Hz, Ha), 3.78
(s, OCH3), 3.76 (s, OCH3), 3.56 (d, J=17.1 Hz, Ha0),
2.32 (td, J=12.6, 4.5 Hz, Hb1), 2.09 (td, J=12.6, 4.5 Hz,
Hb10), 1.53 (m, Hb2), 1.21 (m, Hb20), 0.91 (t, J=7.3 Hz,
Hb3); 13C NMR (CDCl3) d 194.4 (C=O), 162.4* (C40),
160.1* (C4), 157.1* (C2), 132.3 (C200), 130.6 (C6), 130.1
(C20, C60), 129.8 (C10), 122.7 (C1), 118.1 (C300), 117.1
(CꢁN), 114.2 (C30, C50), 104.0 (C5), 99.6 (C3), 68.7
(C100), 55.2 (OCH3), 44.5 (Ca), 43.8 (Cb), 39.4
(Cb1), 18.7 (Cb2),13.9 (Cb3). Anal. (C24H27NO4) C,
H, N.
2-(2,4-Dimethoxyphenyl)-2-methyl-4-(4-(2-propenyloxy)
phenyl)-4-oxobutanenitrile (5). To a cold ( 78 ꢀC) solu-
tion of 4 (3.52 g, 10 mmol) in anhydrous THF (40 mL)
was slowly added LDA (11 mL of a 2 M soln in diethyl
ether, 22 mmol). After 5 min, iodomethane (4.0 mL,
50 mmol) was added and the reaction was stirred for
additional 10 min. The reaction was heated to rt
(30 min) and water (50 mL) was added. The mixture was
extracted with ethyl acetate (3Â50 mL) and the com-
bined organic phases were concentrated in vacuo and
the residue puri®ed by column chromatography, to give
5 (2.85 g, 78.0%) as yellow crystals, mp 77.8±78.5 ꢀC
1-(4-(2-Propenyloxy)phenyl)-3-(2,4-dimethoxyphenyl)-but-
2-enone-1 (7). A solution of 5 (1.38 g, 3.8 mmol) in
anhydrous toluene (60 mL) was added sodium hydride
(1.53 g 60% dispersion, 38.0 mmol) and re¯uxed for
20 min. Water was added and the mixture was extracted
with ethyl acetate (2Â90 mL). The combined organic
phases were concentrated in vacuo and the residue pur-
i®ed by column chromatography, to give 7 (1.18 g,
91.4%) as yellow crystalls, mp 79.7±80.1 ꢀC (ethanol±
water). 1H NMR (CDCl3) d 7.97 (AA0 part of an
AA0MM0 system, H20, H60), 7.20 (d, J=9.0 Hz, H6),
6.96 (s, Ha), 6.91 (MM0 part of an AA0MM0 system,
H30, H50), 6.50 (m, H3, H15), 6.06 (ddq, J=17.3, 10.5,
5.2 Hz, H200), 5.41 (dd, J=17.3, 1.3 Hz, H300trans), 5.31
(dd, J=10.5, 1.3 Hz, H300cis), 4.59 (bd, J=5.2 Hz, H100),
3.83 (s, OCH3), 2.50 (s, b-CH3). In a NOESY spectrum
correlations between Ha and H20, H60 and H6 were
found. 13C NMR (CDCl3) d 190.4 (C=O), 161.8* (C40),
160.9* (C4), 157.7* (C2), 154.3 (Cb), 132.4 (C200), 130.4
(C20, C60), 129.6 (C6), 126.1 (C10), 123.3 (Ca), 118.6
(C1), 118.0 (C300), 114.1 (C30, C50), 104.1 (C5), 98.8
(C3), 68.7 (C100), 55.4 (OCH3), 55.3 (OCH3), 20.5
(b-CH3). Anal. (C21H22O4) C, H.
(ethanol±water). H NMR (CDCl3) d 7.88 (AA0 part of
1
an AA0MM0 system, H20, H60), 7.47 (d, J=8.5 Hz, H6),
6.91 (MM0 part of an AA0MM0 system, H30, H50), 6.50
(dd, J=8.5, 2.3 Hz, H5), 6.46 (d, J=2.3 Hz, H3), 6.04
(ddq, J=17.3, 10.5, 5.2 Hz, H200), 5.42 (dd, J=17.3,
1.3 Hz, H300trans), 5.32 (dd, J=10.5, 1.3 Hz, H300cis),
4.60 (bd, J=5.2 Hz, H100), 3.96 (d, J=17.1 Hz, Ha), 3.84
(s, OCH3), 3.80 (s, OCH3), 3.56 (d, J=17.1 Hz, H-a0),
1.95 (s, CH3); 13C NMR (CDCl3) d 194.2 (C=O),
162.6* (C40), 160.6* (C4), 157.6* (C2), 132.4 (C200),
130.3 (C20, C60), 129.8 (C10), 128.6 (C6), 120.4 (CꢁN),
119.3 (C1), 118.2 (C300), 114.4 (C30, C50), 104.3 (C5), 99.8

942
S. F. Nielsen et al./Bioorg. Med. Chem. 6 (1998) 937±945
1-(4-(2-Propenyloxy)phenyl)-3-(2,4-dimethoxyphenyl)-hex-
2-enone-1 (8). A solution of 6 (0.79 g, 2.0 mmol) in
anhydrous toluene (40 mL) was added sodium hydride
(0.15 g of 60% NaH in oil, 3.8 mmol) and re¯uxed for
90 min. Water was added and the mixture was extracted
with ethyl acetate (2Â50 mL). The combined organic
phases were concentrated in vacuo and the residue pur-
i®ed by column chromatography, to give E-8 (0.13 g,
oil. 1H NMR (CD3CN) d 7.41 (AA0 part of an
AA0MM0 system, H20, H60), 7.31 (d, J=8.3 Hz, H6),
6.90 (MM0 part of an AA0MM0 system, H30, H50), 6.58
(d, J=2.3 Hz, H3), 6.53 (dd, J=2.3, 8.3 Hz, H5), 5.99
(ddq, J=17.3, 10.5, 5.2 Hz, H200), 5.40 (dd, J=17.3,
1.5 Hz, H300trans), 5.36* (d, J=9.7 Hz, Ha), 5.27 (dd,
J=10.5, 1.5 Hz, H300cis), 5.20* (d, J=9.7 Hz, Hb), 4.54
(bd, J=5.2 Hz, H100), 3.87 (s, OCH3), 3.79 (s, OCH3),
1.00 (s, C(CH3)3), 0.04 (s, Si-CH3), 0.13 (s, Si-CH3);
13C NMR (CD3CN) d 160.4* (C2), 158.5* (C4), 156.9*
(C40), 151.9 (C-OSi), 132.9 (C200), 129.8 (C10), 128.2
(C6), 127.3 (C20, C60), 120.1 (C1), 116.4 (C300), 115.8
(CꢁN), 113.6 (C30, C50), 104.4 (C5), 102.5 (Ca), 98.2
(C3), 67.9 (C100), 54.9 (OCH3), 54.5 (OCH3), 26.1 (Cb),
24.5 ((CH3)3-C-Si), 17.3 (C-Si), 5.3 (CH3-Si), 5.4
(CH3-C-Si).
1
18.1%) and Z-8 (0.37 g, 51.0%) as yellow oils. E-8: H
NMR (CDCl3) d 7.97 (AA0 part of an AA0MM0 system,
H20, H60), 7.14 (d, J=9.0 Hz, H6), 6.93 (MM0 part of an
AA0MM0 system, H30, H50), 6.83 (s, Ha), 6.50 (d,
J=2.2 Hz, H3), 6.47 (dd, J=9.0, 2.2 Hz, H5), 6.03 (ddq,
J=17.3, 10.5, 5.2 Hz, H200), 5.41 (dd, J=17.3, 1.3 Hz,
H300trans), 5.32 (dd, J=10.5, 1.3 Hz, H300cis), 4.59 (bd,
J=5.2 Hz, H100), 3.81 (s, OCH3), 2.97 (t, J=7.5 Hz,
Hb1), 1.40 (6.tet, J=7.5 Hz, Hb2), 0.88 (t, J=7.5 Hz,
Hb3). In a NOESY spectrum correlations between Ha
and H20, H60 and H6 were found. 13C NMR (CDCl3) d
190.2 (C=O), 161.8* (C40), 160.7* (C4), 158.3* (C2),
157.6 (Cb), 132.4 (C200), 132.3 (C10), 130.4 (C20, C60),
130.0 (C6), 124.7 (C1), 124.0 (Ca), 117.8 (C300), 114.1
(C30, C50), 104.0 (C5), 98.6 (C3), 68.6 (C100), 55.3
(OCH3), 55.1 (OCH3), 34.4 (Cb1), 21.8 (Cb2), 14.0
(Cb3). HRMS (FAB+): 367.1937 (calcd C23H27O4:
367.1909).
2-(2,4-Dimethoxyphenyl)-3-methyl-4-oxo-4-(4-(propenyl-
oxy)phenyl)-butanenitrile (10). To a solution of 9 (1.16 g,
2.5 mmol) and iodomethane (313 mL, 5.0 mmol) in
anhydrous DMF (12.5 mL) was added cesium ¯ouride
(0.76 g, 5.0 mmol). The mixture was stirred for 6 h, water
(10 mL) was added and the mixture was extracted with
ethyl acetate (4Â20 mL). The combined organic phases
were concentrated in vacuo to give a mixture of the
two epimeric racem pairs of 10 (2.2 mmol, 89.0%) as
colourless crystals, mp 123.6±124.7 ꢀC (ethanol±water).
1H NMR (CDCl3) d 7.95/7.86 (AA0 part of an AA0MM0
system, H20, H60), 7.29/7.23 (d, J=9.1/9.1 Hz, H6),
6.94/6.90 (MM0 part of an AA0MM0 system, H30, H50),
6.42 (m, H5, H3), 6.03 (ddq, J=17.3, 10.5, 5.2 Hz, H200),
5.42 (dd, J=17.3, 1.3 Hz, H300trans), 5.32 (dd, J=10.5,
1.3 Hz, H300cis), 4.58 (bd, J=5.2 Hz, H100), 4.44/4.50 (d,
J=8.9/7.1 Hz, Hb), 4.03 (bp, J&8 Hz, Ha), 3.82/3.85 (s,
OCH3), 3.80/3.76 (s, OCH3), 1.10/1.39 (d, J=7.1/
7.1 Hz, CH3); 13C NMR (CDCl3) d 198.8/198.6 (C=O),
162.6* (C40), 160.8* (C2), 157.6/157.2* (C4), 132.2
(C200), 130.4 (C20, C60), 130.3 (C6), 128.4 (C10) 119.6
(CꢁN), 118.1 (C300), 114.7 (C1), 114.4 (C30, C50), 104.6/
104.2 (C5), 98.6/98.9 (C3), 68.7 (C100), 55.4 (OCH3), 55.2
(OCH3), 41.7/41.9 (Ca), 33.4/34.9 (Cb), 16.3/15.6
(CH3). Anal. (C22H23NO4) C, H, N.
Z-8: 1H NMR (CDCl3) d 7.82 (AA0 part of an AA0MM0
system, H20, H60), 6.90 (d, J=7.9 Hz, H6), 6.81 (MM0
part of an AA0MM0 system, H30, H50), 6.63 (s, Ha), 6.35
(dd, J=9.0, 2.3 Hz, H5), 6.31 (d, J=2.3 Hz, H3), 6.03
(ddq, J=17.3, 10.5, 5.2 Hz, H200), 5.41 (dd, J=17.3,
1.3 Hz, H300trans), 5.32 (dd, J=10.5, 1.3 Hz, H300cis),
4.59 (bd, J=5.2 Hz, H100), 3.70 (s, OCH3), 3.61 (s,
OCH3), 2.52 (t, J=7.1 Hz, Hb1), 1.45 (6.tet, J=7.1 Hz,
Hb2), 0.94 (t, J=7.1 Hz, Hb3). In a NOESY spectrum
correlations between Ha and H20, H60 and the allylic
protons in the propyl group were found. 13C NMR
(CDCl3) d 191.8 (C=O), 161.7* (C40), 160.3* (C4),
156.9* (C2), 152.7 (Cb), 132.6 (C200), 131.4 (C10), 130.7
(C20, C60), 129.7 (C6),124.5 (Ca), 121.8 (C1), 117.9
(C300), 113.8 (C30, C50), 103.9 (C5), 98.5 (C3), 68.6 (C100),
55.1 (OCH3), 55.0 (OCH3), 41.0 (Cb1), 21.0 (Cb2), 13.7
(Cb3). HRMS (FAB+): 367.1938 (calcd C23H27O4:
367.1909).
2-(2,4-Dimethoxyphenyl)-3-propyl-4-oxo-4-(4-(propenyl-
oxy)phenyl)butanenitrile (11). A solution of 9 (0.93 g,
2.0 mmol) and 1-iodopropane (390 mL, 4.0 mmol) in
anhydrous DMF (10 mL) was added cesium ¯ouride
(0.61 g, 4.0 mmol). The mixture was stirred for 6 h, water
(10 mL) was added and the mixture was extracted with
ethyl acetate (4Â20 mL). The combined organic phases
were concentrated in vacuo the residue was puri®ed by
column chromatography to give a mixture of the two
epimeric racemic pairs of 11 (1.2 mmol, 62.1%) as a
1-(2,4-Dimethoxyphenyl)-3-(4-(2-propenyloxy)phenyl)-3-
t-butyldimethylsilyloxy-prop-2-enenitrile (9). A solution
of 4 (3.5 g, 10 mmol) and t-butyldimethylsilyl chloride
(2.0 g, 13 mmol) in anhydrous THF (50 mL) was added
sodium hydride (1.6 g 60% dispersion, 40 mmol). After
violent stirring for 60 min, water (30 mL) was slowly
added. The mixture was extracted with ethyl acetate
(2Â50 mL) and the combined organic phases were con-
centrated in vacuo and the residue puri®ed by column
chromatography to give 9 (3.4 g, 74.0%) as a yellow
yellow oil. H NMR (CDCl3) d 7.87/7.80 (AA0 part of
1
an AA0MM0 system, H20, H60), 7.28/7.12 (d, J=9.0/
9.0 Hz, H6), 6.91/6.87 (MM0 part of an AA0MM0

S. F. Nielsen et al./Bioorg. Med. Chem. 6 (1998) 937±945
943
system, H30, H50), 6.43/6.36 (m, H5, H3), 6.03 (ddq,
J=17.3, 10.5, 5.2 Hz, H200), 5.42 (dd, J=17.3, 1.3 Hz,
H300trans), 5.32 (dd, J=10.5, 1.3 Hz, H300cis), 4.58 (bd,
J=5.2 Hz, H100), 4.44/4.34 (d, J=7.9/8.6 Hz, Hb), 4.10
(m, Ha), 3.84/3.85 (s, OCH3), 3.76/3.71 (s, OCH3), 1.8/
1.9 (m, Ha1), 1.2 (m, Ha2), 0.79/0.85 (t, J=7.2 Hz,
Ha3); 13C NMR (CDCl3) d 199.0/198.9 (C=O), 162.5*
(C40), 160.8* (C2), 157.4* (C4), 132.2 (C200), 130.4/130.5
(C10), 130.3/130.2 (C20, C60), 130.0/130.1 (C6), 120.0/
119.7 (CꢁN), 118.0 (C300), 114.1/114.5 (C1), 114.3/114.2
(C30, C50), 104.4/104.3 (C5), 98.6/98.9 (C3), 68.7 (C100),
55.4 (OCH3), 55.1 (OCH3), 47.0/46.3 (Ca), 35.2 (Cb),
32.9/33.2 (Ca1), 19.8/20.1 (Ca2), 13.7/13.8 (Ca3).
protons in the propyl group and H6 were found. 13C
NMR (CDCl3) d 198.1 (C=O), 161.5* (C40), 161.1*
(C4), 158.5* (C2), 140.1 (Ca), 135.0 (C200), 132.5 (Cb),
132.0 (C20, C60), 131.4 (C10), 130.0 (C6), 117.9 (C300),
117.6 (C1), 113.8 (C30, C50), 104.0 (C5), 98.1 (C3), 68.7
(C100), 55.3 (OCH3), 55.2 (OCH3), 30.1 (Ca1), 21.9
(Ca2), 14,2 (Ca3). HRMS (FAB+): 367.1949 (calcd
C23H27O4: 367.1909).
1,3-Dimethoxy-4-(2,2-dibromoethenyl)benzene (15). To a
solution of 14 (0.88 g, 5 mmol) and triphenyl phosphine
(2.62 g, 10 mmol) in anhydrous dichloromethane
(10 mL) was added a solution of tertabromomethane
(1.91 g, 5.8 mmol) in dichloromethane (3 mL), keeping
the temperature kept below 5 ꢀC. The reaction mixture
was stirred for additional 30 min, ®ltred and con-
centrated in vacuo and the residue puri®ed by column
chromatography to give 15 (1.27 g, 72.1%) as colourless
crystals. mp 147.0±147.8 ꢀC (ethanol±water). 1H NMR
(CDCl3) d 7.67 (d, J=8.4 Hz, H5), 7.51 (s, H10), 6.46
(dd, J=8.4, 2.5 Hz, H6), 6.38 (d, J=2.5 Hz, H2), 3.79 (s,
OCH3), 3.75 (s, OCH3); 13C NMR (CDCl3) d 161.2*
(C1), 157.8* (C3), 132.2 (C10), 129.6 (C5), 117.0 (C4),
104.0 (C6), 98.0 (C2), 87.5 (C20), 55.4 (OCH3), 55.3
(OCH3).
3-(2,4-Dimethoxyphenyl)-2-methyl-1-(4-(propenyloxy)phe-
nyl)prop-2-enone-1 (12).
A solution of 10 (50 mg,
0.14 mmol) in anhydrous toluene (10 mL) was added
sodium hydride (50 mg 60% dispersion, 12.5 mmol) and
re¯uxed for 2 h. Water (5 mL) was added, the mixture
was extracted with ethyl acetate (2Â10 mL) and the
combined organic phases were concentrated in vacuo.
The residue was puri®ed by column chromatography to
give 12 (43.1 mg, 91.0%) as colourless crystals, mp 60.3±
61.7 ꢀC (ethanol±water). H NMR (CDCl3) d 7.79 (AA0
1
part of an AA0MM0 system, H20, H60), 7.38 (d,
J=8.5 Hz, H6), 7.31 (bs, Hb), 6.95 (MM0 part of an
AA0MM0 system, H30, H50), 6.54 (dd, J=8.5, 2.3 Hz,
H5), 6.46 (d, J=2.3 Hz, H3), 6.03 (ddq, J=17.3, 10.5,
5.2 Hz, H200), 5.42 (dd, J=17.3, 1.3 Hz, H300trans), 5.32
(dd, J=10.5, 1.3 Hz, H300cis), 4.58 (bd, J=5.2 Hz, H100),
3.84 (s, OCH3), 3.77 (s, OCH3), 2.18 (d, J=1.4 Hz, a-
CH3). NOE: a-CH3-H20H60, a-CH3-H6; 13C NMR
(CDCl3) d 198.1 (C=O), 161.5* (C40), 161.4* (C4),
158.9* (C2), 136.7 (C200), 134.7 (Ca), 132.7 (C20, C60),
132.0 (Cb), 131.4 (C10), 130.9 (C6), 118.1 (C300), 118.0
(C1), 114.0 (C30, C50), 104.1 (C5), 98.2 (C3), 68.8 (C100),
55.4 (OCH3), 14.8 (a-CH3). Anal. (C21H22O4) C, H.
1,3-Dimethoxy-4-ethynylbenzene (16). A solution of 15
(1.10 g, 3.0 mmol) in THF (20 mL) was cooled to
78 ꢀC, and slowly added n-butyllithium (2.52 mL of a
2.5 M soln, 6.3 mmol). The mixture was stirred for
15 min, water added (10 mL) and extracted with ethyl
acetate (20 mL). The organic phase was concentrated in
vacuo and the residue puri®ed by column chroma-
1
tography to give 16 (0.296 g, 65.6%) as a clear oil. H
NMR (CDCl3) d 7.37 (d, J=9.0 Hz, H5), 6.44 (dd,
J=9.0, 2.3 Hz, H6), 6.42 (d, J=2.3 Hz, H2), 3.86 (s,
OCH3), 3.80 (s, OCH3), 3.25 (s, H20); 13C NMR
(CDCN) d 166.9* (C3), 166.7* (C1), 139.6 (C5), 110.1
(C6), 108.2 (C4), 103.2 (C2), 85.2 (C20), 85.1 (C10), 60.3
(OCH3), 60.1 (OCH3).
3-(2,4-Dimethoxyphenyl)-2-propyl-1-(4-(propenyloxy)phe-
nyl)prop-2-enone-l (13).
A solution of 11 (197 mg,
0.5 mmol) in anhydrous toluene (20 mL) was added
sodium hydride (200 mg 60% dispersion, 15 mmol) and
re¯uxed for 6 h. Water (10 mL) was added, the mixture
was extracted with ethyl acetate (2Â20 mL) and the
combined organic phases was concentrated in vacuo.
The residue was puri®ed by column chromatography to
give 13 (135.8 mg, 74.1%) as a yellow oil. 1H NMR
(CDCl3) d 7.88 (AA0 part of an AA0MM0 system, H20,
H60), 7.33 (d, J=8.4 Hz, H6), 7.16 (bs, Hb), 6.94 (MM0
part of an AA0MM0 system, H30, H50), 6.56 (dd, J=8.4.
2.4 Hz, H5), 6.47 (d, J=2.4 Hz, H3), 6.03 (ddq, J=17.3,
10.5, 5.2 Hz, H200), 5.42 (dd, J=17.3, 1.3 Hz, H300trans),
5.32 (dd, J=10.5, 1.3 Hz, H300cis), 4.58 (bd, J=5.2 Hz,
H100), 3.85 (s, OCH3), 3.72 (s, OCH3), 2.65 (bt, J&8 Hz,
Ha1), 1.55 (6.tet., J&8 Hz, Ha2), 0.94 (t, J&8 Hz,
Ha3). In the NOESY spectrum correlations between the
1-(4-(2-Propenyloxy)phenyl)-3-(2,4-dimethoxyphenyl)-2-
propynone-1 (17). A solution of 16 (1.3 mL, 6.15 mmol),
4-allyloxybenzoyl chloride7 (2.42 g, 12.3 mmol), cop-
per(I)iodide (0.24 g, 1.2 mmol) and bis[triphenylphos-
phine]dichloropalladium(II) (0.24 g) in toluene (9 mL)
and triethylamine (19 mL) was stirred for 16 h at rt The
mixture was washed with water and the organic phase
was concentrated in vacuo. The residue was puri®ed by
column chromatography to give 17 (0.56 g, 28.3%) as
yellow crystals, mp 109.8±110.6 ꢀC (hexane/ethyl acet-
ate). 1H NMR (CDCl3) d 8.26 (AA0 part of an AA0MM0
system, H20, H60), 7.54 (d, J=8.4 Hz, H6), 6.98 (MM0
part of an AA0MM0 system, H30, H50), 6.51 (dd, J=8.4,
2.3 Hz, H5), 6.46 (d, J=2.3 Hz, H3), 6.05 (ddq, J=17.3,
10.5, 5.2 Hz, H200), 5.44 (dd, J=17.3, 1.5 Hz, H300trans),

944
S. F. Nielsen et al./Bioorg. Med. Chem. 6 (1998) 937±945
5.33 (dd, J=10.5, 1.5 Hz, H300cis), 4.62 (bd, J=5.2 Hz,
H100), 3.94 (s, OCH3), 3.85 (s, OCH3); 13C NMR
(CDCl3) d 176.8 (C=O), 163.5* (C2), 163.3* (C40),
163.1* (C4), 136.3 (C200), 132.4 (C6), 132.0 (C20, C60),
130.8 (C10), 118.2 (C300), 114.4 (C30, C50), 105.5 (C5),
102.1 (C1), 98.3 (C3), 91.2* (Cb), 91.1* (Ca), 68.9 (C100),
55.9 (OCH3), 55.6 (OCH3). Anal. (C20H18O4) C, H.
Sciences. We thank Carl Erik Olsen, The Royal Veter-
inary and Agricultural University, for making the mass
determinations. This work was partially funded by a
grant from the European Commissions Science,
Research, and Development, INCO-DC programme.
References and Notes
Biological methods
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pounds; John Wiley: New York, 1981.
E€ect on Leishmania promastigotes. The e€fect of the
chalcones on promastigotes was assessed a described
elswhere.19,51 Brie¯y, progmastigotes of L. major (a
World Health Organization reference vaccine strain
originally isolated from a patient in Iran, MHOM/IL/
LRC-L 137) were incubated at 26 ꢀC in RPMI 1640
containing 25 mM HEPES, 4 mM l-glutamine, 0.02 mg
of gentiamicin per ml, and 10% heat inactivated fetal
calf serum in the presence of di€erent concentration of the
chalcones or the medium alone in 96-well ¯at-bottomed
microtiter plates (NUNC, Denmark). The chalcones
were added to the incubation medium by adding 10 mL
of an appropriate diluted dimethylsulfoxide solution.
After 2 h, 1 mCi of [3H]thymidine (New England
Nuclear, Boston, MA, USA) was added to each well.
Parasites were harvested 18 h later, and [3H]thymidine
incorporation was measured. All experiments were
performed eight times in triplicates.
2. Takagaki, R. Inventor. Extraction of Flavanoids from
Licorice for Pharmaceuticals, Cosmetics and Food. Patent.
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3. Hatano, T.; Kagawa, H.; Yasuhara, T.; Okuda, T., Chem.
Pharm. Bull. 1988, 36, 2090.
4. Okada, K.; Tamura, Y.; Yamamoto, M.; Inoue, Y.; Takagaki,
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E€ect on malaria parasites. The e€ect of the chalcones
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parum (kindly provided by D. Walliker, Edinburgh,
UK) was assessed by a modi®cation of the method
originally described by Jensen et al.52 Fifty microliters
of parasitized erythrocytes (parasitemia of approxi-
mately 1%) at a concentration of 5Â108 cell/mL and
®fty microliters of the medium containing the chalcone
were added into each well of 96-well ¯at-bottomed
microtiter plates (NUNC, Denmark). The cultures were
incubated for 48 h. Twenty four hours before termina-
tion of the cultures, 20 mL of [3H]-hypoxanthine (40 mCi/
mL, New England Nuclear, Boston, MA, USA) were
added to each well. The cultures were harvested on ®lter
paper by a cell harvester (Skatron, Liebyen, Norway)
and counted in a scintillation counter (Minaxi TriCarb
400, United Technologies, Packard Instruments Co. Inc
Rockville, MD, USA). All experiments were performed
at least four times in triplicate.
11. Kyogoku, K.; Hatayama, K.; Yokomori, S.; Saziki, R.;
Nakane, S.; Sasajima, M.; Sawada, J.; Ohzeki, M.; Tanaka, I.
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15. Sogowa, S.; Nihro, Y.; Ueda, H.; Izumi, A.; Miki, T.;
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16. Batt, D. G.; Goodman, R.; Jones, D. G.; Kerr, J. S.;
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Wlech, P. K.; Covington, M. B. J. Med. Chem. 1993, 36, 1434.
17. Koichi, H.; Akio, Y.; Shigehiro, M., Inventors. Chalcone
Derivatives and its Use. Patent. Japan. 1994, JP 0611 6206.
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Olsen, C. E.; Cornett, C.; Theander, T. G.; Kharazmi, A.
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Acknowledgements
19. Chen, M.; Christensen, S. B.; Blom, J.; Lemmich, E.;
Nadelmann, L.; Fich, K.; Theander, T. G.; Kharazmi, A.
Antimicrob. Agents. Chemother. 1993, 37, 2550.
Technical assistance of Puk Holst, Anne Asanovski and
Sascha Elmelund is greatly acknowledged. The NMR
spectrometer is a gift from the Velux Foundation, the
Thorkil Steenbeck Foundation, the Ib Henriksen
Foundation and the Danish Council for Technical
20. Nielsen, S. F.; Chen, M.; Theander, T. G.; Kharazmi, A.;
Christensen, S. B. Synthesis of Antiparasitic Licorice Chal-
cones. Bioorg. Med. Chem. Lett. 1995, 5, 449.

S. F. Nielsen et al./Bioorg. Med. Chem. 6 (1998) 937±945
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