New syntheses and potential antimalarial activities of new 'retinoid-like chalcones'

Article abstract of DOI:10.1016/j.ejmech.2005.05.008

A series of 'retinoid-like chalcones' and diverse derivatives relative to licochalcone A were synthesized from a new enaminone synthon. These syntheses occurred via a new aromatic annelation. These new derivatives have been tested in vitro as potential an

Full text of DOI:10.1016/j.ejmech.2005.05.008

European Journal of Medicinal Chemistry 41 (2006) 142–146
http://france.elsevier.com/direct/ejmech
Short Communication
New syntheses and potential antimalarial activities
of new ‘retinoid-like chalcones’
Alain Valla a,*, Benoist Valla a, Dominique Cartier a, Régis Le Guillou a, Roger Labia a,
Loic Florent b, Sébastien Charneau b, Joseph Schrevel b, Pierre Potier c
a
CNRS, FRE 2125, 6, rue de l’université, 29000 Quimper, France
b
Muséum national d’histoire naturelle, USM 504 biologie fonctionnelle des Protozoaires, 61, rue Buffon, 75231 Paris cedex 5, France
c
UPR 2301 CNRS, avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received 24 December 2004; revised and accepted 30 May 2005
Available online 07 November 2005
Abstract
A series of ‘retinoid-like chalcones’ and diverse derivatives relative to licochalcone A were synthesized from a new enaminone synthon.
These syntheses occurred via a new aromatic annelation. These new derivatives have been tested in vitro as potential antimalarial agents. The
4-hydroxy-chalcone-like (compound 6a, derived from β-ionone) exhibits a good and reproducible inhibitory effect on the in vitro culture of
Plasmodium falciparum, with an IC 50 lower than 10 μM for inhibition of 3H-hypoxanthine uptake by parasites (respectively, 4.93 and
8.47 μM for strains K1 and Thaï).
© 2005 Elsevier SAS. All rights reserved.
Keywords: Plasmodium falciparum; Anti-malaria compounds; Chalcones; Enaminones; Licochalcone A
1. Introduction
chalcone A has been identified as a potent inhibitor of mito-
chondrial functions in Leishmania, such as fumarate reductase
(FRD), succinate dehydrogenase (SDH), NADH dehydrogen-
ase (NDH), and succinate and NADH-cytochrome C reduc-
tases [12–14], but also of protease activities of Plasmodium
and Trypanosomes [7,15–18].
Starting from β-ionone (series a) or α-ionone (series b), we
have synthesized a series of new compounds from new enam-
inone synthons 1a, b (Fig. 2). The term enaminone was intro-
duced by Greenhill [19] in 1977 to describe an enamine of a
1,3-diketone.
Malaria is the major growing parasitic disease in the world
[1,2], at an alarming rate and concerns of the most important
public health in tropical and sub-tropical regions. Moreover,
the continuous evolution of drug resistance is a serious dilem-
ma and thus, the research of new advances in antimalarial che-
motherapy is a vital problem [3]. With the exception of artemi-
sin and its derivatives for the treatment of malaria [4], the
drugs actually utilized have significant toxicity and present ad-
verse side effects [5].
Some of these compounds could be considered as ‘retinoid-
like chalcones’ and possess structural analogy with licochal-
cone A (Fig. 3). Hence, this fact prompt us to test them, in
order to examine their potential antimalarial activity.
Recently, a lot of chalcones and derivatives have been pre-
viously synthesized and identified as potential antimalarials,
using both molecular modeling and in vitro testing against
the intact parasite (for recent Refs. see [6–10]). Licochalcone
A (Fig. 1), isolated from Glycyrrhiza inflata, was initially pro-
posed as a new antimalarial agent in 1994 [11] and a lot of
derivatives of this natural compound have been recently
synthesized and recognized as potential antimalarials. Lico-
* Corresponding author.
E-mail address: alain.valla@cegetel.net (A. Valla).
Fig. 1. Chemical structure of licochalcone A.
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.05.008

A. Valla et al. / European Journal of Medicinal Chemistry 41 (2006) 142–146
143
Table 1
In vitro assays of the given compounds performed using cultures with a 3–6%
parasitemia. Data are IC50 (μM) and “S.D.” standard deviations for the three
experiments
Strain K1
Mean
Strain Thaï
S.D.
Compound
2a
S.D.
6.23
Mean
15.39
6.09
19.11
15.46
23.82
29.82
34.77
44.58
40.64
4.93
Fig. 2. Enaminones synthons.
2b
6.32
6.12
8.25
9.34
11.82
7.30
1.65
0.05
18.87
43.54
52.48
43.16
60.29
54.37
8.47
5.34
9.71
9.71
8.97
6.91
7.45
1.99
0.04
3a
3b
4a
5a
5b
Fig. 3. Chalcones-like retinoids.
6a
Chloroquine
0.13
0.26
2. Chemistry
deviations. Thus, the activity is well reproducible. According
to Liu et al. [10] compounds with I50 values below 10 μM were
considered as having a “very good” activity, even if these va-
lues are higher than those of chloroquine.
Condensations of 1a, b with butyllithium [20] or the dia-
nion derived from ethyl acetoacetate [21] led, in good yield,
to compounds 2 and 3. Similarly, 5-(1-pyrrolidinyl)-4E-
penten-2-one reacted as reported above, leading to the corre-
spondent salicylaldehyde 4. Surprisingly, other selected dia-
nions derivatives afforded the substituted α,β-unsaturated ke-
tones 5-6, ‘retinoid analogs’ of chalcones (Fig. 4).
The sub-structural motif ‘4-hydroxy-phenyl’, present in li-
cochalcone A, has been recognized as an important factor of
activity in a recent work [7] despite a previous report which
shown (in other derivatives), that hydroxylated chalcones were
less active than the corresponding methoxy analogs [8,9]. Ser-
ies 3–5 which bear an ortho or meta phenolic group are con-
siderably less active. Unexpectedly, compounds 2 which have
no aromatic or phenolic subsistent possess some activity.
The targets of chalones on malaria parasites are not yet
clearly identified during the in vitro erythrocytic stages. Chal-
cones are considered as inhibitors of P. falciparum cysteine
protease falcipain [7,15]. It seems credible that the presently
studied compounds have the same mode of action, but this is
not demonstrated.
3. Results and discussion
These new enaminones synthons 1a or 1b allow to obtain
original retinoid compounds (3–6) substituted by an aromatic
ring. These syntheses proceed via a novel annelation procedure
with usually good yields (90–40%). Unexpectedly, compounds
4b and 6b were not isolated properly, and thus were not tested.
In case of derivatives 5 and 6, new retinoid-like chalcones were
obtained. From enaminones synthons, this synthesis procedure
was a new way to obtain aromatic substituted α,β-unsaturated
ketones.
In contrast to the potent inhibitory effect of chalones on the
mitochondrial functions of Leishmania, the action on Plasmo-
dium is questionable since the mitochondria of the blood-stage
malaria parasites was historically considered to be functionally
The results given in Table 1 show that the 4-hydroxy ‘reti-
noid-like’ chalcone 6a is the most active compound with low
IC50 (a 0.93 and 8.47 μM for the two strains) and low standard
Fig. 4. Series a: double bond between C5 and C6; Series b: double bond between C4 and C5.

144
A. Valla et al. / European Journal of Medicinal Chemistry 41 (2006) 142–146
quiescent. However recent bioenergetic experiments [24,25]
and data emerging from the genome project (http://plasmodb.
org) suggest that mitochondria of Plasmodium blood stages are
able to perform oxydative phosphorylation and they could har-
bor a full tricarboxylic acid cycle enzymes.
Product 4a was isolated after workup describe above. The
compound 4b was not obtained with sufficient yield and purity
(degradation during chromatography) for analyses ant tests.
4.1.5. General procedure for the preparation
Present efforts are dealing with synthesis of novel ‘retinoid-
like chalcone’ with variations on the cyclocitral part of the mo-
lecule.
of compounds 5a, b
Fifteen millimol of ethyl dimethylacrylate in 10 ml of anhy-
drous DME were added at –20 °C in 3 min under argon, at
15 mmol of LDA in 10 ml of anhydrous DME. The solution
was stirred at –20 °C for 15 min and 15 mmol of enaminone in
20 ml of anhydrous DME was rapidly. Product 5a, b were
isolated after workup describe above.
4. Experimental protocols
4.1. Chemistry
4.1.6. Procedure for the preparation of compound 6a
4.1.1. General procedures
All experiences were carried out under argon. All starting
products were purchased from Sigma-Aldrich. Melting points
were measured on a Leitz 350 heated stage microscope and
were not corrected. IR spectra were recorded on a Bruker IFS
Fifteen millimol of 3E-4-methoxy-3-buten-2-one in 10 ml
of anhydrous DME were added at –20 °C in 3 min under ar-
gon, at 15 mmol of LDA in 10 ml of anhydrous DME. The
solution was stirred at –20 °C for 15 min and 15 mmol of
enaminone in 20 ml of anhydrous DME was rapidly added.
Product 6a was isolated after workup describe above. The
compound 4b was not obtained with sufficient yield and purity
(degradation during chromatography) for analyses ant tests.
l
55 spectrometer. H and 13C NMR spectra were determined on
a Bruker Avance DPX 400 spectrophotometer (1H, 400 MHz,
13C, 100 MHz), using CDCl3 as solvent. Chemicals shifts were
expressed in ppm downfield from internal TMS and J values
were reported in Hertz. Analyses indicated by the symbols of
the elements were within 0.35 of the theoretical values. Analy-
tical thin layer chromatography was performed on a plastic
sheet (0.2 mm, silica gel 60 F254, Merck). Silica gel 60 (70–
230 mesh, Merck) was used for column chromatography. Mi-
croanalyses indicated by the symbols of the elements or func-
tions were within 0.4% of the theoretical values.
4.1.7. Structural data
1a: According to Hickmott [24] procedure. Yellow crystals
F 70 °C (95% IR: 2962; 2925; 1653; 1621; 1568; 1441; 1362;
1092; 997; 981. 1H RMN (CDCl3): 7.70 (d, 1H, J = 12.5, H11);
7.19 (d, 1H, J = 16, H7); 6.15 (d, 1H, J = 16, H8); 5.18 (d, 1H,
J = 12.5, H10); 3.10 and 2.90 (2s, 6H, N(CH3)2; 2.04 (m, 2H,
2-CH2); 1.77 (s, 3H, 5-CH3); 1.61 (m, 2H, 3-CH2); 1.47 (m,
2H, 4-CH2); 1.07 (s, 6H, 6-CH3). 13C RMN (CO): 186.8 (CH);
152.9; 138.1; 132.2; 96.2 (CH2): 39.6; 33.2; 19.0 (CH3): 28.8;
21.6. Anal. CHN C16H25NO.
4.1.2. General procedure for the preparation of compound 2
Under argon, 15 mmol of enaminone in 10 ml of anhydrous
DME was stirred at –20 °C and then, 15 mmol of the organo-
metallic compound in hexane (MeLi or BuLi) was added drop-
wise. The mixture was stirred and warmed to r.t., then heated at
reflux for 1 h. The crude mixture was cooled at 0 °C and hy-
drolyzed by a cold solution of 1 M HC1. After addition of
50 ml of ether, the organic layer was washed with brine and
dried over MgSO4. After distillation of the solvent under re-
duced pressure, the crude product was purified by column
chromatography (SiO2/CH2Cl2).
1b Beige crystals F 64 °C (95%). IR: 2920; 2862; 1662;
1
1645; 1621; 1545; 1420; 1357; 1269; 1256; 1094; 980. H
RMN (CDCl3): 7.60 (d, 1H, J = 12.5, H11); 6.53 (dd, 1H, J
= 15.4 and 9.8, H7); 6.04 (d, 1H, J = 15.4, H8); 5.40 (sa, 1H,
H3); 3.04 and 2.80 (2 broad s, 6H, N(CH3)2; 2.20 (d, 1H,
J = 9.5, H6); 1.98 (m, 2H, 2-CH2); 1.52 (s, 3H, 5-CH3); 1.46
and 1.13 (2m, 2H, 3-CH2); 0.86 and 0.80 (2s, 6H, 6-CH3).
13C RMN (CDCl3) (CO): 186.5 (CH); 153.5; 143.4; 132.8;
122.1; 95.8 (CH2): 31.6; 23.4 (CH3): 28.2; 27.3; 23.3. Anal.
CHN C16H25NO.
4.1.3. General procedure for the preparation of compound 3
Fifteen millimol of ethyl acetoacetate in 10 ml of anhydrous
DME were added at –20 °C in 3 min under argon, at 15 mmol.
of LDA in 10 ml of anhydrous DME. The solution was stirred
at –20 °C for 15 min and 15 mmol of enaminone in 20 ml of
anhydrous DME was rapidly added. Product 3 was isolated
after workup describe above.
2a: Yellow oil (70%). IR: 2958; 2928; 2862; 1666; 1632;
1
1613; 1456; 1341 987. H RMN (CDCl3): 6.92 (m, 1H, H11);
6.73 (dd, 2H, J = 15,5 and 9,7, H7); 6.35 and 6,29 (2d, 2H,
J = 15,5 and 15,6, H8 + H10); 5.48 (m, 1H, H3); 2.27 (m, 2H,
12-CH2); 2,05 (m, 2H, 2-CH2); 1.58 (s, 3H, 5-CH3); 1,47 and
1.20 (2m, 2H, 3-CH2); 1.47 (m, 2H, 13-CH2); 1.37 (m, 2H, 14-
CH2); 0.93 and 0.86 (2s, 6H, 6-CH3); 0.92 (t, J = 7.2, 15-CH3).
13C RMN (CDCl3) (CO): 189.2 (CH): 148.8; 148.4; 130.4;
128.9; 122.9 (CH2): 32.8; 31.6; 30.7; 23.4; 22.7 (CH3): 28.3;
27.2; 23.3; 14.3. Anal. CHN C18H28O.
4.1.4. Procedure for the preparation of compound 4a
Fifteen millimol of 5-(1-pyrrolidinyl)-4E-penten-2-one in
10 ml of anhydrous DME were added at –20 °C in 3 min under
argon, at 15 mmol of LDA in 10 ml of anhydrous DME. The
solution was stirred at –20 °C for 15 min and 15 mmol of
enaminone in 20 ml of anhydrous DME was rapidly added.
2b: Yellow oil (70%). IR: 2958; 2928; 2862; 1666; 1632;
1
1613; 1456; 1341 987. H RMN (CDCl3): 6.92 (m, 1H, H11);
6.73 (dd, 2H, J = 15.5 and 9.7, H7); 6.35 and 6.29 (2d, 2H,

A. Valla et al. / European Journal of Medicinal Chemistry 41 (2006) 142–146
145
J = 15.5 and 15.6, H8 + H10); 5.48 (m, 1H, H3); 2.27 (m, 2H,
12-CH2); 2.05 (m, 2H, 2-CH2); 1.58 (s, 3H, 5-CH3); 1.47 and
1.20 (2m, 2H, 3-CH2); 1.47 (m, 2H, 13-CH2); 1.37 (m, 2H, 14-
CH2); 0.93 and 0.86 (2s, 6H, 6-CH3); 0.92 (t, J = 7.2, 15-CH3).
13C RMN (CDCl3) (CO): 189.2 (CH): 148.8; 148.4; 130.4;
128.9; 122.9 (CH2): 32.8; 31.6; 30.7; 23.4; 22.7 (CH3): 28.3;
27.2; 23.3; 14.3. Anal. CHN C18H28O.
3a: Yellow oil (70%). IR: 2926; 2863; 1661; 1599; 1573;
1449; 1372; 1336; 1258; 1214; 1170; 1114. 1H RMN (CDCl3):
7.38 (dd, 1H, J = J′ = 8.2, H11); 7.04 (d, 1H, J = 8.2, H12); 6.94
(d, 1H, J = 16, H7); 6.92 (dd, 1H, J = 16.0 and 1.0, H10); 6.43
(dd, 1H, J = 16.0 and 1.0, H8); 4.46 (q, 2H, J = 7.1, 14-
COOCH2); 2.06 (m, 2H, 2-CH2); 1.79 (s, 3H, 5-CH3); 1.65
(m, 2H, 3-CH2); 1.51 (m, 2H, 4-CH2); 1.39 (t, 3H, J = 7.1, 14-
COOCH2CH3); 1.09 (s, 6H, 6-CH3). 13C RMN (CO): 171.0;
162.1 (CH): 134.0; 133.5; 130.0; 119.6; 116.2 (CH2): 61.7;
39.4; 32.7; 19.2 (CH3): 28.8; 21.4; 14.3. Anal. CHN
C20H26O3.
6a: Yellow oil (50%). IR: 3262; 2957; 2930; 1644; 1603;
1320; 1281; 1263; 1222; 1167; 839. H RMN (CDCl3): 8.35
1
(s, 1H, OH); 7.94 (d, 2H, J = 8.5, H11+H15); 7.62 (d, 1H, J
= 15.8, H7); 6.98 (d, 1H, J = 15.8, H8); 6.99 (d, 2H, J = 8.5,
H12+H14); 2.12 (m, 2H, 4-CH2); 1.86 (s, 3H, 5-CH3); 1.64 (m,
2H, 3-CH2); 1.50 (m, 2H, 2-CH2); 1.13 (s, 6H, 6-CH3). 13C
RMN (CO): 190.1; 163.6 (CH): 144.9; 131.7; 130.0; 126.0;
116.1; 115.8 (CH2): 40.3; 34.2; 19.3 (CH3): 29.3; 22.3. Anal.
CHN C18H22O2
4.2. Biology
4.2.1. Parasite cultures
The P. falciparum Thailand strain Thai and strain K1 were
used throughout this work. They gave similar results. Cultures
were grown in complete medium consisting of RPMI 1640
(Life technologies, Inc.) supplemented with 11 mM glucose,
27.5 mM sodium hydrogen carbonate (NaHCO3), 100 UI/ml
penicillin, 100 μg/ml streptomycin and 8% heat-inactivated hu-
man serum albumin, following the procedure of Trager and
Jensen [22]. Parasites were grown, at 37 °C, in human A+ red
blood cells (RBCs) at a 2% hematocrit, under a 3% CO2, 6%
O2 and 91% N2 atmosphere. The in vitro assays were per-
formed using cultures with a 3–6% parasitemia as determined
by counting parasites on Giemsa-stained smears.
3b: Yellow oil (80%). IR: 2960; 2917; 2854; 1660; 1601;
1
1572; 1449; 1372; 1335; 1278; 1254; 1215; 1115. H RMN
(CDCl3): 7.38 (m, 1H, H12); 6.99 (d, 1H, J = 15.4, H8); 6.93
and 6.89 (m, 2H, H13 + H14); 5.80 (dd, 1H, J = J′ = 9.5, H7);
5.43 (m, 1H, H3); 4.46 (q, 2H, J = 7.1, 14-COOCH2); 2.31 (d,
1H, H1); 2.06 (m, 2H, 5-CH2); 1.69 (s, 3H, 2-CH3); 1.54 and
1.25 (2m, 2H, 4-CH2); 1.23 (t, 3H, J = 7.1, 14-COOCH2CH3);
0.98 and 0.94 (2s, 6H, 6-CH3). 13C RMN (CDCl3) (CO):
171.3; 162.2 (CH): 134.5; 134.4; 132.6; 121.6; 120.4; 116.8
(CH2): 62.1; 32.2; 32.7; 27.5 (CH3): 27.3; 23.5; 15.7; 14.8.
Anal. CHN C20H26O3.
4a: Yellow oil (40%). IR: 2927; 2864; 1643; 1605; 1568;
1449; 1327; 1311; 1236; 1192; 1162; 762; 717. 1H RMN
(CDCl3): 10.34 (s, 1H, CHO); 7.46 (dd, 1H, J = J′ = 8.0,
H11); 6.99 (d, 1H, J = 8.0, H12); 6.86 (d, 1H, J = 8.0, H10);
6.85 (d, 1H, J = 16, H7); 6.55 (dd, 1H, J = 16, J′ = 1, H8); 2.06
(m, 2H, 2-CH2); 1.79 (s, 3H, 5-CH3); 1.65 (m, 2H, 3-CH2);
1.51 (m, 2H, 4-CH2); 1.08 (s, 6H, 6-CH3). 13C RMN (CO):
195.9 (CH): 137.5; 135.8; 127.8; 119.0; 116.7 (CH2): 39.8;
33.3; 19.6 (CH3): 29.3; 22.2; 15.7. Anal. CHN C18H22O2.
5a: Yellow crystals, mp: 90 °C (70%). IR: 2931; 2866;
1638; 1575; 1504; 1364; 1351; 1297; 1258; 1234; 1208; 795.
1H RMN (CDCl3): 7.71 (d, 1H, J = 15.6, H7); 7.70 (d, 1H,
J = 8.2, H15); 7.06 (d, 1H, J = 15.6, H8); 6.83 (s, 1H, H12);
6.73 (d, 1H, J = 8.2, H14); 2.37 (s, 3H 13-CH3); 2.14 (m, 2H,
2-CH2); 1.89 (s, 3H, 5-CH3); 1.67 (m, 2H, 3-CH2); 1.53 (m,
2H, 4-CH2); 1.16 (s, 6H, 6-CH3). 13C RMN (CDCl3) (CO):
193.3; 163.6 (CH): 145.1; 129.9; 124.4; 120.5; 119.0 (CH2):
40.3; 34.3; 19.3 (CH3): 53.3; 29.3; 22.4.
4.2.2. Inhibition tests
Increasing concentrations of the different retinoid-like chal-
cones, dissolved in methyl sulfoxide (DMSO), were tested for
their inhibitory effect toward the P. falciparum intraerythrocy-
tic development. Parasites were allowed to grow at 37 °C for
3
24 h in a candle jar, then 0.5 μCi H-hypoxanthine was added
per well. After an additional 24 h incubation period, plates
were freeze–thawed and harvested on filters. Dried filters were
moistened in scintillation liquid mixture (OptiScint, Hisafe)
and counted in a 1450 Microbeta counter (Wallac, Perkin
Elmer).
Growth inhibition in percent was calculated from the para-
site-associated radioactivity. Hundred percent 3H-hypoxanthine
incorporation was determined from control grown in the ab-
sence of the retinoid-like chalcones. Values for the IC50 were
determined according to DesJardins et al. [23]. Each mean con-
centration was estimated from three different experiment sets.
Acknowledgements
We are indebted to Dr. R.H. Dodd and to Dr. C. Deregnau-
court (CNRS), for helpful discussions.
5b: Yellow oil (90%). IR: 2957; 2918; 2865; 1643; 1585;
1
1504; 1365; 1301; 1246; 1149; 793. H RMN (CDCl3): 7.72
References
(d, 1H, J = 8.2, H15); 7.04 (dd, 1H, J = 15.0 and 7.0, H7); 6.98
(d, 1H, J = 15.0, H8); 6.82 (s, 1H, H12); 6.74 (d, 1H, J = 8.2,
H14); 2.37 (s, 3H 13-CH3); 1.90 (m, 2H, 2-CH2); 1.63 (s, 3H,
5-CH3); 1.55 and 1.24 (2 m, 2H, 3-CH2); 0.98 and 0.90 (2s,
6H, 6-CH3). 13C RMN (CDCl3) (CO): 193.1 (CH): 151.3;
130.1; 125.9; 123.3; 120.5; 119.0 (CH2): 31.5; 23.5 (CH3):
28.3; 27.3; 23.3; 22.4. Anal. CHN C19H24O2.
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