Synthesis of Novel G Factor or Chloroquine-Artemisinin Hybrids and Conjugates with Potent Antiplasmodial Activity

Article abstract of DOI:10.1021/acsmedchemlett.9b00669

A series of novel hybrids of artemisinin (ART) with either a phytormone endoperoxide G factor analogue (GMeP) or chloroquine (CQ) and conjugates of the same compounds with the polyamines (PAs), spermidine (Spd), and homospermidine (Hsd) were synthesized and their antiplasmodial activity was evaluated using the CQ-resistant P. falciparum FcB1/Colombia strain. The ART-GMeP hybrid 5 and compounds 9 and 10 which are conjugates of Spd and Hsd with two molecules of ART and one molecule of GMeP, were the most potent with IC50 values of 2.6, 8.4, and 10.6 nM, respectively. The same compounds also presented the highest selectivity indexes against the primary human fibroblast cell line AB943 ranging from 16 372 for the hybrid 5 to 983 for the conjugate 10 of Hsd.

Full text of DOI:10.1021/acsmedchemlett.9b00669

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Letter
Synthesis of novel G factor- or chloroquine-artemisinin
hybrids and conjugates with potent antiplasmodial activity
Dionissia A. Pepe, Dimitra Toumpa, Christiane André-Barrès, Christophe Menendez, Elisabeth Mouray,
Michel Baltas, Philippe Grellier, Dionissios Papaioannou, and CONSTANTINOS M ATHANASSOPOULOS
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/
acsmedchemlett.9b00669 • Publication Date (Web): 24 Mar 2020
Downloaded from pubs.acs.org on March 26, 2020
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Synthesis of novel G factor- or chloroquine-artemisinin hybrids and
conjugates with potent antiplasmodial activity
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Dionissia A. Pepe,† Dimitra Toumpa,† Christiane André-Barrès,‡ Christophe Menendez,‡
§
§
*
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Elisabeth Mouray, Michel Baltas,*, Philippe Grellier, Dionissios Papaioannou,† and
,
‡
*
†
,
Constantinos M. Athanassopoulos
†Synthetic Organic Chemistry Laboratory, Department of Chemistry, University of Patras, GR-26504 Patras,
Greece.
‡LSPCMIB, UMR-CNRS 5068, Université Paul Sabatier-Toulouse III, 118 route de Narbonne, 31062 Toulouse
CEDEX 9, France
§MCAM, UMR 7245 CNRS, Muséum National d’Histoire Naturelle, CNRS, CP52, 57 rue Cuvier, 75005 Paris,
France
ABSTRACT
A series of novel hybrids of artemisinin (ART) with either a phytormone endoperoxide G factor
analogue (GMeP) or chloroquine (CQ) and conjugates of the same compounds with the
polyamines (PAs) spermidine (Spd) and homospermidine (Hsd) were synthesized and their
antimalarial activity were evaluated using the CQ-resistant P. falciparum FcB1/Colombia
strain. The ART-GMeP hybrid 5 and compounds 9 and 10 which are conjugates of Spd and
Hsd with two molecules of ART and one molecule of GMeP, were the most potent with IC50
values of 2.6, 8.4 and 10.6 nM, respectively. The same compounds also presented the highest
selectivity indexes against the primary human fibroblast cell line AB943 ranging from 16,372
for the hybrid 5 to 983 for the conjugate 10 of Hsd.
Keywords: artemisinin, phytormones G-factors, chloroquine, hybrids, conjugates,
antimalarials
Malaria is a serious parasitic disease affecting every year approximately 200 million of humans
and causing almost half a million of deaths among infected individuals, according to WHO
(World Health Organization). Two main families of drugs are essentially being used for the
treatment of malaria. The first one is based on the alkaloid quinine (QN), its more potent
analogue chloroquine (CQ) and other quinoline-based antimalarials (e.g. mefloquine or
piperaquine), that have been developed thereafter (Figure 1).1,2 Unfortunately, P. falciparum
has already developed resistance for CQ and quinoline-based antimalarials. The second family
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is based on the natural product Artemisin (ART), that was first isolated from the Chinese
medicinal plant Artemisia annua L. in 1972 by Tu Youyou.3 ART is a sesquiterpene lactone
which incorporates an endoperoxide functionality demonstrated to be important for its
antimalarial activity.4 Because of its low bioavailability and an unfavorable pharmacokinetic
profile in vivo, intensive research efforts have been concentrated to the development of
improved hemisynthetic and fully synthetic ART analogs and derivatives. These efforts have
been culminated to the development of the C-10 oxa-substituted ART-based drugs, such as the
dihydroartemisinin (DHA), the lipophilic artemether, the hydrophilic sodium artesunate
(Figure 1) but more importantly to the corresponding C-10-carba-substituted ART with
improved ADMET properties. In that respect we can mention as attractive intermediate the
acid (1)8,9 or ART hybrids (see below), such as the anilide 2.9 In addition, C-10-carba-
substituted ART dimers or trimers, molecules with two or even three ART moieties connected
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through symmetric or asymmetric linkers have shown more potent biological (antimalarial or
11,12
anticancer) activity, depending from the nature of the linker.10,
Unfortunately, P.
falciparum resistance to ART derivatives in the South East Asia and particularly in Cambodia
has been observed. 13 In a seminal work,5 molecular marker of ART resistance that is the kelch
propeller protein (K13-propeller) has recently been identified and should be important in the
continuing efforts to restrain ART resistance.6,7
Inspired by ART, many groups developed methods for constructing trioxanes, entities
known to exhibit antimalarial activity in a similar manner to ART. Synthetic molecules of this
type with strong activities have been reported by the groups of Posner, Kepler, Singh,
Griesbeck.14, 15 Of high importance are also the efforts of Meunier’s group towards the
development of trioxaquines that are molecules based on the «covalent bitherapy», obtained
by covalent attachement of a trioxane entity to an aminoquinoline entity.17, 18
Since many years now, we have been interested in the naturally occurring phytormones
known as G- factors (G1, G2, G3) synthesized from syncarpic acid and incorporating an
endocyclic endoperoxide frame.19 The natural compounds and many synthetic analogs have
been synthesized.20, 21 Among them, the methylated compound G3Me (Figure 1) and its
derivatives have been shown to be potent antimalarial agents. In particular, the G3Me-derived
amino-endoperoxide spiro compound (endoperoxide GMeP, 3), suitable for the synthesis of G
factor hybrids through a succinic acid type linker (compound 4), has been developed and two
compounds incorporating also CQ proved to be very active.21
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OR3
O
OMe
O
O
O
O
O
O
O
O
O
O
R2
R1
O
10
O
10
O
N
O
O
R
7
O
X
8
9
Artemisinin
Dihydroartemisinin (DHA): X = OH (10RS)
Artemether: X= OMe (10S)
G1: R1 = Et, R2 = Me, R3 = H
G2: R1 = Me, R2 = Et, R3 = H
G3: R1 = R2 = Me, R3 = H
G3Me: R1 = R2 = R3 = Me
3: R = H
4: R = CO(CH2)2CO2H
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Sodium artesunate: X = OCO(CH2)2CO2Na (10S)
1: X = (CH2)2CO2H (10R)
2: X = (CH2)2CONHPh(4-F) (10R)
N
N
HO
N
N
N
N
H
HN
N
H
N
N
N
CF3
Cl
CF3
Cl
Cl
Piperaquine (PQ)
Chloroquine (CQ)
Mefloquine (MQ)
Figure 1. Molecular structures of known antimalarial agents.
Due to the emerging resistance of P. falciparum to artemisinins, WHO urgently
recommends the use of Artemisinin-based Combination Therapies (ACTs), which involve the
combination of a potent but short-lived ART derivative, e.g. artemether or sodium artesunate,
with one or even two longer-lasting partner drugs with a different mechanism of action, e.g. a
quinoline-based drug. Such combinations are for example ''artesunate-MQ'' or ''artesunate-MQ-
PQ''. Recently, the combination of two antimalarial drugs in one single molecular entity (coined
as hybrid or conjugate) has been described as being more efficient against diseases, such as
malaria and cancer. Hybrid molecules have probably less chance to develop drug resistance.1
Examples of ARTCQ (S1-S2)1,11 or a G-factorCQ (S3) hybrids,12 and of conjugates (S4-
S7) of ART with the naturally occurring polyamines (PAs), e.g. spermidine (Spd) or spermine
(Spm),22-
of relevance to the present work are provided in Figure S1 (Supporting
24
Information). It should be noted that naturally occurring and synthetic PAs, their analogs and
conjugates with other biologically active molecules are compounds with a variety of interesting
biological properties.25, 26 Conjugation of organic or bioorganic molecules with PAs has been
used as a mean to improve or combine the biological properties of the constituent molecules.
PAs can form the basis for the development of novel pharmaceuticals.27, 28
Accordingly, we now wish to report our first results on the synthesis of two types of
artemisinin hybrids/conjugates with the endoperoxide GMeP (3) or the 4-aminosubstituted 7-
chloroquinoline (ACQ) core of CQ, and the biological evaluation of their antimalarial potential.
Hybrids of the first type are the compounds 5, 6 and 7 (Figure 2) in which the two
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pharmacophores are joined with an amide bond using suitable linkers. For the sake of
comparison, the hybrid 819 of endoperoxide-GMeP (3) with ACQ was also synthesized.
Conjugates of the second type (Figure 2) are characterized by two molecules of ART and one
molecule of endoperoxide-GMeP (compounds 9 and 10) or ACQ (compounds 11 and 12). For
the sake of comparison, conjugates bearing two molecules of 3 and one molecule of ACQ (13
and 14) per molecule of PA were also synthesized.
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O
O
O
ART
ART
ACQ
O
ART
ACQ
GMeP
O
N
O
H
N
HN
N
O
N
O
O
O
N
H
OMe
O
N
N
O
GMeP
5
O
7
6
Cl
Cl
8
NH2
H2N
N
H
n
Spd: n = 1
Hsd: n = 2
GMeP
O
ART
ART
H
N
H
N
H
N
O
O
O
N
H
N
n
O
O
N
H
N
N
H
N
O
n
n
O
O
O
O
ART
ART
O
O
GMeP
GMeP
O
NH
NH
13: n = 1
14: n = 2
9: n = 1
10: n = 2
11: n = 1
12: n = 2
ACQ
ACQ
Figure 2. Structures of synthesized ARTendoperoxide GMeP (5), ARTACQ (6 and 7) and
ACQendoperoxide GMeP (8) hybrids, and ARTSpd and Hsd mixed conjugates with
endoperoxide GMeP and ACQ (9, 10 and 11, 12, respectively) and endoperoxide GMePSpd
and Hsd mixed conjugates with ACQ (13 and 14).
With these new hybrids/conjugates, we wished to determine the various factors affecting
their potential antimalarial activity, such as (a) the influence of the other antimalarial agents
linked with ART (comparing for example conjugates 5 and 6 or 9 and 11), (b) the structure
(conformationally restricted or not) or the length (Spd against Hsd chain) of the linker
(comparing for example conjugates 6 and 7 or 9 and 10, respectively) and (c) the number (one
against two) of ART or endoperoxide-GMeP residues in the conjugate (comparing for example
conjugates 5 and 9 or 8 and 13, respectively).
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The synthesis of ART conjugates 5, 6 and 7 requires the ART-derived carboxylic acid 1,
as key-intermediate. This compound was prepared (Scheme S1, Supporting Information) in
58% overall yield from ART, according to a five-steps published procedure.8,9 On the other
hand, endoperoxide GMeP (3) was synthesized from syncarpic acid in a sequence of three in
situ reactions (Mannich, dienol formation, oxygen uptake) followed by tert-butyloxycarbonyl
(Boc) deprotection in an overall yield of 50%, according to our published procedure
(Supporting Information).21 The required syncarpic acid was synthesized (Supporting
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Information), essentially through
a
reported procedure starting from 2',4',6'-
trihydroxyacetophenone.29 An alternative synthesis of this key-intermediate has been
described.19
Finally, the N1-(7-chloroquinolin-4-yl)ethane-1,2-diamine (15) and the 7-chloro-4-
(piperazin-1-yl)quinoline (16) were readily obtained in 56% and 76% yield, respectively, from
the commercially available 4,7-dichloroquinoline through the nucleophilic aromatic
substitution of the latter with 1,2-diaminoethane and piperazine, respectively (Scheme S1,
Supporting Information).21
Having in our hands all the above needed intermediates we proceeded to the synthesis of
the hybrids and conjugates as described in Schemes 1 and 2, respectively. Thus, condensation
of acid 1 with amines 3 (GMeP), 15 and 16, in the presence of the coupling agent HBTU and
DIPEA, produced unexceptionally the anticipated conjugates 5, 6 and 7 in 95%, 80% and 72%
yields, respectively (Scheme 1).
Art
Art
Art
15 / i
O
3 / i
NH
O
GMeP
O
OH
5
1
ACQ
(72%)
6
(80%)
16 / i
H
N
Art
NH2
HN
N
O
N
Cl
N
Cl
N
16
N
15
7
N
(95%)
Cl
O
O
H
N
H
3 / i
ACQ
N
OH
GMeP
ACQ
O
O
8
17
(72%)
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Scheme 1. Synthesis of ARTendoperoxide GMeP (5), ARTACQ (6 and 7) and
ACQendoperoxide GMeP (8) hybrids. Reagents and reaction conditions: (i) HBTU, DIPEA,
CH2Cl2, 0 oC to rt, 3-12 h.
9
10
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On the other hand, the synthesis of the conjugate 8 involved the initial reaction of amine
15 with succinic anhydride to give the corresponding carboxylic acid 17 in 100% yield. This
acid was then coupled with endoperoxide GMeP (3), also in the presence of HBTU and DIPEA,
to give conjugate 8 in 72% yield.
The synthesis of ART-Spd and Art-Hsd mixed conjugates 9, 10, 11 and 12 with
endoperoxide GMeP (3) or ACQ, as well as the endoperoxide GMeP-Spd and endoperoxide
GMeP-Hsd mixed conjugate 13 and 14 with ACQ, required the availability of suitably
31
protected triamines, such as the N1,N8-ditritylspermidine (18)30,
and N1,N9-
ditritylhomospermidine (19). These compounds are readily available, in 48% overall yield,
from butane-1,4-diamine (putrescine, Put) through a three-steps sequence, depicted in Scheme
S1 (Supporting Information).
Reaction of PA derivatives 18 and 19 with succinic anhydride gave the anticipated
monocarboxylic acid derivatives 20 and 21, respectively, in quantitative yield. These
compounds were then coupled with endoperoxide GMeP (3) in the presence of HBTU and
DIPEA to give the protected PA conjugates 22 and 23 in 40% and 67% yield, respectively. The
final products 9 and 10 were obtained in 64% and 40% yield, respectively, upon N-deprotection
followed by coupling with ART-derived acid 1, in the presence of HBTU and DIPEA (Scheme
2).
On the other hand, coupling of partially protected PAs 18 and 19 with the ACQ-derived
acid 17, in the presence of HBTU and DIPEA, produced PA conjugates 24 and 25 in 86% yield.
From these conjugates, the final products 11 and 12 were unexceptionally obtained in 61% and
32% yields upon detritylation and coupling with ART-derived acid 1. Similarly, the conjugates
13 and 14 were readily obtained (Scheme 2) from the same polyamine conjugates 24 and 25,
in 40% and 34% yield, respectively, upon deprotection of the latter followed by coupling with
endoperoxide GMeP-derived acid 4. The latter was readily obtained in 98% from the reaction
of endoperoxide GMeP and succinic anhydride (Scheme S1). The experimental details for the
synthesis of (a) all above described fragments, which are necessary for the assembly of the
proposed hybrids/conjugates, and (b) the final products, that is hybrids/conjugates 5-14, are
provided in the Supporting Information section.
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ACQ
ACQ
ACQ
8
9
HN
O
GMeP
HN
HN
ART
O
O
O
iii,1 / i
O
iii, 4 / i
10
11
12
13
14
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17
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Trt
HN
O
O
O
O
N
NH
Trt
HN
N
HN
N
NH
n
n
NH
n
O
O
24: n = 1; 86%
25: n = 2; 86%
O
11: n = 1; 61%
12: n = 2; 32%
13: n = 1; 40%
14: n = 2; 34%
ART
GMeP
17 / i
Trt
Trt
NH
ii
NH
HN
Trt
N
H
HN
Trt
N
n
O
18: n = 1
19: n = 2
O
OH
20: n = 1; 100%
21: n = 2; 100%
GMeP
3 / i
ART
O
O
O
Trt
iii, 1 / i
NH
HN
N
HN
Trt
N
n
NH
n
O
O
O
GMeP
ART
9: n = 1; 64%
10: n = 2; 40%
22: n = 1; 40%
23: n = 2; 67%
Scheme 2. Synthesis of ARTSpd and Hsd mixed conjugates with endoperoxide GMeP or
ACQ (9-12) and endoperoxide GMePSpd and Hsd mixed conjugates with ACQ (13 and 14).
Reagents and reaction conditions: (i) HBTU, DIPEA, CH2Cl2, 0 oC to rt, 3-12 h; (ii) succinic
anhydride, DMAP, CH2Cl2, 0 oC to rt, 12 h; (iii) 3-6% TFA in CH2Cl2, CF3CH2OH, 0 oC, 2-
12 h.
The synthesized conjugates were evaluated for their antiplasmodial activity against the
CQ-resistant P. falciparum FcB1/Colombia strain, according to published procedure.32,33 The
cytotoxicity of the compounds was evaluated using the primary human fibroblast cell line
AB943, also according to published procedure,34 which allowed the calculation of their
selectivity index (SI). In Table 1 (see also Table S1, Supporting Information), the measured
IC50 values or the % inhibition at 10 nΜ, in cases IC50 values could not be determined, and SIs
for the synthesized hybrids/conjugates are reported. IC50 values for ART, CQ and endoperoxide
GMeP (3) are also provided for the sake of comparison.
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Table 1. Evaluation of antiplasmodial activities of synthesized compounds with CQ-
resistant P. falciparum FcB1/Colombia strain and selectivity indexes (SI).
Compd
IC50 (nΜ) or
% inhibition
at 10 nM
SI
Compd
IC50 (nΜ) or
% inhibition
at 10 nM
SI
5
6
16,372

12
13
328
2.61.0
52.315.9
10
11
12
13
14
15
16
17
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11%
11%
>167
>167


7
14

8
144
2,108
983

ART
CQ
3
>4,545
347

124.340.4
8.43.7
10.62.3
33%
5513.6
727.4
>250
9
10
11
From Table 1 it is apparent that three out of seven of the synthesized hybrids/conjugates
of ART, incorporating one or two molecules of ART per hybrid/conjugate, are significantly
more potent (IC50 values ranging from 2.6 to 10.6 nM) than the parent compound, one
conjugate (12) was almost equipotent to ART but with at least 13 times lower SI value and the
rest showed low inhibition values (11-33%) at 10 nM. In particular the hybrid 5 of ART with
endoperoxide GMeP is the most potent in this series of compounds with an IC50 value 21 times
more potent than that of ART. Interestingly, this compound appears to be the safest compound
for use as antimalarial (SI = 16,372) as its SI is significantly higher than that of ART and ca.
8-17 times higher than the other two best synthesized conjugates (9 and 10). A comparison of
hybrid 5 (IC50=2.6, SI=16,372), bearing one molecule of ART, with the conjugates 9 (IC50=8.4,
SI=2,108) and 10 (IC50=10.6, SI=983), bearing two molecules of ART held together through a
PA chain, showed that a second ART molecule does not offer any particular advantage but also
leads to significant lowering of the SI value. On the other hand, comparison of the two
conjugates 9 and 10, differing only in the length of the PA chain, shows that the two compounds
have comparable IC50 but the one with the Hsd longer chain is ca. 2.1 times less safe than the
one with the Spd shorter chain. On the other hand, the hybrids 6 and 7 of ART with the CQ
core show identically low inhibition values (11% inhibition. at 10 nM), indicating that (a) the
CQ core does not offer any advantage to ART and (b) the structure of the diamine linker seems
not to be important for the antiplasmodial activity.
Comparison of the couples of conjugates 9 (IC50=8.4, SI=2,108) and 11 (33% inh. at 10
nM) and 10 (IC50=10.6, SI=983) and 12 (IC50=52.3, SI=460), bearing the Spd and the Hsd PA
core linkers respectively, two ART molecules and either a molecule of the endoperoxide GMeP
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or the CQ core, shows that the endoperoxide GMeP substructure is more important for
biological activity than the CQ core providing safer conjugates. Finally, the hybrid 8 of
endoperoxide GMeP with the CQ core is almost 2.5 times less active than ART having almost
10 times higher SI value. Moreover, comparison of conjugate 8 (IC50=124.3, SI=144) with the
conjugates 13 (IC50>167) and 14 (IC50>167), incorporating two molecules of endoperoxide
GMeP per molecule of conjugate, shows that the former is slightly more active than the latter
conjugates.
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In conclusion, a series of novel hybrids of ART with either endoperoxide GMeP or the ACQ
core of CQ and conjugates of the same compounds with the PAs Spd (an asymmetric PA) and
Hsd (a symmetric, with longer chain, PA), bearing either two molecules of ART or of
endoperoxide GMeP, were synthesized and their antiplasmodial activities and selectivity
indexes (SI) were evaluated using the CQ-resistant P.falciparum FcB1/Colombia strain and the
primary human fibroblasts cell line AB943 (for SI calculations), respectively. These studies
showed that the most potent combination with the highest SI value was that between ART and
the endoperoxide GMeP, in particular when the two molecules participate in the construct
(hybrid/conjugate) in the ratio 1:1, that is without the intervention of a PA chain. Combinations
between endoperoxide GMeP and ACQ seem not to be particularly effective, whereas the
length of the PA chain or the geometry (symmetric or asymmetric) of the construct, defined by
the PA used, does not seem to play any significant role. It seems that combinations of two
endoperoxide-type compounds can form the basis for the development of more potent and safer
antimalarial and therefore we are currently engaged in this line of research. Moreover, it should
be important to study in a further work, if the three hybrid compounds possessing two different
trioxane frames and different linkers between them can affect the spread of ART resistance and
mitigate its impact on malaria treatment.
Supporting Information. Synthetic and Bioassay protocols, as well as, copies of 1H and 13C
NMR spectra for all the synthesized compounds.
Acknowledgments: We thank the CNRS, the University Paul Sabatier and the University of
Patras for financial support. We thank the Erasmus+ Program for financing D. Pepe’s
traineeship and the University Paul Sabatier for financing the visiting professorship of Assoc.
Prof. C.M. Athanassopoulos, 2017. The authors would like to acknowledge networking
contribution by the COST Action CM1407 “Challenging organic syntheses inspired by nature
- from natural products chemistry to drug discovery”. The NMR Facility (ICT, Toulouse,
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France, http://ict.ups-tlse.fr/?RMN-103) and the Instrumental Analysis Lab (School of Natural
Sciences, University of Patras) are gratefully acknowledged for carrying out the NMR
analyses.
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Dedication: This article is dedicated to the memory of our good friend, Professor Maurizio
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Botta.
AUTHOR INFORMATION
Corresponding Authors
*C.M. Athanassopoulos; Email: kath@chemistry.upatras.gr ;
P. Grellier; Email: philippe.grellier@mnhn.fr
M. Baltas; Email: baltas@chimie.ups-tlse.fr
Author Contributions: D. Pepe and D. Toumpa carried out the synthetic work and prepared
the Supporting Information; C.M. Athanassopoulos conceived and directed the whole project
and wrote part of the manuscript; M. Baltas co-directed the project, followed up the program
in Toulouse and wrote part of the manuscript; C.A.B. followed up synthetic steps in Toulouse
of the G3 endoperoxide part and a final compound; C.M. supported analytical and preparative
chromatography; P. Grellier and E. Mouray directed and performed all biological studies; D.
Papaioannou supervised the polyamine synthetic part and wrote part of the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations: ACQ, 4-amino-7-chloroquinoline; ACTs, Artemisinin-based combination
therapies; ADMET, Absorption, Distribution, Metabolism, Excretion and Toxicity; ART,
artemisinin; Boc, tert-butoxycarbonyl; CQ, chloroquine; DIPEA, diisopropylethylamine;
DMAP, 4-Dimethylaminopyridine; GMeP, phytormone endoperoxide G-factor analogue;
HBTU, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; Hsd,
homospermidine; MQ; mefloquine; PAs, polyamines; PQ, piperaquine; Put, putrescine; QN,
quinine; rt, room temperature; SI, selectivity index; Spd, spermidine; Spm, spermine; TFA,
Trifluoroacetic acid; WHO, World Health Organization.
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Synthesis of novel G factor- or chloroquine-artemisinin hybrids and
conjugates with potent antiplasmodial activity
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Dionissia A. Pepe,† Dimitra Toumpa,† Christiane André-Barrès,‡ Christophe Menendez,‡
§
§
*
Elisabeth Mouray, Michel Baltas,*, Philippe Grellier, Dionissios Papaioannou,† and
,
‡
*
†
,
Constantinos M. Athanassopoulos
†Synthetic Organic Chemistry Laboratory, Department of Chemistry, University of Patras, GR-26504 Patras,
Greece.
‡LSPCMIB, UMR-CNRS 5068, Université Paul Sabatier-Toulouse III, 118 route de Narbonne, 31062 Toulouse
CEDEX 9, France
§MCAM, UMR 7245 CNRS, Muséum National d’Histoire Naturelle, CNRS, CP52, 57 rue Cuvier, 75005 Paris,
France
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