Journal of Organometallic Chemistry 723 (2013) 143e148

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Journal of Organometallic Chemistry

journal homepage: www.elsevier.com/locate/jorganchem

Cyrhetrenyl chalcones: Synthesis, characterization and antimalarial evaluation

Rodrigo Arancibia a, Christophe Biot b, Gerard Delaney b, Pascal Roussel c, Aurélie Pascual d,
Bruno Pradines d, A. Hugo Klahn a, *
a
Instituto de Química, Pontificia Universidad Católica de Valparaíso, casilla 4059, Valparaíso, Chile
b
Université Lille Nord de France, Université Lille1, Unité de Glycobiologie Structurale et Fonctionnelle, CNRS UMR 8576, IFR 147, 59650 Villeneuve d’Ascq Cédex, France
c
Université Lille Nord de France, Université Lille1, Unité de Catalyse et Chimie du Solide e UMR CNRS 8181, 59650 Villeneuve d’Ascq Cédex, France
d
Institut de Recherche Biomédicale des Armées, Unité de Parasitologie, Allée du Médecin-colonel Jamot, Parc le Pharo, 13007 Marseille, France

a r t i c l e i n f o a b s t r a c t

Article history: A new series of hybrid organometallic-organic and dinuclear organometallic chalcones containing the
Received 31 July 2012 cyrhetrenyl fragment were synthesised and characterised. 1H and 13C NMR spectra indicate that these
Received in revised form compounds adopt in solution an E-stereochemistry at the C]C bond, as well as the s-cis conformation of
20 August 2012
the enone moiety. A similar structure was also found for 1-ferrocenyl-3-cyrhetrenyl-2-propen-1-one (2i)
Accepted 22 August 2012
by X-ray crystallography in the solid state. The electron-withdrawing capability of the cyrhetrenyl group
on the ketonic carbonyl and olefinic (Cb) carbons correlate properly with the 13C shift of the carbon nuclei
Keywords:
of the enone moiety. Evaluation of in vitro antimalarial activity of the compounds against the
Cyrhetrenyl
Chalcones
chloroquine-susceptible strain 3D7 and the chloroquine-resistant strain W2 of Plasmodium falciparum,
Antimalarial indicates that these cyrhetrene conjugates are more active compared to their ferrocenic analogues.
Ó 2012 Elsevier B.V. All rights reserved.

1. Introduction antimalarials [10e18]. The activity of FQ is not associated with

Parasitic diseases such as malaria have significant impacts on
the world; especially in the developing countries of Africa where
infections spread over several millions of people and are one of the
significant causes of morbidity and mortality [1]. Antimalarial
drugs have been extensively used, notably 4-aminoquinolines
(chloroquine, CQ), amino-alcohol quinolines (mefloquine,
quinine) and artemisinin. Their efficacy is now severely compro-
mised by the spread of resistance, particularly in Plasmodium fal-
ciparum [2,3]. In this context, new compounds or at least new leads
are still needed.
In the last two decades, organometallic compounds have
attracted attention for medicinal applications [4e6], particularly as
antimalarial agents [7e9]. Indeed, bioorganometallics may over-
come resistance to established drugs via new and possibly metal-
specific modes of action. One of the most relevant examples of
a bioorganometallic compound with antimalarial activity is the
ferrocene analogue of CQ, named ferroquine (FQ, SSR97193), which
is highly active against all P. falciparum strains or field isolates
tested, regardless their levels of resistance to CQ. Moreover, FQ does
not show any significant cross-resistance with other currently used
* Corresponding author. Tel.: þ56 32 2274922.
E-mail address: hklahn@ucv.cl (A.H. Klahn).
transport proteins involved in quinoline resistance [19].
The development of new, effective, cheap and safe drugs for the
treatment of malaria has also been extended to a great number of
natural and synthetic compounds, including chalcones (Fig. 1).
The chemistry of purely organic chalcones and ferrocenyl chal-
cones is well documented [20e33]. Considerable interest has been
focused in their broad range of biological activities such as anti-
bacterial [20], antitumour [21], antioxidant [22], antihyperglycemic
[23] and anti-HIV [24]. Very recently, ferrocenyl chalcones have
also been studied with regard to their nematocidal activities [25],
fluorescent and electrochemical properties [26] as well as radical-
scavenging capacities [27], molecular chemosensor activities [28]
and as precursors for the syntheses of ferrocenyl pyrazolines
[29,30]. Ferrocenyl chalcones have been conveniently prepared by
a base-catalysed ClaiseneSchmidt condensation between ace-
tylferrocene and an appropriately substituted aromatic aldehyde or
ferrocene aldehyde and an appropriately substituted aromatic
ketone.
Even though ferrocenyl chalcones have been known since the
1950s [31], only in the last decade Go et al. have investigated
a series of ferrocenyl chalcones as potential antimalarial agents
[32,33]. These bioorganometallic compounds were synthesised and
evaluated for in vitro antimalarial activity against the chloroquine-
resistant strain K1 of P. falciparum. While the participation of the
ferrocene core in the biological activity is still not well understood,

0022-328X/$ e see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jorganchem.2012.08.024
144 R. Arancibia et al. / Journal of Organometallic Chemistry 723 (2013) 143e148

Fig. 1. Chemical structure of chalcones.

comparative studies on the behaviour of these compounds with

respect to the position of the ferrocenyl group in the enone moiety
have led to the conclusion that it plays an important role in the
observed antimalarial activity. The physicochemical properties of
the ring (lipophilicity, electronic effects and size) were supposed to
play an important role in transport and delivery processes.
Whereas several cymantrenyl chalcones have been known since
1978 [34,35], the corresponding rhenium analogues (cyrhetrenyl
chalcones) are practically unknown. To the best of our knowledge,
only the cyrhetrenyl chalcones 2geh have been described, but their
biological activity remains unreported [36]. We thus undertake
a general synthetic approach for the preparation of several hybrid
organometallic-organic and dinuclear organometallic-chalcones
with the aim of determining if the incorporation of an electron
withdrawing cyrhetrene unit into such compounds can result in
favourable changes in biological efficiency when compared with
their electron donating ferrocene analogues (Fig. 2).
2. Results and discussion
2.1. Synthesis of cyrhetrenyl chalcones
The cyrhetrenyl chalcones were easily accessible following the
procedure described for analogous ferrocenyl chalcones and cym-
antrenyl chalcones through a base-catalysed ClaiseneSchmidt
reaction (Scheme 1), i.e. the reaction of cyrhretenecarbox-
aldehyde or acetylcyrhetrene with organic aldehydes or ketones,
ferrocene aldehyde or acetylferrocene, in the presence of KOH. In all
cases the products were isolated as crystalline solids after crystal-
lization from CH2Cl2ehexane mixture.
The IR spectra of these derivatives showed some interesting
features since the frequencies of the carbonyl groups attached to Re
(n(CO)) allow us to distinguish isomeric cyrhetrenyl containing
chalcones, that is, when the cyrhetrenyl fragment is bound to either
the olefinic or the ketonic carbon of the enone moiety. In the first
case, both n(CO) appear at lower energies (2025, 1931 cm1) and
resemble those reported for the olefin-substituted cyclo-
Scheme 1. Synthesis of cyrhetrenyl chalcones 2.
clearer evidence of the electronic effects of organometallic groups
are obtained from the 13C NMR spectra of these compounds.
The cyrhetrenyl chalcones 2aei exhibit an E-stereochemistry at
the C]C bond as evidenced by the 1H NMR data (3JHH and d of the
two vinylic protons) in agreement with previously reported data
[34] (Table 1). In addition, we also observed the chemical shift of
the proton bound to Cb at a lower field than that measured for the
proton attached to Ca (Table 1). The E-stereochemistry of these
derivatives was also obtained from the X-ray structure of 2i (see
below) in the solid state.
The electronic effects of cyrhetrenyl and ferrocenyl fragments
attached to the ketonic carbonyl and olefinic (Cb) carbons of the
enone moiety were clearly established from the 13C NMR data
(Table 1). First, the 13C chemical shifts of the carbonyl carbon-
bound electron withdrawing cyrhetrenyl group, which are
remarkably comparable (z183.5 ppm), are shifted to higher field
when compared with its ferrocene analogue 2i (d 191.9) and with
those reported for FcCOCHCHR, (Fc ¼ (h5-C5H4)Fe(h5-C5H5), R ¼ 1-
naphthalenyl, 2-naphthalenyl and phenyl) which appear at about
192.9 ppm [33]. The increase in shielding is attributed to the
decreased polarisation of the p bond due to the electron with-
drawing effect of cyrhetrenyl, while the electron donating ferro-
cenyl has an opposite effect (downfield shift) [39].
On the other hand, the upfield shifts observed for the Cb
attached to cyrhetrenyl in 2aec, compared with the one measured
Table 1
Spectral data for cyrhetrenyl chalcones.

pentadienylrheniumtricabonyl [37], whereas in the second case, Cpds 1

H NMR 13
C NMR IR
the n(CO) values at about 2033 and 1941 cm1 are similar to the d Haa a
d Hb 3
JHa Hb dCaa dCba dCOb dCOc nCOc
values reported for the acetylcyrhetrene [38].
2a 6.94 7.20 15.4 122.7 137.2 190.0 192.9 2025
On the other hand, the IR spectra of these compounds also 1932
showed the nC ¼ O and nC ¼ C stretching frequencies in the range 2b 7.31 7.47 15.4 122.7 136.2 189.5 192.9 2026
1610e1630 cm1 in CH2Cl2. However, there is not a clear depen- 1932
dence of these frequencies on the position of electron-withdrawing 2c 7.17 7.41 15.6 118.3 136.2 188.0 192.9 2024
1931
cyrhetrenyl or electron-donor ferrocenyl groups in the enone 2d 6.92 7.82 15.6 119.3 137.9 183.9 191.7 2034
moiety. Similar observations have been found with the closely 1941
related cymantrenyl [34] and ferrocenyl chalcones [33]. Much 2e 7.02 7.84 15.6 120.1 138.1 183.7 191.6 2033
1941
2f 7.03 7.83 15.6 119.7 139.2 183.4 191.7 2034
1942
2g 6.54 7.42 15.6 120.6 136.4 182.9 191.6 2033
192.6 2024
1940
1931
2h 6.52 7.76 15.6 117.2 146.8 183.0 192.1 2033
1940
2i 6.75 7.39 15.6 123.8 132.1 191.9 193.1 2026
1932
a
Refers to ReCHb]CHaeCOeR0 .
b
Ketonic CO.
c
Fig. 2. Structure of the designed cyrhetrenyl chalcones. Terminal CO (Re-CO).
 R. Arancibia et al. / Journal of Organometallic Chemistry 723 (2013) 143e148 145

in 2h which is bound to a ferrocenyl group, follow the same trend to Table 2

that observed in several alkenes containing an electron with- In vitro susceptibilities of P. falciparum strains.

drawing or electron donating substituent directly bound to sp2 Compound Strain 3D7 Strain W2
carbons [40]. IC50 (mM) [95% CI] IC50 (mM) [95% CI]
Finally, it is worth noting that the chemical shifts of the carbon
2a >100 21.7 [15.5e30.4]
nuclei of C5-rings and terminal carbonyl ligand showed no notice- 2b 3.1 [2.9e3.3] 1.6 [1.5e1.8]
able shifts when compared with those reported for analogous 2c 31.4 [25.1e39.3] 11.4 [8.4e15.4]
derivatives. Chalcone complexes 2aei showed a strong molecular 2d 21.8 [20.0e23.8] 35.1 [28.1e43.8]
2e 7.2 [6.1e8.4] 10.4 [7.4e14.6]
ion in their mass spectra and the successive losses of the CO ligands.
2f 6.2 [4.7e8.2] 6.3 [4.7e8.4]
In order to compare the structural parameters of these 2g 18.9 [17.4e20.6] 16.0 [12.2e21.0]
compounds with the crystallographic data reported in literature 2i 26.9 [25.8e28.0] 27.4 [26.2e28.7]
[33], we undertook a crystallographic study of complex 2i (Fig. 3). IC50 (nM) [95% CI] IC50 (nM) [95% CI]
The structure of 2i is the first determination of an heterobimetallic FQ 3.6 [3.3e4.0] 6.8 [6.1e7.5]
chalcone. The E-stereochemistry at the C]C bond and the s-cis CQ 21 [19e26] 563 [478e658]
conformation of the enone moiety are similar in solution and in
IC50 was the geometric mean of at least three independent experiments 95%
solid state. Note that the asymmetric unit contains two molecules, confidence interval: 95% CI.
and that bond distances and angles are within the normal range
found in several ferrocenyl chalcones described in previous studies
[33]. The torsion angles O(1)eC(1)eC(2)eC(3) (13.2 ) and C(1)e When we compared these results with those reported for ferrocenic
C(2)eC(3)eC(4) (179.0 ) in the first molecule, and O(5)eC(22)e analogues, in all cases, we observed a better activity for the cyrhe-
C(23)eC(24) (10.6 ) and C(22)eC(23)eC(24)eC(25) (178.2 ) in the trenyl compounds. This phenomenon could be associated with
second one, reveal that the two Cp rings and enone linkage are better lipophilicity due to the cyrhetrenyl moiety compared to the
almost co-planar, indicating the possibility for electronic commu- ferrocenic derivates, as previously reported by us [41].
nication between the ferrocenyl and cyrhetrenyl groups. However, The dinuclear organometallic-chalcones (2g, 2i) were less active
the bond distances of the enone bridge C(1)eO(1) and C(2)eC(3) than the organometallic-organic hybrids. According to these
and the torsion angle that correlate the ferrocenyl and carbonyl results, the position of cyrhetrenyl group in the enone moiety and
groups C(16)eC(12)eC(1)eC(2) (12.9 ) suggest limited delocaliza- its electron withdrawing properties play an important role in the
tion [33]. In addition, the structure shows a syn conformation of the antimalarial activity of these conjugates [41].
two metallic fragments (FeCp vs Re(CO)3) with respect to the (h5- In addition, the IC50 values could be in relation to the low
C5H4)COCHCH(h5-C5H4) system, hence the syn-s-cis designation. polarisation of the ketonic carbonyl due to the cyrhetrenyl group.
This phenomenon would permit the interaction of cyrhetrenyl
chalcones with the amino acids of the catalytic centres of aspartate
2.2. In vitro antimalarial activities enzymes and cysteine proteases, which are involved in the degra-
dation of haemoglobin [42]. Different chalcones, such as prenylated
To study the influence of the cyrhetrene incorporation into chalcone derivatives of the plant Humulus lupulus or triazole chal-
chalcone skeleton with their antimalarial activity, compounds 2aei cones, were found to inhibit the formation of haem into haemozoin
were measured in vitro against the CQ-susceptible 3D7 clone and [43e45]. Chalcones were also shown to inhibit the activity of
CQ-resistant W2 clone. Table 2 shows the IC50 values found for the falcipain-2 [43,46].
new compounds. For comparison, we have also included the values
of CQ and FQ. 3. Conclusions
Of the two pairs of compound the 1-naphthalenyl and the phenyl
derivatives containing the cyrhetrene bound to the ketonic carbon The cyrhetrenyl fragment was successfully incorporated at two
(2d, 2f) resulted more active compared with the corresponding pairs ends of the chalcone skeleton. These compounds adopt an E-
with the cyrhetrene attached to the olefinic moiety (2a, 2c). The stereochemistry at the C]C bond as well as the s-cis conformation
opposite trend was observed for the 2-naphthalenyl hybrids (2b, 2e). of the enone moiety both in solution and in the solid state. The
electron-withdrawing capability of the cyrhetrenyl group on the
ketonic carbonyl and olefinic (Cb) carbons correlates properly with
the 13C shift of the carbon nuclei of the enone moiety. The results of
an in vitro antimalarial assay of the compounds against the
chloroquine-susceptible strain 3D7 and the chloroquine-resistant
strain W2 of P. falciparum indicated that they are more active
than their ferrocene analogues, therefore suggesting that the
electronic effects of the organometallic fragment play an important
role in the antimalarial activity of these types of bio-
organometallics. The enhanced antimalarial activity of cyrhetrenyl
vs ferrocenyl chalcones is probably associated with the better
lipophilic properties of the rhenium fragment.

4. Materials and methods

4.1. Chemistry

Fig. 3. Molecular structure of 2i in the crystal (one of the two molecules of the
asymmetric unit is shown). Selected bond lengths ( A) and angles ( ): C(1)eO(1)
1.228(17); C(2)eC(3) 1.328(17) and angles ( ): O(1)eC(1)eC(2)eC(3) 13.2; C(1)eC(2)e
C(3)eC(4) 179.0; C(16)eC(12)eC(1)eC(2) 12.9.
All manipulations were conducted under an N2 atmosphere
using Schlenk techniques. Complexes (h5-C5H4CHO)Re(CO)3 1a [47]
and (h5-C5H4COCH3)Re(CO)3 1b [48] were prepared according to
146 R. Arancibia et al. / Journal of Organometallic Chemistry 723 (2013) 143e148
a procedure in the literature. Ferrocenecarboxaldehyde (98%),
acetylferrocene (95%), 10 -acetonaphthone, 20 -acetonaphthone,
acetophenone, 1-naphthaldehyde, 2-naphthaldehyde, benzalde-
hyde (98%) and KOH were obtained from Aldrich. Solvents such as
CH2Cl2, hexane and ethanol were obtained commercially and
freshly dried as per requirement using the standard methods.
Infrared spectra were recorded in solution (NaCl cell) on a Perkine
Elmer FT-1605 spectrophotometer, and 1H and 13C NMR spectra on
a Bruker AVANCE 400 spectrometer. 1H NMR chemical shifts were
referenced using the chemicals shifts of residual solvent reso-
nances, and 13C chemical shifts to solvent peaks. Mass spectra were
obtained on a Thermo-Finnigan MAT 900XP, at the Facultad de
Ciencias Químicas y Farmacéuticas, Universidad de Chile.
4.2. General procedure
Cyrhetrenyl chalcones were prepared following a modification
of the procedure described by Go et al. [32]:
The substituted ketone (1 equiv.) and KOH (3 equiv.) were dis-
solved in anhydrous ethanol (10 mL) in a round bottomed flask and
stirred at room temperature for 0.5 h. An ethanolic solution of the
substituted aldehyde (1 equiv., 5 mL) was added dropwise and the
mixture was stirred at room temperature for 12 h. After this time,
an IR spectrum of the solution showed the complete disappearance
of the starting cyrhetrenyl complexes and the presence of the new
CO absorptions. The reaction was stopped by neutralising the stir-
red solution with 2 M HCl and it was extracted with CH2Cl2
(3  20 mL). The organic layer was dried with anhydrous Na2SO4
and removed by evaporation under reduced pressure to give
a purple or yellow solid. Recrystallisation from CH2Cl2/hexane (1:5)
at 18  C gave the corresponding chalcone (Yield: 70e95%).
4.2.1. 1-Naphthalenyl-3-cyrhetrenyl-2-propen-1-one (2a)
Yellow solid, Yield: 95% (67 mg, 0.13 mmol). IR (CH2Cl2, nCO,
cm1): 2025 (s); 1932 (s). 1H NMR (CDCl3) d: 5.38 (t, 2H, J ¼ 2.2 Hz,
C5H4); 5.71 (t, 2H, J ¼ 2.2 Hz, C5H4); 6.94 (d, 1H, J ¼ 15.4 Hz, CH]CH);
7.20 (d, 1H, J ¼ 15.4 Hz, CH]CH); 7.54 (m, 3H, AreH); 7.71 (d, 1H,
J ¼ 8.2 Hz, AreH); 7.90 (m, 1H, AreH); 7.99 (d, 1H, J ¼ 8.2 Hz, AreH);
8.27 (d, 1H, J ¼ 7.8 Hz, AreH). 13C NMR (CDCl3) d: 83.9 (C5H4); 84.5
(C5H4); 98.1 (C5H4ipso); 122.7 (COeCH]CH); 124.3 (AreC); 126.9
(AreC); 127.8 (AreC); 128.6 (AreC); 128.7 (AreC); 129.5 (AreC);
130.1 (AreC); 133.5 (AreC); 135.9 (AreC); 135.5 (AreC); 137.2
(COeCH]CH); 190.0 (CO-ketone); 192.9 (CO-Re). Mass spectrum
(based on 187Re) m/z: 516 [Mþ]; 488 [Mþ  CO]; 432 [Mþ  3CO].
Anal. (%) Calc. for C21H13O4Re: C 48.93, H 2.52; found: C 48.96, H 2.53.
4.2.2. 1-(2-Naphthalenyl)-3-cyrhetrenyl-2-propen-1-one (2b)
Yellow solid, Yield: 95% (67 mg, 0.13 mmol). IR (CH2Cl2, nCO,
cm1): 2026 (s); 1932 (s). 1H NMR (CDCl3) d: 5.43 (t, 2H, J ¼ 2.2 Hz,
C5H4); 5.82 (t, 2H, J ¼ 2.2 Hz, C5H4); 7.31 (d, 1H, J ¼ 15.4 Hz, CH]
CH); 7.47 (d, 1H, J ¼ 15.4 Hz, CH]CH); 7.60 (m, 2H, AreH); 7.89 (m,
2H, AreH); 8.00 (m, 2H, AreH); 8.45 (s, 1H, AreH). 13C NMR (CDCl3)
d: 84.9 (C5H4); 85.5 (C5H4); 98.1 (C5H4ipso); 122.7 (COeCH]CH);
124.3 (AreC); 125.9 (AreC); 127.0 (AreC); 128.6 (AreC); 128.8
(AreC); 129.5 (AreC); 130.1 (AreC); 132.4 (AreC); 133.5 (AreC);
134.7 (AreC); 136.2 (COeCH]CH); 189.5 (CO-ketone); 192.9 (CO-
Re). Mass spectrum (based on 187Re) m/z: 516 [Mþ]; 488 [Mþ  CO];
432 [Mþ  3CO]. Anal. (%) Calc. for C21H13O4Re: C 48.93, H 2.52;
found: C 48.95, H 2.52.
4.2.3. 1-Phenyl-3-cyrhetrenyl-2-propen-1-one (2c)
Yellow solid, Yield: 95% (60 mg, 0.13 mmol). IR (CH2Cl2, nCO,
cm1): 2024 (s); 1931 (s). 1H NMR (CDCl3) d: 5.41 (t, 2H, J ¼ 2.2 Hz,
C5H4); 5.78 (t, 2H, J ¼ 2.2 Hz, C5H4); 7.17 (d, 1H, J ¼ 15.6 Hz, CH]
CH); 7.41 (d, 1H, J ¼ 15.6 Hz, CH]CH); 7.48 (m, 2H, AreH); 7.58 (m,
1H, AreH); 7.93 (m, 2H, AreH). 13C NMR (CDCl3) d: 84.9 (C5H4); 85.5
(C5H4); 98.1 (C5H4ipso); 118.3 (COeCH]CH); 124.3 (AreC); 126.9
(AreC); 127.3 (AreC); 128.6 (AreC); 129.5 (AreC); 130.1 (AreC);
132.5 (AreC); 136.2 (COeCH]CH); 188.0 (CO-ketone); 192.9 (CO-
Re). Mass spectrum (based on 187Re) m/z: 466 [Mþ]; 438 [Mþ  CO];
382 [Mþ  3CO]. Anal. (%) Calc. for C17H11O4Re: C 43.87, H 2.36;
found: C 43.88, H 2.37.
4.2.4. 1-Cyrhetrenyl-3-naphthalenyl-2-propen-1-one (2d)
Yellow solid, Yield: 70% (48 mg, 0.1 mmol). IR (CH2Cl2, nCO,
cm1): 2032 (s), 1940 (s). 1H NMR (CDCl3) d: 5.38 (t, 2H, J ¼ 2.2 Hz,
C5H4); 5.71 (t, 2H, J ¼ 2.2 Hz, C5H4); 6.94 (d, 1H, J ¼ 15.4 Hz, CH]
CH); 7.20 (d, 1H, J ¼ 15.4 Hz, CH]CH); 7.54 (m, 3H, AreH); 7.71 (d,
1H, J ¼ 8.2 Hz, AreH); 7.90 (m, 1H, AreH); 7.99 (d, 1H, J ¼ 8.2 Hz,
AreH); 8.27 (d, 1H, J ¼ 7.8 Hz, AreH). 13C NMR (CDCl3) d: 83.9
(C5H4); 84.5 (C5H4); 98.1 (C5H4ipso); 122.7 (COeCH]CH); 124.3
(AreC); 126.9 (AreC); 127.8 (AreC); 128.6 (AreC); 128.7 (AreC);
129.5 (AreC); 130.1 (AreC); 133.5 (AreC); 135.9 (AreC); 135.5
(AreC); 137.2 (COeCH]CH); 190.0 (CO-ketone); 192.9 (CO-Re).
Mass spectrum (based on 187Re) m/z: 516 [Mþ]; 488 [Mþ  CO]; 432
[Mþ  3CO]. Mass spectrum (based on 187Re) m/z: 516 [Mþ]; 488
[Mþ  CO]; 432 [Mþ  3CO]. Anal. (%) Calc. for C21H13O4Re: C 48.93,
H 2.52; found: C 48.94, H 2.55.
4.2.5. 1-Cyrhetrenyl-3-(2-naphthalenyl)-2-propen-1-one (2e)
Yellow solid, Yield: 70% (48 mg, 0.1 mmol). IR (CH2Cl2, nCO,
cm1): 2032 (s), 1942 (s). 1H NMR (CDCl3) d: 5.46 (t, 2H, J ¼ 2.2 Hz,
C5H4); 6.14 (t, 2H, J ¼ 2.2 Hz, C5H4); 7.02 (d, 1H, J ¼ 15.4 Hz, CH]CH);
7.53 (m, 2H, AreH); 7.72 (d, 1H, J ¼ 15,4 Hz, CH]CH); 7.86 (m, 3H,
AreH); 8.01 (m, 2H, AreH). 13C NMR (CDCl3) d: 83.9 (C5H4); 84.5
(C5H4); 98.1 (C5H4ipso); 122.7 (COeCH]CH); 124.3 (AreC); 126.9
(AreC); 127.8 (AreC); 128.6 (AreC); 128.7 (AreC); 129.5 (AreC);
130.1 (AreC); 133.5 (AreC); 135.9 (AreC); 135.5 (AreC); 137.2
(COeCH]CH); 190.0 (CO-ketone); 192.9 (CO-Re). Mass spectrum
(based on 187Re) m/z: 516 [Mþ]; 488 [Mþ  CO]; 432 [Mþ  3CO].
Anal. (%) Calc. for C21H13O4Re: C 48.93, H 2.52; found: C 48.94, H 2.53.
4.2.6. 1-Cyrhetrenyl-3-phenyl-2-propen-1-one (2f)
Yellow solid, Yield: 70% (43 mg, 0.1 mmol). IR (CH2Cl2, nCO,
cm1): 2033 (s), 1940 (s). 1H NMR (CDCl3) d: 5.45 (t, 2H, J ¼ 2.2 Hz,
C5H4); 6.11 (t, 2H, J ¼ 2.2 Hz, C5H4); 6.92 (d, 1H, J ¼ 15.6 Hz, CH]
CH); 7.42 (m, 3H, AreH); 7.60 (m, 2H, AreH); 7.82 (d, 1H, J ¼ 15.6 Hz,
CH]CH). 13C NMR (CDCl3) d: 84.9 (C5H4); 85.5 (C5H4); 98.1
(C5H4ipso); 118.3 (COeCH]CH); 124.3 (AreC); 127.3 (AreC); 129.5
(AreC); 132.5 (AreC); 136.2 (COeCH]CH); 188.0 (CO-ketone);
192.9 (CO). Mass spectrum (based on 187Re) m/z: 466 [Mþ]; 438
[Mþ  CO]; 382 [Mþ  3CO]. Anal. (%) Calc. for C17H11O4Re: C 43.87,
H 2.36; found: C 43.90, H 2.36.
4.2.7. 1-Cyrhetrenyl-3-ferrocenyl-2-propen-1-one (2g)
Purple solid, Yield: 80% (57 mg, 0.1 mmol). IR (CH2Cl2, nCO,
cm1): 2033 (s), 1940 (s). 1H NMR (CDCl3) d: 4.18 (C5H5); 4.51 (t, 2H,
J ¼ 2.3 Hz, C5H4 [Fc]); 4.57 (t, 2H, J ¼ 2.3 Hz, C5H4 [Fc]); 5.43 (t, 2H,
J ¼ 2.2 Hz, C5H4 [Cy]); 6.07 (t, 2H, J ¼ 2.2 Hz, C5H4 [Cy]); 6.52 (d, 1H,
J ¼ 15.6 Hz, CH ¼ CH); 7.76 (d, 1H, J ¼ 15.6 Hz, CH]CH). 13C NMR
(CDCl3) d: 69.1 (C5H5); 69.9 C5H4 [Fc]); 71.7 C5H4 [Fc]); 78.0
(C5H4ipso [Fc]); 85.1 (C5H4 [Cy]); 87.7 (C5H4 [Cy]); 98.1 (C5H4ipso
[Cy]); 117.1 (COeCH]CH); 146.5 (COeCH]CH); 183.0 (CO-ketone);
192.1 (CO-Re). Mass spectrum (based on 187Re) m/z: 574 [Mþ]; 546
[Mþ  CO]; 517 [Mþ  2CO]; 490 [Mþ  3CO]. Anal. (%) Calc. for
C21H15O4FeRe: C 43.99, H 2.61; found: C 43.50, H 2.63.
4.2.8. 1-Cyrhetrenyl-3-cyrhetrenyl-2-propen-1-one (2h)
Yellow solid, Yield: 80% (76 mg, 0.11 mmol). IR (CH2Cl2, nCO,
cm1): 2032 (s), 2025 (s), 1940 (s), 1932 (s). 1H NMR (CDCl3) d: 5.41
 R. Arancibia et al. / Journal of Organometallic Chemistry 723 (2013) 143e148
(t, 2H, J ¼ 2.2 Hz, C5H4); 5.44 (t, 2H, J ¼ 2.2 Hz, C5H4); 5.76 (t, 2H,
J ¼ 2.2 Hz, C5H4); 6.04 (t, 2H, J ¼ 2.2 Hz, C5H4); 6.54 (d, 1H,
J ¼ 15.6 Hz, CH]CH); 7.43 (d, 1H, J ¼ 15.6 Hz, CH]CH). 13C NMR
(CDCl3) d: 84.9 (C5H4 [Cy]); 85.4 (2  C5H4 [Cy]); 85.9 (C5H4 [Cy]);
88.0 (C5H4ipso [Cy]); 96.7 (C5H4ipso [Cy]); 120.1 (COeCH]CH); 136.5
(COeCH]CH); 185.0 (CO-ketone); 192.1 (CO-Re). Mass spectrum
(based on 187Re) m/z: 724 [Mþ]; 696 [Mþ  CO]; 668 [Mþ  2CO];
640 [Mþ  3CO]. Anal. (%) Calc. for C19H10O7Re2: C 31.58, H 1.38;
found: C 31.61, H 1.40.
4.2.9. 1-Ferrocenyl-3-cyrhetrenyl-2-propen-1-one (2i)
Purple solid, Yield: 80% (57 mg, 0.1 mmol). IR (CH2Cl2, nCO,
cm1): 2025 (s), 1932 (s). 1H NMR (CDCl3) d: 4.20 (C5H5); 4.59 (t, 2H,
J ¼ 2.2 Hz, C5H4 [Fc]); 4.84 (t, 2H, J ¼ 2.2 Hz, C5H4 [Fc]); 5.41 (t, 2H,
J ¼ 2.2 Hz, C5H4 [Cy]); 5.78 (t, 2H, J ¼ 2.2 Hz, C5H4 [Cy]); 6.75 (d, 1H,
J ¼ 15.6 Hz, CH]CH); 7.39 (d, 1H, J ¼ 15.6 Hz, CH]CH). 13C NMR
(CDCl3) d: 70.0 (C5H4, [Fc]); 70.5 (C5H5); 73.3 (C5H4, [Fc]); 80.3
(C5H4ipso [Fc]); 85.0 (C5H4, [Cy]); 85.6 (C5H4, [Cy]); 98.9 (C5H4ipso,
[Cy]); 123.8 (COeCH]CH); 132.5 (COeCH]CH); 192.2 (CO-
ketone); 193.4 (CO-Re). Mass spectrum (based on 187Re) m/z: 574
[Mþ]; 546 [Mþ  CO]; 517 [Mþ  2CO]; 490 [Mþ  3CO]. Anal. (%)
Calc. for C21H15O4FeRe: C 43.99, H 2.61; found: C 44.02, H 2.61.
4.3. Crystal structure determination
Single crystals suitable for X-ray diffraction of 2i were grown
from CH2Cl2ehexane mixture. The crystals were carefully chosen
using a stereo zoom microscope supported by a rotatable polarising
stage. The data were collected at room temperature on a Bruker
KAPPA APEX II CCD Duo with graphite monochromated Mo-Ka
radiation (0.71073 A). The crystals were glued to a thin glass fibre
using inert oil and mounted on the diffractometer. The intensity
data were processed using a Bruker suite of data processing
programs (Bruker Analytical X-ray Systems, Inc., 2006. Apex2,
Version 2 User Manual, M86-E01078, Madison, WI), and absorption
corrections were applied using SADABS (Siemens Industrial Auto-
mation, Inc., 1996). The crystal structure was solved by the charge
flipping method using SUPERFLIP [49] and the data were refined by
full matrix least-squares refinement on F with anisotropic
displacement parameters for non-H atoms using CRYSTALS [50].
Crystal data of 2i: Molecular formula ¼ C21H15O4FeRe, Formula
weight 573.39, Crystal system ¼ Triclinic, space group ¼ P-1,
a ¼ 5.9543(5)  A; b ¼ 15.9285(15)  A; c ¼ 19.4561(19)  A,
a ¼ 89.298(5); b ¼ 88.408(4); g ¼ 85.233(4), V ¼ 1445.3(3)  A3,
T ¼ 293 K, Z ¼ 4, Dc ¼ 2.072 g cm3, 88,350 reflections measured,
15,152 independent reflections, 10,683 observed reflections [I > 3.0
s(I)], R1_obs ¼ 0.0197, Goodness of fit ¼ 1.099.
4.4. Plasmodium falciparum cultures and in vitro assay
The 3D7 chloroquine-susceptible strain and the W2
chloroquine-resistant strain were maintained in culture in RPMI
1640 (Invitrogen, Paisley, United Kingdom), supplemented with
10% human serum (Abcys S.A. Paris, France) and buffered with
25 mM HEPES and 25 mM NaHCO3. Parasites were grown in A-
positive human blood (Centre de Transfusion Sanguine, Marseille,
France) under controlled atmospheric conditions that consist of
10% O2, 5% CO2 and 85% N2 at 37  C with a humidity of 95%. FQ base
was obtained from SanofieAventis (France). CQ diphosphate was
purchased from Sigma (Saint Louis, MO). FQ and synthetic
compounds were resuspended and then diluted in RPMI-DMSO
(99v/1v) to obtain final concentration ranging from 0.125 to
500 nM and 1 nM to 100 mM, respectively. CQ was resolubilised in
water in concentrations ranging from 5 to 3200 nM. The isotopic
micro drug susceptibility test used was based on the microdilution
147
radioisotope technique of Desjardins. For in vitro isotopic microt-
ests, 25 ml/well of antimalarial drug and 200 ml/well of the para-
sitized red blood cell suspension (final parasitaemia, 0.5%; final
haematocrit, 1.5%) were distributed into 96 well plates. Parasite
growth was assessed by adding 1 mCi of tritiated hypoxanthine with
a specific activity of 14.1 Ci/mmol (PerkineElmer, Courtaboeuf,
France) to each well at time zero. The plates were then incubated
for 48 h in a controlled atmospheric condition. Immediately after
incubation, the plates were frozen and thawed to lyse erythrocytes.
The contents of each well were collected on standard filter micro-
plates (Unifilter GF/B; PerkineElmer) and washed using a cell
harvester (Filter-Mate Cell Harvester; PerkineElmer). Filter micro-
plates were dried, and 25 ml of scintillation cocktail (Microscint O;
PerkineElmer) was placed in each well. Radioactivity incorporated
by the parasites was measured with a scintillation counter (Top
Count; PerkineElmer).
The IC50, the drug concentration able to inhibit 50% of parasite
growth, was assessed by identifying the drug concentration cor-
responding to 50% of the uptake of tritiated hypoxanthine by the
parasite in the drug-free control wells. The IC50 values were
determined by non-linear regression analysis of log-based dosee
response curves (RiasmartÔ, Packard, Meriden, USA).
Acknowledgements
A.H.K. acknowledges FONDECYT-Chile (Project 1110669) and D.I.
Pontificia Universidad Católica de Valparaíso. C.B. thanks FONDE-
CYT-Chile the financial support for a research stay in Valparaiso.
R.A. acknowledges MECESUP and CONICYT for Doctoral scholarship
and D.I.-PUCV and FONDECYT-Chile (Project 3120091) for post-
doctoral position. The "Fonds Européen de Développement
Régional (FEDER)", "CNRS", "Région Nord Pas-de-Calais" and
"Ministère de l’Education Nationale de l’Enseignement Supérieur et
de la Recherche" are acknowledged for fundings of X-ray diffrac-
tometers. The Ministry of Defense (Délégation Générale pour
l’Armement and the Direction Centrale du Service de Santé des
Armées, grant no 10co405) is acknowledged for fundings of
P. falciparum screening.
Appendix A. Supplementary material
CCDC 868346 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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