Absolute configuration and antimalarial activity of erythro-mefloquine enantiomers

Article abstract of DOI:10.1002/cplu.201300074

Mefloquine (MQ), an antimalarial drug, is used as a racemate of (-)- and (+)-enantiomers, which display biological differences. The question concerning their exact configuration remains a matter of debate. The absolute configuration of the two MQ enantiomers as well as their biological activity has been established, thus confirming the importance of the stereochemistry in the design of MQ analogues that have fewer adverse side effects (see figure). Copyright

Full text of DOI:10.1002/cplu.201300074

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DOI: 10.1002/cplu.201300074
Absolute Configuration and Antimalarial Activity of
erythro-Mefloquine Enantiomers
Alexandra Dassonville-Klimpt,[a] Christine Cꢀzard,[a] Catherine Mulliꢀ,[a] Patrice Agnamey,[a]
Alexia Jonet,[a] Sophie Da Nascimento,[a] Mathieu Marchivie,[b] Jean Guillon,[b] and
Pascal Sonnet*[a]
Mefloquine (MQ; Figure 1), a synthetic analogue of quinine
and quinidine, is an antimalarial drug that possesses a schizo-
nticide activity with a long half-life against Plasmodium spe-
cies.[1] MQ is commercially available as a racemate (Lariam), al-
though both enantiomers have been shown to display biologi-
ed the first asymmetric synthesis of (11R, 11S)-MQ and assigned
it to the (+)-isomer.[4b] Meanwhile in a similar approach,
Schmid et al. described the same absolute configuration as-
signment to the (+)-MQ.[5]
In 2002, Karle and Karle rejected this first assignment by
means of X-ray crystallography determination of the (À)-MQ
hydrochloride salt. In their work, the absolute configuration of
the (À)-MQ salt was established as (11R, 12S).[6] In 2008, Xie
et al. reported the asymmetric synthesis of (11R, 12S)-MQ
based on an asymmetric aldol reaction and Beckmann rear-
rangement.[7] The stereochemistry of the key intermediate was
confirmed by the Mosher’s method and led to reconfirmed the
original assignment. More recently in 2012, Reinscheid and co-
workers determined the absolute configuration of (+)-MQ by
using residual dipolar coupling-enhanced spectroscopy in
combination with optical rotary dispersion and CD spectrosco-
py.[8] They concluded that (À)-MQ can be assigned as (11R, 11S)
in agreement with Karle.
Figure 1. Chemical structure and numbering of (À)-mefloquine-1 and
(+)-mefloquine-2 bases. The asterisks indicate the chiral atoms.
Thus the question concerning the exact absolute configura-
tion of (À) and (+)-MQ remained. Herein, to answer this ques-
tion, we report the X-ray crystallography, CD spectroscopy, and
molecular modeling study of both MQ enantiomers along with
their respective antimalarial activities. While this article was
under peer review a related study by Griesinger and co-work-
ers appeared.[9] The authors determined the crystal structures
of two MQ enantiomeric Mosher amides.
cal differences. The antimalarial activities of the two isomers
are close: (+)-MQ is more active by a factor of 1.6–1.8 on
some malaria strains (D6 and W2).[2] The (À)-MQ is 100 to
400 times more potent than the (+)-MQ as an adenosine re-
ceptor agonist; such binding is believed to be responsible for
neuropsychiatric side effects such as depression and psycho-
sis.[3] Nevertheless, the absolute configuration of (+) and (À)-
erythro-MQ still remains a matter of debate. In 1974, Carroll
and Blackwell studied the absolute configuration of the optical
isomers of MQ by comparing their corresponding circular di-
chroism (CD) spectra to those of quinine and quinidine. The
absolute configuration of (+)-MQ hydrochloride was then es-
tablished as (11R, 12S).[4a] A research group from Roche report-
Several methods of HPLC have been described for the enan-
tioselective analysis of MQ in biological fluids.[10] We have de-
veloped a rapid and enantioselective HPLC method for the
separation and analysis of the two isomers of the erythro-me-
floquine using a Chiralpak IA column with amylose tris(3,5-di-
methylphenylcarbamate) as a chiral reagent. The total analysis
time was below 15 minutes and UV detection was set at
280 nm. Enantiomeric purity of the two enantiomers was de-
termined after purification and the enantiomeric excess of the
(À)-(11R, 12S)-erythro MQ-1 and the (+)-(11S, 12R)-erythro MQ-
2 was of 95.5% and 92.3%, respectively (Figure 2). The two
enantiomers were crystallized from methanol, which slowly
evaporated at room temperature.
[a] Dr. A. Dassonville-Klimpt, Dr. C. Cꢀzard, Dr. C. Mulliꢀ, Dr. P. Agnamey,
Dr. A. Jonet, S. Da Nascimento, Prof. Dr. P. Sonnet
Laboratoire des Glucides, CNRS FRE 3517
UFR de Pharmacie, Universitꢀ de Picardie Jules Verne
1, rue des Louvels, 80037 Amiens cedex 01 (France)
Fax: (+33)322827469
The (À)-MQ-1 and (+)-MQ-2 bases (Figure 3) crystallized in
the orthorhombic non-centrosymmetric P212121 space group.
The asymmetric unit of both compounds consists in five inde-
pendent MQ molecules corresponding to five different confor-
mations in the crystal, and were arbitrarily labeled A, B, C, D,
and E (Figure 4). Crystal data and details concerning the X-ray
diffraction experiment and refinement of the single crystal
E-mail: pascal.sonnet@u-picardie.fr
[b] Dr. M. Marchivie, Prof. Dr. J. Guillon
CNRS FRE 3396-Pharmacochimie
UFR de Pharmacie, Universitꢀ Bordeaux Segalen
33076 Bordeaux cedex (France)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cplu.201300074.
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according to the P2 and P3 Hooft parameters (see Ta-
ble SI1). Using the same procedure, the five confor-
mations of (+)-MQ-2 have an absolute configuration
of (11S, 12R) with the same probability (x=À0.03(13)
and y=0.03(4)).
In the two (À)-MQ-1 and (+)-MQ-2 bases, mole-
cules A to E possess nearly identical conformations,
the main difference being in the rotation of the pi-
peridine ring about the C11ÀC12 bond (see Fig-
ure SI1). The quinoline fragments of each MQ mole-
cule are approximately planar (RMSD from 0.016 to
0.030 ꢂ), with carbon C3A, C3B, C4C, C3D, and C4E
showing the maximum deviations from planarity of
the quinolone rings, in the range from 0.030(4) to
0.051(4) ꢂ. The piperidine ring assumes a chair con-
formation with atoms N13, C17, C16, and C14 copla-
nar such that the root mean square deviations from
the average plane through these four atoms are of
0.0016/0.0037, 0.0095/0.00134, 0.0010/0.0008, 0.0040/
0.0004, and 0.0090/0.0144 ꢂ for molecules A, B, C, D,
and E, for (À)-MQ-1 and (+)-MQ-2, respectively. The
aryl group lies equatorial to the piperidine ring, with
the angle between the average plane of the quino-
line ring and the average plane of the piperidine ring
Figure 2. Chromatogram illustrating the enantiomeric purity of the two erythro enantio-
mers of mefloquine after chromatographic purification. Column: Chiralpak IA
(250ꢃ4.6 mm); mobile phase: heptane/isopropanol/diethylamine (70:30:0.1); detection:
280 nm; flow rate: 1.0 mLminÀ1; retention times: (À)-(11R, 12S)-erythro-MQ-1: 4.77 min
and the (+)-(11S, 12R)-erythro-MQ-2: 9.02 min.
ranging from 79.3(2) to 92,4(2)8 for (À)-MQ-1 and from 79.3(2)
to 88.9(2)8 for (+)-MQ-2. The À58.6(4) to À72.0(4)8 range of
torsion angles for the atoms comprising O1-C11-C12-N13 dem-
onstrates that (À)-MQ-1 is gauche about the C12ÀC13 bond,
whereas the same torsion angles in (+)-MQ-2 were found
ranging from 58.2(4) to 72.5(5)8. The C4-C11-C12-N13 torsion
angles of 164.5(3)8, 179.2(3)8, 168.1(3)8, 171.7(3)8, and 177.7(3)8
for the five conformers of (À)-MQ-1 place the amine group
nearly as far away as possible from the quinoline ring. In
(+)-MQ-2, the same C4-C11-C12-N13 torsion angles were ob-
served at À163.6(4)8, À179.7(4)8, À168.5(4)8, À172.(4)8, and
À177.0(3)8 leading to the same observations.
The main role in the packing of MQ molecules in the two
structures studied is played by OÀH···N intermolecular hydro-
gen bonds (see Table SI2). There are no solvent-accessible
voids in the crystal lattice of the MQ molecules. Crystal cohe-
sion is ensured by a monodimensional network of hydrogen
bonds within the 010 crystallographic direction completed by
van der Waals interactions in other directions that essentially
involve the fluorine atoms.
Figure 3. ORTEP views of the molecular structure of (a) (À)-MQ-1 and
(b) (+)-MQ-2 bases with our numbering Scheme for one of the five mole-
cules in the asymmetric unit (molecule A). The numbering scheme for the
other four molecules is the same but the suffix is b, c, d, and e for B, C, D,
and E molecules, respectively. Displacement ellipsoids are drawn at the 30%
probability level.
Geometry optimizations along with frequency calculations
were performed in the gas phase on the two MQ molecules at
the B3LYP/6-31+G* level of theory using the structures ob-
tained by X-ray crystallography as starting points. For both MQ
molecules, the optimized geometries are very close to their
corresponding crystallographic states, indicating local minima.
Moreover, the energies of the two structures are identical im-
plying that the two MQ are “true” enantiomers, as shown in
Figure 5. To check whether these obtained structures are
global minima, additional analyses including conformational
search were carried out. Results show that the crystallographic
structure of (+)-MQ-2 is the actual global minimum of the
(11S, 12R) enantiomer, whereas calculations indicate that the
structures are given in the Table SI1 (see the Supporting Infor-
mation).
The absolute configurations of (À)-1 and (+)-MQ-2 were es-
tablished through single-crystal X-ray crystallography. The ab-
solute configuration of (À)-MQ-1 was determined by observing
and calculating the F(+)/F(À) ratios of Bijvoet pairs with the
mean F value of each independent reflection, and by determin-
ing the Flack factor value (x=0.08(11)).[11] In addition, the
Hooft parameter was determined by using Bayesian statistics
on Bijvoet differences (y=0.04(5)).[12] Based on these results,
the absolute configurations at C11 and C12 were determined
to be R and S, respectively, with a probability close to 100%
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To avoid any bias, the antima-
larial activity of chromatographi-
cally purified (À)-MQ-1 and
(+)-MQ-2 was tested without
previous knowledge of the as-
signment
conclusions.
Also
tested were chloroquine and the
MQ racemate from which puri-
fied (À)-MQ-1 and (+)-MQ-2
were issued. The resulting
IC50 values are summarized in
Table 1. As could be expected,
the IC50 value for MQ racemate
was found to be between those
of (À)-MQ-1 and (+)-MQ-2. The
(À)-MQ-1 displayed an IC50 value
that was 1.4-fold that of (+)-MQ-
2
on Plasmodium falciparum
3D7, hence confirming that
(+)-MQ might be slightly more
active than its (À)-enantiomer,
as previously shown on strains
D6 and W2.[2] However, the dif-
ference between IC50 values of
(À)-MQ-1 and (+)-MQ-2 IC50
Figure 4. ORTEP views of the crystal structure of (À)-MQ-1 bases with our numbering scheme for each of the five
independent molecules in the asymmetric unit. Displacement ellipsoids are drawn at the 30% probability level.
Table 1. Antimalarial activity of chloroquine, MQ racemate, (À)-MQ-1 and
(+)-MQ-2 on Plasmodium falciparum 3D7 strain.
IC50 [nm][a]
95% confidence interval
Chloroquine
MQ racemate
(À)-MQ-1
57.6
110.3
123.9
88.9
[52.54–62.63]
[84.17–136.5]
[92.34–155.46]
[77.85–99.98]
(+)-MQ-2
[a] 50% inhibitory concentration.
Figure 5. Superimposition of the (À)-MQ-1 (red) and (+)-MQ-2 (black) struc-
tures obtained after geometry optimization starting from crystallographic
structures.
failed to reach the 5% statistical significance threshold, as wit-
nessed by slightly overlapping 95% confidence intervals. Other
authors indeed reported no difference in the antimalarial activ-
ities of both enantiomers on P. falciparum strains L-3 and
FCM29.[13]
(11R, 12S) enantiomer is stabilized by an intramolecular
OH···NÀ13 hydrogen bond. Hence, the global minimum of (À)-
MQ-1 is stabilized relative to the crystallographic structure by
1.93 kcalmolÀ1 (see Figure SI2).
Nevertheless, it is worth mentioning that, on the same P. fal-
ciparum 3D7 strain, the (+)-(11S)-enantiomers in a series of MQ
derivatives—bearing a single asymmetric carbon atom at the
C11 position—were found to be up to 14 times more efficient
than their (11R) counterparts.[14] These results give an indica-
tion that the stereochemistry at the C11-position might be
more important than that at the C12-position in regard to the
antimalarial activity of MQ derivatives. Stereochemistry was
also found to be of importance in the antimalarial activity of
cinchona alkaloids through their interactions with Plasmodium
falciparum CRT protein.[15] It has also recently been shown that
(+)-MQ has a better activity in a mouse model of Mycobacteri-
um avium infection than does (À)-MQ.[16]
The CD spectra of (À)-MQ-1 and (+)-MQ-2 bases were also
obtained (Figure 6). Our results are consistent with those re-
ported by Reinscheid[8] on (À)-MQ and (+)-MQ HCl salts. The
spectrum of (+)-MQ shows two positive bands at 222 nm and
298 nm and one negative band at 272 nm, whereas the spec-
trum of the (À)-MQ-1 shows two negative bands at 222 nm
and 300 nm and one positive band at 271 nm. We conclude
that (À)-MQ-1 and (+)-MQ-2 can be assigned, respectively, as
(11R, 12S) and (11S, 12R) in accord with Karle and Reinscheid.
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Circular dichroism (CD) meas-
urements
The CD measurements were per-
formed in methanol on a Jasco J-
815 CD spectrometer at a tempera-
ture of 258C using a concentration
of 0.113 mgmLÀ1 for each enantio-
mer. The experiments were carried
out in rectangular cells with a path
length of 1 mm.
X-ray crystallography
Crystallographic data of (À)-MQ-
1 and (+)-MQ-2 were collected at
293 K with a R-Axis Rapid Rigaku
MSC diffractometer with mono-
chromatic Cu Ka radiation (l=
1.54178 ꢂ) and
a curved image
plate detector. Small crystals were
used to collect the data. At 150 K,
the full sphere data collection was
performed using f scans and w
scans with an exposure time of
12 s per degree. The unit cell de-
Figure 6. Experimental CD spectra of the (À)-MQ-1 (red) and (+)-MQ-2 (black) in methanol.
In conclusion, we establish that the absolute configurations
termination and data reduction were performed using the crystal
clear program suite[17]on the full set of data. For both compounds,
the crystal structures were solved by direct methods and succes-
sive Fourier difference syntheses with the SHELXS-97 program.[18]
The refinements of the crystal structures were performed on F2 by
weighted anisotropic full-matrix least squares methods using the
SHELXL97 program for both compounds. The different pieces of
software were used within the OLEX2 package.[19] No absorption
correction was needed owing to the low absorption coefficient of
these compounds. All non-hydrogen atoms were refined anisotrop-
ically and for both compounds, and H atoms were treated accord-
ing to the riding model during refinement with isotropic displace-
ment parameters, corresponding to the C atom they are linked to.
of (À)-MQ-1 and (+)-MQ-2 are (11R, 12S) and (11S, 12R), re-
spectively. We found that (+)-MQ is slightly more active than
its enantiomer, (À)-MQ, on Plasmodium falciparum 3D7, thus
confirming the importance of stereochemistry in the design of
MQ analogues that have fewer adverse side effects in the
treatment of malaria.
Experimental Section
CCDC 906043 ((À)-MQ-1) and 906044 ((+)-MQ-2) contain the sup-
plementary 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.
Chromatographic methods
The HPLC system used consisted of a solvent delivery pump (Shi-
madzu LC-20AD), an auto-sampler (Shimadzu SIL-10AP), a variable-
wavelength UV/VIS detector (Shimadzu SPD-20A), and a controller
system (Shimadzu SCL-10A VP). The detector was set at a wave-
length of 280 nm. The mobile phase was composed of heptane/
isopropanol/diethylamine (70:30:0.1%, v/v). The flow rate was set
to 1.0 mLminÀ1. The HPLC column was a Chiralpack IA analytical
column consisting of a silica support with a particle size of 5 mm
(250ꢃ4.6 mm; Chiral Technologies Europe) onto which amylose
tris(3,5-dimethylphenylcarbamate) has been immobilized. Analyses
were performed at 258C. To prepare the samples for analysis me-
floquine hydrochloride (20 mg; Sigma Aldrich) was dissolved in
methanol (5 mL) and then diethylamine (100 mL, 10 equivalents)
was added. The solvent was evaporated under reduced pressure
and the free bases obtained were dissolved in the HPLC mobile
phase (8 mL). This solution was injected fifty times (50ꢃ100 mL)
onto the HPLC instrument to separate the two enantiomers, and
resulting in the recovery of each enantiomer (5.5 mg). Solutions of
these two enantiomers were prepared by dissolving them in the
HPLC mobile phase (1 mgmLÀ1). These solutions were injected
(20 mL) and the standard curves for each enantiomer were ob-
tained.
Antimalarial activity
The in vitro antimalarial activities were tested over a concentration
range of 1.13–580 nm against Plasmodium falciparum strain 3D7.
This strain is susceptible to chloroquine but displays a decreased
susceptibility to MQ. The parasites were cultivated in RPMI
medium (Sigma–Aldrich, Lyon, France) supplemented with Albu-
max I (Invitrogen-Life sciences, Saint-Aubin, France), hypoxanthine
(Sigma–Aldrich), gentamicin (Sigma–Aldrich), and human red blood
cells, as described previously.[20] Chloroquine and MQ were routine-
ly included as positive controls as well as negative controls using
solvent. After incubation for 48 h with the drugs, the SYBRGreen I
technique was performed as described previously to determine
growth inhibition.[21] Concentrations inhibiting 50% of the para-
site’s growth (half maximal inhibitory concentration or IC50 values)
were then calculated from the experimental results obtained using
a regression program available on line.[22] The experiments were re-
peated twice.
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All DFT calculations were performed with the Gaussian 09[23] pro-
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We thank the DGA and ANR (project ANR-12-ASTR-003) for finan-
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CNRS, Rꢀgion Picardie and ANR.
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Keywords: absolute configuration
enantiomers · erythro-mefloquine · stereoselectivity · structure
elucidation
· antimalarial activity ·
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