Synthesis and evaluation of hybrid bis-cationic salts as antimalarial drugs

Article abstract of DOI:10.1002/cmdc.200900427

Resistance is futile: A new series of hybrid bis-cations has been synthesized as potent antimalarial agents. These compounds have two different cationic heads derived from bisthiazolium and bisamidine salts. Structure-activity relationships data suggest t

Full text of DOI:10.1002/cmdc.200900427

MED
DOI: 10.1002/cmdc.200900427
Synthesis and Evaluation of Hybrid Bis-cationic Salts as Antimalarial Drugs
Stꢀphanie Ortial,[a] Sꢀverine Denoyelle,[a] Sharon Wein,[b] Olivier Berger,[a] Thierry Durand,[a] Roger Escale,*[a]
Alain Pellet,[c] Henri Vial,[b] and Yen Vo-Hoang[a]
Malaria is one of the most common diseases and is caused by
protozoan parasites of the genus Plasmodium. The World
Health organization (WHO) estimates that 3 billion people live
in areas where malaria transmission occurs. Indeed, it is en-
demic in 109 countries and territories in tropical and subtropi-
cal regions, particularly in sub-Saharian Africa. Each year, malar-
ia affects ~300 million people worldwide and causes between
1 and 1.5 million deaths.[1–4] Moreover, this phenomenon has
Figure 1. Chemical structure of bisthiazolium salts T3 and T4 and bisami-
risen in recent years, probably due to increasing resistance to
antimalarial medicine.[5–8] Plasmodium falciparum is responsible
for the most severe form of the disease, and resistant strains
have emerged to almost all currently used antimalarial agents
(chloroquine, mefloquine, quinine and sulfadoxine/pyrimeth-
amine). An exception is observed for artemisinin and its deriva-
tives, often included in combination therapy.[9,10] However, the
widespread use of artemisinin and related drugs against P. fal-
ciparum malaria raises concern over growing drug resistance.
For many months, there have been reports from Cambodia of
malaria patients showing resistance to artemisinin combination
therapy (ACT). The emergence of artemisinin-resistant parasites
could seriously undermine global malaria control.[11]
dines M34, M40 and M38.
This approach has been validated by the clinical development
of T3 for therapeutic use (unpublished results).
The permanent cationic charges in these agents prevent
them from crossing the gastrointestinal barrier and conse-
quently their oral absorption is low. To improve oral bioavaila-
bility, bisalkylamidines have been prepared as bioisosteric ana-
logues.[24,25] Indeed, the activity of amidines against protozoal
infections, such as trypanosomiasis[26] and leishmaniasis[27] and
malaria is well known.[28] They are strong bases that are pro-
tonated under physiological conditions, and are able to mimic
choline. Initial investigations into the bisalkylamidines gave the
lead compounds M40 (N-monosubstituted amidine), M38
(N-disubstituted amidine) and M34 (primary amidine), with
potent antimalarial activity but insufficient oral bioavailability.
In both the bisthiazolium salts and the bisalkylamidine series,
the two polar heads are linked by a 12 methylene units, the
optimum length required for antimalarial activity.[24] However,
the high flexibility of the linker may be a significant drawback
to membrane permeation.
Consequently, the design of new antimalarial drugs that are
structurally different from the existing agents should be con-
sidered a priority. To counteract chemo-resistance, another
mechanism-of-action has been explored. Plasmodium possess-
es a unique phospholipid machinery, which is essential for its
multiplication during the intraerythrocytic stage.[12] This phos-
phatidylcholine de novo biosynthesis requires the import of
choline from the host and constitutes an encouraging novel
target.[13,14] Choline mimics have been designed to inhibit the
phospholipid metabolism.[15–19] Duplicated cationic heads have
been shown to affect this biosynthetic metabolism and to pos-
sess potent antimalarial activity.[20,21] Bisquaternary ammonium
salts were first synthesized,[16] and bisthiazolium salts represent
the second generation of bis-cationic antimalarial agents. Bis-
thiazolium compounds with hydroxyethyl- (T3) or methoxyeth-
yl- (T4) substituted thiazolium rings (Figure 1) displayed the
highest potency with IC50 values in the nanomolar range.[22,23]
The aim of the work presented herein was to design and
synthesize a new series of hybrid bis-cationic drugs as antima-
larial agents. A thiazolium salt cationic head and an amidine
moiety as second polar head were combined to form asym-
metrical bis-cationic drugs. The cationic heads were selected
from efficient symmetrical derivatives (T3 or T4; M34, M40 or
M38), in anticipation of a synergistic effect between the two
different cationic heads for antimalarial activity. Notably, most
of the compounds synthesized contain the T3 moiety because
the parent compound is currently under clinical development
against P. falciparum.
[a] Dr. S. Ortial, Dr. S. Denoyelle, O. Berger, Dr. T. Durand, Prof. R. Escale,
Dr. Y. Vo-Hoang
Institut des Biomolecules Max Mousseron, UMR 5247 CNRS-UMI-UMII
Universitꢀ de Montpellier I, 34093 Montpellier (France)
Fax: (+33)467548036
To probe the structure–activity relationships of these series,
the thiazolium salt and the amidine moiety were modulated
and the spacer was modified. The first series possess cationic
heads linked by an alkyl chain containing 8 or 12 methylene
units. In the second series, a rigidification has been introduced
via the insertion of an aromatic ring supporting the amidine
function. This modification was incorporated because of the
antimalarial potency exhibited by the well-known and intense-
ly studied pentamidine, an aromatic bisamidine that accumu-
E-mail: roger.escale@univ-montp1.fr
[b] S. Wein, Dr. H. Vial
Dynamique Moleculaire des Interactions Membranaires, UMR 5235
CNRS-UMII, Universitꢀ de Montpellier II, 34095 Montpellier (France)
[c] Dr. A. Pellet
Sanofi-Aventis R&D, 31036 Toulouse (France)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.200900427.
52
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ChemMedChem 2010, 5, 52 – 55

lates at high levels within erythrocytes infected with the para-
site.[29–31] In the final series, the length of the alkyl chain is 8 or
11 methylene units. Thus, the influence of flexibility on anti-
malarial activity should be elucidated.
tion in the presence of sodium hydride in THF,[32] monosubtitu-
tion occurred but a significant amount of disubstituted prod-
uct was also isolated. Disubstitution was minimized by using
milder conditions; a phase transfer catalysis, tetrabutylammoni-
um bromide, in a mixture CH2Cl2/NaOH (2n).[33] Addition of the
thiazole derivative was achieved under microwave conditions
for 3–4 h or in refluxing acetonitrile over three days.[23] These
last conditions afforded 3a, 3b, 3d, 3e, 4a, 4c, 4d and 4 f in
significantly higher yields. Treatment of these cyano derivatives
under Pinner’s conditions (gaseous HCl in EtOH) converted
them to the unstable ethyl imidates 5a, 5b, 5d, 5e, 5g, 5h,
6a, 6c, 6d, 6 f, 6i, 6j, which were immediately reacted with
excess ammonia, isopropylamine or pyrrolidine in methanol to
provide the amidine derivatives 7a, 7b, 7d, 7e, 7g, 7h, 8a,
8c, 8d, 8 f, 8i, 8j. All drugs were isolated as the HCl salt after
purification by reverse-phase chromatography.
Drugs were synthesized as described in Scheme 1. First,
asymmetrical compounds 1a and 1b were prepared by reac-
tion of the appropriate dibromoalkane and potassium cyanide.
The bromine substitution was conducted in a mixture EtOH/
Water 85/15 (v/v) to promote the solubility of starting materi-
als. Optimal results for this monosubstitution were obtained
using dibromoalkane/KCN in a two to one molar ratio. To pre-
pare the cyano derivatives 2a and 2c from the 4-hydroxyben-
zonitrile and the corresponding dibromoalkane, two methodol-
ogies were evaluated. In classical conditions of phenol alkyla-
The in vitro antimalarial activities (Table 1) were evaluated
against a chloroquine-sensitive strain of P. falciparum (Nigerian
strain).[34] All compounds exhibited a potent antimalarial activ-
ity in the very low nanomolar range, except compounds 7a
Table 1. In vitro and in vivo evaluation of the antimalarial activity of
asymmetric compounds 7a–8j.
[b]
Compd R1
R2
TS[a]
Linker
IC50
ED50[c,d] [mgkgÀ1
ip po
]
(CH2)n
Ar
[nM]
M34[25]
M40[25]
M38[25]
T3[23]
T4[23]
7a
7b
7d
7e
7g
7h
8a
8c
8d
8 f
8i
8j
–
–
–
NH2
NHiPr
Pyrrolidine
–
–
NH2
NH2
–
–
–
12
12
12
12
12
8
12
8
12
12
12
8
–
–
–
–
–
–
–
–
0.3 >10
31 4.1
>100
>100
>100
>10
1.4
2.25
0.65
1.3
0.2
0.14 n.d.
H
CH3
H
H
CH3 NH2
CH3 NH2
H
H
H
H
–
T3
T3
T4
T4
T3
430
2.2
440
>20
2.3
n.d.
>180
110
n.d.
60
–
–
–
6.15
4.5
4.5
1.2
1.2
0.9
3
NHiPr
pyrrolidine T3
NH2
NH2
70
57
T3
T3
T4
T4
T3
Phenyl-O
9.3
110
>90
50
>90
23
11 Phenyl-O 22.5
Phenyl-O 10.2
11 Phenyl-O 26
5
0.93
>2
0.31
0.31
CH3 NH2
CH3 NH2
H
H
8
NHiPr
pyrrolidine T3
8
8
Phenyl-O 12.5
Phenyl-O 10.6
17
[a] TS, thiazolium salt; (CH2)n, number of methylene units in the linker; Ar,
aromatic ring. [b] IC50 values—measured against P. falciparum—are given
as the mean of at least two independent experiments conducted in du-
plicate. [b] Antimalarial activities (ED50)—against P. vinckei—were deter-
mined after intraperitoneal (ip) or oral (po) administration of the com-
pounds once daily for 4 days to infected mice. [d] n.d., not determined.
and 7d. This result clearly shows that a shorter chain (8 meth-
ylene units) has a detrimental effect on the biological activity.
Conversely, compounds 8c and 8 f displayed weaker activity
indicating that a linker too long in length between the cationic
heads also decreases the antimalarial activity. According to the
preliminary results obtained in the symmetrical series,[20] the
alkyl chain containing 12 methylene units is necessary for opti-
mal in vitro/in vivo antimalarial activity. Since the linkers com-
posed of 12 or 8 methylene units and a phenoxy group led to
Scheme 1. Synthesis of hybrid bis-cationic drugs. Reagents and conditions:
a) KCN, EtOH/H2O, 608C,12 h (72%); b) Hydroxybenzonitrile, TBABr, NaOH
2n, CH2Cl2, RT, 72 h (69–73%); c) 4-methyl-5-thiazoethanol or 4-methyl-5-(2-
methoxytethyl)thiazole, anhyd CH3CN, reflux, 72 h (76–96%); d) HCl(g), anhyd
EtOH, RT, 12 h; e) 2n NH3, isopropylamine or pyrrolidine in anhyd CH3OH,
RT, 12 h (44–71%).
ChemMedChem 2010, 5, 52 – 55
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www.chemmedchem.org
53

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similar antimalarial activities, the distance between the two
cationic heads prevail over its nature. Synergistic effects arising
due to the two cationic heads is not clearly indicated by these
in vitro results since almost all agents displayed very potent in
vitro antimalarial activities with IC50 values between 2 and
12.5 nm similar to the parent bisthiazolium salts or bisalkylami-
dines.
for ip administration, the presence of the thiazole moiety T4
increases antimalarial activity with ED50 (po) values from 1.8- to
2.2-times lower than those obtained with the analogous T3 de-
rivative. Oral absorptions (estimated through ip/po index: 1.6–
2.7%) of hybrid compounds 7b, 7e, 7g, 7h, 8a, 8d and 8i, 8j
are still weak, and considered to be insufficient for the purpose
of oral antimalarial agents.
The in vivo antimalarial activities were measured against the
P. vinckei petteri strain (279BY) in female Swiss mice.[35] The
mice were treated with compounds by intraperitoneal (ip) or
orally (po) administration once daily for four consecutive days
(days 1–4 post infection). After ip administration, hybrid deriva-
tives displayed a potent antimalarial activity, except molecules
7a and 7d. Indeed, compound 7a was not able to reduce par-
asitemia at 20 mgkgÀ1, which may be due to the linker length
(8 methylene units), whose effect was underlined earlier.
Hence, no in vivo experiments were realized for compound
7d, because of its weak in vitro activity. The benzamidine de-
rivative 8c, with a linker containing 11 methylene units, dis-
played a slightly weaker antimalarial activity compared to 8a.
Asymmetrical compounds 7b, 7e, 7g, 7h, 8a, 8d, 8i and 8j
exhibited good potency, with ED50 (ip) values lower than
5 mgkgÀ1. Notably, changing the N-substituents of the amidine
polar heads for the same T3 thiazolium moiety led to hybrid
drugs that exhibit very close ED50 (ip) values.
In conclusion, we synthesized a new series of hybrid bis-cat-
ionic molecules with potent antimalarial activities. While we
did not observe any synergy between amidine and thiazolium
cationic heads, orally potent drugs emerged from the study
compared to previously reported symmetrical amidines. The
length of the linker plays a critical role in antimalarial activity.
On the other hand, the introduction of an aromatic ring sup-
porting the amidine function slightly affects the in vitro anti-
malarial activity, but readily increases the in vivo efficiency of
the pyrrolidinyl- and isopropyl-containing hybrid drugs.
Experimental Section
Synthesis
The general procedure for the preparation of the most active
hybrid compound 8j is reported herein. The synthesis of all the
bis-cations and their intermediates are described in the Supporting
Information with their relative spectroscopic data.
Asymmetrical compounds 7g (isopropyl) and 7h (pyrroli-
dinyl) exhibited ED50 (ip) values of 0.9 and 1.2 mgkgÀ1, respec-
tively, close to those of symmetrical M38 (pyrrolidinyl) and
M40 (isopropyl). Drug 7b (amino) also displayed a potent anti-
malarial effect (2.3 mgkgÀ1), while symmetrical M34 (amino)
exhibited no antiplasmodial activity when administered ip. In
the benzamidine series, isopropyl (8i) and pyrrolidinyl (8j) de-
rivatives are tenfold more efficient than amino-bearing com-
pound 8a. For the same primary amidine polar head, the sub-
stitution of thiazolium T3 by T4 drastically enhanced antimalar-
ial activity; ED50 (ip) values of compounds 7e and 8d are two-
to threefold lower than those of compounds 7b and 8a. Such
a difference was not observed for the symmetrical parent mol-
ecules T3 and T4, which presented nearly the same ED50 (ip)
values.
5-(2-Hydroxyethyl)-3-(8-{4-[imino(pyrrolidin-1-yl)methyl]phen-
oxy}octyl)-4-methyl-1,3-thiazol-3-ium dichloride (8j): 4-Hydroxy-
benzonitrile (1 equiv) and TBABr (0.1 equiv) were added to a 2n
aqueous solution of NaOH (5 equiv). Separately, a solution of 1,8-
dibromooctane (2.5 equiv) in CH2Cl2 was prepared and added to
the aqueous solution. The mixture was vigorously stirred for 3 d.
The two layers were separated and the organic layer was washed
with brine, dried (MgSO4), filtered and concentrated. Purification by
flash chromatography (EtOAc/cyclohexane; 5:95) gave compound
2a as a white powder. A solution of 2a (1 equiv) and 4-methyl-5-
thiazoethanol (1.5 equiv) in anhyd CH3CN was refluxed for 3 d. The
reaction was then concentrated in vacuo and purified by chroma-
tography on alumina gel (CH2Cl2/CH3OH; 98:2) to give 4a as a
white powder. HCl(g) was bubbled through a solution of 4a in
anhyd EtOH under N2 for 20 h. After completion, the reaction was
concentrated in vacuo for 12 h. The crude was redissolved in
anhyd CH3OH and treated dropwise with pyrrolidine (1.5 equiv).
The mixture was stirred at RT for 24 h. Purification of the crude oil
by reverse phase chromatography (C18, 100% H2O) afforded 8j as
a colorless oil (42%, three steps): Rf =0.32 (CH2Cl2/MeOH, 8:2; alu-
mina gel); 1H NMR (300 MHz, [D6]DMSO): d=10.20 (1H, s), 9.22
(1H, m), 8.83 (1H, m), 7.58 (2H, d, J=8.8 Hz), 7.10 (2H, d, J=
8.8 Hz), 4.48 (2H, t, J=7.6 Hz), 4.05 (2H, t, J=6.4 Hz), 3.63 (2H, t,
J=5.6 Hz), 3.56 (2H, t, J=6.8 Hz), 3.44 (2H, t, J=6.8 Hz), 3.03 (2H,
t, J=5.6 Hz), 2.47 (3H, s), 2.04 (2H, m), 1.87–1.70 (6H, m), 1.33 ppm
(8H, m); 13C NMR (75.47 MHz, CD3OD): d=162.8, 162.2 (C), 155.1
(CH), 142.0, 136.0 (C), 129.4 (CH), 121.5 (C), 114.6 (CH), 68.0, 59.9,
53.3, 51.8, 29.4, 29.0, 28.7, 28.6, 28.5, 25.7, 25.5, 25.1, 24.4 (CH2),
10.3 (CH3). IR (cmÀ1) n 3393, 2937, 2883, 1671, 1609, 1464, 1050,
1023, 1003, 760 ppm; MS (ESI+): m/z (%): 222.7 (100%) [M+H]+/2,
223.2 (43%) [M+2H]/2, 223.7 (15%) [M+3H]+/2, 444.4 (12%) [M]+,
445.4 (4%) [M+H]+; HRMS: m/z [M+H]+ calcd for C25H38N3O2S+:
444.2685, found: 444.2686.
No antimalarial activity could be detected after po adminis-
tration of 100 mgkgÀ1 of symmetrical alkylamidines M34, M38
or M40; the same observation was made for 7a and 7d, which
do not possess the optimum distance between the two cation-
ic heads. The longer alkyl chain (11 methylene units) with the
phenoxy group is likely to have also hampered oral bioavaila-
bility since no effect could be detected at a 90 mgkgÀ1 dose.
On the other hand, hybrid drugs 7e, 7g, 7h, 8d, 8i and 8j ex-
hibited a significant antimalarial activity after their oral admin-
istration to mice. With respect to the amidine N-substituents,
antimalarial potency was improved for 7g (ED50 (po)=
70 mgkgÀ1) and 7h (ED50 (po)=57 mgkgÀ1) derivatives con-
taining isopropyl and pyrrolidinyl moieties, respectively, when
compared to 7b (ED50 (po)=110 mg kgÀ1) with an amino resi-
due. This difference is drastically enhanced in the benzamidine
asymmetrical series since compounds 8i and 8j presented low
ED50 (po) values (23 and 17 mgkgÀ1, respectively). As discussed
54
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ChemMedChem 2010, 5, 52 – 55

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Biological assays
In vitro antimalarial activities were determined against a chloro-
quine-sensitive strain of P. falciparum (Nigerian strain). Growth of
P. falciparum cultures (0.6% initial parasitemia and 1.5% hemato-
crit) was measured in microtiter plates by [3H]hypoxanthine incor-
poration after 48 h of incubation with the compounds to deter-
mine the 50% inhibition concentration (IC50) value, according to
Desjardins et al.[34] Compounds were dissolved in RPMI 1640 or
DMSO (final concentration <0.1%).
All biological experiments were done in accordance with the
French law and the local ethical committee guidelines for animal
research.
Invivo antimalarial activities were determined against the P. vinckei
petteri (279BY) strain in female Swiss mice according to a modified
version of the 4 day suppressive test of Peters et al.[21] Briefly, drugs
and prodrugs were injected in 100 mL of 0.9% NaCl or DMSO via ip
or po administration. Parasitemia levels were monitored using
Giemsa-stained blood smears, and blood samples were collected
for parasite determination on a fluorescence-activated cell sorter.[35]
Acknowledgements
These studies were supported by the European Commission (Anti-
mal integrated project LSHP-CT-2005–018834). We are grateful to
Christophe Tran van Ba and Yann Bordat for their assistance in
testing the compounds.
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Keywords: biological activity · hybrid bis-cations · malaria ·
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Received: October 14, 2009
Published online on November 26, 2009
ChemMedChem 2010, 5, 52 – 55
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