Synthesis and evaluation of bis-thiazolium salts as potential antimalarial drugs

Article abstract of DOI:10.1002/cmdc.201000097

An innovative therapeutic approach based on the use of dicationic derivatives was previously designed to inhibit the biosynthesis of phosphatidylcholine in Plasmodium spp. Among these, bis-thiazolium salts were shown to block proliferation of the malaria

Full text of DOI:10.1002/cmdc.201000097

MED
DOI: 10.1002/cmdc.201000097
Synthesis and Evaluation of Bis-Thiazolium Salts as
Potential Antimalarial Drugs
Sergio A. Caldarelli,[a] Jean-Frꢀdꢀric Duckert,[a] Sharon Wein,[b] Michꢁle Calas,[a]
Christian Pꢀrigaud,[a] Henri Vial,[b] and Suzanne Peyrottes*[a]
An innovative therapeutic approach based on the use of dicat-
ionic derivatives was previously designed to inhibit the biosyn-
thesis of phosphatidylcholine in Plasmodium spp. Among
these, bis-thiazolium salts were shown to block proliferation of
the malaria parasite at concentrations in the low nanomolar
range. However, due to unsuitable molecular properties such
as the presence of the two polar heads and flexibility in the
linker, these compounds have low oral bioavailability. To char-
acterize the structural requirements of the linker that lead to
more rigid analogues with fewer rotatable bonds but which
retain antimalarial activity, a new series of compounds incorpo-
rating an aryl moiety and eventually oxygen atoms were pre-
pared, and their biological activity was evaluated. Structure–ac-
tivity relationships suggest that the optimal linker construct is
an aromatic group with two n-butyl chains branched at the
para position; two new leads (compounds 39 and 40) were se-
lected for further development.
Introduction
Malaria is one of the most prevalent diseases throughout the
tropical and subtropical regions of the world. Approximately
40% of the world’s population is at risk of malaria, which
causes 300 million acute illnesses every year in developing
countries. Malaria is caused by protozoan parasites of the Plas-
modium genus. P. falciparum is the dominant species and is re-
sponsible for nearly one million deaths annually.[1] Owing to
the absence of vaccine and of a widely accessible vector con-
trol strategy, the most efficient way to control malaria remains
chemotherapy.[2,3] The resistance of P. falciparum to most anti-
malarial drugs is a major obstacle to the eradication of this dis-
ease. This is also of considerable concern, in light of a recent
report on decreased sensitivity to artemisinin drugs in South-
east Asia.[4] Thus, new chemotherapeutic approaches based on
innovative mechanisms of action are needed.
lead compound G25 [1,16-hexadecamethylene-bis(N-methyl-
pyrrolidinium) dibromide] efficiently inhibits drug-resistant ma-
laria in vitro, with IC50 values of 0.6–1.2 nm,[13] and eliminates
Plasmodium infection without recrudescence in rodent[14] and
primate[15] models at very low doses. To overcome the low oral
absorption of these permanently charged derivatives, bioiso-
steric analogues such as bis-amidines and bis-thiazolium salts
were envisaged. Among the bis-thiazolium salts, T3 and T4
(Figure 1) exhibited promising activities with in vitro IC50 values
During the last decade, an original approach that targets the
particular lipid characteristics of the parasite has been devel-
oped.[5–7] During its intra-erythrocytic development, the para-
site requires a considerable quantity of phospholipids synthe-
sized from various precursors such as serine, ethanolamine,
choline, and fatty acids that are scavenged from the human
host. With the most abundant lipid in erythrocytes being phos-
phatidylcholine (PC), its content increases sixfold after infec-
tion.[8–10] Therefore, PC biosynthesis has been viewed as an
ideal target for the development of new antimalarials.[11] The
essential role of PC for parasite survival has been demonstrat-
ed through the use of choline analogues, rationally designed
and optimized for their ability to inhibit PC biosynthesis in
Plasmodium.
Figure 1. T3 and T4, lead compounds of the third generation, and the neu-
tral prodrug TE3.
[a] Dr. S. A. Caldarelli, Dr. J.-F. Duckert, Prof. M. Calas, Prof. C. Pꢀrigaud,
Dr. S. Peyrottes
Institut des Biomolꢀcules Max Mousseron (IBMM)
UMR 5247 CNRS-UM1&2, Universitꢀ Montpellier 2, CC1705
Place E. Bataillon, 34095 Montpellier Cedex 5 (France)
Fax: (+33)467-042029
E-mail: suzanne.peyrottes@univ-montp2.fr
[b] S. Wein, Dr. H. Vial
Dynamique des Interactions Membranaires Normales et Pathologiques
UMR 5235 CNRS-UM2, Universitꢀ Montpellier 2, CC107
Place E. Bataillon, 34095 Montpellier Cedex 5 (France)
In this context, three generations of compounds were syn-
thesized and evaluated for their biological and pharmacologi-
cal activities. The first derivatives were bis-ammonium salts in-
corporating a long alkyl chain (ꢀ12 methylene units).[5,6,12] The
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201000097.
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ChemMedChem 2010, 5, 1102 – 1109

Bis-Thiazolium Salts as Potential Antimalarial Drugs
of 2.2 and 0.65 nm against P. falciparum, and in vivo ED90
values of 0.2 and 0.14 mgkgꢁ1 in mice infected by P. vinckei (in-
traperitoneal administration). Thus, T3/SAR97276 was selected
as a clinical candidate and is currently in development by
Sanofi–Aventis (ongoing phase II clinical trials) for the treat-
ment of severe malaria by the parenteral route.
As observed for the first-generation compounds, the bis-
thiazolium salts exhibited low oral bioavailability (<5%). How-
ever, such derivatives could be administered as neutral precur-
sors, which are expected to revert back in vivo (after enzymatic
conversion) to the parent drugs. Thus, a few prodrug ap-
proaches were developed on the basis of T3, and proof-of-
principle demonstrations were carried out in murine models.[16]
These compounds also led to a complete cure of P. cynomolgi
infection, attesting to their suitable pharmacokinetic proper-
ties.[16] For example, the absolute oral bioavailability of the
cyclic thioester prodrug TE3 (Figure 1) reached 15% in rats.[17]
Unfortunately, this remains too weak to envisage further clini-
cal development. Examination of some molecular parame-
ters[18–20] (such as molecular weight, flexibility as determined by
the number of rotatable bounds, and lipophilicity) of the pro-
drugs of T3 revealed that they are unsuitable for oral adminis-
tration. To modulate molecular flexibility, a parameter common
to both the drug and its corresponding prodrug, we envisaged
a new series of T3 analogues in which the linker (dodecyl
chain) is rigidified through the introduction of an aromatic
moiety (Figure 2). The synthesis and antimalarial activities of
such compounds are described below.
Figure 2. General structures of targeted derivatives.
Results and Discussion
Chemistry
3,3’-{4,4’-[Phenylenebis(oxy)]bis(butane-4,1-diyl)}bis-thiazoli-
um salts
Scheme 1. Reagents and conditions: a) 1,4-dibromobutane, 4n NaOH, H2O,
Bu4NHSO4 or K2CO3, DMF, RT, 14 h; b) 4-methyl-5-(2-hydroxyethyl)thiazole,
CH3CN, MW (400 W), 1008C, 5 h; c) TBDMSCl, imidazole, DMF; d) hydroqui-
none or resorcinol or catechol, K2CO3, DMF, 1008C, 48 h; e) HCl (1.25m in
MeOH); f) TsCl, pyridine, CH2Cl2.
Bis-thiazolium salts 4, 5, and 6 were prepared in two steps
from commercially available hydroquinone, resorcinol, and cat-
echol, respectively (Scheme 1A). The 1,4- and 1,3-benzenediols
were coupled to 1,4-dibromobutane (in excess) in the presence
of tetra(n-butyl)ammonium hydrogen sulfate (Bu4NHSO4) in a
concentrated aqueous solution of sodium hydroxide, whereas
1,2-benzenediol was reacted with potassium carbonate in N,N-
dimethylformamide (DMF). The corresponding bromoalkyl link-
ers 1, 2, and 3 were obtained in 71, 65, and 69% yields, re-
spectively. Alkylation of the nitrogen atom of 4-methyl-5-(2-hy-
droxyethyl)thiazole with the bromoalkyl linker was then per-
formed in CH3CN by microwave (MW) irradiation to significant-
ly decrease reaction time; this afforded the thiazolium bromide
salts 4, 5, and 6. The conversion rate was quantitative, but sev-
eral purification steps were required to isolate the target com-
pounds with suitable purity for biological testing (>98% as
determined by NMR and HPLC); consequently, the final yields
ranged between 50 and 80%.
3,3’-{3,3’-[Phenylenebis(oxy)]bis(propane-3,1-diyl)}bis-thiazo-
lium salts
Bis-thiazolium salts 17, 18, and 19 were obtained in four steps
from the same starting materials as above (Scheme 1B). In con-
trast to the synthetic pathway used for derivatives 4–6, the
1,3-bis(3-bromopropoxy)benzene intermediates could not be
isolated with acceptable yields owing to a side reaction (elimi-
nation) that afforded the mono- and bis-allyloxybenzene deriv-
atives. Thus, synthesis of 3,3’-[phenylenebis(oxy)]dipropan-1-ols
11, 12, and 13 was performed using the following steps: 1) al-
kylation of hydroquinone, resorcinol, and catechol with 3-bro-
mopropoxy-tert-butyldimethylsilane 7 in the presence of potas-
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S. Peyrottes et al.
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sium carbonate in DMF at 1008C (compounds 8, 9, and 10
were obtained in 41, 58, and 80% yields, respectively);
2) TBDMS removal under acidic conditions. Finally, toluenesul-
fonylation lead to the intermediates 14, 15, and 16 (in 88, 74,
and 80% respective overall yields), and the desired bis-thiazoli-
um salts were obtained using the same procedure as described
above. The crude material was percolated through an ion-ex-
change resin (Dowex Clꢁ form) before purification to afford the
corresponding chloride salts 17, 18, and 19.
toxy)methyl]benzenes 24 and 25 in 53 and 58% yields, respec-
tively. Treatment of these dibromo intermediates with 4-
methyl-5-(2-hydroxyethyl)thiazole lead us to isolate 29 in low
yield as well as various dicationic derivatives 27, 28, 30, and
31, which resulted from the loss of one or both n-butoxy
chains. Despite modification of the reaction conditions (tem-
perature, MW or thermal heating, and the nature of the leaving
group: iodo, trifluoromethanesulfonate, toluenesulfonate),
these by-products were still observed. Nevertheless, each com-
pound was isolated from the reaction mixture by using RP-18
liquid chromatography.
2,2’-[Phenylenebis(oxy)]bis(ethane-2,1-diyl)bis-thiazolium
salts
Compounds 22 and 23 were prepared in two steps (30 and
25% respective overall yields) from commercially available al-
cohols 1,4- and 1,2-bis(2-hydroxyethoxy)benzene using the
same procedure as for compounds 17 and 19 (Scheme 1C).
3,3’-[3,3’-(1,4-Phenylene)bis(propane-3,1-diyl)]bis-thiazolium
and 3,3’-[4,4’-(1,4-phenylene)bis(butane-4,1-diyl)]bis-thiazoli-
um salts
3,3’-{4,4’-[Phenylenebis(methylene)]bis(oxy)bis(butane-4,1-
diyl)}bis-thiazolium salts
Compounds 37–40 were synthesized in two steps using the
same route as described for derivatives 22 and 23. The starting
materials 3,3’-(1,4-phenylene)dipropan-1-ol and 4,4’-(1,4-phe-
nylene)dibutan-1-ol were prepared beforehand according to
published procedures.[7] Thus, corresponding bis-thiazolium
salts 37, 38, 39, and 40 were isolated in 51–59% yields
(Scheme 3).
Attempts to obtain derivatives 26 and 29 from 1,4- and 1,2-
benzenedimethanols were somewhat puzzling (Scheme 2).
Briefly, excess 1,4-dibromobutane was first reacted with the
diols in the presence of Bu4NHSO4 in an aqueous solution of
concentrated sodium hydroxide; this afforded bis[(4-bromobu-
Scheme 2. Reagents and conditions: a) 1,4-dibromobutane, 4n NaOH, H2O, Bu4NHSO4, RT, 48 h; b) 4-methyl-5-(2-hydroxyethyl)thiazole, CH3CN, MW (400 W),
1508C, 1 h; c) ethylene glycol, NaH, THF; d) TsCl, NEt3, CH2Cl2.
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Bis-Thiazolium Salts as Potential Antimalarial Drugs
spectively, and the activity ranged from 66 nm (compound 4)
to 800 nm (compound 28). Likewise, compound 39 (20.5 nm) is
3.7-fold more active than 37 (77.5 nm), which has a shorter
linker by two methylene units. A similar effect was observed
when the two chains were branched in the meta (compounds
5, 18, 23, and 29) or ortho (compounds 6, 19, and 31) posi-
tions. For compounds with the same chain length but anch-
ored at different positions on the aromatic ring, the para and
meta compounds exhibited similar activity, whereas the ortho
orientation led to a decrease in activity. Thus, compounds 4
and 5 were 1.6-fold more potent than 6 (110 nm), with IC50
values of 66 and 61 nm, respectively. This finding may be asso-
ciated with the overall geometry of the molecule, with more
strained compounds having lower affinity for the pharmaco-
logical target. Furthermore, the presence of oxygen atoms was
detrimental to in vitro activity; compounds 17 (215 nm) and 34
(905 nm) were far less potent than 39. Likewise, compound 22
was 15-fold less active than 37. Asymmetric compounds 27
and 30, the linkers of which are one methylene group shorter
than those of compound 17, exhibited similar activity.
Scheme 3. Reagents and conditions: a) TsCl, pyridine, CH2Cl2; b) 4-methyl-5-
(2-hydroxyethyl)thiazole or 4-methyl-5-(2-methoxyethyl)thiazole, CH3CN, MW
(400 W), 1008C, 5 h.
Antimalarial activity
In vitro biological evaluation
All T3 analogues incorporating phenyl, benzyl moieties, and
eventually oxygen atoms in place of the original dodecyl chain
between the two cationic head groups were evaluated in cell
culture experiments (Table 1). The in vitro antimalarial activities
were monitored by adding the compounds to a P. falciparum-
infected erythrocyte suspension for a complete 48 h parasite
cycle before assessing the parasite viability. First, the influence
of linker length including one aromatic ring and pending
chains from one to six methylene units in length was studied.
As expected, lengthening of the linker led to increased antima-
larial activity. For compounds 4, 17, 22, and 28, the arms in
the para position were 5, 4, 3, and 1 methylene units long, re-
In vivo biological evaluation
Among the thiazolium salts studied in vitro, 13 derivatives
were also evaluated in vivo against P. vinckei in mice (Table 1).
All the compounds containing oxygen atoms within the linker
showed significant clinical toxicity in mice which prevents their
use at higher doses; such toxicity may therefore conceal their
antimalarial activities. We observed a favorable pharmacologi-
cal profile (i.p. ED50 <5 mgkgꢁ1 and p.o. ED90 <50 mgkgꢁ1) for
compounds 39 and 40, which are also the derivatives that ex-
hibit the best in vitro activity. Both compounds, which have a
phenyl group and two n-butyl chains branched at the para po-
sition, were as potent as the lead compound T3 and were able
to clear the malarial infection in mice at very low doses with
respective ED50 values of 2.2 and 0.13 mgkgꢁ1 after i.p. admin-
istration and ED90 values of 53 and 12 mgkgꢁ1 after p.o. admin-
istration.
Table 1. Selected data from in vitro and in vivo antimalarial evaluations.
Compd IC50 [nm][a]
ED50 i.p.[b]
[mgkgꢁ1 [mmolkgꢁ1
ED90 p.o.[b]
[mgkgꢁ1 [mmolkgꢁ1
]
]
]
]
T3
4
5
2.25
66
0.2[c]
0.28
1.5
7.5
25
60
>90
>90
35
90
135
135
Conclusions
>1[d]
61
110
215
180
425
31.5
170
77.5
>5[c]
>5[c]
In addition to the physicochemical parameters described by
Lipinski et al.,[18] other properties[19,20] have been related to oral
bioavailability. Among them, decreased molecular flexibility
(which may be related to the number of rotatable bonds) has
been reported as an important predictor for good oral bio-
availability, independent of molecular weight.[20] Thus, a new
series of bis-thiazolium salts were envisaged to optimize the
molecular properties of the corresponding parent drug T3, and
we initially focused on the study of analogues containing an
aromatic ring. These derivatives were efficiently prepared from
dibromo or ditoluenesulfonyl linker intermediates using micro-
wave irradiation and were evaluated in vitro and in vivo for
their antimalarial properties. The structure–activity relation-
ships suggest that the optimal linker construct is an aromatic
moiety branched with two n-butyl chains at the para position.
Two promising compounds, 39 and 40, incorporating modified
6
7.5
17
18
19
29
30
37
38
39
40
ND
ND
ND
>1[d]
>5[c]
>5[c]
>1[d]
>0.5[d]
>1[d]
2.2[c]
1.7
8.4
7.2
1.6
0.97
1.8
4.0
>90
>90
>90
>90
>120
152
152
130
145
232
36.5
20.5
9
53
12
97
21
0.13[c]
0.23
[a] P. falciparum: data represent the mean of at least two independent ex-
periments carried out in duplicate. [b] P. vinckei antimalarial activities (ef-
fective dose, ED50 or ED90 values) were determined after intraperitoneal
(i.p.) or oral (p.o.) administration of the compounds to infected mice once
daily for four days; ND=not determined. [c] No sign of clinical toxicity
was observed after i.p. or p.o. administration at the doses used.
[d] Treatment at higher doses was stopped due to the appearance of ini-
tial clinical signs of toxicity.
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4.88 min; MS (ESI+): 253.2 [(Mꢁ2Br)/2]2+, 585.3 [MꢁBr]+, 619.3
[Mꢁ2Br+TFA]+; HRMS (TOF-ESI+) calcd for C26H38BrN2O4S2
[MꢁBr]+: 585.1456, found: 585.1447.
3-Bromopropoxy-tert-butyldimethylsilane (7). The title com-
pound was prepared, according to the procedure described by
Choi et al.,[21] from 3-bromopropan-1-ol (1.1 g, 7.19 mmol), tert-bu-
tyldimethylsilyl chloride (1.19 g, 7.19 mmol), imidazole (539 mg,
7.19 mmol), and DMF (6 mL); 1H NMR (300 MHz, CDCl3): d=0 (s,
6H, 2CH3), 0.83 (s, 9H, 3CH3), 1.96 (q, J=6.1 and 4.2 Hz, 2H, CH2),
3.45 (t, J=6.4 Hz, CH2Br), 3.66 ppm (t, J=4 Hz, CH2O); 13C NMR
(75 MHz, CDCl3): d=ꢁ5.4 (2SiCH3), 18.0 (Cq), 26.1 (SitBu), 30.6
(CH2Br), 35.4 (CH2), 60.4 ppm (CH2O).
linkers were identified and were able to cure malarial infection
at very low doses in mice. Synthesis of the corresponding neu-
tral precursors is currently in progress, and will allow evalua-
tion, at the prodrug level, of the influence of decreased molec-
ular flexibility on oral bioavailability.
Experimental Section
General procedure A for the preparation of bis(4-bromobutox-
y)methylbenzene and bromobutoxybenzene compounds 1–3
Benzenedimethanol or benzenediol and Bu4NHSO4 (0.2 equiv) were
dissolved in aqueous 4n NaOH (5 equiv), and 1,4-dibromobutane
(10 equiv) was added. The mixture was stirred for 48 h at 808C.
The aqueous layer was extracted with CHCl3. The organic layer was
washed twice with H2O and dried over Na2SO4. The solvent was re-
moved in vacuo, and the residue was purified by column chroma-
tography (cyclohexane/EtOAc 9.5:0.5!9:1) to afford bis[(4-bromo-
General procedure C for the preparation of bis[3-(tert-butyldi-
methylsilyloxy)propoxy]benzenes 8–10
Benzenediol and K2CO3 (2.5 equiv) were suspended in anhydrous
DMF (2.2 mLmmolꢁ1), and the mixture was stirred at room temper-
ature. After 30 min, a solution of 3-bromopropoxy-tert-butyldime-
thylsilane 7 (2.5 equiv) in DMF (0.2 mLmmolꢁ1) was added drop-
wise, and the reaction mixture was heated at 1008C for 48 h. The
solvent was evaporated under reduced pressure. The residue was
dissolved in EtOAc and washed successively with H2O, brine, and fi-
nally dried over Na2SO4. The solvent was removed in vacuo, and
the residue was purified by column chromatography (PE/Et2O
9.6:0.4) to afford the expected bis[3-(tert-butyldimethylsilyloxy)pro-
poxy]benzene as a colorless liquid.
butoxy)methyl]benzene or bromobutoxybenzene as
powder.
a white
1,4-bis(4-bromobutoxy)benzene (1). According to procedure A,
the title compound (2.5 g, 71%) was obtained from hydroquinone
(1.02 g, 9.08 mmol), NaOH (1.82 g, 46.3 mmol), 1,4-dibromobutane
(10.7 mL, 90.8 mmol), Bu4NHSO4 (0.61 mg, 1.85 mmol), and H2O
(11 mL); 1H NMR (300 MHz, CDCl3): d=1.75–2.10 (m, 8H, 4CH2),
3.41 (t, J=6.5 Hz, 4H, CH2Br), 3.88 (t, J=6 Hz, 4H, CH2OPh),
6.74 ppm (s, 4H, CHar); 13C NMR (75 MHz, CDCl3): d=26.9
(CH2CH2OPh), 28.0 (CH2CH2Br), 33.4 (CH2Br), 67.5 (CH2OPh), 115.4
(CHar), 153.1 ppm (Cqar); HPLC (conditions A): 3.01 min; MS (FAB+,
NBA): 378 [M+H]+.
1,4-bis[3-(tert-butyldimethylsilyloxy)propoxy]benzene (8). Ac-
cording to procedure C, the title compound (0.818 g, 41%) was ob-
tained from hydroquinone (0.348 g, 3.15 mmol), K2CO3 (1.04 g,
7.84 mmol), and 3-bromopropoxy-tert-butyldimethylsilane 7 (2 g,
1
7.84 mmol); H NMR (300 MHz, CDCl3): d=0 (s, 6H, 2CH3), 0.84 (s,
General procedure B for the preparation of bis-thiazolium
salts 4–6, 17–19, 22, 23, 27–31, and 37–40
9H, 3CH3), 1.91 (quintet, J=6.13 Hz, 4H, CH2), 3.75 (t, J=6.05 Hz,
4H, CH2OSi), 3.96 (t, J=6.23 Hz, 4H, CH2OPh), 6.78 ppm (s, 4H,
CHar); 13C NMR (75 MHz, CDCl3): ꢁ5.4 (4CH3), 18.3 (2CqSi), 25.9
(6CH3), 32.5 (2CH2), 59.6 (2CH2OSi), 65.1 (2CH2OPh), 115.3 (2CHar),
153.1 ppm (2Cqar); HPLC (conditions B): 17.03 min; MS (ESI+): 455.1
[M+H]+.
In a sealed 5 mL pressure vial, the appropriate dibromo or ditolue-
nesulfonyl linker was added to a solution of 4-methyl-5-(2-hydroxy-
ethyl)thiazole (3 equiv) in CH3CN. After MW irradiation (400 W), H2O
was added, and the mixture was extracted with Et2O. The aqueous
layer was concentrated under reduced pressure. When required,
the toluenesulfonate counter-ions were exchanged with chloride
by adding to the aqueous phase a Dowex resin (1ꢃ8–400, Clꢁ
form). After stirring for 1 h, the resin was filtered off, and the fil-
trate was evaporated to dryness. The residue was dissolved in a
minimal amount of iPrOH, and the product was precipitated from
Et2O.
General procedure D for the preparation of 3,3’-[1,4-
phenylenebis(oxy)]dipropan-1-ols 11–13
A methanolic solution of HCl (1.25m, 0.35 mLmmolꢁ1) was added
to an ice-cold solution of bis[3-(tert-butyldimethylsilyloxy)propoxy]-
benzene in anhydrous MeOH (2 mLmmolꢁ1). The mixture was
stirred for 1 h at room temperature, and then the solvent was
evaporated under reduced pressure. The residue was dissolved in
EtOAc and washed successively with H2O, brine, and finally dried
over Na2SO4. The solvent was removed in vacuo to afford the ex-
3,3’-{4,4’-[1,4-phenylenebis(oxy)]bis(butane-4,1-diyl)}bis[5-(2-hy-
droxyethyl)-4-methylthiazol-3-ium] bromide (4). According to
procedure B, the title compound was obtained from 1,4-bis(4-bro-
mobutoxy)benzene 1 (420 mg, 1.10 mmol), 4-methyl-5-(2-hydroxy-
ethyl)thiazole (0.53 mL, 4.42 mmol), and CH3CN (0.44 mL) after
5.5 h under MW irradiation at 1008C. The compound was purified
by precipitation and then RP-18 chromatography (gradient: H2O!
H2O/MeOH 9:1) to afford a yellow hygroscopic powder (491 mg,
67%); 1H NMR (300 MHz, [D6]DMSO): d=1.70–2.05 (m, 8H, 4CH2),
2.48 (s, 6H, CH3), 3.03 (t, J=5.4 Hz, 4H, 2CH2CH2OH), 3.65 (q, J=
5.3 Hz, 4H, 2CH2CH2OH), 3.95 (t, J=6.0 Hz, 4H, 2CH2OPh), 4.55 (t,
J=7.4 Hz, 4H, 2CH2N+), 5.21 (t, J=5 Hz, 2H, 2OH), 6.86 (s, 4H,
CHar), 10.09 ppm (s, 2H, CHthiazole); 13C NMR (75 MHz, [D6]DMSO): d=
11.2 (2CH3), 25.4, 25.8 (2CH2), 29.4 (2CH2CH2OH), 52.4 (2CH2N+),
59.6 (2CH2OH), 67.1 (2CH2OPh), 115.3 (4CHar), 135.5 (2CqS), 141.5
(2CqN+), 152.5 (2Cqar), 156.2 ppm (2CHthiazole); HPLC (conditions B):
pected 3,3’-[1,4-phenylenebis(oxy)]dipropan-1-ol as
a
white
powder. The compound was used directly without further purifica-
tion.
3,3’-[1,4-phenylenebis(oxy)]dipropan-1-ol (11). According to pro-
cedure D, the title compound (0.269 g, 88%) was obtained from
1,4-bis[3-(tert-butyldimethylsilyloxy)propoxy]benzene
8
(0.763 g,
1.19 mmol), MeOH (3 mL), and a methanolic solution of HCl
1
(0.5 mL); H NMR (300 MHz, CDCl3): d=1.85 (quintet, J=4H, CH2),
3.55 (q, 4H, CH2OH), 3.98 (t, J= Hz, 4H, CH2OPh), 4.55 (t, J= Hz,
2H, OH), 6.85 ppm (s, 4H, CHar); 13C NMR (75 MHz, CDCl3): d=37.44
(CH2), 62.6 (CH2OH), 70.1 (CH2OPh), 120.4 (CH), 157.8 ppm (Cqar);
HPLC (conditions A): 1.58 min; MS (ESI+): 227.2 [M+H]+.
1106
www.chemmedchem.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2010, 5, 1102 – 1109

Bis-Thiazolium Salts as Potential Antimalarial Drugs
3,3’-{2,2’-[1,4-phenylenebis(oxy)]bis(ethane-2,1-diyl)}bis[5-(2-hy-
droxyethyl)-4-methylthiazol-3-ium] chloride (22). According to
procedure B, the title compound was obtained from intermediate
21 (500 mg, 0.99 mmol), 4-methyl-5-(2-hydroxyethyl)thiazole
(0.355 mL, 2.96 mmol), and CH3CN (0.8 mL) after 1 h under MW irra-
diation at 1508C. After ion-exchange chromatography, the com-
pound was isolated by precipitation to afford a yellow hygroscopic
General procedure E for the preparation of 3,3’-[phenylenebis-
(oxy)]bis(propane-3,1-diyl)bis(4-methylbenzenesulfonates) 14–
16, 20, 21, 33, 35, and 36
Anhydrous pyridine or Et3N (4–6 equiv) and toluene-4-sulfonyl
chloride (3 equiv) were added to an ice-cold solution of 3,3’-
[phenylenebis(oxy)]dipropan-1-ol
in
anhydrous
CH2Cl2
1
(4 mLmmolꢁ1). In a few cases 4-(dimethylamino)pyridine (0.2 equiv)
was also added. The mixture was stirred for 16 h at room tempera-
ture and then diluted with CH2Cl2. The organic layer was washed
successively with H2O, brine, and finally dried over Na2SO4. The sol-
vent was removed in vacuo, and the residue was purified by
column chromatography (cyclohexane/EtOAc 8:2) to afford the ex-
powder (310 mg, 60%); H NMR (300 MHz, CDCl3): d=2.53 (s, 6H,
2CH3), 3.04 (t, J=5.5 Hz, 4H, 2CH2CH2OH), 3.63 (q, J=5.4 Hz, 4H,
2CH2CH2OH), 4.36 (t, J=4.7 Hz, 4H, 2CH2OPh), 4.90 (t, J=4.7 Hz,
4H, 2CH2N+), 5.39 (t, J=5.0 Hz, 2H, OH), 6.87 (s, 4H, CHar),
10.17 ppm (s, 2H, CHthiazole); 13C NMR (75 MHz, CDCl3): d=11.5
(2CH3), 29.4 (2CH2CH2OH), 51.9 (2CH2N+), 59.5 (2CH2CH2OH), 65.8
(2CH2OPh), 115.6 (4CHar), 135.0 (2CqS), 141.8 (2CqN+), 152.0 (2Cqar),
157.7 ppm (2CHthiazole); HPLC (conditions B): 3.90 min; MS (ESI+):
225.1 [(Mꢁ2Cl)/2]2+, 485.2 [MꢁCl]+; HRMS (TOF-ESI+) calcd for
pected
3,3’-[phenylenebis(oxy)]bis(propane-3,1-diyl)bis(4-methyl-
benzenesulfonate).
C22H30ClN2O4S2 [MꢁCl]+: 485.1336, found: 485.1326.
+
3,3’-[1,4-phenylenebis(oxy)]bis(propane-3,1-diyl)bis(4-methyl-
benzenesulfonate) (14). According to procedure E, the title com-
pound (626.1 mg, 88%) was obtained as a white powder from 3,3’-
[1,4-phenylenebis(oxy)]dipropan-1-ol 11 (300 mg, 1.32 mmol), tolu-
ene-4-sulfonyl chloride (708 mg, 3.71 mmol), Et3N (0.74 mL,
5.3 mmol), and CH2Cl2 (8 mL); 1H NMR (200 MHz, CDCl3): d=2.11
(quintet, J=5.9 Hz, 4H, 2CH2), 2.42 (s, 6H, 2CH3), 3.92 (t, J=5.9 Hz,
4H, CH2OTs), 4.26 (t, J=6.0 Hz, 4H, 2CH2OPh), 6.69 (s, 4H, CHar),
7.28 (d, J=8.0 Hz, 2H, CHarTos), 7.78 ppm (d, J=8.3 Hz, 1H, CHarTos);
13C NMR (75 MHz, CDCl3): d=21.6 (CH3), 29.0 (CH2), 63.7 (CH2OTs),
67.1 (CH2OPh), 115.3 (2CHar), 127.8 (CHarTos), 129.8 (CHarTos), 132.9
(Cq-Me), 144.8 (Cq-SO2), 152.8 ppm (Cq-O); HPLC (conditions B):
2.84 min; MS (ESI+): 363.1 [MꢁTsO]+, 535.1 [M+H]+.
1,4-bis[(4-bromobutoxy)methyl]benzene (24). According to pro-
cedure A, the title compound was obtained as a white powder
(3.1 g, 53%) from 1,4-benzenedimethanol (2 g, 14.47 mmol), NaOH
(2.88 g, 72.3 mmol), 1,4-dibromobutane (17 mL, 144.7 mmol),
1
Bu4NHSO4 (0.98 g), and H2O (18 mL); H NMR (200 MHz, CDCl3): d=
1.60–2.00 (m, 8H, 4CH2), 3.30–3.5 (m, 8H, CH2Br), 4.42 (s, 4H,
PhCH2O), 7.22 ppm (m, 4H, CHar); 13C NMR (75 MHz, CDCl3): d=
26.9 (CH2CH2OPh), 28.3 (CH2CH2Br), 33.8 (CH2Br), 69.2 (CH2OPh),
72.7 (PhCH2O), 127.7 (CHar), 137.8 ppm (Cqar); HPLC (conditions A):
2.28 min; MS (ESI+): 406.7 [M+H]+.
3,3’-{4,4’-[1,3-phenylenebis(methylene)]bis(oxy)bis(butane-4,1-
diyl)}bis[5-(2-hydroxyethyl)-4-methylthiazol-3-ium] bromide (29),
5-(2-hydroxyethyl)-3-[3-({4-[5-(2-hydroxyethyl)-4-methylthiazol-
5-(2-hydroxyethyl)-3-[3-(4-{3-[5-(2-hydroxyethyl)thiaz-ol-3-ium-3-
yl]propoxy}phenoxy)propyl]-4-methylthiaz-ol-3-ium
chloride
3-ium-3-yl]butoxy}methyl)benzyl]-4-methylthiazol-3-ium
bro-
(17). According to procedure B, the title compound was obtained
from 1,3-bis(4-bromobutoxy)benzene 2 (500 mg, 1.31 mmol), 4-
methyl-5-(2-hydroxyethyl)thiazole (0.47 mL, 3.95 mmol), and CH3CN
(0.5 mL) after 5.5 h under MW irradiation at 1008C. The compound
was isolated by precipitation to afford a yellow hygroscopic
mide (30), and 3,3’-[1,3-phenylenebis(methylene)]bis[5-(2-hy-
droxyethyl)-4-methylthiazol-3-ium] bromide (31). According to
procedure B, the title compounds were obtained from 1,3-bis[(4-
bromobutoxy)methyl]benzene 25 (500 mg, 1.23 mmol), 4-methyl-5-
(2-hydroxyethyl)thiazole (0.442 mL, 3.68 mmol), and CH3CN
(1.2 mL) after 1 h under MW irradiation at 1508C. The crude was
purified by RP-18 chromatography (gradient: H2O!H2O/MeOH
8:2) to afford compounds 29 (110 mg, 13%) and 30 (156 mg, 20%)
as yellow hygroscopic powders, and 31 as a white solid (39 mg,
6%). Compound 29: 1H NMR (300 MHz, [D6]DMSO): d=1.62 (m,
4H, 2CH2), 1.87 (m, 4H, 2CH2), 2.49 (s, 6H, 2CH3), 3.05 (t, J=5.5 Hz„
4H, 2CH2CH2OH), 3.49 (t, J=6.2 Hz, 4H, 2CH2O), 3.64 (q, J=5.3 Hz,
4H, 2CH2CH2OH), 4.46 (s, 4H, 2PhCH2O), 4.51 (t, J=7.5 Hz, 4H,
2CH2N+), 5.20 (t, J=5.0 Hz, 2H, OH), 7.15–7.45 (m, 4H, CHar),
10.12 ppm (s, 2H, CHthiazole); 13C NMR (75 MHz, CDCl3): d=11.2
(2CH3), 25.8, 26.0 (2CH2), 29.5 (2CH2CH2OH), 52.5 (CH2N+), 59.6
(2CH2CH2OH), 68.9 (2CH2O), 71.8 (PhCH2O), 126.6, 128.2 (4CHar),
135.4 (2CqS), 139.6 (Cqar), 141.5 (2CqN+), 156.2 ppm (2CHthiazole);
1
powder (586 mg, 66%); H NMR (300 MHz, CDCl3): d=2.28 (m, 4H,
2CH2), 2.48 (s, 6H, CH3), 3.04 (t, J=5.6 Hz, 4H, 2CH2CH2OH), 3.65 (q,
J=5.3 Hz, 4H, 2CH2CH2OH), 4.02 (t, J=5.6 Hz, 4H, 2CH2OPh), 4.66
(t, J=6.9 Hz, 4H, 2CH2N+), 5.33 (t, J=5.0 Hz, 2H, 2OH), 6.81 (s, 4H,
CHar), 10.14 ppm (s, 2H, CHthiazole); 13C NMR (75 MHz, [D6]DMSO): d=
11.2 (2CH3), 28.5 (2CH2), 29.4 (2CH2CH2OH), 50.5 (2CH2N+), 59.6
(2CH2OH), 65.0 (2CH2OPh), 115.2 (4CHar), 135.3 (2CqS), 141.6 (2CqN+),
152.2 (2Cqar) 156.7 ppm (2CHthiazole); HPLC (conditions B): 6.07 min;
MS (ESI+): 239.1 [(Mꢁ2Cl)/2]2+, 591.2 [Mꢁ2Cl+TFA]+; HRMS (TOF-
+
ESI+) calcd for C24H34BrN2O4S2
513.1657.
[MꢁBr]+: 513.1649, found:
2,2’-[1,4-phenylenebis(oxy)]bis(ethane-2,1-diyl)bis(4-methylben-
zenesulfonate) (20). According to procedure E, the title compound
(5.57 mg, 72%) was obtained as a white powder from 1,4-bis(2-hy-
droxyethoxy)benzene (3 g, 15.13 mmol), toluene-4-sulfonyl chloride
(8.63 g, 45.4 mmol), pyridine (7.3 mL, 90.8 mmol), and CH2Cl2
(45 mL) and after purification by column chromatography (CH2Cl2/
PE 8:2!CH2Cl2/MeOH 9.8:0.2); 1H NMR (300 MHz, CDCl3): d=2.03
(quintet, J=5.9 Hz, 4H, 2CH2), 2.31 (s, 6H, 2CH3), 3.85 (t, J=5.8 Hz,
4H, CH2OTs), 4.16 (t, J=6.0 Hz, 4H, 2CH2OPh), 6.14 (t, J=2.3 Hz,
1H, CHar), 6.29 (dd, J=2.3 and 8.2 Hz, 2H, CHar), 7.04 (t, J=8.2 Hz,
1H, CHar), 7.19 (d, J=8.0 Hz, 2H, CHarTos), 7.68 ppm (d, J=8.3 Hz,
1H, CHarTos); 13C NMR (75 MHz, CDCl3): 22.6 (CH3), 66.2 (CH2OTs),
68.2 (CH2OPh), 115.7 (CHar), 128.0 (CHarTos), 129.8 (2CHarTos), 132.9
(Cq-Me), 144.9 (Cq-SO2), 152.7 ppm (Cq-O); HPLC (conditions A):
2.78 min; MS (ESI+): 335.2 [MꢁTsO]+, 507.2 [M+H]+.
HPLC (conditions B): 5.01 min; MS (ESI+): 267.2 [(Mꢁ2Br)/2]2+
,
615.3 [MꢁBr]+, 647.4 [Mꢁ2Br+TFA]+; HRMS (TOF-ESI+) calcd for
C28H42BrN2O4S2 [MꢁBrꢁ]+: 613.1769, found: 613.1746. Compound
+
30: 1H NMR (300 MHz, [D6]DMSO): d=1.62 (m, 2H, CH2), 1.89 (m,
2H, CH2), 2.39 (s, 3H, CH3), 2.49 (s, 3H, CH3), 3.03 (m, 4H,
2CH2CH2OH), 3.30–3.80 (m, 6H, CH2O and 2CH2CH2OH), 4.50 (m,
4H, CH2N+ and CH2OPh), 5.87 (s, 2H, PhCH2N+), 7.10–760 (m, 4H,
CHar), 10.15 (s, 1H, CHthiazole) 10.24 ppm (s, 1H, CHthiazole); 13C NMR
(75 MHz, CDCl3): d=11.3, 11.6 (2CH3), 25.7, 26.0 (2CH2), 29.4
(2CH2CH2OH), 52.5 (CH2N+), 55.6 (PhCH2N+), 59.6 (2CH2CH2OH),
68.9 (CH2O), 71.4 (PhCH2O), 126.9, 127.0, 127.9, 129.2 (4CHar), 133.0
(Cqar), 135.4, 136.2 (2CqS), 139.6 (Cqar), 141.5, 141.6 (2CqN+), 156.2,
157.0 ppm (2CHthiazole); HPLC (conditions B): 4.22 min; MS (ESI+):
ChemMedChem 2010, 5, 1102 – 1109
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
1107

S. Peyrottes et al.
MED
1
231.2 [(Mꢁ2Br)/2]2+, 543.3 [MꢁBr]+, 575.3 [Mꢁ2Br+TFA]+; HRMS
(40 mL); H NMR (300 MHz, CDCl3): d=1.85 (m, 4H, 2CH2), 2.39 (s,
6H, 2CH3), 2.53 (t, J=7.6 Hz, 4H, CH2OTs), 3.95 (t, J=6.2 Hz, 4H,
2CH2Ph), 6.88 (s, 4H, CHar), 7.26 (d, J=8.0 Hz, 2H, CHarTos), 7.72 ppm
(d, J=8.3 Hz, 1H, CHarTos); 13C NMR (75 MHz, CDCl3): d=21.6 (CH3),
30.5 (CH2), 31.0 (CH2OTs), 69.6 (CH2Ph), 127.9 (CHar), 128.5 (CHarTos),
129.8 (CHarTos), 133.1 (Cq-Me), 138.2 (Cqar) 144.7 ppm (Cq-SO2);
HPLC (conditions A): 2.82 min; MS (ESI+): 331.2 [MꢁTsO]+, 503.3
[M+H]+.
(TOF-ESI+) calcd for C24H34BrN2O3S2 [MꢁBr]+: 541.1194, found:
+
1
541.1216. Compound 31: H NMR (300 MHz, [D6]DMSO): d=2.35 (s,
6H, 2CH3), 3.05 (t, J=5.5 Hz, 4H, 2CH2CH2OH), 3.66 (t, J=5.5 Hz,
4H, 2CH2CH2OH), 5.88 (s, 4H, 2PhCH2N+), 7.40 (m, 3H, 4CHar), 7.56
(t, J=7.6 Hz, 1H, CHar), 10.24 ppm (s, 2H, CHthiazole); 13C NMR
(75 MHz, CDCl3): d=11.6 (2CH3), 29.4 (2CH2CH2OH), 55.3 (PhCH2N+),
59.6 (2CH2CH2OH), 127.5, 128.3, 130.1 (4CHar), 134.1 (Cqar), 136.2
(2CqS), 141.6 (2CqN+), 157.2 ppm (2CHthiazole); HPLC (conditions B):
3.27 min; MS (ESI+): 195.1 [(Mꢁ2Br)/2]2+, 469.2 [MꢁBr]+; HRMS
4,4’-(1,4-phenylene)bis(butane-4,1-diyl)bis(4-methylbenzene sul-
fonate) (36). According to procedure E, the title compound
(4.73 mg, 78%) was obtained as a white powder from 4,4’-(1,4-phe-
nylene)dibutan-1-ol (2.62 g, 11.8 mmol), toluene-4-sulfonyl chloride
(TOF-ESI+) calcd for C20H26BrN2O2S2 [MꢁBr]+: 469.0619, found:
+
469.0618.
2,2’-[1,4-phenylenebis(methylene)]bis(oxy)diethanol (32). Ethyl-
ene glycol (2.78 mL, 45.46 mmol) dissolved beforehand in anhy-
drous THF (10 mL) was added dropwise to a solution of NaH
(666 mg, 16.6 mmol) in anhydrous THF (10 mL). After stirring for
30 min, 1,4-bis(bromomethyl)benzene (2 g, 7.58 mmol) was added,
and the mixture was held at reflux overnight. The solvent was re-
moved in vacuo, and the residue was purified by column chroma-
tography (PE/EtOAc 3:7!1:9) to afford the expected compound
(6.75 g,
35.40 mmol),
4-(dimethylamino)pyridine
(144 mg,
1.18 mmol), pyridine (5.7 mL, 70.8 mmol), and CH2Cl2 (30 mL);
1H NMR (300 MHz, CDCl3): d=1.50–1.90 (m, 8H, 4CH2), 2.35–2.70 (s,
10H, 2CH2OTs, 2CH3), 4.07 (t, J=6 Hz, 4H, 2CH2Ph), 7.02 (s, 4H,
CHar), 7.38 (d, J=8 Hz, 2H, CHarTos), 7.82 ppm (d, J=8 Hz, 1H,
CHarTos); 13C NMR (75 MHz, CDCl3): d=21.6 (CH3), 27.1 (CH2), 28.3
(CH2), 34.6 (CH2OTs), 70.4 (CH2Ph), 127.9 (CHar), 128.7 (CHarTos), 130.2
(CHarTos), 133.1 (Cq-Me), 139.1 (Cqar) 144.7 ppm (Cq-SO2); HPLC (con-
ditions A): 13.57 min; MS (ESI+): 531.3 [M+H]+.
1
32 as a colorless oil (1.16 g, 68%); H NMR (300 MHz, CDCl3): d=
3.50 (m, 4H, 2CH2OH), 3.70 (m, 4H, 2CH2), 4.53 (s, 4H, 2CH2Ph),
7.32 ppm (s, 4H, CHar); 13C NMR (75 MHz, CDCl3): d=61.8 (2CH2OH),
71.4 (2CH2O), 73.0 (2CH2Ph), 127.8 (4CHar), 137.5 ppm (2Cqar); HPLC
(conditions B): 4.71 min; MS (ESI+): 227.1 [M+H]+.
3,3’-[3,3’-(1,4-phenylene)bis(propane-3,1-diyl)]bis[5-(2-hydroxy-
ethyl)-4-methylthiazol-3-ium] chloride (37). According to proce-
dure B, the title compound was obtained from 3,3’-(1,4-phenylene)-
bis(propane-3,1-diyl)bis(4-methylbenzenesulfonate)
1.99 mmol), 4-methyl-5-(2-hydroxyethyl)thiazole
32
(0.715 mL,
(1 g,
2,2’-[1,4-phenylenebis(methylene)]bis(oxy)bis(ethane-2,1-diyl)-
bis(4-methylbenzenesulfonate) (33). According to procedure E,
the title compound was obtained as a white powder (770 mg,
46%) from 32 (0.7 g, 3.09 mmol), toluene-4-sulfonyl chloride
(1.78 g, 9.28 mmol), pyridine (1.49 mL, 18.56 mmol), and CH2Cl2
(10 mL); 1H NMR (300 MHz, CDCl3): d=2.35 (s, 6H, 3.50) 3.57 (m,
4H, 2CH2), 4.11 (m, 4H, 2CH2), 4.39 (s, 4H, 2CH2Ph), 7.14 (s, 4H,
CHar), 7.23 (d, J=8.0 Hz, 2H, CHarTos), 7.71 ppm (d, J=8.3 Hz, 1H,
CHarTos); 13C NMR (75 MHz, CDCl3): d=14.1 (2CH3), 67.5 (2CH2OTs),
69.3 (2CH2O), 72.9 (2CH2Ph), 127.3 (CHar), 128.0 (CHarTos), 129.8
(2CHarTos), 133.0 (Cq-Me), 137.2 (Cq-CH2O), 144.9 ppm (Cq-SO2);
HPLC (conditions B): 11.97 min; MS (ESI+): 535.3 [M+H]+.
5.97 mmol), and CH3CN (0.8 mL) after 1 h under MW irradiation at
1508C. After ion-exchange chromatography, the compound was
purified by precipitation to afford a yellow hygroscopic powder
1
(573 mg, 51%); H NMR (300 MHz, [D6]DMSO): d=2.05–2.3 (m, 4H,
2CH2), 2.45 (s, 6H, CH3), 2.65 (t, J=7.7 Hz, 4H, 2CH2Ph), 3.02 (t, J=
5.5 Hz, 4H, 2CH2CH2OH), 3.61 (t, J=5.5 Hz, 4H, 2CH2CH2OH), 4.51 (t,
J=7.4 Hz, 4H, 2CH2N+), 7.17 (s, 4H, CHar), 10.2 ppm (s, 2H,
CHthiazole); 13C NMR (75 MHz, [D6]DMSO): d=11.2 (2CH3), 29.4
(2CH2CH2OH), 30.2 (2CH2), 31.1 (2CH2Ph), 52.4 (2CH2N+), 59.5
(2CH2OH), 128.2 (4CHar), 135.3 (2CqS), 138.0 (2Cqar), 141.4 (2CqN+),
156.1 ppm (2CHthiazole); HPLC (conditions B): 4.35 min; MS (ESI+):
223.2 [(Mꢁ2Cl)/2]2+, 481.3 [MꢁCl]+, 559.3 [Mꢁ2Cl+TFA]+; HRMS
(TOF-ESI+) calcd for C24H34ClN2O2S2 [MꢁCl]+: 481.1750, found:
+
3,3’-{2,2’-[1,4-phenylenebis(methylene)]bis(oxy)bis(ethane-2,1-
diyl)}bis[5-(2-hydroxyethyl)-4-methylthiaz-ol-3-ium]
chloride
481.1768.
(34). According to procedure B, the title compound was obtained
from 33 (357 mg, 0.667 mmol), 4-methyl-5-(2-hydroxyethyl)thiazole
(0.24 mL, 2.0 mmol), and CH3CN (0.5 mL) after 1 h under MW irradi-
ation at 1508C. After ion-exchange chromatography, the com-
pound was purified by precipitation and then RP-18 chromatogra-
phy (gradient: H2O!H2O/MeOH 8.5:1.5) to afford a white powder
(273 mg, 74%); 1H NMR (300 MHz, [D6]DMSO): d=2.46 (s, 6H,
2CH3), 3.04 (t, J=5.6 Hz, 4H, 2CH2CH2OH), 3.64 (m, 4H,
2CH2CH2OH), 3.85 (t, 4H, J=4.8 Hz, 2CH2O), 4.50 (s, 4H, 2PhCH2O),
4.76 (t, J=4.8 Hz, 4H, 2CH2N+), 5.47 (m, 2H, OH), 7.17 (s, 4H, CHar),
10.14 ppm (s, 2H, CHthiazole); 13C NMR (75 MHz, CDCl3): d=16.2
(2CH3), 34.2 (2CH2CH2OH), 57.1 (CH2N+), 64.3 (2CH2CH2OH), 71.6
(2CH2O), 76.3 (PhCH2O), 132.1 (4CHar), 139.7 (2CqS), 141.8 (Cqar),
146.5 (2CqN+), 162.0 ppm (2CHthiazole); HPLC (conditions B):
4.23 min; MS (ESI+): 239.1 [(Mꢁ2Cl)/2]2+, 513.3 [MꢁCl]+, 591.3
3,3’-[4,4’-(1,4-phenylene)bis(butane-4,1-diyl)]bis[5-(2-hydroxy-
ethyl)-4-methylthiazol-3-ium] chloride (38). According to proce-
dure B, the title compound was obtained from 4,4’-(1,4-phenylene)-
bis(butane-4,1-diyl)bis(4-methylbenzenesulfonate)
2.98 mmol), 5-(2-hydroxyethyl)-4-methylthiazole
34
(1.5 g,
(1.4 mg,
8.95 mmol), and CH3CN (5.5 mL) after 1.5 h under MW irradiation at
1508C. After ion-exchange chromatography, the compound was
purified by precipitation and then RP-18 chromatography (gradi-
ent: H2O!H2O/MeOH 8.5:1.5) to afford a white powder (827 mg,
51%); 1H NMR (300 MHz, [D6]DMSO): d=2.05–2.25 (m, 4H, 2CH2),
2.45 (s, 6H, CH3), 2.65 (t, J=7.7 Hz, 4H, 2CH2Ph), 3.13 (t, J=5.7 Hz,
4H, 2CH2CH2OH), 3.30 (s, 6H, OCH3), 3.56 (t, J=5.7 Hz, 4H,
2CH2CH2OH), 4.53 (t, J=7.4 Hz, 4H, 2CH2N+), 7.17 (s, 4H, CHar),
10.3 ppm (s, 2H, CHthiazole); 13C NMR (75 MHz, [D6]DMSO): d=11.2
(2CH3), 26.5 (2CH2CH2OH), 30.2 (2CH2), 31.2 (2CH2Ph), 52.4 (2CH2N+),
58.0 (2OCH3), 70.2 (2CH2OH), 128.2 (4CHar), 134.9 (2CqS), 138.0
(2Cqar), 141.6 (2CqN+), 156.8 ppm (2CHthiazole); HPLC (conditions B):
[Mꢁ2Cl+TFA]+; HRMS (TOF-ESI+) calcd for C24H34ClN2O4S2
+
[MꢁCl]+: 513.1649, found: 513.1625.
4.98 min; HRMS (TOF-ESI+) calcd for C26H38ClN2O2S2 [MꢁCl]+:
+
3,3’-(1,4-phenylene)bis(propane-3,1-diyl)bis(4-methylbenzene
sulfonate) (35). According to procedure E, the title compound was
obtained as a white powder (3.79 mg, 73%) from 3,3’-(1,4-phenyl-
ene)dipropan-1-ol (2 g, 10.29 mmol), toluene-4-sulfonyl chloride
(5.9 g, 30.88 mmol), pyridine (4.97 mL, 61.76 mmol) and CH2Cl2
509.2063, found: 509.2052.
5-(2-hydroxyethyl)-3-[4-(4-{4-[5-(2-hydroxyethyl)thiaz-ol-3-ium-3-
yl]butyl}phenyl)butyl]-4-methylthiazol-3-ium chloride (39). Ac-
1108
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ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2010, 5, 1102 – 1109

Bis-Thiazolium Salts as Potential Antimalarial Drugs
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cording to procedure B, the title compound was obtained from
4,4’-(1,4-phenylene)bis(butane-4,1-diyl)bis(4-methylbenzenesulfo-
nate) 34 (0.517 g, 0.975 mmol), 4-methyl-5-(2-hydroxyethyl)thiazole
(0.350 mL, 2.82 mmol), and CH3CN (1 mL) after 1 h under MW irra-
diation at 1508C. After ion-exchange chromatography, the com-
pound was purified by precipitation and then RP-18 chromatogra-
phy (gradient: H2O!H2O/MeOH 8.5:1.5) to afford a white powder
1
(315.3 mg, 59%); H NMR (300 MHz, [D6]DMSO): d=1.5–2.0 (m, 8H,
4CH2), 2.45 (s, 6H, CH3), 2.59 (t, J=7.5 Hz, 4H, 2CH2Ph), 3.03 (t, J=
5.5 Hz, 4H, 2CH2CH2OH), 3.63 (q, J=5.4 Hz, 4H, 2CH2CH2OH), 4.52
(t, J=7.2 Hz, 4H, 2CH2N+), 5.41 (t, J=5.1 Hz, 2H, 2OH), 7.12 (m,
4H, CHar), 10.21 ppm (s, 2H, CHthiazole); 13C NMR (75 MHz,
[D6]DMSO): d=11.2 (2CH3), 27.4 (2CH2), 28.4 (2CH2) 29.5
(2CH2CH2OH), 33.9 (2CH2Ph), 52.4 (2CH2N+), 59.6 (2CH2OH), 128.2
(4CHar), 135.5 (2CqS), 138.9 (2Cqar), 141.6 (2CqN+), 156.3 ppm
(2CHthiazole); HPLC (conditions B): 5.18 min; MS (ESI+): 237.2
[(Mꢁ2Cl)/2]2+
,
509.3 [MꢁCl]+; HRMS (TOF-ESI+) calcd for
C26H38ClN2O2S2 [MꢁCl]+: 509.2063, found: 509.2056.
+
3,3’-[4,4’-(1,4-phenylene)bis(butane-4,1-diyl)]bis[5-(2-methoxy-
ethyl)-4-methylthiazol-3-ium] chloride (40). According to proce-
dure B, the title compound was obtained from 4,4’-(1,4-phenylene)-
bis(butane-4,1-diyl)bis(4-methylbenzenesulfonate) 34 (500 mg,
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Parasitol. 2003, 126, 143–154.
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Resistance, and New Directions in Drug Discovery (Ed. P. J. Rosenthal),
Humana Press, Totowa, NJ, 2001, pp. 347–365.
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Agents Chemother. 2003, 47, 2598–2605.
[15] K. Wengelnik, V. Vidal, M. L. Ancelin, A. M. Cathiard, J. L. Morgat, C. H.
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1311–1314.
[16] H. J. Vial, S. Wein, C. Farenc, C. Kocken, O. Nicolas, M. L. Ancelin, F. Bres-
solle, A. Thomas, M. Calas, Proc. Natl. Acad. Sci. USA 2004, 101, 15458–
15463.
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Bressolle, Antimicrob. Agents Chemother. 2005, 49, 3631–3639.
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Rev. 2001, 46, 3–26.
[19] M. A. Navia, P. R. Chaturvedi, Drug Discovery Today 1996, 1, 179–189.
[20] D. F. Veber, S. R. Johnson, H. Y. Cheng, B. R. Smith, K. W. Ward, K. D.
Kopple, J. Med. Chem. 2002, 45, 2615–2623.
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Chem. Soc. 2004, 126, 8606–8607.
9.42 mmol),
5-(2-methoxyethyl)-4-methylthiazole
(0.444 mL,
2.82 mmol), and CH3CN (1 mL) after 1 h under MW irradiation at
1508C. After ion-exchange chromatography, the compound was
purified by precipitation and then RP-18 chromatography (gradi-
ent: H2O!H2O/MeOH 8.5:1.5) to afford a white powder (573 mg,
51%); 1H NMR (300 MHz, [D6]DMSO): d=1.45–2.00 (m, 8H, 4CH2),
2.46 (s, 6H, CH3), 2.59 (t, J=7.6 Hz, 4H, 2CH2Ph), 3.14 (t, J=5.6 Hz,
4H, 2CH2CH2OMe), 3.30 (s, 6H, OCH3), 3.57 (t, J=5.6 Hz, 4H,
2CH2CH2OMe), 4.53 (t, J=7.3 Hz, 4H, 2CH2N+), 7.12 (m, 4H, CHar),
10.25 ppm (s, 2H, CHthiazole); 13C NMR (75 MHz, [D6]DMSO): d=11.1
(2CH3), 26.5 (2CH2), 27.3 (2CH2CH2OMe), 28.4, (2CH2), 33.9 (2CH2Ph),
52.5 (2CH2N+), 58.0 (2OCH3), 70.2 (2CH2CH2OMe), 128.2 (4CHar),
135.1 (2CqS), 138.9 (2Cqar), 141.6 (2CqN+), 156.6 ppm (2CHthiazole);
HPLC (conditions B): 6.07 min; HRMS (TOF-ESI+) calcd for
C28H42ClN2O2S2 [MꢁCl]+: 537.2376, found: 537.2394.
+
Acknowledgements
This work was supported by the European Community Integrated
Project AntiMal (No. IP-018834) and Sanofi–Aventis. S.A.C. and J.-
F.D. are grateful to Sanofi–Aventis for postdoctoral fellowships.
The authors thank M.-C. Bergogne for manuscript editing and J.-
Y. Puy for technical assistance.
Received: March 8, 2010
Keywords: bioorganic chemistry
·
choline analogues
·
Revised: April 27, 2010
malaria · microwave chemistry · structure–activity relationships
Published online on June 10, 2010
ChemMedChem 2010, 5, 1102 – 1109
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
1109