New bis-thiazolium analogues as potential antimalarial agents: Design, synthesis, and biological evaluation

Article abstract of DOI:10.1021/jm3014585

Bis-thiazolium salts are able to inhibit phosphatidylcholine biosynthesis in Plasmodium and to block parasite proliferation in the low nanomolar range. However, due to their physicochemical properties (i.e., permanent cationic charges, the flexibility, and lipophilic character of the alkyl chain), the oral bioavailability of these compounds is low. New series of bis-thiazolium-based drugs have been designed to overcome this drawback. They feature linker rigidification via the introduction of aromatic rings and/or a decrease in the overall lipophilicity through the introduction of heteroatoms. On the basis of the structure-activity relationships, a few of the promising compounds (9, 10, and 11) were found to exhibit potent antimalarial in vitro and in vivo activities (EC₅₀ < 10 nM and ED₅₀ ip < 0.7 mg/kg).

Full text of DOI:10.1021/jm3014585

Article
pubs.acs.org/jmc
New Bis-thiazolium Analogues as Potential Antimalarial Agents:
Design, Synthesis, and Biological Evaluation
Sergio A. Caldarelli,∥,† Siham El Fangour,∥,† Sharon Wein,‡ Christophe Tran van Ba,‡ Christian Perigaud,†
́
Alain Pellet,§ Henri J. Vial,‡ and Suzanne Peyrottes*,†
†Institut des Biomolec
Bataillon, 34095 Montpellier, France
́ ́
ules Max Mousseron (IBMM), UMR 5247 CNRS-UM1&2, Universite Montpellier 2, cc 1705, place E.
‡Dynamique des Interactions Membranaires Normales et Pathologiques (DIMNP), UMR 5235 CNRS-UM2, Universite
2, cc 107, place E. Bataillon, 34095 Montpellier, France
§Sanofi Research & Development, 195 route d’Espagne, BP 13669, 31036 Toulouse, France
́
Montpellier
S
* Supporting Information
ABSTRACT: Bis-thiazolium salts are able to inhibit phosphatidylcholine
biosynthesis in Plasmodium and to block parasite proliferation in the low
nanomolar range. However, due to their physicochemical properties (i.e.,
permanent cationic charges, the flexibility, and lipophilic character of the alkyl
chain), the oral bioavailability of these compounds is low. New series of bis-
thiazolium-based drugs have been designed to overcome this drawback. They
feature linker rigidification via the introduction of aromatic rings and/or a
decrease in the overall lipophilicity through the introduction of heteroatoms. On
the basis of the structure−activity relationships, a few of the promising
compounds (9, 10, and 11) were found to exhibit potent antimalarial in vitro and
in vivo activities (EC50 < 10 nM and ED50 ip < 0.7 mg/kg).
INTRODUCTION
■
Malaria is a widespread infectious disease in tropical and
subtropical regions. The World Health Organization (WHO)
estimates that half of the world population is at risk of malaria
infection.1 Moreover, Plasmodium falciparum parasites have
become resistant to most marketed antimalarial drugs
(chloroquine, mefloquine, quinine. and sulfadoxine/pyrimeth-
amine), including artemisinin and its derivatives, even when
used in combination therapies (ACTs).2−4 As the emergence of
multichemoresistance parasites could seriously undermine
global malaria control, new chemotherapeutic approaches
based on innovative mechanisms of action are needed.5−9
A decade ago, Vial et al. first described bis-quaternary
ammonium salts as novel antimalarial chemotherapeutic
agents.10 Since then, bis-cationic choline analogues have been
designed to inhibit the phospholipid metabolism.11,12 These
compounds have been shown to affect de novo plasmodial
phosphatidylcholine biosynthesis in infected erythrocytes.13,14
Further studies on structure−activity relationships, etc., led to
the discovery of potent bis-thiazolium salts (T3 and T4, Figure
1) displaying IC50 values in the low nanomolar range.15,16 T3
was the first choline analogue to undergo phase 2 clinical trials,
thus validating the chemotherapeutic approach.11−16
Figure 1. Structures of the lead compounds (T3 and T4) and related
prodrug (TE3).
may be hidden through the use of prodrugs.11,16 These are
neutral derivatives resulting from ring thiazolium opening and
subsequent blocking of the thiol function through the
formation of biolabile linkages. Structural variations in the
prodrug moieties were designed to affect lipophilicity, water
solubility, and enzymatic stabilities.17,18 Some neutral prodrugs
have exhibited potent in vitro antimalarial activity but still
displayed limited oral bioavailability. The most relevant data
was obtained with the cyclic thioester (TE3, Figure 1), which
achieved 15% absolute oral bioavailability in rat.19 Altogether,
these results have shown that it is possible to temporarily hide
the cationic charge and modulate release of the active bis-
thiazolium drug. However, the oral drug-like properties of the
The presence of two permanent cationic charges and the
flexibility and lipophilic character of the associated alkyl chain
prevent intestinal barrier crossing, with each parameter
lowering the oral bioavailability of these compounds. Several
approaches have been developed because the cationic charge
Received: October 9, 2012
© XXXX American Chemical Society
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Figure 2. Targeted compounds.
a
Scheme 1. Synthetic Pathways for Linkers Including a Phenoxy Moiety
a
Reagents and conditions: (a) ethylene carbonate, K2CO3, DMF, 55−95%; (b) TsCl, NEt3, DMAP, CH2Cl2, 59−95%; (c) Br2, P(Ph)3, CH2Cl2,
59%; (d) 4-Me-5-(2-hydroxyethyl)- or 4-Me-5-(2-methoxyethyl)thiazole, CH3CN, MW, then Dowex Cl- for 1a,b and 2, 68−84%; (e) TBDMSCl,
THF, 78%; (f) NaH, 1,5-dibromopentane, 76%; (g) KHSO4, THF/H2O, 77%; (h) SOCl2, CH2Cl2, quantitative.
current prodrugs are limited by the physicochemical properties
of the parent drugs, which include a lipophilic chain and a high
degree of conformational freedom of the spacer that separates
the two cationic heads.20,21
We recently showed that the presence of a phenyl moiety
within the linker of bis-thiazolium derivatives did not
substantially affect the antimalarial activity in cell experiments.22
On the basis of these considerations, we explored further linker
modifications to elucidate structural requirements to obtain a
more rigid and less lipophilic chain while still having bioactive
analogues. The present investigation involved the introduction
of a variety of aryl moieties or heterocycles, such as thiophene
or triazole, within the linker (Figure 2). In addition, we
modified the lipophilic character of the spacer connected to the
B
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a
Scheme 2. Synthetic Pathways for Linkers Including Benzenyl, Bis-phenyl, Naphthyl, and Thiophenyl Moieties
a
Reagents and conditions: (a) Pd[P(Ph)3]4, CuI, NEt3, CH2Cl2, 31−90%; (b) H2, Pd/C, CH3OH, 77−96%; (c) TsCl, NEt3, DMAP, CH2Cl2, 51−
96%; (d) 4-Me-5-(2-hydroxyethyl)- or 4-Me-5-(2-methoxyethyl)thiazole, CH3CN, MW, then Dowex Cl−, 39−60%.
thiazolium heads by incorporating various arrangements of
oxymethylene motifs as well as acetylene units so as to further
restrict the conformational flexibility and geometry. Thus, the
in vitro antiplasmodial activity and in vivo antimalarial activity
of the resulting compounds were studied in relation with the
restriction of conformational flexibility, geometry, and polarity
of the new compounds.
Bis-thiazolium salt 4, structurally related to pentamidine,24,25
was prepared in five steps from 4-hydroxymethylphenol
(Scheme 1B). First, the benzylic alcohol was selectively
protected using tert-butyl-dimethylsilyl chloride (TBDMSCl),
leading to the silylated compound 27 in 78% yield. Then the
phenol was alkylated with 1,5-dibromopentane to give rise to
the bis-phenoxy derivative 28 in 76% yield. Removal of the
TBDMS protecting group was performed under mild acidic
conditions, and the resulting primary alcohols were chlorinated
using thionyl chloride (SOCl2), leading to the intermediate 30
in 77% overall yield. Finally, the desired bis-thiazolium salt 4
was obtained under MW conditions as reported above.
1.2. Benzenyl, Bis-phenyl, Naphthyl, and Thiophenyl Rings
as Scaffold. In this second series of bis-thiazolium salts,
compounds 5a,b and 6a,b were synthesized (Scheme 2A)
beforehand according to a previously published procedure.22 In
addition, new analogues 7, 8a, 8b, 9, 10, 11a, and 11b were
obtained from commercially available dihalogenated aromatic
derivatives (Scheme 2B). First of all, diyne diols 31−35 were
prepared from propargyl alcohol and 1,3-dibromobenzene or
1,4-dibromonaphthalene or 2,7-dibromonaphthalene or 4,4′-
diiodobiphenyl and 2,5-dibromothiophene via double Pd(0)-
mediated Sonogashira coupling.26,27
The resulting diynes were reduced under Pd/C-catalyzed
hydrogenation to generate the corresponding alkyl diol
derivatives 36−40. Then the alcohols were activated using
TsCl, giving rise to the corresponding intermediates 41−45.
Finally, the desired hydrochloride bis-thiazolium salts 7, 8a, 8b,
9, 10, 11a, and 11b were isolated in moderate yields (37−60%)
using the same procedure as described for compound 1a.
1.3. Diethynyl-Benzenyl as Scaffold. The synthesis of bis-
thiazolium salts 12a, 12b, and 13 was initiated with Sonogashira
coupling of 1,4-diiodobenzene with 3-butyn-1-ol or 2-propyn-1-
ol (Scheme 3).28 The resulting diols 46 and 47 were converted
RESULTS AND DISCUSSION
■
1. Chemistry. 1.1. Bis-phenoxy Moiety as Scaffold. Bis-
thiazolium salts 1a, 1b, 2, and 3 were prepared in three steps
from commercially available bis-phenols (Scheme 1A). Thus,
bis-(4-hydroxyphenyl)methane, bis-(4-hydroxy-phenyl) meth-
anone, and 4,4′-dihydroxybiphenyl were coupled to ethylene
carbonate in the presence of K2CO3 to give rise to the diol
derivatives 21−23 in 78, 56, and 95% yields, respectively.23
Then treatment of the compounds 21 and 22 with p-
toluenesulfonyl chloride (TsCl), in the presence of dimethy-
laminopyridine (DMAP), led to the intermediates 24 and 25. A
poorly soluble material was obtained when diol 23 was treated
in the same conditions, making the following purification step
very complex. Therefore, compound 23 was brominated, using
bromine and triphenylphosphine, which gave rise to
intermediate 26 in 59% yield. N-Alkylation of 4-methyl-5-(2-
hydroxyethyl)thiazole or 4-methyl-5-(2-methoxyethyl)thiazole
with tosyl or bromoalkyl intermediates 24−26 was then
performed under microwave (MW) irradiation conditions to
significantly decrease the reaction time. After purification by
reverse-phase chromatography and ion-exchange (using a
Dowex-Cl− resin) the corresponding hydrochloride salts 1a,
1b, and 2 were isolated in 82, 84, and 68% yields. The bromide
salt 3 was obtained in 74% yield after reverse-phase
chromatography.
C
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a
Scheme 3. Synthetic Pathways for Linkers Including Diethynyl-Benzenyl Moiety
a
Reagents and conditions: (a) 1,4-diodobenzene, Pd[P(Ph)3]4, CuI, NEt3, CH2Cl2, 92%; (b) Br2, P(Ph)3, CH2Cl2, quantitative; (c) 4-Me-5-(2-
hydroxyethyl)- or 4-Me-5-(2-methoxyethyl) thiazole, CH3CN, MW, then Dowex Cl−, 31−68%.
a
Scheme 4. Synthetic Pathways for Linkers Including the 1,2,3-Triazole Moiety
a
Reagents and conditions: (a) propargyl bromide, CH3CN, 92%; (b) PBr3, CH2Cl2, 98%; (c) NaN3, DMF, 98% for 54 and 38% for 59; (d) MeI or
BnBr, CH3CN, 75−98%; (e) TsCl, NEt3, DMAP, CH2Cl2, 97%; (f) 4-Me-5-(2-methoxyethyl)thiazole, CH3CN, 70−86%; (g) CuSO4·5H2O−
sodium ascorbate (2% and 10%, respectively), water/tBuOH (1/1, v/v), MW, then Dowex Cl−, 32−56%.
to bromides 48 and 49 using bromine and triphenylphosphine.
Finally, N-alkylation of the thiazolium ring was performed
under MW activation as described above, leading to the desired
bromide salts 12a, 12b, and 13 in moderate yields (31−68%).
1.4. Triazole Ring as Scaffold. Formation of the 1,2,3-
triazole linkage (Figure 2, compounds 16−20) was envisaged
via Huisgen copper(I)-catalyzed 1,3-dipolar cycloaddition
between thiazolium derivatives containing alkynyl- and azide
functionalities, which were synthesized from 4-methyl-5-(2-
hydroxyethyl)- or 4-methyl-5-(2-methoxyethyl)thiazole
(Scheme 4).
Selective O-propargylation of 4-methyl-5-(2-hydroxyethyl)-
thiazole was performed in the absence of a base, leading to
terminal alkyne 50, which in turn was converted to
monothiazolium cations 51 and 52 by N-alkylation using
methyl iodide or benzyl bromide in refluxing acetonitrile.
Alkyne 58 was obtained by N-alkylation of thiazole using the
tosylated intermediate 57, which was prepared from
commercially available 5-pentyn-1-ol.
was performed by bromination of 4-methyl-5-(2-hydroxyethyl)-
thiazole, followed by treatment of the resulting bromide 53 by
NaN3 in refluxing DMF. The last thiazolium-cationic azide, i.e.,
compound 60, was isolated using the same procedure starting
from bromoazidopentane 59, which was obtained by
monoazidation of 1,5-dibromopentane in the presence of
NaN3 in moderate yield (38%).29
Several reaction conditions for the copper(I) catalyzed
azide−alcyne cycloaddition step were tested.30 The selected
ones require oxygen-free solvents, a fresh mixture of
CuSO4·5H2O/sodium ascorbate under MW irradiations.31
The desired bis-thiazolium salts 16 and 17 were obtained
from alkyne 51 and azide 55 and alkyne 52 and azide 56,
respectively. Using the same procedure, compounds 18 and 19
were prepared by coupling azides 55 or 56 with alkyne 58,
respectively. Finally, compound 20 was obtained from alkyne
58 and azide 60 in 32% yield.
As we hypothesized that the molecular properties may
influence the biological effect and especially the oral
bioavailability,11,12,22 all bis-thiazolium derivatives were studied
through molecular modeling (optimization of the geometry,
intercationic distance), and a few parameters related to
lipophilicity (clogP), number of H-bond donors and acceptors,
Thiazolium-cationic azide counterparts 55 and 56 were
generated from the common azide intermediate 54 by N-
alkylation of the thiazole using methyl iodide or benzyl bromide
as described for compounds 51 and 52. Synthesis of azide 54
D
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Figure 3. Molecular models of the selected compounds after optimization of their 3D geometry.
molecular flexibility (number of rotatable bonds, n rotb) were
calculated. Selected data are reported in the following table in
comparison to previously studied drugs such as T3 and
compounds 6a, 6b, 14, and 15. Optimization of the geometry
revealed that most of the compounds had nearly the same
profile, as illustrated in Figure 3, with the same “up and down”
orientation of the thiazolium ring with regard to the rest of the
molecule.
The average intercationic distance of 14.0−16.5 Å (16
compounds among 27) was in agreement with the previously
reported pharmacophore.6 However, for derivatives 12a and
12b, the triple bond on each side of the phenyl ring shortened
the intercationic distance to 12−13 Å and fixed the rigid
geometry with fewer than eight rotatable bonds (n rotb). This
feature was also noted with compounds including a triazole
ring, such as 16, 17, 18, and 19, that exhibited an n rotb ranging
from 8 to 12.
The studied derivatives could be divided in two groups on
the basis of the number of H-bonds. Most of the compounds
had four H-bond acceptors (n ON), whereas derivatives
including either two phenyl rings (1a, 1b, 2, 3, and 4) or a
triazole moiety (16−20) had a higher n ON value of 6 or 7.
2. Antimalarial Activity. The newly synthesized series of
bis-thiazolium derivatives were evaluated against P. falciparum
in cell experiments and in vivo against Plasmodium vinckei in
mice by intraperitoneal (ip) administration (Table 1).
2.1. In Vitro Biological Evaluation. The in vitro
antiplasmodial activities were evaluated against the Nigerian
P. falciparum strain in comparison to the clinical candidate, with
compounds 6a, 6b, 14, and 15 used as reference drugs. Eleven
of the newly designed bis-thiazolium salts exhibited potent
antimalarial activity in the low nanomolar range (IC50 < 100
nM), with eight compounds having an IC50 of below 20 nM.
Compounds 6b and 7, which have the same chain length but
anchored at para and meta positions on the phenyl ring,
exhibited similar activities with IC50 of 8.3 and 9 nM,
respectively. The ortho orientation was previously shown to
decrease the antimalarial activity.22 As for compounds 6b and 7,
a similar effect was obtained with naphthyl moieties when
chains of the same length were anchored at the 1,4 or the 2,7
positions; compounds 8a, 8b, and 9 exhibited similar activities.
Interestingly, compound 8b was 4-fold more active than
compound 6b, showing that the presence of π-systems in the
center of the linker may be an important feature of the
pharmacophore of these derivatives. In addition, compound 9
exerted a low toxic effect against the human Jurkat lymphoblast
cell lines, with an IC50 of 465 μM, i.e., in the same range as our
T3 reference compound (IC50 347 μM), clearly indicating
selective toxicity against Plasmodium-infected erythrocytes.
Consequently, the in vitro therapeutic indexes were ∼170000
and 150000 for compounds 9 and T3, respectively.
For compounds containing two phenyl rings (1a, 1b, 2, 3,
and 4), the in vitro antiplasmodial activities markedly varied
with respect to their relative positions. When the two aromatic
rings were located at the center of the linker, therefore
increasing its rigidity, the antimalarial activity was not affected
(1a, 1b, 3, and 10 with IC50 < 22 nM). On the other hand,
insertion of an alkyl chain between the two phenyl groups
(compound 4) substantially decreased the antimalarial activity
(IC50 313 nM). The presence of a hydrophobic aryl group in
close proximity to the quaternary amine likely induced an
unfavorable modification in the pharmacophore.
More strained compounds incorporating an aromatic ring
conjugated to triple bonds exhibited lower antiplasmodial
activity with IC50 > 100 nM (compounds 12a, 12b, and 13);
the increase in linker rigidity (6 < n rotb < 8) and shortening of
the intercationic distance to 12−13 Å for derivatives 12a and
12b led to a substantial loss of pharmacological activity (IC50
>
400 nM).
Besides, the introduction of oxygen atoms to further decrease
the lipophilicity of the corresponding prodrug did not improve
E
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Table 1. Physicochemical Parameters of the Studied Compounds and Selected Data from in Vitro and in Vivo Antimalarial
Evaluations
F
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Table 1. continued
a
Physicochemical parameters such as n ON (number of hydrogen bond acceptors), n OHNH (number of hydrogen bond donors), and n rotb
b
(number of rotatable bonds) were calculated using the Mol Inspiration software program. The intercationic distance was determined after modeling
and optimization of the geometry of each compound using HyperChem software. IC50 values against P. falciparum in vitro are means of at least two
independent experiments, with each being conducted in duplicate. Antimalarial activities (efficient dose 50, ED50) were determined against P.
c
d
vinckei in mice after intraperitoneal (ip) administration of the compounds once daily for 4 days. ED50 values were determined only when a decrease
in parasitemia of at least 85% was observed during the experiment. When the decrease in parasitemia at the last dose was <10%, the ED50 is indicated
as “≫” at the highest dose. When the decrease in parasitemia at the last dose was between 10 and 50%, the ED50 is indicated as “>” at the highest
e
f
dose. Treatment at higher doses was stopped due to the onset of initial clinical signs of toxicity. No sign of clinical toxicity was observed after ip
administration at the doses used. Nd: not determined.
the antimalarial activity; compound 3 was 7-fold less potent
than derivative 10.
phenyl (11b), and biphenyl (10), with an ED50 ip of 0.5, 0.28,
and 0.7 mg/kg (Figure 4). These three compounds were able
Surprisingly, the compound including thiophene as hetero-
cycle (11b, IC50 = 2.7 nM) appeared to be as potent as our
current clinical candidate, whereas the presence of the triazole
ring dramatically decreased the antimalarial activity (IC50
≫
640 nM). Note that in this last series several parameters may be
considered as unfavorable, i.e., the number of hydrogen bond
acceptors (n ON) was equal to or above 6, the number of
rotatable bonds (n rotb) was lower or equal to 12 (except for
derivative 20), and the intercationic distance was lower than the
average value of 14.0−16.5 Å. The toxicity of compound 11b
against Jurkat cells was moderate (IC50 63 μM).
2.2. In Vivo Biological Evaluation. Only compounds
exhibiting potent in vitro antiplasmodial activity (IC50 < 100
nM) were tested in vivo. In vivo antimalarial activities were
evaluated against the P. vinckei strain (279BY) in female Swiss
mice. The compounds were tested in infected mice by
intraperitoneal (ip) or oral (po) administration once daily for
four consecutive days (days 1−4 postinfection). The para-
sitemia levels were monitored in mice at day 5.
Figure 4. In vivo antimalarial activity of the best compounds (6b, 9,
10, and 11b) in P. vinkei-infected mice. Mice were infected by
intravenous injection of 107 parasites, leading to parasitemia of 0.5−1%
on day 1. The treatment consisted of a daily ip injection for 4
consecutive days. Results are the mean of three mice per dosage
SEM.
Most of the compounds containing bis-phenyl moieties (1a,
1b, 2, 3, and 4) exhibited significant antimalarial activity in
vitro, but the parasitemia clearance was not achieved in vivo, so
the ED50 ip value could not be determined. For compounds
including oxygen atoms within the linker, significant toxicity
was observed in mice, thus overruling their use at higher doses.
Their potential antimalarial activity could have been concealed
by this toxic effect.
to clear antimalarial infections in mice at very low doses,
comparable to that of the lead compound (ED50 = 0.2 mg/kg).
These four derivatives showed common features, such as an n
ON = 4, n OHNH = 0, n rotb = 16 (17 for compound 10), and
an intercationic distance of 14.5−16.0 Å.
CONCLUSION
■
Our previous findings highlighting the presence of a phenyl ring
in the middle of the lipophilic spacer of bisthiazolium salts
resulted in the development of potent new drugs and may be
On the other hand, potent in vivo antimalarial activities were
observed for compounds incorporating naphthyl (9), thio-
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considered as a way to optimize the pharmacophore.10,15 Thus,
we explored new modifications with the aim of decreasing the
molecular flexibility of the linker through the introduction of
biphenyl or naphthyl rings as well as triple bonds. These
modifications may help to optimize the bioavailability after oral
administration of the corresponding neutral prodrugs. Com-
pounds including a biaryl, naphthyl, or thiophenyl moiety were
synthesized by coupling previously prepared halogenated or
tosylated linkers under microwave irradiation. For derivatives
containing a triazole ring, we developed an original approach
involving the formation of a heteroaromatic ring in the last
synthesis step through CuAAC coupling performed with
cationic precursors.
The structure−activity relationships suggested that the
presence of two aromatic groups was well tolerated, leading
to bisthiazolium salts with valuable in vitro and in vivo
activities. Compounds 9 and 10, respectively, incorporating
naphthyl and biphenyl moieties, were thus able to cure malarial
infection in mice at very low doses (<1 mg/kg). We also
assessed the introduction of heterocycles here and found that
the presence of a thiophene ring in the center of the linker
boosted the potency of compound 11b after oral admin-
istration. Further synthesis and studies on the corresponding
neutral precursors will be carried out to evaluate the impact of
such linker modifications on the oral bioavailability.
and brine and finally dried over MgSO4. The solvent was removed in
vacuum, and the residue was purified by column chromatography
(CH2Cl2/MeOH), affording the expected bis-tosylated derivative.
((Methylene Bis(4,4′-phenylene))bis(oxy))bis(ethane-2,1-diyl)bis-
(4-ethylbenzenesulfonate) 24. According to procedure A, the title
compound (1.07 g, 95%) was obtained, as a white solid, from
compound 21. 1H NMR (300 MHz, CDCl3): δ 7.81 (d, 4H, J = 8.3),
7.33 (d, 4H, J = 8.0), 7.03 (d, 4H, J = 8.7), 6.70 (d, 4H, J = 8.7), 4.34
(m, 4H), 4.11 (dd, 4H, J = 4.0, 5.6), 3.83 (s, 2H), 2.44 (s, 6H). MS
(ESI+): 597.3 [M + H]+.
((Carbonylbis(4,4′-phenylene))bis(oxy))bis(ethane-2,1-diyl)bis(4-
ethylbenzenesulfonate) 25. According to procedure A, the title
compound (1.2 g, 59%) was obtained as a white solid from compound
22. 1H NMR (300 MHz, CDCl3): δ 7.82 (d, 4H, J = 8.3), 7.72 (d, 4H,
J = 8.8), 7.35 (d, 4H, J = 8.0), 6.84 (d, 4H, J = 8.8), 4.40 (dd, 4H, J =
3.7, 5.6), 4.23 (dd, 4H, J = 3.7, 5.6), 2.45 (s, 6H).
1,3-Phenylenebis(butane-4,1-diyl)bis(4-methylbenzenesulfonate)
41. According to procedure A, the title compound (3.78 g, 87%) was
1
obtained, as a colorless oil, from compound 36. H NMR (300 MHz,
CDCl3): δ 7.78 (d, 4H, J = 8.0), 7.33 (d, 4H, J = 8.0), 7.15 (m, 1H),
6.90 (m, 3H), 4.02 (t, 4H, J = 6.0), 2.52 (t, 4H, J = 7.1), 2.43 (s, 6H),
1.65 (m, 8H). MS (ESI+): 531.2 [M + H]+.
Naphthalene-1,4-diylbis(butane-4,1-diyl)bis(4-methylbenzene-
sulfonate) 42. According to procedure A, the title compound (2.16 g,
1
84%) was obtained, as a colorless oil, from compound 37. H NMR
(400 MHz, CDCl3): δ 7.95 (dd, 2H, J = 3.3, 6.5), 7.75 (d, 4H, J = 8.3),
7.47 (dd, 2H, J = 3.3, 6.5), 7.29 (d, 4H, J = 8.0), 7.12 (s, 2H), 4.04 (m,
4H), 2.97 (m, 4H), 2.39 (s, 6H), 1.74 (m, 9H).
Naphthalene-2,7-diylbis(butane-4,1-diyl)bis(4-methylbenzene-
sulfonate) 43. According to procedure A, the title compound (0.90 g,
EXPERIMENTAL SECTION
1
■
92%) was obtained, as a colorless oil, from compound 38. H NMR
Chemistry. General Experimental Information. All moisture-
sensitive reactions were carried out under rigorous anhydrous
conditions with argon atmosphere and using oven-dried glassware.
Solvents were dried and distilled prior to use, and solids were dried
(300 MHz, CDCl3): δ 7.77 (dd, 4H, J = 1.6, 8.4), 7.70 (d, 2H, J = 8.4),
7.46 (s, 2H), 7.30 (d, 4H, J = 8.0), 7.20 (dd, 2H, J = 1.6, 8.4), 4.05 (t,
4H, J = 5.8), 2.72 (t, 4H, J = 6.9), 2.42 (s, 6H), 1.72 (m, 8H). MS (ESI
+): 581.2 [M + H]+.
1
over P2O5 under reduced pressure. H NMR and 13C NMR spectra
[1,1′-Biphenyl]-4,4′-diylbis(butane-4,1-diyl)bis(4-methylbenzene-
were recorded at ambient temperature on a Bruker 300 Avance or
DRX 400. Chemical shifts (δ) are quoted in parts per million (ppm)
referenced to the residual solvent peak, (CDCl3 fixed at 7.26 and 77.16
ppm, DMSO-d6 fixed at 2.50 and 39.52 ppm) relative to
tetramethylsilane (TMS). Deuterium exchange and COSY experi-
ments were performed in order to confirm proton assignments.
Coupling constants, J, are reported in hertz. 2D 1H−13C heteronuclear
COSY was recorded for the attribution of 13C signals when needed.
ESI mass and high resolution mass spectra were recorded in the
positive or negative-ion mode on a Micromass Q-TOF. Thin-layer
chromatography was performed on precoated aluminum sheets of
Silica 60 F254 (Merck, Art. 5554), visualization of products being
accomplished by UV absorbance and by charring with a
phosphomolybdic acid solution (20 wt % in ethanol) and heating.
Chromatography was performed on Merck Silica Gel 60 (230−400
mesh ASTM) or on Merck Lichroprep RP18 (25−40 μm) using an
Isco purification system (Tris peristaltic pump, UA-6 UV detector,
type 11 optical unit 254 nm). Analytical HPLC chromatograms were
obtained using a Waters HPLC system (separation module 2695, 996
photodiode array detector 2996) and a Waters Symmetry Shield (50
mm × 4.6 mm, 3.5 μm) RP-18-column with a 1 mL/min flow rate.
The elution solvents were water containing 0.1% (v/v) of TFA
(solvent A) and acetonitrile containing 0.1% (v/v) TFA (solvent B). A
linear gradient was performed from 100% of solvent A to 100% of
solvent B in 7 or 15 min. All tested compounds were confirmed to
have ≥95% purity, determined by HPLC. Molecular models and
optimized geometry were obtained by performing energy minimization
calculations with HyperChem software.
sulfonate) 44. According to procedure A, the title compound (0.63 g,
1
51%) was obtained, as a white solid, from compound 39. H NMR
(300 MHz, CDCl3): δ 7.79 (d, 4H, J = 8.3), 7.47 (d, 4H, J = 8.2), 7.33
(d, 4H, J = 8.0), 7.17 (d, 4H, J = 8.2), 4.05 (m, 4H), 2.60 (m, 4H),
2.44 (s, 6H), 1.70 (m, 9H). MS (ESI+): 607.4 [M + H]+.
Thiophene-2,5-diylbis(butane-4,1-diyl)bis(4-methylbenzenesulfo-
nate) 45. According to procedure A, the title compound (3.33 g, 96%)
1
was obtained, as a yellow oil, from compound 40. H NMR (300
MHz, CDCl3): δ 7.78 (d, 4H, J = 8.5), 7.34 (d, 4H, J = 8.5), 6.48 (s,
2H), 4.02 (t, 4H, J = 6.0), 2.68 (t, 4H, J = 7.0), 2.44 (s, 6H), 1.68 (m,
8H). MS (ESI+): 537.2 [M + H]+.
Pent-4-ynyl 4-Methylbenzenesulfonate 57. According to proce-
dure A, the title compound (8.56 g, 97%) was obtained, as an oil, from
commercially available 5-penty-1-ol (3.0 g, 35.66 mmol). HPLC (rt =
10.05 min, purity 99%). 1H NMR (300 MHz, CDCl3): δ 7.76 (d, 2H, J
= 8.1), 7.32 (d, 2H, J = 8.1), 4.11 (t, 2H, J = 6.1), 2.41 (s, 3H), 2.22
(td, 2H, J = 6.9, 2.6), 1.90−1.76 (m, 3H). MS (ESI +): 239.1.
Procedure B for Bromination of Diol Intermediates,
Compounds 26, 48, and 49. To an ice-cooled solution of
triphenylphosphine (2.7 equiv) in anhydrous CH2Cl2 (8 mL/mmol),
bromine was added (2.5 equiv). The mixture was stirred under
nitrogen until the solution became colorless (ca. 15 min), and then the
alcohol derivative was added. The reaction mixture was stirred for 1 h
and then allowed to reach room temperature and stirred overnight.
The crude material was filtered through a silica gel pad subsequently
washed with CH2Cl2.
4,4′-Bis(2-bromoethoxy)-1,1′-biphenyl 26. According to proce-
dure B, the residue was purified by column chromatography
(petroleum ether/dichloromethane: 8/2) affording the expected
Procedure A for Tosylation of Diol Intermediates, Com-
pounds 24, 25, 41−45, and 57. Anhydrous triethylamine (4 equiv),
4-(dimethylamino)pyridine (0.2 equiv), and toluene-4-sulfonyl
chloride (2.8 equiv) were added to an ice-cooled solution of the
appropriate alcohol derivative in anhydrous CH2Cl2 (0.1 M). The
mixture was stirred at room temperature (2 to 16 h) and then diluted
with CH2Cl2. The organic layer was washed successively with water
1
compound (0.42 g, 59%) as a white solid from compound 23. H
NMR (300 MHz, CDCl3): δ 7.55 (d, 4H, J = 8.8), 7.03 (d, 4H, J =
8.8), 4.36 (t, 4H, J = 5.4), 3.82 (t, 4H, J = 5.4).
1,4-Bis(3-bromoprop-1-yn-1-yl)benzene 48. According to proce-
dure B, the title compound (2.5 g, quantitative) was obtained, as a
slightly yellow solid, from compound 46 (1.5 g, 8.06 mmol). The
H
dx.doi.org/10.1021/jm3014585 | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Article
crude material was used in the next step after a simple filtration over
silica gel. H NMR (300 MHz, CDCl3): δ 7.31 (s, 4H), 4.09 (s, 4H).
5.7), 3.29 (s, 6H), 3.16 (t, 4H, J = 5.7), 2.56 (s, 6H). 13C NMR (75
MHz, DMSO-d6): δ 157.9, 156.7, 142.2, 134.7, 132.9, 127.4, 115.1,
70.3, 65.3, 58.0, 52.1, 26.6, 11.5. HRMS (TOF-ESI+) calcd for
1
1,4-Bis(4-bromobut-1-yn-1-yl)benzene 49. According to proce-
dure B, the title compound (0.8 g, quantitative) was obtained, as a
white solid, from compound 47 (0.5 g, 1.07 mmol). The crude
material was used in the next step after a simple filtration over silica
gel. 1H NMR (300 MHz, CDCl3): δ 7.28 (s, 4H), 3.45 (t, 4H, J = 7.3),
2.91 (t, 4H, J = 7.2).
Procedure C for Preparation of Bis-thiazolium Salts
(Compounds 1a,b, 2−4, 7, 8a,b, 9, 10, 11a,b, 12a,b, and 13)
and Derivatives 58 and 60. To a solution of 4-methyl-5-(2-
hydroxyethyl)thiazole or 4-methyl-5-(2-methoxyethyl)thiazole (3
equiv) in dry acetonitrile was added the appropriate dibromo or
ditosyl intermediate. The reaction mixture was stirred at reflux for
several hours to few days or submitted to MW irradiations (1−3.5 h,
120−150 °C, 400 W), then water was added and the mixture was
extracted with Et2O. The aqueous layer was concentrated under
reduced pressure, and the crude was purified by RP-18 chromatog-
raphy (gradient: H2O to MeOH). When needed, the tosylate
counterions were exchanged to chloride by adding to the aqueous
solution a Dowex resin (1 × 8−400, Cl− form). After 2 h to 5 days
stirring, the resin was filtered off and the filtrate was concentrated and
freeze-dried.
C30H38BrN2O4S2 [M − Br]+, 633.1456; found, 633.1459.
+
3,3′-(((Pentane-1,5-diylbis(oxy))bis(4,1-phenylene))bis-
(methylene))bis(5-(2-ethoxyethyl)-4-methylthiazol-3-ium) Chloride
4. According to procedure C, the title compound (0.24 g, 45%) was
obtained, as a white solid, from compound 30 (0.30 g, 0.85 mmol) and
4-methyl-5-(2-methoxyethyl)thiazole (0.73 g, 1.13 mmol) in acetoni-
trile (10 mL) after 1 h under MW irradiation at 120 °C. HPLC (rt =
1
7.16 min, purity 100%). H NMR (300 MHz, DMSO-d6): δ 10.13 (s,
2H), 7.32 (d, 4H, J = 8.7), 7.00 (d, 4H, J = 8.7), 5.69 (s, 4H), 3.99 (t,
4H, J = 6.3), 3.55 (t, 4H, J = 5.7), 3.29 (s, 6H), 3.12 (t, 4H, J = 5.7),
2.39 (s, 6H), 1.77 (m, 4H), 1.56 (m, 2H). 13C NMR (75 MHz,
DMSO-d6): δ 159.1, 156.9, 141.8, 135.7, 130.1, 124.4, 115.0, 70.2,
67.5, 58.0, 55.5, 28.4, 26.5, 22.2, 11.5.
3,3′-(1,3-Phenylenebis(butane-4,1-diyl))bis(5-(2-methoxyethyl)-
4-methylthiazol-3-ium) Chloride 7. According to procedure C, the
title compound (0.64 g, 60%) was obtained, as a white solid, from
compound 41 (1 g, 1.71 mmol) and 4-methyl-5-(2-methoxyethyl)-
thiazole (0.81 g, 5.15 mmol) in acetonitrile (3.5 mL) after 2 h under
1
MW irradiation at 140 °C. HPLC (rt = 6.05 min, purity 99%). H
NMR (300 MHz, DMSO-d6): δ 10.28 (s, 2H), 7.20 (m, 1H), 7.04 (m,
3H), 4.54 (t, 4H, J = 7.4), 3.57 (t, 4H, J = 5.7), 3.30 (s, 6H), 3.14 (t,
4H, J = 5.7), 2.61 (t, 4H, J = 7.5), 2.46 (s, 6H), 1.81 (m, 4H), 1.61 (m,
4H). 13C NMR (75 MHz, DMSO-d6): δ 156.7, 141.7, 141.6, 135.2,
128.4, 125.8, 70.3, 58.1, 52.6, 34.3, 28.5, 27.4, 26.6, 11.2. HRMS
(TOF-ESI+) calcd for C28H42ClN2O2S2+ [M − Cl]+, 537.2376; found,
537.2366.
3,3′-(((Methylenebis(4,4′-phenylene))bis(oxy))bis(ethane-2,1-
diyl))bis(5-(2-hydroxy ethyl)-4-methylthiazol-3-ium) Chloride 1a.
According to procedure C, the title compound (422 mg, 82%) was
obtained, as a white solid, from compound 24 (0.5 g, 0.84 mmol), 4-
methyl-5-(2-hydroxyethyl)thiazole (0.36 g, 2.51 mmol), and acetoni-
trile (1 mL) after 3.5 h under MW irradiation at 120 °C. HPLC (rt =
1
5.67 min, purity 98%). H NMR (300 MHz, DMSO-d6): δ 10.21 (s,
3,3′-(Naphthalene-1,4-diylbis(butane-4,1-diyl))bis(5-(2-hydrox-
yethyl)-4-methylthiazol-3-ium) Chloride 8a. According to procedure
C, the title compound (340 mg, 53%) was obtained, as a white solid,
from compound 42 (0.62 g, 1.06 mmol) and 4-methyl-5-(2-
hydroxyethyl)thiazole (0.45 g, 3.18 mmol) in acetonitrile (10 mL)
2H), 7.09 (d, 4H, J = 8.5), 6.83 (d, 4H, J = 8.6), 4.92 (t, 4H, J = 4.7),
4.38 (t, 4H, J = 4.8), 3.78 (s, 2H), 3.62 (t, 4H, J = 5.6), 3.03 (t, 4H, J =
5.6), 2.53 (s, 6H). 13C NMR (75 MHz, DMSO-d6): δ 157.7, 155.7,
141.9, 135.0, 134.6, 129.6, 114.5, 65.3, 59.6, 51.9, 39.2, 29.5, 11.5.
HRMS (TOF-ESI+) calcd for C29H36ClN2O4S2+ [M − Cl]+, 575.1805;
found, 575.1808.
1
after 4 days refluxing. HPLC (rt = 5.89 min, purity 100%). H NMR
(300 MHz, DMSO-d6): δ 10.16 (s, 1H), 8.10 (dd, 1H, J = 3.3, 6.5),
7.56 (dd, 1H, J = 3.3, 6.5), 7.30 (s, 1H), 5.37 (t, 1H, J = 5.1), 4.55 (t,
2H, J = 7.3), 3.63 (q, 2H, J = 5.4), 3.05 (m, 4H), 2.47 (s, 3H), 1.94 (s,
2H), 1.70 (s, 2H). 13C NMR (75 MHz, DMSO-d6): δ 156.3, 141.5,
136.1, 135.6, 131.7, 125.7, 125.6, 124.5, 59.6, 52.6, 31.5, 29.5, 28.9,
3,3′-(((Methylenebis(4,4′-phenylene))bis(oxy))bis(ethane-2,1-
diyl))bis(5-(2-ethoxyethyl)-4-methylthiazol-3-ium) Chloride 1b. Ac-
cording to procedure C, the title compound (0.91 g, 84%) was
obtained, as a white solid, from compound 24 (1.0 g, 1.67 mmol) and
4-methyl-5-(2-methoxyethyl)thiazole (0.79 g, 5.03 mmol) in acetoni-
trile (4 mL) after 2.5 h under MW irradiation at 150 °C. HPLC (rt =
+
26.9, 11.3. HRMS (TOF-ESI+) calcd for C30H40ClN2O2S2 [M −
Cl]+, 559.2220; found, 559.2231.
1
6.33 min, purity 98%). H NMR (300 MHz, DMSO-d6): δ 10.27 (s,
3,3′-(Naphthalene-1,4-diylbis(butane-4,1-diyl))bis(5-(2-methox-
yethyl)-4-methylthiazol-3-ium) Chloride 8b. According to procedure
C, the title compound (364 mg, 55%) was obtained, as a white solid,
from compound 42 (0.62 g, 1.05 mmol) and 4-methyl-5-(2-
methoxyethyl)thiazole (0.49 g, 3.15 mmol) in acetonitrile (10 mL)
2H), 7.09 (d, 4H, J = 8.6), 6.83 (d, 4H, J = 8.6), 4.93 (t, 4H, J = 4.7),
4.38 (t, 4H, J = 4.8), 3.78 (s, 2H), 3.55 (t, 4H, J = 5.7), 3.28 (s, 6H),
3.14 (t, 4H, J = 5.7), 2.53 (s, 6H). 13C NMR (75 MHz, DMSO-d6): δ
158.3, 155.7, 142.2, 134.5, 129.6, 114.5, 70.3, 65.4, 60.0, 52.0, 39.2,
1
+
after 4 days refluxing. HPLC (rt = 6.67 min, purity 100%). H NMR
26.5, 11.5. HRMS (TOF-ESI+) calcd for C31H40ClN2O4S2 [M −
Cl]+, 603.2118; found, 603.2109.
(300 MHz, DMSO-d6): δ 10.21 (s, 2H), 8.10 (dd, 2H, J = 3.3, 6.5),
7.55 (dd, 2H, J = 3.3, 6.5), 7.29 (s, 2H), 4.55 (t, 4H, J = 7.4), 3.56 (t,
4H, J = 5.7), 3.29 (s, 6H), 3.10 (dt, 8H, J = 6.6, 15.2), 2.48 (s, 6H),
1.94 (m, 4H), 1.69 (m, 4H). 13C NMR (75 MHz, DMSO-d6): δ 156.6,
141.7, 136.1, 135.2, 131.7, 125.7, 125.6, 124.5, 70.3, 58.0, 52.6, 31.5,
28.8, 26.92, 26.54, 11.20. HRMS (TOF-ESI+) calcd for
3,3′-(((Carbonylbis(4,4′-phenylene))bis(oxy))bis(ethane-2,1-diyl))-
bis(5-(2-methoxyethyl)-4-methylthiazol-3-ium) Chloride 2. Accord-
ing to procedure C, the title compound (730 mg, 68%) was obtained,
as a yellow amorphous solid, from compound 25 (1.0 g, 1.63 mmol)
and 4-methyl-5-(2-methoxyethyl)thiazole (0.77 g, 4.91 mmol) in
acetonitrile (1.5 mL) after 1.5 h under MW irradiation at 150 °C.
HPLC (rt = 6.02 min, purity 100%). 1H NMR (300 MHz, DMSO-d6):
δ 10.39 (s, 2H), 7.67 (d, 4H, J = 8.8), 7.09 (d, 4H, J = 8.8), 5.03 (t,
4H, J = 4.6), 4.57 (t, 4H, J = 4.7), 3.56 (t, 4H, J = 5.7), 3.29 (s, 6H),
3.16 (t, 4H, J = 5.7), 2.57 (s, 6H). 13C NMR (75 MHz, DMSO-d6): δ
193.1, 160,8, 158.4, 142.2, 134.6, 131.8, 130.6, 114.4, 70.3, 65.7, 58.0,
51.8, 26.6, 11.54. HRMS (TOF-ESI+) calcd for C31H38ClN2O5S2+ [M
− Cl]+, 617.1911; found, 617.1910.
+
C32H44ClN2O2S2 [M − Cl]+, 587.2533; found, 587.2539.
3,3′-(Naphthalene-2,7-diylbis(butane-4,1-diyl))bis(5-(2-methox-
yethyl)-4-methylthiazol-3-ium) Chloride 9. According to procedure
C, the title compound (0.20 g, 46%) was obtained, as a white solid,
from compound 43 (0.41 g, 0.69 mmol) and 4-methyl-5-(2-
methoxyethyl)thiazole (0.33 g, 2.09 mmol) in acetonitrile (1.5 mL)
after 2 h under MW irradiation at 150 °C. HPLC (rt = 6.84 min, purity
100%). 1H NMR (300 MHz, DMSO-d6): δ 10.19 (s, 2H), 7.80 (d, 2H,
J = 8.4), 7.62 (s, 2H), 7.33 (d, 2H, J = 9.9), 4.53 (t, 4H, J = 7.3), 3.56
(t, 4H, J = 5.7), 3.29 (s, 6H), 3.13 (t, 4H, J = 5.7), 2.79 (t, 4H, J = 7.4),
2.45 (s, 6H), 1.86 (m, 4H), 1.71 (m, 4H). 13C NMR (75 MHz,
DMSO-d6): δ 156.7, 141.6, 139.2, 135.1, 133.3, 130.2, 127.5, 126.5,
125.7, 70.2, 58.0, 52.7, 34.4, 28.4, 27.2, 26.5, 11.1. (HRMS (TOF-ESI
+) calcd for C32H44ClN2O2S2+ [M − Cl]+, 587.2533; found. 587.2534.
3,3′-([1,1′-Biphenyl]-4,4′-diylbis(butane-4,1-diyl))bis(5-(2-me-
thoxyethyl)-4-ethylthiazol-3-ium) Chloride 10. According to proce-
3,3′-(([1,1′-Biphenyl]-4,4′-diylbis(oxy))bis(ethane-2,1-diyl))bis(5-
(2-methoxyethyl)-4-methyl thiazol-3-ium) Bromide 3. According to
procedure C, the title compound (0.25 g, 74%) was obtained, as a
white solid, from compound 26 (0.19 g, 0.47 mmol) and 4-methyl-5-
(2-methoxyethyl)thiazole (0.22 g, 1.42 mmol) in acetonitrile (10 mL)
1
after 2 days refluxing. HPLC (rt = 6.26 min, purity 100%). H NMR
(300 MHz, DMSO-d6): δ 10.13 (s, 2H), 7.54 (d, 4H, J = 8.8), 6.98 (d,
4H, J = 8.8), 4.94 (t, 4H, J = 4.7), 4.46 (t, 4H, J = 4.8), 3.56 (t, 4H, J =
I
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Journal of Medicinal Chemistry
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dure C, the title compound (0.13 g, 39%) was obtained, as a slightly
yellow solid, from compound 44 (0.30 g, 0.50 mmol) and 4-methyl-5-
(2-methoxyethyl)thiazole (0.23 g, 1.48 mmol) in acetonitrile (1 mL)
after 2 h under MW irradiation at 150 °C. HPLC (rt = 7.57 min, purity
100%). 1H NMR (300 MHz, DMSO-d6): δ 10.17 (s, 2H), 7.56 (d, 4H,
J = 8.2), 7.28 (d, 4H, J = 8.2), 4.53 (t, 4H, J = 7.4), 3.56 (t, 4H, J =
5.7), 3.30 (s, 6H), 3.14 (t, 4H, J = 5.7), 2.67 (t, 4H, J = 7.5), 2.46 (s,
6H), 1.84 (m, 4H), 1.65 (m, 4H). 13C NMR (75 MHz, DMSO-d6): δ
156.6, 141.7, 140.6, 137.7, 135.2, 128.9, 126.4, 70.3, 58.0, 52.6, 33.9,
5-(2-Methoxyethyl)-4-methyl-3-(pent-4-ynyl)thiazol-3-ium 4-
methylbenzenesulfonate 58. According to procedure C, the title
compound (5.75 g, 86%) was obtained, as a yellow oil, from
compound 57 (4.04 g, 16.96 mmol) and 5-(2-methoxyethyl)-4-
methylthiazole (4 g, 25.44 mmol) in acetonitrile (38 mL) after 4 days
reflux. HPLC (rt = 4.04 min, purity 98%). 1H NMR (300 MHz,
DMSO-d6): δ 10.10 (s, 1H), 7.51 (d, 2H, J = 8.0), 7.11 (d, 2H, J =
8.0), 4.52 (t, 2H, J = 7.1), 3.61 (t, 2H, J = 5.4), 3.52 (s, 3H), 3.12 (t,
2H, J = 5.4), 2.92 (t, 1H, J = 2.0), 2.48 (s, 3H), 2.2−2.41 (m, 5H),
1.92−2.06 (m, 2H). 13C NMR (75 MHz, DMSO-d6): δ 155.4, 144.3,
140.4, 136.1, 133.6, 126.6, 124.0, 81.1, 70.8, 68.8, 56.6, 50.5, 26.2, 25.1,
19.3, 13.4, 9.7. MS (ESI+): 224.1.
3-(5-Azidopentyl)-5-(2-methoxyethyl)-4-methylthiazol-3-ium
Bromide 60. According to procedure C, the title compound (1.4 g,
70%) was obtained, as a yellow oil, from compound 59 (1.07 g, 5.73
mmol) and 5-(2-methoxyethyl)-4-methylthiazole (1.35 g, 8.59 mmol)
in acetonitrile (8 mL) at reflux for 4 days. HPLC (rt = 5.11 min, purity
100%). 1H NMR (300 MHz, DMSO-d6): δ 10.11 (s, 1H), 4.49 (t, 2H,
J = 5.8), 3.59 (t, 2H, J = 5.7), 3.40−3.35 (m, 2H). 3.32 (s, 3H), 3.16 (t,
2H, J = 5.7), 2.49 (s, 3H), 1.90−1.80 (m, 2H), 1.66−1.55 (m, 2H),
1.44−1.34 (m, 2H). 13C NMR (75 MHz, DMSO-d6): δ 156.0, 141.2,
134.6, 69.7, 57.5, 52.0, 49.8, 27.8, 27.1, 26.0, 22.3, 10.7. MS (ESI+):
269.1.
2+
28.5, 27.3, 26.5, 11.2. HRMS (TOF-ESI+) calcd for C34H46N2O2S2
[M − 2Cl]2+, 289.1500; found, 289.1478.
3,3′-(Thiophene-2,5-diylbis(butane-4,1-diyl))bis(5-(2-hydroxyeth-
yl)-4-methylthiazol-3-ium) Chloride 11a. According to procedure C,
the title compound (0.28 g, 50%) was obtained, as a slightly yellow
solid, from compound 45 (0.55 g, 1.01 mmol) and 4-methyl-5-(2-
hydroxyethyl) thiazole (0.44 g, 2.78 mmol) in acetonitrile (2 mL) after
3 h under MW irradiation at 140 °C. HPLC (rt = 5.06 min, purity
1
100%). H NMR (300 MHz, DMSO-d6): δ 10.23 (s, 2H), 6.65 (s,
2H), 4.54 (t, 4H, J = 7.4), 3.63 (t, 4H, J = 5.6), 3.03 (t, 4H, J = 5.6),
2.78 (t, 4H, J = 7.5), 2.46 (s, 6H), 1.85 (m, 4H), 1.61 (m, 4H). 13C
NMR (75 MHz, DMSO-d6): δ 156.4, 141.8, 141.4, 135.6, 124.2, 59.6,
52.3, 29.5, 28.6, 28.3, 27.6, 11.2. HRMS (TOF-ESI+) calcd for
+
C24H36ClN2O2S3 [M − Cl]+, 515.1627; found, 515.1619.
Procedure D for Sonogashira Coupling Reaction, Com-
pounds 31−35, 46, and 47. Appropriate commercially available
diiodo- or dibromo-aryl starting material was dissolved in an
anhydrous mixture of CH2Cl2/Et3N (v/v, 1/3, 10 mL/mmol) then
CuI (0.02 equiv), 3-butyn-1-ol, or 2-propyn-1-ol (2.5 equiv) and
tetrakis(triphenylphosphine)palladium (0.01 equiv) were added. The
reaction mixture was refluxed overnight, in the dark, under nitrogen
atmosphere, and the solvent was evaporated under reduced pressure.
The residue was taken up in AcOEt and washed successively with a
saturated ammonium chloride aqueous solution, water, and finally
dried over MgSO4. The solvent was removed in vacuum, and the
residue was purified by column chromatography (petroleum ether/
AcOEt: 1/1) to afford the expected bis-(but-3-yn-1-ol) or bis(prop-2-
yn-1-ol) derivative.
3,3′-(Thiophene-2,5-diylbis(butane-4,1-diyl))bis(5-(2-methox-
yethyl)-4-methylthiazol-3-ium) Chloride 11b. According to proce-
dure C, the title compound (0.31 g, 57%) was obtained, as a slightly
yellow solid, from compound 45 (0.50 g, 0.93 mmol) and 4-methyl-5-
(2-methoxy-ethyl)thiazole (0.44 g, 2.78 mmol) in acetonitrile (2 mL)
1
after 5 days under reflux. HPLC (rt = 5.96 min, purity 100%). H
NMR (300 MHz, DMSO-d6): δ 10.21 (s, 2H), 6.65 (s, 2H), 4.52 (t,
4H, J = 7.4), 3.56 (t, 4H, J = 5.7), 3.30 (s, 6H), 3.14 (t, 4H, J = 5.7),
2.77 (t, 4H, J = 7.5), 2.46 (s, 6H), 1.83 (m, 4H), 1.62 (m, 4H). 13C
NMR (75 MHz, DMSO-d6): δ 156.6, 141.8, 141.7, 135.2, 124.2, 70.3,
58.0, 52.4, 28.7, 28.3, 27.7, 26.5, 11.2. HRMS (TOF-ESI+) calcd for
+
C26H40ClN2O2S3 [M − Cl]+, 543.1940; found, 543.1934.
3,3′-(1,4-Phenylenebis(prop-2-yne-3,1-diyl))bis(5-(2-hydroxyeth-
yl)-4-methylthiazol-3-ium) Bromide 12a. According to procedure C,
the title compound (0.26 g, 68%) was obtained, as a white solid, from
compound 48 (0.20 g, 0.64 mmol) and 4-methyl-5-(2-hydroxyethyl)
thiazole (0.27 g, 1.90 mmol) in acetonitrile (1 mL) after 2 h under
4,4′-(1,3-Phenylene)bis(but-3-yn-1-ol) 31. According to procedure
D, the title compound (2.88 g, 89%) was obtained, as a white solid,
from 1,3-dibromobenzene (3 g, 10.5 mmol), CuI (0.12 g), 3-butyn-1-
1
ol (2 mL), and tetrakis(triphenylphosphine)palladium (0.36 g). H
1
MW irradiation at 150 °C. HPLC (rt = 4.38 min, purity 100%). H
NMR (300 MHz, CDCl3): δ 7.47 (s, 1H), 7.32 (m, 2H), 7.21 (m,
1H), 3.80 (t, 4H, J = 6.3), 2.68 (t, 4H, J = 6.3). MS (ESI+): 215.1 [M
+ H]+.
NMR (300 MHz, DMSO-d6): δ 10.23 (s, 2H), 7.61 (s, 4H), 5.78 (s,
4H), 5.24 (t, 2H, J = 4.9), 3.66 (dd, 4H, J = 5.3, 10.5), 3.06 (t, 4H, J =
5.5), 2.57 (s, 6H). 13C NMR (75 MHz, DMSO-d6): δ 157.0, 141.5,
136.1, 132.1, 121.7, 87.3, 82.7, 59.6, 43.5, 29.4, 11.4. HRMS (TOF-ESI
+) calcd for C24H26BrN2O2S2+ [M − Br]+, 517.0619; found, 517.0605.
3,3′-(1,4-Phenylenebis(prop-2-yne-3,1-diyl))bis(5-(2-methoxyeth-
yl)-4-methylthiazol-3-ium) Bromide 12b. According to procedure C,
the title compound (0.28 g, 68%) was obtained, as a white solid, from
compound 48 (0.20 g, 0.64 mmol) and 4-methyl-5-(2-methoxyethyl)
thiazole (0.30 g, 1.90 mmol) in acetonitrile (6 mL) after 2 h under
4,4′-(Naphthalene-1,4-diyl)bis(but-3-yn-1-ol) 32. According to
procedure D, the title compound (1.85 g, 67%) was obtained, as a
white solid, from 1,4-dibromonaphthalene (3 g, 10.5 mmol), CuI (0.12
g), 3-butyn-1-ol (2 mL), and tetrakis(triphenylphosphine)palladium
1
(0.36 g). H NMR (300 MHz, CDCl3): δ 8.31 (dd, 2H, J = 3.3, 6.5),
7.61 (dd, 2H, J = 3.3, 6.5), 7.55 (s, 2H), 3.90 (t, 4H, J = 6.28), 2.84 (t,
4H, J = 6.28), 1.93 (s, 2H). MS (ESI+): 265.2 [M + H]+.
4,4′-(Naphthalene-2,7-diyl)bis(but-3-yn-1-ol) 33. According to
procedure D, the title compound (1.29 g, 62%) was obtained, as a
white solid, from 2,7-dibromonaphthalene (3 g, 10.5 mmol), CuI (0.12
g), 3-butyn-1-ol (2 mL), and tetrakis(triphenylphosphine)palladium
(0.36 g). 1H NMR (300 MHz, CDCl3): δ 7.97 (s, 2H), 7.87 (d, 2H, J
= 8.5), 7.46 (dd, 2H, J = 1.5, 8.5), 4.94 (t, 2H, J = 5.6), 3.62 (dd, 4H, J
= 6.8, 12.4), 3.33 (s, 2H), 2.60 (t, 4H, J = 6.8). MS (ESI+): 265.1 [M
+ H]+.
4,4′-([1,1′-Biphenyl]-4,4′-diyl)bis(but-3-yn-1-ol) 34. According to
procedure D, the title compound (0.88 g, 31%) was obtained, as a
white solid, from 4,4′-diiodobiphenyl (3 g, 9.6 mmol), CuI (0.11 g), 3-
butyn-1-ol (1.8 mL), and tetrakis(triphenylphosphine)palladium (0.33
g). 1H NMR (300 MHz, CDCl3): δ 7.68 (d, 4H, J = 8.3), 7.47 (d, 4H,
J = 8.3), 4.94 (t, 2H, J = 5.6), 3.59 (q, 4H, J = 6.8), 2.57 (t, 4H, J =
6.8). MS (ESI+): 291.2 [M + H]+.
1
MW irradiation at 150 °C. HPLC (rt = 5.45 min, purity 100%). H
NMR (300 MHz, DMSO-d6): δ 10.25 (s, 2H), 7.61 (s, 4H), 5.78 (s,
4H), 3.58 (t, 4H, J = 5.7), 3.18 (t, 4H, J = 5.7), 2.57 (s, 6H). 13C NMR
(75 MHz, DMSO-d6): δ 157.3, 141.7, 135.8, 132.1, 121.7, 87.3, 82.7,
70.2, 58.0, 43.6, 26.5, 11.3. HRMS (TOF-ESI+) calcd for
+
C26H30BrN2O2S2 [M − Br]+, 545.0932; found, 545.0950.
3,3′-(1,4-Phenylenebis(but-3-yne-4,1-diyl))bis(5-(2-hydroxyethyl)-
4-methylthiazol-3-ium) Bromide 13. According to procedure C, the
title compound (0.15 g, 31%) was obtained, as a white solid, from
compound 49 (0.20 g, 0.59 mmol) and 4-methyl-5-(2-hydroxyethyl)-
thiazole (0.25 g, 1.76 mmol) in acetonitrile (1 mL) after 2 h under
1
MW irradiation at 150 °C. HPLC (rt = 4.90 min, purity 100%). H
NMR (300 MHz, DMSO-d6): δ 10.15 (s, 2H), 7.37 (s, 4H), 5.22 (t,
2H, J = 4.9), 4.75 (t, 4H, J = 6.4), 3.64 (q, 4H, J = 5.4), 3.13 (t, 4H, J =
6.4), 3.04 (t, 4H, J = 5.6), 2.53 (s, 6H). 13C NMR (75 MHz, DMSO-
d6): δ 157.3, 141.6, 135.4, 131.6, 122.1, 87.4, 83.1, 59.6, 50.7, 29.5,
4,4′-(Thiophene-2,5-diyl)bis(but-3-yn-1-ol) 35. According to pro-
cedure D, the title compound (8.2 g, 90%) was obtained, as a slightly
yellow solid, from 2,5-dibromothiophene (3 g, 9.6 mmol), CuI (0.11
g), 3-butyn-1-ol (1.8 mL), and tetrakis(triphenylphosphine)palladium
+
19.9, 11.2. HRMS (TOF-ESI+) calcd for C26H30BrN2O2S2 [M −
Br]+, 545.0932; found, 545.0949.
J
dx.doi.org/10.1021/jm3014585 | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Article
1
(0.33 g). 1H NMR (300 MHz, CDCl3): δ 6.90 (s, 2H), 3.74 (t, 4H, J =
5.9), 2.63 (t, 4H, J = 6.2). MS (ESI+): 221.1 [M + H]+.
100%). H NMR (300 MHz, DMSO-d6): δ 10.27 (s, 1H), 7.49−7.32
(m, 5H), 5.86 (s, 2H), 4.21 (d, 2H, J = 2.4), 3.68 (t, 2H, J = 5.7), 3.50
(t, 1H, J = 2.4), 3.40 (s, 3H), 3.18 (t, 2H, J = 5.7), 2.37 (s, 3H). MS
(ESI+): 272.1.
3,3′-(1,4-Phenylene)bis(prop-2-yn-1-ol) 46. According to proce-
dure D, the title compound (1.95 g, 92%) was obtained, as a white
solid, from commercially available 1,4-diiodobenzene (5 g, 15.2 mmol)
5-(2-Azidoethyl)-3,4-dimethylthiazol-3-ium Iodide 55. According
to procedure F, the title compound (1.67 g, 98%) was obtained, as a
yellow solid, from compound 54 (1.0 g, 5.95 mmol) and methyl iodide
1
and 2-propyn-1-ol (2.9 mL, 37.9 mmol, 2.5 equiv). H NMR 300
MHz, CDCl3): δ 7.38 (s, 4H), 4.50 (s, 4H), 1.6 (s, 2H). 13C NMR (75
MHz, CDCl3): δ 137.1, 127.6, 97.0, 88.3, 54.7.
1
(1.1 mL). HPLC (rt = 2.86 min, purity 100%). H NMR (300 MHz,
4,4′-(1,4-Phenylene)bis(but-3-yn-1-ol) 47. According to procedure
D, the title compound (5.99 g, 92%) was obtained, as a white solid,
from 1,4-diiodobenzene (10 g, 30.3 mmol) and 3-butyn-1-ol (5.7 mL,
DMSO-d6): δ 8.54 (s, 1H), 4.08 (s, 3H), 3.43 (t, 2H, J = 6.8), 2.96 (t,
2H, J = 6.8), 2.35 (s, 3H). MS (ESI+): 183.1.
5-(2-Azidoethyl)-3-benzyl-4-methylthiazol-3-ium Bromide 56.
According to procedure F, the title compound (2.04 g, 76%) was
obtained, as a white solid, from compound 54 (1.76 g, 10.46 mmol)
and benzyl bromide (3.8 mL). HPLC (rt = 5.47 min, purity 100%). 1H
NMR (300 MHz, DMSO-d6): δ 11.23 (s, 1H), 7.36−7.28 (m, 5H),
6.03 (s, 2H), 3.63 (t, 2H, J = 6.1), 3.08 (t, 2H, J = 6.1), 2.42 (s, 3H).
MS (ESI+): 259.1.
Procedure G for Preparation of Azido Derivatives 54 and 59.
To a solution of the appropriate bromo intermediate in DMF (0.2 M)
was added NaN3 (2 equiv). After stirring overnight under reflux, the
mixture was diluted with CH2Cl2, washed with water, and dried over
MgSO4. The solvent was concentrated under reduced pressure, and
the residue was purified by column chromatography, affording the
expected azido derivative.
1
75.8 mmol, 2.5 equiv). H NMR (300 MHz, CDCl3): δ 7.33 (s, 4H),
3.81 (t, 4H, J = 6.3), 2.69 (t, 4H, J = 6.3), 1.81 (s, 2H). MS (ESI+):
215.2 [M + H]+.
Procedure E for Hydrogenation Reaction, Compounds 36−
40. The appropriate bis(but-3-yn-1-ol) or bis(prop-2-yn-1-ol)
derivative was dissolved in methanol (12 mL/mmol), and palladium
on activated charcoal (10% in weight) was added. The reaction
mixture was stirred at room temperature under hydrogen atmosphere
until a completed reaction was observed by TLC. The catalyst was
removed by filtration through Celite and washed with methanol. The
solvent was removed in vacuum, and the residue was purified by
column chromatography (CH2Cl2/MeOH: 98/2).
4,4′-(1,3-Phenylene)bis(butan-1-ol) 36. According to procedure E,
the title compound (1.99 g, 96%) was obtained, as a colorless oil, from
5-(2-Azidoethyl)-4-methylthiazole 54. According to procedure G,
1
compound 31. H NMR (300 MHz, CDCl3): δ 7.18 (m, 1H), 6.99
the title compound (3.77 g, 98%) was obtained, as a yellow oil, from
1
(m, 3H), 3.62 (m, 4H), 2.61 (t, 4H, J = 7.3), 1.67 (m, 8H). MS (ESI
compound 53 (4.9 g, 23.77 mmol). H NMR (300 MHz, CDCl3): δ
+): 223.2 [M + H]+.
8.54 (s, 1H), 3.43 (t, 2H, J = 6.8), 2.96 (t, 2H, J = 6.8), 2.35 (s, 3H).
MS (ESI+): 168.1.
1-Azido-5-bromopentane 59. According to procedure G, the title
4,4′-(Naphthalene-1,4-diyl)bis(butan-1-ol) 37. According to pro-
cedure E, the title compound (0.48 g, 92%) was obtained, as a white
1
solid, from compound 32. H NMR (300 MHz, CDCl3): δ 8.05 (dd,
compound (2.14 g, 38%) was obtained, as an oil, from commercially
1
2H, J = 3.3, 6.5), 7.48 (dd, 2H, J = 3.3, 6.5), 7.21 (s, 2H), 3.63 (t, 4H, J
= 6.5), 3.43 (s, 2H), 3.05 (m, 4H), 1.79 (m, 4H), 1.66 (m, 4H). MS
(EI+): 236.3 [M + 2H2O]+.
available 1,5-dibromopentane (5.1 g, 22.30 mmol). H NMR (300
MHz, CDCl3): δ 3.41 (t, 2H, J = 6.7), 3.29 (t, 2H, J = 6.6), 1.96−1.81
(m, 2H), 1.67−1.47 (m, 4H). MS: 112.1 [M − Br]+
4,4′-(Naphthalene-2,7-diyl)bis(butan-1-ol) 38. According to pro-
Procedure H for Preparation of Bis-thiazolium Salts,
Compounds 16−20. To a mixture of oxygen free solvents H2O/
tBuOH (v/v, 1/1) were added under argon CuSO4·5H2O (0.2 equiv,
0.25 M) and sodium ascorbate (1.2 equiv), and the mixture was stirred
for 15 min. To the resulted orange suspension were added alkyne (1
equiv) and azide (0.9 equiv), and the reaction mixture was submitted
to MW irradiations (1h, 110 °C, 400 W). The solvent was removed in
vacuum, and the residue was diluted with water and extracted three
times with CH2Cl2. The aqueous layer was concentrated and purified
by RP18 column chromatography (H2O/MeOH). When needed, the
counterions were exchanged to chloride by adding to the aqueous
phase a Dowex resin (1 × 8−400, Cl− form). After 2 h to 5 days
stirring, the resin was filtered off and the filtrate was concentrated and
freeze-dried.
cedure E, the title compound (0.52 g, 92%) was obtained, as a white
1
solid, from compound 33. H NMR (300 MHz, CDCl3): δ 7.76 (d,
2H, J = 8.4), 7.58 (s, 2H), 7.30 (d, 2H, J = 8.3), 3.68 (t, 4H, J = 6.2),
2.82 (t, 4H, J = 7.2), 2.08 (s, 2H), 1.73 (m, 8H). MS (ESI+): 273.2 [M
+ H]+.
4,4′-([1,1′-Biphenyl]-4,4′-diyl)bis(butan-1-ol) 39. According to
procedure E, the title compound (0.72 g, quantitative) was obtained,
as a white solid, from compound 34. 1H NMR (300 MHz, CDCl3): δ
7.54 (d, 4H, J = 8.2), 7.25 (d, 4H, J = 8.2), 4.40 (t, 2H, J = 5.2), 3.41
(dd, 4H, J = 6.4, 11.7), 2.60 (t, 4H, J = 7.5), 1.61 (m, 4H), 1.45 (m,
4H). MS (ESI+): 299.3 [M + H]+.
4,4′-(Thiophene-2,5-diyl)bis(butan-1-ol) 40. According to proce-
dure E, the title compound (0.80 g, 77%) was obtained, as a slightly
1
5-(2-(4-((2-(3,4-Dimethylthiazol-3-ium-5-yl)ethoxy)methyl)-1H-
1,2,3-triazol-1-yl)ethyl)-3,4-dimethylthiazol-3-ium Chloride 16. Ac-
cording to procedure H, the title compound (0.16 g, 56%) was
obtained, as a yellow oil, from compound 51 (0.15 g, 0.46 mmol) and
compound 55 (0.22 g, 0.69 mmol). HPLC (rt = 2.97 min, purity 99%).
1H NMR (300 MHz, DMSO-d6): δ 10.5 (s, 1H), 9.99 (s, 1H), 8.22 (s,
yellow oil, from compound 35. H NMR (300 MHz, CDCl3): δ 6.55
(s, 2H), 3.61 (t, 4H, J = 6.4), 2.76 (t, 4H, J = 7.3), 2.27 (s, 2H), 1.68
(m, 8H). MS (ESI+): 229.1 [M + H]+.
Procedure F for N-Alkylation Reaction, Compounds 51, 52,
55, and 56. The appropriate thiazolium derivative and methyl iodide
or benzyl bromide (3 equiv) were dissolved in dry acetonitrile (0.6 M)
and stirred under reflux overnight. Solvent was removed in vacuum,
and the residue was diluted with water and then extracted with diethyl
ether. The aqueous layer was concentrated and purified by RP18
column chromatography (H2O/MeOH) to afford the expected N-
methyl or N-benzyl thiazolium derivatives.
3,4-Dimethyl-5-(2-(prop-2-yn-1-yloxy)ethyl)thiazol-3-ium Iodide
51. According to procedure F, the title compound (1.8 g, 97%) was
obtained, as a yellow solid, from compound 50 (1 g, 4.85 mmol) and
methyl iodide (0.9 mL). HPLC (rt = 3.47 min, purity 100%). 1H NMR
(300 MHz, DMSO-d6) δ 9.98 (s, 1H), 4.21 (d, 2H, J = 2.4), 4.08 (s,
3H), 3.67 (t, 2H, J = 5.7), 3.49 (t, 1H, J = 2.4), 3.18 (t, 2H, J = 5.7),
2.44 (s, 3H). MS (ESI+): 196.1.
1H), 4.66 (t, 2H, J = 6.5), 4.58 (s, 2H), 4.10 (s, 3H), 4.06 (s, 3H), 3.67
(t, 2H, J = 5.7), 3.56 (t, 2H, J = 6.5), 3.17 (t, 2H, J = 5.7), 2.44 (s, 3H),
2.28 (s, 3H). 13C NMR (75 MHz, DMSO-d6): δ 156.7, 156.2, 143.2,
143.1, 141.9, 133.8, 132.1, 124.1, 67.53, 62.8, 48.7, 39.9, 26.3, 26.1,
10.9, 10.6. MS (ESI+): 414.1 [M − Cl]+. HRMS (TOF-ESI+) calcd
+
for C17H24N5OS2 [M − 2Cl]+, 378.1429; found, 378.1422.
3-Benzyl-5-(2-(4-((2-(3-benzyl-4-methylthiazol-3-ium-5-yl)-
ethoxy)methyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-methylthiazol-3-ium
Bromide 17. According to procedure H, the title compound (0.25 g,
52%) was obtained, as a yellow oil, from compound 52 (0.40 g, 1.14
mmol) and compound 56 (0.39 g, 1.14 mmol). HPLC (rt = 5.35 min,
purity 99%). 1H NMR (300 MHz, DMSO-d6): δ 10.24 (s, 1H), 10.21
(s, 1H), 8.20 (s, 1H), 7.48−7.17 (m, 10H), 5.81 (d, 4H, J = 7.0), 4.67
(t, 2H, J = 6.3), 4.49 (s, 2H), 3.64 (t, 2H, J = 5.6), 3.56 (t, 2H, J = 6.3),
3.12 (t, 2H, J = 5.5), 2.35 (s, 3H), 2.10 (s, 3H). 13C NMR (75 MHz,
DMSO-d6): δ 157.6, 156.9, 143.1, 142.7, 141.4, 135.2, 133.7, 132.5,
3-Benzyl-4-methyl-5-(2-(prop-2-ynyloxy)ethyl)thiazol-3-ium Bro-
mide 52. According to procedure F, the title compound (2.1 g, 75%)
was obtained, as a yellow solid, from compound 50 (1.44 g, 7.95
mmol) and benzyl bromide (2.9 mL). HPLC (rt = 5.48 min, purity
K
dx.doi.org/10.1021/jm3014585 | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Article
128.7, 128.7, 128.4, 128.2, 127.5, 127.0, 124.0, 67.4, 62.8, 55.2, 48.7,
2,2′-([1,1′-Biphenyl]-4,4′-diylbis(oxy))diethanol 23. 4,4′-Dihydrox-
ybiphenyl (1.0 g, 5.37 mmol) was dissolved in DMF (6 mL).
Potassium carbonate (0.37 g, 2.68 mmol, 2 equiv) and ethylene
carbonate (1.18 g, 13.42 mmol, 2.5 equiv) were added, and the
reaction mixture was refluxed overnight. Then it was allowed to reach
room temperature, water was added, and the resulting white
precipitate was filtered, washed with water, and dried over MgSO4.
Compound 23 (1.4 g, 95%, white solid) was used in the next step
41.5, 26.4, 26.1, 11.1, 10.6. HRMS (ESI+): 610.1 [M − Br]+. HRMS
+
(TOF-ESI+) calcd for C29H33BrN5OS2 [M − Cl]+, 610.1290; found,
610.1310.
3-(3-(1-(2-(3,4-Dimethylthiazol-3-ium-5-yl)ethyl)-1H-1,2,3-tria-
zol-4-yl)propyl)-5-(2-methoxyethyl)-4-methylthiazol-3-ium Chloride
18. According to procedure H, the title compound (0.20 g, 43%) was
obtained, as a yellow oil, from compound 55 (0.30 g, 0.96 mmol) and
compound 58 (0.38 g, 0.96 mmol). HPLC (rt = 3.50 min, purity
100%). 1H NMR (300 MHz, DMSO-d6: δ 10.03 (s, 1H), 9.97 (s, 1H),
8.01 (s, 1H), 4.57 (dt, 4H, J = 14.9, 7.0), 4.06 (s, 3H), 3.61−3.48 (m,
4H), 3.30 (s, 3H), 3.14 (t, 2H, J = 5.7), 2.71 (t, 2H, J = 6.6), 2.47 (s,
3H), 2.29 (s, 3H), 2.15 (t, 2H, J = 6.6). 13C NMR (75 MHz, DMSO-
d6): δ 156.7, 156.0, 145.0, 143.1, 141.3, 134.6, 132.1, 122.3, 69.7, 57.5,
51.8, 48.6, 40.0, 28.0, 26.3, 26.1, 21.2, 10.9, 10.6. HRMS (TOF-ESI+)
1
without further purification. H NMR (300 MHz, DMSO-d6): δ 7.53
(d, 4H, J = 8.7), 6.99 (d, 4H, J = 8.7), 4.94 (bs, 2H), 4.01 (t, 4H, J =
5.0), 3.73 (t, 4H, J = 5.0). MS (ESI+): 313.2 [M + K]+.
4-(((tert-Butyldimethylsilyl)oxy)methyl)phenol 27. To an ice-bath
cooled solution of 4-hydroxymethylphenol (11.89 g, 97.77 mmol) in
DMF (90 mL) was added tert-butylchlorodimethylsilane (15.88 g,
164.36 mmol, 1.7 equiv). Then triethylamine was slowly added over 1
h period, and the reaction mixture was stirred for 3 h. The solvent was
evaporated under reduced pressure, and the crude material was taken
up in AcOEt and washed successively with water and brine and dried
over MgSO4. The solvent was removed in vacuum, and the residue was
purified by column chromatography (petroleum ether/AcOEt 6:4),
affording the expected compound 27 (18.16 g, 78%) as colorless oil.
1H NMR (300 MHz, CDCl3): δ 7.17 (d, 2H, J = 4.6), 6.76 (d, 2H, J =
+
calcd for C19H29ClN5OS2 [M − Cl]+, 442.1474; found, 442.1502.
3-Benzyl-5-(2-(4-(3-(5-(2-methoxyethyl)-4-methylthiazol-3-ium-
3-yl)propyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-methylthiazol-3-ium
Chloride 19. According to procedure H, the title compound (0.11 g,
38%) was obtained, as a yellow oil, from compound 56 (0.39 g, 1.14
mmol) and compound 58 (0.45 g, 1.14 mmol). HPLC (rt = 4.51 min,
purity 100%). 1H NMR (300 MHz, DMSO-d6): δ 10.21 (s, 1H), 10.14
(s, 1H), 7.96 (s, 1H), 7.49−7.37 (m, 3H), 7.22 (d, 2H, J = 7.5), 5.79
(s, 2H), 4.62 (t, 2H, J = 6.1), 4.52 (t, 2H, J = 7.0), 3.64−3.49 (m, 4H),
3.31 (s, 3H), 3.14 (t, 2H, J = 5.6), 2.63 (t, 2H, J = 7.0), 2.46 (s, 3H),
2.17−2.03 (m, 5H). 13C NMR (75 MHz, DMSO-d6): δ 158.0, 156.7,
145.4, 143.1, 141.7, 135.1, 134.2, 133.0, 129.1, 128.7, 127.5, 122.7,
70.2, 58.0, 55.7, 52.2, 49.1, 28.4, 26.9, 26.5, 21.6, 11.2, 11.0. HRMS
4.8), 5.82 (s, 1H), 4.67 (s, 2H), 1.00 (s, 9H), 0.10 (s, 6H). MS
(ESI−): 237.1 [M − H]−.
1,5-Bis(4-(((tert-butyldimethylsilyl)oxy)methyl)phenoxy)pentane
28. Compound 27 (2.29 g, 9.50 mmol, 2.4 equiv) was dissolved in
anhydrous DMF (10 mL), and potassium carbonate (1.5 g, 10.87
mmol, 2.5 equiv) was added. After 20 min stirring at room
temperature, 1,5-dibromopentane (1.0 g, 4.35 mmol) was added and
the reaction mixture was stirred for 18 h. The solvent was evaporated
under reduced pressure, the residue was taken up in AcOEt, and the
organic layer was washed with water and dried over MgSO4. The
solvent was removed in vacuum, and the residue was purified by
column chromatography (petroleum ether/Et2O 98:2), affording the
expected compound 28 (1.80 g, 76%) as a white solid. 1H NMR (300
MHz, CDCl3): δ 7.23 (d, 4H, J = 8.7), 6.86 (d, 4H, J = 8.6), 4.67 (s,
4H), 3.98 (t, 4H, J = 6.4), 1.86 (m, 4H), 1.66 (m, 2H), 0.93 (s, 18H),
0.09 (s, 12H). MS (EI+): 412.4 [M − OTBDMS − H]+.
+
(TOF-ESI+) calcd for C25H35ClN5OS2 [M − Cl]+, 518.1814; found,
518.1815.
5-(2-Methoxyethyl)-3-(3-(1-(5-(5-(2-methoxyethyl)-4-methylthia-
zol-3-ium-3-yl)pentyl)-1H-1,2,3-triazol-4-yl)propyl)-4-methylthia-
zol-3-ium Chloride 20. According to procedure H, the title compound
(0.12 mg, 32%) was obtained, as a yellow oil, from compound 58
(0.40 g, 1.00 mmol) and compound 60 (0.35 g, 1.0 mmol). HPLC
1
(4.41 min, purity 97%). H NMR (300 MHz, DMSO-d6): δ 10.31 (s,
1H), 10.28 (s, 1H), 8.04 (s, 1H), 4.58 (t, 2H, J = 7.0), 4.49 (t, 2H, J =
7.0), 4.34 (t, 2H, J = 7.0), 4.34 (t, 2H, J = 7.0), 3.57 (t, 4H, J = 5.7),
3.30 (s, 3H), 3.31 (s, 3H), 3.14 (t, 4H, J = 5.6), 2.72 (t, 2H, J = 7.2),
2.49 (s, 6H), 2.24−2.11 (m, 2H), 1.91−1.79 (m, 2H), 1.35−1.20 (m,
2H). 13C NMR (75 MHz, DMSO-d6): δ 156.9, 156.7, 145.1, 141.7,
135.1, 122.2, 70.2, 58.0, 52.4, 52.3, 48.8, 28.9, 28.4, 28.1, 26.5, 22.4,
((Pentane-1,5-diylbis(oxy))bis(4,1-phenylene))dimethanol 29.
Compound 28 (1.16 g, 2.13 mmol) was diluted in 10 mL of a
THF/water solution (v/v, 8/2), and KHSO4 (0.29 g, 2.13 mmol, 1
equiv) was added. The reaction mixture was stirred for 2 h at 50 °C,
and the solvent was evaporated under reduced pressure. The aqueous
residue was taken up in AcOEt; the organic layer was washed with
water and dried over MgSO4. The solvent was removed in vacuum,
and the residue was purified by column chromatography (CH2Cl2/
CH3OH 95:5), affording the expected compound 29 (0.52 g, 77%) as
a white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.20 (d, 4H, J = 8.7),
6.87 (d, 4H, J = 8.7), 5.04 (t, 2H, J = 5.6), 4.40 (d, 4H, J = 5.5), 3.96
(t, 4H, J = 6.3), 1.76 (m, 4H), 1.54 (m, 2H). MS (ESI+): 299.2 [M −
OH]+, 339.2 [M − Na]+.
+
21.8, 11.2, 11.1. HRMS (TOF-ESI+) calcd for C24H39ClN5O2S2 [M
− Cl]+, 528.2196; found, 528.2234.
2,2′-((Methylene Bis(4,4′-phenylene))bis(oxy))diethanol 21. Bis-
(4-hydroxyphenyl)methane (5 g, 24.90 mmol) was dissolved in DMF
(25 mL). Potassium carbonate (0.69 g, 5.00 mmol, 0.2 equiv) and
ethylene carbonate (4.84 g, 54.90 mmol, 2.2 equiv) were added, and
the reaction mixture was refluxed overnight. Then, it was allowed to
reach room temperature and water was added, and the resulting white
precipitate was filtered and taken up with AcOEt. The organic layer
was successively washed with water and brine and dried over MgSO4.
The solvent was removed in vacuum, and the residue was purified by
column chromatography (cyclohexane/AcOEt 3:7), affording com-
pound 21 (5.6 g, 78%) as a white solid. 1H NMR (300 MHz, CDCl3):
δ 7.09 (d, 4H, J = 8.6), 6.84 (d, 4H, J = 8.6), 4.84 (t, 2H, J = 5.5), 3.93
(t, 4H, J = 5.0), 3.79 (s, 2H), 3.69 (dd, 4H, J = 5.3, 10.3). MS (ESI−):
227.0 [M − HOCH2CH2O•].
1,5-Bis(4-(chloromethyl)phenoxy)pentane 30. To a solution of 29
(0.97 g, 3.04 mmol) in dry dichloromethane (20 mL) at 0 °C, thionyl
chloride (0.89 mL, 12.2 mmol, 4 equiv) was added. After 30 min
stirring, the reaction mixture was allowed to reach room temperature
and stirred for an additional hour. The solvent and the excess of
thionyl chloride were removed in vacuum to afford compound 30
(1.07 g, quantitative), which was used in the next step without further
1
Bis(4,4′-(2-Hydroxyethoxy)phenyl)methanone 22. 4,4′-Dihydrox-
ybenzophenone (4.0 g, 18.67 mmol) was dissolved in DMF (80 mL).
Potassium carbonate (0.48 mg, 3.73 mmol, 0.2 equiv) and ethylene
carbonate (3.62 g, 41.07 mmol, 2.2 equiv) were added and the mixture
was refluxed overnight. The solvent was evaporated under reduced
pressure and the residue was taken up in ethanol/water (v/v: 10/1)
and refluxed for 1 h. The reaction mixture was allowed to reach room
temperature and the precipitate was filtered, washed with water and
dried over MgSO4. Compound 22 (3.15 g, 56%, white solid) was used
purification. H NMR (300 MHz, CDCl3): δ 7.34 (d, 4H, J = 8.7),
6.92 (d, 4H, J = 8.7), 4.71 (s, 4H), 3.99 (t, 4H, J = 6.4), 1.77 (m, 4H),
1.58 (m, 2H).
4-Methyl-5-(2-(prop-2-ynyloxy)ethyl)thiazole 50. 4-Methyl-5-(2-
hydroxyethyl)thiazole (2.0 g, 14 mmol) was added to a suspension of
NaH (0.68 g, 16.80 mmol) in dry THF (40 mL) at 0 °C. After 30 min,
propargyl bromide (3 mL, 28 mmol) was added dropwise. The
reaction mixture was stirred overnight and diluted with CH2Cl2, and
water was added. The aqueous layer was extracted twice with CH2Cl2,
and the resulting organic layer was dried over MgSO4. The solvent was
removed under reduced pressure. The crude material was purified by
silica gel column chromatography affording the expected compound
1
in the next step without further purification. H NMR (200 MHz,
DMSO-d6) δ 7.70 (d, 4H, J = 8.7), 7.08 (d, 4H, J = 8.7), 4.95 (s, 2H),
4.09 (t, 4H, J = 4.7), 3.75 (m, 4H). MS (ESI+): 303.2 [M + K]+.
L
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Journal of Medicinal Chemistry
Article
50 (2.51 g, 92%). HPLC (rt = 4.06 min, purity 100%). 1H NMR (300
MHz, CDCl3): δ 8.51 (s, 1H), 4.10 (d,, 2H, J = 2.4), 3.63 (t, 2H, J =
6), 2.98 (t, 2H, J = 6), 2.37 (t, 1H, J = 3), 2.44 (s, 3H). MS (ESI+):
182.1 [M + H]+. HRMS (TOF-ESI+): calcd for C9H12NOS [M + H]+,
182.0640; found, 182.0637.
5-(2-Bromoethyl)-4-methylthiazole 53. To a solution of commer-
cially available 2-(4-methylthiazol-5-yl) ethanol (4.0 g, 27.17 mmol) in
dry CH2Cl2 (100 mL), at 0 °C, was added PBr3 (38 mL, 40.76 mmol).
After stirring overnight at reflux, the reaction mixture was cooled at 0
°C and the excess of PBr3 was hydrolyzed with water. The mixture was
basified to pH 10 using 2N NaOH aqueous solution and extracted
with CH2Cl2. The resulting organic layer was dried over MgSO4 and
concentrated under reduced pressure. The residue was purified by
column chromatography (Petroleum ether/EtOAc = 5/5), affording
the expected compound 53 (5.8 g, 98%). 1H NMR (300 MHz,
CDCl3): δ 8.60 (s, 1H), 3.51 (t, 2H, J = 7.2), 3.31 (t, 2H, J = 7.2), 2.41
(s, 3H). MS (ESI+): 206.9.
respectively, for postdoctoral fellowships. The authors thank
M.-C. Bergogne for manuscript editing and J.-Y. Puy for
technical assistance.
ABBREVIATIONS USED
■
ACTs, artemisinin-based combination therapy; DMAP, 4-
(dimethylamino)pyridine; DMF, N,N-dimethylformamide;
DMSO, dimethylsulfoxide; MW, microwave; TBDMS, tert-
butyl-dimethylsilyl; Ts, p-toluenesulfonyl; WHO, World Health
Organization
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ASSOCIATED CONTENT
■
S
* Supporting Information
Spectroscopic data (1H NMR, HRMS, and HPLC chromato-
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charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Phone: +33 467 144 964. Fax: +33 467 142 029. E-mail:
suzanne.peyrottes@univ-montp2.fr.
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Author Contributions
∥These authors have contributed equally
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the European Community
Integrated Project AntiMal (no. IP-018834) and the InnoMaD
́
programme of EuroBiomed pole of competitiveness (Region
Languedoc Roussillon/FEDER/OSEO). S.C. and S. El F. are
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