LuxR dependent quorum sensing inhibition by N,N′-disubstituted imidazolium salts

Article abstract of DOI:10.1016/j.bmc.2011.06.075

Thirty N,N′-disubstituted imidazolium salts have been synthesized and evaluated as LuxR antagonists. Substitution on one of the imidazolium nitrogen atoms includes benzhydryl, fluorenyl or cyclopentyl substituent, and alkyl chains of various lengths on th

Full text of DOI:10.1016/j.bmc.2011.06.075

Bioorganic & Medicinal Chemistry 19 (2011) 4868–4875
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
LuxR dependent quorum sensing inhibition by N,N0-disubstituted
imidazolium salts
Mohamad Sabbah a,b, Laurent Soulère a,b, , Sylvie Reverchon c, Yves Queneau a,b, Alain Doutheau a,b
⇑
a INSA Lyon, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique et Bioorganique, Bât J. Verne, 20 av A. Einstein, 69621
Villeurbanne Cedex, France
b CNRS, UMR 5246 ICBMS, Université Lyon 1, INSA-Lyon, CPE-Lyon, Bât CPE, 43 bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
c Université de Lyon, F-69622 Lyon France, Université Lyon 1 Villeurbanne, INSA-Lyon F-69621 Villeurbanne, CNRS UMR 5240 Microbiologie, Adaptation et Pathogénie, Lyon, France
a r t i c l e i n f o
a b s t r a c t
Thirty N,N0-disubstituted imidazolium salts have been synthesized and evaluated as LuxR antagonists.
Substitution on one of the imidazolium nitrogen atoms includes benzhydryl, fluorenyl or cyclopentyl
substituent, and alkyl chains of various lengths on the second one. Most of these compounds displayed
antagonist activity, with IC50 reaching the micromolar range for the most active ones. The disubstituted
imidazolium scaffold is thus shown to be a new pertinent pharmacophore in the field of AHL dependent
QS inhibition.
Article history:
Received 18 April 2011
Revised 24 June 2011
Accepted 26 June 2011
Available online 29 June 2011
Keywords:
Quorum sensing
Imidazolium
Antagonist
LuxR
Ó 2011 Elsevier Ltd. All rights reserved.
AHL
1. Introduction
bacterial agents.33 This opened the way for designing a new family
of potential AHLs QS dependent inhibitors. The results of our study
Bacterial quorum sensing (QS) refers to the communication sys-
tem used by bacteria to adapt themselves to their environment.1–9
This communication occurs via small molecules, known as autoin-
ducers, which interact with their cognate proteins, referred to as
transcriptional regulators, enabling the expression of genes encod-
ing for diverse phenotypes such as virulence, bioluminescence and
biofilm formation. Consequently QS inhibition has been considered
as a possible strategy to fight pathogenic bacteria, encouraging in
the last decades, numerous studies focusing either on the biologi-
cal or the chemical points of view.10–19
In Gram negative bacteria, the autoinducers are mainly N-acyl
homoserine lactones (AHLs) and the transcriptional factors are
LuxR-type proteins.19 As part of our research aimed at the discovery
of potential modulators of AHLs-dependent transcriptional regula-
tors,20–25 we recently described the computer aided identification
of several inhibitors of LuxR dependent quorum sensing, all struc-
turally unrelated to AHL.26 Such AHL unrelated analogues are still
less investigated than more classical AHL analogues.14,19,27–31 In this
series, calmidazolium, a N,N0-disubstituted imidazolium salt (Fig. 1),
proved to be the most active. Also, imidazolium derivatives are
known to be biologically relevant molecules,32 particularly as anti-
on various imidazolium derivatives screened as LuxR dependent
QS inhibitors are presented hereafter.
2. Results and discussion
2.1. Design and synthesis of imidazolium derived compounds
Calmidazolium is constituted of a central imidazolium ring
which is substituted on both nitrogen atoms, with a dichlorobe
nzhydryl moiety on one nitrogen atom, and a tetrachloro bisaromat-
ic system on the other. Based on the activity of calmidazolium as QS
inhibitor, the synthesis and the biological evaluation towards QS of
diversely substituted N,N0-disubstituted imidazolium derivatives
were investigated. A first series of analogues incorporate, as substit-
uents on one nitrogen atom of the imidazolium ring, an halogenated
or non halogenated benzhydryl motif (as found in calmidazolium),
and, on the other nitrogen atom, alkyl chains of various length (com-
pounds 11a–g, 12 and 13, Fig. 1 and Scheme 1) unlike in the parent
calmidazolium. A few compounds include an aromatic ring on this
alkyl side chain (11i–k, Scheme 1). In a second series, a fluorenyl
group was used as a conformationally constrained benzhydryl motif
(compound 14). Finally, alkylimidazolium salts with a smaller cyclic
substituent, namely N-cyclopentyl-N-alkyl imidazolium, with alkyl
chains of various length (compound 15) were studied (Fig. 1 and
Scheme 1).
⇑
Corresponding author.
E-mail address: laurent.soulere@insa-lyon.fr (L. Soulère).
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.06.075

M. Sabbah et al. / Bioorg. Med. Chem. 19 (2011) 4868–4875
4869
Figure 1. Structure of calmidazolium and analogues 11–15.
Scheme 1. Synthesis of compounds 6–15.
The synthesis of all compounds was achieved by two successive
2.2. Biological evaluation
nucleophilic substitutions starting from imidazole (Scheme 1). For
the benzhydryl series (compounds 11–13), the first step involved
the reaction of imidazole with commercially available benzhydryl
bromide (1), 4-dichloro-benzhydryl choride (2)34 or bis (2,4-tetra-
chloro-benzydryl)chloride (3) easily obtained from the known alco-
hol bis(2,4-dichlorophenyl)methanol.35 For compounds 14 and 15,
commercially available fluorenyl bromide (4) or cyclopentyl bro-
mide (5) were used. The second nucleophilic substitution was
achieved by reaction of intermediates 6–10 with the appropriate
bromides (Scheme 1). Targets compounds were obtained as their
bromonium salts purified using reverse-phase chromatography.
First, the compounds were tested for their ability to induce bio-
luminescence, but none of them exhibited any agonistic activity.
Then, all compounds were tested for their ability to decrease bio-
luminescence induced by 3-oxo-C6-HSL (Table 1).20 The N-benzhy-
dryl derivatives bearing an alkyl chain ending with a phenyl group
(11i–j) or a benzyl ether substituent (11k) were inactive, as well as
the short chain (butyl) compound 11a. Alkyl substituted benzhy-
dryl imidazolium salts with C6 (11b) to C16 (11g) chains exhibited
activities with IC50 ranging from 153 to 5.2
lM. The maximum
activity was observed for compound 11f equipped with a C14 alkyl

4870
M. Sabbah et al. / Bioorg. Med. Chem. 19 (2011) 4868–4875
Table 1
Inhibition of bioluminescence with compounds 11–15
Chain length
Compounds
11 (R = R1)
12 (R = R2)
13 (R = R3)
14 (R = R4)
15 (R = R5)
R0 = C4H9
11a Inactive
11b 153 ( 2)
11c 76 ( 2)
11d 18 ( 2)
11e 6.1 ( 0.2)
11f 5.2 ( 0.2)
11g 7.3 ( 0.3)
a
b
R0 = C6H13
R’ = C8H17
R0 = C10H21
R0 = C12H25
R0 = C14H29
R0 = C16H33
R0 = C18H37
12b 63 ( 2)
13b 52 ( 4)
12c 9.8 ( 1.1)
12d 5.8 ( 0.4)
12e 6.2 ( 0.4)
12f 75 ( 19)
13c 8.9 ( 0.3)
13d 4.9 ( 0.2)
13e 6.5 ( 0.6)
13f Inactive
14c 35 ( 2)
15c 68 ( 3)
15d 33 ( 2)
15e 11 ( 2)
15f 3.4 ( 0.2)
15g 5.3 ( 0.1)
15h 86 ( 7)
14d 4.0 ( 0.6)
14e 1.40 ( 0.4)
14f 2.7 ( 0.2)
14g 14.7 ( 0.8)
12h Inactive
13h Inactive
a
Concentration (lM) required to reduce to 50% intensity (IC50) the bioluminescence induced by 200 nM of 3-oxo-C6-HSL.
Values are the means of three experiments; standard deviation is given in brackets.
b
chain. This sensitivity to chain length is consistent with the known
importance of hydrophobic interactions within the binding site for
several other families of QS modulators.19
In the case of dichloro- or tetrachloro-benzhydryl compounds
having C6 to C18 alkyl chains (12 and 13), activities were in the same
orenyl moiety occupies the space where the lactone moiety of the
natural ligand 3-oxo-C6-AHL usually binds,24,38 and is involved in
attractive interactions with Trp66 and Trp94 (Fig. 2B). The imi-
dazolium ring, replacing the amide function of the natural ligand,
is located between aromatic residues of Tyr62 and Tyr70 at dis-
order of magnitude (IC50 ranging from 75 to 4.9
lM). However, with
tances compatible with cation-p
interactions.39–41 The proposed
respect to chain length of the alkyl substituent, a ‘C4 shift’ was ob-
served compared to non halogenated compounds, the C10 deriva-
tives being the most active (IC50 5.8 lM for 12d and 4.9 lM for
13d) compared to the C14 11f. In this series, compounds with longer
chains 12f,h and 13f,h (C14 and C18), were significantly less active
(12f) or inactive. This ‘C4 shift’ suggests that the variation of the
occupied volume in the ligand binding site by the benhydryl moiety
due to the presence of several bulky halogen atoms must be com-
pensated by a smaller size of the alkyl side chain.
binding mode also suggests possible electrostatic interactions be-
tween the positively charged imidazolium ring and the carboxylate
function of Asp79 (Fig. 2B). Lastly, the alkyl chain occupies the
space where the alkyl chain of the natural ligand normally sits,
interacting with hydrophobic residues, in particular Ile46, Ile56,
Ile58, Ile76 and Pro48. Similar docking of the other most active
compounds in each series, 11f, 12e, 13d and 15f showed same
overall interactions and binding mode (data not shown).
Fluorenyl derivatives (14c–g) having C8–C16 alkyl chains were
then evaluated and exhibited strong ability for inhibiting biolumi-
3. Conclusion
nescence (IC50 ranging from 35 to 1.4 lM). For these molecules
which are conformationally constrained analogues of the benzhy-
dryl series, increasing activity was observed upon increasing the
In conclusion, the synthesis of new imidazolium derived com-
pounds and their biological evaluation as QS inhibitors have been
accomplished. This study showed that most of these derivatives in-
hibit LuxR dependent quorum sensing, some of them strongly, with
IC50 reaching the micromolar range. It also shows that the benzhy-
dryl motif together with an alkyl chain as substituents on both
nitrogen atoms of an imidazolium ring, can be considered as a
new pharmacophore which allows wide structural variability for
future developments. Modelling suggests that the imidazolium
ring, being located where the amide function of the natural ligands
normally sits, can develop several non-covalent bonding interac-
tions. Preliminary results on the N-cyclopentyl-N-alkyl compounds
show that besides the benzhydryl moiety, but also other types of
cyclic systems can be used for varying the substitution on the imi-
dazolium ring. Alkyl chain length appears as a tuning parameter
balancing the bulkiness of the cyclic or aromatic system.
alkyl chain length up the C12 and C14 compounds (IC50 1.4
lM for
the fluorenyl C12 14e and 2.7 M for the fluorenyl C14 14f), the flu-
l
orenyl C12 14e exhibiting the best activity in the whole study. The
longer C16 analogue 14g was less active.
Finally, the simpler cyclopentyl derivatives (15c–h) having C8–
C18 chain length were tested and exhibited IC50 ranging from 86 to
3.4 M. Activities reached a maximum for the C14–C16 compounds
l
(15f and 15g), showing that for this series, a longer chain is neces-
sary for achieving sufficient binding, balancing a smaller substitu-
ent on the other nitrogen atom. Even the longer N-cyclopentyl-N-
C18 15h remained moderately active.
It was verified that bioluminescence inhibition did not result
from antimicrobial activity rather than QS inhibition. Selected com-
pounds 11e, 14e and 15f were tested using the disk diffusion assay, a
common assay for antibiotic susceptibility standardized according
4. Experimental
4.1. General
to the Clinical and Laboratory Standards Institute guidelines.36
A
control disk diffusion assay was conducted using the relevant kana-
mycin antibiotic. Compounds were tested at concentrations 20 M,
200 M, 2 mM and 20 mM. After overnight incubation at 37 °C, the
l
l
Solvents were distilled and dried before use: dichloromethane
from calcium hydride, tetrahydrofuran from sodium benzophenone
ketyl. Organic solutions were dried over anhydrous sodium sulfate.
The reactions were performed under a constant flow of nitrogen. The
reactions were monitored by t.l.c. on Silica Gel 60 F254 (Merck) and
detection was carried out by UV light (254 nm) and/or charring with
a 5% phosphomolybdic acid solution in ethanol containing 10% of
H2SO4, or a 1% potassium permanganate solution in water. Silica
gel (Kieselgel 60, 70–230 mesh ASTM, Merck) was employed for col-
umn chromatography, and octadecyl-modified silica (C18) HPLC
column for reverse-phase chromatography. Melting points were
determined on a Kofler block apparatus.
inhibition zones of each compound were measured. The minimum
inhibitory concentration (MIC) was found to be ranged from
200 lM to 2 mM for each compounds, that is, several order of mag-
nitude higher than QS inhibition.
2.3. Molecular modelling
The proposed binding mode of the most active compound, that
is, 1-fluorenyl-3-dodecyl imidazol-3-ium derivative 14e, was ob-
tained as a result of flexible docking37 in the ligand binding site
of the LuxR model38 (Fig. 2A). According to the modelling, the flu-

M. Sabbah et al. / Bioorg. Med. Chem. 19 (2011) 4868–4875
4871
Figure 2. Proposed binding mode of 1-fluorenyl-3-dodecyl imidazol-3-ium derivative in the ligand binding site of the LuxR model. (A) Overview of 1-fluorenyl-3-dodecyl
imidazol-3-ium interacting with all residues of the binding site; (B) magnification and simplification of the binding mode showing interactions with conserved residues.
The 1H NMR (300 MHz or 400 MHz) and 13C NMR (75 MHz or
100 MHz) spectra were recorded with a Brucker ALS300, DRX300,
and DRX400 spectrometers. Chemical shifts are given in ppm. Cou-
pling constants are expressed in Hertz and splitting pattern abbre-
viations are: s, singulet; d, doublet; t, triplet; q, quartet; m,
multiplet; M, massif, p, pseudo. Multiplicity (13C NMR) was deter-
mined by DEPT sequences. High resolution mass spectra were
obtained by electro spray technique, positive mode with a Thermo-
Finnigan MAT 95 XL spectrometer.
2H); 13C NMR (75 MHz, CDCl3): d 61.8, 117.7, 120.4, 124.9, 128.1,
129.6, 130, 137, 140.4, 142.26; HRMS ESI+ calcd for C16H13N2
233.1073, found: MH+, 233.1078.
:
þ
4.2.1.3. 1-Cyclopentyl imidazole (10).
From cyclopentyl bro-
mide (1.6 mL, 14.6 mmol) and imidazole (3 g, 43.8 mmol), 10
(1.55 g, 80%) was obtained as a yellow oil after purification by col-
umn chromatography using AcOEt/MeOH (80:20) as eluent. 1H
NMR (300 MHz, CDCl3): d 1.68–1.9 (m, 6H), 2.17 (m, 2H), 4.44
(m, 1H), 6.93 (s, 1H), 7.03 (s, 1H), 7.51 (s, 1H); 13C NMR (75 MHz,
CDCl3): d 23.7, 33.6, 58.3, 117.4, 129.1, 135.9; HRMS ESI+ calcd
for C8H13N2þ: 137.1073, found: MH+, 137.1075.
All calculations were performed with ArgusLab42 as software on
a Dell OPTIPLEX GX 620 PC equipped with a double processor.
Docking experiments were performed with the docking module
of ArgusLab. The protein model of LuxR38 was created using
SWISS-MODEL43 with ClustalW.44
4.2.2. General procedure for the preparation of compounds 11–
15
4.2. Synthesis
A mixture of compound 6–10 (1 equiv) and the alkyl bromide
(1 equiv) in acetonitrile was refluxed at 90 °C for 72 h. The solvent
was removed under vacuum and the residue was purified by re-
verse-phase chromatography using a stepping gradient of solvent
H2O/MeOH (9:1 to 1:9) to provide compounds 11–15.
4.2.1. General procedure for the preparation of compounds 6–
10
These compounds were obtained from compounds 1 to 5 and
imidazole according to the procedure reported by Corelli et al.45
for the preparation of 6. Crude products were purified by flash
chromatography to provide compounds 6–10. Spectroscopic data
for known compounds 6 and 7 were identical to reported ones in
Refs. 45 and 46, respectively.
4.2.2.1. 1-Benzhydryl-3-benzyl imidazol-3-ium bromide (11i).
Compound 11i (206 mg, 99%) was obtained as an oil from 6
(150 mg, 0.64 mmol) and benzyl bromide (76 l
l, 0.64 mmol). 1H
NMR (300 MHz, DMSO): d 5.51 (s, 2H), 7.30 (s, 1H), 7.31–7.6 (m,
15H), 7.8 (s, 1H), 7.96 (s, 1H), 9.49 (s, 1H); 13C NMR (75 MHz,
4.2.1.1. 1-(Bis(2,4-dichlorophenyl)methyl imidazole (8).
solution of bis(2,4-dichlorophenyl)methanol35 (600 mg,
1.86 mmol) in dichloromethane (4 mL) was added SOCl2 (146 l,
To
DMSO): d 52.1, 65.8, 122.7, 123.2, 127.8, 128.1, 128.4, 128.7, 129,
129.2, 134.7, 136.5, 137.1; HRMS ESI+ calcd for C23H21N2
325.1705, found: M+, 325.1706.
:
þ
a
l
2 mmol) and the reaction mixture was stirred at room temperature
overnight. The solvent was then evaporated under vacuum to pro-
vide the crude product 3 as an oil.
4.2.2.2. 1-Benzhydryl-3-(2-phenylethyl) imidazol-3-ium bro-
mide (11j). Compound 11j (180 mg, 83%) was obtained as
an oil from 6 (150 mg, 0.64 mmol) and 2-phenylethyl bromide
(88
l, 0.64 mmol). 1H NMR (300 MHz, CDCl3): d 3.18 (t, 2H),
4.59 (t, J = 6.6 Hz, 2H), 6.49 (s, 1H), 7–7.3 (m, 15H), 7.33 (s, 1H),
7.89 (s, 1H), 9.56 (s, 1H); 13C NMR (75 MHz, CDCl3): d 36.02, 51,
66.3, 121.2, 123, 128.4, 128.5, 128.7, 129.2, 129.5, 129.6, 135.6,
135.7, 138.9; HRMS ESI+ calcd for C24H23N2þ: 339.1861, found:
M+, 339.1861.
From this oil 3 (450 mg) and imidazole (900 mg, 13.2 mmol), 8
(228 mg, 81% over two steps) was obtained as a white solid accord-
ing to the general procedure above, after purification by column
chromatography using AcOEt/pentane (90:10) as eluent.
l
Mp = 142–143 °C. 1H NMR (300 MHz, CDCl3):
d 6.66 (s, d,
J = 2.1 Hz, 2H), 6.76 (s, 1H), 7.03 (s, 1H), 7.12 (s, 1H) 7.23 (dd,
J = 8.4 Hz; 2.1 Hz, 2H), 7.34 (s, 1H), 7.46 (d, J = 2.1 Hz, 2H); 13C
NMR (75 MHz, CDCl3): d 58.6, 119.27, 127.86, 129.61, 130.1,
130.33, 134.2, 134.78, 135.72, 137.42; HRMS ESI+ calcd for
4.2.2.3. 1-Benzhydryl-3-(benzylethoxy) imidazol-3-ium bro-
C
16H11Cl4N2þ: 370.9671, found: MH+, 370.9677.
mide (11k).
an oil from 6 (500 mg, 2.13 mmol) and 2-bromoethoxymethyl ben-
zene (338
l, 2.13 mmol). 1H NMR (300 MHz, CDCl3): d 3.88 (t, 2H),
Compound 11k (650 mg, 68%) was obtained as
4.2.1.2. 1-Fluorenyl imidazole (9).
From 9-bromofluorene
l
(2 g, 8.15 mmol) and imidazole (1.66 g, 24 mmol), 9 (1.1 g, 60%)
was obtained as a yellow solid after purification by column chro-
matography using AcOEt/pentane (80/20) as eluent. Mp = 151–
153 °C. 1H NMR (300 MHz, CDCl3): d 6.7 (s, 1H), 7.06 (s, 1H),
7.26–7.4 (m, 5H), 7.46 (m, 2H), 7.69 (s, 1H), 7.77 (d, J = 7.8 Hz,
4.5(s, 2H), 4.66 (t, J = 4.1 Hz, 2H), 7.11 (s, 1H), 7.05 – 7.37 (m, 15H),
7.39 (s, 1H), 7.75 (s, 1H), 9.8 (s, 1H); 13C NMR (75 MHz, CD3OD): d
50, 68.1, 68.5, 73.8, 123.5, 124.4, 128.7, 128.8, 129.3, 129.3, 129.4,
130.2, 130.3, 137.9, 138.8; HRMS ESI+ calcd for C25H25ON2
369.1967, found: M+, 369.1965.
:
þ

4872
M. Sabbah et al. / Bioorg. Med. Chem. 19 (2011) 4868–4875
4.2.2.4. 1-Benzhydryl-3-butyl imidazol-3-ium bromide (11a).
J = 6.7 Hz, 3H), 1.1–1.3 (m, 26H), 1.89 (m, 2H), 4.31 (t,
J = 7.5 Hz, 2H), 7.12 (s, 1H), 7.15–7.4 (m, 10H), 7.54 (m, 2H),
10.28 (s, 1H); 13C NMR (75 MHz, CDCl3): d 14.2, 22.7, 26.3, 29,
Compound 11a (86 mg, 36%) was obtained as an oil from 6
(150 mg, 0.64 mmol) and 1-bromobutane (69 l
l, 0.64 mmol). 1H
NMR (300 MHz, CDCl3): d 0.83 (t, J = 7.5 Hz, 3H), 1.26 (m, 2H),
1.82 (m, 2H), 4.27 (t, J = 7.5 Hz, 2H), 7.11 (s, 1H), 7.1–7.29 (m,
10H), 7.54 (s, 1H), 7.78 (s, 1H), 10.19 (s, 1H); 13C NMR (75 MHz,
CDCl3): d 14.4, 19.4, 31.9, 50, 66.3, 121.3, 122.8, 128.1, 129.1,
129.2, 136.4, 136.8; HRMS ESI+ calcd for C20H23N2þ: 291.1861,
found: M+, 291.1863.
29.43, 29.45, 29.54, 29.67, 29.75, 30.2, 32, 50.5, 66.6, 121.4,
128.3, 129.3, 129.4, 136.5; HRMS ESI+ calcd for C32H47N2
459.3734, found: M+, 459.3727.
:
þ
4.2.2.11. 1-(Bis(4-chlorophenyl)methyl)-3-hexyl imidazol-3-
ium bromide (12b). Compound 12b (151 mg, 98%) was ob-
tained as an oil from 7 (100 mg, 0.33 mmol) and 1-bromohexane
(139 0.77 (t,
l, 0.99 mmol). 1H NMR (300 MHz, CDCl3):
4.2.2.5. 1-Benzhydryl-3-hexyl imidazol-3-ium bromide (11b).
l
d
Compound 11b (167 mg, 71%) was obtained as an oil from 6
J = 6.9 Hz, 3H), 1.18 (m, 6H), 1.85 (m, 2H), 4.27 (t, J = 7.5 Hz, 2H),
7.19 (d, J = 8.5 Hz, 4H), 7.25 (d, J = 8.5 Hz, 4H), 7.29 (t, J = 1.6 Hz,
1H), 7.72 (t, J = 1.6 Hz, 1H), 7.83 (s, 1H), 10.17 (s, 1H); 13C NMR
(75 MHz, CDCl3): d 13.79, 22.25, 25.77, 29.95, 30.88, 50.41, 64.81,
121.47, 122.73, 129.47, 129.64, 134.68, 135.36, 136.76; HRMS
ESI+ calcd for C22H25Cl2N2þ: 387.1389, found: M+, 387.1374.
(150 mg, 0.64 mmol) and 1-bromohexane (90 l
l, 0.64 mmol). 1H
NMR (300 MHz, CDCl3): d 0.77 (t, J = 6.7 Hz, 3H), 1.15–1.23 (m,
6H), 1.86 (m, 2H), 4.29 (t, J = 7.5 Hz, 2H), 7.13 (s, 1H), 7.15 – 7.35
(m, 10H), 7.58 (s, 1H), 7.71 (s, 1H), 10.19 (s, 1H); 13C NMR
(75 MHz, CDCl3): d 13.6, 20.1, 25.5, 29.8, 30.7, 50, 66.1, 121.2,
122.8, 127.9, 128.9, 129, 136.3, 136.5; HRMS ESI+ calcd for
C22H27N2þ: 319.2174, found: M+, 319.2175.
4.2.2.12. 1-(Bis(4-chlorophenyl)methyl)-3-octyl imidazol-3-ium
bromide (12c).
Compound 12c (191 mg, 78%) was obtained
l,
as an oil from 7 (150 mg, 0.49 mmol) and 1-bromooctane (85
l
4.2.2.6. 1-Benzhydryl-3-octyl imidazol-3-ium bromide (11c).
0.49 mmol). 1H NMR (300 MHz, CDCl3): d 0.83 (t, J = 5.1 Hz, 3H),
1.15–1.3 (m, 10H), 1.88 (m, 2H), 4.3 (t, J = 7.5 Hz, 2H), 7.21 (d,
J = 8.5 Hz, 4H), 7.28 (d, J = 8.5 Hz, 4H), 7.27–7.29 (m, 1H), 7.64 (t,
J = 1.6 Hz, 1H), 7.83 (s, 1H), 10.21 (s, 1H); 13C NMR (75 MHz,
CDCl3): d 12.7. 21.1, 24.8, 27.5, 27.6, 28.7, 30.2, 49.1, 63.5, 120.3,
121.6, 128.1, 128.4, 133.5, 134, 135.2; HRMS ESI+ calcd for
Compound 11c (234 mg, 86%) was obtained as an oil from 6
(150 mg, 0.64 mmol) and 1-bromooctane (111 l
l, 0.64 mmol). 1H
NMR (300 MHz, CDCl3): d 0.77 (t, J = 6.7 Hz, 3H), 1.05–1.3 (m,
10H), 1.83 (m, 2H), 4.27 (t, J = 6 Hz, 2H), 7.13 (s, 1H), 7.15–7.32
(m, 10H), 7.57 (s, 1H), 7.76 (s, 1H), 10.14 (s, 1H); 13C NMR
(75 MHz, CDCl3): d 14, 22.5, 26.1, 28.8, 28.9, 30.1, 31.5, 50.3,
66.4, 121.4, 122.6, 128.2, 129.1, 129.2, 136.5, 136.8; HRMS ESI+
calcd for C24H31N2þ: 347.2487, found: M+, 347.2484.
C
24H29Cl2N2þ: 415.1708, found: M+, 415.1707.
4.2.2.13. 1-(Bis(4-chlorophenyl)methyl)-3-decyl imidazol-3-ium
bromide (12d).
Compound 12d (157 mg, 91%) was obtained
(100 mg, 0.33 mmol) and 1-bromodecane
4.2.2.7. 1-Benzhydryl-3-decyl imidazol-3-ium bromide (11d).
as an oil from
7
(206 l d 0.8 (t,
l, 0.99 mmol). 1H NMR (300 MHz, CDCl3):
Compound 11d (540 mg, 74%) was obtained as an oil from 6
(300 mg, 1.28 mmol) and 1-bromodecane (266 l
l, 1.28 mmol). 1H
J = 6.8 Hz, 3H), 1.15–1.3 (m, 14H), 1.85 (m, 2H), 4.26 (t, J = 7.5 Hz,
2H), 7.21 (d, J = 8.5 Hz, 4H), 7.28 (d, J = 8.5 Hz, 4H), 7.27–7.29 (m,
1H), 7.61 (t, J = 1.6 Hz, 1H), 7.79 (s, 1H), 10.16 (s, 1H); 13C NMR
(75 MHz, CDCl3): d 14.07, 22.61, 26.24, 28.90, 29.19, 29.33, 29.38,
30.09, 31.78, 50.51, 64.87, 121.49, 122.65, 129.54, 129.70, 134.72,
135.46, 136.93; HRMS ESI+ calcd for C26H33Cl2N2þ: 443.2015,
found: M+, 443.1995.
NMR (300 MHz, CDCl3): d 0.79 (t, J = 6 Hz, 3H), 1.15–1.22 (m,
14H), 1.82 (m, 2H), 4.26 (t, J = 7.5 Hz, 2H), 7.14 (s, 1H), 7.15–7.31
(m, 10H), 7.55 (s, 1H), 7.75 (s, 1H), 9.98 (s, 1H); 13C NMR
(75 MHz, CDCl3): d 13.5, 22, 25.6, 28.3, 28.6, 28.7, 28.8, 29.6,
31.2, 49.7, 65.8, 121.1, 122.5, 127.6, 128.6, 128.7, 135.9, 136; HRMS
ESI+ calcd for C26H35N2þ: 375.2801, found: M+, 375.2800.
4.2.2.8. 1-Benzhydryl-3-dodecyl imidazol-3-ium bromide (11e).
Compound 11e (597 mg, 96%) was obtained as an oil from 6
4.2.2.14. 1-(Bis(4-chlorophenyl)methyl)-3-dodecylimidazol-3-
ium bromide (12e).
tained as an oil from 7 (100 mg, 0.33 mmol) and 1-bromododecane
(238
l, 0.99 mmol). 1H NMR (400 MHz, CDCl3): d 0.8 (t, J = 6.8 Hz,
Compound 12e (155 mg, 85%) was ob-
(300 mg, 1.28 mmol) and 1-bromododecane (315 ll, 1.28 mmol).
1H NMR (300 MHz, CDCl3): d 0.79 (m, 3H), 1.1–1.21 (m, 18H),
1.82 (m, 2H), 4.26 (t, J = 7.5 Hz, 2H), 7.12 (s, 1H), 7.13–7.3 (m,
10H), 7.53 (s, 1H), 7.70 (s, 1H), 9.99 (s, 1H); 13C NMR (75 MHz,
CDCl3): d 13.6, 22.1, 25.7, 28.4, 28.7, 28.8, 28.85, 28.9, 29, 31.3,
49.8, 65.9, 121.2, 122.5, 127.6, 128.7, 128.7, 135.9, 136.1; HRMS
ESI+ calcd for C28H40N2þ: 403.3113, found: M+, 403.3112.
l
3H), 1.14 -1.3 (m, 18 H), 1.84 (m, 2H), 4.27 (t, J = 7.5 Hz, 2H), 7.21
(d, J = 8.5 Hz, 4H), 7.27 (d, J = 8.5 Hz, 4H), 7.33 (s, 1H), 7.67 (s, 1H),
7.79 (s, 1H), 10.14 (s, 1H); 13C NMR (100 MHz, CDCl3): d 14.01,
22.55, 26.16, 28.84, 29.20, 29.26, 29.29, 29.35, 29.46, 30.03,
31.76, 50.41, 64.77, 121.50, 122.72, 129.44, 129.63, 134.67,
135.35, 136.72; HRMS ESI+ calcd for C28H37Cl2N2þ: 471.2328,
found: M+, 471.2311.
4.2.2.9. 1-Benzhydryl-3-tetradecyl imidazol-3-ium bromide
(11f).
Compound 11f (179 mg, 82%) was obtained as an oil
from 6 (100 mg, 0.43 mmol) and 1-bromotetradecane (380 ll,
1.28 mmol). 1H NMR (300 MHz, CDCl3): d 0.85 (t, J = 6.7 Hz, 3H),
1.1–1.3 (m, 22H), 1.87 (m, 2H), 4.31 (t, J = 7.5 Hz, 2H), 7.12 (s,
1H), 7.15–7.4 (m, 10H), 7.54 (s, 1H), 7.6 (s, 1H), 10.3 (s, 1H); 13C
NMR (75 MHz, CDCl3): d 14.2, 22.7, 26.3, 29, 29.4, 29.45, 29.5,
4.2.2.15. 1-(Bis(4-chlorophenyl)methyl)-3-tetradecylimidazol-
3-ium bromide (12f).
tained as an oil from 7 (100 mg, 0.33 mmol) and 1-bromotetradec-
ane (294
l, 0.99 mmol). 1H NMR (400 MHz, CDCl3): d 0.86 (t,
Compound 12f (173 mg, 90%) was ob-
l
J = 6.8 Hz, 3H), 1.19–1.3 (m, 22 H), 1.9 (m, 2H), 4.32 (t, J = 7.5 Hz,
2H), 7.27 (d, J = 8.5 Hz, 4H), 7.33 (d, J = 8.5 Hz, 4H), 7.38 (t,
J = 1.6 Hz, 1H), 7.72 (t, J = 1.6 Hz, 1H), 7.86 (s, 1H), 10.22 (s, 1H);
13C NMR (100 MHz, CDCl3): d 14.05, 22.59, 26.21, 28.88, 29.26,
29.31, 29.40, 29.51, 29.55, 29.59, 30.07, 31.82, 50.45, 64.79,
76.84, 77.16, 77.48, 121.50, 122.72, 129.48, 129.66, 134.71,
135.39, 136.80; HRMS ESI+ calcd for C30H41Cl2N2þ: 499.2641,
found: M+, 499.2623.
29.66, 29.71, 29.75, 30.2, 32, 50.5, 66.6, 121.4, 122.2, 128.3,
129.3, 129.4, 136.5, 137.5; HRMS ESI+ calcd for C30H43N2
431.3421, found: M+, 431.3416.
:
þ
4.2.2.10. 1-Benzhydryl-3-hexadecyl imidazol-3-ium bromide
(11g).
Compound 11g (155 mg, 68%) was obtained as an
(100 mg, 0.43 mmol) and 1-bromohexadecane
l, 1.28 mmol). 1H NMR (300 MHz, CDCl3):
(392 l d 0.85 (t,
oil from
6

M. Sabbah et al. / Bioorg. Med. Chem. 19 (2011) 4868–4875
4873
4.2.2.16. 1-(Bis(4-chlorophenyl)methyl)-3-octadecylimidazol-3-
ium bromide (12h). Compound 12h (178 mg, 85%) was ob-
1H), 10.17 (s, 1H); 13C NMR (100 MHz, CDCl3): d 14.13, 22.68,
26.15, 28.99, 29.35, 29.43, 29.49, 29.62, 29.64, 29.65, 29.68,
30.18, 30.95, 31.91, 50.73, 61.33, 122.12, 123.44, 128.65, 130.41,
130.58, 130.87, 134.46, 136.85, 137.82; HRMS ESI+ calcd for
tained as a white solid from 7 (100 mg, 0.33 mmol) and 1-bromo-
octadecane (335 mg, 0.99 mmol). Mp = 80–82 °C; 1H NMR
(400 MHz, CDCl3): d 0.85 (t, J = 6.8 Hz, 3H), 1.2–1.3 (m, 30 H), 1.9
(m, 2H), 4.32 (t, J = 7.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 4H), 7.33 (d,
J = 8.5 Hz, 4H), 7.32 - 7.34 (m, 1H), 7.66 (t, J = 1.6 Hz, 1H), 7.86 (s,
1H), 10.27 (s, 1H); 13C NMR (100 MHz, CDCl3): d 14.1, 22.68,
26.29, 28.95, 29.35, 29.39, 29.49, 29.61, 29.65, 29.69, 30.13,
31.91, 50.55, 64.89, 121.48, 122.63, 129.58, 129.72, 134.75,
135.51, 137.02; HRMS ESI+ calcd for C34H49Cl2N2þ: 555.3267,
found: M+, 555.3251.
C
30H39Cl4N2þ: 567.1862, found: M+, 567.184.
4.2.2.22. 1-(Bis(2,4-dichlorophenyl)methyl)-3-octadecylimidaz
ol-3-ium bromide (13h). Compound 13h (174 mg, 92%) was
obtained as an oil from 8 (100 mg, 0.27 mmol) and 1-bromotetra-
decane (240
l, 0.81 mmol). 1H NMR (400 MHz, CDCl3): d 0.82 (m,
l
3H), 1.1–1.3 (m, 30H), 1.85 (m, 2H), 4.43 (t, J = 7.3 Hz, 2H), 7.06 (m,
2H), 7.2–7.32 (m, 3H), 7.35 (s, 1H), 7.42 (m, 2H), 7.77 (s, 1H), 10.12
(s, 1H); 13C NMR (100 MHz, CDCl3): d 14.04, 22.59, 26.07, 28.91,
29.26, 29.34, 29.37, 29.42, 29.57, 29.59, 29.62, 30.13, 31.82,
50.57, 61.18, 122.13, 123.59, 128.48, 129.43, 129.68, 130.33,
130.36, 130.89, 134.41, 136.70, 137.62; HRMS ESI+ calcd for
C34H47Cl4N2þ: 623.2488, found: M+, 623.2467.
4.2.2.17. 1-(Bis(2,4-dichlorophenyl)methyl)-3-hexyl imidazol-3-
ium bromide (13b).
tained as an oil from 8 (80 mg, 0.21 mmol) and 1-bromohexane
(32
l, 0.21 mmol). 1H NMR (300 MHz, CDCl3): d 0.82 (m, 3H),
Compound 13b (56 mg, 49%) was ob-
l
1.22 (m, 6H), 1.87 (m, 2H), 4.46 (t, J = 7.3 Hz, 2H), 7.1 (d,
J = 2.1 Hz, 2H), 7.26 (s, 1H), 7.32 (dd, J = 2.1 Hz, 8.4 Hz, 2H), 7.35
(s, 1H), 7.44 (d, J = 2.1 Hz, 2H), 7.76 (s, 1H), 10.04 (s, 1H); 13C
NMR (75 MHz, CDCl3): d 13.9. 22.4, 25.8, 30.1, 31, 50.7, 61.4,
122.1, 123.4, 128.7, 130.4, 130.6, 130.9, 134.5, 136.9, 137.8. HRMS
ESI+ calcd for C22H23Cl4N2þ: 455.0610, found: M+, 455.0596.
4.2.2.23. 1-Fluorenyl-3-octyl imidazol-3-ium bromide (14c).
Compound 14c (170 mg, 98%) was obtained as a white solid from
9 (100 mg, 0.4 mmol) and 1-bromooctane (219 ll, 1.2 mmol).
Mp = 149–151 °C; 1H NMR (300 MHz, CDCl3): d 0.74 (t, J = 6.7 Hz,
3H), 1.1–1.25 (m, 14H), 1.8 (m, 2H), 4.21 (t, J = 7.2 Hz, 2H), 6.4 (s,
1H), 6.95 (s, 1H), 7.1 (t, J = 7.5 Hz, 2H), 7.27 (d, J = 7.5 Hz, 2H),
7.31 (t, J = 7.5 Hz, 2H), 7.55 (d, J = 7.5 Hz, 2H), 7.67 (s, 1H), 10.82
(s, 1H); 13C NMR (75 MHz, CDCl3): d 14.4, 22.8, 26.5, 29.2, 29.3,
30.5, 31.9, 50.6, 63, 119.6, 120.9, 123.8, 126, 128.8, 130.7, 137.5,
139.8, 140.9; HRMS ESI+ calcd for C24H29N2þ: 345.2325, found:
M+, 345.2332.
4.2.2.18. 1-(Bis(2,4-dichlorophenyl)methyl)-3-octyl imidazol-3-
ium bromide (13c).
tained as an oil from 8 (70 mg, 0.18 mmol) and 1-bromooctane
(32
l, 0.18 mmol). 1H NMR (300 MHz, CDCl3): d 0.84 (m, 3H),
Compound 13c (71 mg, 67%) was ob-
l
1.19–1.26 (m, 10H), 1.84 (m, 2H), 4.46 (t, J = 7.3 Hz, 2H), 7.16 (d,
J = 8.4 Hz, 2H), 7.23 (t, J = 1.6 Hz, 1H), 7.3–7.36 (m, 3H), 7.46 (d,
J = 2 Hz, 2H), 7.64 (t, J = 1.6 Hz, 1H), 9.96 (s, 1H); 13C NMR
(75 MHz, CDCl3): d 14.1, 22.6, 26.1, 28.9, 29.1, 30.2, 31.6, 50.7,
61.3, 122.1, 123.4, 128.7, 130.4, 130.6, 130.9, 134.5, 136.9, 137.9;
HRMS ESI+ calcd for C24H27Cl4N2þ: 483.0923, found: M+, 483.0909.
4.2.2.24. 1-Fluorenyl-3-decyl imidazol-3-ium bromide (14d).
Compound 14d (129 mg, 70%) was obtained as a white solid
from
9
(100 mg, 0.4 mmol) and 1-bromodecane (267 ll,
1.2 mmol). Mp = 118–120 °C; 1H NMR (300 MHz, CDCl3): d 0.75
(t, J = 6.7 Hz, 3H), 1–1.25 (m, 14H), 1.8 (m, 2H), 4.28 (t,
J = 7.2 Hz, 2H), 6.45 (s, 1H), 6.95 (s, 1H), 7.1 (t, J = 7.5 Hz, 2H),
7.3 (m, 4H), 7.54 (d, J = 7.5 Hz, 2H), 7.63 (s, 1H), 10.86 (s, 1H);
13C NMR (75 MHz, CDCl3): d 13.9, 22.4, 26, 28.7, 29, 29.1, 29.2,
30, 31.6, 50.1, 62.5, 119.1, 120.4, 123.2, 125.2, 128.3, 130.2,
137.1, 139.3, 140.4; HRMS ESI+ calcd for C26H33N2þ: 373.2638,
found: M+, 373.2645
4.2.2.19. 1-(Bis(2,4-dichlorophenyl)methyl)-3-decylimidazol-3-
ium bromide (13d).
tained as an oil from 8 (120 mg, 0.32 mmol) and 1-bromodecane
(200 0.86 (t,
l, 0.97 mmol). 1H NMR (300 MHz, CDCl3):
Compound 13d (145 mg, 88%) was ob-
l
d
J = 6.8 Hz, 3H), 1.1–1.3 (m, 14H), 1.9 (m, 2H), 4.47 (t, J = 7.3 Hz,
2H), 7.09 (d, J = 8.4 Hz, 2H), 7.31 (m, 1H), 7.34 (dd, J = 2 Hz;
8.4 Hz, 2H), 7.39 (s, 1H), 7.46 (d, J = 2 Hz, 2H), 7.83 (t, J = 1.6 Hz,
1H), 10.11 (s, 1H); 13C NMR (75 MHz, CDCl3): d 14.08, 22.62,
26.11, 28.94, 29.21, 29.38, 30.15, 31.80, 50.68, 61.27, 122.14,
123.51, 128.59, 130.38, 130.49, 130.88, 134.44, 136.79, 137.66;
HRMS ESI+ calcd for C26H31Cl4N2þ: 511.1236, found: M+, 511.1218.
4.2.2.25. 1-Fluorenyl-3-dodecyl imidazol-3-ium bromide (14e).
Compound 14e (158 mg, 81%) was obtained as a white solid from 9
(100 mg, 0.4 mmol) and 1-bromodecane (310 ll, 1.2 mmol).
Mp = 122–124 °C; 1H NMR (300 MHz, CDCl3): d 0.76 (t, J = 6.7 Hz,
3H), 1–1.25 (m, 18H), 1.8 (m, 2H), 4.24 (t, = 7.2 Hz, 2H), 6.46 (s,
1H), 6.96 (s, 1H), 7.14 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H),
7.37 (d, J = 7.5 Hz, 2H), 7.57 (s, 1H), 7.58 (d, J = 7.5 Hz, 2H), 10.8
(s, 1H); 13C NMR (75 MHz, CDCl3): d 14, 22.5, 26.1, 28.8, 29.2,
4.2.2.20. 1-(Bis(2,4-dichlorophenyl)methyl)-3-dodecylimidazol-
3-ium bromide (13e).
tained as an oil from 8 (120 mg, 0.32 mmol) and 1-bromododecane
(233
l, 0.97 mmol). 1H NMR (400 MHz, CDCl3): d 0.81 (t, J = 6.8 Hz,
Compound 13e (173 mg, 87%) was ob-
l
29.3, 29.4, 30.1, 31.7, 50, 63, 119.3, 120.5, 123.1, 125.4, 128.4,
130.3, 137.2, 139.5, 140.5; HRMS ESI+ calcd for C28H37N2
401.2951, found: M+, 401.2940
:
þ
3H), 1.1–1.3 (m, 18H), 1.84 (m, 2H), 4.41 (t, J = 7.3 Hz, 2H), 7.02 (d,
J = 8.4 Hz, 2H) 7.25–7.32 (m, 3H), 7.35 (s, 1H), 7.4 (d, J = 2 Hz, 2H),
7.83 (s, 1H), 10.1 (s, 1H); 13C NMR (100 MHz, CDCl3): d 14.03.
22.57, 26.05, 28.89, 29.23, 29.34, 29.38, 29.50, 29.51, 30.11,
31.79, 50.58, 61.17, 122.14, 123.58, 128.49, 130.32, 130.38,
130.88, 134.40, 136.68, 137.55; HRMS ESI+ calcd for
4.2.2.26. 1-Fluorenyl-3-tetradecyl imidazol-3-ium bromide
(14f).
solid from
Compound 14f (201 mg, 97%) was obtained as a white
(100 mg, 0.4 mmol) and 1-bromotetradecane
9
C
28H35Cl4N2þ: 539.1549, found: M+, 539.1525.
(384 l
l, 1.2 mmol). Mp = 127–129 °C; 1H NMR (300 MHz, CDCl3):
d 0.8 (t, J = 6.7 Hz, 3H), 1–1.25 (m, 22H), 1.85 (m, 2H), 4.27 (t,
J = 7.2 Hz, 2H), 6.47 (s, 1H), 7 (s, 1H), 7.16 (t, J = 7.5 Hz, 2H), 7.34
(t, J = 7.5 Hz, 2H), 7.4 (d, J = 7.5 Hz, 2H), 7.56 (s, 1H), 7.6 (d,
J = 7.5 Hz, 2H), 10.92 (s, 1H); 13C NMR (75 MHz, CDCl3): d 14,
22.6, 26.2, 28.9, 29.2, 29.3, 29.4, 29.5, 29.55, 29.6, 30.1, 31.8,
50.3, 62.8, 119.3, 120.5, 123, 125.5, 128.4, 130.3, 137.4, 139.5,
140.6; HRMS ESI+ calcd for C30H41N2þ: 429.3264, found: M+,
429.3264.
4.2.2.21. 1-(Bis(2,4-dichlorophenyl)methyl)-3-tetradecylimidaz
ol-3-ium bromide (13f). Compound 13f (152 mg, 87%) was
obtained as an oil from 8 (100 mg, 0.27 mmol) and 1-bromotetra-
decane (240
l, 0.81 mmol). 1H NMR (400 MHz, CDCl3): d 0.87 (t,
J = 6.8 Hz, 3H), 1.1–1.3 (m, 22H), 1.90 (m, 2H), 4.48 (t, J = 7.3 Hz,
2H), 7.13 (d, J = 8.4 Hz, 2H), 7.31 (t, J = 1.6 Hz, 1H), 7.34 (dd,
J = 2 Hz; 8.4 Hz, 2H), 7.47 (d, J = 2 Hz, 2H), 7.39 (s, 1H), 7.81 (s,
l

4874
M. Sabbah et al. / Bioorg. Med. Chem. 19 (2011) 4868–4875
4.2.2.27. 1-Fluorenyl-3-hexadecyl imidazol-3-ium bromide
(14g). Compound 14g (201 mg, 74%) was obtained as a brown
solid from 9 (100 mg, 0.4 mmol) and 1-bromohexadecane (373 l,
(750 l
l, 2.2 mmol). Mp = 79–81 °C; 1H NMR (400 MHz, CDCl3): d
0.61 (t, J = 6.7 Hz, 3H), 0.8–1.3 (m, 30H), 1.4–1.8 (m, 8H), 2.11 (m,
2H), 4.15 (t, J = 7.2 Hz, 2H), 4.7 (m, 1H), 7.43 (s, 1H), 7.47 (s, 1H),
10.2 (s, 1H); 13C NMR (100 MHz, CDCl3): d 13.6, 22.2, 23.2, 25.8,
l
1.2 mmol). Mp = 118–120 °C; 1H NMR (300 MHz, CDCl3): d 0.8 (t,
J = 6.7 Hz, 3H), 1–1.25 (m, 26H), 1.84 (m, 2H), 4.25 (t, J = 7.2 Hz,
2H), 6.5 (t, J = 1.6 Hz, 1H), 7.01 (s, 1H), 7.15 (t, J = 7.5 Hz, 2H), 7.33
(t, J = 7.5 Hz, 2H), 7.37 (d, J = 7.5 Hz, 2H), 7.58 (d, J = 7.5 Hz, 2H),
7.61 (s, 1H), 10.99 (s, 1H); 13C NMR (75 MHz, CDCl3): d 14, 22.6,
26.2, 28.9, 29.25, 29.3, 29.4, 29.51, 29.56, 29.6, 30.1, 31.8, 50.3,
62.7, 119.3, 120.5, 123.2, 125.4, 128.4, 130.3, 137.4, 139.5, 140.6;
HRMS ESI+ calcd for C32H45N2þ: 457.3577, found: M+, 457.3568
28.6, 28.9, 29.05, 29.05, 29.13, 29.15, 29.16, 29.2, 30, 31.4, 33,
49.4, 61, 120.7, 122.2, 135.5; HRMS ESI+ calcd for C26H49N2
389.389, found: M+, 389.3904.
:
þ
4.3. Molecular modelling
In order to perform docking studies, the ligand binding site of
LuxR was created by selecting residues interacting with calmidazo-
lium, Docking experiments were performed with the following
parameters: Docking box: X = Y = Z = 15 Å, ligand option: flexible;
calculation type: Dock; Docking engine: GADock (Genetic Algo-
rithm).47 Genetic algorithm dock engine settings: default advanced
parameters; hydrogen bonds were assigned within a distance of 3 Å.
4.2.2.28.
(15c).
1-Cyclopentyl-3-octyl imidazol-3-ium bromide
Compound 15c (313 mg, 93%) was obtained as an oil
from 10 (140 mg, 1 mmol) and 1-bromooctane (178 ll, 1 mmol).
1H NMR (300 MHz, CDCl3): d 0.88 (t, J = 6.9 Hz, 3H), 1.25–1.36
(m, 10H), 1.71–2.1 (m, 8H), 2.35- 2.41 (m, 2H), 4.39 (t, J = 7.2 Hz,
2H), 4.94 (m, 1H), 7.27 (m, 2H), 10.71 (s, 1H); 13C NMR (75 MHz,
CDCl3): d 13.6, 22.1, 23.2, 25.8, 28.5, 28.6, 29.4, 31.2, 33, 49.5, 61,
120.7, 122.1, 135.5; HRMS ESI+ calcd for C16H29N2þ: 249.2325,
found: M+, 249.2335.
Acknowledgments
Financial support from MESR, CNRS, and the ‘‘Cluster de recher-
che Chimie/infectiologie de la Région Rhône-Alpes’’ is gratefully
acknowledged. M.S. is the recipient of a scholarship from the
cluster.
4.2.2.29. 1-Cyclopentyl-3-decyl imidazol-3-ium bromide (15d).
Compound 15d (235 mg, 90%) was obtained as an oil from 10
(100 mg, 0.73 mmol) and 1-bromodecane (458 l
l, 2.2 mmol). 1H
NMR (300 MHz, CDCl3): d 0.83 (t, J = 6.7 Hz, 3H), 1.15–1.3 (m,
14H), 1.6–2 (m, 8H), 2.36 (m, 2H), 4.36 (t, J = 7.2 Hz, 2H), 4.93
(m, 1H), 7.41 (s, 1H), 7.43 (s, 1H), 10.53 (s, 1H); 13C NMR
(75 MHz, CDCl3): d 13.8, 22.3, 23.4, 26, 28.7, 28.9, 29.1, 29.2,
30.2, 31.5, 33.3, 49.7, 61.3, 120.7, 122.2, 135.7; HRMS ESI+ calcd
for C18H33N2þ: 277.2638, found: M+, 277.265.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2011.06.075.
References and notes
4.2.2.30. 1-Cyclopentyl-3-dodecyl imidazol-3-ium bromide
1. Camilli, A.; Bassler, B. L. Science 2006, 311, 1113.
2. Miller, M. B.; Bassler, B. L. Annu. Rev. Microbiol. 2001, 55, 165.
3. Waters, C. M.; Bassler, B. L. Annu. Rev. Cell Dev. Biol. 2005, 21, 319.
4. Gonzalez, J. E.; Keshavan, N. D. Microbiol. Mol. Biol. Rev. 2006, 70, 859.
5. Reading, N. C.; Sperandio, V. F. E. M. S. Microbiol. Lett. 2006, 254, 1.
6. Hughes, D. T.; Sperandio, V. Nat. Rev. Microbiol. 2008, 6, 111.
7. Lowery, C. A.; Dickerson, T. J.; Janda, K. D. Chem. Soc. Rev. 2008, 37, 1337.
8. Dickschat, J. S. Nat. Prod. Rep. 2010, 27, 343.
9. Uroz, S.; Dessaux, Y.; Oger, P. ChemBioChem 2009, 10, 205.
10. Persson, T.; Givskov, M.; Nielsen, J. Curr. Med. Chem. 2005, 12, 3103.
11. Rasmussen, T. B.; Givskov, M. Microbiology 2006, 152, 895.
12. Geske, G. D.; O’Neill, J. C.; Blackwell, H. E. Chem. Soc. Rev. 2008, 37, 1432.
13. Janssens, J. C.; De Keersmaecker, S. C.; De Vos, D. E.; Vanderleyden, J. Curr. Med.
Chem. 2008, 15, 2144.
(15e).
Compound 15e (223 mg, 79%) was obtained as an oil
l,
from 10 (100 mg, 0.73 mmol) and 1-bromododecane (511
l
2.2 mmol). 1H NMR (300 MHz, CDCl3): d 0.66 (t, J = 6.7 Hz, 3H),
0.9–1.3 (m, 18H), 1.5–1.8 (m, 8H), 2.16 (m, 2H), 4.18 (t,
J = 7.2 Hz, 2H), 4.76 (m, 1H), 7.43 (s, 1H), 7.47 (s, 1H), 10.13 (s,
1H); 13C NMR (75 MHz, CDCl3): d 13.7, 22.3, 23.3, 26, 28.7, 28.9,
29, 29.1, 29.2, 30, 31.5, 33.1, 49.6, 61.1, 120.7, 122.2, 135.6; HRMS
ESI+ calcd for C20H37N2þ: 305.2951, found: M+, 305.296.
4.2.2.31. 1-Cyclopentyl-3-tetradecyl imidazol-3-ium bromide
14. Ni, N.; Li, M.; Wang, J.; Wang, B. Med. Res. Rev. 2009, 29, 65.
15. Njoroge, J.; Sperandio, V. EMBO Mol. Med. 2009, 1, 201.
16. Hoiby, N.; Bjarnsholt, T.; Givskov, M.; Molin, S.; Ciofu, O. Int. J. Antimicrob.
Agents 2010, 35, 322.
17. Hassett, D. J.; Korfhagen, T. R.; Irvin, R. T.; Schurr, M. J.; Sauer, K.; Lau, G. W.;
Sutton, M. D.; Yu, H.; Hoiby, N. Expert Opin. Ther. Targets 2010, 14, 117.
18. Raina, S.; De Vizio, D.; Odell, M.; Clements, M.; Vanhulle, S.; Keshavarz, T.
Biotechnol. Appl. Biochem. 2009, 54, 65.
19. Stevens, A. M.; Queneau, Y.; Soulere, L.; von Bodman, S.; Doutheau, A. Chem.
Rev. 2011, 111, 4.
20. Reverchon, S.; Chantegrel, B.; Deshayes, C.; Doutheau, A.; Cotte-Pattat, N.
Bioorg. Med. Chem. Lett. 2002, 12, 1153.
(15f).
Compound 15f (253 mg, 84%) was obtained as an oil
l,
from 10 (100 mg, 0.73 mmol) and 1-bromotetradecane (655
l
2.2 mmol). 1H NMR (300 MHz, CDCl3): d 0.71 (t, J = 6.7 Hz, 3H),
0.9–1.4 (m, 22H), 1.5–1.8 (m, 8H), 2.21 (m, 2H), 4.23 (t,
J = 7.2 Hz, 2H), 4.8 (m, 1H), 7.45 (s, 1H), 7.49 (s, 1H), 10.2 (s, 1H);
13C NMR (75 MHz, CDCl3): d 13.9, 22.4, 23.5, 26, 28.8, 29.1, 29.2,
29.3, 29.4, 29.27, 30.2, 31.6, 33.3, 49.7, 61.3, 120.8, 122.3, 135.8;
HRMS ESI+ calcd for C22H41N2þ: 333.3264, found: M+, 333.3278
21. Castang, S.; Chantegrel, B.; Deshayes, C.; Dolmazon, R.; Gouet, P.; Haser, R.;
Reverchon, S.; Nasser, W.; Hugouvieux-Cotte-Pattat, N.; Doutheau, A. Bioorg.
Med. Chem. Lett. 2004, 14, 5145.
22. Frezza, M.; Castang, S.; Estephane, J.; Soulere, L.; Deshayes, C.; Chantegrel, B.;
Nasser, W.; Queneau, Y.; Reverchon, S.; Doutheau, A. Bioorg. Med. Chem. 2006,
14, 4781.
23. Frezza, M.; Soulere, L.; Reverchon, S.; Guiliani, N.; Jerez, C.; Queneau, Y.;
Doutheau, A. Bioorg. Med. Chem. 2008, 16, 3550.
24. Estephane, J.; Dauvergne, J.; Soulere, L.; Reverchon, S.; Queneau, Y.; Doutheau,
A. Bioorg. Med. Chem. Lett. 2008, 18, 4321.
4.2.2.32. 1-Cyclopentyl-3-hexadecyl imidazol-3-ium bromide
(15g).
solid from 10 (100 mg, 0.73 mmol) and 1-bromohexadecane
(670
l, 2.2 mmol), mp = 67–69 °C; 1H NMR (400 MHz, CDCl3): d
Compound 15g (303 mg, 94%) was obtained as a brown
l
0.61 (t, J = 6.7 Hz, 3H), 0.8–1.3 (m, 26H), 1.4–1.8 (m, 8H), 2.11 (m,
2H), 4.15 (t, J = 7.2 Hz, 2H), 4.7 (m, 1H), 7.43 (s, 1H), 7.47 (s, 1H),
10.2 (s, 1H); 13C NMR (100 MHz, CDCl3): d 13.6, 22.1, 23.2, 25.8,
28.5, 28.8, 28.9, 29, 29.1, 29.2, 29.9, 31.4, 33, 49.4, 60.9, 120.7,
122.1, 135.5; HRMS ESI+ calcd for C24H45N2þ: 361.3577, found:
M+, 361.3592.
25. Soulere, L.; Guiliani, N.; Queneau, Y.; Jerez, C. A.; Doutheau, A. J. Mol. Model.
2008, 14, 599.
26. Soulere, L.; Sabbah, M.; Fontaine, F.; Queneau, Y.; Doutheau, A. Bioorg. Med.
Chem. Lett. 2010, 20, 4355.
27. Muh, U.; Hare, B. J.; Duerkop, B. A.; Schuster, M.; Hanzelka, B. L.; Heim, R.;
Olson, E. R.; Greenberg, E. P. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 16948.
28. Muh, U.; Schuster, M.; Heim, R.; Singh, A.; Olson, E. R.; Greenberg, E. P.
Antimicrob. Agents Chemother. 2006, 50, 3674.
4.2.2.33. 1-Cyclopentyl-3-octadecyl imidazol-3-ium bromide
(15h).
Compound 15h (321 mg, 94%) was obtained as a
brown solid from 10 (100 mg, 0.73 mmol) and 1-bromooctadecane

M. Sabbah et al. / Bioorg. Med. Chem. 19 (2011) 4868–4875
4875
29. Borlee, B. R.; Geske, G. D.; Blackwell, H. E.; Handelsman, J. Appl. Environ.
Microbiol. 2010, 76, 8255.
30. Yang, L.; Rybtke, M. T.; Jakobsen, T. H.; Hentzer, M.; Bjarnsholt, T.; Givskov, M.;
Tolker-Nielsen, T. Antimicrob. Agents Chemother. 2009, 53, 2432.
31. Zeng, Z.; Qian, L.; Cao, L.; Tan, H.; Huang, Y.; Xue, X.; Shen, Y.; Zhou, S. Appl.
Microbiol. Biotechnol. 2008, 79, 119.
32. Hindi, K. M.; Panzner, M. J.; Tessier, C. A.; Cannon, C. L.; Youngs, W. J. Chem. Rev.
2009, 109, 3859.
33. Demberelnyamba, D.; Kim, K. S.; Choi, S.; Park, S. Y.; Lee, H.; Kim, C. J.; Yoo, I. D.
Bioorg. Med. Chem. 2004, 12, 853.
37. Rester, U. QSAR Comb. Sci. 2006, 25, 605.
38. Soulere, L.; Frezza, M.; Queneau, Y.; Doutheau, A. J. Mol. Graphics Modell. 2007,
26, 581.
39. Ma, J. C.; Dougherty, D. A. Chem. Rev. 1997, 97, 1303.
40. Zacharias, N.; Dougherty, D. A. Trends Pharmacol. Sci. 2002, 23, 281.
41. Meyer, E. A.; Castellano, R. K.; Diederich, F. Angew. Chem., Int. Ed. 2003, 42,
1210.
42. Thompson, M. A. ArgusLaB 4.0.1 Planetaria Software LLC, Seattle, WA; 2004.
43. Arnold, K.; Bordoli, L.; Kopp, J.; Schwede, T. Bioinformatics 2006, 22, 195.
44. Thompson, J. D.; Higgins, D. G.; Gibson, T. J. Nucleic Acids Res. 1994, 22, 4673.
45. Corelli, F.; Summa, V.; Brogi, A.; Monteagudo, E.; Botta, M. J. Org. Chem. 1995,
60, 2008.
34. Song, K. S.; Lee, S. H.; Chun, H. J.; Kim, J. Y.; Jung, M. E.; Ahn, K.; Kim, S. U.; Kim,
J.; Lee, J. Bioorg. Med. Chem. 2008, 16, 4035.
35. La Regina, G.; D’Auria, F. D.; Tafi, A.; Piscitelli, F.; Olla, S.; Caporuscio, F.;
Nencioni, L.; Cirilli, R.; La Torre, F.; De Melo, N. R.; Kelly, S. L.; Lamb, D. C.;
Artico, M.; Botta, M.; Palamara, A. T.; Silvestri, R. J. Med. Chem. 2008, 51, 3841.
36. Kronvall, G.; Ringertz, S. APMIS 1991, 99, 295.
46. Jones, C. D.; Winter, M. A.; Hirsch, K. S.; Stamm, N.; Taylor, H. M.; Holden, H. E.;
Davenport, J. D.; Krumkalns, E. V.; Suhr, R. G. J. Med. Chem. 1990, 33, 416.
47. Morris, G. M.; Goodsell, D. S.; Halliday, R. S.; Huey, R.; Hart, W. E.; Belew, R. K.;
Olson, A. J. J. Compd. Chem. 1998, 19, 1639.