Antibacterial activities of imidazolium, pyrrolidinium and piperidinium salts

Article abstract of DOI:10.1016/j.bmcl.2011.01.081

The antibacterial activity of various types of imidazolium, pyrrolidinium and piperidinium salts with both propargyl group and alkyl and/or silylalkyl chains of different lengths, are described. Especially, the MIC (μg/ml) of prepared each compound for Es

Full text of DOI:10.1016/j.bmcl.2011.01.081

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1728–1730
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Antibacterial activities of imidazolium, pyrrolidinium and piperidinium salts
⇑
⇑
Noritaka Iwai , Kyosuke Nakayama, Tomoya Kitazume
Graduate School of Bioscience and Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The antibacterial activity of various types of imidazolium, pyrrolidinium and piperidinium salts with both
propargyl group and alkyl and/or silylalkyl chains of different lengths, are described. Especially, the MIC
Received 29 November 2010
Revised 17 January 2011
Accepted 19 January 2011
Available online 31 January 2011
(
l
g/ml) of prepared each compound for Escherichia coli and other several bacteria was determined.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Antibacterial activity
Gram-positive bacteria
Two-component system
Ionic liquid
The development of multi-drug-resistant pathogens has be-
come a serious problem in the chemotherapy of bacterial infec-
tions diseases. One of the strategies to overcome this problem is
to find a new drug with a new molecular target. Recently,
two-component systems are proposed as a new target against
drug-resistant bacteria.1,2 Particularly, yycG(walK)–yycF(walR)
two-component system is essential and conserved among low
G+C Gram-positive pathogen bacteria. In the study of two-compo-
nent systems, it is known that some kinds of 1-alkyl-2-methy-3-
benzylimidazolium salts inhibit the alginate gene activation in
Pseudomonas aeruginosa3 and/or histidine protein kinase of Bacillus
subtilis,4,5 and that the ionic liquid derived from the antifungal drug
miconazole has been prepared.6 Further, a series of 3-alkoxy-
methyl-1-methylimidazolium salts have been investigated for
antimicrobial activities against cocci, rods and fungi.7 Based on
the results of reported minimum inhibitory concentration (MIC)
values, the most active salts against cocci and rods have an alkoxy
group which contains 12 or 14 carbon atoms.7 However, activity
against fungi is significantly different result indicating that no opti-
mum activity is clear with the carbon length. These results showed
the capability of ionic liquid structure for antibacterial activity,
especially for bacterial two-component systems inhibitor. But
more details about structure–activity relationships are desired.
Furthermore, the emergence and spread of multi-drug-resistant
bacteria present a need for new antibiotics with innovative mode
of action.8,9 Consequently, novel approaches for new antibiotics
with innovative mode of action are urgently required.
In this Letter, we would like to describe the antibacterial activ-
ity of various types of imidazolium, pyrrolidinium and piperidini-
um salts with propargyl group instead of benzyl group which
had the specific activity against Gram-positive bacteria.
Minimal inhibitory concentrations (MIC:
lg/ml) of the com-
pounds for several bacteria were determined by the agar-dilution
method using Mueller Hinton Broth (Bexton Dickinson and
Company, MD). The tested bacterial strains were B. subtilis 168,
Staphylococcus aureus subsp., aureus NBRC 15035, Escherichia coli
MG1655, Pseudomonas putida NBRC 14164. The antibacterial activ-
ities were determined based on the method of Japanese Society of
Chemotherapy.
To study on the antibacterial activity of imidazolium deriva-
tives, we have designed the several kinds of materials based on
the 1-cetyl-2-methyl-3-benzylimidazolium iodide (NH125) re-
ported to best derivative by Utsumi and his co-workers. Especially,
we aimed at searching for the specific compounds which had the
activity against only Gram-positive bacteria with the two-compo-
nent systems in this study. We first have designed the structure
with the electron rich group such as propargyl group instead of
benzyl group on one side and alkyl and/or silylalkyl chains of dif-
ferent lengths on other side of the imidazole ring. In order to define
the structure–activity relationship of the chain length of alkyl and/
or silylalkyl groups on 3rd position of imidazole ring, the biological
activities of 17 related compounds were examined.
From the results as shown in Table 1 (Scheme 1) compounds
(entries 1–5) showed antibacterial activities toward Gram-positive
bacteria B. subtilis and S. aureus at a relatively low concentration,
but those compounds showed similar antibacterial activity against
Gram-negative bacteria E. coli like NH125. Thereto the compounds
with carbon chain lengths of 14 and 16 carbon atoms (entries 6 and
7) were effective against only Gram-positive bacterias on the basis
⇑
Corresponding authors. Tel.: +81 45 924 5754; fax: +81 45 924 5780 (T.K.).
E-mail addresses: tkitazum@bio.titech.ac.jp, kitazume.t.aa@m.titiech.ac.jp
(T. Kitazume).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.01.081

N. Iwai et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1728–1730
1729
Table 1
Table 4
Antibacterial activities of propargyl imidazolium derivatives with an alkyl group on
Activity relationship with both substituted groups on 1st and 3rd positions
(MIC: g/ml)
1st position of imidazolium ring (MIC:
l
g/ml)
l
Entry
n
R
B. subtilis
S. aureus
E. coli
P. putida
Entry
R
n
B. subtilis
S. aureus
E. coli
P. putida
1
2
3
4
5
6
7
9
Me
Me
Me
H
Me
Me
Me
0.78
0.78
0.39
0.39
0.39
0.78
1.56
0.78
0.39
0.39
0.39
0.39
0.78
1.56
12.5
3.13
3.13
25
6.25
100
>100
50
50
50
50
50
>100
>100
22
23
24
25
26
27
28
29
30
HC„C
C8H17
Biphenyl
4-C5H11C6H4
4-Me3Si(CH2)2C6H4
4
4
4
4
4
5
6
7
9
>100
1.56
1.56
0.39
0.39
0.78
1.56
1.56
6.25
100
>100
50
100
>100
>100
100
100
100
>100
>100
>100
>100
10
11
12
12
14
16
3.13
0.39
0.39
0.39
0.78
1.56
1.56
>6.25
50
>100
>100
>100
>100
>100
NH125: B. subtilis (1.56), E. coli (3.13).4,5
R
R
R
CnH2n+1
c)
a)
CnH2n+1
N
N
I-
N
N
SiMe
n
3
N
N
SiMe
n
3
N
N
I-
C5H11
Scheme 1. Reagents and conditions: (a) C5H11„CH2Br, KI, CHCl3, reflux, 8 h.
Scheme 4. Reagents and conditions: (c) RX, CHCl3.
of the results in Table 1. These results suggest that the (3-pen-
tyl)propargyl group instead of benzyl group was effective and spe-
cific for the activity bear comparison with the reported compound
NH125.4,5 In the next step, we have designed new types of imidaz-
ole compounds containing both (3-pentyl)propargyl group and sil-
icone atom instead of carbon atom on the each side of the
imidazole ring. All compounds (entries 8–17) have remarkable ef-
fect for the bacterial activities against Gram-positive bacteria, and
then some of them (entries 15–17) showed the strong specificity.
Furthermore, we have designed pyrrolidinium and piperidinium
salts with (3-pentyl)propargyl group as shown in Scheme 3, but
compounds (entries 18–21) are not effective for the activity as
shown in Table 3.
The results shown in Tables 1 and 2(scheme 2) are supports that
the long alkyl chain on 1st position of imidazolium ring is an
important factor for the specific antibiological activity against
Gram-positive bacteria, and that imidazolium ring with methyl
group on 2nd position is ineffective (e.g., entries 15 and 16). Fur-
ther, we have designed the several types of materials based on
the molecular weight. Judging from the results shown in Table
R
R
b)
N
N
SiMe
N
N
I-
SiMe
n
3
n
3
C5H11
Scheme 2. Reagents and conditions: (b) C5H11„CH2Br, KI, CHCl3, reflux.
Table 2
Antibacterial activities of propargyl imidazolium derivatives with a silylalkyl group
on 1st position of imidazolium ring (MIC: g/ml)
l
Entry
n
R
B. subtilis
S. aureus
E. coli
P. putida
8
9
4
4
5
5
6
7
7
9
9
11
H
Me
H
Me
Me
H
Me
H
1.56
1.56
0.39
0.39
0.39
0.39
0.39
0.39
0.39
1.56
3.13
1.56
0.78
0.39
0.39
0.78
0.39
0.78
0.78
1.56
50
50
25
12.5
12.5
25
12.5
100
100
>100
100
100
100
50
10
11
12
13
14
15
16
17
50
100
100
>100
100
>100
Me
Me
Table 3
Antibacterial activities (MIC:
l
g/ml)
Entry
B. subtilis
S. aureus
E. coli
P. putida
18
19
20
21
>50
1.56
>50
1.56
>50
1.56
>50
1.56
>50
>50
>50
50
>50
>50
>50
100
Scheme 3. Reagents and conditions: (b) R1X, KI, CHCl3, reflux.

1730
N. Iwai et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1728–1730
a
b
c
N
N
I-
9
SiMe3
C5H11
control
d
C16H33
N
N
I-
4
SiMe3
Ph
N
N
NH125
Me3SiCH2CH2
I-
Figure 1. The effect of novel imidazolium salts on B. subtilis cell morphology. B. subtilis cells were treated with each compound in about three-fold concentration of MIC in
Table after pregrowth to log-phase. Cell morphology was observed after 2 h from the treatment.
4(Scheme 4), total carbon chain length on the both sides of imidaz-
ole ring and molecular weight are important factors against the
specific antibacterial activity of Gram-positive bacterias.
It is reported that the inhibition of yycG yycF Gram-positive spe-
cific two-component system leads the prevention of cell division in
B. subtilis. Therefore, imidazolium derivatives were treated to B.
subtilis cell, and cell morphology was confirmed. NH125 as a posi-
tive control led cell elongation through cell division inhibition
(Fig. 1b). Compound entries 16 and 26 also led cell elongation,
respectively (Fig. 1c and d). These results suggested that synthetic
novel imidazolium derivatives shown antibacterial activity reason
for the cell division inhibition and the target of these compounds
was specific in Gram-positive low GÀC bacteria possessed yycG
yycF two-component system.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.01.081.
References and notes
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In conclusion, we have found that the (3-pentyl)propargyl
group is effective for the activity bear comparison with benzyl
group, and that silylalkyl group is also useful to generate the anti-
bacterial activity of imidazole salts.
9. Moir, D. T.; Shaw, K. J.; Hare, R. S.; Vovis, G. F. Antimicrob. Agents Chemother.
1999, 43, 439.