Imidazolium ionic liquids containing selenium: Synthesis and antimicrobial activity

Article abstract of DOI:10.1039/c0ob01010c

The synthesis and antimicrobial profile of imidazolium ionic liquids containing selenium are described herein. Minimum inhibitory concentration revealed that these compounds are especially active against algae, and their activity is modulated by substitue

Full text of DOI:10.1039/c0ob01010c

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Imidazolium ionic liquids containing selenium: synthesis and antimicrobial
activity†
Eduardo E. Alberto,a Luana L. Rossato,b Sydney Hartz Alves,b Diego Alvesc and Antonio L. Braga*d
Received 10th November 2010, Accepted 23rd November 2010
DOI: 10.1039/c0ob01010c
The synthesis and antimicrobial profile of imidazolium ionic
liquids containing selenium are described herein. Minimum
inhibitory concentration revealed that these compounds are
especially active against algae, and their activity is modulated
by substituents attached to the selenium moiety as well as by
the counterion.
According to the above mentioned, and our ongoing research
interest in organochalcogen15 and ILs chemistry,16 we decided
to investigate whether any cooperativity might be gained by
combining selenium and ionic liquids, to produce a new class
of antimicrobial agents. In this report, we wish to highlight our
results on the design, synthesis and antimicrobial screening of
novel imidazolium ionic liquids assembled with seleno groups
attached to the side chain. In a straightforward route these
compounds can be conveniently prepared in good yields and in
a modular fashion, which leads to a better understanding of the
structure–activity relationship. In this study we used gram-positive
and gram-negative bacteria, fungi and algae as representative
microorganisms. The minimum inhibitory concentration (MIC)
revealed that these substances are particularly active against algae.
The activity of selenium ILs is modulated by the substituents
attached to the selenium moiety and by the nature of the
counterion.
Preparation of the desired compounds is shown in Table 1. We
focused our study on the use of diaryl diselenides, due to their
stability and ease of handling. Moreover, electronic and steric
effects in the selenium atom could be easily introduced by the
appropriate choice of substituents in the aryl moiety. Reaction of
PhSeSePh 1 (R = H) with NaBH4 in a 1 : 1 mixture of EtOH and
THF in an excess of CH2Cl2 led to the formation of compound 2.17
After work-up 2 was dried over vacuum and used in the next step
without purification. Stirring 2 with N-methylimidazole under
neat conditions (4 h at 100 ◦C) gave product 3a with chloride
as the counterion in 76% overall yield (Table 1, Entry 1). A lower
yield was obtained for the same product by stirring substrate 2 in
MeCN for 48 h under reflux (71% overall yield). Preparation of
compounds 3b and 3c was performed by ion exchange of 3a using
aqueous solutions of NaBF4 and KPF6 for 3b and 3c, respectively.
These products were achieved in 61 and 71% yield, respectively,
from 1 (Table 1, Entry 1). Once that we found the best reaction
conditions to prepare our desired products, we used different
diselenides as starting materials. Electron donating and electron
withdrawing groups attached at the para position were efficiently
used to prepare ionic liquids 4–6 in the range of 45–71% yield
(Table 1, Entries 2, 3 and 4). Diaryl diselenides carrying electron
donating substituents at the ortho position were also prepared
(Table 1, Entries 5 and 6). However, reaction of 2-ClC6H4Se)2
proved to be impractical, giving the desired product in very low
yield. We were also able to prepare compounds 9a–c in good yields
from sterically hindered dimesityl diselenide (Table 1, Entry 7).
Ionic liquids (ILs) have been attracting considerable attention in
the past years. These substances have been extensively used as
solvents in many organic transformations with interesting results
when compared to conventional organic solvents.1 Moreover,
the investigation of the toxicity2 and biological activity (e.g.,
antitumor, anti-cancer, DNA cleavage) of ILs is an emerging area
of research.3 Another important characteristic attributed to ILs
concerns their application as antimicrobial agents. Several studies
have shown that they display great activity against gram-positive
and gram-negative bacteria, fungi and algae.4 Previous reports
have shown that this activity relies mainly on the chain length
of the investigated ILs. In general, a higher activity is attributed
to ILs assembled with longer carbon chain lengths.5 Interesting
is the enhanced antimicrobial activity of ILs containing alkoxy
groups in the side chain, this structural modification allowed the
preparation of more potent substances.6
On the other hand, selenium is recognized as an essential trace
element and is involved in a series of biochemical and biological
processes.7 Very recent reports have described interesting activity
of organoselenium compounds such as: anti-HIV,8 anticancer,9
as enzyme inhibitors,10 enzyme mimetics,11 among others.12 In
addition, organoselenium compounds have been successfully
designed and screened as antimicrobial substances.13 Recently,
the preparation of selenonium based ionic liquids has been
described,14 however, to date no biological information is available
on these compounds.
aDepartamento de Qu´ımica, Universidade Federal de Santa Maria, Santa
Maria, Brazil
bDepartment of Microbiology and Parasitology, Center of Health Sciences,
Universidade Federal de Santa Maria, Santa Maria, Brazil
cDepartamento de Qu´ımica, Universidade Federal de Pelotas, Pelotas, Brazil
dDepartamento de Qu´ımica, Universidade Federal de Santa Catarina,
Floriano´polis, Brazil. E-mail: albraga@qmc.ufsc.br; Tel: +55 (48) 3721-
6844
† Electronic supplementary information (ESI) available: Experimental
procedures and characterization. See DOI: 10.1039/c0ob01010c
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Table 1 Synthesis of selenium based ionic liquids 3–9
Table 2 Antimicrobial profile of selenium ILs 3–9a
P. zopfii S. aureus E. coli P. aeruginosa C. albicans A. fumigatus
#
1 3a 0.22
>0.45 >0.45
>0.42 >0.42
>0.45
>0.42
>0.40
0.40
>0.42
>0.40
>0.39
0.45
>0.45
>0.42
>0.40
>0.40
>0.42
>0.40
0.39
2 4a 0.05
3 5a 0.05
4 6a 0.05
5 7a 0.05
6 8a 0.20
7 9a 0.01
>0.42
>0.40
>0.40
>0.42
>0.40
0.39
>0.40
0.10
0.42
0.10
0.20
>0.42
Entry
1
Product
X
Yield (%)a
>0.40 >0.40
>0.39 0.39
3a
3b
3c
Cl
BF4
PF6
76
61
71
a MIC (triplicates) expressed in mM.
2
3
4a
4b
4c
Cl
BF4
PF6
71
68
69
another assay, E. coli proved to be more susceptible to the action
of the tested compounds, IL 5a and 6a exhibited MIC values of
0.10 and 0.20 mM respectively (Table 2, Column 5, Entries 3 and
4). On the other hand, the tested selenium ILs had a lower activity
against P. aeruginosa (bacteria) and C. albicans and A. fumigatus
(fungus). The MIC values for most of the ILs were higher than
0.40 mM for these microorganisms (Table 2, Columns 6–8, Entries
1–7). However, although our results suggest that the performance
of the tested ILs is modulated by their structure it does not follow
an obvious trend, showing different activities depending on the
microorganism and the calalyst tested.
In order to evaluate the influence of selenium in the biological
activity of the ILs screened, we performed a second set of
experiments (Fig. 1). Once that algae proved to be particularly
susceptible to the action of selenium ILs, compound 1018 was
employed as a selenium “blank” ionic liquid and its activity was
compared to that of IL 3a in the P. zopfii assay. The results clearly
indicate that selenium plays an important role in the activity of
compound 3a, with a MIC value which is less than a half of
that observed for the selenium “blank” IL 10. Nonetheless, the
performance of selenium IL 3 is also intrinsically associated to the
nature of the anionic counterion. Simple replacement of chloride
in IL 3a by BF4 or PF6 in ILs 3b and 3c respectively,19 was reflected
by a decrease in their activity.
5a
5b
5c
Cl
BF4
PF6
51
48
45
4
5
6
6a
6b
6c
Cl
BF4
PF6
69
66
62
7a
7b
7c
Cl
BF4
PF6
66
56
61
8a
8b
8c
Cl
BF4
PF6
65
64
57
7
9a
9b
9c
Cl
BF4
PF6
62
54
54
a Isolated overall yield from 1.
Dialkyl diselenides were also used, but many byproducts were
obtained, making the preparation of these products difficult. All
products described in Table 1 were characterized by 1H, 13C NMR
and HRMS (see ESI†).
Antimicrobial screens were conduced against a panel of mi-
croorganisms including bacteria (Escherichia coli ATCC 25922,
Staphylococcus aureus ATCC 25923, Pseudomonas aeruginosa
ATCC 27853), yeast like fungi (Candida albicans ATCC 24433),
filamentous fungi (Aspergillus fumigatus ATCC 204305), and Pro-
totheca zopfii (algae). The antimicrobialactivityof each compound
was measured by determination of the minimal inhibitory concen-
tration (MIC). The assays were performed by broth microdilution
techniques according to CLSI (Clinical Laboratory Standards
Institute): M07-A8 (2009) for bacteria, M27-A3(2008) for C.
albicans and P. zopfii and M38-A2 (2008) for filamentous fungi.
The results are shown in Table 2.
These results clearly indicate that compounds 3a–9a, all of them
with chloride as counterion were especially active against algae
(Table 2, Column 3, Entries 1–7). Our results also demonstrated
that the activity of these compounds is influenced by their
structures, the most effective (lower MIC values) being ILs 4a,
5a, 6a, 7a and specially 9a (Table 2, Column 3, Entries 2, 3, 4, 5
and 7 respectively). Selenium ionic liquid 6a was also efficiently
employed against bacteria, showing improved activity with MIC
values of 0.10 mM for S. aureus (Table 2, Column 4, Entry 4). In
Fig. 1 Effect of selenium and the anionic counterion in the activity of
selenium ILs 10 and 3a–c against P. zopfii.
Conclusions
To summarize, in this study we described the preparation of
imidazolium based ionic liquids functionalized with selenium
in the side chain. These compounds were efficiently prepared
through a straightforward sequence, allowing the access to a set of
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compounds with modular feature. We also evaluated the antimi-
crobial profile of these new compounds. Of the microorganisms
tested, algae proved to be particularly susceptible to the action of
selenium ILs. The minimum inhibitory concentration (MIC) re-
vealed that the activity of these compounds is modulated by struc-
tural modifications in the aryl group attached to selenium as well
as by the counterion associated with the cationic part. Currently,
we are pursuing other synthetic approaches to prepare selenium
ILs assembled with longer side chains and evaluate this important
feature related to the antimicrobial activity of ionic liquids.
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Acknowledgements
Authors are grateful to CNPq (INCT-Cata´lise), CAPES and
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Org. Biomol. Chem., 2011, 9, 1001–1003 | 1003
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