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Amino Acid Functionalized Imdazolium Salts and Their Silver(I) and Gold(I)
N-Heterocyclic Carbene Complexes
Tina H.T. Hsu, Ivan J.B. Lin
Department of Chemistry, National Dong Hwa University, Shoufeng, Hualien 974,
Taiwan.
Abstract: The amino acid functionalized imdazolium salts (Cn,gly,im-X) and their
silver(I) and gold(I) NHC complexes [M(Cn,gly,imy)2][X] (n = 6, 16 ; M = Ag, Au ; X
= Cl, NO3 ) have been synthesized and characterized. Subsequently, the antibacterial
activity of imdazolium salts Cn,gly,im-Cl (n = 6, 16) was evaluated against three
Gram negative bacteria (A. baumannii, P. aeruginosa and E. coli) and three Gram
positive bacteria (S. aureus, S. msrcesenceSS1, and V. parahaemolyticus93 ). Here, we
found that the imidazolium salt (C16,gly,im-Cl) possessing excellent antibacterial
activity against A. baumannii, E. coli, S. aureus, and V. parahaemolyticus93 strains
bacteria. In general, these imidazolium salts possess excellent, broad spectrum
antimicrobial activity against Gram positive and Gram negative bacteria dependency
on length of the alkyl substituent for activity. However, antibiofilm experiment results
show that these imidazolium salts cannot inhibit the biofilm formation.
Introduction
Bacterial biofilms can cause urethritis, prostatitis, kidney stones, otitis media,
dental caries, periodontitis, bad breath and other diseases. They repeatedly will often
manifest suddenly, and extremely difficult to cure thoroughly. Under the natural
condition, the bacteria have planktonic and the biofilm two kind of growth condition
existence. Environment for the resistance to various unfavorable factors, like
antibiotics sterilization, per acid either alkali environment, phagocytosis by the host
immune cells, single or multiple clumps of bacteria convergence integrated to form a
single walk-state cells with the corresponding biofilm. In bacterial biofilms, the
bacteria itself represents less than 1 / 3 the size of the remaining space is secreted by
the bacteria, "extracellular matrix" of the sticky substance occupies. It is these viscous
substances linked to thousands of bacteria. According to the U.S. Centre for Disease
Control and Prevention experts estimate that more than 65% of human bacterial
infections have relations with bacterial biofilms. Biofilm bacteria for antibiotic
resistance with a natural, it's very different resistance mechanisms with a single
bacterial. Biofilm formation is associated with the virulence of pathogenic bacteria,
and cells included within a biofilm are generally more resistant (up to 1000-fold) to
antibiotics and disinfectants than free-living bacteria.1 Biofilms are a major concern
in medicine and in medical environments, but also in all domains where their growth
constitutes a source of contamination for humans or animals (food industry, cooling
towers, water pipes, etc) or leads to economic losses (biofouling of boats and
immersed structures, material biocorrosion, etc). The development of antibiofilm
strategies is major interest and currently constitutes an important field of
investigation.
Recently, a great deal of effort has been made toward imidazolium salts directly
due to their wide range of potential applications in the chemistry fields, such as ionic
liquids,
2 , 3
ionic
liquid
crystals,
4
N-heterocyclic
carbenes,
5
medicinal
chemistry, 6,7,8,9,10,11 …etc. Several types of antimicrobial compounds, a series of
imidazolium compounds have been reported and they showed significant antibacterial
and antifungal activities. 12,13,14,15,16,17,18,19,20,21,22,23 It was found that the type of
substituent and the length of the alkyl chain have an important effect on the
antimicrobial activities. In recent years, Sedden and et al. reported the antibiofilm
activities of 1-alkyl-3-methylimidazolium salts. It catches our attention, because these
imidazolium salts have potential applications in antibiofilm martial. However, no
reports were focused on amino acid imidazolium cation salts for antimicrobial.
Therefore, in this work, we study the antibacterial and antibiofilm Properties of
different type functionalized imidazolium salt.
Result and Discussion
Imidazolium salts
The compounds [Cn-im-amino][Cl], the specific notation of En is designated for
type E compounds with n numbers of 16. (Scheme 5-1)
Scheme 5-1. Structures of imidazolium compounds and their NHCs
In this study, we used two methods to measure the minimum inhibitory
concentration (MIC) values, method 1 is improve from filter paper disc agar diffusion
method and method 2 is common used method. The antibacterial property of these
imidazolium salts was tested on three Gram negative bacteria (A. baumannii, P.
aeruginosa and E. coli) and three Gram positive bacteria (S. aureus, S. msrcesenceSS1,
and V. parahaemolyticus93 )
Antibacterial assay:
Method 1
As show in Table 5-1, the MIC values for the compound En of n = 16 is 83 µM
for A. baumannii, 2648 µM for P. aeruginosa, 662 µM for E. coli, 83 µM for S.
aureus , 1324 µM for S. msrcesenceSS1, 41 µM for V. parahaemolyticus93,
respectively. The data No data available means the compounds have no antibacterial
effect at the highest concentrations (0.1g/10 mL).
Most of these imidazolium salts
with longer alkyl chains have significant antibacterial activity, the reason may due to
the lipophilicity and bacterial compatibility of the imidazolium salts. We find most of
mono-cation imidazolium salts have no antibacterial effect toward P. aeruginosa and
S. msrcesenceSS1, and di-cation imidazolium salts have better antibacterial effect for
more bacterial.
Table 5-1. MIC values for [C16-im-amino][Cl] in µM
Bacteria
[C16-im-amino][Cl]
Gram negative
A.baumannii
MIC
83
P. aeruginosa
MIC
2648
E. coli
MIC
662
S. aureus
MIC
83
S. msrcesenceSS1
MIC
1324
Gram positive
V. parahaemolyticus93 MIC
Antibiofilm experiment result
41
Recently, Sedden and et al. reported the antibiofilm activities of 1-alkyl-3methylimidazolium salts. They measure the minimum biofilm eradication
concentration. It means in this concentration, the biofilm would be destroying.
However, in our purpose we want to know these imidazolium salts can inhibition the
biofilm formation or not. After the biofilm formation assays and observation, beside
MBC, other concentrations of imidazolium salts have both formation biofilm.
Therefore, these imidazolium salts cannot inhibit the biofilm formation.
Conclusion
In summary, these imidazolium salts possess excellent, broad spectrum
antimicrobial activity against Gram positive and Gram negative bacteria dependency
on length of the alkyl substituent for activity. We strongly believe that, the amino acid
functionalized in imidazolium salts may improve hydrophilicity and possible
interactions with proteins and genes to be a bioactive molecule, or increase
degradability for imidazolium salts. Further, the anticancer studies of amino acid
functionalized NHC complexes are under investigation.
Reference
1 D. J. Musk and P. J. Hergenrother, Curr. Med. Chem., 2006, 13, 2163–2177.
2 S. J. Zhang and X. M. Lu in Ionic Liquids: From Fundamentals to Applications, Science Press,
Beijing, 2006, pp.149 –193.
3 T. L. Greaves and C. J. Drummond, Chem. Rev., 2008, 108, 206–237.
4 K. Binnemans, Chem. Rev., 2008, 105, 4148–4204.
5 A. M. Voutchkova, L. N. Appelhans, A. R. Chianese and R. H. Crabtree, J. Am. Chem. Soc., 2005,
127, 17624–17625.
6 P. Rajakumar, K. Sekar, V. Shanmugaiah and N. Mathivanan, Bioorg. Med. Chem. Lett., 2008, 18,
4416–4419.
7 D. Demberelnyamba, K. S. Kim, S. Choi, S. Y. Park, H. Lee, C. J. Kim and I. D. Yoo, Bioorg. Med.
Chem., 2004, 12, 853–857.
8 M. Hindi, T. J. Siciliano, S. Durmus, M. J. Panzner, et al., J. Med. Chem. 2008, 51, 1577–1583.
9 X. D. Yang, X. H. Zeng, Y. L. Zhang, C. Qing, et al., Bioorg. Med. Chem. Lett. 2009, 19, 1892–
1895.
10 C. G. Fortuna, V. Barresi, G. Berellini and G. Musumarra, Bioorg. Med. Chem. 2008, 16, 4150–
4159.
11 Q. L. Li, J. Huang, Q. Wang, N. Jiang, C. Q. Xia, H. H. Lin, J. Wu and X. Q. Yu, Bioorg. Med.
Chem., 2006, 14, 4151–4157.
12 J. Ranke, A. Skrzypczak, G. Lota and E. Frackowiak, Chem. Eur. J., 2007, 13, 3106–3112.
13 J. Pernak and P. Chwala, Eur. J. Med. Chem., 2003, 38, 1035–1042.
14 J. pernak, M. Smiglak, S. T. Griffin, W. L. Hough, T. B. Wilson, A. pernak, J. Zabielska-Matejuk, A.
Fojutowski, K. Kita and R. D. Rogers, Green Chem., 2006, 8, 798–806
15 J.Cybulski, A. Wiśniewska, A. Kulig-Adamiak, L. lewicka, A. Cieniecka-Rostonkiewicz, K. Kita,
A. Fojutowski, J. Nawrot, K. Materna and J. Pernka, Chem. Eur. J., 2008, 14, 9305–9311.
74
16 A. Busetti, D. E. Crawford, M. J. Earle, M. A. Gilea, B. F. Gilmore, S. P. Gorman, G. Laverty, M.
McLaughlin and K. R. Seddon, Green Chem., 2010, 12, 420–425.
17 J. Pernak and P. Chwala, Eur. J. Med. Chem., 2003, 38, 1035–1042.
18 J. Pernak, K. Sobaszkiewicz and J. Foksowicz-Flaczyk, Chem. Eur. J., 2004, 10, 3479–3485.
19 J. Pernak, K. Sobaszkiewicz and I. Mirska, Green Chemistry., 2003, 5, 52–56.
20 K. M. Docherty and C. F. Kulpa, Green Chem., 2005, 7, 185–189.
21 J. Pernak, I. Goc and I. Mirska, Green Chem., 2004, 6, 323–329.
22 L. Carson, P. K. W. Chau, M. J. Earle, M. A. Gilea, B. F. Gilmore, S. P. Gorman, M. T. McCann
and K. R. Seddon, Green Chem., 2009, 11, 492–497.
23 S. Kanjilal, S. Sunitha, P. S. Reddy, K. P. Kumar, U. S. N. Murty and R. B. N. Prasad, Eur. J. Lipid
Sci. Technol. 2009, 111, 941–948.
75
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