Synthesis and antimicrobial characterization of novel l-lysine gemini surfactants pended with reactive groups

Article abstract of DOI:10.1016/j.tetlet.2008.01.079

A series of novel quaternary ammonium gemini surfactants of l-lysine containing ester group were synthesized with high yield rate. The antibacterial and antifungal activities of these gemini surfactants were evaluated by quantifying the minimal inhibitory concentration (MIC). The results indicated that the quaternary ammonium gemini surfactants exhibited improved activity against a broad spectrum of Gram-positive and Gram-negative bacteria as well as fungi. The pended ester group provides a reactive site for incorporating the surfactant into polymers, thus leading to the polymers with high antimicrobial efficiency.

Full text of DOI:10.1016/j.tetlet.2008.01.079

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Tetrahedron Letters 49 (2008) 1759–1761
Synthesis and antimicrobial characterization of novel L-lysine
gemini surfactants pended with reactive groups
Hong Tan, Huining Xiao *
Department of Chemical Engineering, University of New Brunswick, Fredericton, NB, Canada E3B 5A3
Received 19 September 2007; revised 15 January 2008; accepted 16 January 2008
Available online 20 January 2008
Abstract
A series of novel quaternary ammonium gemini surfactants of L-lysine containing ester group were synthesized with high yield rate. The
antibacterial and antifungal activities of these gemini surfactants were evaluated by quantifying the minimal inhibitory concentration
(
MIC). The results indicated that the quaternary ammonium gemini surfactants exhibited improved activity against a broad spectrum
of Gram-positive and Gram-negative bacteria as well as fungi. The pended ester group provides a reactive site for incorporating the
surfactant into polymers, thus leading to the polymers with high antimicrobial efficiency.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Gemini surfactants; Antimicrobial; Quaternary ammonium groups; MIC
With the increasing public health awareness about the
effects of bacteria and microorganisms, developing antibac-
terial or antimicrobial materials has stimulated substantial
research interest. Infection control is of utmost importance
in a variety of places, which require a high level of hygiene.
A variety of antimicrobial agents, such as iodine, quater-
nary ammonium (QAS), biguanides, phosphonium salt,
fluoroquinolones and the polymers containing these
species, have been employed to various circumstances
including the disinfection of hospital equipment, pharma-
the least development of resistance. Several new types of
QAS as antimicrobial agents have been reported in the
1
1–17
past.
gemini surfactants,
activities than the conventional surfactants.
Recently, much attention has been paid to
1
3–17
which exhibit higher antibacterial
15–17
Mean-
while, antimicrobial polymers have also attracted consider-
able research interests due to their non-toxicity and
non-irritant properties with the improved and prolonged
antimicrobial activities, compared with the ordinary
3
,18–22
low-molecular-weight antibacterial agents.
1
–7
ceutical production units and food processing facilities.
Currently, there are two general approaches employed
for the attachment of the antimicrobial agents to polymers.
One involves the introduction of functional groups or
chains to monomers to create the antimicrobial monomers
or macromonomers, followed by their polymerization;
another is to link the antibacterial agents directly onto
polymers backbones to render the polymer as antimicro-
Among these antimicrobial agents, quaternary ammonium
salts have been the most widely used ones owing to their
excellent cell membrane penetration properties, low toxicity,
good environmental stability, non-irritation, low corrosiv-
ity and extended residence time and biological activity in
8
,9
comparison with other antimicrobial agents. However,
the use of QAS in some fields has been limited due to the
2
2–25
bial.
To date, very few papers have reported that
1
0
developed microbial resistance against QAS. Therefore,
it is urgent to develop the antibacterial and antifungal
agents capable of killing harmful microorganisms with
gemini surfactant with broad-spectrum antibacterial activ-
ities has been specifically designed and synthesized in an
attempt to prepare the polymers with extremely high anti-
microbial efficiency.
*
In this study, a series of novel L-lysine gemini surfact-
ants with high yield were synthesized via an efficient and
Corresponding author. Tel.: +1 506 4533532; fax: +1 506 453 3591.
E-mail address: hxiao@unb.ca (H. Xiao).
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.079

1760
H. Tan, H. Xiao / Tetrahedron Letters 49 (2008) 1759–1761
simple approach. The route of synthesis is shown in
Scheme 1. N,N -Bisbromoacetyl-L-lysine ethyl ester was
times higher. It appears that the introduction of a fluori-
nated chain increased the activity against Candida albicans
substantially. In an attempt to further improve the anti-
microbial activities of gemini surfactant, a range of novel
gemini surfactants pended with functional groups were
designed and synthesized. The resulting compounds will
be used for synthesizing gemini (macro)monomers or
polymers.
0
obtained through the reaction of L-lysine ethyl ester with
26
bromoacetic bromide. Fluorinated or hydrocarbon fatty
acid (3-dimethyl amino-propyl) amides were synthesized
by the reaction of 1,3-(dimethylamino)-1 -prolylamine with
2
6
the corresponding chloride. Then L-lysine gemini surfact-
ants were prepared with the two compound analogues
2
6
described above in the isopropanol refluxing. The anti-
bacterial and antifungal activities of these gemini surfac-
tants were evaluated via determining the minimal
inhibitory concentration (MIC) using a commercially avail-
able n-dodecyl-trimethylammonium bromide (DTAB) as
reference. As can be seen from the MIC values presented
in Table 1, DPDAQ and FOAQ are more efficient against
Gram-positive bacteria, Gram-negative bacteria, yeast and
mould than ODAQ. The antibacterial and antifungal activ-
ities of as-synthesized gemini surfactants are superior to
that of the reference antibacterial agent DTAB. Specifi-
cally, the activity against Staphylococcus aureus of
DPDAQ is 128 times higher than that of DTAB; whereas
the corresponding activity against Escherichia coli is 64
In summary, a series of novel quaternary ammonium
gemini surfactants containing functional ester group with
high yield rate were successfully synthesized. The surfac-
tants possess the broad-spectrum antimicrobial activities;
and the synthesis route potentially provides a new strategy
for developing the antimicrobial polymers with extremely
high activities owing to the polycationic structure. It is well
known that polycationic compounds tend to increase the
permeability of cell membranes, thus improving the patho-
2
6
2
7,28
gen deactivation.
Acknowledgements
The financial support for this work from NSERC Can-
ada is acknowledged. We would also like to thank Ms.
Qiang Wang and Professor Qiling Sun in College of Life
Science at Sichuan University in China for antimicrobial
testing.
NH2
O
NH2
CH3
CH3
O
NH2
RCOCl
N
Supplementary data
BrCH2COBr
Spectral data, synthetic procedures of the compounds
and the antimicrobial evaluation in this Letter are pro-
vided. Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.
CH3
CH3
NH
O
NH
Br
RCONH
N
Br
O
O
O
a : R, C7F15
b : R, C7H15
c : R, C9H19
2008.01.079.
O
O
CH3
CH3
References and notes
NH
NH
N
N
NH
R
R
NH
Br
Br
CH3
1
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O
CH3
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O
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1
DPDAQ: R, C9H19
FOAQ: R, C7F15
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The minimal inhibitory concentration (MIC) results of L-lysine gemini
ꢀ1
surfactant series and commercial reference (lmol L
)
Samples Staphylococcus
Escherichia Candida
Aspergillus
d
niger
a
b
c
aureus
coli
250
62.5
3.91
31.25
albicans
DTAB
ODAQ
DPDAQ
FOAQ
a
250
62.5
1.95
7.81
500
250
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62.5
62.5
62.5
62.5
7.81
4
7, 627.
1
1
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d
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H. Tan, H. Xiao / Tetrahedron Letters 49 (2008) 1759–1761
1761
1
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115.93: 4C; 118.89–119.78; 158.87: m, 2C; 162.85: 1C; 162.94: 1C;
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1
9
1
1
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(
F NMR: 300 MHz, TMS CDCl
3
): d ppm ꢀ81.28: 6F; ꢀ119.57 to
ꢀ119.79: 4F; ꢀ122.04: 4F; ꢀ122.46: 4F; ꢀ122.80: 4F; 123.22: 4F;
ꢀ126.62: 4F.
2
+
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1
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Ms (positive) theoretical: 1412; observed ((m ꢀ2Br)/2z): 626.
1
Data for DPDAQ ( H NMR: 300 MHz, DMSO): d ppm 0.89: t,
J = 6.3 Hz, 6H; 1.23: t, J = 7.2 Hz, 3H; 1.28: m, 22H; 1.34–1.44: 4H;
1.52: m, 6H; 1.75: m, 2H; 1.88: m, 4H; 2.10: t, J = 7.5 Hz, 4H; 3.13: m,
6H; 3.22, s, 12H; 3.50: m, 4H; 4.11: s, 2H; 4.16: m, 2H; 4.21: s, 2H;
4.26: m, 1H; 7.97: m, 2H; 8.65: m, 1H; 9.08: m, 1H.
1429.
1
3
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Antimicrob. Agents Chemother. 1986, 30, 132.
( C NMR: 300 MHz, DMSO): d ppm 14.90: 2C; 14.99: 1C; 23.05:
2C; 23.76: m, 4C; 26.15: 2C; 29.04: 1C; 29.65: 2C; 29.69: 2C; 29.80:
2C; 29.86: 2C; 30.93: 1C; 32.24: 2C; 36.38: 2C; 39.23: 1C; 52.09: 4C;
53.32: 1C; 61.74: 2C; 62.57: 1C; 62.82: 1C; 63.76: 1C; 64.03: 1C;
163.85: 1C; 164.32: 1C; 172.11: 1C; 173.36: 2C.
2
2
2. Tashiro, T. Macromol. Mater. Eng. 2001, 286, 63.
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Ms (positive) theoretical: 928.8; observed ((mꢀ2Br)/2z): 384.3.
1
5
738.
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585.
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Data for ODAQ ( H NMR: 300 MHz, DMSO): d ppm 0.90: t,
2
2
2
J = 6.3 Hz, 6H; 1.23: t, J = 7.2 Hz, 3H; 1.28–1.40: m, 18H; 1.52: m,
6H; 1.75: m, 2H; 1.88: m, 4H; 2.10: t, J = 7.2 Hz, 4H; 3.13: m, 6H;
3.22, s, 12H; 3.50: m, 4H; 4.11: s, 2H; 4.16: m, 2H; 4.20: s, 2H; 4.26:
m, 1H; 7.97: m, 2H; 8.64: m, 1H; 9.08: m, 1H.
1
1
3
6. Experimental details are given in Supplementary data. The selected
( C NMR: 300 MHz, DMSO): d ppm 14.84: 2C; 14.97: 1C; 22.98:
1
spectral data are as follows. Data for FOAQ ( H NMR: 300 MHz,
2C; 23.70: m, 4C; 26.10: 2C; 29.00: 1C; 29.39: 2C; 29.61: 2C; 30.89:
1C; 32.07: 2C; 36.35: 2C; 39.21: 1C; 52.06: 4C; 53.30: 1C; 61.71: 2C;
62.57: 1C; 62.82: 1C; 63.76: 1C; 64.04: 1C; 163.81: 1C; 164.28: 1C;
172.06: 1C; 173.30: 2C.
TMS CDCl
3
): d ppm 1.27: t, J = 7.2 Hz, 3H; 1.56: m, 3H; 1.69: m,
H; 1.88: m, 2H; 2.32: m, 6H; 3.40: s, 3H; 3.42: s, 6H; 3.47: s, 3H;
.56: m, 4H; 3.64: m, 2H; 3.77: m, 2H; 4.17: m, 2H; 4.41: m, 2H; 4.56:
1
3
m, 2H; 4.83: m, 1H; 8.52: m, 2H; 8.80: m, 1H; 8.96: m, 1H.
Ms (positive) theoretical: 872.8; observed ((mꢀ2Br)/2z): 356.3.
27. Hansen, H. C.; Haataja, S.; Finne, J.; Magnusson, G. J. Am. Chem.
Soc. 1997, 119, 6974.
28. Franklin, T. J.; Snow, G. A. Biochemistry of Antimicrobial Actions,
4th ed.; Chapman and Hall: London, 1987.
1
3
(
3
C NMR: 300 MHz,TMS CDCl ): d ppm 14.34: 1C; 23.02: 2C;
2
1
6
3.12: 1C; 27.68: 1C; 29.51: 1C; 37.25: 1C; 38.63: 1C; 52.43: 2C; 52.91:
C; 53.12: 1C; 53.64: 1C; 61.95: 2C; 63.15: 1C; 63.57: 1C; 64.43: 1C;
4.95: 1C; 105.80–108.42: m, 2C; 108.94–111.59: m, 4C; 112.95–