ChemComm
Communication
for use in coating implants to prevent the onset of bacterial
infection.15,26 Self-assembled soft materials are good candidates
for application in therapeutic delivery26 as they can be easily
moulded, shaped and made to be responsive to external stimuli,
such as pH.25 Since the above urea gels were reversibly formed1b
we anticipated that our systems could also ‘naturally’ degrade
with time, for instance, upon interactions with biological anions,
such as carboxylates,2b which could competitively interrupt the
hydrogen bonding networks within the gels. This we demonstrated
by subjecting the gels formed from 6, and the AgNO3 based gel of 1,
to a solution of acetate. These showed that while the degradation
was initially slow, the gels indeed ‘dissolved’ over a period of days.
As these gels can host other organic substrates (e.g. cresol red), this
result potentially also allows for their application as drug delivery
systems; whereupon such degradation, substrates such as known
Fig. 4 (a) Kirby–Bauer disk diffusion susceptibility test results for compounds
12 (top) and 11 (bottom, showing no clearance) using MRSA (A) 0.72 mmol,
(B) 1.8 mmol and (C) 3.6 mmol of 12, respectively. (b) Liquid turbidity test
studies for gels 1 and 6 using E. coli demonstrating that bacterial growth is
inhibited over 18 hours.
Kirby–Bauer disk diffusion method or in the case of the gels, a antibacterial drugs can be released. We are currently investigating
liquid turbidity test. The areas of clearance were measured for the formation of such dual functional gels and their antimicrobial
compounds 1–12 (see ESI†) to compare relative activities. Of properties in greater detail.
these, 9 and 12 gave the most interesting and promising results,
We thank the Science Foundation Ireland (SFI 2008 RFP,
where 9 showed good activity against both strains, while 12 2010 PI Awards and ISAC Indian Initiative), FEMS TCD Indian
showed more activity towards MRSA after 18 hours of incubation Scheme (KP), and Marie Curie IEF Postdoctoral Grant (SB) for
at 37 1C, Fig. 4, at three different concentrations (denoted as financial support. We thank Prof. Uday Maitra (IISc Bangalore)
A to C in Fig. 4). The Kirby–Bauer disk diffusion results for the and Prof. D. Clive Williams (TCD) for their support and encourage-
2-nitro substituted analogue 11 are also shown in Fig. 4a.
ment, Dr Neal Leddy, TCD CMA, for assisting with SEM imaging,
Interestingly, of the three-pyridyl families (i.e. 1–4; 5–8 and 9–12), and Joseph Byrne (TCD) and Sam Bradberry (TCD) for their help.
compounds 1–4 were seen to have the least activity (area of clearance
Notes and references
1 (a) L. Meazza, J. A. Foster, K. Fucke, P. Metrangolo, G. Resnati and
of 7 mm, 6 mm and 10 mm when 4.3 mmol, 3.9 mmol, and 3.6 mmol,
were applied to the disc for 1, 3 and 4 using MRSA), displaying a
moderate selectivity in most cases for MRSA, while the 3-pyridine
analogues 7 and 8 showed moderate activity towards E. coli both
resulting in an area of clearance of 8 mm and 7 mm. However, and
as demonstrated for 12 in Fig. 4a, the 4-pyridyl family gave the most
potent activity [e.g. 12 area of clearance of 13 mm (1.8 mmol) and
20 mm (3.6 mmol) for MRSA]. In addition to these experiments, we
also carried out Alamar blue viability assays on these compounds
using HeLa cells. These showed that the compounds were either not
toxic or only slightly toxic. Hence, we were unable to determine EC50
values for these.
Having demonstrated that these structurally simple pyridyl ureas
could function as antibacterial agents, we next investigated the
abilities of the hydro- and organogels for such activity using the
aforementioned liquid turbidity test. The results demonstrated
that in the gel form, all were able to inhibit bacterial growth over
16–18 hours. Even compound 1, which showed moderate activity
(MIC = 4.3) prevented bacterial growth for both MRSA and E. coli
as demonstrated in Fig. 4b, which also shows the bacterial
growth in a solution (as cloudy solution) in a control experiment
after 18 hours. These results clearly demonstrate that the supra-
molecular nature of the systems, i.e. the formation of a self-
assembly gel, changes the antibacterial properties of the pyridyl
urea structures. While this phenomenon is not well understood,
it is possible that the overall supramolecular structure can give
J. W. Steed, Nat. Chem., 2013, 5, 42–47; (b) A. Nangia, J. Chem. Sci.,
2010, 122, 295–310; (c) A. R. Hirst, B. Escuder, J. F. Miravet and
D. K. Smith, Angew. Chem., Int. Ed., 2008, 47, 8002–8018.
2 (a) M.-O. M. Piepenbrock, G. O. Lloyd, N. Clarke and J. W. Steed, Chem.
Rev., 2010, 110, 1960–2004; (b) J. A. Foster, M.-O. M. Piepenbrock,
G. O. Lloyd, N. Clarke, J. A. K. Howard and J. W. Steed, Nat. Chem.,
2010, 2, 1037–1043.
3 M. C. Etter, Acc. Chem. Res., 1990, 23, 120–126.
4 (a) L. S. Reddy, S. K. Chandran, S. George, N. J. Babu and A. Nangia,
Cryst. Growth Des., 2007, 7, 2675–2690; (b) L. S. Reddy, S. Basavoju,
V. R. Vangala and A. Nangia, Cryst. Growth Des., 2006, 6, 161–173;
(c) S. K. Chandran, R. Thakuria and A. Nangia, CrystEngComm, 2008,
10, 1891–1898.
5 S. Boileau, L. Bouteiller, F. Laupretre and F. Lortie, New J. Chem.,
2000, 24, 845–848.
6 (a) J. R. Hiscock, P. A. Gale, N. Lalaoui, M. E. Light and N. J. Wells,
Org. Biomol. Chem., 2012, 10, 7780–7788; (b) P. A. Gale, J. R. Hiscock,
N. Lalaoui, M. E. Light, N. J. Wells and M. Wenzel, Org. Biomol.
Chem., 2012, 10, 5909–5915.
7 (a) R. M. Duke, E. B. Veale, F. M. Pfeffer, P. E. Kruger and
T. Gunnlaugsson, Chem. Soc. Rev., 2010, 39, 3936–3959; (b) P. A. Gale
and T. Gunnlaugsson, Chem. Soc. Rev., 2010, 39, 3595–3596.
8 T. Gunnlaugsson, P. E. Kruger, P. Jensen, J. Tierney, H. D. P. Ali and
G. M. Hussey, J. Org. Chem., 2005, 70, 10875–10878.
9 (a) E. M. Boyle, S. Comby, J. K. Molloy and T. Gunnlaugsson, J. Org. Chem.,
2013, 78, 8312–8319; (b) R. M. Duke, T. McCabe, W. Schmitt and
T. Gunnlaugsson, J. Org. Chem., 2012, 77, 3115–3126; (c) E. B. Veale,
G. M. Tocci, F. M. Pfeffer, P. E. Kruger and T. Gunnlaugsson, Org. Biomol.
Chem., 2009, 7, 3447–3454; (d) F. M. Pfeffer, P. E. Kruger and
T. Gunnlaugsson, Org. Biomol. Chem., 2007, 5, 1894–1902; (e) C. M. G.
dos Santos, T. McCabe and T. Gunnlaugsson, Tetrahedron Lett., 2007, 48,
3135–3139.
rise to multiple hydrogen bonding interactions that can interact 10 (a) S. J. Moore, M. Wenzel, M. E. Light, R. Morley, S. J. Bradberry,
´
´
´
P. Gomez-Iglesias, V. Soto-Cerrato, R. Perez-Tomas and P. A. Gale, Chem.
Sci., 2012, 3, 2501–2509; (b) N. Busschaert, S. J. Bradberry, M. Wenzel,
C. J. E. Haynes, J. R. Hiscock, I. L. Kirby, L. E. Karagiannidis, S. J. Moore,
N. J. Wells, J. Herniman, G. J. Langley, P. N. Horton, M. E. Light,
with the bacterial cell wall and possibly disrupt it or prevent its
formation. Such properties are highly desirable, particularly as
the soft-matter is easily applicable and as such highly attractive
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 10819--10822 | 10821