The antibacterial activity of 4,4′-bipyridinium amphiphiles with conventional, bicephalic and gemini architectures

Article abstract of DOI:10.1016/j.bmcl.2012.04.079

Dialkyl 4,4′-bipyridinium compounds are widely employed for their useful redox properties, and are commonly known as viologens due to their intense coloration upon reduction. Despite their prevalence and amphiphilic nature, the antibacterial activity of these compounds remains largely unreported. We have thus prepared a series of mono- and bis-alkylated analogs of 4,4′-bipyridine to investigate structure-activity relationships in their inhibition of a battery of Gram positive and Gram negative bacteria. The prepared cationic compounds were conventional (one cationic head, one non-polar tail), bicephalic (two heads, one tail), or gemini (two heads, two tails) in their amphiphilic structure. Additionally, an isomeric series of six bis-alkylated compounds ranging from symmetric (PQ-11,11) to highly asymmetric (PQ-20,2) were prepared. Four themes of bioactivity emerged: (1) the most bioactive compounds were gemini in structure; (2) 22 carbons in the alkyl chains, with little to modest asymmetry, led to optimal activity; (3) bicephalic compounds were generally comparable to conventional amphiphiles, though only about 12 carbons in the alkyl chains were solubilized in water by each cationic nitrogen; (4) the effects of counterion identity were not evident between chlorides and bromides; however, the presence of the iodide counterion inhibited dissolution in all compounds tested. Three isomeric compounds with little to no asymmetry in tail length, PQ-11,11, PQ-12,10, and PQ-14,8, prepared as the bromide salts, showed comparable and highly potent activity, with MIC levels around 2 μM against 3 of 4 bacteria tested. The simple (one- to two-step) syntheses of potent antimicrobials portend well for future optimization.

Full text of DOI:10.1016/j.bmcl.2012.04.079

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4055–4058
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
0
The antibacterial activity of 4,4 -bipyridinium amphiphiles with conventional,
bicephalic and gemini architectures
a
a
b
b
a
Melissa C. Grenier , Robert W. Davis , Kelsey L. Wilson-Henjum , Jade E. LaDow , Jacob W. Black ,
c
b
a,
⇑
Kevin L. Caran , Kyle Seifert , Kevin P.C. Minbiole
Department of Chemistry, Villanova University, 800 E. Lancaster Avenue, Villanova, PA 19085, United States
Department of Biology, James Madison University, Harrisonburg, VA 22807, United States
a
b
c
Department of Chemistry and Biochemistry, James Madison University, Harrisonburg, VA 22807, United States
a r t i c l e i n f o
a b s t r a c t
0
Article history:
Dialkyl 4,4 -bipyridinium compounds are widely employed for their useful redox properties, and are
Received 19 March 2012
Revised 12 April 2012
Accepted 16 April 2012
Available online 25 April 2012
commonly known as viologens due to their intense coloration upon reduction. Despite their prevalence
and amphiphilic nature, the antibacterial activity of these compounds remains largely unreported. We
have thus prepared a series of mono- and bis-alkylated analogs of 4,4 -bipyridine to investigate
0
structure–activity relationships in their inhibition of a battery of Gram positive and Gram negative bac-
teria. The prepared cationic compounds were conventional (one cationic head, one non-polar tail), bice-
phalic (two heads, one tail), or gemini (two heads, two tails) in their amphiphilic structure. Additionally,
an isomeric series of six bis-alkylated compounds ranging from symmetric (PQ-11,11) to highly asym-
metric (PQ-20,2) were prepared. Four themes of bioactivity emerged: (1) the most bioactive compounds
were gemini in structure; (2) 22 carbons in the alkyl chains, with little to modest asymmetry, led to opti-
mal activity; (3) bicephalic compounds were generally comparable to conventional amphiphiles, though
only about 12 carbons in the alkyl chains were solubilized in water by each cationic nitrogen; (4) the
effects of counterion identity were not evident between chlorides and bromides; however, the presence
of the iodide counterion inhibited dissolution in all compounds tested. Three isomeric compounds with
little to no asymmetry in tail length, PQ-11,11, PQ-12,10, and PQ-14,8, prepared as the bromide salts,
Keywords:
Amphiphile
Antibacterial
Bicephalic
Bipyridinium
Paraquat
showed comparable and highly potent activity, with MIC levels around 2 lM against 3 of 4 bacteria
tested. The simple (one- to two-step) syntheses of potent antimicrobials portend well for future
optimization.
Ó 2012 Elsevier Ltd. All rights reserved.
Amphiphiles have long served as a privileged platform for
antimicrobial agents, from simple soaps and benzalkonium chlo-
rides, to more complex antimicrobial peptides and dendrimeric
architectures. While disruption of intracellular processes is key to
the bioactivity of some amphiphiles,1 membrane disruption is
often the primary pathway leading to microbial death. Membrane
targeting can be advantageous in terms of reduced development of
cells likely allows hydrophobic alkyl groups to insert into and
1
,4,9–11
disrupt bacterial cell membranes.
A recent review points to
cationic amphiphiles as a promising motif for antibacterial lead
1
2
structures.
,2
In 2011, our laboratories reported a series of compounds with
strong and broad antibacterial activity, based on a bicephalic
5
amphiphilic arene platform (1, Fig. 2). Correlations were drawn
3
bacterial resistance. Our research program aims to develop and
between antimicrobial activity and structural characteristics
including proximity of the cations, number of cations, and length
of chain. Longer alkyl chains corresponded to lower MIC values
and shorter time required to kill bacteria; 3,5-substitution patterns
on the arene (relative to the alkoxy group) led to optimal activity.
Subsequent to this report, we have observed a significant increase
in activity when switching the cationic headgroups to pyridinium
analogs (manuscript in preparation); this is consistent with
numerous reports of the antibacterial activity of pyridinium-based
understand the physical and biological characteristics of novel
cationic polycephalic (multiheaded) amphiphiles—amphiphiles
with multiple polar headgroups and a single alkyl chain (Fig. 1).
This class of amphiphiles has recently emerged as a particularly
efficient group of membrane disruptors, killing bacteria at low
concentrations through a mechanism of action that may depend
on their cone-shaped structure.4 Mechanistically, the Coulombic
attraction of the cationic groups to the anionic surface of bacterial
–8
6
,10,13–17
amphiphiles.
In order to expand on our preliminary obser-
vation that bispyridinium compounds may display strong antimi-
⇑
Corresponding author. Tel.: +1 610 519 4873; fax: +1 610 519 7167.
E-mail address: kevin.minbiole@villanova.edu (K.P.C. Minbiole).
1
8
crobial activity,
particularly in the context of amphiphilic
0
960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.04.079

4
056
M. C. Grenier et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4055–4058
recrystallization. After purification, yields ranging from 24% to 64%
were obtained. Bisalkylation (Scheme 1, bottom) required an in-
crease of equivalents of the alkyl bromide (4 equiv); other condi-
tions remained unchanged and yields were comparable (17–69%).
In our hands, microwave conditions led to variable and somewhat
diminished yields for these compounds, though reaction times were
2
5
shorter. Compounds are designated by the shorthand PQ-n,n to
indicate the chain lengths of any alkyl groups attached; full syn-
thetic detail for all compounds is presented in the Supplementary
data.
Figure 1. Comparison of amphiphile architectures. Blue sphere = polar head; red
line = non-polar tail; black line = linker. Conventional amphiphiles in this work
have one cationic head and one tail, bicephalic amphiphiles have two cations and
one tail, and gemini amphiphiles have two cations and two tails.
In order to prepare bicephalic amphiphilic compounds that had
two cationic nitrogens but only one long alkyl chain (and one short
chain of 1–2 carbons), we set out to prepare the PQ-n,1 and PQ-n,2
series, where n is the number of carbons in the alkyl group and the
second alkyl group is methyl or ethyl, respectively. This began with
N(CH
Br
3 3
)
2
H2m+1C
m
N
N
C H
n
2n+1
0
the monomethylation of 4,4 -bipyridine, which was accomplished
2
by heating to reflux in methyl iodide for one hour (16, 99% yield,
Scheme 2). Subsequent alkylation with the corresponding longer
chain alkyl bromides (C12–C20, 48 h, CH CN, D) prepared the
3
2
X
O
PQ-m,n
n
bis-trimethylammonium
bisalkylated 4,4'-pyridinium
PQ-n,1 series (17–21), all of which contain one bromide and one
iodide counterion. For the preparation of the PQ-n,2 series, it was
found to be more convenient to begin with the alkylated com-
pounds 3–6; exposure of each to bromoethane led to the corre-
sponding PQ-n,2 compounds in 16–60% yields. Microwave
irradiation (130–150 °C, 30 min) was employed for the preparation
of compounds 23–25.
For preparation of compounds with alternate halogen counteri-
ons, 4 equiv of the corresponding alkyl halide were used, as indi-
cated in Scheme 3. As expected, a distinct difference in reactivity
was noted between the chloride and iodide. Whereas the alkyl
iodides led to alkylation in 63–74% isolated yields in 24 h, the
less-reactive chlorides required 7 days to react, and provided the
products in very low yields (610%). Alternate solvents (DMF) and
heating regimes (microwave) did not improve purified yields,
though standard purification conditions provided ample quantities
for biological assessment.
aryl ethers 1
compounds 2
Figure 2. Aryl-based bicephalic amphiphiles (left) and paraquats (right).
0
structure, we turned our attention towards bisalkyl 4,4 -bipyridini-
um compounds (2). Such ‘paraquats’ (PQs) are commonly known
1
9
as viologens due to their tendency to turn violet in color when
reduced. Scores of paraquats have been studied in electrochromic
and photochromic applications, and are as such exploited in
biological systems as sensors of membrane transport and other
2
0,21
biological events.
Amphiphilic paraquats, despite their preva-
lence, have scarcely been reported for antimicrobial applications.
0
0
Heptyl viologen (1,1 -diheptyl-4,4 -bipyridinium dibromide, or
2
2
23
PQ-7,7) and decyl viologen (PQ-10,10) are reported to exhibit
micromolar antibacterial activity; Kourai et al. reported micromo-
lar bioactivity of a series of alkyl bipyridinium diiodides, which are
significantly less soluble than salts bearing alternate counterions
(
vide infra), against a single Escherichia coli strain.24 Intrigued by
Finally, in order to investigate the effect of asymmetry on bioac-
tivity, we prepared a series of isomers with a total of 22 carbons in
the alkyl chains: PQ-12,10 (34), PQ-14,8 (35), PQ-16,6 (36), PQ-18,4
this pervasive and promising class of amphiphiles, we embarked
on a systematic investigation of analogs of the paraquat backbone,
to correlate the effects of chain length, counterion, and amphiphilic
structure (conventional, bicephalic, or gemini) with bioactivity
against Gram positive and Gram negative bacteria.
(37), and PQ-20,2 (38). Synthesis of these compounds began with
the corresponding monoalkylated species PQ-12,0 through PQ-
2
0,0 (3–7), and yields ranged from 10% to 68% (Scheme 4).
The compounds prepared above were tested for biological
To prepare a substantial set of compounds for bioactivity analy-
0
activity against a panel of four bacteria, including both Gram
positive (Staphylococcus aureus and Enterococcus faecalis) and Gram
negative (Pseudomonas aeruginosa and E. coli) strains. The broth
microdilution for determining the MIC of the compounds was
sis, we began with the alkylation of the inexpensive 4,4 -bipyridine.
Monoalkylation was accomplished via exposure to the correspond-
ing alkyl bromide (1 equiv) in acetonitrile at reflux for 24 h
(Scheme 1, top). While minor amounts of the starting materials
5
performed as previously reported ; details are reported in the
and bis-alkylated products were generally observed, compounds 3
through 7 were purified by simple vacuum filtration, rinsing, and
Supplementary data.
3
, PQ-12,0; n = 12, 24%
C H2n+1Br (1 equiv)
n
4, PQ-14,0; n = 14, 50%
5, PQ-16,0; n = 16, 46%
6, PQ-18,0; n = 18, 64%
N
N
N
N C H
n 2n+1
CH CN, reflux, 24h
3
Br
7
, PQ-20,0; n = 18, 37%
8
9
1
1
1
1
1
1
, PQ-8,8; n = 8, 47%
, PQ-10,10; n = 10, 46%
0, PQ-11,11; n = 11, 48%
1, PQ-12,12; n = 12, 53%
2, PQ-13,13; n = 13, 44%
3, PQ-14,14; n = 14, 48%
4, PQ-16,16; n = 16, 69%
5, PQ-18,18; n = 18, 17%
C H2n+1Br (4 equiv)
n
H2n+1Cn
N
N
C H
n 2n+1
N
N
CH CN, reflux, 24h
3
2
Br
Scheme 1. Synthesis of conventional amphiphiles (PQ-n,0) and gemini amphiphiles (PQ-n,n).

M. C. Grenier et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4055–4058
4057
CH I, reflux, 1 h
3
1
6, PQ-1,0, 99%
N
N
CH3
N
N
I
1
7, PQ-12,1; 49%
8, PQ-14,1; 26%
9, PQ-16,1; 24%
C H2n+1Br (3 equiv)
n
1
N
N
I
CH3
H2n+1Cn
N
N
N
CH3
1
CH CN, reflux, 48h
3
20, PQ-18,1; 24%
I
Br
2
1, PQ-20,1; 21%
C H Br (4-8 equiv)
2
5
2
2, PQ-12,2; 16%
CH CN
3
23, PQ-14,2; 60%
N
N
R
H2n+1Cn
N CH CH3
2
2
2
4, PQ-16,2; 36%
5, PQ-18,2; 23%
reflux, 24 hor
µwave, 130-150 ºC, 30 min
3
-6
Br
2 Br
Scheme 2. Preparation of bicephalic amphiphiles 17–25.
2
6, PQ-10,10Cl; X = Cl, 1.6%
C H2n+1Cl (4 equiv)
n
27, PQ-10,10I; X = I, 74%
28, PQ-11,11Cl; X = Cl, 3.5%
29, PQ-11,11I; X = I, 72%
30, PQ-12,12Cl; X = Cl, 2.6%
31, PQ-12,12I; X = I, 67%
CH CN, reflux, 7d
3
N
N
H2n+1Cn
N
N C H
n 2n+1
OR
C H2n+1I (4 equiv)
2 X
n
3
3
2, PQ-16,16Cl; X = Cl, 10%
3, PQ-16,16I; X = I, 63%
CH CN, reflux, 24h
3
Scheme 3. Preparation of symmetrical amphiphiles with varying counterion.
3
3
4, PQ-12,10; 68%
5, PQ-14,8; 52%
C H2n+1Br (4 equiv)
n
N
N R
Br
H2m+1Cm
N
N C H
n 2n+1
36, PQ-16,6; 28%
37, PQ-18,4; 24%
38, PQ-20,2; 10%
CH CN, reflux, 24h
3
3-7
2 Br
Scheme 4. Preparation of asymmetric amphiphiles bearing 22 carbons in the side chains.
The data summarized in Table 1 demonstrated some clear
trends in bioactivity. In the symmetric gemini amphiphiles series
hampered by poor solubility, which appeared in PQ-16,16 and PQ-
18,18.
(
PQ-n,n; compounds 8–15, 39) there was a clear optimum for bio-
activity, with undecyl chains on each of the pyridinium nitrogens
PQ-11,11; 10) leading to MIC values of 2 M against three bacte-
ria, and 16 M versus the more difficult to kill P. aeruginosa. This
Thirdly, the effects of counterion nature on bioactivity were
found to be negligible in the shorter-chained compounds. For
example, PQ-10,10 showed an identical set of MIC values (2, 4, 8,
(
l
l
and 63 lM vs the four bacteria) irrespective of the counterion pres-
represents a fourfold improvement over the MIC of benzalkonium
chloride in all four cases. The decyl and dodecyl analogs (PQ-10,10
and PQ-12,12; 9 and 11, respectively) were nearly as effective.
Shorter chains displayed less activity, and greater chain lengths
led to diminished water solubility. Similarly optimized lengths of
ent (chlorides, bromides, or iodides). However, the iodide counter-
ion severely hampered solubility, and thus bioactivity, in chain
lengths exceeding 12 carbons. In fact all compounds with iodide
counterions were incompletely soluble in water before warming.
A dropoff in activity was even noted in moving from decyl to unde-
cyl chains (PQ-10,10I, 27, vs PQ-11,11I, 29). Similar counterion
effects have been noted by others, and further counterion optimi-
zation has been reported to improve performance; separate reports
13,15
hydrophobic sections are precedented,
our group; for example, Roy and Das studied a class of cationic
amphiphiles capable of forming hydrogels with tail lengths from
including in work by
5
1
3
26
1
0 to 18 carbons and found the greatest bactericidal activity
indicate acetate and pentanoate as optimal anions.
against Gram positive bacteria for compounds with 12–14 car-
bons. There is likely a tradeoff to incorporating longer lipophilic
sections in the amphiphiles: water solubility of the amphiphile
diminishes, while effectiveness in membrane insertion and subse-
quent disruption increases.
Comparing the antibacterial activity of conventional (one cat-
ionic head, one non-polar tail), bicephalic (two heads, one tail), or
gemini (two heads, two tails) amphiphiles shows that our initial
hypothesis of superior activity of bicephalic compounds did not hold
in this bipyridinium system. Biscationic species did not show uni-
formly superior antibacterial activity to monocationic ones; MIC’s
of PQ-n,0 and PQ-n,1 analogs were within a single dilution in most
cases. A major exception was for PQ-20,0 and PQ-20,1, where the
longer chain compounds showed increased water solubility when
a second cation was present, thus improving activity. Importantly,
gemini compounds outperformed bicephalic compounds, unless
Finally, we were surprised to observe that a modest level of
asymmetry of the alkyl chains led to comparable bioactivity levels.
Starting with the highly active gemini compound, PQ-11,11 (10),
we compared the effect of distributing the 22 alkyl carbons asym-
metrically on either side of the dipyridine core. Three of these iso-
mers with little to no asymmetry, PQ-11,11 (10), PQ-12,10 (34),
and PQ-14,8 (35), showed comparable and highly potent activity,
9
with MIC levels around 2
estingly, PQ-12,10 was one of only two compounds displaying
MIC values below 10 M against all four bacteria; the other was
lM against 3 of 4 bacteria tested. Inter-
l
PQ-11,11Cl (28). More significant asymmetry (e.g., PQ-16,6) led
to a significant dropoff in activity. This perhaps illustrates a wa-
tershed in the transition from gemini to bicephalic amphiphile
architectures.
In total, we have exploited the viologen structural motif to inves-
tigate trends correlating amphiphilic structure to antimicrobial

4
058
M. C. Grenier et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4055–4058
Table 1
Micromolar minimum inhibitory concentrations in growth inhibition assays
as well as to investigate activity against red blood cells to optimize
the therapeutic index for this class of compounds.
PQ-n,n
#
S. aureus E. faecalis E. coli P. aeruginosa
PQ-1,1I27
PQ-8,8
Acknowledgments
39 >250
>250
250
4
2
4
>250
>250
8
2
4
>250
>250
63
16
31
8
9
125
2
PQ-10,10
PQ-11,11
PQ-12,12
PQ-13,13
PQ-14,14
PQ-16,16
PQ-18,18
PQ-12,0
This work was supported by a Multi-Investigator Cottrell
College Science Award from the Research Corporation for Science
Advancement (to K.L.C., K.P.C.M., and K.S.; MICCSA 10709), as well
as James Madison University and Villanova University.
10
11
12
2
2
8
⁄
⁄
⁄
⁄
8
16
250
>250
>250
>250
>250
250
>250
125
125
250
>250
125
250
>250
63
125
>250
>250
63
63
63
8
16
63
16
31
31
>250
>250
>250
8
16
31
125
>250
>63
13 16
14 250
15 >250
31
>250
>250
63
63
250
16
31
31
16
31
63
31
31
31
>250
31
4
4
4
2
2
8
4
4
16
>250
>250
>250
2
2
8
31
31
8
250
>250
>250
63
125
250
31
63
63
63
31
Supplementary data
3
16
⁄
⁄
⁄
⁄
⁄
PQ-12,1I/Br
PQ-12,2
PQ-14,0
17 31
22 63
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.04.079.
4
8
4
8
8
4
PQ-14,1I/Br
PQ-14,2
18
23
5
⁄
References and notes
PQ-16,0
PQ-16,1I/Br
19
⁄
⁄
1. Jenssen, H.; Hamill, P.; Hancock, R. E. W. Clin. Microbiol. Rev. 2006, 19, 491.
2. Brogden, K. A. Nat. Rev. Microbiol. 2005, 3, 238.
PQ-16,2
PQ-18,0
24 16
63
>250
31
6
16
8
8
3.
4.
5.
Zasloff, M. N. Engl. J. Med. 2002, 347, 1199.
Gilbert, P.; Moore, L. E. J. Appl. Microbiol. 2005, 99, 703.
LaDow, J. E.; Warnock, D. C.; Hamill, K. M.; Simmons, K. L.; Davis, R. W.;
Schwantes, C. R.; Flaherty, D. C.; Willcox, J. A.; Wilson-Henjum, K.; Caran, K. L.;
Minbiole, K. P. C.; Seifert, K. Eur. J. Med. Chem. 2011, 46, 4219.
PQ-18,1I/Br
PQ-18,2
20
25
7
31
⁄
PQ-20,0
>250
>250
125
8
8
8
2
2
8
4
4
16
>250
>250
>250
2
2
8
31
125
31
PQ-20,1I/Br
PQ-10,10Cl
PQ-10,10
PQ-10,10I
PQ-11,11Cl
PQ-11,11
PQ-11,11I
PQ-12,12Cl
PQ-12,12
PQ-12,12I
PQ-16,16Cl
21 16
26
9
2
2
2
2
2
4
2
2
8
6. Haldar, J.; Kondaiah, P.; Bhattacharya, S. J. Med. Chem. 2005, 48, 3823.
7. Maisuria, B. B.; Actis, M. L.; Hardrict, S. N.; Falkinham, J. O.; Cole, M. F.; Cihlar, R.
L.; Peters, S. M.; Macri, R. V.; Sugandhi, E. W.; Williams, A. A.; Poppe, M. A.;
Esker, A. R.; Gandour, R. D. Bioorg. Med. Chem. 2011, 19, 2918.
8. Falkinham III, J. O.; Macri, R. V.; Maisuria, B.B.; Actis, M. L.; Sugandhi, E. W.;
Willians, A. A.; Snyder, A. V.; Jackson, F. R.; Poppe, M. A.; Chen, L.; Ganesh, K.;
Gandour, R. D. Tuberculosis, in press. doi:http://dx.doi.org/10.1016/j.tube.
⁄
27
28
10
29
30
11
31
⁄
2011.12.002.
⁄
9. Roy, S.; Das, P. K. Biotechnol. Bioeng. 2008, 100, 756.
10. Debnath, S.; Shome, A.; Das, D.; Das, P. K. J. Phys. Chem. B 2010, 114, 4407.
⁄
32 >250
14 250
33 >250
1
1
1. Madaan, P.; Tyagi, V. K. Surf. Res. Lett. 2008, 15, 531.
2. Findlay, B.; Zhanel, G. G.; Schweizer, F. Antimicrob. Agents Chemother. 2010, 54,
⁄
⁄
PQ-16,16
PQ-16,16I
4049.
PQ-12,10
PQ-14,8
PQ-16,6
PQ-18,4
PQ-20,2
34
35
36
37
2
2
2
8
13. Bhadani, A.; Singh, S. Langmuir 2009, 25, 11703.
14. Brahmachari, S.; Debnath, S.; Dutta, S.; Das, P. K. Beilstein J. Org. Chem. 2010, 6,
859.
15. Pernak, J.; Kalewska, J.; Ksyci n´ ska, H.; Cybulski, J. Eur. J. Med. Chem. 2001, 36,
38 16
8
899.
Benzalkonium chloride
16. Maeda, T.; Okazaki, K.; Nagamune, H.; Manabe, Y.; Kourai, H. Biol. Pharm. Bull.
1998, 10, 1057.
Counterions are bromide unless indicated otherwise. Compounds marked with an
asterisk displayed incomplete water solubility upon mixing, which was addressed
by warming before dilution.
17. Sambhy, V.; Peterson, B. R.; Sen, A. Angew. Chem., Int. Ed. 2008, 47, 1250.
18. Imam, T.; Devinsky, F.; Lacko, I.; Mlynarcik, D.; Krasnec, L. Pharmazie 1983, 38,
308.
1
2
2
9. Michaelis, L.; Hill, E. S. J. Gen. Physiol. 1933, 16, 859.
0. Bird, C. L.; Kuhn, A. T. Chem. Soc. Rev. 1981, 10, 49.
1. Monk, P. M. S.; Hodgkinson, N. M. Electrochim. Acta 1998, 43, 245.
activity. Potent antibacterial compounds were prepared from inex-
pensive starting materials, often in a single step (generally 30–60%
yield). A bicephalic architecture has not proven to be an a priori de-
sign element in this system, though modest asymmetry may hold
promise, if only to increase solubility of longer chained compounds
by inhibiting crystallization. We aim to broaden our investigations
into compounds with modified core structures, looking to extend
solubility in the presence of more and longer hydrophobic sections,
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