Synthesis, antibacterial and anti-MRSA activity, in vivo toxicity and a structure-activity relationship study of a quinoline thiourea

Article abstract of DOI:10.1016/j.bmcl.2015.11.058

We report the synthesis, antibacterial evaluation of a series of thiourea-containing compounds. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)-((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea 5, was the most active against a rang

Full text of DOI:10.1016/j.bmcl.2015.11.058

Accepted Manuscript
Synthesis, antibacterial and anti-MRSA activity, in vivo toxicity and a structure-
activity relationship study of a quinoline thiourea
Niamh Dolan, Declan P. Gavin, Ahmed Eshwika, Kevin Kavanagh, John
McGinley, John C. Stephens
PII:
S0960-894X(15)30266-3
DOI:
http://dx.doi.org/10.1016/j.bmcl.2015.11.058
BMCL 23314
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
22 October 2015
13 November 2015
17 November 2015
Please cite this article as: Dolan, N., Gavin, D.P., Eshwika, A., Kavanagh, K., McGinley, J., Stephens, J.C.,
Synthesis, antibacterial and anti-MRSA activity, in vivo toxicity and a structure-activity relationship study of a
quinoline thiourea, Bioorganic & Medicinal Chemistry Letters (2015), doi: http://dx.doi.org/10.1016/j.bmcl.
2015.11.058
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Niamh Dolan, Declan P. Gavin, Ahmed Eshwika, Kevin Kavanagh, John McGinley and John C. Stephens

Bioorganic & Medicinal Chemistry Letters
Synthesis, antibacterial and anti-MRSA activity, in vivo toxicity and a
structure-activity relationship study of a quinoline thiourea
Niamh Dolana, Declan P. Gavina†, Ahmed Eshwikab, Kevin Kavanaghb, John McGinleya and John C.
Stephensa,*
aDepartment of Chemistry, Maynooth University, Maynooth, Co. Kildare, Ireland
bDepartment of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
We report the synthesis, antibacterial evaluation of a series of thiourea-containing compounds.
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)-((1S,2S,4S,5R)-5-
vinylquinuclidin-2-yl)methyl)thiourea 5, was the most active against a range of Gram-positive
and Gram-negative bacteria, and exhibited bacteriostatic activity against methicillin resistant
Staphylococcus aureus (MRSA) comparable to that of the well-known antibacterial agent
vancomycin. Quinoline thiourea 5 was subjected to a detailed structure-activity relationship
study, with 5 and its derivatives evaluated for their bacteriostatic activity against both Gram-
negative and Gram-positive bacteria. A number of structural features important for the overall
activity of quinoline thiourea 5 have been identified. A selection of compounds, including 5, was
also evaluated for their in vivo toxicity using the larvae of the Greater wax moth, Galleria
mellonella. Compound 5, and a number of derivatives, were found to be non-toxic to the larvae
of Galleria mellonella. A new class of antibiotic can result from the further development of this
family of compounds.
Keywords:
MRSA
Antibacterial
Quinoline
Thiourea
Structure activity relationship
2009 Elsevier Ltd. All rights reserved.
The European Centre for Disease Prevention and Control
(ECDC) has estimated that on any given day 1 in 18 hospitalised
patients are suffering with a healthcare-associated infection
(HAI).1 The four most frequently isolated microorganisms from
HAIs are Staphylococcus aureus (S. aureus), Escherichia coli (E.
coli), Enterococcus spp. and Pseudomonas aeruginosa (P.
aeruginosa).2 Of the S. aureus derived HAIs, 41% are caused by
Methicillin Resistant S. aureus (MRSA), with 23% of E. coli
HAIs resulting from cephalosporin-resistant strains.2 In addition,
the ECDC has reported that infections resulting from Gram-
negative multidrug-resistant (MDR) bacteria are on the rise.3,4 In
the United States (U.S.) at least 2 million people become infected
each year with antibiotic resistant bacteria.5 Of the 2 million
infections, approximately 23,000 people die as a direct result.5
antibiotics’, coupled with the paucity of new classes of
antibiotics, means that there is an urgent need for antibacterial
research with a focus on the discovery of new antibiotic
classes.5,8
We employed a building block approach in our search for
new antibacterial agents, where we wanted to consider
compounds that: (a) bear moieties/blocks that are found in
established antimicrobial agents or are known to enhance
biological activity and (b) once the blocks are combined, still
have the potential to become a new class of antibiotic. This
building block approach aimed to include structural moieties, or
blocks, such as functional groups bearing fluorine atoms,
quinoline bicycles, saturated nitrogen heterocycles and thioureas,
which are all recognised motifs in antimicrobial agents.9,10
This increase in prevalence of antibiotic-resistant bacterial
infections and emergence of new resistant strains are only part of
the problem. The lack of development of new classes of
antibacterial agents also plays a significant role. Of the
antibiotics used today almost all of them belong to classes
discovered before the 1980s, with the exception of the
lipopeptides.6 Most of the advances that have been made since
The addition of fluorine is known to enhance drug potency by
improving bioavailability, metabolic stability and protein-ligand
interactions (e.g. Flurithromycin), whilst the quinoline bicycle is
structurally similar to the well-known antibacterial agents, the
quinolones.12,7 Additionally, quinine, a compound most well-
known for its antimalarial properties, has also been shown to be
bactericidal to a number of Gram-positive and Gram-negative
bacteria.13,14,15
the
1980s
have
been
achieved
through
modifications/improvements to existing antibiotic classes.6 For
example, the fluoroquinolones are more effective antimicrobial
agents than nalidixic acid.7 The global spread of antibiotic-
resistance and the emergence of bacteria resistant to ‘last-resort
Thiourea-based compounds are well-known for their
antithyroid activity, however, a vast array of biological activities
including antitubercular, insectididal, rodenticidal, antiviral,

Figure 1. Compounds screened for antibacterial activity.
antifungal and antibacterial activities have also been associated
Compound 7 did exhibit higher activity against E. coli than
compound 5. However, the almost nanomolar activity of
compound 5 against S. aureus prompted us to consider
compound 5 in more detail. As such, compound 5 was subjected
to a detailed structure-activity relationship (SAR) study in order
to help understand its impressive biological activity and to
identify the moieties/functional groups responsible for this
activity.
with thiourea-based compounds.10,11 A recent study on thiourea-
based compounds incorporating a hippuric acid moiety was
carried out by Abbas et al.16 The majority of these compounds
exhibited broad spectrum antimicrobial activity with a number of
them demonstrating activity comparable to, and in some cases
better than, ciprofloxacin.16
As such, a number of compounds containing some or all of
these moieties/functional groups were chosen and screened for
their antibacterial activity (Figure 1).17-19
An initial investigation explored the affect the OMe, CF3 and
thiourea groups had on the biological activity of compound 5.
We generated derivatives 5a-c for this purpose (Scheme 1).
Compound 5a was synthesized as described by Oliva et al.20
(Scheme 1). As shown in Scheme 1, the nucleophilic addition of
5a to 3,5-bis(trifluoromethyl) phenyl isothiocyanate generated
compound 5. Alternatively, the reaction of 5a with phenyl
isothiocyanate gave 5c. The synthesis of 5b was carried out using
the same method as described for 5, however, cinchonidine was
used in place of quinine in the Mitsunobu reaction (Scheme 1).
Each compound was evaluated for their bacteriostatic activity
against the Gram-positive bacterium S. aureus and the Gram-
negative bacterium E. coli. The results of the antibacterial
screening have been summarised in Table 1 and are expressed as
the MIC90, that is, the minimum inhibitory concentration that is
required to inhibit 90% of bacterial growth
Table 1. MIC90 values for compounds 1-10.
S. aureusa
E. colib
Each of the compounds, 5 and 5a-c, were evaluated for their
in vitro bacteriostatic activity using the susceptibility assay
described by Kelly et al.21 The three bacteria chosen were, E.
coli, P. aeruginosa and S. aureus, as these are three of the most
frequently isolated microorganisms from HAIs.2
Compound
MIC90 (M)
> 200
MIC90 (M)
> 200
1
2
79.44 +/- 22.2
> 200
> 200
> 200
3
Scheme 1. Synthesis of compound 5 and derivatives 5a-5c.
114.8 +/- 25.9
< 6.25
> 200
4
> 200
5
> 200
> 200
6
23.8 +/- 0.1
189.2 +/- 2.2
> 200
119.9 +/- 13.8
> 200
7
8
> 200
9
124.9 +/- 35.6c
> 200
10
a
b
c
S. aureus NCIMB 12702, E. coli NCIMB 9485, value given for
compound 10 is the MIC82
o
Reactants and conditions: (i) PPh3, DIAD, 0 oC (ii) DPPA, rt, 12 h and 50 C,
2 h (iii) PPh3, 50 oC, 2 h (iv) (CF3)2C6H3NCS or PhNCS, rt, 12 h.
Compounds 5 and 7 were found to be the most active of those
screened (Table 1). As shown in Table 1, compound 5 exhibited
remarkable anti-Staphylococcal activity, with a MIC90 of <6.25
, which was superior to all other compounds screened.
The S. aureus and E. coli strains used in this study were
clinical isolates obtained from St. James Hospital, Dublin,

Ireland and P. aeruginosa (10145) was obtained from the
American Type Culture Collection (ATCC). The results are
summarised in Table 2. The results are expressed as the MIC50
and MIC90 range. Vancomycin hydrochloride (Van HCl) was
chosen as the positive control as it is a well-known antibacterial
agent that is often used as a last resort drug in the treatment of
drug-resistant infections, such as MRSA.9 The vancomycin result
has also been included in Table 2.
the presence of the methoxy group is not important for its overall
activity.
The effect of removing the two CF3 groups was investigated
using 5c. Compound 5c was found to be less active than
compound 5, displaying a 10- and 14-fold decrease in the MIC50
range against both S. aureus and E. coli, respectively (Table 2).
These results indicate that the CF3 groups appear to be very
important in the overall activity of 5.
Table 2. Antibacterial activity of compounds 5 and 5a-5c
as MIC50 and MIC90 ranges.
As previously discussed, the inclusion of fluorine is known to
enhance drug potency and in addition can increase the lipophilic
character of a compound.12 A useful way of comparing the
lipophilicity of compounds is by calculating their LogP value.9,26
The greater the LogP value, the more lipophilic the molecule.
The cLogP of 5 was found to be approximately 7.33, while that
of 5c was found to have a cLogP of approximately 4.35.27
Therefore the loss of the CF3 groups, and hence reduction in
lipophilicity, may be impairing the hit compound’s ability to
cross the cell membranes and bind to its target site.
E. coli
S. aureus
MIC90
Compound
MIC50
MIC90
MIC50
(M)
(M)
(M)
(M)
1.58-2.10
2.63-3.95
> 309.41
5.54-8.32
4.21-6.31
7.90-10.52
> 309.41
1.58-2.10
3.95-5.26
> 309.41
4.21-6.31
Van HCl
10.52-15.78
> 309.41
5
5a
5b
Having established the importance of the CF3 and thiourea
groups we then continued our exploration of the structure activity
relationship of compound 5 by maintaining the CF3 substituted
aryl thiourea core and introducing variation to other parts of the
molecule.
8.32-11.08
8.32-11.08
16.62-22.16
40.92-
54.56
81.84-
109.12
54.56-
81.84
163.68-
218.24
5c
In the initial screen (Table 1), compound 5 and 7 were found
to be the compounds that exhibited greatest activity. These
compounds share similarities in their structures with both
compounds bearing a 3,5-bis(trifluoromethyl)-phenyl thiourea
moiety attached to a tertiary amine via a two-carbon chain
(Figure 2). To further explore the importance of these structural
similarities compounds 11a, 11b and 12 were designed and
synthesised. These compounds have lower molecular weights
than 5 and 7 yet possess the same connectivity (Figure 2).
{Values are the mean of three experiments.}
None of the compounds tested displayed significant activity
against P. aeruginosa (hence these results have been omitted
from Table 2). This lack of activity could be due to the intrinsic
resistant mechanisms associated with P. aeruginosa. For
example, the uptake of molecules by P. aeruginosa is very slow
(in comparison to E. coli) due to its inefficient porins.22 P.
aeruginosa can also form a capsule providing it with an
additional physical barrier to prevent the entry of antibiotics.23,23
Furthermore, P. aeruginosa is well-known for its ability to grow
as a biofilm thus aiding its escape from the action of antibiotics.25
Perhaps one or a combination of these mechanisms is responsible
for the lack of bacteriostatic activity observed.
As can be seen in Table 2, compound 5 exhibited good
activity against E. coli, resulting in an MIC50 in the range of 2.63-
3.95  and 3.95-5.26  against S. aureus. Compound 5 also
inhibited E. coli and S. aureus growth by 90% at MIC’s
comparable to that obtained for the reference antibacterial agent,
vancomycin hydrochloride (Table 2).
The results from the susceptibility assays of 5a revealed that
it exhibited little or no activity against E. coli, P. aeruginosa and
S. aureus (Table 2). This is an interesting result as quinine itself
has been shown by others to exhibit bactericidal activity against
all three bacteria.14 However, the small structural differences
between 5a and quinine, that is the replacement of the OH with
the NH2 and 5a having the opposite stereochemistry to quinine,
may be the reasons behind this lack of activity. Alternatively, the
lack of activity exhibited by 5a could be due to the presence of a
third basic nitrogen group, the NH2, in comparison with quinine.
When 5a is in solution it has the potential to become protonated,
which, in turn, may prevent it from crossing the lipid membrane
of the bacteria. Consequently, 5a may not be able to inhibit
bacterial growth.
FiFigure 2. Structural similarity of compounds 1, 7 and 11-12.
In addition, compounds 13a, 13b, 14 and 15 were also
generated, which allowed us to explore the significance of the
basic tertiary amine group (Scheme 2).
Scheme 2. Synthesis of compounds 11-15.
Reactants and conditions: (i) rt, overnight.
As can be seen from Table 2, 5b exhibited activity against
both E. coli and S. aureus. The MIC50 values obtained for 5b
were slightly higher than those exhibited by 5, with the MIC90
values obtained very close to those of 5 (Table 2). Although
methoxy groups can be of importance for binding to target sites
through their H-bonding ability,9 these results indicate that for 5,
Compounds 11-15 were synthesized using a method similar
to that described by Andrés et al.28, with modifications (Scheme
2).
As with compounds 5-5c, each of the new derivatives, along
with compound 7, were evaluated for their bacteriostatic activity
against all three bacteria. The results of which have been

summarized in Tables 3 and 4. Any inactive compounds have
been excluded from the tables.
increase in lipophilicity improves activity although the change in
cLogP is marginal. Additionally, these results suggest that the
more sterically bulky quinuclidine ring is favourable for activity.
Again, none of the compounds, 7 and 11-15, exhibited
activity against the Gram-negative bacterium P. aeruginosa. In
fact, 13a exhibited little or no activity against each of the three
bacteria examined suggesting that the simple 3,5-
bis(trifluoromethyl)phenyl thiourea moiety alone is not the
source of activity. As shown in Table 3, 13b only demonstrated
activity against E. coli resulting in a MIC50 of 158.20-237.31 .
Although this is a slight improvement on 13a, the MIC50
achieved by 13b is far removed from that observed for compound
5 (2.63-3.95 ). Furthermore, 13b was unable to inhibit any
more than 50% of bacterial growth suggesting that the simple
thiourea structure, and the addition of a two-carbon chain, is not
enough to produce significant antibacterial activity.
Comparing results for 13b with 12 suggest that a basic
tertiary nitrogen, in combination with steric bulk/lipophilicity,
has a beneficial effect on activity. To further investigate this
theory compounds 14 and 15 were synthesised, which do not
have a basic nitrogen but retained some steric and lipophilic
properties (Scheme 2). Both 14 and 15 were evaluated for their
bacteriostatic activity. Compound 14 exhibited activity against
both E. coli and S. aureus resulting in MIC50 ranges of 101.33-
135.10 and 135.10-202.65  respectively (Table 3). Compound
15 on the other hand only exhibited activity against E. coli,
however, the MIC50 obtained was lower than that of 14 (Table 3).
Additionally, an increase in 15 concentration resulted in an
increase in percentage of growth inhibition, whereas 14 did not
inhibit greater than 50% of bacterial growth (Table 3 and 4). In
terms of structure, both 14 and 15 contain a lipophilic six-
membered carbon ring with the difference being that, in 15 it is
planar and aromatic whereas for 14 it is non-planar and of greater
steric bulk (Charton values: Ph = 0.57 and cyclohexyl = 0.8729).
Both compounds, 14 and 15, were significantly less active than
12 and 5, suggesting that the presence of a basic nitrogen is of
paramount importance.
Similar to 13a, compound 11a demonstrated little or no
bacteriostatic activity against all three bacteria. Compound 11b
on the other hand resulted in an MIC50 of 96.87-129.16 
against both E. coli and S. aureus. Furthermore, 11b had the
ability to inhibit up to 90% of bacterial growth, although a higher
concentration was required to do so (Table 4). These results
indicate that although the addition of the two-carbon chain bound
to a simple dimethyl tertiary amine did not improve bacteriostatic
activity (compound 11a), the addition of a slightly more
hydrophobic and slightly larger tertiary amine (diethylamine)
was beneficial for activity. What is more, in comparison to 13b,
which was inactive against S. aureus, the addition of the –NEt2
group, 11b, resulted in a compound that can inhibit up to 80% of
S. aureus growth at a concentration range of 129.16-193.74 
(see supporting information).
As
a result of this synthetic and evaluation study,
considerable information was attained relating compound
structure to biological activity and the outcomes from this SAR
exercise are summarized in Figure 3.
Table 3. Antibacterial activity of compounds 5, 7 and 11-
15 as MIC50 and MIC90 ranges.
E. coli
S. aureus
Compound
MIC50
MIC90
MIC50
MIC90
(M)
(M)
(M)
(M)
1.58-2.10
4.21-6.31
1.58-2.10
4.21-6.31
Van HCl
5
10.52-
15.78
2.63-3.95
7.90-10.52
3.95-5.26
60.51-
90.77
121.02-
181.54
60.51-
90.77
90.77-
121.02
7
Figure 3. SAR study summary of quinoline thiourea 5.
96.87-
129.16
193.74-
258.32
96.87-
129.16
193.74-
258.32
The antibacterial activity of several compounds, particularly
compounds 5 and 5b, was quite promising and as a result
additional testing against the resistant strain MRSA was
performed. The anti-MRSA results for compounds 5, 5b, 7, 11b
and 12, the top five compounds against S. aureus, are shown in
Table 4.
11b
12
42.89-
57.19
85.78-
114.38
42.89-
57.19
85.78-
114.38
158.20-
237.30
>316.41
>270.20
>316.41
>316.41
>270.20
>274.69
13b
14
101.33-
135.10
135.10-
202.65
Table 4. Anti-MRSA activity of compounds 5, 5b, 7, 11b
and 12 as MIC50 and MIC90 ranges.
51.50-
68.67
206.02-
274.69
>274.69
15
MRSA
MRSA
Compound
MIC50 (M)
11.44a
10.81 a
21.54 a
13.47 a
20.73 a
-
MIC90 (M)
17.74 a
{Values are the mean of three experiments}
5
As shown in Table 3, 12 (containing a quinuclidine
heterocycle, as found in compound 5) was more active than 13b
and 11b against both E. coli and S. aureus. Furthermore, 12 can
inhibit the growth of both E. coli and S. aureus by 50%, at the
same concentration, with an increase in concentration resulting in
an increase in bacteriostatic activity (Table 3 and 4).
18.11 a
32.25 a
23.52 a
31.44 a
5b
7
11b
12
1.35b
Vancomycin
The cLogP of compound 12 was calculated to be
approximately 5.63, which is a slight increase in cLogP
compared to that of 11b (5.09 +/- 0.54).27 Therefore, perhaps this
a
b
Clinical isolate, {values are the mean of four experiments}, published
literature data 30,31

All five compounds displayed significant activity levels
against MRSA, with MIC50 and MIC90 values in the low M
range. Compounds 5 and 5b were the most impressive, exhibiting
low MIC90 values of 17.74 and 18.11 M respectively. This
compares favourably with the reported anti MRSA MIC90 value
for vancomycin of 1.35 M or 2 mg/L (vancomycin is the
antibacterial agent commonly used in the treatment of MRSA
infection).30,31 As such, the quinoline thiourea structure, as found
in compound 5, has significant potential as a new antibacterial
agent class.
testing against the resistant strain MRSA. Both compounds 5 and
5b displayed significant anti MRSA activity, again comparable to
vancomycin. Additionally, and importantly, compound 5, and a
number of derivatives, were also found to be non-toxic to G.
mellonella larvae at concentrations of up to 1000 µg/mL (in the
case of compound 5). Overall, these results suggest that the
quinoline thiourea structure, as found in compound 5, has
potential as a new class of non-toxic, anti MRSA agent.
Acknowledgments
In developing new antibacterial agents it is important to
determine, as early as possible, if the antibacterial properties are
simply due to the compounds being toxic in nature (i.e. not
selective for bacteria). To investigate this possibility, in vivo
toxicity studies were carried out, as described by Rowan et al.32
using the larvae of the Greater wax moth, Galleria melonella (G.
melonella), (Figure S25 in supplementary information).
This research was funded through the Irish Higher Education
Authority Programme for Research in Third Level Institutions –
Cycle 4 and co-funded by the European Union under the
European Regional Development Fund.
† Present address, Sir Robert Kane Building, UCC, College
Road, Co. Cork, Ireland.
The similarities between the innate immune system of insects
and mammals have led to the use of insects as in vivo models for
investigating the virulence of many human pathogens including
Gram-negative bacteria, Gram-positive bacteria, and fungi.33,34,35
The larvae of the Greater wax moth, G. mellonella, have been
used as an in vivo model in a number of studies to investigate the
virulence of human pathogens.34,35 G. mellonella larvae have also
been used to evaluate both the therapeutic effect of current and
novel antimicrobial agents and the in vivo tolerance of novel
antimicrobial agents.36,37 An investigation into the toxicity of
copper(II) and silver(I) complexes by McCann et al.38 has
demonstrated that the level of toxicity exhibited by the test
compounds in G. mellonella was similar to that observed in
Swiss mice.
References and notes
1.
2.
ECDC Surveillance Report 2013, Summary. Point Prevalence
survey of healthcare-associated infections and antimicrobial use in
European hospitals 2011-2012.
ECDC Surveillance Report 2013. Suetens, C.; Hopkins, S.;
Kolman, J.; Högberg, L. D., European Centre for Disease
Prevention and Control. Point prevalence survey of healthcare-
associated infections and antimicrobial use in European acute care
hospitals 2011-2012.
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ECDC Annual Epidemiological Report 2013. Reporting on 2011
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EARS-Net Report for Quater 1 2013.
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Antriole, V. T. The Quinolones, 3rd ed.; Academic Press.; San
Diego, California, 2000.
Compound 5, and a selection of derivatives that exhibited
antibacterial activity (5b, 5c, 11b, 12 and 15) were chosen for the
evaluation of their toxicity. Almost all compounds tested
displayed a 100% survival rate of G. mellonella larvae at a range
of concentrations. Compounds 5b, 5c, 11b, 12 and 15, at a
concentration of 1 µg/mL, all displayed a 100% survival rate
after 72 hours. Increasing the administration dose to 10, 50 and
100 µg/mL did not appear to affect the G. mellonella larvae. A
100% survival rate was observed, at each of these concentrations,
for every compound tested, including compound 5. The in vivo
toxicity of our most active compound, compound 5, was also
evaluated at the higher concentration of 1000 µg/mL, and once
more was found to be non-toxic. A table of results showing
survival rates (100% in almost all cases) at 24, 48 and 72 h, and
at a range of concentrations, can be found in the supplementary
information.
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The G. mellonella larvae were also monitored for their
development, that is, whether or not the larvae proceeded along
their normal developmental pathway to form pupae. It was found
that after seven days, at each test compound concentration, the
number of the G. mellonella larvae that had pupated was similar
to that observed for the untreated G. mellonella (≥ 60%). These
results indicate that not only were the compounds non-toxic to
the larvae of the Greater wax moth but they also did not appear to
interfere with larval development.
In conclusion, we have described the identification of a new
quinoline thiourea antimicrobial agent, compound 5. All
compounds were evaluated for their bacteriostatic, and not
bactericidal, activity. The antibacterial activity of the quinoline
thiourea 5 was discovered when screening selected compounds
against E. coli, P. aeruginosa and S. aureus. The compelling
activity of compound 5 against E. coli and S. aureus, activity
comparable to vancomycin hydrochloride, necessitated an
exploration of its structure activity relationship and additional

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Supplementary Material
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Supplementary data associated with this article, including
synthetic procedures, compound characterization data, NMR
spectra and biological assay protocols/results, can be found in the
online version, at XXX.
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