New classes of Gram-positive selective antibacterials: Inhibitors of MRSA and surrogates of the causative agents of anthrax and tuberculosis

Article abstract of DOI:10.1016/j.bmcl.2008.09.085

An antimicrobial phenolic stilbene, (E)-3-hydroxy-5-methoxystilbene, 1 was recently isolated from the leaves of Comptonia peregrina (L.) Coulter and shown to possess inhibitory activity against several Gram-positive bacteria, including isolates of methici

Full text of DOI:10.1016/j.bmcl.2008.09.085

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5745–5749
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
New classes of Gram-positive selective antibacterials: Inhibitors of MRSA
and surrogates of the causative agents of anthrax and tuberculosis
M. Shahjahan Kabir a, Kathleen Engelbrecht c, Rebecca Polanowski c, Sarah M. Krueger c, Rachel Ignasiak c,
Marc Rott c, William R. Schwan c, Mary E. Stemper d, Kurt D. Reed d, , David Sherman e, James M. Cook a,
,
*
Aaron Monte b,
*
a Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA
b Department of Chemistry, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA
c Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA
d Marshfield Clinic Research Foundation, Marshfield, Wisconsin, WI 54449, USA
e Seattle Biomedical Research Institute and Department of Global Health, University of Washington, Seattle, WA 98109, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An antimicrobial phenolic stilbene, (E)-3-hydroxy-5-methoxystilbene, 1 was recently isolated from the
leaves of Comptonia peregrina (L.) Coulter and shown to possess inhibitory activity against several
Gram-positive bacteria, including isolates of methicillin-resistant Staphylococcus aureus (MRSA), Myco-
bacterium bovis BCG, and avirulent Bacillus anthracis (Sterne strain), among others. These results
prompted the design and synthesis of two new classes of compounds, phenoxystyrenes and phenothio-
styrenes, as analogs of the natural antimicrobial stilbene. These and additional stilbenoid analogs were
synthesized using new, efficient, copper-mediated coupling strategies. Minimum inhibitory concentra-
tion (MIC) antimicrobial assays were performed on all compounds prepared. These preliminary struc-
ture–activity relationship studies indicated that both new classes of synthetic analogs, as well as the
stilbenes, show promising activity against Gram-positive bacteria when at least one phenolic moiety is
present, but not when absent. The potencies of the phenolic phenoxystyrenes and phenothiostyrenes
were found to be comparable to those of the phenolic stilbenes tested.
Received 18 August 2008
Revised 19 September 2008
Accepted 22 September 2008
Available online 26 September 2008
Keywords:
Stilbene
Phenoxystyrene
Phenothiostyrene
Gram-positive antibacterial
Staphylococcus aureus
Mycobacterium spp.
Bacillus spp.
Ó 2008 Elsevier Ltd. All rights reserved.
As part of our ongoing ethnopharmacological efforts to discover
new molecules that might be used to combat clinically significant
bacterial infections, we identified the phenolic stilbene, (E)-3-hy-
droxy-5-methoxystilbene, 1 in the leaves of the shrub, Comptonia
peregrina (L.) Coulter (‘sweet fern’).1 This plant has been used tra-
ditionally for its antimicrobial and other biological properties by a
number of native North American cultures of the Great Lakes and
Maritime regions.2 Although the cytoxic compound, methyl-p-
coumarate had previously been found in this plant,3 along with
numerous other compounds isolated from the essential oil,4 stil-
bene 1 had not previously been reported to be present in C. pere-
grina. Interestingly, compound 1 was identified in the plants,
Didymochlaena truncatala (Sw.) J. Sm (Dryopteridaceae)5 and Alpi-
nia katsumadai Hayata.6 However, the antimicrobial properties of
this natural stilbene 1 were not reported in either of the prior
studies.
After the purification of the natural product 1, a battery of
minimum inhibitory concentration (MIC) assays was performed
to assess the range of antimicrobial activity.7 Analysis of those
studies indicated that 1 exhibited selective inhibition of the
growth of numerous clinically relevant Gram-positive bacteria
at reasonably low concentrations.1 For example, 1 was found to
inhibit the growth of methicillin-resistant Staphylococcus aureus
(MRSA) with an MIC of 32
enterococci (VRE) with an MIC of 16
l
g/mL and of vancomycin-resistant
l
g/mL (Table 1).1 Currently,
MRSA and VRE are two bacterial species of growing concern to
the medical community because of the development of wide-
spread resistance to existing frontline drugs.8–10 In addition, 1
also showed very good inhibitory activity against the Sterne
strain of Bacillus anthracis (MIC 8 lg/mL), the attenuated variant
of the causative species of anthrax, as well as promising activity
against other related Bacillus species (Table 1). Furthermore, nat-
ural product 1 was found to be effective in inhibiting the growth
* Corresponding authors. Tel.: +1 414 229 5856; fax: +1 414 229 5530 (J.M. Cook),
tel.: +1 608 785 8260; fax: +1 608 785 8281 (A. Monte).
E-mail addresses: capncook@uwm.edu (J.M. Cook), monte.aaro@uwlax.edu (A.
Monte).
Present address: Department of Pathology, Feinberg School of Medicine, North-
western University, Chicago, IL 60611, USA.
of Mycobacterium bovis with an MIC of 26 lg/mL, which indicated
it might serve as a promising lead scaffold in the development of
drugs used to combat drug resistant Mycobacterium tuberculosis
infections.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.09.085

5746
M. S. Kabir et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5745–5749
Table 1
bial studies on the natural stilbene 1, the design and synthesis of
chemically novel analogs of these compounds was undertaken.1
It was envisioned that functionalized analogs of E-phenoxysty-
renes and E-phenothiostyrenes might fill this role; consequently,
new synthetic approaches were developed to create these new
agents.1 In addition, the synthetic methods developed for the prep-
aration of the phenoxystyrenes and phenothiostyrenes was ex-
tended to the construction of several substituted E-stilbenoid
analogs to explore the structure–antimicrobial activity relation-
ships of these classes of compounds related to 1 in greater detail.
Initially, it was decided to prepare gram quantities of the active
natural stilbene 1, and this was accomplished using a Horner–
Wadsworth–Emmons process, as shown in Scheme 1.16 This novel
approach to creating the substituted stilbenes was convenient and
inexpensive, and the relatively high yields easily produced gram
quantities of the desired targets. The condensation of the benzyl
bromide-derived phosphorate and 3,5-dimethoxybenzaldehyde,
under basic conditions, yielded a mixture of stilbenes 1a in a Z:E
ratio of approximately 1:4 (Scheme 1). The pure E-3,5-dimethoxy-
stilbene 1a was obtained from this mixture by crystallization from
methanol and water. Subsequent mono-demethylation of (E)-1a
using BBr3 at ꢀ78 °C gave the desired phenolic stilbene 1 in good
yield.
To begin construction of derivatives of 1 for SAR studies, a prac-
tical synthesis was developed using a Negishi cross-coupling pro-
cess that was directly applied to thiophenes 3 and 4 to give the
2- and 3-styrylthiophenes 5, 6, 8, and 9 (Scheme 2).27 This ap-
proach, gratifyingly, gave only the desired (E)-alkene isomers,
thereby eliminating the need for the tedious separation of the un-
wanted (Z)-isomer. Importantly, the phenolic 2- and 3-styrylthi-
ophenes 8 and 9, respectively, were produced efficiently using
this one-pot process.27 Thus, coupling between the TBDPS-pro-
tected arylvinyl iodide 7 and the thiophenyl zinc reagent, followed
by deprotection using TBAF–THF, afforded the target phenolic sty-
rylthiophenes without the requirement of an extra demethylation
step.
Minimum inhibitory concentrations (MIC) of (E)-3-hydroxy-5-methoxystilbene
1
purified from C. peregrina against several species of bacteriaa
Organisms
Gram reaction
MIC (lg/mL)
Corynebacterium xerosis
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
16
32
16
32
32
32
32
16
16
16
32
64
32
16
8
16
64
16
8
26
>128
>128
Corynebacterium diphtheriae Tox-
Corynebacterium pseudodipthericum
Staphylococcus aureus ATCC 29213
Staphylococcus aureus ATCC 25923
Staphylococcus aureus MRSA MC-1
Staphylococcus aureus MRSA MC-4
Enterococcus faecium VRE 1
Enterococcus faecium VRE 14
Enterococcus faecalis ATCC 29212
Listeria monocytogenes
Streptococcus mitis
Streptococcus agalactiae
Streptococcus pyogenes
Streptococcus pneumoniae ATCC 49619
Bacillus cereus
Bacillus megaterium
Bacillus subtilis
Bacillus anthracis (Sterne strain)
Mycobacterium bovis BCG
Escherichia coli
+
+
+
N/A
–
–
Pseudomonas aeruginosa
a
Values represent the mean of three experiments. ATCC, American Type Culture
Collection; MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycin-
resistant enterococci.
Organic and medicinal chemists have found trans-stilbene scaf-
folds to be an intriguing structural class of compounds (e.g., see
methoxylated and phenolic stilbenes, Fig. 1).11,12 These stilbene
scaffolds may be considered to be ‘privileged structures’ because
of their wide variety of biological activity.11,12 Indeed, (E)-stilbe-
noid compounds are widely distributed throughout nature,13–15
and natural methoxylated and phenolic stilbenes are found in
numerous medicinal plants and food products.11,12 For instance,
the natural phenolic stilbene, resveratrol (trans-3,5,40-trihydroxy-
stilbene), has been shown to possess a diverse range of biological
and potential therapeutic properties.11–26 Specifically, resveratrol
and its related substituted (E)-stilbenes have been forwarded as
potential: (i) cancer chemotherapeutic agents that inhibit in vitro
growth of human cancer cell lines;11–15 (ii) anti-inflammatory
agents that act through the cyclooxygenase (COX) enzyme inhibi-
tion mechanism;16–18 and (iii) antioxidants,18 which may serve as
chemo-protective agents. Resveratrol and its analogs also may pre-
vent heart disease due to the lipid lowering effects and through the
inhibition of lipid peroxidation.14 Additional properties of resvera-
trol, such as radical scavenging,15 neuroprotection,15 antiviral
activity,15 antibacterial activity,18–23 inhibition of SARS coronavirus
replication,24 anti-platelet aggregation,25 anti-carcinogenic activ-
ity,25 anti-HIV activity,25 and inhibition of human cytochrome
P450 1B126 have all recently been documented.
It was then felt extension of the vinyl linkage of the stilbenes by
addition of either an oxygen or sulfur heteroatom would yield no-
vel, unnatural phenoxystyrene and phenothiostyrene scaffolds that
might exhibit enhanced antimicrobial activity. Therefore, the phe-
nolic phenoxystyrene analogs 10-15 and the phenolic phenoxy-
thiostyrene analog 16 were prepared employing copper(I)-
catalyzed coupling reactions that were recently developed in this
laboratory (Scheme 3).28 This process involved the cross-coupling
between the aryl vinyl iodide 7 and the corresponding phenols or
thiophenol.28 In similar fashion to the sequence outlined in Scheme
2, this copper-mediated coupling reaction and the subsequent
deprotection could be carried out conveniently in one reaction ves-
sel. Overall, this approach provided an efficient and high-yielding
access to these new classes of phenolic stilbene analogs.
Motivated by the positive results obtained from the reactions
outlined in Scheme 3, the corresponding oxy-functionalized, dime-
thoxy phenoxystyrene and phenothiostyrene analogs 17–23, were
On the basis of the many reports on the activity of substituted
stilbenes such as resveratrol, as well as the promising antimicro-
O
b
Br
a
P
EtO OEt
X
92%
R3O
HO
MeO
c
OR5
R3 = Me, R5 = H, X = H, 1
R3 = R5 = H, X = p-OH, resveratrol
R3 = R5 = Me, X = H, "methoxylated stilbenes"
OMe
1a, 85%
OMe
1, 75%
R
3 = Me, R5 = H, X = H, "phenolic stilbenes"
Scheme 1. Reagents and conditions: (a) P(OEt)3, 130 °C, 3 h; (b) NaH, DMF, 0 °C,
3,5-dimethoxybenzaldehyde, rt, 3 h; (c) BBr3, CH2Cl2, ꢀ78 °C, 12 h.
Figure 1. General structures of methoxylated and phenolic (E)-stilbenes.

M. S. Kabir et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5745–5749
5747
S
S
S
MeO
I
+
MeO
or
MeO
X
S
a. i, ii
Y
OMe
OMe
5, 82%
OMe
6, 84%
3 X = Br, Y = H
4 X = H, Y = Br
2
S
TBDPSO
I
+
HO
HO
X
S
b. i, ii, iii
or
Y
OMe
OMe
9, 81%
OMe
8, 77%
3 X = Br, Y = H
4 X = H, Y = Br
7
Scheme 2. Reagents and conditions: (a) i—3 or 4, n-BuLi, ꢀ78 °C, 30 min, ZnCl2, 0 °C, 1 h; ii—2, Pd2(dba)3, THF, rt, 2 h; (b) i—3 or 4, n-BuLi, ꢀ78 °C, 30 min, ZnCl2, 0 °C, 1 h;
ii—7, Pd2(dba)3, THF, rt, 2 h; iii—TBAFꢁTHF, rt, 2 h.
R1
OH
HO
HO
OMe
OMe
O
b, c
a
I
TBDPSO
HO
X
R2
R3
a, b
OH
OSPDBT
25, 33%
OMe
OMe
26, 68%
OMe
24
OMe
10-16
7
O
OMe
MeO
OH
I
d
10, R1 = R2 = R3 = H, X = O, 81%
11, R1 = Me, R2 = R3 = H, X = O, 79%
13, R1 = R2 = H, R3 = Me, X = O, 59%
15, R1 = R2 = H, R3 = OMe, X = O, 69%
+
12, R1 = R3 = H, R2 = Me, X = O, 68%
14, R1 = R3 = H, R2 = OMe, X = O, 75%
16, R1 = R2 = R3 = H, X = S, 82%
OMe
27
28
29, 77%
Scheme 5. Reagents and conditions: (a) TBDPSCl, imidazole, DMF, ꢀ20 °C, 10 min;
(b) 28, Cu(I)Cl, NMM, Cs2CO3, toluene, reflux, 16 h; (c) TBAFꢁTHF, rt, 2 h; (d) Cu(I)Cl,
NMM, Cs2CO3, toluene, reflux, 12 h.
Scheme 3. Reagents and conditions: (a) ArXH, Cu(I)Cl, NMM, Cs2CO3, toluene,
reflux, 12–16 h; (b) TBAFꢁTHF, rt, 2 h.
also prepared using the same copper(I) mediated coupling ap-
proach (Scheme 4).28 These cross-coupling reactions were carried
out between dimethoxy aryl vinyl iodide 2 and the same phenols,
or thiophenol presented in Scheme 3.
sayed for the ability to inhibit the growth of five selected strains of
clinically significant bacteria. The results of these MIC (minimum
inhibitory concentration) assays are presented in Table 2. The
in vitro MIC determinations for each compound were performed
according to the National Committee for Clinical Laboratory Stan-
dards (NCCLS) guidelines.7 For safety reasons, Gram-positive
microorganisms, Bacillus cereus and Mycobacterium smegmatis
were used as surrogates for the more virulent strains of B. anthracis
and M. tuberculosis, respectively.29,30 All of the analogs were also
tested for their ability to inhibit the growth of Escherichia coli as
a representative Gram-negative microorganism.
Analysis of the results reported in Table 2 illustrates a number
of interesting antimicrobial structure–activity features of the stilb-
enoid compounds and their extended, heteroatom-containing
phenoxystyrene and phenothiostyrene analogs. As expected, none
of the compounds exhibited antimicrobial activity against the rep-
resentative Gram-negative species, E. coli. This is in line with the
results of preliminary assays performed using the natural stilbene
1 in which no Gram-negative bacteria were affected by this agent
(see data in Table 1).
From examination of the data in Table 2, it is clear that the pres-
ence of at least one phenolic group is required for activity in this
class of compounds. All of the dimethoxylated compounds, 1a, 5–
6, 17–23, and 29, were devoid of inhibitory activity against the
Gram-positive (and Gram-negative) species investigated. However,
natural product 1 and all of its analogs that contain a meta-hydroxy
group (8–16, 26) exhibited inhibitory activity against Gram-posi-
tive organisms, even when this moiety was located in the phenoxy
ring as opposed to the styryl ring, as seen in compound 26. These
results are not surprising because phenolic compounds are viewed
as one of the major classes of natural antimicrobial agents.31
Perhaps the most exciting finding in this study is that both the
phenoxystyrene and phenothiostyrene analogs (10–16, 26) of the
phenolic stilbenes (1, 8–9) are roughly equivalent in their potency
in the MIC assays performed. Although none of these vinyl ether or
vinyl thioether analogs was significantly better at inhibition of the
growth of Gram-positive microorganisms than the original natural
The apparent versatility of this coupling method for this class of
compounds prompted the modification of the asymmetric phen-
oxystyrene scaffold by placing the hydroxy/methoxy groups on
the phenoxy ring rather than the styryl ring, as represented in
compounds 26 and 29 (Scheme 5). As shown in the scheme, the
O-protected monophenol 25 gave the ‘reversed’ phenolic phenoxy-
styrene 26 after coupling with phenylvinyl iodide 28 and subse-
quent deprotection. Similarly, the dimethoxy phenoxystyrene 29
was obtained after coupling between 28 and 3,5-dimethoxyphenol
27.
All compounds prepared in Schemes 2–5 were purified by flash
column chromatography using silica gel and an appropriate solvent
system. After purification of the phenoxystyrene and phenothiosty-
rene targets shown in Schemes 3–5, the stability of selected agents
was evaluated under acidic (1 M HCl), basic (1 M NaOH), and neutral
aqueous media to assess chemical stability. After stirring under
these conditions for 36 h, it was found that all of the novel phenoxy
and phenothio analogs were stable, and no hydrolysis/degradation
products were observed in the solutions (TLC).
Each of the stilbene, phenoxystyrene, and phenothiostyrene tar-
get compounds synthesized, as illustrated in Schemes 1–5, was as-
R1
MeO
I
MeO
X
R2
R3
a
OMe
OMe
2
17-23
17, R1 = R2 = R3 = H, X = O, 84%
18, R1 = Me, R2 = R3 = H, X = O, 82%
20, R1 = R2 = H, R3 = Me, X = O, 51%
22, R1 = R2 = H, R3 = OMe, X = O, 62%
19, R1 = R3 = H, R2 = Me, X = O, 64%
21, R1 = R3 = H, R2 = OMe, X = O, 73%
23, R1 = R2 = R3 = H, X = S, 78%
Scheme 4. Reagents and conditions: (a) ArXH, Cu(I)Cl, NMM, Cs2CO3, toluene,
reflux, 12–16 h.

5748
M. S. Kabir et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5745–5749
Table 2
Minimum inhibitory concentration (MIC
l
g/mL) values for natural stilbene 1 and the synthetic analogsa
Compound
S. aureus ATCC 29213
MRSA MC-1
B. cereus
M. smegmatis
E. coli
1
1a
5
6
8
16
>512
>512
>512
16
32
32
16
16
16
16
16
16
>512
>512
>512
>512
>512
>512
>512
32
16
>512
>512
>512
32
32
64
32
32
32
64
64
32
>512
>512
>512
>512
>512
>512
>512
32
16
>512
>512
>512
32
32
32
64
32
64
64
64
16
>512
>512
>512
>512
>512
>512
>512
64
64
>512
>512
>512
128
64
128
>128
64
>128
128
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
>512
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
26
29
128
128
>512
>512
>512
>512
>512
>512
>512
128
>512
>512
>512
>512
a
MIC values represent the mean of three experiments. ATCC, American Type Culture Collection; MRSA, methicillin-resistant Staphylococcus aureus.
product 1, many were approximately equipotent in the assays. For
example, the phenolic ether 12 was equipotent to 1 in the inhibi-
Linn, and Shamim Ara for their assistance throughout this work.
This study was supported by the Research Growth Initiative of
the University of Wisconsin-Milwaukee (J.M.C.) and a UW-System
Applied Research Grant (A.M.).
tion of the growth of both S. aureus and M. smegmatis (16
and only 2-fold less potent than 1 in the inhibition of the growth
of methicillin-resistant S. aureus (MRSA) and B. cereus (32 g/
lg/mL)
l
mL). Likewise, phenolic thioether 16 had the same MIC value as
References and notes
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(16
(32
l
l
g/mL), and was only 2-fold less potent than 1 against MRSA
g/mL) and M. smegmatis (128 g/mL). These initial results
l
are highly encouraging in consideration of the viability of using
phenoxystyrene and phenothiostyrene scaffold structural analogs
of bioactive antimicrobial stilbenes to treat disease because they
are stable at low and high pH values. Indeed, these novel scaffolds
may serve as excellent starting points for further chemical optimi-
zation and the development of new drugs that are certainly needed
to combat threatening MRSA, tuberculosis, and anthrax infections.
Furthermore, because trans-stilbenes have been shown to possess
such a diverse array of biological activity,11–26 these findings
should promote additional SAR studies of stilbenoid compounds
for additional therapeutic areas.
In conclusion, the antibacterial activity of a phenolic (E)-stil-
bene 1 isolated from C. peregrina has been evaluated and demon-
strated to be active against a range of Gram-positive bacteria,
including drug resistant S. aureus and enterococci spp., but not
Gram-negative bacteria. Importantly, 1 was active against M. bovis
(BCG) and against B. anthracis, as well as three related Bacillus spe-
cies. When the phenolic stilbene scaffold was modified with other
aryl moieties or extended by one heteroatom to create the novel
phenoxystyrene and phenothiostyrene derivatives, these agents
also demonstrated promising antimicrobial activity, given that at
least one phenolic moiety was present, as in compounds 8–16
and 26. Consequently, further exploration of these novel scaffolds
is warranted from both synthetic and microbiological perspectives.
Additional SAR studies of these novel homologous stilbenoid com-
pounds and more extensive microbiological characterization of the
active agents are currently underway.
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Acknowledgments
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