The synthesis and SAR study of phenylalanine-derived (Z)-5-arylmethylidene rhodanines as anti-methicillin-resistant Staphylococcus aureus (MRSA) compounds

Article abstract of DOI:10.1016/j.bmcl.2013.08.059

A focused library of rhodanine compounds containing novel substituents at the C5-position was synthesized and tested in vitro against a panel of clinically relevant MRSA strains. The present SAR study was based on our lead compound 1 (MIC = 1.95 μg/mL), with a focus on identifying optimal C5-arylidene substituents. In order to obtain this objective, we condensed several unique aromatic aldehydes with phenylalanine-derived rhodanine intermediates to obtain C5-substituted target rhodanine compounds for evaluation as anti-MRSA compounds. These efforts produced three compounds with significant efficacy: 23, 32 and 44, with MIC values ranging from 0.98 to 1.95 μg/mL against all tested MRSA strains as compared to the reference antibiotics penicillin G (MIC = 15.60-250.0 μg/mL) and ciprofloxacin (MIC = 7.80-62.50 μg/mL) and comparable to that of vancomycin (MIC = 0.48 μg/mL). In addition, compounds 24, 28, 37, 41, 46 and 48 (MIC = 1.95-3.90 μg/mL) were efficacious against all MRSA strains. The majority of the synthesized compounds had bactericidal activity at concentrations only two to fourfold higher than their MIC. Overall, the results suggest that compounds 23, 32 and 44 may be of potential use in the treatment of MRSA infections.

Full text of DOI:10.1016/j.bmcl.2013.08.059

Bioorganic & Medicinal Chemistry Letters xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The synthesis and SAR study of phenylalanine-derived
(Z)-5-arylmethylidene rhodanines as anti-methicillin-resistant
Staphylococcus aureus (MRSA) compounds
⇑
⇑
Bhargav A. Patel, Charles R. Ashby Jr., Diane Hardej , Tanaji T. Talele
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A focused library of rhodanine compounds containing novel substituents at the C5-position was synthe-
sized and tested in vitro against a panel of clinically relevant MRSA strains. The present SAR study was
based on our lead compound 1 (MIC = 1.95 lg/mL), with a focus on identifying optimal C5-arylidene sub-
stituents. In order to obtain this objective, we condensed several unique aromatic aldehydes with phen-
ylalanine-derived rhodanine intermediates to obtain C5-substituted target rhodanine compounds for
evaluation as anti-MRSA compounds. These efforts produced three compounds with significant efficacy:
Received 22 July 2013
Revised 9 August 2013
Accepted 13 August 2013
Available online xxxx
Keywords:
Rhodanine
Ullmann condensation
Knoevenagel condensation
MRSA
23, 32 and 44, with MIC values ranging from 0.98 to 1.95
pared to the reference antibiotics penicillin G (MIC = 15.60–250.0
62.50 g/mL) and comparable to that of vancomycin (MIC = 0.48
37, 41, 46 and 48 (MIC = 1.95–3.90 g/mL) were efficacious against all MRSA strains. The majority of the
l
g/mL against all tested MRSA strains as com-
g/mL) and ciprofloxacin (MIC = 7.80–
g/mL). In addition, compounds 24, 28,
l
l
l
l
synthesized compounds had bactericidal activity at concentrations only two to fourfold higher than their
MIC. Overall, the results suggest that compounds 23, 32 and 44 may be of potential use in the treatment
of MRSA infections.
Serum
Stereochemistry
Ó 2013 Elsevier Ltd. All rights reserved.
In the last two decades, methicillin-resistant Staphylococcus
aureus (MRSA) has become one of the major health threats in the
United States as well as globally. It has been estimated that >50%
of all staphylococcus infections are due to MRSA. The death toll
from MRSA infections in 2005 exceeded those from HIV/AIDS in
the United States. MRSA infection is typically classified into two
major types, hospital (HA)- and community-acquired (CA) MRSA,
which differ in their epidemiology, DNA sequence, populations in-
fected and sites of infection.1–3 HA-MRSA occurs in patients with
specific risk factors,4–6 whereas CA-MRSA can occur in healthy
individuals that do not have predisposing factors.7–9 Typically,
HA-MRSA infections occur in the urine, lungs, bloodstream and
surgical sites, whereas CA-MRSA primarily produces skin and skin
structure infections, as well as invasive infections, although to a
lesser extent.3,10 Until the mid-1990s, MRSA infections primarily
occurred in individuals in health care facilities (HA-MRSA).11,12
Subsequently, the CA-MRSA strains have become widespread in
the community11,13 and the USA300 strain has been found on all
continents except Antarctica.14 Recent data indicates that CA-MRSA
strains have become successfully established as nosocomially.15–17
The CA-MRSA strains, like HA-MRSA, are broadly resistant to
b-lactam and macrolide/azalide antibiotics; however, CA-MRSA
infections, particularly those in skin and skin structures, can be
treated with minocycline, doxycycline, sulfamethoxazole +
trimethoprim and clindamycin.2,18,19 Nonetheless, resistance rates
are increasing and there are limited treatment options for invasive
MRSA infections. Therefore, the development of new and potent
anti-MRSA drugs is imperative.
Previously, we reported that the
danine lead compound 1 was active against various MRSA strains,
with MIC values ranging from 1.95 to 3.90
g/mL. Recently we20
L-phenylalanine-derived rho-
l
and others have reported that the rhodanine class of compounds
possesses antibacterial action.21–24 Here, we report the subsequent
optimization of lead compound 1 with respect to identifying opti-
mal C5-arylidene substituents and determining the influence of
stereo-configuration on various MRSA strains. A variety of strains
of Staphylococcus aureus were used for this study and were ob-
tained from the American Type Culture Collection (ATCC). Strains
were selected to represent the scope of Staphylococcus variants that
might be present in a number of clinical, community and quality
control situations. The ATCC strain 34404 is commonly used as a
quality control organism for susceptibility testing. Strains
700698, 700787 and BAA39 represent nosocomial or hospital-ac-
quired strains from distant global locations and body sites (i.e.,
pneumonia patient from Japan, blood culture from New York and
⇑
Corresponding authors. Tel.: +1 (718) 990 6370; fax: +1 (718) 990 1877 (D.H.);
tel.: +1 (718) 990 5405; fax: +1 (718) 990 1877 (T.T.T).
E-mail addresses: hardejd@stjohns.edu (D. Hardej), talelet@stjohns.edu
(T.T. Talele).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.08.059
Please cite this article in press as: Patel, B. A.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.08.059

2
B. A. Patel et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
nasal culture from Hungary, respectively). Strain BAA1680 is a
community-acquired MRSA (CA-MRSA) strain from the skin of a
patient from Michigan, U.S.A. In addition, a sasX-positive MRSA
strain was tested (ST239 HS770). SasX is a mobile genetic element
that plays a key role in MRSA colonization and pathogenesis.25 The
strains chosen, while all resistant to methicillin, have varying resis-
tance to other antimicrobial agents as well. ATCC 700698 is suscep-
tible to vancomycin, strain ATCC 700787 has reduced susceptibility
to vancomycin and ATCC BAA-39 is a strain resistant to numerous
antibiotics (tetracycline, erythromycin, clindamycin, tobramycin,
gentamicin, imipenem, various first- and second-generation ceph-
alosporins, penicillin, oxacillin and amoxicillin). The variety of
strains used present a cross-section of MRSA that might be present
in given populations with varying susceptibility to currently avail-
able antibacterial drugs and underscores the urgent need for addi-
tional effective drugs in the event of potential multi-resistance.
To explore the SAR around the phenoxy group of compound 1,
we had to synthesize unique benzaldehydes as these compounds
were either commercially expensive or unavailable. The synthesis
of a few of the intermediate benzaldehydes has been recently re-
ported by us.26 The other intermediates were prepared according
to Scheme 1, adhering to the procedures described in the above
mentioned report. The alkyloxy benzaldehydes 2 and 3 were made
by alkylating 3-hydroxybenzaldehyde with propargyl chloride and
cyclopropylmethyl bromide, respectively, in the presence of potas-
sium carbonate in acetonitrile. The substituted 2-phenoxybenzal-
dehyde 4 was prepared using the Ullmann condensation, where
2-bromobenzaldehyde was coupled with 3,4-dichlorophenol in
the presence of cupric oxide and potassium carbonate. To prepare
the isosteric analogs, the requisite benzaldehydes 5–10 were syn-
thesized by palladium catalyzed cross-coupling of the appropriate
formylphenyl boronic acid. Intermediates 5 and 7 were prepared
starting from 2-formylphenyl boronic acid and benzaldehydes 6,
8, 9 and 10 were made beginning with 3-formylphenyl boronic
acid. The 2-hydroxybenzaldehyde and the 3-hydroxybenzaldehyde
were treated with corresponding arylalkyl bromides or chlorides in
the presence of potassium carbonate to prepare 2-substituted
intermediates 11, 14 and 3-substituted intermediate 13, respec-
tively. Compound 12 was synthesized by alkylating 2-hydroxy-
benzaldehyde with phenylethyl bromide using cesium carbonate
as base. As shown in Scheme 2, the target compounds were synthe-
sized by Knoevenagel condensation of rhodanine intermediates
Scheme 2. Reagents and conditions: (a) ArCHO, ammonium acetate, toluene, reflux,
4–6 h.
L-15 and D-42 with the prepared benzaldehydes. The synthesis
of phenylalanine-derived L-15 and D-42, as well as target
compounds 18–25, 28–29, 32, 37, 41, 43–47, was described in
our recent report.26 The enantiomeric excess values for selected
L
- and D-isomers were also stated in that report. As previously
demonstrated,27,28 the Knoevenagel condensation reaction with
aromatic aldehydes provided only the Z-isomer, as determined
by the chemical shift of the methine proton ranging from
7.7–8.5 ppm as a singlet (chemical shift for corresponding methine
proton of E-isomer is calculated to be 6.8 ppm). The target com-
pounds 16–41 (
L
-isomers) and 43–48 ( -isomers) were subjected
D
to evaluation against various strains of MRSA.
All synthesized rhodanine analogs were tested for their in vitro
activity against a panel of MRSA strains (MRSA ATCC 34404, MRSA
ATCC 700787, MRSA ATCC 700698, MRSA ATCC BAA-39, MRSA CA
ATCC BAA-1680 and MRSA ST239 HS770), together with reference
antibiotics ciprofloxacin, vancomycin and penicillin G in a microdi-
lution minimum inhibition concentration (MIC) assay. The assay
was performed in a sterile 96 well plates in triplicate. Briefly, the
assay involves observing the turbidity in a media containing the
bacterial strain cell suspension and the compound being tested.
The cells in the control wells were incubated only with the vehicle
for the test compounds. The MIC value was recorded based on the
visual absence of turbidity when compared to control wells. The
MBC values (data not shown) indicating 0.1% survival in subculture
on suitable agar plates were also determined to evaluate bacterici-
dal activity. The results are presented in Table 1.
In our earlier study, we observed that the phenylalanine at the
N3 position and the 3-phenoxy benzylidene group at C5 position of
the rhodanine ring (compound 1, MIC = 1.95 lg/mL) significantly
Scheme 1. Reagents and conditions: (a) K2CO3, CH3CN, rt, 3–6 h; (b) 3,4-dichlorophenol, CuO, K2CO3, pyridine, quinoline, 170 °C, overnight; (c) RBr, Pd(PPh3)4, K2CO3, THF,
80 °C, overnight; (d) (a) R’Br or R’Cl, K2CO3 or Cs2CO3, CH3CN, rt, 14–18 h.
Please cite this article in press as: Patel, B. A.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.08.059

B. A. Patel et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
3
Table 1
Anti-MRSA activity of compounds 1, 16–41 and 43–48 (MIC l
g/mL)b
Ph
O
HOOC
N
Ar
S
S
Compda
Ar
MIC
l
g/mLb
MRSA
MRSA
MRSA
ATCC
MRSA
ATCC
MRSA
MRSA
ST239
HS770
ATCC
ATCC
CA ATCC
BAA-1680
34404
700787
700698
BAA-39
1
3-Phenoxyphenyl
1.95
3.90
3.90
3.90
1.95
NDc
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
43
44
45
46
47
48
Cipro
Vanco
Pen-G
3-(3-Prop-2-ynyloxy)phenyl
3-(3-Cyclopropylmethoxy)phenyl
3-(3-Chloro)phenoxyphenyl
3-(3-Fluoro)phenoxyphenyl
3-(4-Methoxy)phenoxyphenyl
3-(4-Chloro)phenoxyphenyl
3-(4-Fluoro)phenoxyphenyl
3-(3,4-Dichloro)phenoxyphenyl
2-Phenoxyphenyl
4-Phenoxyphenyl
2-(3,4-Dichloro)phenoxyphenyl
2-Benzylphenyl
3-Benzylphenyl
3-Benzoylphenyl
3-(3,4-Dichlorobenzyl)phenyl
2-Biphenyl
3-Biphenyl
3-(3,4-Dichlorophenyl)phenyl
3-(Thiazol-2-yl)phenyl
3-(Pyrimidin-5-yl)phenyl
2-Benzyloxyphenyl
15.60
15.60
15.60
15.60
7.80
7.80
7.80
0.98
1.95
1.95
3.90
15.60
1.95
3.90
31.25
7.80
0.98
31.25
15.60
15.60
31.25
7.80
15.60
7.80
3.90
1.95
7.80
3.90
7.80
3.90
7.80
62.50
15.60
1.95
62.50
15.60
15.60
15.60
7.80
7.80
7.80
1.95
1.95
1.95
7.80
7.80
3.90
31.25
15.60
15.60
15.60
7.80
7.80
7.80
1.95
3.90
3.90
3.90
7.80
1.95
3.90
15.60
7.80
0.98
3.90
7.80
125.0
15.60
1.95
15.60
31.25
15.60
1.95
3.90
1.95
1.95
1.95
1.95
1.95
7.80
31.25
15.60
15.60
31.25
15.60
15.60
7.80
1.95
1.95
1.95
3.90
3.90
1.95
3.90
31.25
7.80
1.95
7.80
31.25
125.0
7.80
1.95
7.80
15.60
31.25
1.95
1.95
1.95
1.95
1.95
3.90
1.95
7.80
60.48
125.0
62.50
15.60
ND
ND
ND
ND
ND
ND
ND
7.80
1.95
15.60
ND
7.80
ND
31.25
15.60
1.95
15.60
7.80
1.95
1.95
3.90
125.0
7.80
1.95
15.60
15.60
15.60
1.95
3.90
1.95
1.95
1.95
3.90
1.95
62.50
60.48
250.0
3.90
3.90
7.80
15.60
125.0
7.80
31.25
125.0
15.60
3.90
15.60
31.25
31.25
1.95
3.90
3.90
3.90
1.95
31.25
125.0
7.80
3.90
7.80
31.25
31.25
1.95
1.95
3.90
3.90
1.95
1.95
3.90
15.60
60.48
15.60
3-Benzyloxyphenyl
1.95
2-Phenethyloxyphenyl
3-Phenethyloxyphenyl
2-Cinnamyloxyphenyl
3-Cinnamyloxyphenyl
3-Phenoxyphenyl
3-(3-chloro)phenoxyphenyl
3-(4-Chloro)phenoxyphenyl
3-(4-Fluoro)phenoxyphenyl
3-(3,4-Dichloro)phenoxyphenyl
3-Benzylphenyl
15.60
31.25
15.60
1.95
3.90
0.98
1.95
1.95
1.95
1.95
15.60
3.90
62.50
1.95
60.48
60.48
31.25
60.48
62.50
62.50
a
Compounds 1, 18–25, 28–29, 32, 37, 41, and 43–47 were synthesized previously26 whereas compounds 16–17, 26–27, 30–31, 33–36, 38–40, and 48 were synthesized in
this Letter.
b
Results of average values obtained from two independent experiments in duplicate; Cipro = ciprofloxacin, Vanco = vancomycin, Pen-G = penicillin G.
ND = not determined.
c
enhanced anti-MRSA activity across all strains. In this letter, 32
rhodanine analogues based on lead compound 1 were assessed in
the MRSA inhibition assay with the aim to optimize the phenoxy
group as well as to determine the effect of configurational isomer-
ism in the phenylalanine segment. Foremost, we wanted to vali-
date that an aromatic ring substitution is required in the
benzylidene moiety for anti-bacterial activity. Two compounds
with aliphatic substitutions on the benzylidene moiety, the alkyne
with methoxy (compound 20, MIC = 7.80–15.60
(compound 21, MIC = 7.80–15.60 g/mL) and fluoro (compound
22, MIC = 7.80 g/mL) groups also decreased the antibacterial
action. Interestingly, replacement of the phenoxy ring with 3,4-
dichlorophenoxy group (compound 23) improved the overall effi-
lg/mL), chloro
l
l
cacy, with the lowest MIC value of 0.98 lg/mL against the MRSA
strain ATCC 34404. Based on this finding, we decided to optimize
the position of the phenoxy ring on the benzylidene fragment.
The transfer of the phenoxy ring to the 2nd position (compound
24) of the benzylidene function maintained the activity against
derivative
MIC = 15.60–62.50
pound 17, MIC = 15.60
3-(3-prop-2-ynyloxy)phenyl
g/mL) and the cyclopropyl ring analog (com-
g/mL) were tested for anti-MRSA activity.
(compound
16,
l
l
MRSA ATCC 34404 (MIC = 1.95
(MIC = 3.90 g/mL) and MRSA CA ATCC BAA-1680 (MIC = 1.95
mL), with improved inhibition against MRSA ATCC 700787
(MIC = 1.95 g/mL) and MRSA ATCC 700698 (MIC = 1.95 g/mL)
as compared to antimicrobial profile of compound 1. In contrast,
the 4-phenoxy analog (compound 25, MIC = 1.95–7.80 g/mL)
was not more efficacious when compared to the 3-phenoxy
l
g/mL), MRSA ATCC BAA-39
The data clearly indicates the importance of the terminal aromatic
ring on the benzylidene fragment. Continuing with the phenoxy
ring as in compound 1, attempts to further enhance the activity
l
lg/
l
l
with 3-chloro (compound 18, MIC = 15.60
(compound 19, MIC = 15.60–31.25 g/mL) substitutions on the
phenoxy group were unsuccessful. Similarly, 4-position substitutions
lg/mL) and 3-fluoro
l
l
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4
B. A. Patel et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
counterpart (1). Also, the 4-phenoxy analog had a MIC of 7.80
l
g/mL
bovine serum (FBS). These results indicated only a twofold increase
in the MIC values with 10% FBS as compared to MIC values ob-
tained in the absence of 10% FBS. These findings suggest that these
compounds do not significantly bind to serum proteins.
Based on the present data, it is evident that (i) a hydrophobic
aromatic group is essential at the third-position of the benzylidene
ring, (ii) the distance between the two aromatic rings is critical,
and (iii) stereochemistry plays a role in the potent anti-MRSA
activity of the tested rhodanine derivatives.
against the newly available MRSA strain ST239 HS770. As a result
of a slight increase in the overall inhibition profile for 2-phenoxy
compound, we incorporated a 3,4-dichloro substitution on the
phenoxy ring (compound 26) in an attempt to obtain enhanced
activity against the various MRSA strains. However, this replace-
ment (MIC = 1.95–7.80 lg/mL) proved to be less active.
Thereafter, we sought to understand the importance of the lin-
ker atom in addition to the length of the linker between the two
aromatic rings. The ether linkage was replaced with –CH2– in
2-benzylbenzylidene and 3-benzylbenzylidene analogs and
–C(@O)– in the 3-benzoylbenzylidene analog in order to identify
the role of the oxygen atom as a linker. The 2-benzylbenzylidene
In our future studies, we will optimize the antibacterial activity
of compounds 37 and 41 with respect to the substitution pattern
on the terminal phenyl ring as well as evaluate the influence of
D-stereochemistry. Furthermore, compound 29, a benzophenone
(compound 27, MIC = 3.90–15.60
ene (compound 29, MIC = 3.90–7.80
found to be ineffective, whereas the 3-benzylbenzylidene analog
(compound 28, MIC = 1.95–3.90 g/mL) had similar antimicrobial
l
g/mL) and 3-benzoylbenzylid-
analog, will be explored for optimal substituents at the terminal
phenyl ring. Compound 29 and its derivatives could serve as photo-
phores to understand the antibacterial mechanism of action. These
data will be reported in a future publication.
l
g/mL) derivatives were
l
efficacy as that of compound 1. Subsequently, the 3-benzyl ring
was substituted with 3,4-dichloro (compound 30, MIC = 15.60–
62.50 lg/mL), but this lead to a decrease in efficacy. Continuing
the aforementioned strategy, we removed the linker and attached
the terminal phenyl ring directly on the benzylidene moiety. This
resulted in 2-phenylbenzylidene analog (compound 31,
Compounds 23, 24, 28, 32, 37, 41, 44, 46, 47 and 48 were found
to be active against globally widespread strains used in this study
including the sasX-positive MRSA strain ST239 HS770. Several aryl-
alkylidene rhodanines have been reported to interact with PBPs29
and all MRSA strains harbor the SCCmec gene that codes for the
PBP2a protein.30–32 Hence, it is possible that these compounds
may produce their anti-MRSA action by inhibiting PBP2a, although
this remains to be proven experimentally.
In summary, lead optimization was attempted using our previ-
ously reported phenylalanine derived rhodanine analogue 1. The
SAR data clearly emphasizes the importance of a hydrophobic aro-
matic substituent on the benzylidene moiety. However, the effect
of the configurational isomerism requires further study. Several
compounds were significantly more efficacious than the reference
antibiotics penicillin G and ciprofloxacin against a panel of MRSA
strains. Among these, three compounds 23, 32, and 44 were highly
efficacious against MRSA ATCC 34404 and MRSA ATCC BAA-39.
Currently, the mechanism of action of the compounds tested in this
study is unknown. Typically, antibiotics can produce a bactericidal
effect by inhibiting cell wall synthesis or DNA synthesis. Thus, it is
possible that the bactericidal compounds in this study could pro-
duce their anti-MRSA activity via these targets, although this re-
mains to be proven.
MIC = 7.80–15.60
However, the 3-phenylbenzylidene (compound 32, MIC = 0.98–
1.95 g/mL) analog was more efficacious in terms of overall anti-
MRSA activity, with an MIC of 0.98 g/mL against MRSA ATCC
34404 and MRSA ATCC BAA39. Based on this, we synthesized the
3,4-dichlorophenyl analog (compound 33, MIC = 1.95–7.80 g/
lg/mL), which was not favorable for activity.
l
l
l
mL), which displayed decreased efficacy. We hypothesized that
the space occupied by the phenyl ring in the 3-phenylbenzylidene
compound was producing ‘steric crowding’ for further substitu-
tion. Therefore, we replaced the phenyl ring with aromatic hetero-
cycles viz. thiazole (compound 34, MIC = 3.90–31.25
lg/mL) and
pyrimidine (compound 35, MIC = 125.0 g/mL) to grasp the nature
l
of the enunciated vicinity. In general, these modifications produced
a significant decrease in the efficacy against the MRSA strains.
These results suggest that aromaticity, coupled with hydrophobic
nature of the terminal phenyl ring, is required for activity against
MRSA. Furthermore, to ascertain the extent of the binding pocket,
we assayed six compounds (36–41) with two, three or four atom
length linkers between the two aromatic rings of compound 1. Of
these compounds, only 3-benzyloxybenzylidene (compound 37,
Acknowledgments
MIC = 1.95–3.90
pound 41, MIC = 1.95
indicating the tolerance of two and four-atom linkers between
the two aryl rings. To further identify the importance of chirality,
l
g/mL) and 3-cinnamyloxybenzylidene (com-
This research was supported by the Department of Pharmaceu-
tical Sciences of St. John’s University and St. John’s University Seed
Grant No. 579-1110 to T.T.T. We also sincerely thank Dr. Michael
Otto, Laboratory of Human Bacterial Pathogenesis, NIAID, NIH, for
providing the SasX strain of S. aureus.
l
g/mL) retained the original activity, thus
we tested the
43, MIC = 1.95–3.90
idene (compound 44, MIC = 0.98–3.90
rophenoxy)benzylidene (compound 45, MIC = 1.95–3.90
ee = 78%), 3-(4-fluorophenoxy)benzylidene (compound 46,
MIC = 1.95 g/mL, ee = 85%), 3-(3,4-dichlorophenoxy)benzylidene
(compound 47, MIC = 1.95 –15.60 g/mL, ee = 93%), 3-benzylben-
zylidene (compound 48, MIC = 1.95–3.90 g/mL) of compounds 1
(MIC = 1.95–3.90 g/mL, ee = 85%), 18 (MIC = 15.60 g/mL,
ee = 93%), 21 (MIC = 7.80–15.60 g/mL, ee = 86%), 22 (MIC =
7.80 g/mL, ee = 84%), 23 (MIC = 0.98–3.90 g/mL, ee = 77%) and
28 (MIC = 1.95–3.90 g/mL), respectively. It seems that a configu-
D
-counterparts 3-phenoxybenzylidene (compound
g/mL, ee = 84%), 3-(3-chlorophenoxy)benzyl-
g/mL, ee = 75%), 3-(4-chlo-
g/mL,
l
l
Supplementary data
l
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.08.
059.
l
l
l
l
l
l
References and notes
l
l
1. Gordon, R. J.; Lowy, F. D. Clin. Infect. Dis. 2008, 46, S350.
2. Patel, M. Drugs 2009, 69, 693.
3. Chavez, T. T.; Decker, C. F. Disease-a-Month; MRSA: Methicillin-Resistant
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