Synthesis and evaluation of novel sulfenamides as novel anti Methicillin-resistant Staphylococcus aureus agents

Article abstract of DOI:10.1016/j.bmcl.2012.11.103

A total of 29 novel sulfenamide compounds were synthesized, spectroscopically characterized and evaluated in vitro for antimicrobial activity against various infectious pathogens. Compounds 1b and 2c exhibited potent inhibition against clinical Methicillin-resistant Staphylococcus aureus (MRSA) strains with minimum inhibitory concentration (MIC) values of 1.56 μg/mL.

Full text of DOI:10.1016/j.bmcl.2012.11.103

Bioorganic & Medicinal Chemistry Letters 23 (2013) 724–727
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of novel sulfenamides as novel anti
Methicillin-resistant Staphylococcus aureus agents
Jian-Li Shang a, , Hui Guo b,c, , Zai-Shun Li a, Biao Ren b,c, Zheng-Ming Li a, Huan-qin Dai b, Li-Xin Zhang b,
,
⇑
Jian-Guo Wang a,
⇑
a State-Key Laboratory and Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
b CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100190, PR China
c Graduate University of Chinese Academy of Sciences, Beijing 100049, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2012
Revised 7 November 2012
Accepted 22 November 2012
Available online 3 December 2012
A total of 29 novel sulfenamide compounds were synthesized, spectroscopically characterized and eval-
uated in vitro for antimicrobial activity against various infectious pathogens. Compounds 1b and 2c
exhibited potent inhibition against clinical Methicillin-resistant Staphylococcus aureus (MRSA) strains
with minimum inhibitory concentration (MIC) values of 1.56
lg/mL.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Sulfenamide
Antimicrobial activity
Methicillin-resistant Staphylococcus aureus
Pharmaceutical agent
The majority of sulfur–nitrogen bonding compounds refer to
the sulfonyl amino compounds.1 For examples, sulfonylureas are
a class of important herbicides,2,3 while sulfanilamides are com-
mon drugs treating infections.4,5 In some cases, the sulfinyl amides
are also frequently mentioned.6–8 However, compounds containing
an N–S bond (referred as N-thiolated compound or sulfenamide)
have seldom been explored. Previously, the N–S bond is mainly
used in the protection of amino groups for peptide synthesis.9 Very
recently, some sulfenyl amino compounds were reported to
display herbicidal activity or insecticidal activity for pesticide
research.10–13 Turos’s research group has showed that some N-thi-
olated b-lactams possess considerable antibacterial activity.14–21 It
is interesting to further investigate the biological activities of the
N–S bonding compounds.
Infections caused by resistant microbes such as Methicillin-
resistant Staphylococcus aureus (MRSA) have become a major
global health concern,22 which makes it urgent to develop novel
anti-MRSA agents.23–25 Previously, we had identified some sulfena-
mide compounds of different skeletons with antibacterial activity
via a high-throughput screening of a synthetic compound library
(unpublished result). In the present study, we have designed and
synthesized more derivatives of the sulfenamides and investigated
their antimicrobial activity. With the expectation that compounds
contaning an N–S bond may have diverse structural space, the N
moieties of the sulfenamides are from L-tryptophan esters, L-glu-
tamic acid esters or substituted isatins, while the S parts are from
various arenesulfenyl chlorides. To our excitement, some of the
target compounds display remarkable anti-MRSA activity.
The synthesis procedures for groups 1, 2 and 3 of the sulfena-
mides are shown in Scheme 1. The chemical synthesis and charac-
terizations of the compounds are detailed in the Supplementary
data. For groups 1 and 2, the solvent is anhydrous diethyl ether
and the temperature is low using an ice–salt bath for the reaction.
For group 3, the solvent for the reactants is N,N-dimethylformam-
ide and the reaction occurs at room temperature. Except 1i and 1j,
most compounds in the previous two series have low melting
points, while most compounds in the last series have relatively
higher melting points. Generally, the yields of the reaction are
>50%. The chemical structures of all compounds are listed in Table
1.
The preliminary antibacterial activity screening results of the
target compounds are shown in Table 2. All compounds exhibit
no measurable inhibition against the Gram-negative Pseudomonas
aeruginosa (PA, PAO1) even at a high concentration of 100 lg/mL.
⇑
Corresponding authors. Tel./fax: +86 10 62566511 (L.-X. Z.); tel.: +86 22
Interestingly, some of the compounds display considerable inhibi-
tion against the Gram-positive Bacillus subtilis (BS, ATCC6633) and
MRSA (a clinical isolate from Beijing Chaoyang Hospital). Most
23499414; fax: +86 22 23503627 (J.-G. W.).
E-mail addresses: zhanglixin@im.ac.cn (L.-X. Zhang), nkwjg@nankai.edu.cn
(J.-G. Wang).
compounds in groups
1 and 2 have minimum inhibitory
These authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.11.103

J.-L. Shang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 724–727
R1'
725
H
H
H
R1OOC
R1OOC
NH2
+
S
R2'
R1'
N
Et3N
R2'
SCl
ether, -5oC
N
H
N
H
1
R1'
R2'
R1'
S
NH2
COOR1
Et3N
ether, -5oC
HN
+
R2'
SCl
R1OOC
R1OOC
COOR1
2
O
R2
R1'
O
O
R2
Et3N
DMF, r.t.
N
S
R2'
SCl
O
+
R1
N
R2'
H
R1
R1'
3
Scheme 1. Outline of the synthesis of the various sulfenamide compounds.
Table 1
Chemical structures of the sulfenamide compounds
0
0
0
0
Compd
R1
R2
R1
R2
Compd
R1
R2
R1
R2
1a
1b
1c
1d
1e
1f
1g
1h
1i
CH3
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
NO2
NO2
NO2
H
H
H
H
H
H
H
H
CH3
CH3
NO2
NO2
NO2
H
2f
CH(CH3)2
H
H
H
H
H
H
Cl
Cl
Cl
Br
Br
Br
Br
—
H
H
H
H
H
H
H
H
H
H
H
Br
Br
NO2
NO2
H
H
COOCH3
COOCH2CH3
NO2
NO2
H
H
CH3
H
H
NO2
H
H
H
H
CH2CH3
CH(CH3)2
CH3
CH2CH3
CH2CH3
CH(CH3)2
CH3
CH3
CH2CH3
CH3
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
NO2
NO2
NO2
NO2
NO2
H
COOCH3
COOCH2CH3
NO2
COOCH2CH3
NO2
1j
2a
2b
2c
2d
2e
3j
3k
3l
CH2CH3
CH3
CH3
H
H
H
H
NO2
NO2
NO2
NO2
NO2
3m
COOCH2CH3
CH2CH3
concentrations (MICs) <50
pounds in group 3 do not have a measureable MIC value even at
100 g/mL concentration. It is noteworthy that both compounds
1b and 2c exhibit remarkable MICs of 1.56 g/mL against MRSA,
comparable to the reference drug vancomycin (MIC = 1.0 g/mL).
The MICs of compounds 1a and 1c against MRSA are 3.13 g/mL,
and the MIC of compound 3g is 6.25 g/mL. The remaining
compounds exhibit very weak activity against MRSA. The MIC of
compound 2c against BS is 3.13 g/mL, and compound 1b has an
MIC 6.25 g/mL. For compounds 1a and 1c, their MIC data against
BS are both 12.5 g/mL. There is a general correlation between the
lg/mL against BS, while most com-
Table 2
Antimicrobial activity of the sulfenamide compounds
l
Compd
BSa
MRSAa
PAa
Compd
BSa
MRSAa
PAa
l
l
l
1a
1b
1c
1d
1e
1f
1g
1h
1i
12.5
6.25
12.5
25
25
25
25
25
25
25
25
25
3.13
50
50
3.13
1.56
3.13
50
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
2f
25
>100
25
>100
25
50
>100
50
12.5
>100
6.25
12.5
>100
12.5
>100
25
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
3a
3b
3c
3d
3e
3f
3g
3h
3i
l
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
0.5
25
l
>100
>100
>100
>100
>100
12.5
25
1.56
>100
>100
l
l
anti-MRSA and anti-BS activity.
1j
Since the sulfenamides display desirable anti-MRSA activity, we
reevaluated the biological activity of compounds 1a, 1b, 1c, 2c and
3g with ATCC standard strain and various clinical isolated Methicil-
lin-susceptible Staphylococcus aureus (MSSA) and MRSA strains. On
the other hand, it is interesting to judge whether these compounds
belong to bactereostatic or bactericidal agents, the minimum bac-
tericidal concentrations (MBCs) were also determined in this
study. Table 3 lists the MICs and the MBCs of the selected com-
pounds. For SA ATCC6538 and MSSA 309-1, the MICs are in the
2a
2b
2c
2d
2e
3j
3k
3l
3m
25
1.0
Vanb
The MIC data are expressed in
l
g/mL.
a
BS = Bacillus subtilis (ATCC6633), PA = Pseudomonas aeruginosa (PAO1), MRSA is
a clinical isolate from Chaoyong hospital, Beijing.
b
Van = vancomycin.

726
J.-L. Shang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 724–727
Table 3
MIC data of selected sulfenamides and related compounds against vaious clinical isolated MRSA and MSSA strains
Compd.
SA ATCC6538
MSSA 309-1a
MRSA Chaoyanga
MRSA 6-42a
MRSA 309-4a
MRSA 309-7a
MRSA 309-8a
MICb
MBCb
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
MIC
MBC
1a
1b
1c
2c
6.25
6.25
6.25
6.25
12.5
1
>100
>100
3.13
>100
>100
>100
>100
>100
2
>100
>100
>100
25
12.5
25
6.25
12.5
1
>100
>100
1.56
>100
>100
>100
>100
>100
1
>100
>100
>100
3.13
1.56
3.13
1.56
6.25
1
>100
>100
1.56
>100
>100
>100
>100
>100
1
>100
>100
>100
3.13
1.56
3.13
1.56
6.25
1
>100
>100
1.56
>100
>100
>100
>100
>100
1
>100
>100
>100
25
12.5
25
6.25
12.5
0.5
>100
>100
1.56
>100
>100
>100
>100
>100
1
>100
>100
>100
12.5
6.25
6.25
3.13
6.25
1
>100
>100
1.56
>100
>100
>100
>100
>100
1
>100
>100
>100
25
>100
>100
>100
>100
>100
1
>100
>100
>100
6.25
6.25
3.13
12.5
0.5
>100
>100
1.56
3g
Vanc
L-Trpc
L-Gluc
4-Nitrobenzenethiol
a
MSSA 309-1 is a clinical isolated strain of MSSA from the 309th hospital of Chinese People’s Liberation Army in Beijing, MRSA Chaoyang is a MRSA clinical isolated strain
from Chaoyang hospital in Beijing (the same with the MRSA isolate in Table 2), MRSA 6-42 is a MRSA clinical isolated strain from the 306th hospital of Chinese People’s
Liberation Army in Beijing, MRSA 309-4, MRSA 309-7 and MRSA 309-8 are three MRSA clinical isolated strains from the 309th hospital of Chinese People’s Liberation Army in
Beijing.
b
MIC and MBC values are expressed in
l
g/mL.
c
Van = vancomycin, L-Trp =
L-tryptophan ethyl ester, L-Glu = L-glutamic acid dimethyl ester.
range of 6.25–25
strains, the MIC data range from 1.56
be noted that for compounds 1b and 2c, their MIC data against
MRSA chaoyang strain and MRSA 6-42 strain are all 1.56 g/mL.
When tested against the MRSA strains of 309-4, 309-7 and 309-
8, 2c shows better MIC data than 1b, however, the best MIC data
l
g/mL, while for the different MRSA clinical
1b and 1c, their whole molecular structures are very similar, thus
their anti-MRSA activities are at similar level. It is quite possible
that the disassociation of the N–S bond is highly influenced by
the different N moiety of the compounds. For the S part of the mol-
ecule, from the preliminary result, it seems that a single –NO2
l
g/mL to 25 g/mL. It should
l
l
0
0
group in either the R1 or R2 position leads to desirable activity.
0
0
of 2c increase to 3.13
all compounds are >100
are bactereostatic compounds. It is clear that vancomycin is bacte-
l
g/mL. It can be seen that the MBC data of
However, when both the R1 and R2 positions are –NO2 groups,
the sulfonamides do not display good inhibition of MRSA. The –
lg/mL, suggesting that these sulfenamides
0
0
CH3 in R2 position or –COOR in R1 position of the compound offers
poor activity. It is expected that some groups such as –CF3 will lead
to promising activity. More derivatives of the sulfonamides will be
synthesized in the future and detailed study on their biological
activity and cytotoxic data will be carried out for the discovery of
new anti-MRSA agents.
ricidal, and the MICs of which are 0.5–1
ratios for vancomycin are 1:2.
lg/mL and the MBC/MIC
Actually, this is not the first report indicating that compounds
containing an N–S bond possess inspiring antimicrobial activity,
Turos et al. have systematically investigated the antibacterial
activity of the N–S linking compounds.14–21 However, they only
focus on the N-thiolated b-lactams and N-thiolated 2-oxazolidi-
nones, and the most potent compound they have found exhibits
similar ani-MRSA MIC value with vancomycin.16 Turos et al. found
that the anti-MRSA activity of N-thiolated b-lactams has relation-
ship with fatty acid synthesis (FAS),17 and their latest research
indicated that these agents are unique since their effects do not
unimpeded by exogenous FAs.16
Acknowledgments
This work was financially supported by Key Natural Science
Foundation from Tianjin S&T (No. 12JCZDJC25700), National Basic
Research Program of China (No. 2013CB734004), Natural Science
Foundation of China (No. 31125002 and No. 81261120389), the
CAS Pillar Program (XDA04074000) and the Ministry of Science
and Technology of China (2011ZX11102-011-11). Li-Xin Zhang is
an Awardee for National Distinguished Young Scholar Program in
China.
As the N-thiolated b-lactams were proposed as prodrugs,17 it is
necessary to investigate whether the N part or S part plays a major
role in MRSA inhibition, which has not been experimentally stud-
ied by any previous literature. Thus we further evaluated the bio-
logical activity of L-tryptophan ethyl ester (L-Trp), L-glutamic acid
Supplementary data
dimethyl ester (L-Glu) and 4-nitrobenzenethiol against the MSSA
and MRSA strains in our laboratory in that they have close struc-
tural relationship with compounds 1b and 2c in this study. The
bioassay data are also shown in Table 3, from which L-Trp and L-
Glu do not show anti-MRSA or anti-MSSA activity even at
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
11.103.
100
inhibitory activity. For the standard strain of SA (ATCC6538), the
MIC data of 4-nitrobenzenethiol is 3.13 g/mL, and for the clinical
isolated MSSA and MRSA strains, the corresponding MIC data are
all 1.56 g/mL. This result strongly indicates that, the anti-MRSA
lg/mL concentration, while 4-nitrobenzenethiol shows strong
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