Synthesis, biological evaluation of new oxazolidino-sulfonamides as potential antimicrobial agents

Article abstract of DOI:10.1016/j.ejmech.2013.01.034

A number of linezolid-like oxazolidino-sulfonamides (7a-y and 8a-b) were designed and synthesized with a view to develop antimicrobial agents with improved properties. Most of the synthesized compounds showed good to moderate activity against a panel of standard Gram-positive and Gram-negative bacteria and fungal strains. The compounds 7i and 7v exhibited significant activity, with a MIC value of 2.0-6.0 μg/mL against a panel of Gram-positive and Gram-negative bacteria. These compounds also showed activity against Candida albicans, with a MIC value of 4.0 μg/mL. A correlation of the antimicrobial activity with calculated lipophilicity values (C log P) is also presented.

Full text of DOI:10.1016/j.ejmech.2013.01.034

European Journal of Medicinal Chemistry 62 (2013) 661e669
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, biological evaluation of new oxazolidino-sulfonamides
as potential antimicrobial agents
*
Ahmed Kamal , P. Swapna, Rajesh V.C.R.N.C. Shetti, Anver Basha Shaik,
M.P. Narasimha Rao, Soma Gupta
Division of Organic Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A number of linezolid-like oxazolidino-sulfonamides (7aey and 8aeb) were designed and synthesized
with a view to develop antimicrobial agents with improved properties. Most of the synthesized com-
pounds showed good to moderate activity against a panel of standard Gram-positive and Gram-negative
bacteria and fungal strains. The compounds 7i and 7v exhibited significant activity, with a MIC value of
Received 28 October 2012
Received in revised form
15 January 2013
Accepted 27 January 2013
Available online 5 February 2013
2.0e6.0
showed activity against Candida albicans, with a MIC value of 4.0
microbial activity with calculated lipophilicity values (C log P) is also presented.
Ó 2013 Elsevier Masson SAS. All rights reserved.
m
g/mL against a panel of Gram-positive and Gram-negative bacteria. These compounds also
m
g/mL. A correlation of the anti-
Keywords:
Antimicrobial agents
Linezolid
Oxazolidinones
Sulfonamides
1. Introduction
have been published by different groups on oxazolidinone anti-
bacterial research [16,21e27].
The emergence of antibiotic resistance has posed a serious
threat to the well-being of mankind [1,2]. Infections caused by
drug resistant Gram-positive bacteria cause serious health prob-
lems and can be fatal at times. Methicillin-resistant Staphylococcus
aureus (MRSA), methicillin-resistant coagulase negative Staphylo-
cocci (MR-CNS), penicillin-resistant Streptococcus pneumoniae
(PRSP) and vancomycin-resistant Enterococcus (VRE) are a few
organisms that have developed multidrug resistance [3e5]. Line-
zolid [6,7] 1 is the first and only oxazolidinone drug which was
approved by FDA in the year 2000 for the treatment of multidrug
resistant Gram-positive bacterial infections. Within a short span of
its launch, linezolid-resistant strains of S. aureus and Enterococcus
faecium [9,10] began to emerge. There is an urgent necessity for
newer and improved antibiotics with broad antimicrobial spec-
trum that are also active against linezolid-resistant strains.
Numerous efforts have been carried out to improve the potency
and the antimicrobial spectrum of this drug [11e15]. Some
research groups have modified or replaced the C-ring of the oxa-
zolidinone that resulted in considerable improvement in the po-
tency of oxazolidinones [16e20]. So many interesting reviews
The oxazolidino-sulfonamide derivative 2 [28] was designed
and synthesized (Fig. 1) as a part of our previous studies directed at
the development of new class of antibiotics to counter drug-
resistant microbes [28e30]. In continuation of these efforts we
report the design, synthesis and antimicrobial evaluation of
a number of oxazolidino-sulfonamides (7aey and 8aeb). In addi-
tion, attempts have also been made to correlate antimicrobial ac-
tivity to physicochemical properties, such as, lipophilicity
(calculated as the C log P values) of the compounds.
2. Chemistry
The synthesis of the target compounds (7aey and 8aeb) was
carried out as outlined in Scheme 1 from the chiral azide de-
rivatives 5aec, which in turn was prepared in good yield as
described previously [7,8]. The structures of target compounds are
listed in Table 1. Further chemical transformation of 5aec to 6aec
involved the reduction of azide group to afford the corresponding
chiral amines [7,8]. Subsequently, the amines 6aec were treated
with commercially available aryl/heteroaryl sulfonyl chlorides in
the presence of triethylamine to furnish the corresponding
oxazolidinone-sulfonamide derivatives 7aey. Deprotection of the
tert-butoxycarbonyl group on the piperazine N-4-position of the
* Corresponding author. Tel.: þ91 40 27193157; fax: þ91 40 27193189.
E-mail address: ahmedkamal@iict.res.in (A. Kamal).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.01.034

662
A. Kamal et al. / European Journal of Medicinal Chemistry 62 (2013) 661e669
O
N A
O
O
O
F
O C N
B
H
N
O
N
N
H
N
O
S
O
CH3
F
2
1
F
O
Fig. 1. Chemical structures of linezolid 1 and lead molecule 2.
compounds 7xey, carried out by using trifluoroacetic acid in
CH2Cl2, generated the piperazine derivative 8aeb.
and C. albicans MTCC 3017 (4.0
m
g/mL). 7l showed very good ac-
tivity against all the tested organisms B. subtilis MTCC 121 (4.0
mL), Staphylococcus MLS-16 MTCC 2940 (4.0 g/mL), P. aeruginosa
MTCC 2453 (4.0 g/mL), S. aureus MTCC 96 (4.0 g/mL) and C.
albicans MTCC 3017 (4.0 g/mL). The active compounds 7i, 7v, 8a
and 8b showed very good inhibitory zone at 20 g/mL concentra-
mg/
m
m
m
3. Results and discussion
m
m
The newly synthesized oxazolidino-sulfonamides (7aey and
8aeb) were evaluated for their antimicrobial activity against
a panel of standard Gram-positive bacteria like Bacillus subtilis
(MTCC 121), Staphylococcus MLS-16 MTCC 2940, Micrococus luteus
MTCC 2470 and S. aureus MTCC 96, as well as Gram-negative bac-
teria, Escherichia coli (MTCC 739), Pseudomonas aeruginosa MTCC
2453 and Klebsiella planticola MTCC 530. Additionally, the anti-
fungal activity was also evaluated against Candida albicans MTCC
tion when compared to standard compounds such as, linezolid and
fluconazole (Table 3). However, when the new compounds (7aey
and 8aeb) were evaluated for their potency against M. tuber-
culosis H37Rv, no significant activity was observed.
The structure activity relationship (SAR) analysis reveals that
the compounds having electron-withdrawing groups like F,e
COCH3 and CF3 (7b, 7c, 7l, 8a and 8b) on aryl ring of sulfon-
amides can confer significant antimicrobial activity. This effect is
more pronounced when the electron withdrawing substituent is
at the 4-position of the aryl sulfonamide unit. Compounds pos-
sessing chlorinated aryl rings (7a and 7k) showed only moderate
levels of activity against all the tested strains. The oxazolidinone-
sulfonamides with unprotected nitrogen on the piperazine ring
(8aeb) exhibited better antibacterial activity than the corre-
sponding N-Boc protected compounds (7xey). The phenyl ring of
compound 2 was replaced with a variety of heterocyclic rings
(7eeg, 7i, 7ret and 7v). Among these compounds, the derivatives
7i and 7v where the benzene ring of sulphonamide was replaced
by a thiophene unit, displayed significant increase in activity.
3017. The minimum inhibitory concentrations (MICs,
mg/mL)
determined by the agar dilution method on Mueller-Hinton (HM)
agar for these compounds are summarized in Table 2.
The results illustrate that most of these compounds show sig-
nificant antimicrobial activity against the tested strains (MIC values
ranging from 2.0 to 8.0
mg/mL) except E. coli MTCC 739 and K.
planticola MTCC 530 (Table 2). Interestingly, compound 2, which
had shown good activity against Mycobacterium tuberculosis H37Rv
[28], was not active against the above mentioned strains. Com-
pound 7v showed excellent activity against B. subtilis MTCC 121
(2.0
mg/mL), Staphylococcus MLS-16 MTCC 2940 (4.0 mg/mL), S.
aureus MTCC 96 (4.0
mg/mL), P. aeruginosa MTCC 2453 (4.0
mg/mL)
F
H
N
O
O
7 steps
+
X
N
N
X
F
N3
NO2
4a X = O
F
4b
X = S
5a X = O
5b X = S
5c
3
4c X = N-Boc
(i)
X = N-Boc
O
O
O
N
O
S
O
X
N
F
(ii)
O
NH
R
R
X
N
N
NH2
F
6a X = O
6b X = S
6c
7a-y
X = O, S, N-Boc
X = N-Boc
R = aryl/heteroaryl
O
O
O
N
(iii)
O
O
S
O
BocN
N
F
O
S
HN
N
N
NH
NH
R
F
O
7x-y
8a-b
R = aryl
R = aryl
Scheme 1. Synthetic route of oxazolidino-sulfonamides (7aey and 8aeb): Reagents & conditions: (i) Pd/C, ethanol, H2, 4 h; (ii) aryl/heteroaryl sulfonyl chlorides, TEA, THF, rt, 1 h;
(iii) TFA, dry CH2Cl2, 0 ꢀC-rt, 1 h.

A. Kamal et al. / European Journal of Medicinal Chemistry 62 (2013) 661e669
663
Table 1
Structures of compounds (7aey and 8aeb).
Compd
X
R
M. formula
M. wt
C log P
2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
S
S
S
S
S
S
S
S
S
4-FeC6H4
3-CleC6H4
C20H21F2N3O5S
C20H21ClFN3O5S
C22H24FN3O6S
C20H20ClF2N3O5S
C26H26FN3O6S
C20H24FN5O6S2
C23H23FN4O5S
C24H24FN3O7S3
C21H21F4N3O5S
453.4
469.9
477.5
487.9
527.5
513.5
486.5
581.6
503.4
441.5
487.9
504.3
489.4
471.4
485.9
493.5
503.9
543.6
529.6
502.5
597.7
519.5
457.5
469.5
602.6
552.5
502.4
452.4
2.39
2.96
2.03
3.21
4.04
1.81
2.64
2.93
3.35
1.86
2.91
3.78
2.68
2.57
3.79
2.86
4.04
4.87
2.64
3.47
3.77
4.19
2.69
3.22
5.45
4.48
3.34
2.37
7a
7b
7c
7d
7e
7f
7g
7h
7i
4-COCH3eC6H4
3-Cl,4-FeC6H3
4-OC6H5eC6H4
2-Acetamido-4-methyl-5-thiazolyl-
8-Quinolinyl-
4-(Phenylsulfonyl)-2-thiophenyl-
4-CF3eC6H4
2-Thiophenyl-
2-Cl,4-FeC6H3
3,5-Cl2eC6H3
2,3,4-F3C6H2
3,4-F2eC6H3
3-CleC6H4
4-COCH3eC6H4
3-Cl,4-FeC6H3
4-OC6H5eC6H4
2-Acetamido-4-methyl-5-thiazolyl-
8-Quinolinyl-
4-(Phenylsulfonyl)-2-thiophenyl-
4-CF3eC6H4
2-Thiophenyl-
4-FeC6H4
4-CF3eC6H4
4-FeC6H4
C18H20FN3O5S2
7j
7k
7l
C20H20ClF2N3O5S
C20H20Cl2FN3O5S
C20H19F4N3O5S
C20H20F3N3O5S
C20H21ClFN3O4S2
C22H24FN3O5S2
C20H20ClF2N3O4S2
C26H26FN3O5S2
C20H24FN5O5S3
C23H23FN4O4S2
C24H24FN3O6S4
C21H21F4N3O4S2
C18H20FN3O4S3
C20H21F2N3O4S2
C26H30F4N4O6S
C25H30F2N4O6S
C21H22F4N4O4S
C20H22F2N4O4S
7m
7n
7o
7p
7q
7r
7s
7t
7u
7v
7w
7x
7y
8a
8b
N-Boc
N-Boc
NH
NH
4-CF3eC6H4
4-FeC6H4
In an attempt to correlate the biological activity with calculated
physical properties of the synthesized compounds, a lipophilicity
estimation using the software Chem Draw version 10.0 was carried
out. Lipophilicity values are represented by C log P values listed in
Table 1, as obtained from Chem Draw 10.0 [31]. As a rule of thumb
for a drug like molecule, the C log P value must be lower than 5 to
by-pass the cell barrier. Interestingly, the MIC values of the active
compounds seems to correlate to some extent with the hydro-
phobicity (C log P), 7d (X ¼ O, R ¼ eC6H4(4-OC6H5), C log P: 4.04;
5. Experimental section
5.1. Characterization
All chemicals were purchased from Lancaster (Alfa Aesar,
Johnson Matthey Co, Ward Hill, MA, USA), SigmaeAldrich (St Louis,
MO, USA) and Spectrochem Pvt Ltd (Mumbai, India). Reactions
were monitored by TLC, performed on silica gel glass plates con-
taining 60 F-254 and visualization on TLC was achieved by UV light
or iodine indicator. Column chromatography was performed with
Merck (Navi Mumbai, India) 60e120 mesh silica gel. 1H NMR
spectra were recorded on Avance (300 MHz); Bruker, Fallanden,
MIC: 4.0
aureus MTCC 96), 7i (X ¼ O, R ¼ 2-thiophenyl-, C log P: 1.86; MIC:
4.0 g/mL against B. subtilis MTCC 121, Staphylococcus MLS-16 MTCC
mg/mL against Staphylococcus MLS-16 MTCC 2940 and S.
m
2940, P. aeruginosa MTCC 2453, S. aureus MTCC 96 and C. albicans
MTCC 3017) and 7v (X ¼ O, R ¼ 2-thiophenyl-, C log P: 2.69; MIC:
Switzerland instruments. Chemical shifts (d) were reported in ppm,
downfield from internal TMS standard. Spectral patterns were
designated as s, singlet; d, doublet; dd, double doublet; t, triplet; bs,
broad singlet; m, multiplet. ESI spectra were recorded on Micro
mass, Quattro LC using ESIþ software with capillary voltage of
3.98 kV and ESI mode positive ion trap detector. High-resolution
mass spectra (HRMS) were recorded on QSTAR XL Hybrid MS/MS
mass spectrometer. IR spectra were recorded on an FT-IR spec-
2.0
mg/mL against B. subtilis MTCC 121 and 4.0 mg/mL against
Staphylococcus MLS-16 MTCC 2940, P. aeruginosa MTCC 2453, S.
aureus MTCC 96 and C. albicans MTCC 3017).
4. Conclusion
In conclusion, a number of newly synthesized oxazolidino-
sulfonamide derivatives (7aey and 8aeb) demonstrated signifi-
cant in vitro antimicrobial activity comparable to reference com-
pounds, namely, linezolid and fluconazole. Incorporation of
electron withdrawing substituents on the 4-position of the aryl ring
of the sulphonamide subunit is beneficial. Replacement of the
phenyl ring of the aryl sulphonamide moiety by a thiophene unit
also improved the antimicrobial activity.
trometer and only major peaks are reported in cmꢁ1
.
5.1.1. (R)-3-Chloro-N-((3-(3-fluoro-4-morpholinophenyl)-2-
oxooxazolidin-5-yl)methyl)-benz-enesulfonamide (7a)
The target compound 7a was obtained by reacting 6a (295 mg,
1
mmol) with 3-Chlorobenzenesulfonyl chloride (253 mg,
1.2 mmol), and triethylamine (50 mg, 2 mmol) in dry CH2Cl2
(15 mL). After stirring the reaction mixture for 3 h, the reaction

664
A. Kamal et al. / European Journal of Medicinal Chemistry 62 (2013) 661e669
1414, 1325, 1159, 814. 1H NMR (CDCl3, 300 MHz):
d 7.85 (s, 1H, Are
Table 2
Antibacterial and antifungal activity of the compounds (7aey and 8aeb) against
several standard strains (MICs, g/mL).
H), 7.75 (d,1H, J ¼ 7.7 Hz AreH), 7.53 (t,1H, J ¼ 7.9 Hz, AreH), 7.47 (t,
1H, J ¼ 7.7 Hz, AreH), 7.07 (dd, 1H, J ¼ 15.0, 2.4 Hz, oxa-AreH), 7.07
(dd, 1H, J ¼ 9.0 Hz, oxa-AreH), 6.86 (t, 1H, J ¼ 9.0 Hz, oxa-AreH),
5.85 (bs, 1H, eNH), 4.81 (m, 1H, oxa-CHe), 4.05e3.90 (m, 2H,
oxa-CH2e), 3.87 (t, 4H, J ¼ 4.5 Hz, morpholineOCH2e), 3.42e3.20
(m, 2H, oxa-CH2e), 3.05 (t, 4H, J ¼ 4.5 Hz, morpholineCH2e); 13C
m
Compd
B. sa
S. Mb
M. lc
S. ad
M. te
E. cf
P. ag
K. ph
C. ai
2
10.0
6.0
6.0
6.0
8.0
8.0
8.0
ej
10.0
6.0
6.0
6.0
4.0
20.0
10.0
ej
ej
NT
1.0
ek
ek
ek
ek
ek
ek
ek
ek
ek
ek
ek
ek
ek
ek
ek
ek
ek
ek
ek
ek
ek
ek
ek
ek
ek
NT
NT
NT
ej
ej
ej
ej
ej
ej
ej
ej
ej
ej
ej
ej
NT
ej
ej
ej
ej
ej
ej
ej
ej
ej
ej
ej
ej
ej
ej
e
10.0
ej
NT
ej
ej
ej
ej
ej
ej
ej
ej
ej
ej
ej
ej
NT
ej
ej
ej
ej
ej
ej
ej
ej
ej
ej
ej
ej
ej
ej
e
10.0
8.0
6.0
6.0
6.0
20.0
20.0
ej
7a
7b
7c
7d
7e
7f
7g
7h
7i
8.0
6.0
6.0
8.0
ej
6.0
6.0
6.0
4.0
20.0
10.0
ej
ej
ej
ej
NMR (CDCl3, 75 MHz): d 155.7, 153.5, 141.5,135.6, 134.4, 131.9, 129.9,
126.3, 124.4, 118.2, 113.3, 106.9, 106.7, 70.5, 66.2, 50.4, 46.6, 44.6;
8.0
6.0
ej
H)þ; HRMS (ESI) m/z calcd. for
8.0
ej
ESIMS: m/z 470 (M
þ
C20H22ClFN3O5S (M þ H)þ, 470.0953; found, 470.0941.
8.0
4.0
8.0
8.0
6.0
10.0
20.0
10.0
10.0
ej
10.0
4.0
20.0
8.0
6.0
10.0
ej
8.0
6.0
ej
10.0
4.0
20.0
8.0
6.0
NT
8.0
4.0
ej
20.0
4.0
7j
7k
7l
ej
5.1.2. (R)-4-Acetyl-N-((3-(3-fluoro-4-morpholinophenyl)-2-
oxooxazolidin-5-yl)methyl)-benzenesulfonamide (7b)
ej
40.0
8.0
10.0
10.0
ej
8.0
6.0
ej
The compound 7b was prepared according to the above
7m
7n
7o
7p
7q
7r
7s
7t
7u
7v
7w
7x
7y
8a
8b
LZ
FLZ
ej
10.0
described method using 6a (295 mg,
1 mmol) and 4-
ej
ej
ej
8.0
8.0
8.0
8.0
6.0
6.0
8.0
4.0
10.0
10.0
10.0
6.0
8.0
1.5
e
ej
8.0
8.0
8.0
8.0
6.0
6.0
8.0
4.0
10.0
10.0
10.0
6.0
8.0
1.5
e
20.0
20.0
20.0
8.0
8.0
8.0
Acetylbenzenesulfonyl chloride (262 mg, 1.2 mmol) with yield
262 mg (55%), m.p: 193e195 ꢀC; IR (KBr pellet, cmꢁ1): 3290, 2918,
2849, 1749, 1687, 1518, 1380, 1327, 1158, 831; 1H NMR (CDCl3,
ej
ej
ej
20.0
8.0
8.0
8.0
8.0
4.0
10.0
10.0
20.0
8.0
4.0
e
10.0
8.0
8.0
10.0
2.0
8.0
8.0
20.0
8.0
10.0
1.5
e
ej
300 MHz):
d
8.41e8.36 (m, 2H, AreH), 7.51e7.46 (dd, 1H, J ¼ 15.0,
ej
2.6 Hz, oxa-AreH), 7.34e7.31 (d, 2H, J ¼ 8.3 Hz, AreH), 7.07 (dd, 1H,
J ¼ 9.0 Hz, oxa-AreH), 6.91 (t, 1H, J ¼ 9.0 Hz, oxa-AreH), 6.52 (bs,
1H, eNH), 4.76 (m, 1H, oxa-CHe), 4.02 (t, 1H, J ¼ 9.0 Hz oxa-CHHe),
3.87 (t, 1H, J ¼ 9.0 Hz oxa-CHHe), 3.82 (t, 4H, J ¼ 4.5 Hz,
morpholineOCH2e), 3.59 (m, 2H, oxa-CH2e), 3.13 (t, 4H, J ¼ 4.5 Hz,
morpholineCH2e), 3.01 (s, 3H, eCOCH3); 13C NMR (CDCl3,
ej
ej
8.0
4.0
6.0
10.0
20.0
10.0
8.0
4.0
1.0
e
10.0
20.0
10.0
10.0
8.0
75 MHz): d 196.0, 156.9, 153.8, 144.0, 139.6, 133.1, 128.7, 126.9, 120.7,
e
113.7, 107.3, 107.0, 70.8, 66.2, 53.0, 47.0, 44.9, 27.5; ESIMS: m/z 478
(M þ H)þ; HRMS (ESI) m/z calcd. for C22H25FN3O6S (M þ H)þ,
478.1448; found, 478.1453.
e
e
e
1.0
The tests were performed in duplicate and repeated thrice. NT (not tested); LZ
(linezolid); FLZ (fluconazole).
a
Bacillus subtilis MTCC 121.
Staphylococcus MLS-16 MTCC 2940.
Micrococcus luteus MTCC 2470.
Staphylococcus aureus MTCC 96.
Mycobacterium tuberculosis H37Rv.
Escherichia coli MTCC 739.
Pseudomonas aeruginosa MTCC 2453.
Klebsiella planticola MTCC 530.
5.1.3. (R)-3-Chloro-4-fluoro-N-((3-(3-fluoro-4-morpholinophenyl)-
2-oxooxazolidin-5-yl)methyl)benzenesulfonamide (7c)
b
c
d
The compound 7c was prepared according to the above
described method using 6a (295 mg, 1 mmol) and 3-Chloro-4-
fluorobenzenesulfonyl chloride (275 mg, 1.2 mmol) with yield
317 mg (65%) m.p: 150e151 ꢀC; IR (KBr pellet, cmꢁ1): 3292, 2914,
2839, 1741, 1519, 1332, 1149, 826; 1H NMR (CDCl3, 300 MHz):
e
f
g
h
i
Candida albicans MTCC 3017.
Not active at 80
Not active at 32
j
m
m
g/mL.
g/mL.
d
7.78 (t, 1H, J ¼ 6.5 Hz, AreH), 7.63 (t, 1H, J ¼ 6.5 Hz, AreH), 7.42e
k
7.37 (dd, 1H, J ¼ 15.0, 2.6 Hz, oxa-AreH), 7.22 (t, 1H, J ¼ 7.3 Hz,
AreH), 7.07 (dd, 1H, J ¼ 9.0, 1.8 Hz, oxa-AreH), 6.91 (t, 1H,
J ¼ 9.0 Hz, oxa-AreH), 5.70 (bs, 1H, eNH), 4.82e4.72 (m, 1H, oxa-
CHe), 4.04 (t, 1H, J ¼ 9.0 Hz, oxa-CHHe), 3.93 (t, 1H, J ¼ 9.0 Hz,
oxa-CHHe), 3.88e3.85 (t, 4H, J ¼ 4.5 Hz, morpholineOCH2e),
The bold signifies low MIC values.
mixture was poured on to crushed ice (5 g) and the reaction mix-
ture extracted with CH2Cl2 (2 ꢂ 10 mL) and purified by column
chromatography with chloroform/methanol (50/1) as eluent to
afford final product as white solid (Yield 281 mg, 60%), m.p: 180e
182 ꢀC. IR (KBr pellet, cmꢁ1): 3320, 2978, 2834, 1746, 1616, 1574,
3.56e3.35 (m, 2H, oxa-CH2e), 3.05 (t, 4H,
morpholineCH2e); 13C NMR (CDCl3, 75 MHz):
J
¼
4.5 Hz,
d
155.0, 153.9,
152.1, 135.1, 133.2, 132.0, 128.6, 126.5, 123.4, 120.2, 118.6, 112.1,
105.3, 104.9, 70.5, 66.2, 50.4, 46.6, 44.6; ESIMS: m/z 488 (M þ H)þ;
HRMS (ESI) m/z calcd. for C20H21ClF2N3O5S (M þ H)þ, 488.0859;
found, 488.0840.
Table 3
Preliminary antibacterial and antifungal activity of oxazolidinone-sulfonamides
(zone of inhibition in mm) at 20 mg/mL.
Compd
B. sa
S. Mb
M. lc
S. ad
E. ce
P. af
K. pg
C. ah
5.1.4. (R)-N-((3-(3-Fluoro-4-morpholinophenyl)-2-oxooxazolidin-
5-yl)methyl)-4-phenoxy-benzenesulfonamide (7d)
7i
20
23
16
20
10
e
18
17
15
17
18
e
15
14
13
14
20
e
20
18
17
17
28
e
NT
NT
NT
NT
NT
e
19
17
16
18
12
e
NT
NT
NT
NT
NT
e
18
16
15
16
e
7w
8a
8b
LZ
The compound 7d was prepared according to the above
described method using 6a (295 mg,
1 mmol) and 4-
Phenoxybenzenesulfonyl chloride (322 mg, 1.2 mmol) with yield
358 mg (68%), m.p: 193e194 ꢀC; IR (KBr pellet, cmꢁ1): 3338, 2910,
2838, 2360, 1736, 1584, 1518, 1487, 1154, 835; 1H NMR (CDCl3,
FLZ
20
The tests were performed in duplicate and repeated thrice; NT (not tested); LZ
(linezolid); FLZ (fluconazole).
a
300 MHz):
d
7.77 (d, 2H, J ¼ 8.1 Hz, AreH), 7.44 (m, 2H, AreH), 7.40
Bacillus subtilis MTCC 121.
Staphylococcus MLS-16 MTCC 2940.
Micrococcus luteus MTCC 2470.
Staphylococcus aureus MTCC 96.
Escherichia coli MTCC 739.
Pseudomonas aeruginosa MTCC 2453.
Klebsiella planticola MTCC 530.
Candida albicans MTCC 3017.
b
(dd, 1H, J ¼ 15.0, 2.6 Hz, oxa-AreH), 7.21 (m, 1H, AreH), 7.08e7.01
(m, 3H, AreH and oxa-AreH), 6.91 (t,1H, J ¼ 9.0 Hz, oxa-AreH), 5.35
(bs, 1H, eNH), 4.79e4.71 (m, 1H, oxa-CHe), 4.02 (t, 1H, J ¼ 9.0 Hz,
oxa-CHHe), 3.92 (t, 1H, J ¼ 9.0 Hz, oxa-CHHe), 3.86 (t, 4H,
J ¼ 4.5 Hz, morpholineOCH2e), 3.39e3.20 (m, 2H, oxa-CH2e), 3.05
(t, 4H, J ¼ 4.5 Hz, morpholineCH2e); 13C NMR (CDCl3, 75 MHz):
c
d
e
f
g
h

A. Kamal et al. / European Journal of Medicinal Chemistry 62 (2013) 661e669
665
d
161.7, 156.5, 154.9, 154.6, 154.1, 137.6, 134.5, 132.8, 130.1, 129.1,
5.1.8. (R)-N-((3-(3-Fluoro-4-morpholinophenyl)-2-oxooxazolidin-
125.0, 120.2, 117.7, 113.9, 107.6, 107.4, 71.1, 66.2, 53.2, 47.2, 45.0;
ESIMS: m/z 528 (M þ H)þ; HRMS (ESI) m/z calcd. for C26H27FN3O6S
(M þ H)þ, 528.1605; found, 528.1586.
5-yl)methyl)-4-(trifluoromethyl)benzenesulfonamide (7h)
The compound 7h was prepared according to the above
described method using 6a (295 mg, 1 mmol) and 4-(tri-
fluoromethyl)benzene-1-sulfonyl chloride (294 mg, 1.2 mmol) with
yield 302 mg (60%), m.p: 143e144 ꢀC; IR (KBr pellet, cmꢁ1): 3297,
2921, 2360, 1746, 1519, 1326, 1160, 834; 1H NMR (CDCl3, 300 MHz):
5.1.5. (R)-N-(5-(N-((3-(3-Fluoro-4-morpholinophenyl)-2-
oxooxazolidin-5-yl)methyl)sulfamoyl)-4-methylthiazol-2-yl)
acetamide (7e)
The compound 7e was prepared according to the above described
method using 6a (295 mg, 1 mmol) and 2-acetamido-4-methyl-1,3-
thiazole-5-sulfonyl chloride (305 mg, 1.2 mmol) with yield 231 mg
(45%), m.p: 200e201 ꢀC; IR (KBr pellet, cmꢁ1): 3302, 3276, 2961,
2834, 2360, 1736, 1693, 1514, 1336, 1152, 859; 1H NMR (DMSO-d6,
d
7.99 (d, 2H, J ¼ 8.7 Hz, AreH), 7.78 (d, 2H, J ¼ 8.7 Hz, AreH), 7.39
(dd, 1H, J ¼ 14.6, 2.4 Hz, oxa-AreH), 7.06 (d, 1H, J ¼ 8.9 Hz, oxa-Are
H), 6.90 (t, 1H, J ¼ 8.9 Hz, oxa-AreH), 5.66 (bs, 1H, eNH), 4.77e4.72
(m, 1H, oxa-CHe), 4.02 (t, 1H, J ¼ 8.9 Hz, oxa-CHHe), 3.90 (t, 1H,
J ¼ 8.9 Hz, oxa-CHHe), 3.86 (t, 4H, J ¼ 4.5 Hz, morpholineOCH2e),
3.42e3.31 (m, 2H, oxa-CH2e), 3.05 (t, 4H, J ¼ 4.5 Hz, morpholine
300 MHz):
d
12.27 (s, 1H, eNHCOe), 8.21 (t, 1H, J ¼ 6.5 Hz, AreH),
CH2e); 13C NMR (CDCl3, 75 MHz):
d 155.7, 153.5, 135.6, 134.4,
7.68 (s, 1H, thiopheneeH), 7.47 (dd, 1H, J ¼ 14.5, 2.4 Hz, oxa-AreH),
7.07 (dd, 1H, J ¼ 9.0, 1.8 Hz, oxa-AreH), 6.95 (t, 1H, J ¼ 9.0 Hz, oxa-
AreH), 5.70 (bs, 1H, eNH), 4.77e4.69 (m, 1H, oxa-CHe), 4.02 (t, 1H,
J ¼ 9.0 Hz, oxa-CHHe), 3.94 (t,1H, J ¼ 9.0 Hz, oxa-CHHe), 3.82 (t, 4H,
J ¼ 4.5 Hz, morpholineOCH2e), 3.27e3.23 (m, 2H, oxa-CH2e), 3.07 (t,
4H, J ¼ 4.5 Hz, morpholineCH2e), 2.20 (s, 3H, eCOCH3), 2.05 (s, 3H, e
131.9, 129.9, 126.3, 124.4, 119.6, 118.2, 113.3, 106.9, 106.7, 70.5, 66.2,
50.4, 46.6, 44.6; ESIMS: m/z 504 (M þ H)þ; HRMS (ESI) m/z calcd. for
C21H22F4N3O5S (M þ H)þ, 504.1216; found, 504.1223.
5.1.9. (R)-N-((3-(3-Fluoro-4-morpholinophenyl)-2-oxooxazolidin-
5-yl)methyl)thiophene-2-sulfonamide (7i)
CH3); 13C NMR (CDCl3, 75 MHz):
d
172.3, 155.3, 153.4, 142.3, 134.5,
The compound 7i was prepared according to the above descri-
bed method using 6a (299 mg, 1 mmol) and 2-thiophenesulfonyl
chloride (219 mg, 1.2 mmol) with yield 264 mg (60%) m.p: 140e
142 ꢀC; IR (KBr pellet, cmꢁ1): 3290, 2921, 2360, 1732, 1510, 1326,
132.8, 125.3, 124.4, 118.7, 112.9, 107.4, 71.9, 66.8, 50.8, 47.5, 41.8, 23.4,
12.5; ESIMS: m/z 514 (M þ H)þ; HRMS (ESI) m/z calcd. for
C20H25FN5O6S2 (M þ H)þ, 514.1230; found, 514.1253.
1160, 831; 1H NMR (CDCl3, 300 MHz):
d 7.62 (m, 2H, thiopheneeH),
5.1.6. (R)-N-((3-(3-Fluoro-4-morpholinophenyl)-2-oxooxazolidin-
5-yl)methyl)quinoline-8-sulfonamide (7f)
7.40 (dd, 1H, J ¼ 14.6, 2.4 Hz, oxa-AreH), 7.11 (m, 1H, thiopheneeH),
7.06 (d, 1H, J ¼ 9.0 Hz, oxa-AreH), 6.91 (t, 1H, J ¼ 9.0 Hz, oxa-AreH),
5.55 (bs, 1H, eNH), 4.79e4.74 (m, 1H, oxa-CHe), 4.02 (t, 1H,
J ¼ 8.9 Hz, oxa-CHHe), 3.93 (t, 1H, J ¼ 8.9 Hz, oxa-CHHe), 3.86 (t,
4H, J ¼ 4.5 Hz, morpholineOCH2e), 3.43e3.30 (m, 2H, oxa-CH2e),
3.05 (t, 4H, J ¼ 4.5 Hz, morpholineCH2e); 13C NMR (CDCl3,
The compound 7f was prepared according to the above
described method using 6a (295 mg,
1 mmol) and 8-
quinolinesulfonyl chloride (273 mg, 1.2 mmol) with yield 243 mg
(50%), m.p: 183e184 ꢀC; IR (KBr pellet, cmꢁ1): 3306, 2854, 2360,
1733, 1516, 1320, 1116, 834; 1H NMR (DMSO-d6, 300 MHz):
d
9.06
75 MHz): d 156.5, 153.5, 135.6, 126.3, 126.2, 124.4, 118.2, 118.2, 113.3,
(d, 1H, J ¼ 3.7 Hz, quino-H), 8.38 (d, 1H, J ¼ 6.0 Hz, quino-H), 8.23
(d, 1H, J ¼ 8.3 Hz, quino-H), 8.01 (d, 1H, J ¼ 8.3 Hz, quino-H), 7.59e
7.55 (m, 1H, quino-H), 7.29 (dd, 1H, J ¼ 14.6, 2.6 Hz, oxa-AreH),
6.89 (dd, 1H, J ¼ 9.0, 1.8 Hz, oxa-AreH), 6.83 (t, 1H, J ¼ 9.0 Hz,
oxa-AreH), 4.74e4.66 (m, 1H, oxa-CHe), 3.97e3.95 (m, 2H, oxa-
CHHe), 3.82 (t, 4H, J ¼ 4.5 Hz, morpholineOCH2e), 3.27e3.24
(m, 2H, oxa-CH2e), 3.02 (t, 4H, J ¼ 4.5 Hz, morpholineCH2e);
106.9, 106.7, 70.5, 66.2, 50.4, 46.6, 44.6; ESIMS: m/z 442 (M þ H)þ;
HRMS (ESI) m/z calcd. for C18H21FN3O5S2 (M þ H)þ, 442.0907;
found, 442.0913.
5.1.10. (R)-2-Chloro-4-fluoro-N-((3-(3-fluoro-4-
morpholinophenyl)-2-oxooxazolidin-5-yl)-methyl)
benzenesulfonamide (7j)
13C NMR (DMSO-d6, 75 MHz):
d
175.2, 151.6, 142.8, 137.0, 135.4,
The compound 7j was prepared according to the above descri-
133.6, 132.8, 132.4, 130.7, 130.4, 128.7, 125.6, 122.5, 121.1, 118.7,
113.8, 107.2, 70.9, 66.9, 50.9, 47.2, 45.3; ESIMS: m/z 487 (M þ H)þ;
HRMS (ESI) m/z calcd. for C23H24FN4O5S (M þ H)þ, 487.1446;
found, 487.1448.
bed method using 6a (299 mg, 1 mmol) and 2-chloro-4-
fluorobenzenesulfonyl chloride (275 mg, 1.2 mmol) with yield
297 mg (61%), m.p: 153e154 ꢀC; IR (KBr pellet, cmꢁ1): 3328, 2901,
2360, 1736, 1519, 1239, 1164, 839; 1H NMR (CDCl3, 300 MHz):
d 8.06
(d, 1H, J ¼ 8.6, 5.6 Hz, AreH), 7.35 (dd, 1H, J ¼ 14.6, 2.5 Hz, oxa-Are
H), 7.21 (dd, 1H, J ¼ 8.0, 2.5 Hz, AreH), 7.10 (td, 1H, J ¼ 7.3, 2.4 Hz,
AreH), 7.03 (t, 1H, J ¼ 8.9 Hz, oxa-AreH), 6.86 (t, 1H, J ¼ 8.9 Hz, oxa-
AreH), 5.76 (bs, 1H, eNH), 4.73e4.65 (m, 1H, oxa-CHe), 3.98 (t, 1H,
J ¼ 8.9 Hz, oxa-CHHe), 3.86 (t, 1H, J ¼ 8.9 Hz, oxa-CHHe), 3.83 (t,
4H, J ¼ 4.5 Hz, morpholineOCH2e), 3.42e3.23 (m, 2H, oxa-CH2e),
3.02 (t, 4H, J ¼ 4.5 Hz, morpholineCH2e); 13C NMR (CDCl3,
5.1.7. (R)-N-((3-(3-Fluoro-4-morpholinophenyl)-2-oxooxazolidin-
5-yl)methyl)-4-(phenylsulfonyl)thiophene-2-sulfonamide (7g)
The compound 7g was prepared according to the above
described method using 6a (295 mg, 1 mmol) and 4-(phenyl-
sulfonyl)thiophene-2-sulfonylchloride (387 mg, 1.2 mmol) with
yield 232 mg (40%) m.p: 153e155 ꢀC; IR (KBr pellet, cmꢁ1): 3306,
2901, 2360, 1760, 1733, 1516, 1336, 1143, 829; 1H NMR (DMSO-d6,
75 MHz):
d 162.9, 157.0, 153.8, 136.6, 133.3, 132.9, 132.5, 119.6, 119.2,
300 MHz):
d
8.57 (t, 1H, J ¼ 5.3 Hz, AreH), 8.41 (d, 1H, J ¼ 5.3 Hz,
118.7, 114.7, 114.4, 113.9, 107.6, 107.2, 70.8, 66.9, 50.9, 47.1, 45.3;
AreH), 7.97 (d, 2H, J ¼ 7.3 Hz, AreH), 7.80 (s, 1H, AreH), 7.67 (t,
2H, J ¼ 7.3 Hz, AreH), 7.59 (t, 2H, J ¼ 7.3 Hz, AreH), 7.49 (d, 1H,
J ¼ 14.6, 2.4 Hz, oxa-AreH), 7.06 (d, 1H, J ¼ 9.0 Hz, oxa-AreH),
6.94 (t, 1H, J ¼ 9.0 Hz, oxa-AreH), 4.78e4.72 (m, 1H, oxa-CHe),
4.04 (t, 1H, J ¼ 8.9 Hz, oxa-CHHe), 3.88 (t, 1H, J ¼ 8.9 Hz, oxa-
CHHe), 3.83 (t, 4H, J ¼ 4.5 Hz, morpholineOCH2e), 3.34e3.32
(m, 2H, oxa-CH2e), 3.08 (t, 4H, J ¼ 4.5 Hz, morpholineCH2e);
ESIMS: m/z 470 (M
þ
H)þ; HRMS (ESI) m/z calcd. for
C20H21ClF2N3O5S (M þ H)þ, 488.0859; found, 488.0912.
5.1.11. (R)-3,5-Dichloro-N-((3-(3-fluoro-4-morpholinophenyl)-2-
oxooxazolidin-5-yl)methyl)-benzenesulfonamide (7k)
The compound 7k was prepared according to the above
described method using 6a (295 mg,
1 mmol) and 3,5-
13C NMR (DMSO-d6, 75 MHz):
d
152.2, 151.7, 143.3, 140.2, 139.0,
dichlorobenzenesulfonyl chloride (295 mg, 1.2 mmol) with yield
317 mg (63%), m.p: 166e167 ꢀC; IR (KBr pellet, cmꢁ1): 3328, 2910,
2361, 1736, 1516, 1240, 1164, 849; 1H NMR (CDCl3, 300 MHz):
135.3, 134.2, 132.3, 131.7, 128.0, 127.1, 125.8, 117.3, 112.3, 105.6,
105.2, 69.3, 64.9, 49.2, 45.4, 43.9; ESIMS: m/z 582 (M þ H)þ;
HRMS (ESI) m/z calcd. for C24H25FN3O7S3 (M þ H)þ, 582.0839;
found, 582.0825.
d
8.38 (bs, 1H, eNH), 7.76 (d, 2H, J ¼ 1.7 Hz, AreH), 7.55 (t, 1H,
J ¼ 1.7 Hz, AreH), 7.46 (dd, 1H, J ¼ 14.6, 2.5 Hz, oxa-AreH), 7.07

666
A. Kamal et al. / European Journal of Medicinal Chemistry 62 (2013) 661e669
(dd, 1H, J ¼ 9.0, 1.8 Hz, oxa-AreH), 6.91 (t, 1H, J ¼ 9.0 Hz, oxa-Are
H), 4.76e4.68 (m, 1H, oxa-CHe), 4.03 (t, 1H, J ¼ 9.0 Hz, oxa-CHHe
), 3.88 (t, 1H, J ¼ 9.0 Hz, oxa-CHHe), 3.79 (t, 4H, J ¼ 4.5 Hz,
morpholineOCH2e), 3.26e3.18 (m, 2H, oxa-CH2e), 3.01 (t, 4H,
5.1.15. (R)-4-Acetyl-N-((3-(3-fluoro-4-thiomorpholinophenyl)-2-
oxooxazolidin-5-yl)methyl)-benzenesulfonamide (7o)
The compound 7o was prepared according to the above
described method using 6b (311 mg,
1 mmol) and 4-
J ¼ 4.5 Hz, morpholineCH2e); 13C NMR (CDCl3, 75 MHz):
d
155.2,
acetylbenzenesulfonyl chloride (262 mg, 1.2 mmol) with yield
271 mg (55%), m.p: 193e194 ꢀC; IR (KBr pellet, cmꢁ1): 3294, 2918,
2849, 1749, 1687, 1518, 1380, 1327, 1158, 844; 1H NMR (CDCl3,
153.1, 141.1, 136.7, 135.6, 128.7, 127.2, 125.8, 124.6, 123.1, 121.0,
119.6, 112.9, 71.9, 66.7, 50.9, 47.5, 42.5; ESIMS: m/z 504 (M þ H)þ;
HRMS (ESI) m/z calcd. for C20H21Cl2FN3O5S (M þ H)þ, 504.0563;
found, 504.0535.
300 MHz):
d
8.06 (d, 2H, J ¼ 7.7 Hz, AreH), 7.94 (d, 2H, J ¼ 7.7 Hz,
AreH), 7.38 (dd, 1H, J ¼ 14.8, 2.6 Hz, oxa-AreH), 7.05 (dd, 1H,
J ¼ 8.6 Hz, oxa-AreH), 6.92 (t, 1H, J ¼ 8.6 Hz, oxa-AreH), 5.75 (bs,
1H, eNH), 4.79e4.69 (m, 1H, oxa-CHe), 4.00 (t, 1H, J ¼ 9.0 Hz oxa-
CHHe), 3.90 (t, 1H, J ¼ 9.0 Hz, oxa-CHHe), 3.39e3.35 (m, 2H, oxa-
CH2e), 3.29 (t, 4H, J ¼ 4.5 Hz, thiomorpholineSCH2e), 2.85 (t, 4H,
J ¼ 4.5 Hz, thiomorpholineCH2e), 2.64 (s, 3H, eCOCH3); 13C NMR
5.1.12. (R)-2,3,4-Trifluoro-N-((3-(3-fluoro-4-morpholinophenyl)-2-
oxooxazolidin-5-yl)methyl)benzenesulfonamide (7l)
The compound 7l was prepared according to the above descri-
bed method using 6a (295 mg,
1
mmol) and 2,3,4-
trifluorobenzenesulfonyl chloride (0.17 mL, 1.2 mmol) with yield
327 mg (67%), m.p: 144e145 ꢀC; IR (KBr pellet, cmꢁ1): 3328, 2901,
2360, 1736, 1519, 1330, 1239, 1164, 839; 1H NMR (CDCl3, 300 MHz):
(CDCl3, 75 MHz): d 196.0, 156.9, 153.8, 144.0, 139.6, 133.1, 128.7,
126.9, 120.7, 113.7, 107.3, 107.0, 70.8, 53.0, 47.0, 44.9, 27.7, 26.6;
ESIMS: m/z 494 (M þ H)þ; HRMS (ESI) m/z calcd. for C22H25FN3O5S2
(M þ H)þ, 494.1220; found, 494.1241.
d
7.74 (d, 1H, J ¼ 8.0 Hz, AreH), 7.56 (d, 1H, J ¼ 7.9 Hz, AreH), 7.36
(dd, 1H, J ¼ 14.6, 2.5 Hz, oxa-AreH), 7.06 (dd, 1H, J ¼ 9.0, 1.8 Hz, oxa-
AreH), 6.94 (t, 1H, J ¼ 9.0 Hz, oxa-AreH), 5.42 (bs, 1H, eNH), 4.80e
4.70 (m, 1H, oxa-CHe), 4.03 (t, 1H, J ¼ 9.0 Hz, oxa-CHHe), 3.91 (t,
5.1.16. (R)-3-Chloro-4-fluoro-N-((3-(3-fluoro-4-
thiomorpholinophenyl)-2-oxooxazolidin-5-yl)methyl)
benzenesulfonamide (7p)
1H,
J
¼
9.0 Hz, oxa-CHHe), 3.37e3.24 (m, 6H, oxa-CH2e,
morpholineOCH2e), 2.80 (t, 4H, J ¼ 4.5 Hz, morpholineCH2e);
The compound 7p was prepared according to the above
described method using 6b (311 mg, 1 mmol) and 3-chloro-4-
fluorobenzenesulfonyl chloride (275 mg, 1.2 mmol) with yield
262 mg (52%), m.p: 155e156 ꢀC; IR (KBr pellet, cmꢁ1): 3310, 2902,
13C NMR (CDCl3, 75 MHz):
d
156.4, 155.5, 154.5, 154.1, 153.4, 135.6,
132.8, 129.7, 128.2, 124.9, 118.8, 114.1, 107.6, 71.3, 67.0, 51.0, 47.3,
45.5; ESIMS: m/z 490 (M þ H)þ; HRMS (ESI) m/z calcd. for
C20H20F4N3O5S (M þ H)þ, 490.1060; found, 490.1071.
2839, 1735, 1519, 1332, 1162, 826; 1H NMR (CDCl3, 300 MHz):
d 8.39
(bs, 1H, eNH), 7.77 (t, 1H, J ¼ 8.1 Hz, AreH), 7.63 (t, 1H, J ¼ 8.1 Hz,
AreH), 7.44 (dd, 1H, J ¼ 15.0, 2.6 Hz, oxa-AreH), 7.25 (t, 1H,
J ¼ 7.3 Hz, AreH), 7.07 (dd, 1H, J ¼ 9.0, 1.8 Hz, oxa-AreH), 6.95 (t, 1H,
J ¼ 9.0 Hz, oxa-AreH), 4.76 (m, 1H, oxa-CHe), 4.05e3.93 (m, 2H,
oxa-CH2e), 3.41e3.33 (m, 2H, oxa-CH2e), 3.28 (t, 4H, J ¼ 4.5 Hz,
thiomorpholineSCH2e), 2.79 (t, 4H, J ¼ 4.5 Hz, thiomorpholine
5.1.13. (R)-3,4-Difluoro-N-((3-(3-fluoro-4-morpholinophenyl)-2-
oxooxazolidin-5-yl)methyl)-benzenesulfonamide (7m)
The compound 7m was prepared according to the above
described method using 6a (295 mg,
1 mmol) and 3,4-
difluorobenzenesulfonyl chloride (0.16 mL, 1.2 mmol) with yield
310 mg (65%), m.p: 153e154 ꢀC; IR (KBr pellet, cmꢁ1): 3328, 2910,
2360, 1736, 1521, 1330, 1239, 1164, 839; 1H NMR (CDCl3, 300 MHz):
CH2e); 13C NMR (CDCl3, 75 MHz):
d 155.0, 153.9, 152.1, 135.1,
133.2, 132.0, 128.6, 126.5, 123.4, 120.2, 118.6, 112.1, 105.3, 104.9, 69.3,
51.5, 45.3, 43.5, 25.9; ESIMS: m/z 504 (Mþ þ H); HRMS (ESI) m/z
calcd. for C20H21ClF2N3O4S2 (M þ H)þ, 504.0630; found, 504.0638.
d
7.78 (t,1H, J ¼ 8.0 Hz, AreH), 7.61 (t,1H, J ¼ 7.9 Hz, AreH), 7.35 (dd,
1H, J ¼ 14.6, 2.5 Hz, oxa-AreH), 7.22 (s, 1H, AreH), 7.06 (dd, 1H,
J ¼ 9.0, 1.8 Hz, oxa-AreH), 6.87 (t, 1H, J ¼ 9.0 Hz, oxa-AreH), 5.70
(bs, 1H, eNH), 4.80e4.72 (m, 1H, oxa-CHe), 4.02 (t, 1H, J ¼ 9.0 Hz,
oxa-CHHe), 3.93 (t, 1H, J ¼ 9.0 Hz, oxa-CHHe), 3.83 (t, 4H,
J ¼ 4.5 Hz, morpholineOCH2e), 3.54e3.36 (m, 2H, oxa-CH2e), 3.03
(t, 4H, J ¼ 4.5 Hz, morpholineCH2e); 13C NMR (CDCl3, 75 MHz):
5.1.17. (R)-N-((3-(3-Fluoro-4-thiomorpholinophenyl)-2-
oxooxazolidin-5-yl)methyl)-4-phenoxybenzenesulfonamide (7q)
The compound 7q was prepared according to the above
described method using 6b (311 mg,
1 mmol) and 4-
d
156.3, 155.4, 154.0, 153.3, 135.5, 132.6, 129.6, 128.1, 124.8, 118.7,
phenoxybenzenesulfonyl chloride (322 mg, 1.2 mmol) with yield
271 mg (50%), m.p: 144e145 ꢀC; IR (KBr pellet, cmꢁ1): 3328, 2901,
2838, 2360, 1760, 1518, 1487, 1154, 834; 1H NMR (CDCl3, 300 MHz):
114.1, 107.9, 107.7, 71.9, 66.8, 50.8, 47.5, 41.8; ESIMS: m/z 472
(M þ H)þ; HRMS (ESI) m/z calcd. for C20H21F3N3O5S (M þ H)þ,
472.1154; found, 490.1162.
d
7.77 (d, 2H, J ¼ 8.1 Hz, AreH), 7.44 (m, 2H, AreH), 7.40 (dd, 1H,
J ¼ 15.0, 2.6 Hz, oxa-AreH), 7.34 (d, 2H, J ¼ 8.1 Hz, AreH), 7.19 (m,
1H, AreH), 7.14 (t, 2H, J ¼ 6.7 Hz, AreH), 7.07 (dd, 1H, J ¼ 9.0, 1.8 Hz,
oxa-AreH), 6.95 (t, 1H, J ¼ 9.0 Hz, oxa-AreH), 5.57 (bs, 1H, eNH),
4.76 (m, 1H, oxa-CHe), 4.05e3.93 (m, 2H, oxa-CH2e), 3.41e3.33 (m,
2H, oxa-CH2e), 3.28 (t, 4H, J ¼ 4.5 Hz, thiomorpholineSCH2e), 2.79
(t, 4H, J ¼ 4.5 Hz, thiomorpholineCH2e); 13C NMR (CDCl3, 75 MHz):
5.1.14. (R)-3-Chloro-N-((3-(3-fluoro-4-thiomorpholinophenyl)-2-
oxooxazolidin-5-yl)methyl)-benzenesulfonamide (7n)
The compound 7n was prepared according to the above
described method using 6b (311 mg,
1 mmol) and 3-
chlorobenzenesulfonyl chloride (253 mg, 1.2 mmol) with yield
281 mg (58%), m.p: 155e156 ꢀC; IR (KBr pellet, cmꢁ1): 3292, 2902,
2839, 1735, 1519, 1332, 1162, 806; 1H NMR (CDCl3, 300 MHz):
d
161.7, 156.5, 154.9, 154.6, 154.1, 137.6, 134.5, 132.8, 130.1, 129.1,
125.0, 120.2, 117.7, 113.9, 107.6, 107.4, 71.1, 53.2, 47.2, 45.3, 27.9;
ESIMS: m/z 544 (M þ H)þ; HRMS (ESI) m/z calcd. for C26H27FN3O5S2
(M þ H)þ, 544.1376; found, 544.1382.
d
7.85 (s, 1H, AreH), 7.75 (d, 1H, J ¼ 7.7 Hz AreH), 7.53 (t, 1H,
J ¼ 7.9 Hz, AreH), 7.47 (t, 1H, J ¼ 7.7 Hz, AreH), 7.07 (dd, 1H,
J ¼ 15.0, 2.4 Hz, oxa-AreH), 7.07 (dd, 1H, J ¼ 9.0 Hz, oxa-AreH),
6.86 (t, 1H, J ¼ 9.0 Hz, oxa-AreH), 5.85 (bs, 1H, eNH), 4.81 (m,
1H, oxa-CHe), 4.05e3.90 (m, 2H, oxa-CH2e), 3.41e3.34 (m, 2H,
oxa-CH2e), 3.29 (t, 4H, J ¼ 4.5 Hz, thiomorpholineSCH2e), 2.80 (t,
4H, J ¼ 4.5 Hz, thiomorpholineCH2e); 13C NMR (CDCl3, 75 MHz):
5.1.18. (R)-N-(5-(N-((3-(3-Fluoro-4-thiomorpholinophenyl)-2-
oxooxazolidin-5-yl)methyl)-sulfamoyl)-4-methylthiazol-2-yl)
acetamide (7r)
The compound 7r was prepared according to the above described
method using 6b (311 mg, 1 mmol) and 2-acetamido-4-methyl-1,3-
thiazole-5-sulfonyl chloride (305 mg, 1.2 mmol) with yield 211 mg
(40%), m.p: 184e185 ꢀC; IR (KBr pellet, cmꢁ1): 3276, 3178, 2961, 2834,
2360, 1733, 1681, 1514, 1149, 1336, 861; 1H NMR (DMSO-d6,
d
155.8, 152.9, 141.0, 135.9, 133.6, 131.3, 129.5, 125.6, 123.8, 119.1,
112.7, 106.1105.8, 70.0, 52.1, 46.0, 44.1, 26.7; ESIMS: m/z 470
(M þ H)þ; HRMS (ESI) m/z calcd. for C20H22ClFN3O4S2 (M þ H)þ,
486.0724; found, 486.0751.

A. Kamal et al. / European Journal of Medicinal Chemistry 62 (2013) 661e669
667
300 MHz):
d
12.26 (s,1H, eNHCOe), 8.22 (t,1H, J ¼ 6.5 Hz, AreH), 7.67
J ¼ 4.5 Hz, thiomorpholineSCH2e), 2.79 (t, 4H, J ¼ 4.5 Hz,
thiomorpholineCH2e); 13C NMR (CDCl3, 75 MHz):
156.2, 153.1,
135.6, 128.7, 128.6, 119.6, 115.4, 115.1, 112.9, 112.5, 106.5, 106.1, 70.2,
52.5, 46.2, 44.2, 26.8; ESIMS: m/z 520 (M þ H)þ; HRMS (ESI) m/z
calcd. for C21H22F4N3O4S2 (M þ H)þ, 520.0988; found, 520.0995.
(s, 1H, thiopheneeH), 7.47 (dd, 1H, J ¼ 14.5, 2.4 Hz, oxa-AreH), 7.07
(dd, 1H, J ¼ 9.0, 1.8 Hz, oxa-AreH), 6.96 (t, 1H, J ¼ 9.0 Hz, oxa-AreH),
5.70(bs,1H, eNH), 4.77e4.69 (m,1H, oxa-CHe), 4.02 (t,1H, J ¼ 9.0 Hz,
oxa-CHHe), 3.94 (t,1H, J ¼ 9.0 Hz, oxa-CHHe), 3.41e3.33 (m, 2H, oxa-
CH2e), 3.28 (t, 4H, J ¼ 4.5 Hz, thiomorpholineSCH2e), 2.88 (t, 4H,
J ¼ 4.5 Hz, thiomorpholineCH2e), 2.20 (s, 3H, eCOCH3), 2.06 (s, 3H, e
d
5.1.22. (R)-N-((3-(3-Fluoro-4-thiomorpholinophenyl)-2-
oxooxazolidin-5-yl)methyl)-thiophene-2-sulfonamide (7v)
CH3); 13C NMR (CDCl3, 75 MHz):
d
172.3, 155.3, 153.4, 142.3, 134.5,
132.8,125.3,124.4,118.7,112.9,107.4, 70.2, 52.5, 46.2, 44.2, 27.2, 23.4,
12.5; ESIMS: m/z 530 (Mþ þ H); HRMS (ESI) m/z calcd. for
C20H25FN5O5S3 (M þ H)þ, 530.1002; found, 530.1030.
Thecompound7vwas prepared according totheabovedescribed
method using 6b (311 mg, 1 mmol) and 2-thiophenesulfonyl chlo-
ride (219 mg,1.2 mmol) withyield 256 mg(56%), m.p:133e135 ꢀC; IR
(KBr pellet, cmꢁ1): 3289, 2919, 2360, 1735, 1510, 1326, 1160, 829; 1H
5.1.19. (R)-N-((3-(3-Fluoro-4-thiomorpholinophenyl)-2-
NMR (CDCl3, 300 MHz): d 7.61 (m, 2H, thiopheneeH), 7.42 (dd, 1H,
oxooxazolidin-5-yl)methyl)quinoline-8-sulfonamide (7s)
J ¼ 14.6, 2.4 Hz, oxa-AreH), 7.11 (m, 1H, thiopheneeH), 7.06 (d, 1H,
J ¼ 9.0 Hz, oxa-AreH), 6.91 (t,1H, J ¼ 9.0 Hz, oxa-AreH), 5.55 (bs,1H,
eNH), 4.79e4.74 (m,1H, oxa-CHe), 4.02 (t,1H, J ¼ 8.9 Hz, oxa-CHHe
), 3.93 (t, 1H, J ¼ 8.9 Hz, oxa-CHHe), 3.41e3.33 (m, 2H, oxa-CH2e),
3.28 (t, 4H, J ¼ 4.5 Hz, thiomorpholineSCH2e), 2.80 (t, 4H,
The compound 7s was prepared according to the above descri-
bed method using 6b (311 mg, 1 mmol) and 8-quinolinesulfonyl
chloride (273 mg, 1.2 mmol) with yield 251 mg (45%), m.p: 177e
178 ꢀC; IR (KBr pellet, cmꢁ1): 3291, 2854, 2360, 1733, 1516, 1320,
1120, 836; 1H NMR (DMSO-d6, 300 MHz):
d
9.06 (d, 1H, J ¼ 3.7 Hz,
J ¼ 4.5 Hz, thiomorpholineCH2e); 13C NMR (CDCl3, 75 MHz):
d 155.3,
quino-H), 8.38 (d, 1H, J ¼ 6.0 Hz, quino-H), 8.23 (d, 1H, J ¼ 8.3 Hz,
quino-H), 8.01 (d, 1H, J ¼ 8.3 Hz, quino-H), 7.59e7.55 (m, 1H, quino-
H), 7.29 (dd, 1H, J ¼ 14.6, 2.6 Hz, oxa-AreH), 6.89 (dd, 1H, J ¼ 9.0,
1.8 Hz, oxa-AreH), 6.83 (t, 1H, J ¼ 9.0 Hz, oxa-AreH), 4.74e4.66 (m,
1H, oxa-CHe), 3.97e3.95 (m, 2H, oxa-CHHe), 3.41e3.33 (m, 2H,
oxa-CH2e), 3.28 (t, 4H, J ¼ 4.5 Hz, thiomorpholineSCH2e), 2.79 (t,
4H, J ¼ 4.5 Hz, thiomorpholineCH2e); 13C NMR (DMSO-d6,
152.4,152.0,139.7,135.3,135.2,132.1,132.0,130.3,129.9,125.9,118.8,
112.2, 105.5, 105.2, 69.4, 51.6, 45.5, 43.8, 26.1; ESIMS: m/z 458
(M þ H)þ; HRMS (ESI) m/z calcd. for C18H21FN3O4S3 (M þ H)þ,
458.0678; found, 458.0688.
5.1.23. (R)-4-Fluoro-N-((3-(3-fluoro-4-thiomorpholinophenyl)-2-
oxooxazolidin-5-yl)methyl)-benzenesulfonamide (7w)
75 MHz):
d
155.3, 153.4, 149.7, 143.2, 142.3, 136.1, 134.1, 132.8,
The compound 7w was prepared according to the above descri-
bed method using 6b (311 mg, 1 mmol) and 4-flurobenzenesulfonyl
chloride (234 mg, 1.2 mmol) with yield 286 mg (61%) m.p: 153e
154 ꢀC; IR (KBr pellet, cmꢁ1): 3328, 2901, 2360, 1736, 1519, 1239,
128.5, 127.8, 125.3, 124.4, 122.3, 121.1, 118.7, 112.9, 70.1, 52.5, 46.3,
44.2, 27.4; ESIMS: m/z 503 (Mþ þ H); HRMS (ESI) m/z calcd. for
C23H24FN4O4S2 (M þ H)þ, 503.1223; found, 503.1237.
1164, 839; 1H NMR (CDCl3, 300 MHz):
d 7.85e7.80 (m, 2H, AreH),
5.1.20. (R)-N-((3-(3-Fluoro-4-thiomorpholinophenyl)-2-
oxooxazolidin-5-yl)methyl)-4-(phenylsulfonyl)thiophene-2-
sulfonamide (7t)
The compound 7t was prepared according to the above descri-
bed method using 6b (311 mg, 1 mmol) and 4-(phenylsulfonyl)
thiophene-2-sulfonylchloride (387 mg, 1.2 mmol) with yield
251 mg (42%), m.p: 163e164 ꢀC; IR (KBr pellet, cmꢁ1): 3299, 2901,
2360, 1760, 1733, 1516, 1336, 1131, 825; 1H NMR (DMSO-d6,
7.72e7.71 (m, 2H, AreH), 7.42 (dd, 1H, J ¼ 15.0, 2.4 Hz, oxa-AreH),
7.07 (dd, 1H, J ¼ 8.7 Hz, oxa-AreH), 6.86 (t, 1H, J ¼ 9.3 Hz, oxa-Are
H), 6.02 (bs, 1H, eNH), 5.11 (m, 1H, oxa-CHe), 4.34e3.97 (m, 2H,
J ¼ 9.3 Hz, oxa-CH2e), 3.44e3.35 (m, 2H, oxa-CH2e), 3.28 (t, 4H,
J ¼ 4.5 Hz, thiomorpholineSCH2e), 2.79 (t, 4H, J ¼ 4.5 Hz,
thiomorpholineCH2e); 13C NMR (CDCl3, 75 MHz):
d 165.5, 156.2,
153.1, 135.6, 128.7, 119.6, 115.4, 115.1, 112.9, 106.5, 106.1, 70.2, 52.5,
46.2, 44.2, 26.8; ESIMS: m/z 470 (M þ H)þ; HRMS (ESI) m/z calcd. for
C20H22F2N3O4S2 (M þ H)þ, 470.1020; found, 470.1039.
300 MHz):
d
8.57 (t, 1H, J ¼ 5.3 Hz, AreH), 8.41 (d, 1H, J ¼ 5.3 Hz,
AreH), 7.97 (d, 2H, J ¼ 7.3 Hz, AreH), 7.80 (s, 1H, AreH), 7.67 (t, 2H,
J ¼ 7.3 Hz, AreH), 7.59 (t, 2H, J ¼ 7.3 Hz, AreH), 7.49 (d, 1H, J ¼ 14.6,
2.4 Hz, oxa-AreH), 7.06 (d, 1H, J ¼ 9.0 Hz, oxa-AreH), 6.94 (t, 1H,
J ¼ 9.0 Hz, oxa-AreH), 4.78e4.72 (m, 1H, oxa-CHe), 4.04 (t, 1H,
J ¼ 8.9 Hz, oxa-CHHe), 3.88 (t,1H, J ¼ 8.9 Hz, oxa-CHHe), 3.39e3.34
(m, 2H, oxa-CH2e), 3.28 (t, 4H, J ¼ 4.5 Hz, morpholineOCH2e), 2.84
(t, 4H, J ¼ 4.5 Hz, morpholineCH2e); 13C NMR (DMSO-d6, 75 MHz):
5.1.24. (R)-4-(2-Fluoro-4-(2-oxo-5-((4-(trifluoromethyl)
phenylsulfonamido)methyl)-oxazolidin-3-yl)phenyl)piperazin-1-yl
pivalate (7x)
The compound 7x was prepared according to the above
described method using 6c (394 mg, 1 mmol) and 4-(tri-
fluoromethyl)benzene-1-sulfonyl chloride (294 mg, 1.2 mmol) with
yield 367 mg (61%) m.p: 166e167 ꢀC; IR (KBr pellet, cmꢁ1): 3150,
2930, 2858, 2360, 1759, 1698, 1513, 1409, 1160, 846; 1H NMR (CDCl3,
d
157.2, 153.0, 144.0, 141.1, 139.6, 136.1, 132.9, 128.7, 127.9, 127.1,
126.5, 119.0, 112.9, 106.5, 106.1, 69.9, 52.3, 46.2, 44.5, 26.9; ESIMS:
m/z 598 (M þ H)þ; HRMS (ESI) m/z calcd. for C24H25FN3O6S4
(M þ H)þ, 598.0610; found, 598.0635.
300 MHz):
d
7.99 (d, 2H, J ¼ 8.3 Hz, AreH), 7.78 (d, 2H, J ¼ 8.3 Hz,
AreH), 7.38 (dd, 1H, J ¼ 14.6, 2.4 Hz, oxa-AreH), 7.04 (d, 1H,
J ¼ 9.0 Hz, oxa-AreH), 6.89 (t, 1H, J ¼ 8.9 Hz, oxa-AreH), 5.95 (bs,
1H, eNH), 4.78e4.70 (m, 1H, oxa-CHe), 4.02 (t, 1H, J ¼ 8.9 Hz, oxa-
CHHe), 3.92 (t, 1H, J ¼ 8.9 Hz, oxa-CHHe), 3.58 (t, 4H, J ¼ 4.7 Hz,
piperzineeNCH2e), 3.41e3.22 (m, 2H, oxa-CH2e), 2.98 (t, 4H,
J ¼ 4.7 Hz, piperzineeCH2e), 1.45 (s, 9H, eC(CH3)3); 13C NMR
5.1.21. (R)-N-((3-(3-Fluoro-4-thiomorpholinophenyl)-2-
oxooxazolidin-5-yl)methyl)-4-(trifluoromethyl)benzenesulfonamide
(7u)
The compound 7u was prepared according to the above
described method using 6b (311 mg, 1 mmol) and 4-(tri-
fluoromethyl)benzene-1-sulfonyl chloride (294 mg, 1.2 mmol) with
yield 301 mg (58%), m.p: 155e156 ꢀC; IR (KBr pellet, cmꢁ1): 3295,
2921, 2360, 1746, 1516, 1326, 1160, 829; 1H NMR (CDCl3, 300 MHz):
(CDCl3, 75 MHz):
d 155.0, 154.4, 154.0, 152.2, 143.3, 137.3, 127.5,
127.4, 126.4, 119.3, 114.1, 107.8, 107.4, 104.8, 79.9, 71.0, 50.6, 50.5,
47.2, 45.4, 28.4; ESIMS: m/z 603 (M þ H)þ; HRMS (ESI) m/z calcd. for
C26H31F4N4O6S (M þ H)þ, 603.1894; found, 603.1889.
d
7.99 (d, 2H, J ¼ 8.3 Hz, AreH), 7.78 (d, 2H, J ¼ 8.3 Hz, AreH), 7.39
(dd, 1H, J ¼ 14.6, 2.4 Hz, oxa-AreH), 7.06 (d, 1H, J ¼ 8.9 Hz, oxa-Are
H), 6.91 (t, 1H, J ¼ 8.9 Hz, oxa-AreH), 5.66 (bs, 1H, eNH), 4.77e4.70
(m, 1H, oxa-CHe), 4.02 (t, 1H, J ¼ 8.9 Hz, oxa-CHHe), 3.92 (t, 1H,
J ¼ 8.9 Hz, oxa-CHHe), 3.41e3.33 (m, 2H, oxa-CH2e), 3.28 (t, 4H,
5.1.25. (R)-4-(2-Fluoro-4-(5-((4-fluorophenylsulfonamido)methyl)-
2-oxooxazolidin-3-yl)phenyl)piperazin-1-yl pivalate (7y)
The compound 7y was prepared according to the above
described method using 6c (394 mg,
1 mmol) and 4-

668
A. Kamal et al. / European Journal of Medicinal Chemistry 62 (2013) 661e669
flurobenzenesulfonyl chloride (234 mg, 1.2 mmol) with yield
348 mg (63%) m.p: 152e153 ꢀC; IR (KBr pellet, cmꢁ1): 3112, 2937,
2858, 2360, 1760, 1696, 1513, 1409, 1160, 846; 1H NMR (CDCl3,
indicated that DMSO has no inhibitory effect on the tested strains
and which was taken as a negative control. Linezolid was used as
the reference compound.
300 MHz):
d
7.90e7.85 (m, 2H, AreH), 7.43 (dd, 1H, J ¼ 15.0, 2.4 Hz,
oxa-AreH), 7.21e7.15 (m, 2H, AreH), 7.07e7.00 (m, 2H, oxa-AreH),
5.74 (bs, 1H, eNH), 4.74 (m, 1H, oxa-CHe), 4.04e3.90 (m, 2H,
J ¼ 9.3 Hz, oxa-CH2e), 3.63 (t, 4H, J ¼ 4.7 Hz, piperzineeNCH2e),
3.37e3.19 (m, 2H, oxa-CH2e), 3.04 (t, 4H, J ¼ 4.7 Hz, piperzinee
5.3. Antifungal assay
The method followed for antifungal bioassay was similar to that
followed for antibacterial assay where the medium was potato
dextrose agar 39 g/L. The equivalent amount of solvent (DMSO) did
not exhibit any activity in the assay. The treated compounds and the
controls were kept in an incubator at 28 ꢃ 2 ꢀC for 48 h. All the
compounds were tested for minimum inhibitory concentration
(MIC). Fluconazole was used as positive control.
CH2e), 1.48 (s, 9H, eC(CH3)3); 13C NMR (CDCl3, 75 MHz):
d 163.4,
154.6, 154.1, 136.6, 135.7, 129.7, 129.5, 119.3, 119.2, 116.6, 116.3, 114.0,
107.7, 107.4, 79.9, 71.1, 50.6, 50.5, 47.2, 45.3, 28.4; ESIMS: m/z 470
(M þ H)þ; HRMS (ESI) m/z calcd. for C25H31F2N4O6S (M þ H)þ,
553.1932; found, 553.1955.
5.1.26. (R)-N-((3-(3-Fluoro-4-(piperazin-1-yl)phenyl)-2-
oxooxazolidin-5-yl)methyl)-4-(trifluoromethyl)benzenesulfonamide
(8a)
5.4. Antimycobacterial assay
The antimycobacterial activities of new oxazolidino-
sulfonamides (7aey and 8aeb) were evaluated against
M. tuberculosis H37Rv using microplate dilution assay [33,34]. All
the compounds were initially screened against M. tuberculosis
The target compound 8a was obtained by slow addition of tri-
fluoroacetic acid (4 mmol) to the solution of 7x (241 mg, 0.4 mmol)
in dry dichloromethane (25 mL) at 0 ꢀC to room temperature for
1 h, after completion of reaction as indicate by TLC the reaction
mixture was neutralized by aq NaHCO3 solution, the isolated
product was triturated in ether and then recrystallized from
methanol. (Yield 160 mg, 80%) m.p: 173e174 ꢀC; IR (KBr pellet,
cmꢁ1): 3150, 2930, 2858, 2360, 1759, 1512, 1160, 846; 1H NMR
H37Rv at the single concentration of 32 mg/mL in triplicate in a mi-
crotiter plate. The active compounds from this screening were
further tested for Minimum Inhibitory Concentration (MIC) deter-
mination using the broth microdilution assay. The microtiter plates
were incubated for 2e3 weeks at 37 ꢀC in CO2 incubator and read
visually for the absence of growth turbidity.
(DMSO-d6, 300 MHz):
d
7.99 (d, 2H, J ¼ 8.3 Hz, AreH), 7.78 (d, 2H,
J ¼ 8.3 Hz, AreH), 7.38 (dd, 1H, J ¼ 14.6, 2.4 Hz, oxa-AreH), 7.04 (d,
1H, J ¼ 9.0 Hz, oxa-AreH), 6.89 (t, 1H, J ¼ 8.9 Hz, oxa-AreH), 5.95
(bs, 1H, eNH), 4.78e4.70 (m, 1H, oxa-CHe), 4.05e3.89 (m, 2H, oxa-
CHHe), 3.58 (t, 4H, J ¼ 4.7 Hz, piperzineeNCH2e), 3.41e3.23 (m,
2H, oxa-CH2e), 2.98 (t, 4H, J ¼ 4.7 Hz, piperzineeCH2e); 13C NMR
Acknowledgement
The authors PS, ABS and MPNR are thankful to CSIR, New Delhi
and UGC, New Delhi for the award of their research fellowship and
also Dr Inshad Ali Khan, Clinical Microbiology Division, CSIR-Indian
Institute of Integrative Medicine, Jammu, India for performing the
antimycobacterial tests.
(DMSO-d6, 75 MHz):
d 155.0, 154.4, 154.0, 143.3, 137.3, 127.5, 127.4,
126.4, 119.3, 114.1, 107.8, 107.4, 104.8, 71.0, 50.6, 50.5, 47.2, 45.4;
ESIMS: m/z 470 (M þ H)þ; HRMS (ESI) m/z calcd. for C21H23F4N4O4S
(M þ H)þ, 503.1376; found, 503.1385.
Appendix A. Supplementary data
5.1.27. (R)-4-Fluoro-N-((3-(3-fluoro-4-(piperazin-1-yl)phenyl)-2-
oxooxazolidin-5-yl)methyl)-benzenesulfonamide (8b)
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2013.01.034.
The compound 8b was prepared according to the above
described method using 7y (221 mg, 0.4 mmol). (Yield 148 mg,
82%), m.p: 166e167 ꢀC; IR (KBr pellet, cmꢁ1): 3112, 2937, 2858,
2360, 1760, 1513, 1160, 846; 1H NMR (DMSO-d6, 300 MHz):
d 7.89e
References
7.84 (m, 2H, AreH), 7.42 (dd, 1H, J ¼ 15.0, 2.4 Hz, oxa-AreH), 7.20e
7.14 (m, 2H, oxa-AreH), 7.04e6.86 (m, 2H, oxa-AreH), 5.73 (bs, 1H,
eNH), 4.76e4.69 (m, 1H, oxa-CHe), 4.03e3.89 (m, 2H, oxa-CH2e),
3.62 (t, 4H, J ¼ 4.7 Hz, piperzineeNCH2e), 3.36e3.18 (m, 2H, oxa-
CH2e), 3.03 (t, 4H, J ¼ 4.7 Hz, piperzineeCH2e); 13C NMR (DMSO-
[1] R.F. Service, Science 270 (1995) 724.
[2] S.B. Levy, B. Marshall, Nat. Med. 10 (2004) S122eS129.
[3] C. Walsh, Nature 406 (2000) 775e781.
[4] C.T. Walsh, Nat. Rev. Microbiol. 1 (2003) 65.
[5] K.K. Karthikeyan, A.T. Mark, R.W. Timothy, B. Jay, B. Fafhana, B. Ravikumar,
C. Uma, D. Michel, G.G. Christian, I. Seema, K. Padma, V.K. Anil, M. Sunil,
M. Shazad, N. Tabassum, L.P. David, P. Andrew, P. Claire, P. Rachel, R. Bhargavi,
R. Ujjwayini, B.S. Jayanta, S. Madhu, S. Elizabeth, A.T. Mandayam, T. Jane,
U. Supriya, W. Marina, W. William, M.L. David, W. Neil, Lancet Infect. Dis. 10
(2010) 597e602.
[6] M.R. Sarbachyn, C.W. Ford, Angew. Chem. Int. Ed. 42 (2003) 2010e2030.
[7] S.J. Brickner, D.K. Hutchinson, M.R. Barbachyn, P.R. Manninen, D.A. Ulanowicz,
S.A. Garmon, K.C. Grega, S.K. Hendges, D.S. Toops, C.W. Ford, G.E. Zurenko,
J. Med. Chem. 39 (1996) 673e679.
d6, 75 MHz):
d 163.4, 154.6, 136.6, 135.7, 129.7, 129.5, 119.3, 119.2,
116.6,116.3, 114.0, 107.7, 107.4, 71.1, 50.6, 50.5, 47.2, 45.3; ESIMS: m/z
453 (M þ H)þ; HRMS (ESI) m/z calcd. for C20H23F2N4O4S (M þ H)þ,
453.1402; found, 453.1396.
5.2. Antibacterial assay
[8] M.R. Barbachyn, D.K. Hutchinson, S.J. Brickner, M.H. Cynamon, J.O. Kilburn,
S.P. Klemens, S.E. Glickman, K.C. Grega, S.K. Hendges, D.S. Toops, C.W. Ford,
G.E. Zurenko, J. Med. Chem. 39 (1996) 680e685.
[9] S. Tsiodras, H.S. Gold, G. Sakoulas, G.M. Eliopoulos, C. Wennersten,
L. Venkataraman, R.C. Moellering, M.J. Ferraro, Lancet 358 (2001) 207e208.
[10] J. Seedat, G. Zick, I. Klare, C. Konstabel, N. Weiler, H. Sahly, Antimicrob. Agents
Chemother. 50 (2006) 4217e4219.
[11] F. Reck, F. Zhou, M. Girardot, G. Kern, C.J. Eyermann, N.J. Hales, R.R. Ramsay,
M.B. Gravestock, J. Med. Chem. 48 (2005) 499e506.
[12] G. Poce, G. Zappia, G.C. Porretta, B. Botta, M. Biava, Expert Opin. Ther. Pat. 18
(2008) 97e121.
All the test compounds were dissolved in DMSO of 2 mg/mL.
Empty sterilized disks of 6 mm were impregnated with compounds
in the range from 1 to 80 mg/disk and placed in triplicate in the
medium inoculated with fresh bacteria (1e2 ꢂ 104 cfu mLꢁ1) on the
freshly prepared sterile Mueller Hilton agar plates [32]. The plates
were incubated at 35 ꢀC for 24 h for zone of inhibition, if any,
around the disks. The lowest concentration (higher dilution) of the
test compound required to arrest the growth of tested strains was
[13] O.A. Phillips, E.E. Udo, A.A.M. Ali, S.M. Samuel, Eur. J. Med. Chem. 42 (2007)
214e225.
[14] O.A. Phillips, E.E. Udo, M.E. Abdel-Hamid, R. Varghese, Eur. J. Med. Chem. 44
(2009) 3217e3227.
regarded as minimum inhibitory concentrations (MICs). 20 mL of
DMSO was loaded on sterile disc and placed on the culture. After
incubation for 24 h, observed no zone of inhibition around the disc,

A. Kamal et al. / European Journal of Medicinal Chemistry 62 (2013) 661e669
669
[15] S.-Y. Kim, H.B. Park, J.-H. Cho, K.H. Yoo, C.-H. Oh, Bioorg. Med. Chem. 19 (2009)
2558e2561.
[27] B.K. Srivastava, R. Soni, J.Z. Patel, M.R. Jain, P.R. Patel, Anti-infect. Agents Med.
Chem. 7 (2008) 258e280.
[16] A.R. Renslo, G.W. Luehr, M.F. Gordeev, Bioorg. Med. Chem. 14 (2006) 4227e4240.
[17] T. Komine, A. Kojima, Y. Asahina, T. Saito, H. Takano, T. Shibue, Y. Fukuda,
J. Med. Chem. 51 (2008) 6558e6562.
[18] Y.W. Jo, W.B. Im, J.K. Rhee, M.J. Shim, W.B. Kim, E.C. Choi, Bioorg. Med. Chem.
12 (2004) 5909e5915.
[19] F. Reck, F. Zhou, C.J. Eyermann, G. Kern, D. Carcanague, G. Ioannidis,
R. Illingworth, G. Poon, M.B. Gravestock, J. Med. Chem. 50 (2007) 4868e4881.
[20] Q. Xin, H. Fan, B. Guo, H. He, S. Gao, H. Wang, Y. Huang, Y. Yang, J. Med. Chem.
54 (2011) 7493e7502.
[21] D.K. Hutchinson, Curr. Top. Med. Chem. 3 (2003) 1021e1042.
[22] R. Sood, T. Bhadauriya, M. Rao, R. Gautam, S. Malhotra, T.K. Barman,
D.J. Upadhyay, Infect. Disord. Drug Targets 6 (2006) 343.
[23] J.V.N. Vara Prasad, Curr. Opin. Microbiol. 10 (2007) 454.
[24] S.J. Brickner, Curr. Pharm. Des. 2 (1996) 175.
[28] A. Kamal, R.V.C.R.N.C. Shetti, S. Azeeza, P. Swapna, M.N.A. Khan, A.M. Reddy,
I.A. Khan, S. Sharma, S.T. Abdullah, Eur. J. Med. Chem. 46 (2011) 893e900.
[29] A. Kamal, K.S. Reddy, S.K. Ahmed, M.N.A. Khan, R.K. Sinha, J.S. Yadav,
S.K. Arora, Bioorg. Med. Chem. 14 (2006) 650e658.
[30] A. Kamal, R.V.C.R.N.C. Shetti, S. Azeeza, S.K. Ahmed, P. Swapna, A.M. Reddy,
I.A. Khan, S. Sharma, S.T. Abdullah, Eur. J. Med. Chem. 45 (2010) 4545e4553.
[31] Calculated log P (C log P) Values were Computed by Using the CS Chem-Draw
Ultra Version 10.0 by CambridgeSoft.Com, Cambridge, MA, USA.
[32] National Committee for Clinical Laboratory Standards, Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically
Approved Standard. NCCLS document M7-A4, fourth ed., National Committee
for Clinical Laboratory Standards, Villanova, PA, 1997.
[33] R. Maccari, R. Ottana, F. Monforte, M.G. Vigorita, Antimicrob. Agents Chemo-
ther. 46 (2002) 294e299.
[25] B. Riedel, R. Endermann, Expert Opin. Ther. Pat. 9 (1999) 625.
[26] M.J. Genin, Expert Opin. Ther. Pat. 10 (2000) 1405.
[34] R.J. Wallace, D.R. Nash, L.C. Steele, V. Steingrube, J. Clin. Microbiol. 24 (1986)
976e981.