RETRACTED ARTICLE: Design, synthesis of novel oxazolidino-amides/sulfonamides conjugates and their impact on antibacterial activity

Article abstract of DOI:10.1007/s11696-017-0298-1

Abstract: In view of generating new compounds for future drug development, we have synthesized oxazolidinones library of aryl amides and aryl sulfonamide derivatives. These compounds were screened in vitro against panel of susceptible and resistant Gram-p

Full text of DOI:10.1007/s11696-017-0298-1

Chem. Pap.
DOI 10.1007/s11696-017-0298-1
ORIGINAL PAPER
Design, synthesis of novel oxazolidino-amides/sulfonamides
conjugates and their impact on antibacterial activity
Yarlagadda Bharath1 Gopi Reddy Alugubelli2 Reddymasu Sreenivasulu3
Mandava. V. Basaveswara Rao4
•
•
•
Received: 2 May 2017 / Accepted: 16 September 2017
Ó Institute of Chemistry, Slovak Academy of Sciences 2017
Abstract In view of generating new compounds for future
drug development, we have synthesized oxazolidinones
library of aryl amides and aryl sulfonamide derivatives.
These compounds were screened in vitro against panel of
susceptible and resistant Gram-positive (Staphylococcus
aureus and Bacillus subtilis), Gram-negative bacteria
(Pseudomonas aeruginosa), fungi (Candida albicans)
strains, and Mycobacterium tuberculosis (Mtb). Among
them, 10d and 11a compounds have been evaluated against
12 fungal strains and have displayed significant antimy-
cotic activities approximately 37 folds more potent than
fluconazole.
Graphical Abstract
O
F
O
F
a) BF3.Et2O,
CH2Cl2, rt;
O
O
X
N
N
H
N
X
N
N
NH2
Ar
b)Aryl/ heteryl acid,
EDCI, HOBt,DCM, rt,
8h
8a-b
11a-j
8a: X = NBoc
8b: X = S
5-nitro furoic acid,
antimycobacterial activity
EDCI, DCM,
rt, 8h
sulfonyl chloride,
pyridine, rt, 2h
F
O
O
F
O
O
O
O
S
N
N
N
H
BocN
N
N
H
N
N
R
NO2
NO2
O
O
O
O
10a-j
9a
Keywords Oxazolidinones Á Antitubercular activity Á
Antimycobacterial activity Á EDC Á Anti-fungal activity
Introduction
The oxazolidinones represent a new class of antimicrobials
with a unique mechanism of action. They are having
admirable activity against susceptible and resistant Gram-
positive organisms such as MRSA (methicillin-resistant
Staphylococcus aureus), VRE (vancomycin-resistant En-
terococci) and PRSP (penicillin-resistant Streptococcus
pneumoniae), and a good adverse effect profile; they can be
administered both intravenously and orally. In addition,
oxazolidinone class antibacterials have good activity
against multidrug-resistant Mycobacterium tuberculo-
sis infections, which are one of the most threatening, wide-
spreading infectious diseases, causative medium for this
infection and have resistance to antibiotics (Martone et al.
1998). Patients suffering from these infections do not
respond to general antibiotic treatments. Most of these
infections are caused by Gram-positive pathogens; among
them most problematic are MRSA, VRE, and PRSP.
Electronic supplementary material The online version of this
article (doi:10.1007/s11696-017-0298-1) contains supplementary
material, which is available to authorized users.
& Mandava. V. Basaveswara Rao
vbrmandava@yahoo.com
1
Division of Chemistry, Department of Sciences and
Humanities, Vignan’s Foundation for Science, Technology
and Research University (VFSTR University), Vadlamudi,
Guntur 522 213, Andhra Pradesh, India
2
Department of Pharmacy, Osmania University, Hyderabad,
Telangana, India
3
Department of Chemistry, University College of Engineering
(Autonomous), Jawaharlal Nehru Technological University,
Kakinada 533 003, Andhra Pradesh, India
4
Department of Chemistry, Dr. MRAR. PG Centre, Krishna
University, Nuzvid 521 201, Andhra Pradesh, India
123

Chem. Pap.
Furthermore, certain Gram-negative strains like Klebsiella
pneumoniae and Pseudomonas aeruginosa also develop
drug resistance towards leading antibiotics (Fridkin et al.
2001; Leclercq et al. 1988; Whitney et al. 2000).
the focus has been on improving the activity and limiting
the cytotoxicity of oxazolidinone based derivatives.
Herein, we describe the synthesis and evaluation of
bacterial and anti-tubercular activity of oxazolidino-aryl
amides and sulfonamide conjugates particularly for drug
resistance bacteria (Barbachyn and Ford 2003; Bar-
bachyn et al. 1999; Johnson et al. 2002; Joseph et al.
2008; Quesnella et al. 2005; Sakoulas et al. 2003;
Tsiodras et al. 2001).
Oxazolidinones are the first new class of antibiotics to
be developed in the past 20 years. In 1978, EI DuPont
de Nemours & Company initially discovered that certain
oxazolidinones had activity against plant pathogens, but
limited activity against human pathogens. Further
development of this class in the late 1980s occurred with
the description of DuP-721 and DuP-105, which had
activity against human pathogens (Brickner 2007; Ford
et al. 2001; Hutchinson 2003; Zurenko et al. 1997). The
discovery of lethal bone marrow toxicity in drug safety
studies performed in rats led to the extinction of
development. Observing for this new class of synthetic
antibacterial agents, Pharmacia and Upjohn began
development and patented many chemical oxazolidinone
congeners (Barbachyn et al. 1997; Brickner 1996).
Oxazolidinones reveal a novel mechanism of action by
inhibiting the initiation of protein synthesis at a site
different from other protein synthesis inhibitors. Pre-
sently, there are only two oxazolidinones: linezolid
(Moise et al. 2002; Peppard and Weigelt 2006), and
eperezolid. Linezolid was an approved drug in the Uni-
ted States and is now accessible in Canada. The chem-
ical structures of these two agents differ with their side
chains on the benzene ring and the addition of a fluorine
atom. Oxazolidinones have activity against many
antibiotic-resistant organisms (mostly Gram-positives),
even those cross-resistant to other protein synthesis
inhibitors (Apodaca and Rakita 2003; Bergeron et al.
2005; Bressler et al. 2004; Gillman 2003; Kalamazoo
2003; Kuter and Tilloston 2001; Wigen and Goetz 2002;
Zivkovic and Lacomis 2005). Exploitation of the
chemical structure continues to broaden the spectrum of
activity and to diminish or eliminate adverse effects.
We synthesized and evaluated a focused library of
oxazolidinone analogs, a currently narrow spectrum class
of antibacterials active only against Gram-positive bac-
teria. In this series, we have explored the effectiveness
for improving Gram-positive activity by identifying and
combining beneficial structural modifications in the
C-ring region (Boyer et al. 2007) and C-5 substituted
(Roehrig et al. 2005; Das et al. 2009; Chen et al. 2015)
When combined in hybrid C-ring modified and C-5 arm
modified oxazolidino-arylamido/sulfonamides (Aoki
et al. 2002; Bobkova et al. 2003; Lin et al. 1997;
Matassaova et al. 1999; Park et al. 1992; Patel et al.
2001; Shinabarger et al. 1997; Zhou et al. 2002; Cooper
et al. 2017; Cano et al. 2006) analogs, seems to largely
overcome the efflux and/or penetrable barriers, resulting
in improved anti-bacterial activity. In the present work,
Results and discussion
Chemistry
The preparation of intermediates oxazolidinyl methyl
amines (Steven et al. 1996) (8a and 8b) had been carried
out by the sequence illustrated in Scheme 1. The treat-
ment of commercially available tert-butyl piperazine-1-
carboxylate (2) with 3, 4-difluoronitrobenzene (1) in
acetonitrile in the presence of diisopropyl ethyl amine
under reflux at 80 °C affords the compounds 3a-b. The
nitro compounds in the presence of 5% Pd/C and H2 are
reduced to their corresponding amines and protected
with benzyl chloroformate to afford compounds 4a-b.
The benzyloxy N-protected compounds (4a-b) have been
treated with (R)-glycidyl butyrate in presence of n-butyl
lithium at -78 °C to gives compounds oxazolidinyl
methanol (5a-b). The intermediates 5a-b treated with
methyl sulfonyl chloride in the presence of triethylamine
in dichloromethane as solvent afford compounds 6a-b.
The mesylated intermediate further undergo in SN2
nucleophilic substitution by azide in presence of sodium
azide under reflux in dimethyl formamide to afford
oxazolidinone azide 7a-b. Further, on reduction in the
presence of hydrogen and palladium carbon in ethyl
acetate, azide (7a-b) converted into corresponding ami-
nes 8a-b.
The synthesis of target compounds 10a-j and 11a-j were
achieved by the procedure described in Scheme 2. The
amine intermediates (8a-b) on coupling reaction with dif-
ferent acids and sulfonyl chlorides to afford final conju-
gates. The oxazolidinone amines (8a-b) treated with 5-nitro
furoic acid in the presence of EDC in dry CH2Cl2, afforded
the amide-coupled compound 9a. Further, the deprotection
of intermediate (9a) by BF3ÁEt2O in CH2Cl2 followed by
treatment with the different sulfonyl chloride in dry pyr-
idine at room temperature afforded C-5 modified oxazolo
sulfonamide analogs (10a-j). The intermediate 8a reacted
with different carboxylic acids and EDC in DCM solvent at
room temperature over 8 h time period then afforded cor-
responding final conjugates 11a-j in good yields.
123

Chem. Pap.
Scheme 1 Reagents and
F
F
F
conditions: (i) ACN, DIEA,
reflux, 3 h; (ii) Pd/C 10%, H2,
methanol, 12 h; (iii) benzyl
chloroformate, acetone, aq.
NaHCO3, 12 h; (iv) (R)-(-)-
glycidylbutyrate, THF, n-BuLi,
-78 °C to rt, 12 h; (v) MsCl,
CH2Cl2, TEA, 5 h; (vi) NaN3,
DMF, reflux, 5 h; (vii) H2, Pd/
C, methanol, 2 h
H
N
F
ii
X
N
NHCbz
i
X
N
NO2
iii
X
4a-b
NO2
3a-b
2
1
iv
O
F
O
F
vi
O
O
v
X
N
O
N
X
N
N
OMs
OH
6a-b
5a-b
O
F
O
F
vii
O
X
N
N
X
N
N
NH2
N3
8a-b
7a-b
a X = NBoc
b X = S
Scheme 2 Reagents and
O
F
O
F
conditions: (viii) 5-nitro furoic
acid, EDC, CH2Cl2, rt, 8 h; (ix)
carboxylic acid, EDC, CH2Cl2,
rt, 8 h; (x) (a) BF3ÁEt2O,
O
viii
O
X
N
N
BocN
N
N
H
NH2
N
NO2
O
8a-b
9a
O
8a: X = NBoc
8b: X = S
CH2Cl2, rt; (b) sulfonyl
chloride, pyridines, rt, 2 h
x
ix
O
F
O
F
O
O
O
S
N
N
N
H
N
X
N
N
H
N
O R
NO2
O
10a-j
R1
O
11a-j
10a: R = Methyl
11a: R1 = (E)-2, 3-diphenylacrylic acid , X=S
11b: R1 = Benzofuran-3-carboxylic acid ,X=S
11c R1 = Pyrazine-2-carboxylic acid ,X=S
11d: R1 = 5-methylbenzo[b]thiophene-2-carboxylic acid , X=S
11e: R1= (E)-3-(5-(4-chlorophenyl)furan-2-yl)acrylic acid , X=S
11f: R1 = N-Boc piperazine-1-carboxylic acid , X=S
11g: R1 = N-Boc piperazine-1-carboxylic acid , X = NBoc
11h: R1 = Pyrazine-2-carboxylic acid , X = NBoc
10b: R = 4-Methylphenyl
10c: R = 4-Acetylphenyl
10d: R = 3-Trifluoromethylphenyl
10e: R = 4-Methoxyphenyl
10f: R = 4-Chlorophenyl
10g: R = 4-Fluorophenyl
10h: R = 2.4-Difluorophenyl
10i: R = 3,4-Difluorophenyl
10j: R = 8-Quinolyl
11i: R1 = 5-methyl-1H-indole-2-carboxylic acid , X= NBoc
11j: R1 = 2-chloronicotinic acid , X= NBoc
Biological activity
aureus (MTCC96), Bacillus subtilis (MTCC121), S. aureus
(MLS-16)(MTCC2940), Gram-negative strain P. aerugi-
nosa bacteria (MTCC 2453) and the antifungal activity was
evaluated against yeast Candida albicans (MTCC 3017).
The inhibitory zones (in mm) are determined by agar well
method (Amsterdam and Loman 1996; Wallace et al.
Antimicrobial activity
The compounds 10a-j and 11a-j have been screened for
their antibacterial activity against Gram-positive strains S.
123

Chem. Pap.
1986), Neomycin and fluconazole are used as positive
controls against bacteria and fungi, respectively.
surface. This procedure was repeated by streaking two
more times, rotating the plate approximately 60 °C each
time to ensure even distribution of the inoculums. As a
final step, the rim of the agar was also swabbed. After
allowing the inoculums to dry at room temperature, 6 mm
diameter wells were prepared in the agar with the help of
sterilized cork bore. The different concentrations of test
compounds (50, 100 lg/ml) were prepared by dissolving in
dimethyl sulfoxide (DMSO) and introduced into duplicate
wells. The plates were incubated at 37 °C for 24 h. Sub-
sequently, the plates were examined for bacterial growth
inhibition and the inhibition zone diameters (IZD) mea-
sured to the nearest millimeter.
The results summarized in Table 1 show that all com-
pounds exhibited moderate to good antibacterial activity.
All compounds have shown significant inhibition against
all the bacteria tested and were not strain dependent. In the
C-ring modified series, the compound and 10a, 10d, 10g,
10h and 10i are the most active due to containing fluorine
atom; the sensible introduction of fluorine into a molecule
can productively influence conformation, pKa, intrinsic
potency, membrane permeability, metabolic pathways,
pharmacokinetic properties and shows good activity com-
pared to remaining compounds. The compounds 11b, 11d
and 11e showed good anti-bacterial activity due to the
presence of benzfuran, benzothiophene and furan structural
moieties in the parent structures. The antibacterial screen-
ing of the synthesized compounds was determined by the
well diffusion method according to Lindsay. Three to five
identical colonies from each agar plate were lifted with a
sterile wire loop and transferred into a tube containing
5 mL of Nutrient Agar. Nutrient Agar plates were inocu-
lated by streaking the swab over the entire sterile agar
Based on the above antibacterial study, we performed
antifungal screening of two compounds 10d and 11a car-
ried out fewer than twelve strains of C. albicans. The
investigation of antifungal screening data is summarized in
Table 2, which reveals that both the compounds showed
good fungal inhibition. The oxazolidinone derivatives (10d
and 11a) exhibited very good inhibitory activity against
fungal strain C. albicans (1.17–2.34 lg/mL). The method
followed for antifungal assay, where the medium is potato
Table 1 Antibacterial and antifungal activity of oxazolidinones (10a-j and 11a-j)
Compounds Minimum inhibitory concentration (lg/mL)
Staphylococcus
aureus (MTCC 96)
Bacillus subtilis
(MTCC 121)
Staphylococcus aureus (MLS- Pseudomonas aeruginosa Candida albicans
16) (MTCC 2940)
(MTCC 2453)
(MTCC 3017)
10a
18.75
37.5
37.5
150
4.68
4.68
75
1.1
4.68
18.75
4.6
1.1
1.1
10b
2.34
37.5
18.75
37.5
9.37
75
4.68
4.6
4.68
4.6
10c
10d
75
75
37.5
–
10e
–
–
10f
9.37
37.5
18.75
18.75
9.37
75
4.68
75
9.37
37.5
9.37
18.75
9.37
18.75
4.6
10g
10h
37.5
37.5
–
37.5
37.5
2.34
9.37
37.5
2.34
2.34
2.34
37.5
9.37
37.5
37.5
–
18.75
18.75
4.68
3.37
18.75
4.68
4.68
4.68
18.75
75
10i
10j
11a
18.75
37.5
18.75
37.5
37.5
37.5
–
11b
18.75
4.68
18.75
4.68
18.75
75
11c
4.68
4.68
4.68
4.6
11d
11e
11f
11g
37.5
4.6
11h
37.5
37.5
–
18.75
4.6
18.75
4.6
11i
18.75
–
11j
–
–
Neomycin
Fluconazole
18.75
–
18.75
–
18.75
–
9.45
–
–
75
Standard drug for bacteria: Neomycin and Standard drug for fungi: Fluconazole (zone of inhibition internal diameter: 6 mm)
123

Chem. Pap.
Table 2 Antimycotic activity
of oxazolidinone derivatives
(10d and 11a) against twelve
different strains of Candida
albicans
Test organism
Minimum inhibitory concentration (lg/mL)
10d
11a
Fluconazole
Candida albicans MTCC 183 (ATCC 2091)
Candida albicans MTCC 227 (ATCC 10231)
Candida albicans MTCC 854
1.17
2.34
2.34
1.17
2.34
2.34
1.17
2.34
2.34
2.34
2.34
2.34
2.34
2.34
2.34
2.34
2.34
2.34
2.34
2.34
2.34
2.34
2.34
2.34
37.5
37.5
37.5
75
Candida albicans MTCC 1637 (ATCC 18804)
Candida parapsilosis MTCC 1744
18.75
37.5
37.5
75
C. albicans MTCC 3018 (ATCC 24433)
Candida albicans MTCC 3958
C. albicans MTCC 3017 (ATCC 90028)
Candida glabrata MTCC 3019 (ATCC 90030)
Issatchenkia orientalis MTCC 3020 (ATCC 749)
Issatchenkia hanoiensis MTCC 4755
75
150
150
75
Candida aaseri MTCC 1962 (ATCC 18805)
dextrose agar (39 g/L). All test compounds were studied
for their antifungal activity at concentration 50–100 lg/mL
using DMSO as a solvent. The solvent did not exhibit any
activity at the concentrations used. The treated and the
controls were kept in an incubator at 28 2 °C for 48 h
and inhibition zones were measured to the nearest mil-
limeter value. Three replicates were maintained for each
treatment for each treatment. Fluconazole (50 lg/mL) was
used as positive control.
Table 3 Anti-mycobacterial activity of oxazolidinones against M.
tuberculosis (H37Rv) expressed in MIC (lg/mL)
Compound
C log P
CMR
MIC (lg/ml)
9a
3.22
1.25
2.92
3.07
3.14
3.21
3.64
4.05
3.09
2.80
2.50
3.42
2.92
4.10
2.40
2.67
4.75
3.17
3.81
4.95
3.08
–
13.06
11.89
13.94
13.95
13.97
13.97
14.43
14.92
14.56
15.17
14.90
14.40
15.42
15.63
15.27
14.55
15.79
15.01
14.45
14.82
13.52
–
1
10a
10b
10c
10d
10e
10f
2
8
8
8
8
8
Antimycobacterial activity
10g
10h
10i
16
16
All the synthesized compounds (10a-j and 11a-j) have
been evaluated for the antimycobacterial activity and the
results are summarized in Table 3. All compounds were
initially screened against M. tuberculosis H37Rv at the
single concentration of 100 (lg/mL). Minimum inhibitory
concentrations (MIC in lg/ml) of compounds against of
mycobacterium were determined by reference agar dilution
method (Ramos et al. 2008) as per the NCCLS-M24-T2
recommendations. The compounds and reference drug
were dissolved in DMSO and diluted twofold to obtained
ten serial dilutions of compound. Appropriate volumes of
compounds were incorporated into duplicate plates of
Middle brook 7H10 agar medium supplemented with 10%
Middle brook supplement oleic acid-albumin-dextrose-
catalase (OADC) enrichment at concentration of
0.03–16 lg/mL. Test organisms (mycobacterium strains)
were grown in Middle brook 7H9 broth containing 0.05%
Tween-80 and 10% ADC supplement. After 10 days of
incubation at 37 °C, the broths were adjusted to the tur-
bidity of 0.5 McFarland standards. The organisms were
further diluted tenfold in sterile water containing 0.01%
Tween-80. The resulting mycobacterial suspension were
spotted (3–5 ll/spot) onto drug-supplemented 7H10 media
[ 16
16
10j
11a
11b
11c
11d
11e
11f
8
[ 16
[ 16
[ 16
8
[ 16
[ 16
8
11g
11h
11i
16
11j
[ 16
1
Linezolid
C log P (hydrophobicity); and CMR (molar refractivity) calculated
using the ChemDraw Ultra, version 10.0
plates. The MIC was recorded as the highest dilution/
lowest concentration of drug that completely inhibited the
growth of mycobacterial cultures. Rifampicin was used as
reference drug; most of these compounds have shown
activity between 1 and 16 lg/mL. Among these, C-5 sub-
stituted compounds showed promising in vitro antimyco
123

Chem. Pap.
bacterial activity than the standard drug linezolid. C log P
(Hydrophobicity); and CMR (molar refractivity) was cal-
culated using the ChemDraw Ultra, version 10.0.
temperature until completion of the reaction as indicated by
TLC. The reaction mixture was neutralized by sodium
bicarbonate solution and extracted with CH2Cl2. The organic
layer was washed with brine, dried over MgSO4, and con-
centrated under reduced pressure. The residue, thus,
obtained was purified by column chromatography on silica
gel using ethyl acetate/hexane (7:3) to afford pure compound
(9a). Yield: 88%; 1HNMR (300 MHz, CDCl3): d 7.99 (1H, t,
J = 6.04 Hz), 7.39 (1H, dd, J = 12.27, 2.45 Hz), 7.33 (1H,
d, J = 3.77 Hz), 7.26 (1H, d, J = 3.77 Hz), 7.06 (1H, dd,
J = 6.98, 1.88 Hz), 6.89 (1H, t, J = 9.25, 8.87 Hz), 4.92
(1H, m), 4.14 (1H, t, J = 9.06, 8.87 Hz), 4.00–3.92 (1H, m),
3.84–3.74 (2H,m), 3.58 (4H, m), 2.97 (4H, m), 1.48 (9H, s);
ESI–MS: m/z = 534 (M ? l)?.
Conclusion
In conclusion, we synthesized some oxazolidinones to
investigate the effect of the C-ring and C-5 substituents for
antibacterial activity. It was proved that the antibacterial
activity was greatly affected by an alternation of the C-ring
and C-5 substituents has been designed, synthesized and
evaluated against M. tuberculosis H37Rv, bacterial strains
and fungal strains. The compounds 10a, 10d, 10g, 10h, 10i
and 11b, 11d, 11e and 11f have shown remarkable
antimycobacterial activity better than equal to linezolid.
Further, the compounds 10d and 11a were found to be
more potent against twelve fungal strains than the standard
drug ‘‘fluconazole’’. Therefore, it is worth further evalua-
tion for new generation oxazolidinone candidate that will
be available for the clinical treatment of serious infections
caused by multi-drug Gram-positive bacteria.
General procedure for the synthesis of (S)-N-((3-(3-
Fluoro-4-(4-(methyl sulfonyl) piperazin-1-yl)
phenyl)-2-oxooxazolidin-5-yl) methyl) -5-nitrofuran-
2-carboxamide (10a)
The target compound 10a was obtained by treating 9a
(533 mg, 1 mmol) with BF3ÁEtO2 (2 mL, 1.5 mmol) in
CH2Cl2 in first step, the crude deprotected compound was
directly reacted with methyl sulfonyl chloride (1.2 ml,
1 mmol) in the presence of triethyl amine (3.3 mL,
3 mmol) in dry THF (50 ml). After stirring the reaction
mixture for 6 h, the reaction mixture was poured on to
crushed ice (1.4 g) and the reaction mixture extracted and
purified by column chromatography affords final product
10a as yellow solid. (Yield 400 mg, 78%); 1HNMR
(300 MHz, CDCl3): d 7.51–7.43 (1H, dd, J = 11.33,
2.26 Hz), 7.36 (1H, d, J = 3.7 Hz), 7.28 (1H, d,
J = 3.7 Hz), 7.08 (1H, dd, J = 7.5,1.5 Hz), 6.93 (1H, t,
J = 9.0, 8.3 Hz), 4.89 (1H, m), 4.12 (1H, dd, J = 9.05,
4.5 Hz), 4.00-3.90 (1H, dd, J = 11.3, 7.55 Hz), 3.77 (1H,
dd, I = 7.5 Hz), 3.41 (4H, t, J = 5.2, 4.5 Hz), 3.14 (4H, t,
J = 5.2, 4.5 Hz), 2.83 (3H, S); 13CNMR (75 MHz,
CDCl3): d 28.90, 42.32, 44.33, 48.14, 50.98, 80.26, 114.23,
119.64, 133.47, 136.96, 143.13, 143.92, 144.70, 148.10,
154.21 (d, J = 243.6 Hz), 155.03, 157.50, 164.30;
Experimental
General: All commercially available chemicals were used
without further purification. The 1H NMR spectra were
recorded on Bruckner Avance 300 magnetic resonance
spectrometer at 300 MHz in CDCl3 and 13C NMR 75 MHz
in CDCl3 with TMS as internal standard (chemical shifts
and ppm). Coupling constant (j) is reported in hertz (Hz).
ESI–MS were obtained on Thermo-Finningan MAT-1020B
instrument. Elemental analysis was carried out with a
Perkin Elmer 2400 Series IICHNS/O elemental ana-
lyzer(Elemental Analyzer, Model PE2400 CHNS/O
(PerkinElmer, Shelton, CT, USA) with PC based data
system, PE Data manager 2400 for Windows and a Perk-
inElmer AD-6 Ultra Micro Balance. This instrument can be
run in three different modes; carbon, hydrogen and nitro-
gen (CHN) mode, CHNS mode or oxygen mode). All
moisture sensitive reactions were conducted under a
nitrogen atmosphere in oven-dried glassware.
ESI–MS: m/z = 512 (M ? 1)?. Elemental analysis
Calcd for C20H22FN5O8S: C, 46.96; H, 4.34; N, 13.69; O,
25.02; S, 6.27; Found: C, 46.98; H, 4.38; N, 13.83; O,
25.12; S, 6.32.
General procedure for the synthesis of (R)-tert-
butyl-4-(2-fluoro-4-(5-((5-nitrofuran-2-
carboxamido) methyl)-2-oxooxazolidin-3-yl) phenyl)
piperazine-1-carboxylate (9a)
(S)-N-((3-(3-Fluoro-4-(4-tosylpiperazin-1-yl)
phenyl)-2-oxooxazolidin-5-yl) methyl)-5-nitrofuran-
2-carboxamide (10b)
To a stirred solution of 8a (394 mg, 1 mmol) in CH2Cl2
(15 mL) was added l-(3-dimethylaminopropyl)-3-ethylcar-
bodimide hydrochloride (EDC) (382 mg, 2 mmol) in ice
bath followed by the addition of 5-nitro furoic acid (314 mg,
2 mmol). The resulting mixture was stirred at room
The compound (10b) was obtained from 9a (533 mg,
1 mmol) and 4-methylbenzene-l-sulfonyl chloride
(380 mg, 2 mmol) according to the procedure as described
for 10a.
123

Chem. Pap.
1
Yield: 80%; HNMR (300 MHz, CDCl3): d 8.95 (1H,
m), 7.67 (2H, d, J = 7.5 Hz), 7.51–7.30 (5H, m), 7.07 (1H,
dd, J = 8.30 Hz), 6.91 (1H, dd, J = 9.06 Hz), 4.89 (1H,
m), 4.07 (1H, dd, J = 9.06, 8.30 Hz), 3.7 (6H, m), 3.47
(1H, dd, J = 6.7 Hz), 3.13 (4H, m), 2.46 (3H, s); 13CNMR
(75 MHz, CDCl3) d 27.90, 41.32, 45.33, 48.14, 51.98,
80.26, 115.23, 120.64, 133.47, 136.96, 144.13, 145.92,
144.70, 148.10, 155.03, 155.21(d, J = 242.6 Hz), 156.50,
164.30; ESI–MS: m/z = 588 (M ? 1)?. Elemental analy-
sis Calcd for C26H26FN5O8S: C, 53.15; H, 4.46; N, 11.92;
O, 21.78; S, 5.46; Found: C, 53.18; H, 4.48; N, 11.94; O,
21.82; S, 5.49.
134.91, 140.14, 144.47, 146.31, 152.08, 154.88 (d,
J = 243 Hz), 156.45, 164.61; ESI–MS: m/z = 642
(M ? 1)?. Elemental analysis. Calcd for C26H23F4N5O8S:
C, 48.68; H, 3.61; N, 10.92; O, 19.95; S, 5.00; Found: C,
48.71; H, 3.62; N, 10.94; O, 19.95; S, 5.04.
(S)-N-((3-(3-Fluoro-4-(4-(4-methoxyphenylsulfonyl)
piperazin-1-yl)] phenyl)-2-oxooxazolidin-5-yl)
methyl)-5-nitrofuran-2-carboxamide (10e)
The compound (10e) was obtained from 9a (533 mg,
1 mmol) and 4-methoxybenzene-l-sulfonyl chloride
(307 mg, 1.5 mmol) according to the procedure as descri-
bed for 10a.
(S)-N-((3-(4-(4-(4-acetylphenylsulfonyI) piperazin-l-
yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl)-5-
nitrofuran-2-carboxamide (10c)
Yield: 80%; 1H NMR (300 MHz, CDCl3): d 7.73 (2H, d,
J = 9.00 Hz), 7.41 (1H, d, J = 12.0. 2.02 Hz), 7.34 (1H,
d, J = 4.00 Hz), 7.21 (2H, dd, J = 6.00 Hz), 7.12 (1H, t,
J = 6.0 Hz), 7.02 (2H, d, J = 9.0 Hz), 6.89 (1H, t,
J = 9.00 Hz), 4.83 (1H, m), 4.06 (1H, m), 3.94 (1H, m),
3.8 (3H, s), 3.7 (2H, m), 3.15 (4H, m), 3.10 (4H, m);
13CNMR (75 MHz, CDCl3): d 42.67, 47.61, 46.37, 50.45,
70.72, 105.89, 112.12, 115.38, 115.57, 120.08, 127.50,
127.48, 133.32, 134.71, 138.64, 139.75, 147.60, 150.97,
153.10, 153.69 (d, J = 242.6 Hz), 157.88, 164.92; ESI–
MS: m/z = 604 (M ? 1)?. Elemental analysis Calcd for
C26H26FN5O9S: C, 51.74; H, 4.34; N, 11.60; O, 23.86; S,
5.31; Found: C, 51.76; H, 4.38; N, 11.70; O, 23.86; S, 5.34.
The compound (10c) was obtained from 9a (533 mg,
1 mmol) and 4-acetylbenzene-l-sulfonyl chloride (434 mg,
2 mmol) according to the procedure as described for 10a.
Yield: 82%; 1H NMR (300 MHz, CDCl3): d 8.11 (2H, d,
J = 7.99 Hz), 7.89 (2H, d, J = 7.99 Hz), 7.39 (1H, d,
J = 13.99 Hz), 7.34 (1H, d, J = 7.99 Hz), 7.22 (1H, d,
J = 7.9 Hz), 7.05 (1H, d, J = 7.99 Hz), 6.88 (1H, t,
J = 8.99 Hz), 4.17 (1H, m), 4.08 (1H, dd, J = 7.99,
8.99 Hz), 3.95 (2H, m), 3.77 (H, dd, J = 8.99, 6.99 Hz),
3.21 (4H, m), 3.12 (4H, m), 2.66(3H, s); 13CNMR
(75 MHz, CDCl3): d 26.02, 41.24, 45.18, 46.94, 49.02,
70.00, 106.11, 106.90, 111.69, 113.06, 115.14, 118.60,
127.14, 128.14, 132.92, 138.02, 139.32, 147.17, 150.54,
153.23, 155.92 (d, J = 242.6 Hz), 156.45, 195.61; ESI–
MS: m/z = 616 (M ? 1)?. Elemental analysis Calcd for
C27H26FN5O9S: C, 52.68; H, 4.26; N, 11.38; O, 23.39; S,
5.21; Found: C, 52.71; H, 4.32; N, 11.44; O, 23.42; S, 5.29.
(S)-N-((3-(4-(4-(4-Chlorophenylsulfonyl) piperazin-
l-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl)-
5-nitrofuran-2-carboxamide (10f)
The compound (10f) was obtained from 9a (533 mg,
1 mmol) and 4-chlorobenzene-1-sulfonyl chloride
(313 mg, 1.5 mmol) according to the procedure as descri-
bed for 10a.
(S)-N-((3-(3-fluoro-4-(4-(3-(trifluoro methyl)phenyl
sulfonyl) piperazin-l-yl) phenyl)-2-oxooxazolidin-5-
yl) methyl)-5-nitrofuran-2-carboxamide (10d)
1
Yield: 84%; H NMR (300 MHz, CDCl3): d 8.91 (1H,
m), 7.79 (2H, d, J = 8.70 Hz), 7.49 (1H, dd, J = 9.18,
2.26 Hz), 7.36 (1H, d, J = 4.37 Hz), 7.13 (2H, d,
J = 5.17 Hz), 7.02 (1H, t, J = 5.17 Hz), 6.96 (2H, d,
J = 8.70 Hz), 4.81 (1H, m), 4.01 (1H, m), 3.89 (1H, m),
3.65 (2H, m), 3.17 (4H, m), 3.09 (4H, m); 13CNMR
(75 MHz, CDCl3): d 41.67, 45.61, 47.37, 49.45, 70.72,
106.89, 112.12, 113.38, 115.57, 119.08, 127.50, 128.48,
133.32, 134.71, 138.64, 139.75, 147.60, 150.97, 153.10,
153.69 (d, J = 243.6 Hz), 156.88, 165.21; ESI–MS: m/
z = 608 (M ? 1)?. Elemental analysis Calcd for C25H23-
ClFN5O8S: C, 49.39; H, 3.81; Cl, 5.83; N, 11.52; O, 21.05;
S, 5.27; Found: C, 49.41; H, 3.85; N, 11.60; O, 21.06; S,
5.29.
The compound (10d) was obtained from 9a (533 mg,
1 mmol) and 3-(trifluoromethyl) benzene-l-sulfonyl chlo-
ride (366 mg, 1.5 mmol) according to the procedure as
described for 10a.
1
Yield: 75%; H NMR (300 MHz, CDCl3): d 8.99 (1H,
m), 8.49 (1H, t, J = 7.65 Hz), 8.16 (1H, s), 8.08 (1H, d,
J = 5.74), 7.99 (2H, m), 7.84 (1H, dd, J = 7.65 Hz), 7.69
(1H, d, J = 7.65 Hz), 7.54 (1H, t, J = 7.65 Hz), 7.3 (1H,
d, J = 2.87 Hz), 7.1 (1H, d, J = 8.6 Hz), 4.86 (1H, m),
4.08 (1H, t, J = 8.92 Hz), 3.95 (1H, dd, J = 8.9, 4.9 Hz),
3.74 (1H, m), 3.21 (4H, m), 3.11 (4H, m); 13CNMR
(75 MHz, CDCl3): d 41.33, 44.10, 45.45, 45.62, 47.73,
111.48, 114.11, 118.03, 123.92, 125.45, 125.67, 128.33,
128.77 (q, J = 272.4 Hz), 129.71, 129.96, 130.86, 133.36,
123

Chem. Pap.
1
(S)-N-((3-(3-Fluoro-4-(4-(4-fluorophenylsulfonyl)
piperazin-1-yl) phenyl)-2-oxooxazolidin-5-yl)
methyl)-5-nitrofuran-2-carboxamide (10g)
Yield: 88%; H NMR (300 MHz, CDCl3): d 9.01 (1H,
m), 8.09 (1H, d, J = 7.65 Hz), 8.04–7.97 (2H, m),
7.84–7.82 (1H, m), 7.68 (1H, d, J = 8.68 Hz), 7.53 (1H, d,
J = 7.65, 6.7 Hz),7.34–7.29 (1H, m), 7.10 (1H, t,
J = 8.61 Hz), 4.94–4.90 (1H, m), 4.11 (1H, t, J = 4.7 Hz),
3.95 (1H, m), 3.84 (2H, m), 3.67–3.62 (4H, m), 3.49-3.45
(4H, m); 13C NMR (75 MHz), CDCl3): d 41.78, 44.47,
46.00, 48.18, 69.71, 111.57, 111.93, 114.51, 118.48,
127.74, 128.78, 129.44, 130.10, 130.40, 131.33, 140.59,
145.05, 146.35, 146.68, 150.01, 152.53 (d, J = 242.6 Hz),
153.78 (d, J = 242.4 Hz), 155.45 (d, J = 243.2 Hz),
158.12, 164.29; ESI–MS: m/z = 610 (M ? 1)?. Elemental
analysis Calcd for C25H22F3N5O8S: C, 49.26; H, 3.64; N,
11.49; O, 21.00; S, 5.26; Found: C, 49.29; H, 3.65; N,
11.49; O, 21.06; S, 5.29.
The compound (10g) was obtained from 9a (533 mg,
1 mmol) and 4-fluorobenzene-l-sulfonyl chloride (289 mg,
1.5 mmol) according to the procedure as described for 10a.
1
Yield: 86%; H NMR (300 MHz, CDCl3): d 8.95 (1H,
m), 8.12 (2H, d, J = 8.00 Hz), 7.90 (2H, d, J = 8.00 Hz),
7.42(1H, dd, J = 11.99, 2.00 Hz), 7.35 (1H, d,
J = 4.00 Hz), 7.22 (1H, m), 7.07 (1H, d, J = 8.00 Hz),
6.89 (1H, t, J = 9.0 Hz), 4.91 (1H, m), 3.97–3.93 (2H, m),
378–3.74 (2H, m), 3.24–3.21 (4H, m), 3.13-3.11 (4H, m);
13CNMR (75 MHz, CDCl3): d 41.70, 45.63, 47.47, 49.48,
70.75, 112.18, 115.63, 119.05, 125.37, 127.18, 128.77,
129.19, 132.70, 134.59, 145.30, 145.88, 147.56, 151.03 (d,
J = 243.4 Hz), 153.76 (d, J = 242.6 Hz), 156.88, 162.34;
ESI–MS: m/z = 592 (M ? 1)?. Elemental analysis Calcd
for C25H23F2N5O8S: C, 50.76; H, 3.92; N, 11.84; O, 21.64;
S, 5.42; Found: C, 50.79; H, 3.95; N, 11.88; O, 21.66; S,
5.44.
(S)-N-((3-(3-Fluoro-4-(4-(quinolin-8-ylsulfonyl)
piperazin-1-yl) phenyl)-2-oxooxazolidin-5-yl)
methyl)-5-nitrofuran-2-carboxamide (10j)
The compound (10j) was obtained from 9a (533 mg,
1 mmol) and quinoline-8-sulfonyl chloride (339 mg,
1.5 mmol) according to the procedure as described for 10a.
Yield: 89%; 1H NMR (300 MHz, CDCl3): d 9.09 (1H, d,
J = 2.26 Hz), 8.86 (1H, m), 8.50 (1H, dd, J = 7.51,
1.52 Hz), 8.25 (1H, dd, J = 6.79, 1.5 Hz), 8.06 (1H, dd,
J = 6.79, 1.5 Hz), 7.67–7.62 (1H, dd, J = 8.30, 7.5 Hz),
7.54 (1H, m), 7.44–7.34 (3H, m), 7.09–7.04 (1H, m), 6.91
(1H, t, J = 8.30 Hz), 4.87 (1H, m), 4.14–4.07 (2H, m),
3.80–3.74 (2H, m), 3.63–3.59 (4H, m), 3.12–3.08 (4H, m);
13C NMR (75 MHz, CDCl3): d 41.78, 44.47, 46.00, 48.18,
69.71, 111.57, 111.93, 114.51, 118.48, 127.74, 128.78,
129.44, 130.10, 130.40, 131.33, 140.59, 145.05, 146.35,
146.68, 150.01, 152.53, 153.91 (d, J = 242.3 Hz), 155.45,
158.12; ESI–MS: m/z = 625 (M ? 1)?. Elemental analy-
sis Calcd for C28H25FN6O8S: C, 53.84; H, 4.03; N, 13.46;
O, 20.49; S, 5.13; Found: C, 53.89; H, 4.05; N, 13.49; O,
20.49; S, 5.19.
(S)-N-((3-(4-(4-(2, 4-Difluorophenylsulfonyl)
piperazin-l-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)
methyl)-5-nitrofuran-2-carboxamide (10h)
The compound (10h) was obtained from 9a (533 mg,
1 mmol) and 2, 4-difluorobenzene-l-sulfonylchloride
(316 mg, 1.5 mmol) according to the procedure as descri-
bed for 10a.
1
Yield: 86%; H NMR (300 MHz, CDCl3): d 8.93 (1H,
m), 7.67 (1H, d, J = 3.77 Hz), 7.50–7.35 (4H, m), 7.31
(1H, d, J = 3.02 Hz), 6.91 (1H, t, J = 8.30, 2.2.6 H), 4.88
(1H, m), 4.12–4.02 (1H, m), 3.89–3.85 (1H, m), 3.79–3.73
(2H, m), 3.19–3.07 (4H, m), 2.98–2.94 (4H, m); 13C NMR
(75 MHz), CDCl3): d 42.78, 45.47, 47.00, 48.50, 67.71,
115.57, 111.93, 115.51, 118.48, 125.74, 128.78, 130.44,
130.10, 130.40, 131.33, 140.59, 145.05, 146.35, 146.68,
150.01, 152.53 (d, J = 242.3 Hz), 153.45 (d,
J = 243.1 Hz), 155.45 (d, J = 242.6 Hz), 156.12, 162.92,
165.31; ESI–MS: m/z = 610 (M ? 1)?. Elemental analy-
sis Calcd for C25H22F3N5O8S: C, 49.26; H, 3.64; N, 11.49;
O, 21.00; S, 5.26; Found: C, 49.29; H, 3.65; N, 11.49; O,
21.06; S, 5.27.
General procedure for the synthesis of (S)-N-((3-(3-
Fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-
yl) methyl)-2, 3-diphenylacrylamide (11a)
Compound 11a prepared by amide bond formation between
(R)-5-(amino methyl)-3-(3-fluoro-4-thiomorpholinophenyl)
oxazolidin-2-one (8b, 155 mg, 0.50 mmol) and (E)-2,
3-diphenylacrylic acid (156 mg, 0.7 mmol) in dry CH2Cl2.
The coupling reagents EDC (1.2 mmol) and HOBt
(1.2 mmol) were added, and the reaction mixture was
stirred at room temperature for 10 h. After completion of
reaction as indicated by TLC, the reaction mixture was
quenched with NaHCO3 and extracted in EtOAc
(4 9 25 ml) from the ice-cold aqueous layer and dried
(S)-N-((3-(4-(4-(3, 4-Difluorophenylsulfonyl)
piperazin-l-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)
methyl)-5-nitrofuran-2-carboxamide (10i)
The compound (10i) was obtained from 9a (533 mg,
1 mmol) and 2, 4-difluorobenzene-l-sulfonylchloride
(316 mg, 1.5 mmol) according to the procedure as descri-
bed for 10a.
123

Chem. Pap.
over anhydrous MgSO4. The resulting product 10a was
purified by column chromatography to afford 232 mg, a
3.99–3.94 (1H, m), 8.87–8.82 (1H, m), 3.80–3.77 (1H, dd,
J = 9.00, 6.25 Hz), 3.58 (4H, m), 2.68 (4H,m); 13C NMR
(100.6 MHz, CDCl3): d 25.98, 42.20, 49.58, 51.18, 72.55,
103.60, 111.76, 115.05, 128.47, 142.72, 144.31, 147.64,
151.14, 155.98 (d, J = 242.8 Hz), 157.31, 159.28, 163.81;
ESI–MS: m/z = 418 (M ? 1)?. Elemental analysis Calcd
for C19H20FN5O3SC, 54.67; H, 4.83; N, 16.78; O, 11.50; S,
7.68; Found: C, 54.69; H, 4.84; N, 16.79; O, 11.52; S, 7.69.
1
yellow solid. Yield: 90%; H NMR (300 MHz; CDCl3) d
7.87 (1H, s), 7.47–7.43 (3H, m), 7.27–7.13 (6H, m), 7.00
(2H, d), 6.63–6.55 (2H, m), 5.98 (1H, t, J = 6.04 Hz), 4.80
(1H, m), 3.98 (1H, t, J = 8.87 Hz), 3.79–3.69 (3H, m),
3.59 (4H, m), 2.69 (4H, m); 13C NMR (75 MHz, CDCl3): d
25.55, 28.11, 42.72, 50.78, 72.36, 103.12, 103.43, 111.35,
127.85, 132.70 135.58, 137.89, 139.32, 139.93, 142.90,
143.80, 150.68,154.17, 156.01 (d, J = 243.6 Hz), 159.62,
174.97; ESI–MS: m/z = 518 (M ? 1) ?. Elemental anal-
ysis Calcd for C29H28FN3O3S: C, 67.29; H, 5.45; N, 8.12;
O, 9.27; S, 6.19; Found: C, 67.59; H, 5.55; N, 8.19; O,
9.29; S, 6.20.
(S)-3-Chloro-N-((3-(3-fluoro-4-
thiomorpholinophenyl)-2-oxooxazolidin-5-yl)
methyl)-6-methylbenzo[b]thiophene-2-carboxamide
(11d)
The compound 11d was prepared by the method as
described for the preparation of compound 11a, employing
(R)-5-(amino methyl)-3-(3-fluoro-4-thiomorpholinophenyl)
oxazolidin-2-one (8b, 155 mg, 0.50 mmol) and 5-methyl-
benzo[b]thiophene-2-carboxylic acid (134 mg, 0.7 mmol)
to afford the pure compound 11d as a yellow solid in
(S)-N-((3-(3-Fluoro-4-thiomorpholinophenyl)-2-
oxooxazolidin-5-yl) methyl) benzofuran-3-
carboxamide (11b)
The compound 11b was prepared by the method as
described for the preparation of the compound 11a,
employing (R)-5-(amino methyl)-3-(3-fluoro-4-thiomor-
pholinophenyl) oxazolidin-2-one (8b, 155 mg, 0.50 mmol)
and benzofuran-3-carboxylic acid (113 mg, 0.7 mmol) to
afford pure compound 11b as a yellow solid in 193 mg,
1
194 mg, 80% yield. H NMR (400 MHz, CDCl3) d 7.76
(1H, d, J = 8.39 Hz), 7.62 (1H, s), 7.57 (1H, t,
J = 5.95 Hz), 7.31 (1H, d, J = 7.62 Hz), 7.23 (1H, t,
J = 9.00, 8.85 Hz), 6.59–6.53 (2H, m), 4.93 (1H, m), 4.06
(1H, t, J = 9.00, 8.85 Hz), 3.99–3.88 (2H, m), 3.79 (1H,
dd, J = 9.00, 6.45 Hz), 3.56 (4H, m), 2.67 (4H, m), 2.50
(3H, s); 13C NMR (100.6 MHz, CDCl3): d 25.80, 32.86,
41.92, 49.63, 51.05, 72.66, 103.71, 103.40, 110.84, 111.62,
114.80, 122.82, 123.64, 127.06, 128.26, 147.81, 150.89,
154.70, 156.06 (d, J = 243.6 Hz), 156.58, 159.42, 159.87,
162.35; ESI–MS: m/z = 520 (M ? 1)?. Elemental analy-
sis Calcd for C24H25ClFN3O3S2: C, 55.22; H, 4.83; N,
8.05; O, 9.19; S, 12.28; Found: C, 55.24; H, 4.84; N, 8.09;
O, 9.19; S, 12.29.
1
85% yield. H NMR (300 MHz, CDCl3) d 7.68 (1H, d,
J = 7.78 Hz), 7.53 (1H, d, J = 8.39 Hz), 7.5 0 (1H, s),
7.44 (1H, t, J = 7.17, 1.22 Hz), 7.31 (1H, t, J = 7.17,
0.76 Hz), 7.25–7.21 (2H, m), 6.58–6.53 (2H, m), 4.91 (1H,
m), 4.07 (1H, t, J = 9.00, 8.85 Hz), 4.01–3.96 (1H, m),
3.84–3.77 (2H, m), 3.56 (4H, m), 2.67 (4H, m); 13C NMR
(75 MHz, CDCl3): d 25.37, 41.49, 49.20, 50.62, 72.23,
102.98, 103.28, 110.42, 111.43, 122.17, 123.21, 126.63,
127.83, 147.38, 150.59, 154.28, 155.63 (d, J = 243.4 Hz),
158.80, 159.44; ESI–MS: m/z = 456 (M ? 1)?. Elemental
analysis Calcd for C23H22FN3O4S: C, 60.65; H, 4.87; N,
9.23; O, 14.05; S, 7.04; Found: C, 60.69; H, 4.88; N, 9.29;
O, 14.09; S, 7.08.
(S)-3-(5-(4-Chlorophenyl) furan-2-yl)-N-((3-(3-
fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-
yl) methyl) acrylamide (11e)
(S)-N-((3-(3-Fluoro-4-thiomorpholinophenyl)-2-
oxooxazolidin-5-yl) methyl) pyrazine-2-carboxamide
(11c)
The compound 11e was prepared by the method as
described for the preparation of compound 11a, employing
(R)-5-(amino methyl)-3-(3-fluoro-4-thiomorpholinophenyl)
oxazolidin-2-one (8b, 155 mg, 0.50 mmol) and (E)-3-(5-
The compound 11c was prepared by the method as
described for the preparation of compound 11a, employing
(R)-5-(amino methyl)-3-(3-fluoro-4-thiomorpholinophenyl)
oxazolidin-2-one (8b, 155 mg, 0.50 mmol) and pyrazine-2-
carboxylic acid (87 mg, 0.7 mmol) to afford the pure
(4-chlorophenyl)furan-2-yl)acrylic
acid
(173 mg,
0.7 mmol) to afford the pure compound 11e as a yellow
solid in 243 mg, 90% yield; 1H NMR (300 MHz, CDCl3) d
7.63 (2H, d, J = 9.06 Hz), 7.45–7.34 (3H, m), 7.25 (1H, d,
J = 8.30 Hz), 6.69 (1H, d, J = 3.02 Hz), 6.66–6.51 (4H,
m), 4.88 (1H, m), 4.02 (1H, t, J = 8.30 Hz), 3.84–3.75
(3H, m), 3.54 (4H, m), 2.65 (4H, m); 13C NMR (75 MHz,
CDCl3): d 25.62, 41.78, 49.31, 50.79, 72.82, 103.23,
107.63, 111.36, 114.74, 116.03, 117.52, 125.01, 127.58,
128.01, 128.64, 133.50, 150.52, 150.65, 153.90, 156.15 (d,
1
compound 11c as a yellow solid in 173 mg, 82%yield. H
NMR (400 MHz, CDCl3) d 9.41 (1H, s), 8.79 (1H, d,
J = 2.44 Hz), 8.57 (1H, dd, J = 1.52, 0.91 Hz), 8.29 (1H,
t, J = 6.25 Hz), 7.21 (1H, t, J = 9.00, 8.85 HZ), 6.60–6.53
(2H, m), 4.90 (1H, m), 4.06 (1H, t, J = 9.00, 8.85 Hz),
123

Chem. Pap.
(S)-tert-butyl 4-(2-fluoro-4-(2-oxo-5-((pyrazine-2-
carboxamido) methyl) oxazolidin-3-yl) phenyl)
piperazine-l-carboxylate (11h)
J = 242.6 Hz), 157.00, 158.98, 166.53; ESIMS: m/
z = 542 (M ? 1)?. Elemental analysis Calcd for C27H25-
ClFN3O4S: C, 59.83; H, 4.65; N, 7.75; O, 11.81; S, 5.92;
Found: C, 59.83; H, 4.66; N, 7.75; O, 11.89; S, 5.93.
The compound 11h was prepared by the method as
described for the preparation of compound 11a, employing
(R)-tert-butyl 4-(4-(5-(amino methyl)-2-oxooxazolidin-3-
yl)-2-fluorophervyl) piperazine-l-carboxylate (8a, 197 mg,
0.50 mmol) and pyrazine-2-carboxylic acid (86 mg,
0.7 mmol) to afford the pure compound 11h as a yellow
solid in 232 mg, Yield: 93%; 1H NMR (400 MHz, CDCl3)
d 9.38 (1H, s), 8.78 (1H, d, J = 2.44 Hz), 8.55 (1H, dd,
J = 2.44, 1.52 Hz), 8.27 (1H, t, J = 6.40 Hz), 7.42 (1H,
dd, J = 11.59, 2.59 Hz), 7.06 (1H, dd, J = 7.01, 2.59 Hz),
6.90 (1H, t, J = 9.00 Hz), 4.89 (1H, m), 4.09 (1H, t,
J = 9.00 Hz), 3.99–3.94 (1H, m), 3.88–3.80 (2H, m), 3.58
(4H, m), 2.97 (4H, m), 1.48 (9H, s); 13C NMR
(100.6 MHz, CDCl3): d 28.35, 41.89, 47.88, 50.69, 71.59,
79.82, 107.29, 107.55, 113.75, 119.20, 133.08, 136.52,
142.69, 143.51, 144.26, 147.67, 154.06, 154.71, (d,
J = 243.6 Hz) 157.06, 163.87;
(S)-tert-Butyl4-((3-(3-fluoro-4-
thiomorpholinophenyl)-2-oxooxazolidin-5-
yl)methylcarbamoyl) piperazine-1-carboxylate (11f)
The compound 11f was prepared by the method as described
for the preparation of compound 10a, employing (R)-5-
(aminomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazo-
lidin-2-one (8b, 155 mg, 0.50 mmol) and 4-(tert-butoxy-
carbonyl)piperazine-l-carboxylic acid (161 mg, 0.7 mmol)
to afford the pure compound 11f as a yellow solid in
1
248 mg, Yield: 95%; H NMR (300 MHz, CDCl3) d 7.46
(1H, dd, J = 9.78, 2.44 Hz), 7.08 (1H, J = 6.77, 1.73 Hz),
6.94 (1H, t, J = 9.00 Hz), 6.43 (1H, t, J = 6.27, 6.04 Hz),
4.79 (1H, m), 4.16–3.98 (3H, m), 3.77 (1H, dd, J = 6.39,
2.44 Hz), 3.69 (4H, m), 3.62 (4H,m), 3.01 (4H,m), 2.74 (4H,
m), 1.49 (9H, s); 13C NMR (75 MHz, CDCl3): d 25.43,
42.50, 49.10, 72.18, 76.14, 103.41, 111.29, 127.65, 129.33,
134.88, 137.40, 155.50 (d, J = 243.6 Hz), 156.17, 159.46,
167.45, 173.41; ESI–MS: m/z = 524 (M ? 1)?. Elemental
analysis Calcd for C23H32FN5O5S: C, 54.21; H, 6.33; N,
13.74; O, 15.70; S, 6.29; Found: C, 54.23; H, 6.36; N, 13.75;
O, 15.74; S, 6.29.
ESI–MS: m/z = 493 (M ? 1)?. Elemental analysis
Calcd for C23H33FN6O5: C, 56.09; H, 6.75; N, 17.06; O,
16.24; Found: C, 56.11; H, 6.77; N, 17.19; O, 16.24.
(S)-tert-Butyl-4-(2-fluoro-4-(5-((5-methyl-lH-indole-
2-carboxamido) methyl)-2-oxooxazolidin-3-yl)
phenyl) piperazine-l-carboxylate (11i)
(S)-tert-butyl4-((3-(4-(4-(tert-butoxycarbonyl)
piperazin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-
yl) methylcarbamoyl) piperazine-l-carboxylate (11g)
The compound 11i was prepared by the method as
described for the preparation of compound 11a, employing
(R)-tert-butyl 4-(4-(5-(amino methyl)-2-oxooxazolidin-3-
yl)-2-fluorophenyl) piperazine-l-carboxylate (8a, 197 mg,
0.50 mmol) and 5-methyl-1H-indole-2-carboxylic acid
(122 mg, 0.7 mmol) to afford the pure compound 11i as a
yellow solid in 250 mg, Yield: 91%;
1H NMR (400 MHz, CDCl3) d 11.20 (1H, s), 7.62-7.41
(2H, m), 7.22-7.02 (4H, m), 6.93 (1H, t, J = 9.06 Hz), 4.91
(1H, m), 4.11 (1H, t, J = 8.87, 8.68 Hz), 3.92 (1H, m),
3.78 (2H, m), 3.55 (4H, m), 2.96 (4H, m), 2.59 (3H, s), 1.45
(9H, s), 7.76 (1H, s); 13C NMR (100.6 MHz, CDCl3): d
27.80, 40.25, 47.33, 49.99, 77.56, 78.18, 78.56, 103.21,
106.76, 111.88, 113.44, 118.91, 119.37, 121.08, 123.11,
126.67, 130.64, 132.13, 136.27, 138.43, 151.79, 153.68 (d,
J = 243.6 Hz), 158.16, 161.77; ESI–MS: m/z = 538
(M ? 1)?. Elemental analysis Calcd for C28H32FN5O5: C,
62.56; H, 6.00; N, 13.03; O, 14.88; Found: C, 62.57; H,
6.07; N, 13.05; O, 14.89.
The compound 11g was prepared by the method as
described for the preparation of compound 11a, employing
(R)-tert-butyl 4-(4-(5-(amino methyl)-2-oxooxazolidin-3-
yl)-2-fluorophenyl) piperazine-l-carboxylate (8a, 197 mg,
0.50 mmol) and 4-(tert-butoxycarbonyl) piperazine-l-car-
boxylic acid (161 mg, 0.7 mmol) to afford the pure com-
1
pound 11g as a yellow solid in 260 mg, Yield: 86%; H
NMR (300 MHz, CDCl3) d 7.43 (1H, dd, J = 11.7,
2.45 Hz), 7.04 (1H, J = 6.98,1.7 Hz), 6.91 (1H, t,
J = 9.06 Hz), 6.41 (1H, t, J = 6.23, 6.04 Hz), 4.77 (1H,
m), 4.16–3.98 (3H, m), 3.76 (1H, dd, J = 6.41, 2.4 Hz),
3.69 (4H, m), 3.59 (4H, m), 2.99 (4H, m), 2.72 (4H, m),
1.48 (9H, s), 1.44 (9H, s); 13C NMR (75 MHz, CDCl3): d
28.42, 29.47, 41.98, 47.79, 50.46, 71.50, 79.97, 113.83,
119.29, 142.28, 143.59, 144.35, 147.75, 154.03, 154.91 (d,
J = 243.6 Hz), 157.15, 163.95; ESI–MS: m/z = 593
(M ? 1) ?. Elemental analysis Calcd for C28H41FN6O7: C,
56.74; H, 6.97; N, 14.18; O, 18.90; Found: C, 56.75; H,
6.98; N, 14.19; O, 18.94.
123

Chem. Pap.
antibacterial activity. Part 1: substituted pyrazoles. Bioorg Med
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Bressler AM, Zimmer SM, Gilmore JL, Somani J (2004) Peripheral
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serious gram-positive infections. Compr Med Chem II.
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(S)-tert-Butyl4-(4-(5-((2-chloronicotinamido)
methyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)
piperazine-1-carboxylate (11j)
The compound 11j was prepared by the method as
described for the preparation of compound 11a, employing
(R)-tert-butyl 4-(4-(5-(amino methyl)-2-oxooxazolidin-3-
yl)-2-fluorophenyl) piperazine-l-carboxylate (8a, 197 mg,
0.50 mmol) and 2-chloronicotinic acid (109 mg,
0.7 mmol) to afford the pure compound 11j as a yellow
solid in 234 mg, Yield: 88%; 1H NMR (300 MHz, CDCl3)
Cano M, Palomer A, Guglietta A (2006) Preparation of oxazolidinone
compounds and compositions for the treatment of bacterial
infections. From PCT Int. Appl. WO 2006010756 A1 Feb 02,
2006
d
8.43 (1H, dd, J = 4.5, 3.02 Hz), 7.92 (1H, d,
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(2015) Novel oxazolidinone antibacterial analogues with a
substituted ligustrazine C-ring unit. Chem Biol Drug Des
86:682–690. doi:10.1111/cbdd.12537
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Preparation of substituted phenyl oxazolidinones for antimicro-
bial therapy. PCT Int Appl WO 2017015106A1 Jan 26, 2017
Das B, Rajarao AVS, Rudra S, Yadav A, Ray A, Pandya M, Rattan A,
Mehta A (2009) Synthesis and biological activity of novel
oxazolidinones. Bioorg Med Chem Lett 19:6424–6428. doi:10.
1016/j.bmcl.2009.09.054
J = 6.04 Hz), 7.39 (1H, dd, J = 2.26, 12.06 Hz),
7.34–7.28 (2H, m), 7.04 (1H, d, J = 9.06 Hz), 6.90 (1H, t,
J = 9.06 Hz), 4.91 (1H, m), 4.09 (1H, t, J = 9.06 Hz),
3.98–3.78 (3H, m), 3.58 (4H, m), 2.99 (4H, m), 1.47 (9H,
s); 13C NMR (75 MHz, CDCl3): d 28.31, 42.03, 43.94,
47.66, 50.50, 71.86, 79.83, 106.99, 107.38, 113.89, 122.72,
119.35, 131.29, 132.92, 136.13, 138.82, 147.15, 150.77,
153.70, 154.57 (d, J = 243.4 Hz), 156.96, 166.33; ESI–
MS: m/z = 534 (M ? 1)?. Elemental analysis Calcd for
C25H29ClFN5O5: C, 56.23; H, 5.47; N, 13.12; O, 14.98;
Found: C, 56.25; H, 5.49; N, 13.15; O, 14.99.
Ford CW, Zurenko GE, Barbacyn MR (2001) The discovery of
linezolid, the first oxazolidinone antibacterial agent. Curr Drug
Target. doi:10.2174/1568005014606099
Fridkin SK, Edwards JR, Courval JM, Hill H, Tenover FC, Lawton R,
Gaynes RP, McGowan JE (2001) The effect of vancomycin and
third-generation cephalosporins on prevalence of vancomycin-
resistant Enterococci in 126 U.S. adult intensive care units. Ann
Intern Med 135:175–183. doi:10.7326/0003-4819-135-3-
200108070-00009
Author Contribution M.V.B.Rao and R.S designed and supervised
the study, Y.B synthesized and characterized compounds, and mea-
sured spectral data, biological activity was carried at CCMB (The
Centre for Cellular & Molecular Biology, Hyderabad).
Gillman PK (2003) Linezolid and serotonin toxicity. Clin Infect Dis
37:1274–1275. doi:10.1086/378895
Hutchinson DK (2003) Oxazolidinone antibacterial agents: a critical
review. Curr Top Med Chem 3:1021–1042. doi:10.2174/
1568026033452195
Johnson AP, Tysall L, Stockdale M, Woodford N, Kanufmann ME,
Warner M, Livermore DM, Asboth F, Allerberger FJ (2002)
Emerging linezolid resistant Enterococcus faecalis and Entero-
coccus faecium isolated from two Austrian patients in the same
intensive care unit. Eur J Clin Microbiol Infect Dis 21:751–754.
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