Synthesis and in vitro antibacterial activities of novel oxazolidinones

Article abstract of DOI:10.1016/j.ejmech.2007.05.003

Design and synthesis of novel piperazinylaryloxazolidinones possessing heteroaryl groups are described and their in vitro antibacterial activities have been evaluated by MIC assay. Compounds (S)-N-[3-{3-fluoro-4-[4-[3-(5-nitrofuran-2-yl)-acryloyl]-piperazin-1-yl] -phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide (6o), (S)-N-[3-{3-fluoro-4-[4-[3-(5-nitrothien-2-yl)-acryloyl]-piperazin-1-yl] -phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide (6p) and N-oxide of (S)-N-[3-{3-fluoro-4-[4-[3-(5-nitrofuran-2-yl)-acryloyl]-piperazin-1-yl] -phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide (9) showed superior antibacterial activities than linezolid and also active against the linezolid resistant Staphylococcus aureus strains.

Full text of DOI:10.1016/j.ejmech.2007.05.003

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European Journal of Medicinal Chemistry 43 (2008) 683e693
http://www.elsevier.com/locate/ejmech
Original article
Synthesis and in vitro antibacterial activities of novel oxazolidinones*
*
Brijesh Kumar Srivastava , Mukul R. Jain, Manish Solanki, Rina Soni, Darshan Valani,
Sunil Gupta, Bhupendra Mishra, Vijay Takale, Prashant Kapadnis, Harilal Patel, Purvi Pandya,
Jayendra Z. Patel, Pankaj R. Patel
Zydus Research Centre, Department of Medicinal Chemistry, Sarkhej-Bavla N.H.8A, Moraiya, Ahmedabad 382210, Gujarat, India
Received 3 March 2007; received in revised form 1 May 2007; accepted 10 May 2007
Available online 27 May 2007
Abstract
Design and synthesis of novel piperazinylaryloxazolidinones possessing heteroaryl groups are described and their in vitro antibacterial
activities have been evaluated by MIC assay. Compounds (S )-N-[3-{3-fluoro-4-[4-[3-(5-nitrofuran-2-yl)-acryloyl]-piperazin-1-yl]-phenyl}-2-
oxo-oxazolidin-5-yl-methyl] acetamide (6o), (S )-N-[3-{3-fluoro-4-[4-[3-(5-nitrothien-2-yl)-acryloyl]-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-
5-yl-methyl] acetamide (6p) and N-oxide of (S )-N-[3-{3-fluoro-4-[4-[3-(5-nitrofuran-2-yl)-acryloyl]-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-
5-yl-methyl] acetamide (9) showed superior antibacterial activities than linezolid and also active against the linezolid resistant Staphylococcus
aureus strains.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Piperazinylaryloxazolidinone; Antibacterial activity; Linezolid resistant Staphylococcus aureus strain; In vitro MIC
1. Introduction
[8e30] during the last decade in order to get more efficacious
and less toxic drug. Presently, linezolid 3 (ZyvoxÔ) is the first
and the only oxazolidinone class of compound in clinical use
since 2000 after US-FDA approval [31]. Linezolid acts via
a novel mechanism of action by inhibiting protein synthesis
at the initiation phase via binding to 23S rRNA of the 50S
ribosomal subunit of prokaryotes [32e34]. Unfortunately,
linezolid resistant Enterococcus and S. aureus have been iso-
lated from patients receiving prolonged treatment [35e38].
This has led to an urgent need to develop useful antibacterial
chemotherapy, through extensive modifications of oxazolidi-
nones [39,40].
Eperezolid, a piperazine analogue has been subjected to
major modification and has been used for further optimization
by several researchers such as a 5-nitrofuryl derivative ranbe-
zolid 5 (RBx 7644) in clinical development by Ranbaxy Re-
search Laboratories [41,42].
Multi drug-resistant strains of Gram-positive clinical path-
ogens are increasingly posing a serious threat to society, par-
ticularly methicillin resistant Staphylococcus aureus (MRSA)
and vancomycin resistant Enterococci (VRE) [1e3]. As a re-
sult, interest in antibacterial research to combat these organ-
isms is growing. Furoxone 1 an oxazolidinone class of
compound was initially reported in 1953 to possess antibacte-
rial activity [4]. In the late 1980s scientists at DuPont devel-
oped Dup 721 2 [5], which was discontinued because of
toxicity in rodents [6]. The first few oxazolidinones to emerge
as potential drug candidates from biological testing were
linezolid 3 and eperezolid 4 (Fig. 1) [7].
Hence oxazolidinone class of antibacterials has attracted
considerable attention of a number of research groups
Earlier, we have reported novel piperazinylaryloxazolidi-
none having interesting antibacterial activity [43e50], how-
ever, none of the compounds could be studied further due to
their poor solubility and bioavailabilty.
*
ZRC Communication No. 181.
* Corresponding author. Tel.: þ91 2717 250801; fax: þ91 2717 250603.
E-mail addresses: brijeshsrivastava@zyduscadila.com, bksri2000@yahoo.
com (B.K. Srivastava).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.05.003

684
B.K. Srivastava et al. / European Journal of Medicinal Chemistry 43 (2008) 683e693
O
O
3. Results and discussion
O
O
O
O
N
N
N
O2N
NHAc
NHAc
NHAc
Recently, we have reported the synthesis and SAR of piper-
azinylaryloxazolidinone compounds containing the unsubsti-
tuted cinnamoyl moiety as well as compounds with different
substitutions on the phenyl ring of cinnamoyl group [46]. In
order to see the effect of heteroaryl groups in the place of phe-
nyl ring of the cinnamoyl moiety, we prepared several hetero-
aryl analogs (Fig. 2, Schemes 1and 2). Small changes in the
structure of aromatic ring have been found to impart large ef-
fects on their antibacterial activity. Furanyl and thienyl groups
rendered better antibacterial activity to the compounds.
The thiophene and furan derivatives 6a and 6c, respectively,
exhibited nearly equal activity as that of linezolid and epere-
zolid (Table 1). When the point of attachment of these hetero-
cycles were varied to get compounds 6b and 6d, they were
found to be equipotent as their position isomers 6a and 6c, re-
spectively. Among the five membered heterocycles, pyrrole
moiety containing compound (6e) showed activities with
MIC values in the range of 1e2 mg/mL in various Gram-pos-
itive strains. Similarly, six membered heterocycle groups such
as pyridine containing compounds (6f and 6g) were also found
to be equipotent as compounds with five membered heterocy-
cles (Table 1).
Oxazolidinones with 3-indolyl moiety resulted in com-
pound 6h, which was found to be slightly superior in antibac-
terial activity against Bacillus cereus and Streptococcus
pyogenes, than rest of the heterocycles examined. In a bid to
further see the effect of different substituents on the heterocy-
clic ring, especially furan ring, we synthesized the compounds,
a methyl derivative of furan 6i, a formyl derivative of furan 6j,
hydroxymethyl derivative of furan 6k and the corresponding
acetoxymethyl derivative 6l.
1
2
Furoxone
DuP 721
O
O
HO
O
O
O
N
N
N
N
N
NHAc
O
F
F
3
4
Linezolid
Eperezolid
Fig. 1.
Recently, number of groups have reported oxazolidinone
analogs substituted with different heteroaryls, which have
shown impressive antibacterial activities [41,51e54]. The ob-
jective of the present study is to evaluate new oxazolidinones
featuring different heteroaryls substituted alkenones 6, alkenes
7 and 8 and N-oxide 9 (Fig. 2) at the 4-position of piperaziny-
laryloxazolidinones, with a view to identify antibacterials ef-
fective against linezolid resistant strains. The minimum
inhibitory concentration (MIC) for bacterial growth was deter-
mined by microbroth dilution technique using the Clinical and
Laboratory Standards Institute Guidelines (formerly, National
Committee for Clinical Laboratory Standards, NCCLS) [55].
2. Chemistry
The piperazinylaryloxazolidinones 6 have been synthesized
as outlined in Scheme 1 and described in our earlier communi-
cations [46]. The acrylic acids 10 and acrolein 12 were prepared
by literature methods [56,57]. Piperazinylaryloxazolidinone de-
rivative 11 was synthesized by standard methods [6]. The piper-
azinylaryloxazolidinone derivative 11 was coupled with acrylic
acid derivative 10 using 1-hydroxy-benzotriazole monohydrate
and [1-(3-dimethylaminopropyl)-3-ethylcarbodiimide] hydro-
chloride in the presence of triethylamine at 27e28 ꢀC to afford
6. Oxazolidinone 6o was converted into N-oxide derivative 9 us-
ing magnesium monoperoxyphthalate (Scheme 1) [58]. On the
other hand, reductive amination of the piperazinylaryloxazolidi-
none derivative 11 with acrolein derivative 12 gave compounds
7 and 8 (Scheme 2) [41].
The compounds 6i and 6j showed antibacterial activities in
MIC assay but derivatives 6k and 6l showed inferior antibac-
terial activities as compared to linezolid and eperezolid.
The carboxylic acid 6m and sodium salt of carboxylic acid
6n when screened against selected Gram-positive bacteria,
they remained inactive upto a concentration of 16 mg/mL.
However, when a nitro group was introduced in furan ring to
get 6o and in thiophene ring to get 6p, the compounds showed
far superior in vitro activity than that of linezolid. However, an
electron donating eCH3 group at position 5 of the furan ring,
O2N
O
N
R
O
O
O
O
N
N
N
N
N
N
N
NHAc
NHAc
NHA
O
F
F
5
6
RBx7644
O2N
O
N
O
N
R
O
O–
F
O
O
N
N+
NHAc
O
F
7 & 8
9
Fig. 2.

B.K. Srivastava et al. / European Journal of Medicinal Chemistry 43 (2008) 683e693
685
O
N
O
N
(i)
O
O
R
OH
+
R
HN
N
N
N
NHAc
NHAc
NHAc
O
O
F
F
10
6
11
(ii)
O
O
6o: R =
O2N
O
(ii)
O
R
N
N
N
9:R = O2N
O
O
F
9
Scheme 1. Reagents and conditions: (i) EDC-HCl, HOBt.H2O, TEA, CH2Cl2, 27e28 ꢀC, 0.5e1 h, (method A); (ii) magnesium monoperoxyphthalate, MeOH, 29e
30 ꢀC, 1 h, (method B).
diminished the antibacterial activity (compare 6i and 6c),
whereas an electron withdrawing eNO2 group at position 5
of the furanyl ring increased the activity (compare 6o and
6i). Furthermore, we attempted to replace the eC]O group
linked to piperazine ring by eCH2e to get compounds 7
and 8 (Fig. 2). The compound 7 was inferior in its potency
in MIC assay compared to 6c, similarly compound 8 was
found to be much inferior to 6o. However, both the compounds
7 and 8 exhibited almost similar antibacterial activities to that
of linezolid and eperezolid (Table 2).
Some of the selected compounds such as 6o and 6p, which
showed MIC values in the range of 0.125e1 mg/mL against
the strains mentioned in Table 1, were further evaluated in
an extended panel of Gram-positive susceptible strains like
Enterococcus faecalis and S. aureus and against resistant or-
ganisms such as methicillin resistant S. aureus, vancomycin
resistant E. faecalis, penicillin resistant Streptococcus pneu-
moniae and linezolid resistant S. aureus. Both the compounds
were found to be superior to linezolid in these bacterial strains
(Table 3).
In view of emerging resistance to linezolid, Gordeev et al.
have reported compounds which are active against linezolid
resistant S. aureus [24,25] and we also tested few selected ox-
azolidinone derivatives against linezolid resistant S. aureus
NRS 119 and NRS 120, which has G 2576T mutations in
DNA encoding the central loop of domain V of 23S rRNA
and these mutations have been reported to develop microor-
ganism having linezolid resistance [60] (we are registered
user of Network on Antimicrobial Resistance in S. aureus,
www.narsa.net). Compounds 6o and 6p showed good antibac-
terial activity with in vitro MIC values in the range of 2e4
mg/mL against linezolid resistant S. aureus (Table 3, linezo-
lid ꢁ 16 mg/mL). Thus, appropriate substitution on oxazolidi-
none would give compounds, which may work even in
linezolid resistant organisms. However, at this stage the corre-
lation between SAR and antibacterial activity of compounds
against linezolid resistant organisms could not be established.
Compound 6o, which showed in vitro MIC values in the
range of 0.125e0.25 mg/mL (Table 1) and remained active
in the broader panel of Gram-positive strains as well as found
to have activity against resistant organisms (Table 3), was
selected for pharmacokinetic studies. However, the compound
6o remained unabsorbed via per-oral route in Spraguee
Dawley rats. It has been reported that several amines, which
generally show poor bioavailability, can be converted into N-
oxide derivatives resulting in improvement of pharmacokinetic
parameters [58]. These N-oxides although act as pro-drug
become water-soluble and are expected to improve bioavail-
ability. The most potent compound having amide side chain
on the 5 position of oxazolidinone ring 6o was converted to
its corresponding N-oxide affording 9 (Fig. 2). The compound
9 was found to be 2e4 times more active than linezolid in
MIC assay in several Gram-positive strains (Table 4).
Pharmacokinetic behavior of N-oxide 9 was done in male
SpragueeDawley rats to study the effect of this modification.
The rate of conversion of N-oxide 9 via per-oral and intrave-
nous routes to 6o was very fast and 9 itself was absent in
plasma samples. The parent amine 6o appeared in plasma im-
mediately and quantifiable levels persisted for about 40 min
after intravenous and 1.0 h after per-oral administration of
the corresponding N-oxide 9.
The pharmacokinetic parameters were calculated for the
parent amine 6o rather than that of the corresponding N-oxide
(Table 5). The overall per-oral bioavailability of 6o was found
to be 60%, whereas linezolid is known to be 100% bioavail-
able (Table 5) [59]. The data suggests that 9 could serve as
a pro-drug for the parent amine 6o.
O
R
H
O
HN
+
N
N
NHAc
O
F
12
11
(i)
O
O
7: R =
R
N
N
N
NHCOMe
O
F
7 & 8
4. Conclusion
8: R = O2N
O
In summary, we have studied a series of heteroaryl
substituted piperazinyloxazolidinones as antibacterial agents.
Scheme 2. Reagents and conditions: (i) NaBH(OAc)3, MS 4A, THF, 29e
30 ꢀC, 15 h, (method C).

686
B.K. Srivastava et al. / European Journal of Medicinal Chemistry 43 (2008) 683e693
Table 1
In vitro MIC [minimum inhibitory concentration in mg/mL] values of oxazolidinones 6 in various Gram-positive bacteriaa
R
O
O
N
N
N
NHAc
O
F
6
Compound
R
B.p.
B.c.
S.p.
S.e.
E.f.
S.a.
S
6a
0.5e1
0.5e1
0.5e1
1e2
0.5e1
0.5e1
0.5e1
1e2
1e2
0.5e1
0.5e1
1e2
6b
6c
6d
ND
ND
1e2
1e2
0.5e1
0.5e1
1e2
0.5e1
0.5e1
1e2
S
O
0.5e1
0.5e1
O
N
H
6e
1e2
1e2
1e2
0.5e1
1e2
1e2
N
6f
1e2
1e2
1e2
1e2
0.5e0.25
0.5e1
2e4
2e4
2e4
4e8
1e2
6g
0.5e1
N
6h
0.5e1
0.25e0.5
0.12e0.25
1e2
0.5e1
2e4
N
H
Me
O
6i
1e2
1e2
4e8
4e8
1e2
2e4
2e4
4e8
0.5e1
1e2
0.5e1
2e4
1e2
2e4
2e4
4e8
2e4
4e8
4e8
2e4
OHC
HO
O
6j
6k
6l
O
1e2
1e2
AcO
O
2e4
2e4

B.K. Srivastava et al. / European Journal of Medicinal Chemistry 43 (2008) 683e693
687
Table 1 (continued)
Compound
R
B.p.
B.c.
S.p.
S.e.
E.f.
S.a.
HOOC
O
6m
6n
6o
>16
>16
>16
>16
>16
>16
NaOOC
O2N
O
>16
>16
>16
>16
>16
>16
O
ꢂ0.12
0.5e1
ꢂ0.12
ꢂ0.12
ꢂ0.12
ꢂ0.12
0.25e0.5
0.5e1
0.12e0.25
0.25e0.5
O2N
S
6p
1e2
0.12e0.25
3
4
a
0.5e1
1e2
2e4
2e4
1e2
0.5e1
1e2
2e4
1e2
2e4
2e4
2e4
MIC were determined by broth microdilution technique. B.p. ¼ Bacillus pumilus ATCC 14884, B.c. ¼ Bacillus cereus ATCC 11778, S.p. ¼ Streptococcus pyo-
genes ATCC 14289, S.e. ¼ Staphylococcus epidermidis ATCC 155, E.f. ¼ Enterococcus faecalis ATCC 35550, S.a. ¼ Staphylococcus aureus ATCC 25923, N
D ¼ Not done.
The antibacterial activity of the compounds 6o, and 9 against
a large variety of Gram-positive strains, methicillin resistant S.
aureus, vancomycin resistant E. faecalis and penicillin resis-
tant S. pneumoniae has been found good. A few selected com-
pounds 6o, 6p and 9 were also found to be effective against
linezolid resistant organisms.
The most active compound 6o is 4e16 times more active
than linezolid and eperezolid in different strains. The com-
pound 6o which is orally unabsorbed could be made 60% bio-
available by converting it to its N-oxide 9. Further studies of
some of the active compounds are under progress.
5. Experimental protocols
5.1. In vitro antibacterial activities (MIC)
The in vitro (MIC) antibacterial activity of the compounds
against Gram-positive Bacillus pumilus, B. cereus, S. aureus,
Staphylococcus epidermidis, S. pyogenes, Streptococcus pneu-
moniae, E. faecalis was tested as growth inhibition with the
use of broth microdilution method according to NCCLS
[55]. Compounds were dissolved in DMSO and water was
added to get stock solution in 80% DMSO. The working
Table 2
In vitro MIC values of oxazolidinones 7 and 8 in various Gram-positive bacteriaa
O
R
O
N
N
N
NHAc
F
7 & 8
Compound
R
B.p.
B.c.
S.p.
S.e.
E.f.
S.a.
O
7
2e4
0.5e1
0.5e1
8e16
2e4
2e4
O2N
O
8
0.25e0.5
0.25e0.5
0.12e0.25
0.5e1.0
1e2
1e2
3
4
a
0.5e1
1e2
2e4
2e4
1e2
0.5e1
1e2
2e4
1e2
2e4
2e4
2e4
Please see the foot notes of Table 1.

688
B.K. Srivastava et al. / European Journal of Medicinal Chemistry 43 (2008) 683e693
Table 3
In vitro MIC values of selected oxazolidinones against broader panel of both susceptible and resistant Gram-positive strainsa
Compound
E.f. 1
E.f. 2
E.f. 3
S.a. 1
S.a. 2
S.a. 3
S.a. 4
S.a 5
S.a 6
S.p 1
6o
6p
3
0.25e0.5
0.25e0.5
1e2
0.5e1
0.5e1.0
1e2
0.12e0.25
0.5e1.0
1e2
0.12e0.25
0.25e0.5
2e4
0.12e0.25
0.25e0.5
2e4
0.12e0.25
0.25e0.5
1e2
0.12e0.25
0.25e0.5
1e2
2e4
4e8
>16
>16
2e4
4e8
>16
>16
0.25e0.5
ꢂ0.125
0.25e0.5
0.5e1
4
1e2
1e2
1e2
2e4
2e4
1e2
1e2
a
MIC were determined by broth microdilution technique. E.f. 1 ¼ E. faecalis ATCC 14506, E.f. 2 ¼ multi-resistant E. faecalis ATCC 700802, E.f.
3 ¼ vancomycin resistant Enterococcus faecium ATCC 700221, S.a. 1 ¼ S. aureus ATCC 29213, S.a. 2 ¼ S. aureus, ATCC 9144, S.a. 3 ¼ S. aureus ATCC
14154, S.a. 4 ¼ methicillin resistant S. aureus ATCC 700699, S.a 5 ¼ linezolid resistant S. aureus NRS 119, S.a 6 ¼ linezolid resistant S. aureus NRS 120,
S.p 1 ¼ multi-resistant Streptococcus pneumoniae ATCC 700904, N D ¼ Not done.
solution was prepared by diluting the stock solution 1:10 times
in 4e8% DMSO in water or medium. With each set of exper-
iment concurrent sterility controls and inoculum (bacterial cul-
ture) viability controls were examined. Sterility controls meant
to check sterility of each component of the test which contains
sterility conformation for media, vehicle, working drug solu-
tion and saline. While inoculum viability controls were done
to evaluate the growth inhibitory action of the vehicle itself
to each bacterial strain. They contain positive control (plain
medium) and highest three dilutions of the vehicle (i.e., 4%,
2% and 1% of DMSO) in presence of the final inoculum
and the dissolved compounds were evaluated in the concentra-
tions of 0.125, 0.25, 0.5, 1, 2, 4, 8, and 16 mg/mL.
10 mg/kg was administered through tail vein. After the admin-
istration of the test compounds, blood samples were withdrawn
at various time intervals through retro-orbital plexus and col-
lected into heparinized micro-centrifuge tubes. Plasma was sep-
arated by centrifugation at 4000 rpm for 5 min at ambient
temperature and analyzed immediately. Remaining samples
were stored at ꢃ20 ꢀC until analyzed.
Analysis was carried out by taking aliquots of 180 mL
plasma and 20 mL of internal standard (Atorvastatin) and
was extracted with 2.5 mL of extracting solvent (ethyl aceta-
te:acetonitrile, 80:20, v/v) in glass test-tube by vortexing
with spinix vortex mixture for a minute. This was then centri-
fuged at 2000 rpm for 2.0 min. The supernatant was trans-
ferred to another glass test-tube and the solvent was
evaporated under nitrogen using Zymark evaporator at
40 ꢀC. Finally, the tubes were reconstituted with 0.1 mL dilu-
ent (acetonitrile:methanol:water 40:40:20). The reconstituted
samples were analyzed on Agilent 1100 Series HPLC system
with a mobile phase of 0.05% v/v trifluoroacetic acid in
water:acetonitrile (32:68, v/v); flowing at a flow rate of
1.0 mL/min through a Kromasil 250 mm ꢄ 4.6 mm ꢄ 5 mm
column maintained at 30 ꢀC. Chromatographic separation
was achieved within 15 min. Agilent software version Chem-
station Rev.A.09.01 (1206) was used to acquire and process
all chromatographic data. Quantification was based on a series
of calibrators ranging from 0.031 to 32 mg/mL, prepared by
adding test compound to drug free rat plasma. Quality control
samples were analyzed in parallel to verify that the system
5.2. Pharmacokinetics
Pharmacokinetics of the test compounds (6o and 9) was stud-
ied via per-oral and intravenous routes of administration in male
SpragueeDawley rats of 8e10 weeks of age. Animals were
fasted for 18 h and food was supplied after 4.0 h of administra-
tion of the test compound. There was free access to water
throughout the study. A homogenous suspension of the test sub-
stance was prepared in 0.5% w/v CMC in normal saline and
a per-oral dose of 30 mg/kg was administered. For intravenous
administration, the test compounds were dissolved in a cocktail
(polyethyleneglycol PEG-400 17.48%, cremophore ELP 4.85%
v/v, ethanol 4.85% v/v, propylene glycol 9.7% v/v and normal
saline 63.11% v/v) to obtain a clear solution and a dose of
Table 4
In vitro MIC values of oxazolidinone 9 against broader panel of both susceptible and resistant Gram-positive strainsa
O2N
O
O
O–
+N
O
N
N
NHAc
O
F
9
Compd.
S.p.
S.e.
E.f.
S.a.
S.a. 1
S.a. 3
S.a. 4
E.f. 2
E.f. 3
S.p 1
S.a 5
S.a 6
9
3
4
a
0.12e0.25
1e2
0.5e1
0.12e0.25
1e2
2e4
1e2
1e2
2e4
0.5e1
2e4
2e4
1e2
2e4
2e4
1e2
1e2
1e2
0.5e1
1e2
1e2
1e2
1e2
1e2
0.5e1
1e2
1e2
0.25e0.5
0.25e0.5
0.5e1
2e4
>16
>16
2e4
>16
>16
Please see the footnotes of Tables 1 and 3.

B.K. Srivastava et al. / European Journal of Medicinal Chemistry 43 (2008) 683e693
689
Table 5
Mean pharmacokinetic parameters of 9 and linezolid in male SpragueeDawley ratsa
Compound
Route
Dose (mg/kg)
tmax (h)
Cmax (mg/mL)
t1/2 (h)
AUC (0eN) (h. mg/mL)
Bioavailability %
60
9
i.v
10
30
10
25
0.00
0.17 ꢅ 0.01
0.00
9.18 ꢅ 1.96
1.21 ꢅ 0.37
n
0.95 ꢅ 0.05
0.97 ꢅ 0.36
0.95 ꢅ 0.08
1.05 ꢅ 0.03
1.03 ꢅ 0.22
p.o
i.v
1.87
n
Linezolid [59]
100
p.o
0.31 ꢅ 0.17
15.8 ꢅ 3.3
n
a
Compound 9 gets converted to 6o in vivo and hence concentration of 6o can only be measured, n ¼ not reported.
performs in control. Pharmacokinetic parameters namely;
maximum plasma concentration (Cmax), time point of maxi-
mum plasma concentration (tmax), area under the plasma con-
centrationꢃtime curve from 0 h to infinity (AUC0ꢃN) and
100%). The solid was taken in EtOAc (10 mL) and heated
on a water bath at 40e45 ꢀC for 15 min. The hot slurry of
the compound in EtOAc was filtered on a Buchner funnel
under suction and the residue obtained was washed with
diethyl ether (10 mL) to afford N-[3-{3-fluoro-4-[4-(3-thien-
2-yl-acryloyl)-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-
methyl] acetamide as a white solid (75 mg, 78%), 97.3%
purity by HPLC; mp: 225 ꢀC; IR (KBr): 3292, 1693, 1554,
half-life of drug elimination during the terminal phase (t1/2
)
were calculated from plasma concentration versus time data,
by standard non-compartmental methods, using the WinNon-
Lin software version 4.0.1 procured from Pharsight Corpora-
tion, USA.
1
1448 cmꢃ1; H NMR (CDCl3): d 7.84 (d, J ¼ 15.09 Hz, 1H,
vinyl-H ), 7.46 (dd, J ¼ 16.20, 2.56 Hz, 1H, phenyl-H ), 7.33
(d, J ¼ 5.06 Hz, 1H, phenyl-H ), 7.23 (d, J ¼ 3.48 Hz, 1H,
phenyl-H ), 7.06e7.03 (m, 2H, thienyl-H ), 6.92 (t, J ¼ 9.05
Hz, 1H, thienyl-H ), 6.70 (d, J ¼ 15.06 Hz, 1H, vinyl-H ),
6.20 (bs, 1H, ꢃNHCOe), 4.77 (m, 1H, oxazolidinone ring
C5-H ), 4.02 (t, J ¼ 9.06 Hz, 1H, ꢃCH2e), 3.81e3.74 (bs, 4H,
piperazine-H), 3.72 (m, 1H, eCH2e), 3.30e3.23 (m, 2H, ꢃCH2
of oxazolidinone ring), 3.08 (bs, 4H, piperazine-H), 2.27 (s, 3H,
ꢃCOCH3); ESI-MS: 473 (M þ H)þ.
5.3. Chemistry
1H spectral data are recorded using a 300 MHz H NMR
1
spectrometer (M-300) and reported in d scale, using tetra-
methyl silane as an internal standard. IR spectra are recorded
on FTIR 8300 Shimadzu in KBr pellets. Mass spectra are re-
corded on Perkin Elmer Sciex API 3000. HPLC analysis were
carried out at lmax 220 nm using column ODS C-18,
150 mm ꢄ 4.6 mm ꢄ 4 mm on AGILENT 1100 series. Melting
points were recorded on scientific melting point apparatus and
are uncorrected. The oxazolidinones evaluated in antibacterial
screening assay were ca. 90e99% in purity by HPLC analysis
and 1H NMR spectrophotometry. Considering the intrinsic
variability to the standard broth microdilution assay, which
is generally considered accurate within one dilution, ꢁ90%
chemical purity supports the meaningful SAR studies.
The following compounds have been prepared as per
method A.
5.3.1.1. (S )-N-[3-{3-Fluoro-4-[4-(3-thien-3-yl-acryloyl)-piper-
azin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl]
(6b). Yield: 82%; 98% purity by HPLC; mp: 250 ꢀC; IR
(KBr): 3294, 1733, 1647, 1596 cmꢃ1 1H NMR
acetamide
;
(CDCl3 þ CD3OD): d 7.68 (d, J ¼ 15.08 Hz, 1H, vinyl-H ),
7.51e7.48 (m, 3H, phenyl-H ), 7.34 (m, 2H, thienyl-H ),
6.97 (t, J ¼ 9.06 Hz, 1H, thienyl-H ), 6.75 (d, J ¼ 15.27 Hz,
1H, vinyl-H ), 6.07 (s, 1H, eNHCOe), 4.77 (m, 1H, oxazoli-
dinone ring C5-H ), 4.04 (t, J ¼ 9.03 Hz, 1H, eCH2e), 3.89e
3.83 (bs, 4H, piperazine-H ), 3.74 (m, 1H, eCH2e), 3.62 (m,
2H, eCH2e of oxazolidinone ring), 3.09 (bs, 4H, piperazine-
H ), 2.01 (s, 3H, eCOCH3); ESI-MS: 473 (M þ H)þ.
5.3.1. Typical procedure for the synthesis of (S )-N-[3-{3-
fluoro-4-[4-(3-thien-2-yl-acryloyl)-piperazin-1-yl]-phenyl}-
2-oxo-oxazolidin-5-yl-methyl] acetamide (6a), method A
To a stirred solution of 3-thien-2-yl-acrylic acid 10
(45.8 mg, 0.2974 mmol) in dichloromethane (20 mL) 1-hy-
droxy benzotriazole-hydrate (102 mg, 0.7548 mmol), 1-(3-di-
methylaminopropyl)-3-ethyl carbodiimide hydrochloride (104 mg,
0.5425 mmol), and N-(3-{3-fluoro-4-piperazin-1-yl-phenyl}-
2-oxo-oxazolidin-5-yl-methyl)acetamide 11 (100 mg, 0.2976
mmol) was added followed by triethylamine (0.2 mL,
1.5536 mmol). The reaction mixture was stirred at 28e29 ꢀC
for 2 h. The progress of the reaction was monitored by TLC
using the mobile phase CHCl3:MeOH (7:3). The reaction
mixture was poured into demineralised water (80 mL) and
extracted with dichloromethane (2 ꢄ 50 mL). The dichlorome-
thane layer was separated and dried over anhydrous Na2SO4
and filtered.
5.3.1.2. (S )-N-[3-{3-Fluoro-4-[4-(3-furan-2-yl-acryloyl)-piper-
azin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide (6c).
Yield: 47%; 94% purity by HPLC; mp: 124e126 ꢀC; IR
1
(KBr): 3292, 1735, 1643, 1517, 1409 cmꢃ1; H NMR (CDCl3):
d 7.48 (d, J ¼ 15.09 Hz, 1H, vinyl-H), 7.46 (m, 2H, phenyl-
H), 7.08 (dd, J ¼ 10.41, 1.56 Hz, 1H, phenyl-H), 6.92 (t,
J ¼ 9.02 Hz, 1H, furyl-H), 6.83 (d, J ¼ 15.06 Hz, 1H, vinyl-
H), 6.56 (d, J ¼ 3.33 Hz, 1H, furyl-H), 6.46 (dd, J ¼ 5.13,
1.77 Hz, 1H, furyl-H), 5.98 (s, 1H, eNHCOe), 4.77 (m, 1H,
oxazolidinone ring C5-H), 4.02 (t, J ¼ 9.06 Hz, 1H, eCH2e),
3.89e3.82 (bs, 4H, piperazine-H), 3.74 (m, 1H, eCH2e), 3.70
The solvents were evaporated on a rotatory evaporator un-
der reduced pressure to afford an off-white solid (140 mg,

690
B.K. Srivastava et al. / European Journal of Medicinal Chemistry 43 (2008) 683e693
(m, 2H, eCH2e of oxazolidinone ring), 3.08 (bs, 4H, piperazine-
H), 2.08 (s, 3H, eCOCH3); ESI-MS: 457.4 (M þ H)þ.
(bs, 4H, piperazine-H ), 3.77 (m, 1H, eCH2e), 3.53 (m, 2H,
eCH2 of oxazolidinone ring), 3.10 (bs, 4H, piperazine-H ),
1.95 (s, 3H, eCOCH3); ESI-MS: 468 (M þ H)þ.
5.3.1.3. (S )-N-[3-{3-Fluoro-4-[4-(3-furan-3-yl-acryloyl)-piperazin-
1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide (6d). Yield:
41%; 99% purity by HPLC; mp: 250e255 ꢀC; IR (KBr): 3313,
1739, 1654, 1598, 1550 cmꢃ1; 1H NMR (DMSO-d6): d 8.23 (bs,
1H, eNHCOe), 8.03 (s, 1H, phenyl-H), 7.70 (s, 1H, phenyl-H),
7.43 (d, J ¼ 15.16 Hz, 1H, vinyl-H), 7.41 (s, 1H, phenyl-H), 7.17
(dd, J ¼ 10.97, 2.14 Hz, 1H, furyl-H), 7.11e7.00 (m, 3H, vinyl-H
and furyl-H), 4.77 (m, 1H, oxazolidinone ring C5-H), 4.07
(t, J ¼ 8.96 Hz, 1H, eCH2e), 3.81e3.71 (bs, 4H, piperazine-H),
3.68 (m, 1H, eCH2e), 3.38 (m, 2H, eCH2e of oxazolidinone
ring), 2.97 (bs, 4H, piperazine-H), 1.81 (s, 3H, eCOCH3); ESI-
MS: 457.4 (M þ H)þ.
5.3.1.7. (S )-N-[3-{3-Fluoro-4-[4-(3-1H-indol-3-yl-acryloyl)-piper-
azin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide (6h).
Yield: 73%; 97% purity by HPLC; mp: 218e220 ꢀC; IR (KBr):
1
3323, 1743, 1614, 1560 cmꢃ1; H NMR (DMSO-d6): d 11.61
(s, 1H, indolyl-NH), 8.21 (s, 1H, eNHCOe), 7.93 (d, J ¼
9.02 Hz, 1H, indolyl-H), 7.83 (d, J ¼ 2.58 Hz, 1H, indolyl-H),
7.76 (d, J ¼ 15.27 Hz, 1H, vinyl-H), 7.45e7.40 (m, 2H, indolyl-
H), 7.15e7.10 (m, 4H, indolyl-H and phenyl-H), 6.98 (d, J ¼
15.36 Hz, 1H, vinyl-H), 4.80 (m, 1H, oxazolidinone ring C5-
H), 4.09 (t, J ¼ 9.06 Hz, 1H, eCH2e), 3.88e3.79 (bs, 4H, piper-
azine-H), 3.76 (m, 1H, eCH2e) and 3.72e3.69 (m, 2H, eCH2e
of oxazolidinone ring), 3.00 (bs, 4H, piperazine-H), 2.42 (s, 3H,
eCOCH3); ESI-MS: 506.3 (M þ H)þ.
5.3.1.4. (S )-N-[3-{3-Fluoro-4-[4-(3-1H-pyrrol-2-yl-acryloyl)-
piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] acet-
amide (6e). Yield: 10%; 94% purity by HPLC; mp: 198e
5.3.1.8. (S )-N-[3-{3-Fluoro-4-[4-(3-methylfuran-2-yl-acryloyl)-
piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide
(6i). Yield: 33%; 96% purity by HPLC; mp: 205e206 ꢀC;
1
200 ꢀC; IR (KBr): 3280, 1751, 1641, 1550, 1517 cmꢃ1; H
NMR (DMSO-d6): d 12.47 (bs, 1H, pyrrolyl-NH ), 7.49e7.44
(dd, J ¼ 17.07, 2.14 Hz, 1H, phenyl-H ), 7.12e7.08 (m, 1H,
phenyl-H ), 6.95e6.91 (m, 2H, phenyl-H and pyrrolyl-H ),
6.73 (d, J ¼ 12.62 Hz, 1H, vinyl-H ), 6.46 (t, J ¼ 1.69 Hz, 1H,
pyrrolyl-H ), 6.24 (t, J ¼ 2.92 Hz, 1H, pyrrolyl-H ), 6.02 (s,
1H, eNHCOe), 5.82 (d, J ¼ 12.50 Hz, 1H, vinyl-H ), 4.77
(m, 1H, oxazolidinone ring C5-H ), 4.07 (t, J ¼ 8.95 Hz, 1H,
eCH2e), 3.71 (bs, 4H, piperazine-H ), 3.66 (m, 1H, eCH2e),
3.39 (m, 2H, eCH2e of oxazolidinone ring), 2.97 (s, 4H, piper-
azine-H ), 1.82 (s, 3H, eCOCH3); ESI-MS: 456 (M þ H)þ.
1
IR (KBr): 3301, 1733, 1643, 1517 cmꢃ1; H NMR (CDCl3):
d 7.49e7.43 (m, 2H, phenyl-H and vinyl-H ), 7.06 (dd,
J ¼ 10.41, 1.59 Hz, 1H, phenyl-H ), 6.92 (t, J ¼ 9.04 Hz, 1H,
phenyl-H ), 6.73 (d, J ¼ 14.97 Hz, 1H, vinyl-H ), 6.45 (d, J ¼
3.18 Hz, 1H, furyl-H ), 6.06 (m, 2H, furyl-H and eNHCOe),
4.77 (m, 1H, oxazolidinone ring C5-H ), 4.02 (t, J ¼ 8.98 Hz,
1H, eCH2e), 3.87 (bs, 4H, piperazine-H), 3.75 (m, 1H, eCH2e),
3.72e3.68 (m, 2H, eCH2e of oxazolidinone ring), 3.07 (bs,
4H, piperazine-H ), 2.35 (s, 3H, eCOCH3), 2.02 (s, 3H,
eCH3); ESI-MS: 471.3 (M þ H)þ.
5.3.1.5. (S )-N-[3-{3-Fluoro-4-[4-(3-pyridin-4-yl-acryloyl)-pi-
perazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide
(6f). Yield: 46%; 95% purity by HPLC; mp: 244e246 ꢀC; IR
5.3.1.9. (S )-N-[3-{3-Fluoro-4-[4-(5-5-formylfuran-2-yl-acryloyl)-
piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide
(6j). Yield: 50%; 93% purity by HPLC; mp: 191e193 ꢀC; IR
1
(KBr): 3292, 1733, 1651, 1546 cmꢃ1; H NMR (DMSO-d6):
d 8.60 (d, J ¼ 5.65 Hz, 2H, pyridinyl-H ), 8.23 (bs, 1H,
eNHCOe), 7.69 (d, J ¼ 6.05 Hz, 2H, pyridinyl-H ), 7.56 (dd,
J ¼ 15.48 Hz, 1H, vinyl-H ), 7.52 (m, 1H, phenyl-H ), 7.47 (d,
J ¼ 14.45 Hz, 1H, vinyl-H ), 7.16 (dd, J ¼ 12.77, 2.27 Hz, 1H,
phenyl-H ), 7.08 (t, J ¼ 9.21 Hz, 1H, phenyl-H ), 4.77 (m, 1H,
oxazolidinone ring C5-H ), 4.07 (t, J ¼ 8.94 Hz, 1H, eCH2e),
3.87e3.73 (bs, 4H, piperazine-H ), 3.67 (m, 1H, eCH2e),
3.38 (m, 2H, eCH2e of oxazolidinone ring), 2.99 (bs, 4H, piper-
azine-H ), 1.81 (s, 3H, eCOCH3); ESI-MS: 468.3 (M þ H)þ.
1
(KBr): 3276, 1728, 1676, 1598 cmꢃ1; H NMR (DMSO-d6):
d 9.61 (s, 1H, eCHO), 8.22 (bs, 1H, eNHCOe), 7.59
(d, J ¼ 3.69 Hz, 1H, furyl-H), 7.47 (m, 1H, phenyl-H), 7.43
(d, J ¼ 15.35 Hz, 1H, vinyl-H), 7.26 (d, J ¼ 15.36 Hz, 1H,
vinyl-H), 7.14 (d, J ¼ 3.64 Hz, 2H, phenyl-H and furyl-H), 7.07
(t, J ¼ 9.24 Hz, 1H, phenyl-H), 4.69 (m, 1H, oxazolidinone ring
C5-H), 4.07 (t, J ¼ 8.98 Hz, 1H, eCH2e), 3.85e3.81 (bs, 4H,
piperazine-H), 3.69 (m, 1H, eCH2e), 3.39 (m, 2H, eCH2e of
oxazolidinone ring), 2.99 (bs, 4H, piperazine-H), 1.81 (s, 3H,
eCOCH3); ESI-MS: 485 (M þ H)þ.
5.3.1.6. (S )-N-[3-{3-Fluoro-4-[4-(3-pyridin-3-yl-acryloyl)-pi-
perazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide
(6g). Yield: 80%; 97% purity by HPLC; mp: 248e250 ꢀC;
5.3.1.10. (S )-N-[3-{3-Fluoro-4-(4-[3-(5-hydroxymethylfuran-2-
yl-acryloyl)-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl]
acetamide (6k). Yield: 45%; 95% purity by HPLC; mp: 190e
;
IR (KBr): 1730, 1649, 1604, 1517 cmꢃ1 1H NMR
1
(CD3OD þ CDCl3): d 8.74 (d, J ¼ 1.71 Hz, 1H, pyridinyl-
H ), 8.49 (dd, J ¼ 6.21, 1.38 Hz, 1H, pyridinyl-H ), 8.09 (d,
J ¼ 8.04 Hz, 1H, pyridinyl-H ), 7.69 (d, J ¼ 15.57 Hz, 1H, vi-
nyl-H ), 7.51e7.44 (m, 2H, pyridinyl-H and phenyl-H ), 7.28
(d, J ¼ 15.57 Hz, 1H, vinyl-H ), 7.11 (m, 1H, phenyl-H ),
7.01 (t, J ¼ 8.97 Hz, 1H, phenyl-H ), 4.77 (m, 1H, oxazolidi-
none ring C5-H ), 4.09 (t, J ¼ 9.01 Hz, 1H, eCH2e), 3.89
192 ꢀC; IR (KBr): 3307, 1751, 1635 cmꢃ1; H NMR (CDCl3):
d 7.46 (dd, J ¼ 16.66, 2.45 Hz, 1H, phenyl-H), 7.43 (d, J ¼
15.04 Hz, 1H, vinyl-H), 7.06 (d, J ¼ 8.73 Hz, 1H, phenyl-H),
6.90 (t, J ¼ 9.03 Hz, 1H, phenyl-H), 6.81 (d, J ¼ 15.05 Hz, 1H,
vinyl-H), 6.50 (d, J ¼ 3.41 Hz, 1H, furyl-H), 6.36 (m, 2H,
furyl-H and eNHCOe), 4.77 (m, 1H, oxazolidinone ring
C5-H), 4.64 (s, 2H, eCH2OH), 4.02 (t, J ¼ 9.12 Hz, 1H,

B.K. Srivastava et al. / European Journal of Medicinal Chemistry 43 (2008) 683e693
691
eCH2e), 3.86 (bs, 4H, piperazine-H), 3.76 (m, 1H, eCH2e),
3.66 (m, 2H, eCH2e of oxazolidinone ring), 3.06 (bs, 4H, piper-
azine-H), 2.02 (s, 3H, eCOCH3); ESI-MS: 487 (M þ H)þ.
(s, 1H, phenyl-H ), 7.35 (d, J ¼ 3.75 Hz, 1H, furyl-H ), 7.17
(d, J ¼ 15.18 Hz, 1H, vinyl-H ), 7.09 (dd, J ¼ 10.56, 1.83 Hz,
1H, phenyl-H ), 6.92 (t, J ¼ 9.06 Hz, 1H, phenyl-H ), 6.70 (d,
J ¼ 3.78 Hz, 1H, furyl-H ), 5.99 (bs, 1H, eNHCOe), 4.77
(m, 1H, oxazolidinone ring C5-H ), 4.02 (t, J ¼ 8.91 Hz, 1H,
eCH2e), 3.91e3.84 (bs, 4H, piperazine-H ), 3.75 (m, 1H,
eCH2e), 3.68e3.62 (m, 2H, eCH2e of oxazolidinone
ring), 3.10 (bs, 4H, piperazine-H ), 2.02 (s, 3H, eCOCH3);
ESI-MS: 502.2 (M þ H)þ.
5.3.1.11. Acetic acid (S )-[3-(4-{4-[5-(acetylamino-methyl)-2-
oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-3-oxo-pr-
openyl}furan-2-yl-methyl ester (6l). Yield: 55%; 98% purity
by HPLC; mp: 200e202 ꢀC; IR (KBr): 3280, 1726, 1643,
1
1596, 1550 cmꢃ1; H NMR (CDCl3): d 7.47 (dd, J ¼ 16.68,
2.55 Hz, 1H, phenyl-H ), 7.45 (d, J ¼ 15.06 Hz, 1H, vinyl-
H ), 7.08 (dd, J ¼ 10.68, 1.86 Hz, 1H, phenyl-H ), 6.92 (t,
J ¼ 9.03 Hz, 1H, phenyl-H ), 6.85 (d, J ¼ 15.09 Hz, 1H, vi-
nyl-H ), 6.49 (dd, J ¼ 20.07, 3.33 Hz, 2H, furyl-H ), 6.02 (bs,
1H, eNHCOe), 5.07 (s, 2H, eCH2OAc), 4.77 (m, 1H, oxazo-
lidinone ring C5-H ), 4.02 (t, J ¼ 6.02 Hz, 1H, eCH2e), 3.88e
3.82 (bs, 4H, piperazine-H ), 3.74 (m, 1H, eCH2e), 3.64 (m,
1H, eCH2e of oxazolidinone ring), 3.08 (bs, 4H, piperazine-
H ), 2.11 (s, 3H, eOCOCH3), 2.02 (s, 3H, eCOCH3); ESI-
MS: 529.3 (M þ H)þ.
5.3.1.15. (S )-N-[3-{3-Fluoro-4-[4-[3-(5-nitrothien-2-yl)-acry-
loyl]-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] ac-
etamide (6p). Yield: 22%; 93% purity by HPLC; mp: 235e
1
237 ꢀC; IR (KBr): 3284, 1726, 1662, 1517, 1448 cmꢃ1; H
NMR (CDCl3): d 7.85 (d, J ¼ 4.26 Hz, 1H, thienyl-H ), 7.73
(d, J ¼ 15.24 Hz, 1H, vinyl-H ), 7.48 (dd, J ¼ 16.65, 2.43 Hz,
1H, phenyl-H ), 7.14 (m, 1H, phenyl-H ), 7.08 (dd, J ¼ 8.97,
2.01 Hz, 1H, phenyl-H ), 6.91 (m, 1H, thienyl-H ), 6.89 (d,
J ¼ 15.12 Hz, 1H, vinyl-H ), 5.93 (bs, 1H, eNHCOe), 4.76
(m, 1H, oxazolidinone ring C5-H ), 4.02 (t, J ¼ 8.94 Hz, 1H,
eCH2e), 3.91e3.79 (bs, 4H, piperazine-H ), 3.72 (m, 1H, e
CH2e), 3.68e3.63 (m, 2H, eCH2e of oxazolidinone ring),
3.10 (bs, 4H, piperazine-H ), 2.02 (s, 3H, eCOCH3); ESI-
MS: 518 (M þ H)þ.
5.3.1.12. (S )-5-[3-(4-{4-[5-(Acetylamino-methyl)-2-oxo-oxazo-
lidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-3-oxo-propenyl}-
furan-2-carboxylic acid (6m). Yield: 35%; 96% purity by
HPLC; mp: 213e216 ꢀC; IR (KBr): 3276, 1728, 1676,
1598 cmꢃ1; 1H NMR (DMSO-d6): d 13.29 (bs, 1H, eCOOH ),
8.20 (bs, 1H, eNHCOe), 7.49(dd, J ¼ 17.19, 2.34 Hz, 1H,
phenyl-H ), 7.37 (d, J ¼ 15.27 Hz, 1H, vinyl-H ), 7.27 (d,
J ¼ 3.64 Hz, 1H, furyl-H ), 7.17 (dd, J ¼ 11.7 and 2.2 Hz,
1H, phenyl-H), 7.10 (m, 1H, phenyl-H ), 7.07 (d, J ¼ 15.33
Hz, 1H, vinyl-H ), 7.02 (d, J ¼ 3.64 Hz, 1H, furyl-H ), 4.69
(m, 1H, oxazolidinone ring C5-H ), 4.07 (t, J ¼ 8.97 Hz, 1H,
eCH2e), 3.79e3.71 (bs, 4H, piperazine-H ), 3.68 (m, 1H, e
CH2e), 3.36 (m, 2H, eCH2e of oxazolidinone ring), 2.99
(bs, 4H, piperazine-H ), 1.81 (s, 3H, eCOCH3); ESI-MS:
501 (M þ H)þ.
5.3.2. Typical procedure for synthesis of N-oxide of (S )-N-
[3-{3-fluoro-4-[4-[3-(5-nitrofuran-2-yl)-acryloyl]-
piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl]
acetamide (9)), method B
To a stirred solution of [N-[3-{3-fluoro-4-[4-[3-(5-nitrofu-
ran-2-yl)-acryloyl]-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-
5-yl-methyl] acetamide] 6o (0.237 g, 0.482 mmol) in dry
methanol (25 mL) at 29e30 ꢀC magnesium monoperoxyph-
thalate hexahydrate (0.286 g, 0.577 mmol) was added and
the mixture was stirred at 29e30 ꢀC over a period of 1 h.
The progress of the reaction was monitored by TLC using
the mobile phase CHCl3:MeOH (9:1). The reaction mixture
was filtered through celite and the filtrate was concentrated
on a rotatory evaporator under reduced pressure to afford oil.
To the oil, diisopropyl ether (10 mL) and diethyl ether (5 mL)
are added and triturated to get a crude solid (0.150 mg). The
crude compound was purified using column chromatography
on silica gel (100e230 mesh) with 0e0.6% methanolic-NH3
in chloroform as eluent. The fractions were pooled and the sol-
vents were evaporated on a rotatory evaporator to afford N-oxide
5.3.1.13. Sodium salt of (S )-5-[3-(4-{4-[5-(acetylamino-
methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-
yl)-3-oxo-propenyl]furan-2-carboxylic acid (6n). Yield: 60%;
98% purity by HPLC; mp: 222e223 ꢀC; IR (KBr): 3276,
1
1728, 1676, 1598 cmꢃ1; H NMR (DMSO-d6): d 13.29 (bs,
1H, eCOOH ), 8.20 (bs, 1H, eNHCOe), 7.49 (dd,
J ¼ 17.19, 2.34 Hz, 1H, phenyl-H ), 7.37 (d, J ¼ 15.27 Hz,
1H, vinyl-H ), 7.17 (dd, J ¼ 11.7 and 2.2 Hz, 1H, phenyl-
H), 7.10 (m, 1H, phenyl-H ), 7.07 (d, J ¼ 15.33 Hz, 1H,
vinyl-H ), 7.02 (d, J ¼ 3.64 Hz, 1H, furyl-H ), 4.69 (m, 1H, ox-
azolidinone ring C5-H ), 4.07 (t, J ¼ 8.97 Hz, 1H, eCH2e),
3.79e3.71 (bs, 4H, piperazine-H ), 3.68 (m, 1H, eCH2e),
3.36 (m, 2H, eCH2e of oxazolidinone ring), 2.99 (bs, 4H, pi-
perazine-H ), 1.81 (s, 3H, eCOCH3); ESI-MS: 501
(M ꢃ Na)þ.
of
(S )-N-[3-{3-fluoro-4-[4-[3-(5-nitrofuran-2-yl)-acryloyl]-
piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] acet-
amide as a white solid.
Yield: 37% (0.090 g), 99% purity by HPLC; mp: 162e
1
163 ꢀC; IR (KBr): 3084, 1751, 1602, 1487 cmꢃ1; H NMR
(CD3OD þ CDCl3): d 8.38 (bs, 1H, eNHCOe), 7.83 (dd,
J ¼ 18.12, 2.30 Hz, 1H, phenyl-H ), 7.48 (d, J ¼ 15.29 Hz,
1H, vinyl-H ), 7.47 (d, J ¼ 3.83 Hz, 1H, furyl-H ), 7.41 (dd,
J ¼ 11.23, 2.01 Hz, 2H, phenyl-H ), 7.33 (d, J ¼ 15.36 Hz,
1H, vinyl-H ), 6.99 (d, J ¼ 3.82 Hz, 1H, furyl-H ), 4.77
(m, 1H, oxazolidinone ring C5-H ), 4.17 (t, J ¼ 9.06 Hz, 1H,
eCH2e), 3.90e3.8 (bs, 4H, piperazine-H ), 3.63 (m, 1H,
5.3.1.14. (S )-N-[3-{3-Fluoro-4-[4-[3-(5-nitrofuran-2-yl)-acry-
loyl]-piperazin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] ac-
etamide (6o). Yield: 27%; 98% purity by HPLC; mp:
1
170 ꢀC; IR (KBr): 3084, 1751, 1602, 1487 cmꢃ1; H NMR
(DMSO-d6): d 7.48 (d, J ¼ 15.12 Hz, 1H, vinyl-H ), 7.49

692
B.K. Srivastava et al. / European Journal of Medicinal Chemistry 43 (2008) 683e693
eCH2e), 3.55 (m, 2H, eCH2e of oxazolidinone ring), 3.20
(bs, 4H, piperazine-H ), 1.95 (s, 3H, eCOCH3); ESI-MS:
518 (M þ H)þ.
ethereal-HCl (0.5 mL) at 0e5 ꢀC and stirred for 2 h. Fil-
tration on a Buchner funnel afforded the title compound
as a white solid. Yield: 84% ((0.09 g), 96.7% purity by
HPLC; mp: 158e160 ꢀC; IR (KBr): 3398, 2231, 1726,
5.3.3. Typical procedure for synthesis of (S )-N-[3-{3-fluoro-
4-[4-(3-(5-nitrofuran-2-yl)-allyl)-piperazin-1-yl]-phenyl}-2-
oxo-oxazolidin-5-yl-methyl] acetamide hydrochloride (8)),
method C
1541 cmꢃ1
;
1H NMR (CDCl3):
d
7.46e7.40 (d,
J ¼ 14.24, 1H, furyl-H ), 7.30 (d, J ¼ 15.70 Hz, 1H, vi-
nyl-H ), 7.08e7.05 (dd, J ¼ 8.75, 1.75 Hz, 1H, phenyl-
H ), 6.93 (t, J ¼ 9.06 Hz, 1H, phenyl-H ), 6.85e6.65 (m,
1H, phenyl-H ), 6.48e6.42 (d, 2H, vinyl-H and furyl-H ),
6.02 (bs, 1H, eNHCOe), 4.78 (m, 1H, oxazolidinone
ring C5-H ), 4.01 (t, J ¼ 8.98 Hz, 1H, eCH2e), 3.76e
3.73 (m, 1H, eCH2e), 3.71e3.67 (m, 2H, eCH2e of ox-
azolidinone ring), 3.25 (d, 2H, eCH2eCH]CHe), 3.12
(bs, 4H, piperazine-H ), 2.70 (bs, 4H, piperazine-H ),
2.02 (m, 3H, eCOCH3); ESI-MS: 488 (M þ H)þ.
(a) 3-(5-Nitrofuran-2-yl)-2-propenal: to a stirred solution of 5-
nitrofurfural (5 g, 35.46 mmol) in benzene (12 mL) acetal-
dehyde (3 g, 54.5 mmol) at 0e5 ꢀC was added over a
period of 10 min. To this, catalytic mixture of piperidine
(0.1 g, 1.17 mmol) and acetic acid (0.075 g, 11.16 mmol)
in benzene (10 mL) were added drop wise over a period
of 3 h at 0e5 ꢀC. The mixture was stirred at 26e27 ꢀC
for 8 h and then heated on steam bath at 72e74 ꢀC for
6 h. Reaction mixture was cooled to 26e27 ꢀC. The ben-
zene layer was decanted and the mixture was extracted
with hot benzene (2 ꢄ 100 mL). The combined organic
layer was treated with animal charcoal and filtered on
a Buchner funnel through a bed of hy-flow (0.2 g). The fil-
trate was concentrated on a rotary evaporator to afford [3-
(5-nitrofuran-2-yl)-2-propenal] 12 (R ¼ 5-nitro-2-furyl) as
a brown solid (0.6 g, 9%). Mp: 114e116 ꢀC; IR (KBr):
The following compound has been synthesized as per
method C.
5.3.3.1. (S )-N-[3-{3-Fluoro-4-[4-(3-furan-2-yl-allyl)-piperazin-
1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide (7).
Yield: 50%; 96% purity by HPLC; mp: 125e128 ꢀC; IR
(KBr): 3292, 1735, 1643, 1517, 1409 cmꢃ1
;
1H NMR
(CDCl3): d 7.43 (dd, J ¼ 16.76, 2.46 Hz, 1H, phenyl-H ),
7.34 (m, 1H, vinyl-H ), 7.04 (d, J ¼ 2.05 Hz, 1H, phenyl-H ),
6.93 (t, J ¼ 9.06 Hz, 1H, phenyl-H ), 6.37 (m, 2H, furyl-H ),
6.46 (m, 2H, furyl-H and vinyl-H ), 6.10 (bs, 1H, eNHCOe
), 4.81 (m, 1H, oxazolidinone ring C5-H ), 4.01 (t,
J ¼ 8.98 Hz, 1H, eCH2e), 3.76e3.73 (m, 1H, eCH2e),
3.70e3.66 (m, 2H, eCH2e of oxazolidinone ring), 3.20 (d,
2H, eCH2eCH]CHe), 3.12e3.09 (bs, 4H, piperazine-H ),
2.70 (bs, 4H, piperazine-H ), 2.01 (s, 3H, eCOCH3); ESI-
MS: 443 (M þ H)þ.
3327, 1676, 1521, 1471 cmꢃ1 1H NMR (DMSO-d6):
;
d 9.70 (d, J ¼ 7.63 Hz, 1H, eCHO), 7.78 (d, J ¼
3.93 Hz, 1H, furyl-H ), 7.21 (d, J ¼ 15.96 Hz, 1H, vinyl-
H ), 7.43 (d, J ¼ 3.92 Hz, 1H, furyl-H ), 6.78 (dd, J ¼
23.58, 7.63 Hz, 1H, vinyl-H ); ESI-MS: 168 (M þ H)þ.
(b) (S)-N-[3-{3-Fluoro-4-[4-(3-(5-nitrofuran-2-yl)-allyl)-piper-
azin-1-yl]-phenyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide
hydrochloride (8): to a stirred solution of N-[3-(3-fluoro-
4-piperazin-1-yl-phenyl)-2-oxo-oxazolidin-5-yl-methyl]
acetamide 11 (0.5 g, 1.49 mmol) in dry tetrahydrofuran
(50 mL) molecular sieves (10 g, 4) were added followed
by [3-(5-nitrofuran-2-yl)-2-propenal] 12 (R ¼ 5-nitro-2-
furyl) (0.25 g, 1.49 mmol) and the reaction mixture was
stirred at 26e27 ꢀC for 3 h. To this sodium triacetoxy
borohydride (1.25 g, 5.91 mmol) was added and stirred
at 26e27 ꢀC for 12 h. The progress of the reaction was
monitored by TLC using the mobile phase chloroform:
methanol (9:1). The precipitate formed was filtered on
a Buchner funnel through a bed of hy-flow. The filtrate
was washed with water (200 mL). The organic layer was
separated and dried over anhydrous Na2SO4 and filtered.
The solvents were evaporated on a rotatory evaporator to
afford a gummy mass. The crude gummy mass was puri-
fied by column chromatography on silica gel (230e400
mesh) using eluent 0e4% methanol in chloroform. The
required fractions were pooled and the solvents were evap-
orated on a rotatory evaporator under reduced pressure to
give a white solid (0.25 g, 34%). The solid obtained
was converted into hydrochloride salt. Thus, N-[3-{3-flu-
oro-4-[4-(3-(5-nitrofuran-2-yl)-allyl)-piperazin-1-yl]-phe-
nyl}-2-oxo-oxazolidin-5-yl-methyl] acetamide (0.1 g,
0.205 mmol) was taken in diethyl ether (10 mL) and added
Acknowledgement
Authors are thankful to NARSA, USA for providing line-
zolid resistant strains. We thank Dr. B.B. Lohray and Dr.
V.B. Lohray for valuable suggestions, Mr. Sidharth Sankar
Kar for help in preparing the manuscript and the analytical de-
partment for support.
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