Anti-tubercular agents. Part 6: Synthesis and antimycobacterial activity of novel arylsulfonamido conjugated oxazolidinones

Article abstract of DOI:10.1016/j.ejmech.2010.12.028

As a part of investigation of new anti-tubercular agents in this laboratory, herein we describe the synthesis of a new class of arylsulfonamido conjugated oxazolidinones. The in vitro activity of these conjugated (6a-f, 7a-d, 9a-c and 11a-c) molecules aga

Full text of DOI:10.1016/j.ejmech.2010.12.028

European Journal of Medicinal Chemistry 46 (2011) 893e900
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Anti-tubercular agents. Part 6: Synthesis and antimycobacterial activity
of novel arylsulfonamido conjugated oxazolidinones
,
a
a
a
a
Ahmed Kamal a , Rajesh V.C.R.N.C. Shetti , Shaik Azeeza , P. Swapna , M. Naseer A. Khan ,
*
Inshad Ali Khan b, Sandeep Sharma b, Sheikh Tasduq Abdullah c
a Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
b Clinical Microbiology Division, Indian Institute of Integrative Medicine, Jammu 180 001, India
c PK-PD Toxicology Division, Indian Institute of Integrative Medicine, Jammu 180 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
As a part of investigation of new anti-tubercular agents in this laboratory, herein we describe the synthesis
of a newclass of arylsulfonamido conjugated oxazolidinones. The in vitro activity of these conjugated (6aef,
7aed, 9aec and 11aec) molecules against Mycobacterium tuberculosis H37Rv by using rifampicin and
linezolide as positive controls is discussed, compounds 7c and 9aec are found to be the most active
members in this series. Further, cytotoxicity of the potent conjugates of the series (7c, and 9aec) was
evaluated on human foreskin fibroblast (HFF) cells by using MTT assay. Finally, these studies suggest that
compounds 7c and 9a may serve as promising lead scaffolds for further generation of newas anti-TB agents.
Ó 2011 Elsevier Masson SAS. All rights reserved.
Received 6 August 2010
Received in revised form
6 December 2010
Accepted 28 December 2010
Available online 9 January 2011
Keywords:
Anti-tubercular agents
Oxazolidinones
Benzothiadiazines
MDR- and XDR-TB
1. Introduction
The search for novel chemotherapeutic agents for the treatment
of TB is an active research field stimulated by the discovery of new
Tuberculosis (TB), one of the earliest recorded human diseases,
remains the leading single-agent killer in the world [1]. The World
Health Organization (WHO) estimates that approximately one-
third of the global community is infected with Mycobacterium
tuberculosis and more than 9 million incident cases and approxi-
mately 2 million deaths have occurred world wide due to TB [2e4].
The frightening TB is due to use and misuse of existing antibiotics
and poor compliance with the long duration of current chemo-
therapy that involves four different drugs for two months and two
drugs for four months that have created an epidemic of drug
resistant TB. The prevalence of multi-drug resistant and extensively
drug resistant tuberculosis (MDR- and XDR-TB) strains is reported
to be high in the countries where adequate supplies of the drugs are
not available [5,6]. Further, after synergism with HIV co-infection,
the current trends suggest that TB will be among the 10 leading
causes of global disease burden in the year 2020 [7]. Hence, there is
an urgent need to identify new regimens involving novel mecha-
nism of action to address resistance crisis as well as the global
health emergency.
biological targets, eventually to develop new drugs without serious
side effects. Linezolid (1, Fig. 1) is the first and only oxazolidinone
that belongs to the bacterial RNA inhibitor class of synthetic anti-
bacterial drug which is available for the treatment of Gram-positive
bacteria including first-line drug resistance infections in humans
[8,9]. Recently, this drug has also been suggested as an alternative
treatment for patients infected with M. tuberculosis isolates [10].
However, the in vitro activity of linezolid against M. tuberculosis
remains limited [11]. On the other hand, the benzothiadiazine
1,1-dioxides (BTDs) belong to a class of cyclic sulfonamides that have
been extensively studied as potassium channel openers [12] and has
also shown broad spectrum of activity against several bacterial
pathogens including M. tuberculosis [13,14]. From this laboratory
several series of compounds based on benzothiadiazine 1,1-dioxide
scaffold have been reported with good in vitro antimycobacterial
activity. Amongst all the compounds tested, compounds 2 and 3
(Fig. 1) have displayed potential inhibitory activity against M.
tuberculosis with an MIC of 0.75 and 1
mg/mL, respectively [15e18].
These results have encouraged us for the synthesis of new arylsul-
fonamido conjugates of oxazolidinones and evaluated for their anti-
tubercular activity. Hence herein, we anticipated that the present
work would reveal novel agents in chemotherapy of tuberculosis.
* 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 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.12.028

894
A. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 893e900
O
O
O
O
O
S
N
S
N
O
N
N
A
B
N
N
O
C
H
N
NO2
N
NHCOCH3
arm
O
5
N
H
N
H
N
F
Ph
Me
2
O
de
si
C5
3
Linezolid (1)
Fig. 1. Linezolid and promising benzothiadiazines.
2. Chemistry
M. tuberculosis H37Rv using the microplate alamar blue assay
(MABA) at 1e6.25 g/mL concentrations. The drugs in clinical use,
m
The key intermediates (S)-N-[[3-(3-fluoro-4-(morpholinyl/thio-
morpholinyl/piperzinyl)phenyl)-2-oxo-5-oxazolidinyl]methyl]
amine (4aec) and 3-chloro-4-(alkyl/aryl)-4H-1,2,4-benzothiadia-
zine 1,1-dioxide (5aec) were synthesized from previously
described literature procedures [15,19,20]. The C5-side arm modi-
fied oxazolidinoneeBTD series (6aef) was prepared by the
coupling reaction between (S)-N-[[3-(3-fluoro-4-(morpholinyl/thi-
omorpholinyl)phenyl)-2-oxo-5-oxazolidinyl]methyl]amine (4aeb)
and 3-chloro-4-(alkyl/aryl)-4H-1,2,4-benzothiadiazine 1,1-dioxide
(5aec) employing triethylamine as a base in good yields. The
other series, C5-side armed modified oxazolidinones (7aed) were
prepared by the formation of the sulfonamide bond between aryl-
sulfonyl chlorides and (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-
oxo-5-oxazolidinyl]methyl]amine (4a) employing NaH in dry THFas
illustrated in Scheme 1.
rifampicin and linezolid were included in these assays as reference
compounds [21,22]. The in vitro test results for these conjugates are
outlined in Table 1 as minimum inhibitory concentration (MIC) and
the activity ranges from 1 to >6.25 mg/mL.
In the structure activity relationship (SAR) studies, some inter-
esting trends have been observed in these conjugates. The deriva-
tization with various arylsulfonyl chlorides instead of acyl group
at C5-side arm of oxazolidinones, one of the conjugate 7c
(R ¼ 4F-C6H4; MIC ¼ 1
mg/mL) has shown good activity against M.
tuberculosis. Whereas the introduction of a bulky group like ben-
zothiadiazine (6aef) with various substituents in its ring at C5-side
arm has led to loss of anti-tubercular activity, indicating that
modification with arylsulfonyl chlorides is preferable at C5-side
arm. Among the C-ring modified compounds (9aec), these conju-
gated with BTD (9a, 9b) have shown promising antimycobacterial
The C-ring modified oxazolidinoneeBTD series of compounds
9aecwaspreparedasoutlinedinScheme2. N-acylationofcompound
4c with acetic anhydride in pyridine affords N-acylated-piperzinyl-
oxazolidinone intermediate, this upon cbz deprotection by Pd/C in
MeOH gave compound 8. The coupling reaction between 3-chloro-4-
(alkyl/aryl)-4H-1,2,4-benzothiadiazine 1,1-dioxide (5aec) and com-
pound 8 by employing triethylamine as a base obtained conjugates
9aec in good yields.
The conjugates 11aec were obtained from the coupling reaction
of 4c with 5aec affords compounds 10aec. Compounds 10aec
undergoes cbz deprotection with Pd/C in methanol followed by
amide coupling with 4-(5-(4-chlorophenyl)-furan-2-yl)-2-acrylic
acid, employing EDCI and HoBt, to provide a new series of C-ring
and C5-side arm modified oxazolidinoneearylsulfonamido conju-
gates (11aec) in good yields as outlined in Scheme 3.
activity with an MIC ¼ 1
mg/mL, thus suggesting that modification
at this position is also preferable. But, the modifications on both C5-
side arm and C-ring of the oxazolidinones (11aec) have exhibited
significant reduction in activity. Further, the in vivo anti-
mycobacterial activity evaluation of these new potent agents is
underway to assess their clinical potential. The physicochemical
parameters are listed in Table 1, C log P refers to calculated hydro-
phobicity of the compounds, respectively, C log P have been
calculated from ChemDraw version 9.0. The thumb rule for C log P
values, to a drug like molecule must be lower than “5” to by-pass
the cell barrier. The MIC values of the active conjugates seem to
correlate to some extent with the lipophilicity (C log P), 7c (R ¼ 4-
fluorophenyl, C log P: 2.75; MIC: 1), 9a (R ¼ methyl, C log P: 0.70;
MIC: 1), 9b (R ¼ ethyl, C log P: 1.23; MIC: 1), and 9c (R ¼ phenyl, C
log P: 2.20; MIC: 6.25).
3. Results and discussion
3.2. Cytotoxicity assay
3.1. Antimycobacterial activity
As described in experimental procedure, the maximum toler-
ated test (MTT) was performed to evaluate the in vitro cytotoxicity
of the promising compounds (7c and 9aec) against human foreskin
fibroblast (HFF) cells. These compounds were not cytotoxic as
The antimycobacterial activities of the novel oxazolidinone
conjugates (6aef, 7aed, 9aec, and 11aec) were evaluated against
O
O
O
O
O
O
S
S
O
(i)
N
O
N
X
N
N
+
N
N
X
NH2
NH
N
R
Cl
N
R
4a X = O
4b X = S
F
F
6a−f
5a R = Me
5b R = Et
5c R = Ph
6a X = O, R = Me
6b X = O, R = Et
6c X = O, R = Ph
6d X = S, R = Me
6e X = S, R = Et
6f X = S, R = Ph
(ii)
O
O
S
7a R = Ph
O
O
7b R = 4Cl-C6H4
7c R = 4F-C6H4
7d R =4(CH3)-C6H4
R
O
N
N
NH
F
7a−d
Scheme 1. Synthetic route for the preparation of C-5 side arm modified oxazolidinoneebenzothiadiazine/arylsulfonamido conjugates (6aef and 7aed): Reagents and conditions;
(i) TEA, THF, 0 ꢀCert, 6 h; (ii) aryl sulfonylchlorides, NaH, dry THF, 0 ꢀC, 6 h.

A. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 893e900
895
O
O
O
(i), (ii)
O
N
Cbz
N
N
HN
N
N
NH2
NHAc
F
8
4c
F
(iii)
O
S
O
O
N
N
O
N
N
N
NHAc
R
F
9a−c
9a R = Me
9b R = Et
9c R = Ph
Scheme 2. Synthetic route for the preparation of C-ring modified oxazolidinoneebenzothiadiazine conjugates (9aec): Reagents and conditions; (i) Ac2O, pyridine, rt, 1 h; (ii) Pd/C,
H2, MeOH, rt, 12 h; (iii) 5aec, TEA, THF, rt, 6 h.
indicated by their IC50 values. The MIC and IC50 values of the tested
compounds (7c and 9aec) suggest that compounds 7c and 9a
exhibit in vitro antimycobacterial activity at non-cytotoxic
concentrations. The IC50 and selective index (SI) values of these are
5.1.1. Antimycobacterial assay
The antimycobacterial activities of oxazolidinone-arylsulfona-
mido conjugates (6aef, 7aed, 9aec, and 11aec) were evaluated
against M. tuberculosis H37Rv. All the compounds were initially
screened against M. tuberculosis H37Rv at the single concentration
shown in Table 2 [23]. The good selectivity index values (SI ¼ IC50
/
MIC) for these conjugates indicate its potential usefulness in the
drug development for tuberculosis.
of 100 (mg/mL) by Tube Method with minor modifications. The
active compounds from this screening were further tested for
Minimum Inhibitory Concentration (MIC) determination using the
broth micro-dilution assay [24,25]. The tubes and micro titer plates
were incubated for 3e4 weeks at 37 ꢀC in CO2 incubator and read
visually for the absence of growth turbidity.
4. Conclusion
In conclusion, our work demonstrates the synthesis and bio-
logical evaluation of novel benzothiadiazine/arylsufonamido
conjugated oxazolidinones as potential antimycobacterial agents.
Amongst the oxazolidanone derivatives, 7c, 9a and 9b have shown
good in vitro activity against M. tuberculosis H37Rv. Impressively,
active compounds 7c and 9a were nontoxic toward HFF cells
5.1.2. Cytotoxicity assay
The potent conjugates 7c and 9aec were evaluated for cytotoxic
effect on human foreskin fibroblast (HFF cells) cell lines using MTT
assay, in a 96 well plate format. Cells were incubated in Dulbecco’s
Modified Eagle’s Medium (DMEM) containing 10% fetal calf serum
(FCS) with the test material (2e100 m
g/ml) for 24 h at 37 ꢀC in CO2
(IC50 > 100 mM). In addition these new agents, merit further
incubator. After the completion of incubation 3-(4,5-dimethylth-
iazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was added and
cells were further incubated for 3 h at 37 ꢀC in CO2 incubator.
Formation of formazan salt by mitochondrial dehydrogenases and
was determined by Elisa reader at 565 nm (Multiskan Spectrum;
Thermo Electron Corporation, USA). The percentage cytotoxicity
was calculated with respect to the untreated cells.
studies to explore them as potential chemotherapeutics for
tuberculosis and for lead optimization to design novel anti-
tubercular agents.
5. Experimental section
5.1. Pharmacology
5.2. Characterization
All the new synthesized conjugates and reference compounds
rifampicin, linezolid were initially screened against M. tuberculosis
and the active compounds were tested for their cytotoxicity data by
using MTT assay.
Reactions were monitored by TLC, performed on silica gel glass
plates containing 60 F-254 and visualization on TLC was achieved
by UV light or iodine indicator. Column chromatography was
O
O
N
O
O
O
S
(i)
O
N
N
N
Cbz
H
N
+
NH2
5a−c
Cbz
N
N
N
N
R
F
10a−c
F
4c
(ii), (iii)
O
O
O
S
O
O
N
N
N
N
H
N
N
R
F
O
11a−c
11a R = Me
11b R = Et
11c R = Ph
Cl
Scheme 3. Synthetic route for the preparation of C-ring and C-5 side arm modified oxazolidinoneebenzothiadiazine conjugates (11aec): Reagents and conditions: (i) TEA, THF,
ꢀCert, 12 h; (ii) Pd/C, H2, MeOH, rt, 12 h; (iii) 4-(5-(4-chlorophenyl)-furan-2-yl)-2-acrylic acid, EDCI, HoBt, rt, over night.
0

896
A. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 893e900
Table 1
eNH), 4.93e4.98 (m, 1H, oxaeCHe), 4.05e4.11 (m, 2H, oxaeCH2e),
3.79e3.83 (m, 4H, J ¼ 4.1 Hz, oxaemorpholineeOCH2e), 3.66e3.75
(m, 2H, oxaeCH2e), 3.63 (s, 3H, BTDeCH3), 2.97e3.01 (m, 4H,
Antimycobacterial activity of arylsulfonamido conjugated oxazolidinones (6aef,
7aed, 9aec and 11aec) in g/mL.
m
C log Pb
R
X
MIC (mg/mL)
oxaemorpholineeNCH2e); 13C NMR (CDCl3, 75 MHz):
d 156.8, 154.7,
Compounds
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
9a
9b
2.25
2.78
3.29
3.24
3.77
4.28
2.31
3.32
2.75
2.80
0.70
1.23
2.20
5.23
5.85
6.36
Me
Et
Ph
Me
Et
Ph
H
Cl
O
O
O
S
S
S
O
O
O
O
e
e
e
e
e
e
>6.25
>6.25
>6.25
>6.25
>6.25
>6.25
>6.25
>6.25
1
>6.25
1
1
6.25
>6.25
>6.25
>6.25
0.12
153.5, 152.5, 137.3, 136.4, 132.8, 125.3, 124.5, 123.9, 118.7, 115.4, 114.0,
107.4, 71.4, 66.7, 50.8, 47.9, 41.4, 39.1; ESIMS: m/z 490 (M þ H)þ, 512
(M þ Na)þ; HRMS: (ESI m/z) for C22H24FN5O5S calcd. 490.1582, found
490.1558(M þ H)þ;Anal. calcd.forC22H24FN5O5S:C,53.98;H, 4.94;N,
14.31. Found: C, 53.92; H, 4.93, N, 14.28.
5.2.2. (R)-[{N-3-[3-fluoro-4-(4-morphonyl)phenyl]-2-oxo-5-
oxazolidinyl}amine]4-ethylyl-1,4-dihydro-1,2,4-benzothiadiazine
1,1-dioxide (6b)
F
OMe
Me
Et
Ph
Me
Et
Thecompound6bwaspreparedaccordingtotheabove-described
method using 4a (295 mg, 1.0 mmol) and 5b (244 mg, 1.0 mmol)
9c
11a
11b
11c
RMPa
Linezolid
(yield 327 mg, 65%).1H NMR (300 MHz, CDCl3):
d
7.87 (dd,1H, J ¼ 7.7,
1.3 Hz, BTDeH), 7.57 (t,1H, J ¼ 8.49 Hz, BTDeH), 7.42 (dd,1H, J ¼ 14.5,
2.4 Hz, oxaeAreH) 7.38 (t, 1H, J ¼ 7.4 Hz, BTDeH), 7.17 (d, 1H,
J ¼ 8.4 Hz, BTDeH), 7.02 (d, 1H, J ¼ 7.5 Hz, oxaeAreH), 6.82 (t, 1H,
9.0 Hz, oxaeAreH), 6.54 (bs,1H, eNH), 4.98e5.06 (m,1H, oxaeCHe),
4.10 (q, 2H, BTDeCH2CH3), 4.02e4.12 (m, 2H, oxaeCH2e), 3.79e3.82
(m, 4H, J ¼ 4.3 Hz, oxaemorpholineeNCH2e), 3.64e3.76 (m, 2H,
oxaeCH2e), 2.97e3.03 (t, 4H, J ¼ 4.9 Hz, oxaemorpholineeNCH2e),
1.39 (t, 3H, J ¼ 6.7 Hz, BTDeCH2CH3); 13C NMR (CDCl3, 75 MHz):
Ph
2
a
Rifampicin.
b
C log P (hydrophobicity) was calculated using the ChemDraw Ultra, version 9.0.
performed with Merck (Navi Mumbai, India) 60e120 mesh silica
gel. Spectral patterns were designated as s, singlet; d, doublet; dd,
double doublet; t, triplet; bs, broad singlet; m, multiplet. 1H NMR
spectra were recorded on Gemini (200 MHz) (Varian Inc, Palo Alto,
CA, USA) or [Avance (300 MHz); Bruker, Fallanden, Switzerland]
d
156.8,154.7,153.5,152.5,137.3,136.4,132.8,125.3,124.5,123.9,118.7,
115.4, 114.0, 107.4, 71.4, 66.7, 50.8, 47.9, 45.3, 41.4, 12.8; ESIMS: m/z
504 (M þ H)þ, 572 (M þ Na)þ; HRMS: (ESI m/z) for C23H26FN5O5S
calcd. 504.5464, found 504.5458 (M þ H)þ; Anal. calcd. for
C23H26FN5O5S: C, 54.86; H, 5.20; N,13.91. Found: C, 54.80; H, 5.20, N,
13.90.
instruments. Chemical shifts (d) were reported in ppm, downfield
from internal TMS standard. The LCeMS was recorded on instru-
ment LC-MSD-Trap-SL. 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. Elemental analyses were performed on an elemental
analyzer (Model: VARIO EL, Elementar, Hanau, Germany). Starting
materials and reagents were purchased from Lancaster (Alfa Aesar,
Johnson Matthey Co, Ward Hill, MA, USA), SigmaeAldrich (St Louis,
MO, USA) and Spectrochem Pvt Ltd (Mumbai, India).
5.2.3. (R)-[{N-3-[3-fluoro-4-(4-morphonyl)phenyl]-2-oxo-5-
oxazolidinyl}amine]4-phenyl-1,4-dihydro-1,2,4-benzothiadiazine
1,1-dioxide (6c)
The compound 6c was prepared according to the above-
described method using 4a (295 mg, 1.0 mmol) and 5c (293 mg,
1.0 mmol) (yield 358 mg, 65%). 1H NMR (300 MHz, CDCl3):
d 7.90
(dd, 1H, J ¼ 9.4 Hz, BTDeH), 7.62 (d, 1H, J ¼ 8.1 Hz, BTDeH),
7.53e7.52 (m, 2H, BTDeAreH), 7.44e7.42 (m, 3H, J ¼ 9.05,
BTDeAreH, oxaeAreH), 7.38 (t, 1H, J ¼ 7.5 Hz, BTDeH), 7.21e7.17
(m, 2H, J ¼ 8.4 Hz, BTDeH, BTDeAreH), 6.96 (t, 1H, J ¼ 8.6,
oxaeAreH), 6.84 (t, 1H, J ¼ 9.0 Hz, oxaeAreH), 5.43 (bs, 1H, eNH),
4.83e5.03 (m, 1H, oxaeCHe), 4.03e3.89 (m, 2H, oxaeCH2e),
3.78e3.80 (t, 4H, oxaemorpholineeOCH2e), 3.64e3.77 (t, 2H,
oxaeCH2e) 2.96e3.00 (t, 4H, oxaemorpholineeNCH2e); 13C NMR
5.2.1. (R)-[{N-3-[3-fluoro-4-(4-morphonyl)phenyl]-2-oxo-5-
oxazolidinyl}amine]4-methyl-1,4-dihydro-1,2,4-benzothiadiazine
1,1-dioxide (6a)
To a solution of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-
5-oxazolidinyl]methyl]amine (4a) (295 mg, 1.0 mmol) and triethyl-
amine (0.4 mL, 3 mmol) in dry dichloromethane (25 mL), 3-chloro-4-
methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (5a) (230 mg,
1.0 mmol) was added and the reaction mixture was stirred at room
temperature for 6 h. After completion of reaction as indicated by TLC,
the solvent was removed under reduced pressure and the product
was purified by column chromatography by using ethyl acetate,
hexane(7:3) system gives the product 6a (yield 415 mg, 85%).1H NMR
(CDCl3, 75 MHz):
d 156.8, 153.8, 153.5, 150.9, 138.0, 136.2, 134.4,
132.5, 132.2, 131.7, 131.0, 129.3, 124.8, 123.9, 118.7, 116.5, 113.7, 107.3,
70.9, 66.7, 50.8, 47.4, 44.8; ESIMS: m/z 552 (M þ H)þ, 575
(M þ Na)þ; HRMS: (ESI m/z) for C27H26FN5O5S calcd. 552.1769,
found 552.1753 (M þ H)þ; Anal. calcd. for C27H26FN5O5S: C, 58.79;
H, 4.75; N, 12.70. Found: C, 58.80; H, 4.70, N, 12.74.
(300 MHz, CDCl3):
d
7. 95 (dd, 1H, J ¼ 7.7, 1.3 Hz, BTDeH), 7.58 (t, 1H,
5.2.4. (R)-[{N-3-[3-fluoro-4-(4-thiomorphonyl)phenyl]-2-oxo-5-
oxazolidinyl}amine]4-methyl-1,4-dihydro-1,2,4-benzothiadiazine
1,1-dioxide (6d)
J ¼ 7.3 Hz, BTDeH), 7.45 (dd, 1H, J ¼ 14.5, 2.4 Hz, oxaeAreH), 7.36 (t,
1H, J ¼ 7.55 Hz, BTDeH) 7.14 (t, 1H, J ¼ 7.5 Hz, BTDeH), 7.02 (d, 1H,
J ¼ 8.4 Hz, oxaeAreH), 6.89 (t, 1H, 9.0 Hz, oxaeAreH), 6.52 (bs, 1H,
The compound 6d was prepared according tothe above-described
method using 4b (311 mg, 1.0 mmol) and 5a (230 mg, 1.0 mmol)
(yield 343 mg, 68%). 1H NMR (300 MHz, CDCl3):
d 7.86 (dd, 1H,
Table 2
J ¼ 8.05, BTDeH), 7.59 (t,1H, J ¼ 8.7 Hz, BTDeH), 7.42 (dd,1H, J ¼ 13.7,
2.1 Hz, oxaeAreH), 7.38 (dd, 1H, J ¼ 7.54 Hz, BTDeH), 7.26 (d, 1H,
BTDeH), 7.10 (d, 1H, J ¼ 8.05 Hz, oxaeAreH), 6.97 (d, 1H, J ¼ 9.5 Hz,
oxaeAreH), 6.50 (bs, 1H, eNH), 4.91e5.03 (m, 1H, oxaeCHe),
4.08e4.15 (m, 2H, oxaeCH2e), 3.64e3.88 (m, 2H, oxaeCH2e), 3.52 (s,
3H, BTDeCH3), 3.22e3.27 (m, 4H, oxaethiomorpholineeSCH2e),
2.75e2.77 (m, 4H, oxaethiomorpholineeNCH2e); 13C NMR (CDCl3,
IC50 (mM) and selectivity index (SI) values of active compounds (7c and 9aec).
Entry
Compounds
MIC (
m
g/mL)
IC50
(
m
M)
SI
1
2
3
4
7c
9a
9b
9c
1
1
1
6.25
>100
>100
>50
>100
>100
>50
>8
>50

A. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 893e900
897
75 MHz):
d
157.0, 154.7, 153.7, 152.5, 137.3, 136.4, 132.6, 125.4, 124.6,
m/z 436 (M þ þ H); Anal. calcd. for C20H22FN3O5S: C, 55.16; H, 5.09;
124.0,120.2,115.4,114.0,107.4, 71.4, 53.2, 47.9, 41.4, 39.2, 27.8; ESIMS:
m/z506(M þ H)þ, 529(M þ Na)þ;HRMS:(ESIm/z)forC22H24FN5O4S2
calcd. 506.1254, found 506.1246 (M þ H)þ; Anal. calcd. for
C22H24FN5O4S2: C, 52.26; H, 4.78; N,13.84. Found: C, 52.20; H, 4.76, N,
13.84.
N, 9.65. Found: C, 55.14; H, 5.307 N, 9.64.
5.2.8. (R)-[{N-3-[3-fluoro-4-(4-morphonyl)phenyl]-2-oxo-5-
oxazolidinyl}methyl]4-chlorobenzensulfonamide (7b)
The compound 7b was prepared according to the above-
described method using 4a (295 mg, 1 mmol). (Yield 328 mg, 70%)
5.2.5. (R)-[{N-3-[3-fluoro-4-(4-thiomorphonyl)phenyl]-2-oxo-5-
oxazolidinyl}amine]4- ethyl-1,4-dihydro-1,2,4-benzothiadiazine 1,1-
dioxide (6e)
1H NMR (CDCl3, 300 MHz):
d 7.81e7.76 (m, 2H, AreH), 7.74e7.70 (m,
2H, AreH), 7.44 (dd, 1H, J ¼ 15.0, 2.4 Hz, oxaeAreH), 7.05 (dd, 1H,
J ¼ 8.7 Hz, oxaeAreH), 6.95 (t, 1H, J ¼ 9.3 Hz, oxaeAreH), 6.05 (bs,
1H, eNH), 4.95e5.10 (m, 1H, oxaeCHe), 4.32e4.01 (m, 2H,
oxaeCH2e), 3.65e3.77 (m, 4H, morpholineOeCH2e), 3.38e4.26 (m,
2H, oxaeCH2e), 2.61e3.04 (m, 4H, J ¼ 4.5 Hz, morpholineNeCH2e);
The compound 6e was prepared according to the above-
described method using 4b (311 g, 1.0 mmol) and 5b (244 mg,
1.0 mmol) (yield 352 mg, 68%). 1H NMR (300 MHz, CDCl3):
d 7.87
(dd, 1H, J ¼ 8.0 Hz, BTDeH), 7.59 (t, 1H, J ¼ 8.7 Hz, BTDeH), 7.42 (dd,
1H, J ¼ 13.9, 2.1 Hz, oxaeAreH), 7.38 (t, 1H, J ¼ 7.5 Hz, BTDeH), 7.30
(t, 1H, J ¼ 7.3 Hz, BTDeH), 7.14 (d, 1H, J ¼ 8.7 Hz, oxaeAreH), 6.99
(dd, 1H, J ¼ 8.7, 2.1 Hz, BTDeH), 6.63 (bs, 1H, eNH), 5.05e4.98 (m,
1H, oxaeCHe), 3.65e4.01 (m, 6H, 2ꢁ oxa-CH2e, BTDeCH2CH3),
3.22e3.26 (m, 4H, J ¼ 5.1 Hz, oxaethiomorpholineeSCH2e),
2.73e2.78 (m, 4H, oxaethiomorpholineeNCH2e), 1.40 (t, 3H,
13C NMR (CDCl3, 75 MHz):
d 155.3, 154.4, 140.1, 138.7, 136.4, 132.8,
129.1,128.4,118.7,113.9,107.4, 71.9, 66.8, 50.8, 47.5, 41.8; ESIMS: m/z
470 (M þ þ H); Anal. calcd. for C20H21ClFN3O5S: C, 51.12; H, 4.50; N,
8.94. Found: C, 51.14; H, 4.48, N, 8.92.
5.2.9. (R)-[{N-3-[3-fluoro-4-(4-morphonyl)phenyl]-2-oxo-5-
oxazolidinyl}methyl]4-fluorobenzensulfonamide (7c)
J ¼ 7.2 Hz, BTDeCH2CH3); 13C NMR (CDCl3, 75 MHz):
d
157.0, 154.7,
The compound 7c was prepared according to the above-
described method using 4a (295 mg, 1 mmol). (Yield 317 mg, 70%)
153.7, 152.5, 137.3, 136.4, 132.6, 125.4, 124.6, 124.0, 120.2, 115.4,
114.0, 107.4, 71.4, 53.2, 47.9, 45.3, 41.4, 27.8, 12.8; ESIMS: m/z 520
(M þ H)þ, 543 (M þ Na)þ; HRMS: (ESI m/z) for C23H26FN5O4S2 calcd.
520.1442, found 520.1434 (M þ H)þ; Anal. calcd. for C23H26FN5O4S2:
C, 53.16; H, 5.04; N, 13.48. Found: C, 53.14; H, 5.00, N, 13.40.
1H NMR (CDCl3, 300 MHz):
d 7.85e7.80 (m, 2H, AreH), 7.72e7.71
(m, 2H, AreH), 7.42 (dd, 1H, J ¼ 15.0, 2.4 Hz, oxaeAreH), 7.07 (dd,
1H, J ¼ 8.7 Hz, oxaeAreH), 6.86 (t, 1H, J ¼ 9.3 Hz, oxaeAreH), 6.02
(bs, 1H, eNH), 4.97e5.11 (m, 1H, oxaeCHe), 4.34e3.97 (m, 2H,
oxaeCH2e), 3.68e3.75 (m, 4H, J ¼ 4.5 Hz, morpholineOCH2e),
3.44e3.35 (m, 2H, oxaeCH2e), 2.67e3.06 (m, 4H, J ¼ 4.5 Hz,
5.2.6. (R)-[{N-3-[3-fluoro-4-(4-thiomorphonyl)phenyl]-2-oxo-5-
oxazolidinyl}amine]4-phenyl-1,4-dihydro-1,2,4-benzothiadiazine
1,1-dioxide (6f)
morpholineCH2e); 13C NMR (CDCl3, 75 MHz):
d 168.5, 155.3, 154.4,
136.9, 136.4, 132.8, 130.8, 118.7, 118.5, 113.9, 107.4, 71.9, 66.8, 50.8,
47.5, 41.8; ESIMS: m/z 454 (Mþ þ H); Anal. calcd. for C20H21F2N3O5S:
C, 52.97; H, 4.67; N, 9.27. Found: C, 52.95; H, 4.64, N, 9.25.
The compound 6f was prepared according to the above-described
method using 4b (311 mg, 1.0 mmol) and 5c (293 mg, 1.0 mmol)
(yield 368 mg, 65%). 1H NMR (CDCl3, 300 MHz):
d 7.91 (dd, 1H,
J ¼ 8.7 Hz, BTDeH), 7.66e7.52 (m, 3H, J ¼ 8.0 Hz, BTDeH, BTDe
AreH), 7.45e7.41 (m, 3H, J ¼ 14.2 Hz, BTDeAreH, oxaeAreH) 7.39
(dd, 1H, J ¼ 7.4 Hz, BTDeH), 7.29 (t, 1H, J ¼ 7.4 Hz, BTDeAreH),
6.82e7.11 (m, 2H, J ¼ 8.7 Hz, BTDeH, oxaeAreH), 6.72 (d, 1H, J ¼
8.7 Hz, oxaeAreH), 5.37 (bs,1H, eNH), 4.94e5.03 (m,1H, oxaeCHe),
4.03e3.94 (m, 2H, oxaeCH2e), 3.73e3.97 (m, 2H, oxaeCH2e)
3.26e3.21 (t, 4H, oxaethiomorpholineeSCH2e) 2.73e2.76 (t, 4H,
5.2.10. (R)-[{N-3-[3-fluoro-4-(4-morphonyl)phenyl]-2-oxo-5-
oxazolidinyl}methyl]4-methylbenzensulfonamide (7d)
The compound 7d was prepared according to the above-
described method using 4a (295 mg, 1 mmol). (Yield 314 mg, 70%)
1H NMR (CDCl3, 300 MHz):
d 7.42e7.29 (m, 5H, AreH) 7.45 (dd, 1H,
J ¼ 15.0, 2.4 Hz, oxaeAreH), 7.06 (dd, 1H, J ¼ 8.7 Hz, oxaeAreH),
6.94 (t, 1H, J ¼ 9.3 Hz, oxaeAreH), 6.02 (bs, 1H, eNH), 5.11 (m, 1H,
oxaeCHe), 4.34e3.97 (m, 2H, J ¼ 9.3 Hz, oxaeCH2e), 3.75e3.87 (m,
4H, J ¼ 4.5 Hz, morpholineeOeCH2e), 3.36e3.44 (m, 2H,
oxaeCH2e), 2.63e3.06 (m, 4H, J ¼ 4.5 Hz, morpholineeNeCH2e),
oxaethiomorpholineeNCH2e); 13C NMR (CDCl3, 75 MHz):
d 157.1,
154.8, 153.5, 151.9, 137.0, 136.2, 134.4, 132.5, 132.2, 131.7, 131.0, 129.3,
124.8,123.9,118.7,116.5,113.7,107.3, 71.4, 53.3, 47.4, 41.4, 27.7; ESIMS:
m/z 568 (M þ H)þ, 591 (M þ Na)þ; HRMS: (ESI m/z) for
C27H26FN5O4S2 calcd. 568.1430, found 568.1454 (M þ H)þ; Anal.
calcd. forC27H26FN5O4S2:C, 57.13;H, 4.62;N,12.34.Found:C,57.10;H,
4.55, N, 12.32.
2.34 (s, 3H, AreCH3); 13C NMR (CDCl3, 75 MHz):
d 155.3, 154.4,
142.2, 137.8, 136.4, 132.8, 1301.2, 126.4, 118.7, 113.9, 107.4, 71.9, 66.8,
50.8, 47.5, 41.8, 20.8 ESIMS: m/z 450 (Mþ þ H); Anal. calcd. for
C21H24FN3O5S: C, 56.11; H, 5.38; N, 9.35. Found: C, 56.10; H, 5.36, N,
9.33.
5.2.7. (R)-[{N-3-[3-fluoro-4-(4-morphonyl)phenyl]-2-oxo-5-
oxazolidinyl}methyl] benzensulfonamide (7a)
5.2.11. (S)eN-((3-(3-fluoro-4-(piperazin-1-yl)phenyl)-2-oxo-5-
oxazolidin-yl)methyl)acetamide (8)
The target compound 7a was obtained by reacting 4a (295 mg,
1.0 mmol) with benzenesulphonyl chloride (211 mg,1.2 mmol), and
NaH (50 mg, 2.0 mmol) in dry THF (50 mL). After stirring the
reaction mixture for 6 h, the reaction mixture was poured on to
crushed ice (5 g) and the reaction mixture extracted and purified by
column chromatography affords final product as white solid. (Yield
The compound 4c (428 mg, 1 mmol) was dissolved in CH2Cl2
(40 mL), treated with pyridine (0.10 mL, 2.0 mmol) followed by
Ac2O (0.094 mL, 1.0 mmol), and allowed to stir at 25 ꢀC for 1 h. Then
the reaction solution was washed with H2O followed by brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification by silica gel chromatography (1.5e3.5% MeOH/CHCl3)
gave N-acylated-piperzinyl-oxazolidinone intermediate as an off-
white solid (68 mg, 61%). The obtained intermediate (470 mg,
1 mmol) was dissolved in MeOH (15 mL) was degassed, then 10 wt
% Pd/C (450 mg, 3.00 mmol) was added. The mixture was degassed,
charged with H2, and stirred overnight. The mixture was filtered
through a bed of Celite, washed with methanol, the filtrate was
dried over anhydrous Na2SO4, filtered and filtered, and concen-
trated to afford compound 8 as a light yellow glass (303 mg, 90%).
304 mg, 70%). 1H NMR (CDCl3, 300 MHz):
d 7.75e7.68 (m, 2H,
AreH), 7.62e7.55 (m, 2H, AreH), 7.44 (dd, 1H, J ¼ 14.4, 2.7 Hz,
oxaeAreH), 7.25e7.20 (m, 1H, AreH), 7.07 (dd, 1H, J ¼ 8.7 Hz,
oxaeAreH), 6.98 (t, 1H, J ¼ 9.3 Hz, oxaeAreH), 6.0 (bs, 1H, eNH),
4.99e5.04 (m, 1H, oxaeCHe), 4.32e3.99 (m, 2H, oxaeCH2e),
3.78e3.82 (m, 4H, J ¼ 4.5 Hz, morpholineOCH2e), 3.40 (m, 2H,
oxaeCH2e), 2.98e3.02 (m, 4H, J ¼ 4.5 Hz, morpholineeNCH2e); 13
C
NMR (CDCl3, 75 MHz):
d 155.3, 154.4, 142.3, 136.4, 135.2, 132.8,
129.3, 127.3, 118.7, 113.9, 107.4, 71.9, 66.8, 50.8, 47.5, 41.8; ESIMS:

898
A. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 893e900
1H NMR (300 MHz, CDCl3)
d
7.42 (dd, 1H, J ¼ 14.4, 2.6 Hz,
oxaeAreH), 6.84 (t, 1H, J ¼ 9.0 Hz, oxaeAreH), 6.31 (bs, 1H, eNH),
oxaeAreH), 7.06 (dd, 1H, J ¼ 8.8, 1.8 Hz, oxaeAreH), 6.98e6.86 (m,
1H, oxaeAreH), 6.33e6.23 (m, 1H, eNH), 4.83e4.69 (m, 1H,
oxaeCHe), 4.02 (t, 1H, J ¼ 9.0 Hz, oxaeCH2e), 3.75 (dd, 1H, J ¼ 8.8,
6.7 Hz, oxaeCH2e), 3.70 (ddd, 1H, J ¼ 14.7, 5.9, 2.9 Hz, oxaeCH2e),
3.61 (dt, 1H, J ¼ 14.6, 6.1 Hz, oxaeCH2e), 3.09e3.05 (m, 4H,
piperazineeCH2e), 3.04e3.01 (m, 4H, piperazineeCH2e), 2.12 (s,
3H, eCOeCH3); HRMS (ESI) [M þ H]þ calcd. for C16H21FN4O3
337.1676, found 337.1670.
4.71e4.80 (m, 1H, oxoeCHe), 4.10e4.00 (m, 2H, J ¼ 9.0 Hz,
oxaeCH2), 3.84e3.92 (m, 6H, oxaeCH2, piperazineeCH2e),
3.14e3.06 (m, 4H, piperazineeCH2e), 2.15 (s, 3H, eCOeCH3); 13C
NMR (CDCl3, 75 MHz):
d 171.5, 156.8, 153.8, 153.5, 150.9, 138.0,
137.2, 134.4, 132.9, 132.6, 131.7, 131.0, 129.3, 124.8, 123.9, 119.4,
116.5, 114.1, 113.9, 107.6, 107.3, 71.9, 52.2, 47.9, 45.6, 42.4, 23.3;
ESIMS: m/z 593 (M þ H)þ, 616 (M þ Na)þ; HRMS: (ESI m/z) for
C29H29FN6O5S calcd. 593.1834, found 593.1827 (M þ H)þ; Anal.
calcd. for C29H29FN6O5S: C, 58.77, H, 4.93, N, 14.83. Found: C, 58.75;
H, 4.91, N, 14.79.
5.2.12. (R)-[{N-3-[3-fluoro-4-(4-(4-methyl-1,1-dioxo-1,4-dihydro-
1,2,4-benzothiadiazine-3-yl)piperzino)phenyl]-2-oxo-5-
oxazolidinyl}methyl]acetamide (9a)
5.2.15. (R)-[{N-3-[3-fluoro-4-(4-(4-carbobenzoxy)piperzino)
phenyl]-2-oxo-5-oxazolidinyl}methyl]amino-4-methyl-1,4-dihydro-
1,2,4-benzothiadiazine 1,1-dione (10a)
To a solution of 3-chloro-4-methyl-4H-1,2,4-benzothiadiazine1,1-
dioxanes (5a, 230 mg, 1.0 mmol) and triethylamine (0.4 mL,
3.0 mmol)indrydichloromethane(25 mL), (R)-N-[[3-[3-fluoro-4-(N-
1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide (8)
(336 mg,1.0 mmol)wasaddedandthereactionmixturewasstirredat
roomtemperaturefor6 h. Aftercompletionofreactionasindicatedby
TLC, the solvent was removed under reduced pressure and the
product was purified by column chromatography by using chloro-
form, methanol (10:1) system gives the product (9a) (yield 371 mg,
To a solution of 3-chloro-4-methyl-4H-1,2,4-benzothiadiazine
1,1-dioxanes (5a, 276 mg, 1.2 mmol) and triethylamine (3.0 mmol)
in dry dichloromethane (25 mL), compound 4c (428 mg,
1.0 mmol) was added and the reaction mixture was stirred at
room temperature for 12 h. After completion of reaction as indi-
cated by TLC, the solvent was removed under reduced pressure
and the product was purified by column chromatography by
using chloroform, methanol (10:1) system gives the product
70%). 1H NMR (CDCl3, 300 MHz):
d
7.88 (dd, 1H, J ¼ 8.0 Hz, BTDeH),
7.55 (t, 1H, J ¼ 8.0 Hz, BTDeH), 7.44 (dd, 1H, J ¼ 2.9, 13.9 Hz,
oxaeAreH), 7.36e7.30 (m, 2H, BTDeH), 7.02 (d, 1H, J ¼ 8.0 Hz,
oxaeAreH), 6.86 (t, 1H, J ¼ 8.7 Hz, oxaeAreH), 6.38 (bs, 1H, eNH),
4.76e4.80 (m, 1H, oxaeCHe), 3.89e4.07 (m, 2H, oxaeCH2e), 3.75 (s,
3H, BTDeCH3), 3.62e3.71 (m, 6H, piperazineeCH2e, oxaeCH2e),
2.68e3.10 (m, 4H, piperazineeCH2e), 2.15 (s, 3H, eCOeCH3); 13C
(10a). (Yield 460 mg, 74%). 1H NMR (CDCl3, 300 MHz):
d 7.83 (dd,
1H, J ¼ 8.0 Hz, BTDeH), 7.58 (t, 1H, J ¼ 6.8 Hz, BTDeH), 7.45 (dd,
1H, J ¼ 14.0, 2.5 Hz, oxaeAreH), 7.32 (d, 1H, J ¼ 6.5 Hz, BTDeH),
7.29e7.27 (m, 4H, BTDeH, 3ꢁ cbzeAreH), 7.09 (d, 1H, J ¼ 8.0 Hz,
oxaeAreH), 6.92 (dd, 1H, J ¼ 9.0 Hz, oxaeAreH), 6.76 (m, 2H,
cbzeAreH), 5.55 (bs, 1H, eNH), 5.06 (s, 2H, cbzeCH2e), 4.82e4.90
(m, 1H, oxaeCHe), 3.93e3.84 (m, 2H, oxaeCH2e), 3.75e3.71 (m,
2H, oxaeCH2e), 3.67 (s, 3H, BTDeCH3), 3.56e3.65 (m, 4H,
piperazineeCH2e), 2.87 (m, 4H, piperazineeCH2e); ESIMS: m/z
623 (M þ H)þ.
NMR (CDCl3, 75 MHz): d 171.3, 156.5, 154.9, 154.6, 153.5, 152.4, 137.3,
136.4, 132.9, 132.8, 125.4, 124.6, 123.8, 119.3, 119.2, 115.4, 114.1, 114.0,
107.8, 107.6, 72.1, 52.0, 47.9, 45.9, 42.2, 37.5, 23.3; ESIMS: m/z 531
(M þ H)þ, 554 (M þ Na)þ, HRMS: (ESI m/z) for C24H27FN6O5S calcd.
531.1818, found 531.1805 (M þ H)þ; Anal. calcd. for C24H27FN6O5S: C,
54.33; H, 5.13; N, 15.84. Found: C, 54.29; H, 5.09; N, 15.82.
5.2.16. (R)-[{N-3-[3-fluoro-4-(4-(4-carbobenzoxy)piperzino)
phenyl]-2-oxo-5-oxazolidinyl}methyl]amino-4-ethyl-1,4-dihydro-
1,2,4-benzothiadiazine 1,1-dione (10b)
5.2.13. (R)-[{N-3-[3-fluoro-4-(4-(4-ethyl-1,1-dioxo-1,4-dihydro-
1,2,4-benzothiadiazine-3-yl)piperzino)phenyl]-2-oxo-5-
oxazolidinyl}methyl]acetamide (9b)
The compound 10b was prepared according to the above-
described method using 5b (292 mg, 1.2 mmol). (Yield 445 mg,
Thecompound 9bwaspreparedaccordingtotheabove-described
70%). 1H NMR (CDCl3, 300 MHz):
d
7.83 (d, 1H, J ¼ 8.0 Hz, BTDeH),
method using 5b (244 mg, 1.0 mmol) (Yield 353 mg, 65%). 1H NMR
7.59 (t, 1H, J ¼ 6.8 Hz, BTDeH), 7.45 (m, 1H, J ¼ 14.2, 2.5 Hz,
oxaeAreH), 7.32 (d, 1H, J ¼ 6.5 Hz, BTDeH), 7.27e7.23 (m, 4H,
BTDeH, cbzeAreH), 7.10 (d, 1H, J ¼ 8.0 Hz, oxaeAreH), 6.94e6.98
(m, 1H, J ¼ 9.0 Hz, oxaeAreH), 6.76 (m, 2H, cbzeAreH), 5.58 (bs,
1H, eNH), 5.06 (s, 2H, cbzeCH2e), 4.85e4.93 (m, 1H, oxaeCHe),
4.06 (q, 2H, BTDeCH2CH3), 3.93e3.85 (m, 2H, oxaeCH2e),
3.56e3.75 (m, 6H, oxaeCH2e, piperazineeCH2e), 2.87 (m, 4H,
piperazineeCH2e), 1.30 (t, 3H, BTDeCH2CH3); ESIMS: m/z 637
(M þ H)þ.
(CDCl3, 300 MHz):
d
7.92 (dd, 1H, J ¼ 8.0 Hz, BTDeH), 7.57e7.60 (m,
1H, J ¼ 8.0 Hz, BTDeH), 7.44 (dd, 1H, J ¼ 13.9, 2.9 Hz, oxaeAreH),
7.37e7.28 (m, 2H, BTDeH), 7.02 (d, 1H, J ¼ 8.0 Hz, oxaeAreH),
6.85e6.91 (m, 1H, J ¼ 8.7 Hz, oxaeAreH), 6.38 (bs, 1H, eNH),
4.74e4.80 (m, 1H, oxaeCHe), 4.08 (t, 2H oxaeCH2e), 4.07 (q,
2H, BTDeCH2CH3), 3.81e3.75 (m, 2H, oxaeCH2e), 3.62e3.70 (m, 4H,
piperazineeCH2e), 3.09e3.15 (m, 4H, piperazineeCH2e), 2.16 (s, 3H,
eCOeCH3), 1.24 (t, 3H, BTDeCH2CH3); 13C NMR (CDCl3, 75 MHz):
d
171.3,156.5,154.9,154.6,153.5,152.4,137.3,136.4,132.9,132.8,125.4,
124.6,123.8,119.3,119.2,115.4,114.1,114.0,107.8,107.6, 72.1, 52.0, 47.9,
45.9, 45.3, 42.2, 23.3, 12.4; ESIMS: m/z 545 (M þ H)þ, 568 (M þ Na)þ;
HRMS: (ESI m/z) for C25H29FN6O5S calcd. 545.1838, found 545.1826
(M þ H)þ; Anal. calcd. for C25H29FN6O5S: C, 55.14; H, 5.37; N, 15.43.
Found: C, 55.12; H, 5.34, N, 15.40.
5.2.17. (R)-[{N-3-[3-fluoro-4-(4-(4-carbobenzoxy)piperzino)
phenyl]-2-oxo-5-oxazolidinyl}methyl]amino-4-phenyl-1,4-dihydro-
1,2,4-benzothiadiazine 1,1-dione (10c)
The compound 10c was prepared according to the above-
described method using 5c (350 mg, 1.2 mmol). (Yield 478 mg,
70%). 1H NMR (CDCl3, 300 MHz):
d
7.92 (d, 1H, J ¼ 7.3 Hz, BTDeH),
5.2.14. (R)-[{N-3-[3-fluoro-4-(4-(4-phenyl-1,1-dioxo-1,4-dihydro-
1,2,4-benzothiadiazine-3-yl)piperzino)phenyl]-2-oxo-5-
oxazolidinyl}methyl]acetamide (9c)
7.54e7.62 (m, 3H, J ¼ 7.3 Hz, BTDeH, BTDeAreH), 7.45e7.42 (m, 2H,
J ¼ 9.0 Hz, BTDeH), 7.39 (d, 1H, J ¼ 13.6 Hz, oxaeH), 7.35e7.33 (m,
2H, BTDeAreH), 7.26 (m, 5H, cbzeAreH, BTDeH), 6.96 (d, 1H,
J ¼ 8.0 Hz, oxaeAreH), 6.83 (t, 1H, J ¼ 9.5 Hz, oxaeAreH), 6.29 (d,
1H, J ¼ 8.0 Hz), 5.58 (bs, 1H, eNH), 5.10 (s, 2H, cbzeCH2e),
4.83e4.90 (m, 1H, oxaeCHe), 4.78e4.05 (m, 2H, oxaeCH2e),
The compound 9c was prepared according to the above-
described method using 5c (292 mg, 1.0 mmol). (Yield 391 mg,
66%). 1H NMR (CDCl3, 300 MHz):
d
7.94 (dd, 1H, J ¼ 7.4 Hz, BTDeH),
7.54e7.59 (m, 1H, J ¼ 6.8 Hz, BTDeH), 7.54e7.52 (m, 4H, J ¼ 3.77 Hz,
BTDeAreH), 7.48e7.41 (m, 3H, J ¼ 14.4, 2.7, BTDeH, oxaeAreH),
7.35e7.30 (m, 2H, J ¼ 9.05 Hz, BTDeH), 7.04 (d, 1H, J ¼ 9.0 Hz,
3.72e3.87
(m,
2H,
oxaeCH2e),
3.62e3.67
(m,
4H,
piperazineeCH2e), 2.95e3.01 (m, 4H, piperazineeCH2e); ESIMS:
m/z 685 (M þ H)þ.

A. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 893e900
899
5.2.18. (R)-[{N-3-[3-fluoro-4-(4-(4-(E)-3-[5-(4-chlorophenyl)-2-
furyl]-2-propenyoyl)piperzino)phenyl]-2-oxo-5-oxazolidinyl}
methyl]amino-4-methyl-1,4-dihydro-1,2,4-benzothiadiazine-1,1-
dioxide (11a)
(684 mg, 1.0 mmol) gives piperzinyl-oxo-BTD intermediate
(500 mg, 91%), then this intermediate (550 mg, 1.0 mmol) on amide
bond formation reaction with (E)-3-[5-(4-chlorophenyl)-2-furyl]-
2-propenoic acid (248 mg, 1 mmol) affords the product 11c
(550 mg, 1 mmol). (Yield 491 mg, 63%). 1H NMR (CDCl3, 300 MHz):
The target compound was prepared by cbz deprotection
compound 10a (622 mg, 1.0 mmol) by using Pd/C under hydrogen
atmosphere afforded deprotected compound (439 mg, 90%). Then
this compound (488 mg, 1.0 mmol) undergoes amide bond for-
mation with (E)-3-[5-(4-chlorophenyl)-2-furyl]-2-propenoic acid
(248 mg, 1 mmol) in dry DMF, by using coupling agent EDC (77 mg,
0.5 mmol) and hydroxybenzotriazole (13.5 mg, 0.1 mmol). Reaction
mixture was stirred at room temperature for 12 h, After completion
of reaction as indicated by TLC, the reaction was poured into crushed
ice (10 g) and extract with ether and the crude product purified by
column chromatography by using chloroform, methanol (10:1)
system gives the product (11a) (yield 465 mg, 65%). 1H NMR (CDCl3,
d
7.95 (m, 1H, J ¼ 9.4 Hz, BTDeH), 7.72e7.66 (m, 4H, BTDeAreH,
AreH), 7.62 (d, 1H, J ¼ 8.6 Hz, eCH]CHe), 7.56 (dd, 1H, J ¼ 11.7 Hz,
BTDeH), 7.47 (d, 1H, J ¼ 14.8 Hz, oxaeAreH), 7.39e7.36 (m, 3H,
J ¼ 8.6 Hz, BTDeH, AreH), 7.30e7.26 (m, 3H, J ¼ 9.4 Hz, BTDeAreH),
7.24e7.18 (m, 2H, BTDeH, eCH]CHe), 7.01 (dd, 1H, J ¼ 8.6 Hz,
oxaeAreH), 6.84 (d, 1H, J ¼ 14.9 Hz, oxaeAreH), 6.76 (d, 1H,
J ¼ 3.3 Hz, furaneH), 6.64 (d, 1H, J ¼ 3.3 Hz, furaneH), 6.31 (bs, 1H,
eNH), 4.96e4.99 (m, 1H, oxaeCHe), 4.02e4.13 (m, 2H, oxaeCH2e),
3.86e3.95 (m, 6H, piperazineeCH2e, oxaeCH2e), 3.07e3.13 (m, 4H,
piperazineeCH2e); 13C NMR (CDCl3, 75 MHz):
d 159.3, 156.8, 153.8,
153.7, 153.5, 150.9, 150.1, 138.0, 136.2, 134.4, 132.9, 132.5, 132.2,
131.7, 131.0, 130.0, 129.3, 128.6, 128.1, 125.4, 124.8, 123.9, 118.7, 117.1,
116.5, 116.1, 113.7, 108.6, 107.3, 80.1, 70.9, 50.8, 46.3, 44.8; ESIMS:
m/z 781 (M þ H)þ, 803 (M þ Na)þ; HRMS: (ESI m/z) for
C40H34ClFN6O6SNa calcd. 803.1838, found 803.1829 (M þ Na)þ;
Anal. calcd. for C40H34ClFN6O6S: C, 61.48, H, 4.39, N, 10.76. Found: C,
61.49; H, 4.38, N, 10.78.
300 MHz):
d
7.93 (d, 1H, J ¼ 7.9 Hz, BTDeH), 7.65e7.60 (d, 2H,
J ¼ 8.4 Hz, AreH), 7.54e7.48 (m, 2H, J ¼ 9.6 Hz, BTDeH, eCH]CHe),
7.43 (dd, 1H, J ¼ 14.2, 2.5 Hz, oxaeAreH), 7.39e7.29 (m, 3H, BTDeH,
AreH), 7.12 (d, 1H, J ¼ 8.4 Hz, BTDeH), 7.04 (d, 1H, J ¼ 9.3 Hz,
oxaeAreH), 6.85 (m, 2H, oxaeAreH), 6.68 (d, 1H, J ¼ 8.4 Hz eCH]
CHe), 6.62 (d, 1H, furaneH), 6.35 (bs, 1H, eNH), 4.98e5.00 (m, 1H,
oxaeCHe), 4.12e4.05 (m, 2H, oxaeCH2e), 3.74e3.92 (m, 6H,
oxaeCH2e, piperazineeCH2e), 3.03e3.16 (m, 4H, piperazineeCH2e),
Acknowledgement
2.09 (s, 3H, eNCH3); 13C NMR (CDCl3, 75 MHz):
d 159.3, 156.8, 154.7,
153.8, 153.5, 152.5, 150.1, 137.3, 136.4,132.9, 132.8, 130.0,128.6, 128.1,
125.4, 125.3, 124.5, 123.9, 118.7, 117.1, 116.1, 115.4, 114.0, 108.6, 107.4,
80.1, 71.4, 50.8, 46.3, 41.4, 39.1; ESIMS: m/z 720 (M þ H)þ, 742
(M þ Na)þ; HRMS: (ESI m/z) for C35H32ClFN6O6SNa calcd. 741.1634,
found 741.1628 (M þ Na)þ; Anal. calcd. for C35H32ClFN6O6S: C, 58.45,
H, 4.48, N, 11.69. Found: C, 58.49; H, 4.46, N, 11.70.
We thank to Department of Science Technology (DST: SR/S1/OC-
42/2008), New Delhi for financial assistance. The authors RVCRNCS,
SA, PS, SS are thankful to CSIR, New Delhi for the award of their
research fellowship.
References
5.2.19. (R)-[{N-3-[3-fluoro-4-(4-(4-(E)-3-[5-(4-chlorophenyl)-2-
furyl]-2-propenyoyl) piperzino)phenyl]-2-oxo-5-oxazolidinyl}
methyl]amino-4-ethyl-1,4-dihydro-1,2,4-benzothiadiazine 1,1-
dioxide (11b)
This compound was prepared according to the method described
for the compound 11a, deprotection of compound 10b (636 mg,
1.0 mmol) gives piperzinyl-oxo-BTD intermediate (446 mg, 89%),
then this intermediate (502 mg, 1. mmol) on amide bond formation
reaction with (E)-3-[5-(4-chlorophenyl)-2-furyl]-2-propenoic acid
(248 mg, 1 mmol) affords the product 11b (yield 468 mg, 64%). 1H
[1] C. Dye, S. Scheele, P. Dolin, V. Pathania, M.C. Raviglione, J. Am. Assoc. 282
(1999) 677e686.
[2] J.B. Bass, L.S. Farer, P.C. Hopewell, R. O’Brein, R.F. Jacob, F. Ruben, D.E. Snider Jr.,
G. Thornton, Am. J. Respir. Crit. Care Med. 149 (1994) 1359e1374.
[3] D. Campos-Outcalt, J. Family Pract. 52 (2003) 792e798.
[4] P. Farmer, J. Bayona, M. Becerra, J. Furin, C. Henry, H. Hiatt, J.Y. Kim, C. Mitnick,
E. Nardell, S. Shin, Int. J. Tuberc. Lung Dis. 2 (1998) 869e876.
[5] H. Tomioka, Curr. Pharm. Des. 12 (2006) 4047e4070.
[6] D. Maher, M. Raviglione, Clin. Chest Med. 26 (2005) 168e182.
[7] C.J. Murray, J.A. Solomon, Proc. Natl. Acad. Sci. U S A 95 (1999) 13881e13886.
[8] M.R. Sarbachyn, C.W. Ford, Angew Chem. Int. Ed. 42 (2003) 2010e2030.
[9] D.L. Stevens, B. Dotter, K. Madaras-Kelly, Expert Rev. Anti Infect. Ther. 2 (2004)
51e59.
[10] J.C. Rodríguez, M. Ruiz, M. Lopez, G. Royo, Int. J. Antimicrob. Agents 20 (2002)
464e467.
[11] Z. Erturan, M. Uzun, Int. J. Antimicrob. Agents 26 (2005) 78e80.
[12] P. De Tullio, L. Dupont, P. Francotte, S. Counerotte, P. Lebrun, B. Pirotte, J. Med.
Chem. 49 (2006) 6779e6788.
[13] M. Di Bella, A. Monzani, M.G. Andrisano, U. Fabio, G.P. Quaglio, Farmaco [Sci.]
38 (1983) 466.
[14] M. Di Bella, A. Monzani, M.G. Andrisano, U. Fabio, G.P. Quaglio, Farmaco [Sci.]
34 (1979) 189.
[15] 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.
[16] A. Kamal, S.K. Ahmed, K.S. Reddy, M.N.A. Khan, R.V.C.R.N.C. Shetti,
B. Siddhardha, U.S.N. Murty, I.A. Khan, M. Kumar, S. Sharma, A.B. Ram, Bioorg.
Med. Chem. Lett. 17 (2007) 5419e5422.
[17] 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.
[18] A. Kamal, M.N.A. Khan, K.S. Reddy, K. Rohini, G.N. Sastry, B. Sateesh, B. Sridhar,
Bioorg. Med. Chem. Lett. 17 (2007) 5400e5405.
NMR (CDCl3, 300 MHz):
d
7.95 (d, 1H, J ¼ 7.6 Hz, BTDeH), 7.66e7.64
(m, 2H, J ¼ 8.4 Hz, AreH), 7.59e7.42 (m, 3H, BTDeH, oxaeArH,
eCH]CHe), 7.38e7.33 (m, 3H, J ¼ 8.4 Hz, BTDeH, AreH), 7.19 (d,1H,
J ¼ 8.5 Hz, BTDeH), 7.04 (d,1H, J ¼ 9.3 Hz, oxaeAreH), 6.92e6.86 (m,
2H, oxaeArH, eCH]CHe), 6.72e6.69 (d, 1H, J ¼ 3.4 Hz, furaneH),
6.65e6.66 (d,1H, J ¼ 3.4 Hz, furaneH), 6.36 (bs,1H, eNH), 4.97e5.00
(m, 1H, oxaeCHe), 4.12e4.08 (m, 2H, oxaeCH2e), 4.02 (q, 2H,
eNeCH2CH3), 3.88e3.68 (m, 6H, oxaeCH2e, piperazineeCH2e),
3.07e3.12 (m, 4H, piperazineeCH2e), 1.44 (t, 3H, eNeCH2CH3); 13
NMR (CDCl3, 75 MHz): 159.3, 156.8, 154.7, 153.8, 153.5, 152.5,
C
d
150.1,137.3,136.4,132.9,132.8,130.0,128.6,128.1,125.4,125.3,124.5,
123.9,118.7,117.1,116.1,115.4,114.0,108.6,107.4, 80.1, 71.4, 50.8, 46.3,
45.3, 41.4, 12.8; ESIMS: m/z 733 (M þ H)þ, 755 (M þ Na)þ; HRMS:
(ESI m/z) for C36H34ClFN6O6S calcd. 733.1933, found 733.1928
(M þ H)þ; Anal. calcd. for C36H34ClFN6O6S: C, 58.97, H, 4.67, N,11.46.
Found: C, 58.95; H, 4.65, N, 11.44.
[19] S.J. Brickner, M.R. Barbachyn, D.K. Hutchinson, P.R. Manninen, J. Med. Chem.
51 (2008) 1981e1990.
[20] 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.
[21] R.J. Wallace Jr., D.R. Nash, L.C. Steele, V. Steingrube, J. Clin. Microbiol. 24 (1986)
976e981.
[22] J. Boogaard, G.S. Kibiki, E.R. Kisanga, M.J. Boeree, R.E. Aarnoutse, Antimicrob.
Agents Chemother 53 (2009) 849e862.
[23] I. Orme, J. Secrist, S. Anathan, C. Kwong, J. Maddry, R. Reynolds,
A. Poffenberger, M. Michael, L. Miller, J. Krahenbuh, L. Adams, A. Biswas,
5.2.20. (R)-[{N-3-[3-fluoro-4-(4-(4-(E)-3-[5-(4-chlorophenyl)-2-
furyl]-2-propenyoyl)piperzino)phenyl]-2-oxo-5-oxazolidinyl}
methyl]amino-4-ethyl-1,4-dihydro-1,2,4-benzothiadiazine 1,1-
dioxide (11c)
This compound was prepared according to the method
described for the compound 11a, deprotection of compound 10c

900
A. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 893e900
S. Franzblau, D. Rouse, D. Winfield, J. Brooks, Antimicrob. Agents Chemother.
45 (2001) 1943e1946.
[24] M. Kumar, I.A. Khan, V. Verma, N. Kalyan, G.N. Qazi, Diag. Microbiol. Infect. Dis.
[25] Clinical and Laboratory Standards Institute, Methods for Antimicrobial
Susceptibility Testing of Aerobic Bacteria Approved standard M07-A8,
ninth ed. National Committee for Clinical Laboratory Standards, Wayne, PA,
2008.
53 (2005) 121e124.