Anti-tubercular agents. Part 7: A new class of diarylpyrrole-oxazolidinone conjugates as antimycobacterial agents

Article abstract of DOI:10.1016/j.ejmech.2013.03.027

In an effort to discover new anti-tubercular agents, a series of new diarylpyrrole-oxazolidinone conjugates have been designed and synthesized. The anti-tubercular activity of these new conjugates (4a-n and 5a-d) against Mycobacterium tuberculosis H₃

Full text of DOI:10.1016/j.ejmech.2013.03.027

European Journal of Medicinal Chemistry 64 (2013) 239e251
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Anti-tubercular agents. Part 7: A new class of diarylpyrrolee
oxazolidinone conjugates as antimycobacterial agents
,
a
a
a
Ahmed Kamal a , P. Swapna , Rajesh V.C.R.N.C. Shetti , Anver Basha Shaik ,
M.P. Narasimha Rao a, Farheen Sultana a, Inshad Ali Khan b, Sandeep Sharma b,
Nitin Pal Kalia b, Sunil Kumar b, Bagul Chandrakant c
*
a Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
b Clinical Microbiology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
c Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Hyderabad 500037, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In an effort to discover new anti-tubercular agents, a series of new diarylpyrroleeoxazolidinone con-
jugates have been designed and synthesized. The anti-tubercular activity of these new conjugates (4aen
and 5aed) against Mycobacterium tuberculosis H37Rv and drug resistance strains such as M. tuberculosis
RifR and M. tuberculosis XDR are discussed, wherein compound 4i has been found to be the most potent
amongst the series. MTT assay was performed on the active conjugates of the series (4bef, 4i and 5c)
against mouse macrophage (J-774) cells to evaluate cytotoxic effects and selective index values. In
addition, these conjugates (4aen and 5aed) are also tested against a panel of Gram-positive and Gram-
negative bacterial strains. The docking studies have been carried out to provide some insight into the
mechanism of action for this class of compounds.
Received 24 September 2012
Received in revised form
10 March 2013
Accepted 13 March 2013
Available online 22 March 2013
Keywords:
Anti-tubercular agents
Mycobacterium tuberculosis
MDR- and XDR-TB
Antibacterial
Ó 2013 Published by Elsevier Masson SAS.
Oxazolidinones
1. Introduction
resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB)
are particularly alarming [7,8]. There has been an increase in the
Despite the availability of efficacious treatment and diagnosis
for tuberculosis (TB), caused by the bacillus Mycobacterium tuber-
culosis (MTB), TB still remains a major health problem. In 1993, the
World Health Organization (WHO) declared TB as a global emer-
gency [1]; at that time when an estimated 7e8 million cases and
1.3e1.8 million deaths occurred each year. In 2010, there were an
estimated 8.8 million cases of TB, 1.1 million deaths among HIV-
negative cases of TB and an additional 0.35 million deaths among
people who were HIV-positive [2]. Inspite of improved sanitation,
better lifestyle and the widespread use of the bovine Calmettee
Guerin vaccine, MTB still persists as a leading bacterial infection
problem [3,4]. The efficacy of currently available drugs used in
standard tuberculosis treatment regimen is seriously limited by
several factors: including HIV-1 infection, long treatment regimens
and multiple drug treatment regimens [5,6]. Moreover, the
increasing emergences of drug resistant TB, especially multidrug
number of TB patients diagnosed with MDR-TB in the last five years.
For the first time in 40 years, there is a coordinated portfolio of
promising new drugs on the horizon. There are 10 new or repur-
posed TB drugs in trials, which have the potential to shorten the
treatment of drug-susceptible TB and to improve the treatment of
multidrug-resistant TB. Some notable examples that are under
different stages of clinical trials include gatifloxacin (1a), moxi-
floxacin (1b), levofloxacin (1c) and linezolid (2a) as shown in Fig. 1
[1,9]. Linezolid is the first and only oxazolidinone which is effective
for the treatment of Gram-positive bacteria including first-line drug
resistance infections in humans and recently has been suggested as
an alternative treatment for patients infected with M. tuberculosis
isolates [10e12]. The oxazolidinones, represent a new class of
synthetic antibacterial agents that emerged in the last four decades
having potent activity against multidrug-resistant Gram-positive
bacteria. Oxazolidinones target the bacterial protein synthesis prior
to the chain initiation step by binding to the 23S rRNA of 50S ri-
bosomal subunit and interfering with the initiator fMET-rRNA
binding to the P-site of the ribosomal peptidyltransferase center
[13,14]. Many efforts have been made on developing new
* Corresponding author. Tel.: þ91 40 27193157; fax: þ91 40 27193189.
E-mail address: ahmedkamal@iict.res.in (A. Kamal).
0223-5234/$ e see front matter Ó 2013 Published by Elsevier Masson SAS.
http://dx.doi.org/10.1016/j.ejmech.2013.03.027

240
A. Kamal et al. / European Journal of Medicinal Chemistry 64 (2013) 239e251
oxazolidinones toward extending the spectrum of activity and
reducing the toxic effects. Recent studies have shown that the
conversion of the acetamide group of linezolid to the triazolyl,
example PH-027 (2b) as shown in Fig. 1 could restore its antibac-
terial activities [15e18]. On the other hand, diarylpyrroles were first
reported by Biava and coworkers as antimycobacterials and
amongst them BM212 (3) is the most potent derivative which
showed promising activity toward several strains of MTB [19,20].
In an effort to global fight against tuberculosis, from our labo-
ratory many series of compounds have been designed and syn-
thesized that exhibit promising antimycobacterial activity and
some are undergoing detailed investigations [21e23]. In the pre-
sent investigation we have introduced a new class of diarylpyrrolee
oxazolidinone conjugates as potential antimycobacterial agents. In
this context the diarylpyrrole group has been attached to (R)-3-(3-
fluoro-4-(piperazin-1-yl)phenyl)-5-((4-aryl/heteroaryl-1H-1,2,3-
triazol-1-yl)methyl)oxazolidin-2-one at the distal piperazine NeH
position in order to identify new molecules with improved anti-
mycobacterial activity. Additionally, phenyl, m-tolyl, 2-pyridyl and
1H-methyl-5-imidazolyl groups have been introduced at the 4th
position of the 1H-1,2,3-triazole ring. Attempts have also been
made to correlate the structure to antimycobacterial activity of
these compounds.
previously described [24,25]. The union of these two fragments
(9aeh) and 10 was achieved by employing Mannich reaction be-
tween them to produce 11aeh (Table 1). The azido compounds
(11aeh), thus obtained were then converted to diarylpyrroleetri-
azolyloxazolidinone conjugates (4aen) by click chemistry using
aryl/heteroaryl acetylenes in the presence of copper sulfate and
catalytic amount of sodium ascorbate in t-BuOH and water (3:1) as
illustrated in Scheme 2 [26,27].
In addition, the diarylpyrroleeoxazolidinone conjugates (5aed)
were prepared as outlined in Scheme 2. The amino compounds
12aed were obtained from the reduction of azide group of 11a, 11b,
11f and 11h in the presence of ammonium formate and catalytic
amount of zinc dust in methanol (Table 1). On acylation of the
amino compounds (12aed) in the presence of acetyl chloride in dry
CH2Cl2 employing triethylamine as a base, the corresponding
acetamides were obtained (5aed).
3. Results and discussion
3.1. Antimycobacterial activity
These newly synthesized diarylpyrroleeoxazolidinones (4aen
and 5aed) were evaluated for their antimycobacterial activity
against M. tuberculosis isolates using the microplate dilution assay
2. Chemistry
at 1e16 mg/mL concentrations. The drugs in clinical use rifampicin
and linezolid were used as reference compounds. The in vitro test
results for this new class of compounds are outlined in Table 2 as
minimum inhibitory concentration (MIC) and the activity ranges
The synthetic pathways employed for the generation of different
products in the series are described in Schemes 1 and 2. Various
substituted diarylpyrroles have been prepared from the corre-
sponding 1,4-diketones and anilines. Synthesis of diarylpyrroles is
depicted in Scheme 1, wherein the reaction of a suitable benzal-
dehyde with methyl vinyl ketone, under Stetter conditions to yield
1,4-diketones (8aef) [20], followed by modified PaaleKnorr
condensation procedure using Gd(OTf)3 as catalyst. In the Paale
Knorr condensation, the intermediates (8aef) were treated with
the appropriate amines in the presence of Gd(OTf)3 for cyclization
to yield the required diaryl pyrroles (9aeh) in good yields.
from 2 to >6.25 mg/mL. Moreover, these compounds have also been
screened against M. tuberculosis RifR and M. tuberculosis XDR. At
primary screening, the compounds 4aed, 4eei and 5aec showed
significant inhibition against MTB. Amongst the evaluated conju-
gates, the conjugate (5R)-3-(3-fluoro-4-(4-((1-(4-fluorophenyl)-2-
methyl-5-o-tolyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)phen-yl)-
5-((4-(1-methyl-1H-imidazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)
oxazolidin-2-one (4i) was found to be more active against MTB
(2
over, compound 4i exhibited very good activity against the resistant
strains such as, rifampicin resistant MTB (4 g/mL) and XDR-TB
(8 g/mL).
In the structure activity relationship (SAR) studies, some inter-
mg/mL) compared to the other compounds in this series. More-
The key intermediate (S)-N-[[3-(3-fluoro-4-(piperzinyl)phenyl)-
2-oxo-5-oxazolidinyl]methyl]-azide (10) has been synthesized as
m
m
esting trends have been observed in these conjugates. In the
substituted triazole series, the conjugates having pyridyl group
(4aee) and 1-methyl-1H-imidazol-5-yl group (4fei) at 4-position
of triazole ring have shown promising activity (2e16
mg/mL)
compared to the compounds having phenyl/m-tolyl group at 4-
position of triazole ring (4jen). This observation indicates the
importance of the presence of 2-pyridyl/1-methyl-1H-imidazol-5-
yl group (4fei) at 4-position of the triazole ring which is playing
key role in exhibiting the activity against Mycobacterium. Com-
pounds 5aed that possess a C5-acetamide group as in case of
linezolid also showed moderate activity against M. tuberculosis (4e
16 mg/mL).
3.2. Cytotoxicity assay
As described in experimental procedure, the maximum toler-
ated test (MTT) was performed to evaluate the in vitro cytotoxicity
of the promising compounds (4bef, 4i and 5c) against mouse
macrophage (J-774) cell lines. These compounds were not cytotoxic
as indicated by their IC50 values. The IC50 and selective index (SI)
values of these compounds are shown in Table 3. The good selec-
tivity index values for these compounds indicate its potential
usefulness in the drug development for tuberculosis.
Fig. 1. Potent anti-tubercular agents and antibacterial agents.

A. Kamal et al. / European Journal of Medicinal Chemistry 64 (2013) 239e251
241
O
O
(i)
(ii)
N
H
R1
R1
R1
O
7
O
6a f
-
8a f
-
R2
9a h
1
6a 8a
,
R = 2,4-F2
6b
6c
6d
,
8b R1 = 4-Me
8c R1 = 3-Cl
-
,
,
8d R1 = 4-Cl,3-F
6e 8e
,
,
R
1 = 2-Me
R
1 = 4-iPr
6f 8f
Scheme 1. Synthesis of substituted diarylpyrroles (9aeh): Reagents and conditions: (i) 1,3-ethyl-5-(2-hydroxyethyl)-4-methyl-thiazolium bromide, NEt3, 75e78 ꢀC, 5 h, 2N HCl; (ii)
R2-NH2, cat. Gd(OTf)3, 30 ꢀC, 30 min.
3.3. Antibacterial activity
organisms and insignificant activity against Gram-negative
organisms.
These compounds have also been evaluated for their antibac-
terial activity against a panel of Gram-positive and Gram-negative
pathogens and compared with linezolid as a reference antibacte-
rial. The antibacterial evaluation of the compounds reported as the
Conjugates like 4aed, 4f, 4jel and 5aed that showed significant
activity in the primary screening against Gram-positive bacteria.
Then these were further evaluated at different concentrations to
find MICs and the results are outlined in Table 4. Compounds 4c and
5b are found to be most active against Staphylococcus aureus MTCC
minimum inhibitory concentrations (MICs, mg/mL) determined by
the agar dilution method on MuellereHinton (HM) agar is sum-
marized in Table 4. It is observed from the results that some of the
conjugates show good antibacterial activity against Gram-positive
96 (MIC 0.5
Micrococcus luteus MTCC 2470 with MIC 0.5
pounds showed very good inhibitory zone (12e40 mm) when
m
g/mL), whereas compound 4l was active against
mg/mL. These com-
O
O
O
N
N
N
N
(i)
O
N3
HN
N
N
R1
F
N3
N
R1
F
R2
11a-h
10
9a h
-
R2
11a 11d 11f and 11h
,
,
(ii)
(iii)
O
O
O
N
N
N
O
NH2
N
N
N
N
N
N
R3
F
N
12a d
-
R1
F
N
R1
4a n
-
R2
(vi)
R2
4a: R1 = 4-CH3, R2 = 3,4-Cl2, R3 = 2-Py
O
4b: R1 = 4-Cl,3-F, R2 = 4-OCF3, R3 = 2-Py
O
N
N
N
H
N
4c: R1 = 2,4-F2, R2 = 4-F, R3 = 2-PY
4d
: R1 = 2-CH3, R2 = 3,4-F2, R3 = 2-Py
F
O
4e
N
: R1 = 2,4-F2, R2 = 2-Br,5-F, R3 = 2-Py
R1
5a d
-
4f: R1 = 4-iPr , R2 = 2,4-F2, R3 = 1-Me-5-imd
4g: R1 = 2,4-F2, R2 = 4-F, R3 = 1-Me-5-imd
4h: R1 = 2-CH3, R2 = 3,4-F2, R3 = 1-Me-5-imd
4i
R2
1
: R = 2-CH3, R2 = 4-F, R3 = 1-Me-5-imd
5a: R1 = 2,4-F2, R2 = 2-Br,5-F
5b: R1 = 3-Cl, R2 = 2-F
: R1 = 3-Cl, R2 = 2-F, R3 = Ph
4j
4k: R1 = 4-Cl,3-F, R2 = 4-OCF3, R3 = Ph
4l: R1 = 4-CH3, R2 = 3,4-Cl2, R3 = Ph
4m: R1 = 2,4-F2, R2 = 2-Br,5-F, R3 = Ph
5c: R1 = 4-iPr , R2 = 2,4-F2
5d
: R1 = 2-CH3, R2 = 4-F
: R1 = 2-CH3, R2 = 4-F, R3 = 3-Tol
4n
Scheme 2. Synthetic route of diarylpyrroleetriazolyl oxazolidinone conjugates (4aen and 5aed): Reagents and conditions: (i) HCHO, cat. ACOH, CH3CN, 0 ꢀCert, 6 h; (ii) aryl/
heteroaryl acetylenes, CuSO4, cat. Sodium ascorbate, t-BuOH þ H2O (3:1), 4 h; (iii) Pd/C, H2 gas, EtOH, rt, 3 h; (iv) acetyl chloride, TEA, dry DCM, 0 ꢀCert, 1 h.

242
A. Kamal et al. / European Journal of Medicinal Chemistry 64 (2013) 239e251
Table 1
Structural interpretation of the compounds 9aeh, 11aeh and 12aed.
Entry
Compd
R1
R2
X
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
9g
9h
11a
11b
11c
11d
11e
11f
11g
11h
12a
12b
12c
12d
2,4-F2
2,4-F2
4-CH3
3-Cl
2-Br,5-F
4-F
3,4-Cl2
2-F
4-OCF3
2,4-F2
3,4-F2
4-F
2-Br,5-F
4-F
3,4-Cl2
2-F
4-OCF3
2,4-F2
3,4-F2
4-F
2-Br,5-F
2-F
2,4-F2
4-F
H
H
H
H
H
H
H
H
A
A
A
A
A
A
A
A
B
4-Cl,3-F
4-iPr
2-CH3
2-CH3
2,4-F2
2,4-F2
4-CH3
3-Cl
9
10
11
12
13
14
15
16
17
18
19
20
4-Cl,3-F
4-iPr
2-CH3
2-CH3
2,4-F2
3-Cl
B
B
B
4-iPr
2-CH3
compared to standard reference drugs (Table 5). Compounds with
pyridyl group at 4-position of triazole ring (4aed) and compounds
with C5-acetamide group (5aed) displayed enhanced activity
against Gram-positive strains. On the other hand, the moieties that
have 1-methyl-1H-imidazol-2-yl group at 4-position of the triazole
ring (4fei) showed lower activity against Gram-positive strains.
Interestingly, compounds with phenyl group at 4-position of tri-
azole ring (4jel) were active against Gram-positive organisms.
correlated with the structures. These novel oxazolidinone conjugates
have shown significant antimycobacterial activity against
M. tuberculosis H37Rv and promising activity against M. tuberculosis
RifR and M. tuberculosis XDR strains. Furthermore, the MTT assay
performed on these conjugates confirms that these molecules have
no cytotoxic effect and possess good selective index values. Amongst
the new oxazolidinones, 4i is found to be the most active derivative
and will be taken up for lead optimization to design novel anti-
tubercular agents. In addition, some of the new compounds such as
4c, 5a and 5d have shown good activity against a panel of Gram-
positive organisms. Docking studies revealed that the binding mode
is the hydrogen bonding interactions with G2540 in the 50S unit of
the ribosome. The active conjugates have showngood docking scores,
which were in the range of the co-crystal ligand linezolid. Further
investigations on this oxazolidinone scaffold are ongoing in our lab-
oratory with a view to develop improved antimycobacterial agents.
3.4. Docking studies in 50S unit of ribosome
To provide some insight into the mechanism of action for this class
of compounds, the docking studies have been carried out. The basic
scaffold of diarylpyrroleeoxazolidinone conjugates (4aen and 5aed)
is similar to that of the linezolid, a drug candidate from oxazolidinone
class. Hencethesemoleculesareexpectedtobindtothe50Sunitof the
ribosome similarly to that of the linezolid. Docking studies of the
selected conjugates (4aec, 4f, 4i, 4l, 5a, 5c and 5d) were performed
using Gold docking software. The docking studies were performed to
get further insight for the binding mode of the molecules in the 50S
unitof the ribosome and the fitting scores of allthe compounds (4aec,
4f, 4i, 4l, 5a, 5cand 5d) were listed inTable 6. Docking studies revealed
that the binding mode is the hydrogen bonding interactions with
G2540. For all the tested molecules, docking scores were in the range
of the co-crystal ligand linezolid. The binding pose for the molecule 4i
in 50S unit of ribosome was shown in Fig. 2.
5. Experimental protocols
5.1. General
All chemicals were purchased from Aldrich (SigmaeAldrich, St.
Louis, MO, USA), Lancaster (Alfa Aesar, Johnson Matthey Company,
Ward Hill, MA, USA) or Spectrochem Pvt. Ltd (Mumbai, India) and
were used without further purification. Reactions were monitored
by TLC, performed on silica gel glass plates containing 60 GF-254,
and visualization on TLC was achieved by UV light or iodine indi-
cator. Column chromatography was performed with Merck 60e
120 mesh silica gel. 1H NMR and 13C NMR spectra were recorded on
Gemini Varian-VXR-unity (200 MHz) or Bruker UXNMR/XWIN-
NMR (300 MHz) instruments. Chemical shifts are reported in
4. Conclusion
In the present investigation, we have designed and synthesized a
new class of diarylpyrroleeoxazolidinone conjugates. The anti-
mycobacterial activities of these compounds are evaluated and
parts per million
(d in ppm) relative to the peak for

A. Kamal et al. / European Journal of Medicinal Chemistry 64 (2013) 239e251
243
Table 2
Anti-tubercular activity of the compounds (4aen and 5aed) against Mycobacterium tuberculosis H37Rv and clinical isolates.
Compd
R1
R2
R3
M. ta
M. tb
M. tc
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
5a
5b
5c
5d
4-CH3
4-Cl,3-F
2,4-F2
2-CH3
2,4-F2
4-iPr
3,4-Cl2
4-OCF3
4-F
3,4-F2
2-Br,5-F
2,4-F2
4-F
3,4-F2
4-F
4-OCF3
3,4-Cl2
2-Br,5-F
4-F
A
A
A
A
A
B
B
B
B
C
C
C
C
D
e
e
e
e
4.0
4.0
4.0
4.0
NT
4.0
>6.25
>6.25
2.0
>16.0
>16.0
>16.0
>16.0
>16.0
8.0
4.0
4.0
8.0
4.0
NT
8.0
8.0
8.0
16.0
>16.0
16.0
16.0
NT
4.0
16.0
>16.0
8.0
>16.0
>16.0
>16.0
>16.0
>16.0
>16.0
>16.0
16.0
2,4-F2
2-CH3
2-CH3
4-Cl,3-F
4-CH3
2,4-F2
2-CH3
2-CH3
2,4-F2
3-Cl
4.0
>16.0
>16.0
>16.0
>16.0
>16.0
8.0
8.0
4.0
NT
4-F
2-Br,5-F
2-F
2,4-F2
4-F
8.0
4.0
NT
4-iPr
2-CH3
NT
Rif
LZ
0.2
1.0
>128
2.0
2.0
4.0
A ¼ 2-pyridyl; B ¼ 1-methyl-1H-imidazol-5-yl; C ¼ phenyl; D ¼ m-tolyl; the tests were performed in duplicate and repeated thrice; LZ (Linezolid); AT-B (Amphotericin); NT
(Not Tested). Bold represents MIC values of the active compounds.
a
M. t (Mycobacterium tuberculosis H37Rv).
b
M. t (Mycobacterium tuberculosis RifR).
c
M. t (Mycobacterium tuberculosis XDR-1).
tetramethylsilane (TMS) as an internal standard, coupling constants
are reported in Hertz (Hz). Spectral patterns were designated as s,
singlet; d, doublet; dd, double doublet; t, triplet; bs, broad singlet;
m, multiplet. ESI spectra were recorded on Micromass, Quattro LC
using ESIþ software with capillary voltage 3.98 kV and ESI mode
positive ion trap detector. High-resolution mass spectra (HRMS)
were recorded on QSTAR XL Hybrid MS/MS mass spectrometer. IR
spectra were recorded on a FT-IR spectrometer and only major
fluorobenzenamine (190 mg, 1.0 mmol) was added and the reac-
tion mixture was stirred at room temperature for 30 min. After
completion of reaction as indicated by TLC, water (10 mL) was
added to the reaction mixture and extracted by using ester. The
product was purified by column chromatography by using hexane,
ethyl acetate (10:1) system gives the product (9a) (yield 351 mg,
94%). 1H NMR (CDCl3, 300 MHz):
d
7.49 (d, 1H, J ¼ 2.2 Hz, AreH),
7.39 (d, 1H, J ¼ 2.9 Hz, AreH), 7.34 (d, 1H, J ¼ 2.2 Hz, AreH), 7.22 (d,
1H, J ¼ 2.9 Hz, AreH), 7.02 (s, 1H, AreH), 6.85 (s, 1H, AreH), 6.21 (d,
1H, J ¼ 3.4 Hz, pyreH), 5.97 (d, 1H, J ¼ 3.4 Hz, pyreH), 2.06 (s, 3H,
pyreCH3); ESIMS: m/z 366 (M þ H)þ.
peaks are reported in cmꢁ1
.
5.2. Preparation of the compounds 9aeh
5.2.2. 2-(2,4-Difluorophenyl)-1-(4-fluorophenyl)-5-methylpyrrole
(9b)
5.2.1. 1-(2-Bromo-5-fluorophenyl)-2-(2,4-difluorophenyl)-5-
methyl-1H-pyrrole (9a)
The compound 9b was prepared according to the above-
described method using 1-(2,4-difluorophenyl)-1,4-pentanedione
(8a, 254 mg, 1.2 mmol) and 4-fluoroaniline (111 mg, 1.0 mmol)
To a solution of 1-(2,4-difluorophenyl) pentane-1,4-dione (8a,
254 mg, 1.2 mmol) in acetonitrile (3 mL), 2-bromo-5-
Table 3
(yield 275 mg, 96%). 1H NMR (CDCl3, 300 MHz):
d 7.10e6.97 (m, 5H,
IC50
(mM) and selectivity index (SI) values of active compounds (4bef, 4i and 5c)
AreH), 6.73e6.62 (m, 2H, AreH), 6.28 (d, 1H, J ¼ 3.7 Hz, pyreH),
6.09 (d, 1H, J ¼ 3.7 Hz, pyreH), 2.12 (s, 3H, pyreCH3); ESIMS: m/z
288 (M þ H)þ.
against mouse macrophage cell lines (J-774).
Entry Compound MIC ( g/mL) in % cell inhibition IC50
m
SI index
approximation IC50/MIC
M. tb H37Rv
at 40 mg/mL
1
2
3
4
5
6
7
4b
4c
4d
4e
4f
4.0
4.0
4.0
4.0
4.0
4.0
4.0
37.7
31.9
40.0
43.9
44.7
49.3
40.2
>40
>40
>40
>40
>40
>40
>40
>10
>10
>10
>10
>10
>10
>10
5.2.3. 1-(3,4-Dichlorophenyl)-2-methyl-5-p-tolyl-1H-pyrrole (9c)
The compound 9c was prepared according to the above-
described method using 1-p-tolylpentane-1,4-dione (8b, 228 mg,
1.2 mmol) and 3,4-dichlorobenzenamine (162 mg, 1.0 mmol) (yield
4i
5c
302 mg, 96%). 1H NMR (CDCl3, 300 MHz):
d
7.23 (d, 2H, J ¼ 3.1 Hz,
AreH), 7.03 (t, 2H, J ¼ 2.2 Hz, AreH), 7.00 (t, 2H, J ¼ 2.2 Hz, AreH),

244
A. Kamal et al. / European Journal of Medicinal Chemistry 64 (2013) 239e251
Table 4
pentanedione
trifluoromethoxyaniline (177 mg, 1.0 mmol) (yield 349 mg, 95%).
1H NMR (CDCl3, 300 MHz):
7.14e7.19 (m, 2H, AreH), 7.09e7.11 (m, 1H, J ¼ 8.3 Hz, AreH), 6.76
(dd, 1H, J ¼ 10.5, 2.2 Hz, AreH), 6.66 (d, 1H, J ¼ 9.0 Hz, AreH), 6.33
(d, 1H, J ¼ 3.7 Hz, pyreH), 6.04 (d, 1H, J ¼ 3.7 Hz, pyreH), 2.12 (s, 3H,
pyreCH3); ESIMS: m/z 352 (M þ H)þ.
(8f,
273
mg,
1.2
mmol)
and
4-
Antibacterial activity of the compounds (4aen and 5aed) against several standard
strains.
d
7.26e7.23 (m, 2H, J ¼ 9.0 Hz, AreH),
Compd S. aureusa S. MLS e 16b M. luteusc B. subtilisd E. colie P. aeruginosaf
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
5a
5b
5c
5d
8.0
>30.0
0.5
>30.0
NT
8.0
16.0
10.0
10.0
>40.0
>40.0
8.0
NT
>40.0
3.0
>40.0
9.0
6.0
5.0
NT
>30.0
>30.0
>30.0
>30.0
10.0
>40.0
9.0
NT
>40.0
5.0
2.5
8.0
3.0
>30.0
NT
>30.0
>30.0
10.0
>30.0
8.0
8.0
0.5
NT
>40.0
5.0
1.5
3.0
1.5
1.0
16.0
1.0
12.0
NT
>30.0
>30.0
>30.0
>30.0
>40.0
>40.0
2.5
NT
9.0
2.5
1.5
1.5
3.0
>40.0 >40.0
>40.0 >40.0
>40.0 >40.0
>40.0 >40.0
NT
NT
5.2.6. 1-(3,4-Difluorophenyl)-2-(4-isopropylphenyl)-5-methyl-1H-
pyrrole (9f)
>40.0 >40.0
>40.0 >40.0
>40.0 >40.0
>40.0 >40.0
>40.0 >40.0
>40.0 >40.0
>40.0 >40.0
The compound 9f was prepared according to the above-
described method using 1-(2-methylphenyl)-1,4-pentanedione
(8e, 261 mg, 1.2 mmol) and 2,4-difluoroaniline (129 mg,
1.0 mmol) (yield 293 mg, 94%). 1H NMR (CDCl3, 300 MHz):
d 7.55 (d,
NT
NT
1H, J ¼ 2.3 Hz, AreH), 7.31 (t, 2H, J ¼ 3.0 Hz, AreH), 7.24 (t, 2H,
J ¼ 3.0 Hz, AreH), 7.18 (d, 1H, J ¼ 2.3 Hz, AreH), 7.09 (s, 1H, AreH),
6.22 (d, 1H, J ¼ 3.4 Hz, pyreH), 5.96 (d, 1H, J ¼ 3.4 Hz, pyreH), 2.85e
2.76 (m,1H, eCH(CH3)2), 2.06 (s, 3H, pyreCH3),1.6 (d, 6H, J ¼ 6.9 Hz,
eCH(CH3)2); ESIMS: m/z 312 (M þ H)þ.
>40.0 >40.0
>40.0 >40.0
>40.0 >40.0
>40.0 >40.0
>40.0 >40.0
0.5
2.0
1.5
2.0
6.0
5.0
LZ
1.5
0.5
1.0
0.5
e
e
5.2.7. 1-(3,4-Fluorophenyl)-2-methyl-5-(2-methylphenyl)-pyrrole
(9g)
The tests were performed in duplicate and repeated thrice; NT (Not Tested) LZ
(Linezolid); AT-B (Amphotericin). Bold represents MIC values of the active
compounds.
The compound 9g was prepared according to the above-
described method using 1-(2-methylphenyl)-1,4-pentanedione
(8e, 228 mg, 1.2 mmol) and 3,4-difluoroaniline (129 mg,
a
S. aureus (Staphylococcus aureus MTCC 96).
S. MLS-16 (Staphylococcus MLS-16 MTCC 2940).
M. luteus (Micrococcus luteus MTCC 2470).
B. subtilis (Bacillus subtilis MTCC 121).
E. coli (Escherichia coli MTCC 739).
P. aeruginosa (Pseudomonas aeruginosa MTCC 2453).
b
c
1.0 mmol) (yield 271 mg, 96%). 1H NMR (CDCl3, 300 MHz):
d 7.15e
d
e
7.13 (m, 2H, AreH), 7.10e7.01 (m, 3H, AreH), 6.87 (td, 2H, J ¼ 7.2,
2.0 Hz, AreH), 6.35 (m, 1H, J ¼ 3.4 Hz, pyreH), 6.13 (d, 1H, J ¼ 3.4 Hz,
pyreH), 2.16 (s, 3H, AreCH3), 2.10 (s, 3H, pyreCH3); ESIMS: m/z 284
(M þ H)þ.
f
6.86 (d, 2H, J ¼ 3.1 Hz, AreH), 6.75 (s, 1H, AreH), 6.24 (d, 1H,
J ¼ 3.2 Hz, pyreH), 6.03 (d, 1H, J ¼ 3.2 Hz, pyreH), 2.11 (s, 3H, pyre
CH3); ESIMS: m/z 316 (M þ H)þ.
5.2.8. 1-(4-Fluorophenyl)-2-methyl-5-o-tolyl-1H-pyrrole (9h)
The compound 9h was prepared according to the above-
described method using 1-(2-methylphenyl)-1,4-pentanedione
(8e, 228 mg, 1.2 mmol) and 4-fluoroaniline (111 mg, 1.0 mmol)
5.2.4. 2-(3-Chlorophenyl)-1-(2-fluorophenyl)-5-methylpyrrole (9d)
The compound 9d was prepared according to the above-
described method using 1-(3-chlorophenyl)-1,4-pentanedione (8c,
252 mg, 1.2 mmol) and 2-fluoroaniline (111 mg, 1.0 mmol) (yield
(yield 271 mg, 96%). 1H NMR (CDCl3, 500 MHz):
d 7.09e7.10 (m, 2H,
AreH), 6.99e7.01 (m, 4H, AreH), 6.70 (td, 2H, J ¼ 7.2, 2.0 Hz, AreH),
6.35 (m, 1H, J ¼ 3.4 Hz, pyreH), 6.13 (d, 1H, J ¼ 3.4 Hz, pyreH), 2.15
(s, 3H, AreCH3), 2.10 (s, 3H, pyreCH3); ESIMS: m/z 266 (M þ H)þ.
273 mg, 96%). 1H NMR (CDCl3, 300 MHz):
d
7.48 (d, 1H, J ¼ 2.2 Hz,
AreH), 7.30 (s, 1H, AreH), 7.24 (dd, 1H, J ¼ 8.3, 2.2 Hz, AreH), 7.12
(dd, 1H, J ¼ 8.3, 2.2 Hz, AreH), 7.09 (d, 1H, J ¼ 2.7 Hz, AreH), 7.02 (d,
1H, J ¼ 8.8 Hz, AreH), 6.85 (dd,1H, J ¼ 8.8, 3.2 Hz, AreH), 6.40 (d,1H,
J ¼ 3.2 Hz, AreH), 6.27 (d, 1H, J ¼ 3.6 Hz, pyreH), 6.07 (d, 1H,
J ¼ 3.6 Hz, pyreH), 2.03 (s, 3H, pyreCH3); ESIMS: m/z 286 (M þ H)þ.
5.3. General procedure for the preparation of compounds 11aeh
The compounds (11aeh) were prepared by means of the Man-
nich reaction as shown in Scheme 1, starting from a suitable pyrrole
(9aeh) and (R)-5-(azidomethyl)-3-(3-fluoro-4-(piperazin-1-yl)
phenyl)oxazolidin-2-one in acetonitrile and acetic acid, in the
presence of formaldehyde. In detail, to a stirred solution of an
appropriate pyrrole (0.6 mmol), in acetonitrile (5 mL), a mixture of
(R)-5-(azidomethyl)-3-(3-fluoro-4-(piperazin-1-yl)phenyl)oxazoli-
din-2-one (0.19 g, 0.6 mmol), formaldehyde (0.6 mmol) (40% in
water), and 0.5 mL of acetic acid, was added drop wise at 0 ꢀC. After
the addition was complete, the mixture was stirred at room
5.2.5. 1-(4-Trifluoromethoxyphenyl)-2-methyl-5-(4-chloro-3-
fluorolphenyl)-pyrrole (9e)
The compound 9e was prepared according to the above-
described
method
using
1-(4-chloro-3-fluorophenyl)-1,4-
Table 5
Preliminary antibacterial activity of diarylpyrroleetriazolyloxazolidinones against
Gram-positive bacteria (zone of inhibition in mm) at 20 g/mL.
m
Entry
Compd
S. aureusa
S. MLS e 16b
M. luteusc
B. subtilisd
1
2
3
4
5
4c
4l
5a
5b
5c
39
21
20
18
16
40
19
18
23
15
36
17
19
27
18
24
14
14
18
12
Table 6
Docking scores for the compounds (4aec, 4f, 4i, 4l, 5a, 5c and 5d).
Entry
Compound
Fitness score
1
2
3
4
5
6
7
8
9
4a
4b
4c
4f
4i
4l
5a
5c
5d
74.92
61.45
83.37
72.66
78.27
70.04
72.93
64.27
68.38
6
7
LZ
AT-B
28
e
18
e
20
e
20
e
The tests were performed in duplicate and repeated thrice; LZ Linezolid (20 mg/mL);
AT-B Amphotericin (20 mg/mL).
a
S. aureus (Staphylococcus aureus MTCC 96).
S. MLS-16 (Staphylococcus MLS-16 MTCC 2940).
M. luteus (Micrococcus luteus MTCC 2470).
B. subtilis (Bacillus subtilis MTCC 121).
b
c
d

A. Kamal et al. / European Journal of Medicinal Chemistry 64 (2013) 239e251
245
Fig. 2. Binding pose for 4i in 50S unit of ribosome.
temperature for 6 h. The mixture was then treated with a solution
of sodium hydroxide (20%, w/v) and extracted with chloroform. The
organic extracts were combined, washed with water, and dried.
After the removal of solvent, the residue was purified by column
chromatography, using aluminum oxide and chloroform. The elu-
ates were combined after TLC control, and the solvent was removed
to give 11aeh as solids in satisfactory yield. Recrystallization from
diethyl ether gave the required products.
7.35e7.27 (m, 3H, AreH), 7.02 (t, 1H, J ¼ 1.9 Hz, oxaeAreH), 6.97e
6.84 (m, 2H, AreH and 1H, oxaeAreH), 6.30 (s, 1H, pyreH), 5.08e
5.04 (m, 1H, oxaeCHe), 4.73e4.08 (m, 2H, oxaeCH2e), 4.16 (dd, 1H,
J ¼ 6.8, 2.9 Hz, oxaeCHHe), 3.93 (dd, 1H, J ¼ 6.8, 2.9 Hz, oxaeCHHe
), 3.65 (s, 2H, pyreCH2), 3.18e3.16 (t, 4H, piperazineeH), 2.86e2.82
(t, 4H, piperazineeH), 2.27 (s, 3H, AreCH3), 2.11 (s, 3H, pyreCH3);
ESIMS: m/z 649 (M)þ.
5.3.4. (5R)-5-(Azidomethyl)-3-(4-(4-((5-(3-chlorophenyl)-1-(2-
fluorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)-3-
fluorophenyl)oxazolidin-2-one (11d)
5.3.1. (5R)-5-(Azidomethyl)-3-(4-(4-((1-(2-bromo-5-
fluorophenyl)-5-(2,4-difluorophenyl)-2-methyl-1H-pyrrol-3-yl)
methyl)piperazin-1-yl)-3-fluorophenyl)oxazolidin-2-one (11a)
The compound 11a was prepared according to the above-
described method using 9a (0.220 g, 0.6 mmol) and 10 (0.192 g,
The compound 11d was prepared according to the above-
described method using 9d (0.171 g, 0.6 mmol) and 10 (0.192 g,
0.6 mmol) (yield 0.330 g, 89%). 1H NMR (CDCl3, 500 MHz):
d 7.61
0.6 mmol) (yield 0.334 g, 80%). 1H NMR (CDCl3, 300 MHz):
d
7.48 (d,
(dd, 1H, J ¼ 2.6 Hz, AreH), 7.41 (dd, 1H, J ¼ 14.6, 2.4 Hz, oxaeAreH),
7.21 (td, 1H, J ¼ 8.8, 1.7 Hz, AreH), 7.17 (d, 2H, J ¼ 5.2 Hz, AreH),
7.12e7.09 (m, 2H, AreH), 7.07 (s, 1H, AreH), 7.02 (dd, 1H, J ¼ 8.8,
2.2 Hz, oxaeAreH), 6.95 (d, 1H, J ¼ 9.0 Hz, AreH), 6.90 (dt, 1H,
J ¼ 6.7, 1.8 Hz, oxaeAreH), 6.39 (s, 1H, pyreH), 4.77e4.68 (m, 1H,
oxaeCHe), 3.97 (dd, 1H, J ¼ 9.0, 6.1 Hz, oxaeCHHe), 3.87 (dd, 1H,
J ¼ 9.1, 6.2 Hz, oxaeCHHe), 3.64e3.59 (m, 2H, oxaeCH2e), 3.47 (s,
2H, pyreCH2), 3.15e3.07 (t, 4H, piperazineeH), 2.74e2.63 (t, 4H,
piperazineeH), 1.99 (s, 3H, pyreCH3); ESIMS: m/z 619 (M þ H)þ.
1H, J ¼ 2.2 Hz, AreH), 7.40 (dd, 1H, J ¼ 14.6, 2.4 Hz, oxaeAreH), 7.39
(d, 1H, J ¼ 2.9 Hz, AreH), 7.34 (d, 1H, J ¼ 2.2 Hz, AreH), 7.22 (d, 1H,
J ¼ 2.9 Hz, AreH), 7.04 (d,1H, J ¼ 9.0 Hz, oxaeAreH), 7.02 (s,1H, Are
H), 6.89 (t,1H, J ¼ 8.9 Hz, oxaeAreH), 6.85 (s,1H, AreH), 6.21 (d,1H,
J ¼ 3.4 Hz, pyreH), 4.78e4.70 (m, 1H, oxaeCHe), 4.00 (dd, 1H,
J ¼ 6.1 Hz, 9.0 Hz, oxaeCHHe), 3.73 (dd, 1H, J ¼ 9.1, 6.2 Hz, oxae
CHHe), 3.57e3.48 (m, 2H, oxaeCH2e), 3.47 (s, 2H, pyreCH2), 3.12e
3.07 (t, 4H, piperazineeH), 2.74e2.63 (t, 4H, piperazineeH), 2.02 (s,
3H, pyreCH3); ESIMS: m/z 698 (M)þ.
5.3.5. (R)-5-(Azidomethyl)-3-(4-(4-((5-(4-chloro-3-fluorophenyl)-
2-methyl-1-(4-(trifluoromethoxy)phenyl)-1H-pyrrol-3-yl)methyl)
piperazin-1-yl)-3-fluorophenyl)oxazolidin-2-one (11e)
5.3.2. (5R)-5-(Azidomethyl)-3-(4-(4-((5-(2,4-difluorophenyl)-1-(4-
fluorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)-3-
fluorophenyl)oxazolidin-2-one (11b)
The compound 11e was prepared according to the above-
described method using 9e (0.214 g, 0.6 mmol) and 10 (0.192 g,
The compound 11b was prepared according to the above-
described method using 9b (0.172 g, 0.6 mmol) and 10 (0.192 g,
0.6 mmol) (yield 0.336 g, 80%). 1H NMR (CDCl3, 500 MHz):
d 7.35
0.6 mmol) (yield 0.278 g, 70%). 1H NMR (CDCl3, 300 MHz):
d
7.35
(dd, 1H, J ¼ 12.0, 1.7 Hz, oxaeAreH), 7.26e7.23 (m, 2H, AreH), 7.14e
7.19 (m, 2H, AreH), 7.11e7.06 (m, 2H, oxaeAreH, AreH), 6.90 (t, 1H,
J ¼ 9.0 Hz, oxaeAreH), 6.73e6.63 (m, 2H, AreH), 6.33 (s, 1H, pyre
H), 5.13e5.05 (m, 1H, oxaeCHe), 4.82e4.79 (m, 2H, oxaeCH2e),
4.15 (dd, 1H, J ¼ 6.2, 3.1 Hz, oxaeCHHe), 3.85 (dd, 1H, J ¼ 6.4, 3.0 Hz,
oxaeCHHe), 3.69 (s, 2H, pyreCH2), 3.18e3.16 (t, 4H, piperazineeH),
2.87e2.85 (t, 4H, piperazineeH), 2.17 (s, 3H, pyreCH3); ESIMS: m/z
703 (M þ H)þ.
(dd, 1H, J ¼ 14.0, 1.7 Hz, oxaeAreH), 7.10e7.04 (m, 3H, oxaeAreH,
AreH), 7.00 (d, 2H, J ¼ 6.5 Hz, AreH), 6.90 (t, 1H, J ¼ 9.0 Hz, oxae
AreH), 6.73e6.63 (m, 3H, AreH), 6.33 (s, 1H, pyreH), 5.13e5.05 (m,
1H, oxaeCHe), 4.82e4.79 (m, 2H, oxaeCH2e), 4.15 (dd, 1H, J ¼ 6.2,
3.1 Hz, oxaeCHHe), 3.85 (dd, 1H, J ¼ 6.4, 3.0 Hz, oxaeCHHe), 3.69
(s, 2H, pyreCH2), 3.18e3.16 (t, 4H, piperazineeH), 2.87e2.85 (t, 4H,
piperazineeH), 2.17 (s, 3H, pyreCH3); ESIMS: m/z 620 (M þ H)þ.
5.3.3. (R)-5-(Azidomethyl)-3-(4-(4-((1-(3,4-dichlorophenyl)-2-
methyl-5-p-tolyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)-3-
fluorophenyl)oxazolidin-2-one (11c)
5.3.6. (R)-5-(Azidomethyl)-3-(4-(4-((1-(2,4-difluorophenyl)-5-(4-
isopropylphenyl)-2-methyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)-
3-fluorophenyl)oxazolidin-2-one (11f)
The compound 11c was prepared according to the above-
described method using 9c (0.189 g, 0.6 mmol) and 10 (0.192 g,
The compound 11f was prepared according to the above-
described method using 9f (0.187 g, 0.6 mmol) and 10 (0.192 g,
0.6 mmol) (yield 0.330 g, 85%). 1H NMR (CDCl3, 500 MHz):
d
7.42
0.6 mmol) (yield 0.320 g, 83%). 1H NMR (CDCl3, 500 MHz):
d
7.61
(dd, 1H, J ¼ 14.6, 2.4 Hz, oxaeAreH), 7.40 (d, 2H, J ¼ 6.7 Hz, AreH),
(dd, 1H, J ¼ 2.6 Hz, AreH), 7.41 (dd, 1H, J ¼ 14.6, 2.4 Hz, oxaeAreH),

246
A. Kamal et al. / European Journal of Medicinal Chemistry 64 (2013) 239e251
7.21 (td, 1H, J ¼ 8.8, 1.7 Hz, AreH), 7.17 (d, 2H, J ¼ 5.2 Hz, AreH),
7.12e7.09 (m, 2H, AreH), 7.07 (s, 1H, AreH), 7.02 (dd, 1H, J ¼ 8.8,
2.2 Hz, oxaeAreH), 6.95 (d, 1H, J ¼ 9.0 Hz, oxaeAreH), 6.39 (s, 1H,
pyreH), 4.77e4.68 (m, 1H, oxaeCHe), 3.97 (dd, 1H, J ¼ 6.1, 9.0 Hz,
oxaeCHHe), 3.87 (dd, 1H, J ¼ 9.1, 6.2 Hz, oxaeCHHe), 3.64e3.59
(m, 2H, oxaeCH2e), 3.47 (s, 2H, pyreCH2), 3.15e3.07 (t, 4H, piper-
azineeH), 2.74e2.63 (t, 4H, piperazineeH), 1.99 (s, 3H, pyreCH3);
ESIMS: m/z 644 (M þ H)þ.
(s, 2H, pyreCH2), 3.09 (t, 4H, pipeH), 2.74e2.63 (t, 4H, pipeH), 2.02
(s, 3H, pyreCH3); ESIMS: m/z 672 (M)þ, 674 (M þ 2)þ.
5.4.2. (5S)-5-(Aminomethyl)-3-(4-(4-((5-(3-chlorophenyl)-1-(2-
fluorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)-3-
fluorophenyl)oxazolidin-2-one (12b)
The compound 12b was prepared according to the above-
described method using 11d (0.123 g, 0.2 mmol) (yield 0.110 g,
93%). 1H NMR (CDCl3, 500 MHz):
d
7.61 (dd, 1H, J ¼ 2.6 Hz, AreH),
5.3.7. (5R)-5-(Azidomethyl)-3-(3-fluoro-4-(4-((1-(4-fluorophenyl)-
2-methyl-5-o-tolyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)phenyl)
oxazolidin-2-one (11g)
7.41 (dd, 1H, J ¼ 14.6, 2.4 Hz, oxaeAreH), 7.21 (td, 1H, J ¼ 8.8,
1.7 Hz, AreH), 7.17 (d, 2H, J ¼ 5.2 Hz, AreH), 7.12e7.09 (m, 2H, Are
H), 7.07 (s, 1H, AreH), 7.02 (dd, 1H, J ¼ 8.8, 2.2 Hz, oxaeAreH), 6.95
(d, 1H, J ¼ 9.0 Hz, AreH), 6.90 (dt, 1H, J ¼ 6.7, 1.8 Hz, oxaeAreH),
6.62 (t, 2H, J ¼ 5.2, eNH2), 6.39 (s, 1H, pyreH), 4.77e4.68 (m, 1H,
oxaeCHe), 3.97 (dd, 1H, J ¼ 6.1 Hz, 9.0 Hz, oxaeCHHe), 3.87 (dd,
1H, J ¼ 9.1, 6.2 Hz, oxaeCHHe), 3.64e3.59 (m, 2H, oxaeCH2e),
3.47 (s, 2H, pyreCH2), 3.15e3.07 (t, 4H, piperazineeH), 2.74e2.63
(t, 4H, piperazineeH), 1.99 (s, 3H, pyreCH3); ESIMS: m/z 593
(M þ H)þ.
The compound 11g was prepared according to the above-
described method using 9g (0.170 g, 0.6 mmol) and 10 (0.192 g,
0.6 mmol) (yield 0.304 g, 85%). 1H NMR (CDCl3, 300 MHz):
d 7.39
(dd,1H, J ¼ 12.0, 1.7 Hz, oxaeAreH), 7.06 (d,1H, J ¼ 9.0 Hz, oxaeAre
H), 6.99 (d, 2H, AreH), 6.91 (t,1H, J ¼ 9.0 Hz, oxaeAreH), 6.83 (s,1H,
AreH), 6.85e6.81 (m, 3H, AreH), 6.73e6.63 (m, 2H, AreH), 6.33 (s,
1H, pyreH), 5.13e5.05 (m, 1H, oxaeCHe), 4.82e4.79 (m, 2H, oxae
CH2e), 4.15 (dd,1H, J ¼ 6.2, 3.1 Hz, oxaeCHHe), 3.84 (dd, 1H, J ¼ 6.4,
3.0 Hz, oxaeCHHe), 3.69 (s, 2H, pyreCH2), 3.18e3.16 (t, 4H, piper-
azineeH), 2.87e2.85 (t, 4H, piperazineeH), 2.17 (s, 3H, pyreCH3);
ESIMS: m/z 598 (M þ H)þ.
5.4.3. (5S)-5-(Aminomethyl)-3-(4-(4-((1-(2,4-difluorophenyl)-5-
(4-isopropylphenyl)-2-methyl-1H-pyrrol-3-yl)methyl)piperazin-1-
yl)-3-fluorophenyl)oxazolidin-2-one (12c)
The compound 12c was prepared according to the above-
described method using 11f (0.128 g, 0.6 mmol) (yield 0.112 g,
5.3.8. (5R)-5-(Azidomethyl)-3-(4-(4-((1-(3,4-difluorophenyl)-2-
methyl-5-o-tolyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)-3-
fluorophenyl)oxazolidin-2-one (11h)
91%). 1H NMR (CDCl3, 500 MHz):
d
7.41 (dd, 1H, J ¼ 14.6, 2.4 Hz,
oxaeAreH), 7.21 (td, 1H, J ¼ 8.8, 1.7 Hz, AreH), 7.17 (d, 2H,
J ¼ 5.2 Hz, AreH), 7.12e7.09 (m, 2H, AreH), 7.07 (s, 1H, AreH), 7.02
(dd, 1H, J ¼ 8.8, 2.2 Hz, oxaeAreH), 6.97e6.94 (d, 1H, J ¼ 9.0 Hz,
AreH), 6.90 (dt, 1H, J ¼ 6.7, 1.8 Hz, oxaeAreH), 6.39 (s, 1H, pyreH),
4.77e4.68 (m, 1H, oxaeCHe), 3.97 (dd, 1H, J ¼ 6.1, 9.0 Hz, oxae
CHHe), 3.87 (dd, 1H, J ¼ 9.1, 6.2 Hz, oxaeCHHe), 3.64e3.59 (m,
2H, oxaeCH2e), 3.47 (s, 2H, pyreCH2), 3.15e3.07 (t, 4H, pipera-
zineeH), 2.74e2.63 (t, 4H, piperazineeH), 1.99 (s, 3H, pyreCH3);
ESIMS: m/z 618 (M þ H)þ.
The compound 11h was prepared according to the above-
described method using 9h (0.159 g, 0.6 mmol) and 10 (0.192 g,
0.6 mmol) (yield 0.306 g, 83%). 1H NMR (CDCl3, 300 MHz):
d 7.43
(dd, 1H, J ¼ 14.5, 3.0 Hz, oxaeAreH), 7.06 (s, 1H, AreH), 7.01e6.98
(m, 4H, AreH and 1H, oxaeAreH), 6.95e6.92 (m, 2H, AreH and 1H,
oxaeAreH), 6.20 (s, 1H, pyreH), 4.78e4.72 (m, 1H, oxaeCHe), 3.99
(dd, 1H, J ¼ 9.0, 6.1 Hz, oxaeCHHe), 3.76e3.73 (m, 3H, oxaeCH2e,
oxaeCHHe), 3.67e3.59 (t, 4H, piperazineeH), 3.47 (s, 2H, pyre
CH2), 3.25 (t, 4H, piperazineeH), 2.15 (s, 3H, NHCOCH3), 2.12 (s, 3H,
AreCH3), 2.01 (s, 3H, pyreCH3); ESIMS: m/z 616 (M þ H)þ.
5.4.4. (5S)-5-(Aminomethyl)-3-(3-fluoro-4-(4-((1-(4-
fluorophenyl)-2-methyl-5-o-tolyl-1H-pyrrol-3-yl)methyl)piperazin-
1-yl)phenyl)oxazolidin-2-one (12d)
5.4. General procedure for the preparation of compounds 12aed
The compound 12d was prepared according to the above-
described method using 11h (0.123 g, 0.6 mmol) (yield 0.101 g,
The compounds (12aed) were prepared by reduction of azide
group of compounds 11a, 11d, 11f and 11h in the presence of Pd/C
under H2 gas in ethanol. In detail, to a stirred solution of appro-
priate azido compound (0.2 mmol) in ethanol (5 mL), slowly Pd/C
(1 mmol) was added. After the addition was complete, the mixture
was stirred at room temperature for 3 h under hydrogen gas. After
completion of reaction as indicated by TLC, The reaction mixture
was filtered by using celite and from filtrate solvent was removed
under reduced pressure and the product was recrystallized from
ethanol.
89%). 1H NMR (CDCl3, 300 MHz):
d
7.43 (dd, 1H, J ¼ 14.5, 3.0 Hz,
oxaeAreH), 7.06 (s, 2H, AreH), 7.01e6.98 (m, 4H, AreH and 1H,
oxaeAreH), 6.95e6.92 (m, 2H, AreH and 1H, oxaeAreH), 6.43e
6.32 (bs, 2H, eNH2), 6.20 (s, 1H, PyreH), 4.78e4.72 (m, 1H, oxae
CHe), 4.01e3.97 (dd, 1H, J ¼ 6.1 Hz, 9.0 Hz, oxaeCHHe), 3.76e3.73
(m, 3H, oxaeCH2e, oxaeCHHe), 3.67e3.59 (t, 4H, piperazineeH),
3.47 (s, 2H, pyreCH2), 3.25 (t, 4H, piperazineeH), 2.12 (s, 3H, Are
CH3), 2.01 (s, 3H, pyreCH3); ESIMS: m/z 572 (M þ H)þ.
5.5. General procedure for the preparation of compounds 4aen
5.4.1. (5S)-5-(Aminomethyl)-3-(4-(4-((1-(2-bromo-5-
The compounds (4aen) were prepared from azido compounds
(11aeh) and aryl/heteroaryl acetylenes by employing CuAAC re-
action. In detail, to a stirred solution of appropriate azido com-
pound (0.15 mmol) in 3:1 of t-BuOH and H2O (5 mL), CuSO4
(0.10 mmol) was added. Then appropriate aryl/heteroacetylene
(0.15 mmol) was added to the reaction mixture followed by addi-
tion of catalytic amount of sodium ascorbate. The mixture was
stirred at room temperature for 4 h. After completion of reaction as
indicated by TLC, water (5 mL) was added to reaction mixture and
the product was extracted with dichloromethane (2 ꢂ 5 mL). The
organic layers were combined, solvent was removed under reduced
pressure and the product was purified by column chromatography
by using chloroform methanol (10:1) system to give the product.
fluorophenyl)-5-(2,4-difluorophenyl)-2-methyl-1H-pyrrol-3-yl)
methyl)piperazin-1-yl)-3-fluorophenyl)oxazolidin-2-one (12a)
The compound 12a was prepared according to the above-
described method using 11a (0.139 g, 0.2 mmol) (yield 0.127 g,
95%). 1H NMR (CDCl3, 300 MHz):
d
7.48 (d, 1H, J ¼ 2.2 Hz, AreH),
7.40 (dd, 1H, J ¼ 14.6, 2.4 Hz, oxaeAreH), 7.39 (d, 1H, J ¼ 2.9 Hz, Are
H), 7.34 (d, 1H, J ¼ 2.2 Hz, AreH), 7.22 (d, 1H, J ¼ 2.9 Hz, AreH), 7.04
(d, 1H, J ¼ 9.0 Hz, oxaeAreH), 7.02 (s, 1H, AreH), 6.89 (t, 1H,
J ¼ 8.9 Hz, oxaeAreH), 6.85 (s, 1H, AreH), 6.21 (d, 1H, J ¼ 3.4 Hz,
pyreH), 5.97 (d, 1H, J ¼ 3.4 Hz, pyreH), 4.78e4.70 (m, 1H, oxaeCHe
), 4.00 (dd, 1H, J ¼ 6.1 Hz, 9.0 Hz, oxaeCHHe), 3.74 (dd, 1H,
J ¼ 6.2 Hz, 9.1 Hz, oxaeCHHe), 3.57e3.48 (m, 2H, oxaeCH2e), 3.47

A. Kamal et al. / European Journal of Medicinal Chemistry 64 (2013) 239e251
247
5.5.1. (R)-3-(4-(4-((1-(3,4-Dichlorophenyl)-2-methyl-5-p-tolyl-1H-
pyrrol-3-yl)methyl)piperazin-1-yl)-3-fluorophenyl)-5-((4-(pyridin-
2-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one (4a)
5.5.4. (5R)-3-(4-(4-((1-(3,4-Difluorophenyl)-2-methyl-5-o-tolyl-
1H-pyrrol-3-yl)methyl)piperazin-1-yl)-3-fluorophenyl)-5-((4-
(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one (4d)
The compound 4a was prepared according to the above-
described method using 11c (0.097 g, 0.15 mmol) (yield 0.090 g,
The compound 4d was prepared according to the above-
described method using 11g (0.123 g, 0.15 mmol) (yield 0.091 g,
80%). 1H NMR (CDCl3, 500 MHz):
d
8.57 (d, 1H, J ¼ 6.0 Hz, pyridinee
85%). 1H NMR (CDCl3, 500 MHz):
d
8.59e8.58 (d, 1H, J ¼ 4.3 Hz,
H), 8.35 (s, 1H, triazoleeH), 8.10 (d, 1H, J ¼ 7.9 Hz, pyridineeH), 7.77
(tb, 1H, J ¼ 7.7, 1.7 Hz, pyridineeH), 7.71e7.50 (m, 1H, pyridineeH),
7.42 (d, 1H, J ¼ 14.0 Hz, oxaeAreH), 7.37e7.30 (m, 2H, AreH), 7.22
(dd, 1H, J ¼ 7.3, 2.4 Hz, AreH), 7.03 (d, 1H, J ¼ 8.1 Hz, oxaeAreH),
7.00e6.95 (m, 3H, oxaeAreH, AreH), 6.93 (s,1H, AreH), 6.88 (d,1H,
J ¼ 3.7 Hz, AreH), 6.31 (s, 1H, pyreH), 5.12e5.04 (m, 1H, oxaeCHe),
4.13 (dd,1H, J ¼ 6.2, 3.1 Hz, oxaeCHHe), 3.94 (dd,1H, J ¼ 6.4, 3.0 Hz,
oxaeCHHe), 3.70e3.63 (m, 2H, oxaeCH2e), 3.18e3.16 (t, 4H,
piperazineeH), 2.87e2.85 (t, 4H, piperazineeH), 2.27 (s, 3H, pyre
pyridineeH), 8.35 (s, 1H, triazoleeH), 8.11 (d, 1H, J ¼ 7.7 Hz, pyri-
dineeH), 7.79 (t, 1H, J ¼ 7.9 Hz, pyridineeH), 7.34 (dd, 1H, J ¼ 12.0,
1.7 Hz, oxaeAreH), 7.10e7.04 (m, 2H, oxaeAreH and pyridineeH),
7.00 (d, 2H, AreH), 6.91 (t, 1H, J ¼ 9.0 Hz, oxaeAreH), 6.83 (s, 1H,
AreH), 6.85e6.81 (m, 3H, AreH), 6.73e6.63 (m, 2H, AreH), 6.33 (s,
1H, pyreH), 5.13e5.05 (m, 1H, oxaeCHe), 4.82e4.79 (m, 2H, oxae
CH2e), 4.15 (dd, 1H, J ¼ 6.2, 3.1 Hz, oxaeCHHe), 3.88e3.83 (dd, 1H,
J ¼ 6.4, 3.0 Hz, oxaeCHHe), 3.69 (s, 2H, pyreCH2), 3.18e3.16 (t, 4H,
piperazineeH), 2.87e2.85 (t, 4H, piperazineeH), 2.17 (s, 3H, pyre
CH3), 2.11 (s, 3H, CH3); 13C NMR (CDCl3, 75 MHz):
d
153.2, 150.1,
CH3); 13C NMR (CDCl3, 75 MHz):
d 168.2, 168.0, 157.9, 156.2, 155.2,
149.4, 148.9, 136.9, 135.5, 132.9, 131.1, 130.8, 130.7, 130.4, 130.1,
129.4,129.0,128.7,127.8,127.7,126.6,123.5,123.1,120.2,119.4,114.0,
111.1, 107.7, 107.4, 70.3, 53.5, 52.2, 51.5, 48.7, 32.8, 21.3, 10.9; ESIMS:
m/z 751 (M)þ; HRMS: (ESI m/z) for C40H38Cl2FN8O2 calcd: 751.2478,
found: 751.2468 (M)þ.
151.3, 139.9, 136.1, 136.0, 130.4, 129.8, 128.6, 123.7, 122.6, 122.3,
122.2, 122.1, 120.3, 119.1, 119.0, 118.5, 118.0, 112.9, 110.4, 107.6, 107.5,
70.6, 54.5, 53.9, 49.5, 46.2, 24.0, 11.9; ESIMS: m/z 719 (M þ H)þ;
HRMS: (ESI m/z) for C40H38F3N8O2 calcd: 719.3069, found: 719.3082
(M þ H)þ.
5.5.2. (R)-3-(4-(4-((5-(4-Chloro-3-fluorophenyl)-2-methyl-1-(4-
(trifluoromethoxy)phenyl)-1H-pyrrol-3-yl)methyl)piperazin-1-yl)-
3-fluorophenyl)-5-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)
oxazolidin-2-one (4b)
5.5.5. (5R)-3-(4-(4-((1-(2-Bromo-5-fluorophenynel)-5-(2,4-
difluorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)-
3-fluorophenyl)-5-((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)
oxazolidin-2-one (4e)
The compound 4b was prepared according to the above-
described method using 11e (0.105 g, 0.15 mmol) (yield 0.090 g,
The compound 4e was prepared according to the above-
described method using 11a (0.104 g, 0.15 mmol) (yield 0.092 g,
77%). 1H NMR (CDCl3, 500 MHz):
d
8.59 (d, 1H, J ¼ 4.3 Hz, pyridinee
77%). 1H NMR (CDCl3, 300 MHz):
d
8.60e8.58 (d, 1H, J ¼ 4.3 Hz,
H), 8.36 (s, 1H, triazoleeH), 8.12 (d, 1H, J ¼ 7.7 Hz, pyridineeH), 7.79
(t, 1H, J ¼ 7.9 Hz, pyridineeH), 7.35 (dd, 1H, J ¼ 12.0 Hz, 1.7 Hz, oxae
AreH), 7.26e7.23 (m, 3H, J ¼ 9.0 Hz, pyridineeH, AreH), 7.14e7.19
(m, 2H, AreH), 7.11e7.06 (m, 2H, oxaeAreH, AreH), 6.90 (t, 1H,
J ¼ 9.0 Hz, oxaeAreH), 6.87e6.85 (m, 2H, AreH), 6.32 (s,1H, pyreH),
5.13e5.05 (m, 1H, oxaeCHe), 4.82e4.79 (m, 2H, oxaeCH2e), 4.15
(dd,1H, J ¼ 6.2, 3.1 Hz, oxaeCHHe), 3.85 (dd,1H, J ¼ 6.4, 3.0 Hz, oxae
CHHe), 3.69 (s, 2H, pyreCH2), 3.18e3.16 (t, 4H, piperazineeH),
2.87e2.85 (t, 4H, piperazineeH), 2.27 (s, 3H, pyreCH3); 13C NMR
pyridineeH), 8.38 (s, 1H, triazoleeH), 8.12 (d, 1H, J ¼ 7.7 Hz, pyri-
dineeH), 7.70 (t, 1H, J ¼ 7.9 Hz, pyridineeH), 7.49 (d, 1H, J ¼ 2.2 Hz,
AreH), 7.40 (dd, 1H, J ¼ 14.6, 2.4 Hz, oxaeAreH), 7.10e7.04 (m, 2H,
pyridineeH, AreH), 7.40e7.35 (m, 1H, AreH), 7.23 (d, 1H, J ¼ 2.9 Hz,
AreH), 7.04 (d, 1H, J ¼ 9.0 Hz, oxaeAreH), 7.02 (s,1H, AreH), 6.89 (t,
1H, J ¼ 8.9 Hz, oxaeAreH), 6.85 (s, 1H, AreH), 6.29 (d, 1H, J ¼ 3.4 Hz,
pyreH), 5.13e5.07 (m, 1H, oxaeCHe), 4.82e4.75 (m, 2H, oxaeCH2e
), 4.15 (dd, 1H, J ¼ 6.2, 3.1 Hz, oxaeCHHe), 3.89 (dd, 1H, J ¼ 6.4,
3.0 Hz, oxaeCHHe), 3.66 (s, 2H, pyreCH2), 3.18e3.16 (t, 4H, piper-
azineeH), 2.87e2.85 (t, 4H, piperazineeH), 2.12 (s, 3H, pyreCH3);
(CDCl3, 75 MHz): d 158.4,153.2,150.1,149.4,148.9,136.9,135.5,132.9,
131.1,130.8,130.6,130.4,130.0,129.6,129.0,128.7,127.8,127.7,126.5,
125.5, 123.5, 123.2, 120.2, 119.4, 114.0, 111.1, 107.7, 107.4, 70.3, 53.1,
52.0, 51.5, 48.7, 38.6,11.2; ESIMS: m/z 805 (M þ H)þ; HRMS: (ESI m/z)
for C40H35ClF5N8O3 calcd: 805.2441, found: 805.2449 (M þ H)þ.
13C NMR (CDCl3, 75 MHz):
d 169.4, 160.7, 156.8, 153.8, 153.3, 148.4,
148.2, 138.5, 136.2, 132.4, 131.7, 130.8, 130.6, 130.2, 130.1, 129.2,
129.0, 128.8, 128.4, 127.9, 127.7, 126.0, 125.7, 121.0, 119.0, 114.1, 113.8,
111.1, 107.7, 107.4, 70.4, 53.8, 52.1, 51.9, 49.5, 47.3, 38.7, 10.9; ESIMS:
m/z 801 (M)þ; HRMS: (ESI m/z) for C39H34BrF4N8O2 calcd: 801.1924,
found: 801.1969 (M)þ.
5.5.3. (5R)-3-(4-(4-((5-(2,4-Difluorophenyl)-1-(4-fluorophenyl)-2-
methyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)-3-fluorophenyl)-5-
((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one
(4c)
5.5.6. (5R)-3-(4-(4-((1-(2,4-Difluorophenyl)-5-(4-
isopropylphenyl)-2-methyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)-
3-fluorophenyl)-5-((4-(1-methyl-1H-imidazol-5-yl)-1H-1,2,3-
triazol-1-yl)methyl)oxazolidin-2-one (4f)
The compound 4c was prepared according to the above-
described method using 11b (0.092 g, 0.15 mmol) (yield 0.085 g,
79%). 1H NMR (CDCl3, 500 MHz):
d
8.59 (d, 1H, J ¼ 4.3 Hz, pyridinee
The compound 4f was prepared according to the above-
described method using 11f (0.096 g, 0.15 mmol) (yield 0.084 g,
H), 8.38 (s, 1H, triazoleeH), 8.12 (d, 1H, J ¼ 7.7 Hz, pyridineeH), 7.79
(t,1H, J ¼ 7.9 Hz, pyridineeH), 7.35 (dd,1H, J ¼ 12.0,1.7 Hz, oxaeAre
H), 7.10e7.04 (m, 4H, pyridineeH, oxaeAreH, AreH), 7.00 (d, 2H,
J ¼ 6.5 Hz, AreH), 6.90 (t, 1H, J ¼ 9.0 Hz, oxaeAreH), 6.73e6.63 (m,
3H, AreH), 6.33 (s, 1H, pyreH), 5.13e5.05 (m, 1H, oxaeCHe), 4.82e
4.79 (m, 2H, oxaeCH2e), 4.15 (dd, 1H, J ¼ 6.2, 3.1 Hz, oxaeCHHe),
3.85 (dd, 1H, J ¼ 6.4, 3.0 Hz, oxaeCHHe), 3.69 (s, 2H, pyreCH2),
3.18e3.16 (t, 4H, piperazineeH), 2.87e2.85 (t, 4H, piperazineeH),
75%). 1H NMR (CDCl3, 500 MHz):
d 7.90 (s, 1H, triazoleeH), 7.53e
7.50 (m, 1H, imidazoleeH), 7.32e7.27 (d, 1H, J ¼ 2.9 Hz, oxaeAreH),
7.25 (s, 1H, imidazoleeH), 7.06 (d, 2H, J ¼ 1.9 Hz, AreH), 7.05e6.91
(m, 4H, AreH, oxaeAreH), 6.96 (d, 1H, J ¼ 1.9 Hz, AreH), 6.94e6.91
(t, 2H, J ¼ 8.7 Hz, oxaeAreH), 6.89e6.87 (d, 1H, J ¼ 9.68 Hz), 6.35 (s,
1H, pyreH), 5.08e5.04 (m, 1H, oxaeCHe), 4.73e4.83 (m, 2H, oxae
CH2e), 4.16e4.15 (dd, 1H, J ¼ 6.7, 2.9 Hz, oxaeCHHe), 3.95e3.92
(dd, 1H, J ¼ 2.9 Hz, 6.78 Hz, oxaeCHHe), 3.85 (s, 3H, NeCH3), 3.58
(s, 2H, pyreCH2), 3.13 (t, 4H, piperazineeH), 2.85e2.78 (m, 1H,
CH3eCHeCH3), 2.76 (t, 4H, piperazineeH), 2.05 (s, 3H, pyreCH3),
1.19e1.17 (d, 6H, J ¼ 6.9 Hz, CH(CH3)2); 13C NMR (CDCl3, 75 MHz):
2.17 (s, 3H, pyreCH3); 13C NMR (CDCl3, 75 MHz):
d 168.7, 163.1,
160.2, 156.8, 153.2, 150.1, 149.4, 148.9, 136.9, 132.9, 130.8, 130.6,
130.4, 130.0, 129.6, 129.0, 128.7, 127.8, 126.5, 125.5, 123.5, 123.2,
120.2, 119.4, 114.0, 111.1, 107.7, 107.4, 70.4, 53.2, 52.0, 51.5, 48.7, 38.6,
11.1; ESIMS: m/z 723 (M þ H)þ; HRMS: (ESI m/z) for C39H35F4N8O2
calcd: 723.2819, found: 723.2843 (M þ H)þ.
d
163.1, 160.2, 153.6, 153.3, 139.5, 139.0, 137.1, 136.9, 134.7, 131.9,
138.8, 129.9, 129.6, 129.5, 129.0, 125.7, 122.3, 119.0, 115.8, 115.4,

248
A. Kamal et al. / European Journal of Medicinal Chemistry 64 (2013) 239e251
114.2, 112.6, 110.9, 110.7, 107.7, 107.4, 103.8, 103.4, 70.2, 54.2, 52.4,
52.3, 50.2, 47.4, 33.3, 31.3, 29.6, 11.1; ESIMS: m/z 750 (M þ H)þ;
HRMS: (ESI m/z) for C41H43F3N9O2 calcd: 750.3491, found:
750.3458 (M þ H)þ.
129.7, 129.5, 127.2, 125.1, 122.4, 122.1, 119.1, 115.6, 115.2, 114.2, 113.9,
111.5, 111.3, 107.8, 107.3, 70.2, 54.2, 52.3, 50.2, 47.4, 33.4, 29.4, 20.4,
11.2; ESIMS: m/z 704 (M þ H)þ; HRMS: (ESI m/z) for C39H40F2N9O2
calcd: 704.3273, found: 704.3293 (M þ H)þ.
5.5.7. (5R)-3-(4-(4-((5-(2,4-Difluorophenyl)-1-(4-fluorophenyl)-2-
methyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)-3-fluorophenyl)-5-
((4-(1-methyl-1H-imidazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)
oxazolidin-2-one (4g)
5.5.10. (5R)-3-(4-(4-((5-(3-Chlorophenyl)-1-(2-fluorophenyl)-2-
methyl-1H-pyrrol-3-yl)methyl)-piperazin-1-yl)-3-fluorophenyl)-5-
((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one (4j)
The compound 4j was prepared according to the above-
described method using 11d (0.092 g, 0.15 mmol) (yield 0.082 g,
The compound 4g was prepared according to the above-
described method using 11b (0.092 g, 0.6 mmol) (yield 0.078 g,
76%). 1H NMR (CDCl3, 500 MHz):
d 7.98 (s, 1H, triazoleeH), 7.61 (dd,
1
72%). H NMR (CDCl3, 500 MHz):
d
7.90 (s, 1H, triazoleeH), 7.53e
1H, J ¼ 2.6 Hz, AreH), 7.33e7.27 (m, 1H, oxaeAreH and 1H, AreH),
7.17 (d, 2H, J ¼ 5.2 Hz, AreH), 7.08e7.05 (m, 2H, AreH), 7.01e6.97
(m, 2H, AreH and 2H, oxaeAreH), 6.94 (d, 2H, J ¼ 9.0 Hz, AreH),
6.91e6.88 (m, 3H, AreH), 6.15 (s, 1H, pyreH), 5.08e5.04 (m, 1H,
oxaeCHe), 4.84e4.73 (m, 2H, oxaeCH2e), 4.17e4.14 (dd,1H, J ¼ 6.8,
2.9 Hz, oxaeCHHe), 3.90 (dd, 1H, J ¼ 6.8, 2.9 Hz, oxaeCHHe), 3.56
(s, 2H, pyreCH2), 3.11 (t, 4H, piperazineeH), 2.73 (t, 4H, piperazinee
7.50 (m, 1H, imidazoleeH), 7.32e7.27 (d, 1H, J ¼ 2.9 Hz, oxaeAreH),
7.25 (s, 1H, imidazoleeH), 7.10e7.04 (m, 4H, pyridineeH, oxaeAre
H, AreH), 7.00 (d, 2H, J ¼ 6.5 Hz, AreH), 6.90 (t, 1H, J ¼ 9.0 Hz, oxae
AreH), 6.73e6.63 (m, 3H, AreH), 6.21 (s, 1H, pyreH), 5.13e5.05 (m,
1H, oxaeCHe), 4.82e4.79 (m, 2H, oxaeCH2e), 4.10e4.08 (dd, 1H,
J ¼ 6.2, 3.1 Hz, oxaeCHHe), 3.87 (m, 1H, oxaeCHe), 3.85 (s, 3H, Ne
CH3), 3.69 (s, 2H, pyreCH2), 3.18e3.16 (t, 4H, piperazineeH), 2.87e
2.85 (t, 4H, piperazineeH), 2.17 (s, 3H, pyreCH3); 13C NMR (CDCl3,
H), 2.17 (s, 3H, pyreCH3); 13C NMR (CDCl3, 75 MHz):
d 169.1, 160.5,
153.3, 148.5, 146.8, 138.5, 136.1, 132.2, 130.7, 130.2, 130.1, 129.1,
128.9, 128.8, 128.7, 128.4, 128.0, 127.7, 125.6, 125.5, 121.0, 119.1, 114.1,
113.8,111.0, 107.8, 107.4, 70.4, 53.8, 52.0, 51.8, 49.5, 47.3, 11.2; ESIMS:
m/z 720 (M)þ; HRMS: (ESI m/z) for C40H36ClF2N7O2 calcd: 720.2665,
found: 720.2671 (M)þ.
75 MHz): d 168.7, 163.1, 160.2, 156.8, 153.6, 153.3, 148.4, 138.9, 136.1,
134.7, 132.1, 131.8, 130.8, 128.9, 128.5, 125.7, 122.3, 119.0, 115.8, 114.2,
112.6, 111.1, 110.6, 107.9, 107.7, 102.9, 103.5, 70.2, 54.2, 52.1, 51.9, 47.4,
30.2, 29.6, 11.1; ESIMS: m/z 726 (M þ H)þ; HRMS: (ESI m/z) for
C38H36F4N9O2 calcd: 726.2928, found: 726.2958 (M þ H)þ.
5.5.11. (R)-3-(4-(4-((5-(4-Chloro-3-fluorophenyl)-2-methyl-1-(4-
(trifluoromethoxy)phenyl)-1H-pyrrol-3-yl)methyl)piperazin-1-yl)-
3-fluorophenyl)-5-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)
oxazolidin-2-one (4k)
5.5.8. (5R)-3-(4-(4-((1-(3,4-Difluorophenyl)-2-methyl-5-o-tolyl-
1H-pyrrol-3-yl)methyl)piperazin-1-yl)-3-fluorophenyl)-5-((4-(1-
methyl-1H-imidazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-
2-one (4h)
The compound 4k was prepared according to the above-
described method using 11e (0.105 g, 0.15 mmol) (yield 0.093 g,
The compound 4h was prepared according to the above-
described method using 11g (0.089 g, 0.15 mmol) (yield 0.080 g,
79%). 1H NMR (CDCl3, 500 MHz):
d 7.94 (s, 1H, triazoleeH), 7.78 (d,
74%). 1H NMR (CDCl3, 500 MHz):
d
7.91 (s, 1H, triazoleeH), 7.53e
1H, J ¼ 7.1 Hz, AreH), 7.38 (dd, 1H, J ¼ 12.0, 1.7 Hz, oxaeAreH),
7.30e7.23 (m, 2H, AreH), 7.19e7.14 (m, 2H, AreH), 7.11e7.06 (m, 2H,
oxaeAreH, AreH), 7.01 (t, 1H, J ¼ 9.0 Hz, oxaeAreH), 6.95e6.91 (m,
4H, AreH), 6.82e6.79 (m, 2H, AreH), 6.36 (s, 1H, pyreH), 5.10e5.00
(m, 1H, oxaeCHe), 4.79e4.74 (m, 2H, oxaeCH2e), 4.13 (dd, 1H,
J ¼ 6.2, 3.1 Hz, oxaeCHHe), 3.88 (dd, 1H, J ¼ 6.4, 3.0 Hz, oxaeCHHe
), 3.47 (s, 2H, pyreCH2), 3.10e3.06 (t, 4H, piperazineeH), 2.72e2.66
(t, 4H, piperazineeH), 2.07 (s, 3H, pyreCH3); 13C NMR (CDCl3,
7.50 (m, 1H, imidazoleeH), 7.30 (d, 1H, J ¼ 2.9 Hz, oxaeAreH), 7.25
(s, 1H, imidazoleeH), 7.10e7.04 (m, 2H, oxaeAreH, AreH), 7.00 (d,
2H, AreH), 6.91 (t, 1H, J ¼ 9.0 Hz, oxaeAreH), 6.83 (s, 1H, AreH),
6.85e6.81 (m, 2H, AreH), 6.73e6.63 (d, 1H, AreH), 6.33 (s, 1H, pyre
H), 5.13e5.05 (m, 1H, oxaeCHe), 4.82e4.79 (m, 2H, oxaeCH2e),
4.15 (dd,1H, J ¼ 6.2, 3.1 Hz, oxaeCHHe), 3.87 (dd, 1H, J ¼ 6.4, 3.0 Hz,
oxaeCHHe), 3.85 (s, 3H, imidazoleeNeCH3), 3.51 (s, 2H, pyreCH2),
3.18e3.16 (t, 4H, piperazineeH), 2.87e2.85 (t, 4H, piperazineeH),
2.13 (s, 3H, AreCH3), 2.12 (s, 3H, pyreCH3); 13C NMR (CDCl3,
75 MHz): d 176.6, 167.2, 160.8, 155.8, 148.6, 131.3, 130.1, 129.8, 129.7,
128.8, 128.7, 128.4, 127.1, 125.8, 125.6, 123.6, 121.6, 121.5, 119.2, 115.7,
115.4, 115.1, 114.2, 114.0, 112.3, 110.4, 107.9, 107.6, 105.8, 70.4, 54.0,
52.3, 52.2, 49.9, 47.4, 11.1; ESIMS: m/z 804 (M þ H)þ; HRMS: (ESI m/
z) for C41H36ClF5N7O3 calcd: 804.2488, found: 804.2490 (M þ H)þ.
75 MHz): d 162.7, 160.7, 156.9, 153.2, 146.6, 139.6, 139.1, 137.2, 132.1,
131.4, 129.8, 129.6, 129.5, 127.1, 125.0, 122.3, 122.1, 119.1, 115.5, 115.2,
114.1, 113.9, 111.5, 111.3, 107.8, 107.4, 70.2, 54.2, 52.3, 50.1, 47.4, 33.4,
29.3, 20.5, 11.3; ESIMS: m/z 722 (M þ H)þ; HRMS: (ESI m/z) for
C39H39F3N9O2 calcd: 722.3178, found: 722.3178 (M þ H)þ.
5.5.12. (R)-3-(4-(4-((1-(3,4-Dichlorophenyl)-2-methyl-5-p-tolyl-
1H-pyrrol-3-yl)methyl)piperazin-1-yl)-3-fluorophenyl)-5-((4-
phenyl-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one (4l)
5.5.9. (5R)-3-(3-Fluoro-4-(4-((1-(4-fluorophenyl)-2-methyl-5-o-
tolyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)phenyl)-5-((4-(1-
methyl-1H-imidazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-
2-one (4i)
The compound 4l was prepared according to the above-
described method using 11c (0.097 g, 0.15 mmol) (yield 0.082 g,
73%). 1H NMR (CDCl3, 500 MHz):
d 7.98 (s, 1H, triazoleeH), 7.45e
The compound 4i was prepared according to the above-
described method using 11h (0.092 g, 0.15 mmol) (yield 0.074 g,
7.43 (m, 2H, AreH) 7.42 (dd,1H, J ¼ 14.6, 2.4 Hz, oxaeAreH), 7.40 (d,
2H, J ¼ 6.7 Hz, AreH), 7.35e7.27 (m, 3H, AreH), 7.02 (t, 1H,
J ¼ 1.9 Hz, oxaeAreH), 6.97e6.84 (m, 5H, AreH and 1H, oxaeAre
H), 6.30 (s, 1H, pyreH), 5.08e5.04 (m, 1H, oxaeCHe), 4.73e4.08 (m,
2H, oxaeCH2e), 4.17e4.14 (dd, 1H, J ¼ 6.8, 2.9 Hz, oxaeCHHe), 3.93
(dd, 1H, J ¼ 6.8, 2.9 Hz, oxaeCHHe), 3.65 (s, 2H, pyreCH2), 3.14 (t,
4H, piperazineeH), 2.83 (t, 4H, piperazineeH), 2.27 (s, 3H, AreCH3),
71%). 1H NMR (CDCl3, 500 MHz):
d 7.89 (s, 1H, triazoleeH), 7.48 (s,
1H, imidazoleeH), 7.28e7.24 (dd, 1H, J ¼ 14.6, 2.4 Hz, oxaeAreH),
7.25 (s, 1H, imidazoleeH), 7.06 (d, 2H, J ¼ 1.9 Hz, AreH), 7.06e6.91
(m, 2H, AreH and 2H, oxaeAreH), 6.96 (d,1H, J ¼ 1.9 Hz), 6.94e6.91
(t, 2H, J ¼ 8.7 Hz), 6.89e6.87 (d, 1H, J ¼ 9.6 Hz, oxaeAreH), 6.15 (s,
1H, pyreH), 5.08e5.04 (m, 1H, oxaeCHe), 4.73e4.08 (m, 2H, oxae
CH2e), 4.17e4.14 (dd, 1H, J ¼ 6.8, 2.9 Hz, oxaeCHHe), 3.93 (dd, 1H,
J ¼ 6.8, 2.9 Hz, oxaeCHHe), 3.87 (s, 3H, imidazoleeNeCH3), 3.53 (s,
2H, pyreCH2), 3.10 (t, 4H, piperazineeH), 2.71 (t, 4H, piperazinee
H), 2.12 (s, 3H, AreCH3), 2.11 (s, 3H, pyreCH3); 13C NMR (CDCl3,
2.11 (s, 3H, pyreCH3); 13C NMR (CDCl3, 75 MHz):
d 169.4, 153.3,
148.4, 139.5, 138.2, 136.2, 135.5, 132.1, 131.5, 130.8, 130.1, 128.8,
128.4, 127.0, 127.6, 125.7, 124.4, 123.9, 123.5, 122.1, 121.0, 119.1, 114.2,
111.1, 107.8, 107.4, 70.4, 53.8, 52.1, 51.9, 49.5, 47.3, 30.2, 10.9; ESIMS:
m/z 750 (M)þ; HRMS: (ESI m/z) for C41H39Cl2FN7O2 calcd: 750.2526,
found: 750.2561 (M)þ.
75 MHz): d 160.7, 156.9, 153.2, 139.6, 139.1, 137.2, 132.1, 131.4, 129.9,

A. Kamal et al. / European Journal of Medicinal Chemistry 64 (2013) 239e251
249
5.5.13. (5R)-3-(4-(4-((1-(2-Bromo-5-fluorophenyl)-5-(2,4-
difluorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)-
3-fluorophenyl)-5-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)
oxazolidin-2-one (4m)
H), 7.45e7.37 (dd, 1H, J ¼ 14.6, 2.4 Hz, oxaeAreH), 7.40e7.38 (d, 1H,
J ¼ 2.9 Hz, AreH), 7.35e7.33 (d, 1H, J ¼ 2.2 Hz, AreH), 7.24e7.21 (d,
1H, J ¼ 2.9 Hz, AreH), 7.04 (d, 1H, J ¼ 9.0 Hz, oxaeAreH), 7.02 (s, 1H,
AreH), 6.89 (t,1H, J ¼ 8.9 Hz, oxaeAreH), 6.85 (s,1H, AreH), 6.21 (d,
1H, J ¼ 3.4 Hz, pyreH), 4.78e4.70 (m,1H, oxaeCHe), 4.03e3.97 (dd,
1H, J ¼ 9.1, 6.2 Hz, oxaeCHHe), 3.76e3.70 (dd, 1H, J ¼ 9.1, 6.2 Hz,
oxaeCHHe), 3.57e3.48 (m, 2H, oxaeCH2e), 3.47 (s, 2H, pyreCH2),
3.09 (t, 4H, piperazineeH), 2.74e2.63 (t, 4H, piperazineeH), 2.06 (s,
3H, NHCOCH3), 2.02 (s, 3H, pyreCH3); 13C NMR (CDCl3, 75 MHz):
The compound 4m was prepared according to the above-
described method using 11a (0.104 g, 0.15 mmol) (yield 0.099 g,
83%). 1H NMR (CDCl3, 500 MHz):
d 7.97 (s, 1H, triazoleeH), 7.80 (d,
2H, J ¼ 7.1 Hz, AreH), 7.51 (dd, 1H, J ¼ 14.6, 2.4 Hz, oxaeAreH), 7.41
(t, 2H, J ¼ 7.1 Hz, AreH), 7.35e7.31 (m, 1H, AreH), 7.06 (d, 2H,
J ¼ 7.8 Hz, AreH), 7.01e6.93 (m, 2H, AreH and oxaeAreH), 6.87 (t,
2H, J ¼ 8.9 Hz, oxaeAreH), 6.34 (s, 1H, pyreH), 5.08e5.04 (m, 1H,
oxaeCHe), 4.73e4.08 (m, 2H, oxaeCH2e), 4.17e4.14 (dd,1H, J ¼ 6.8,
2.9 Hz, oxaeCHHe), 3.93 (dd, 1H, J ¼ 6.8, 2.9 Hz, oxaeCHHe), 3.65
(s, 2H, pyreCH2), 3.11 (t, 4H, piperazineeH), 2.77 (t, 4H, piperazinee
d
171.2, 166.4, 163.3, 160.2, 156.8, 153.2, 134.4, 133.8, 132.5, 130.8,
130.1, 129.2, 128.7, 127.1, 126.0, 125.1, 124.6, 119.1, 116.7, 113.8, 111.8,
107.5, 107.2, 71.8, 53.9, 52.1, 49.9, 47.6, 46.3, 38.6, 22.9, 11.9. ESIMS:
m/z 714 (M þ H)þ; HRMS: (ESI m/z) for C34H33BrF4N5O3 calcd:
714.1702, found: 714.1676 (M)þ.
H), 2.02 (s, 3H, pyreCH3); 13C NMR (CDCl3, 75 MHz):
d 171.1, 167.9,
162.0, 156.5, 156.2, 155.0, 153.1, 148.6, 146.8, 144.0, 141.0, 137.0,
134.0, 131.1, 130.8, 128.8, 128.7, 125.8, 124.5, 121.0, 120.8, 120.4,
115.5, 113.0, 110.7, 107.8, 107.4, 104.3, 68.1, 53.9, 49.4, 48.0, 47.4, 38.7,
11.0; ESIMS: m/z 800 (M)þ; HRMS: (ESI m/z) for C40H35BrF4N7O2
calcd: 800.1971, found: 800.2000 (M)þ.
5.6.2. N-(((S)-3-(4-(4-((5-(3-Chlorophenyl)-1-(2-fluorophenyl)-2-
methyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)-3-fluorophenyl)-2-
oxooxazolidin-5-yl)methyl)acetamide (5b)
The compound 5b was prepared according to the above-
described method using 12b (0.088 g, 0.15 mmol) (yield 0.077 g,
82%). 1H NMR (CDCl3, 500 MHz):
d
7.61 (dd, 1H, J ¼ 2.6 Hz, AreH),
5.5.14. (5R)-3-(3-Fluoro-4-(4-((1-(4-fluorophenyl)-2-methyl-5-o-
tolyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)phenyl)-5-((4-m-tolyl-
1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one (4n)
7.41 (dd, 1H, J ¼ 14.6, 2.4 Hz, oxaeAreH), 7.21 (td, 1H, J ¼ 8.8, 1.7 Hz,
AreH), 7.17 (d, 2H, J ¼ 5.2 Hz, AreH), 7.12e7.09 (m, 2H, AreH), 7.07
(s, 1H, AreH), 7.02 (dd, 1H, J ¼ 8.8 Hz, 2.2 Hz, oxaeAreH), 6.97e6.94
(d, 1H, J ¼ 9.0 Hz, AreH), 6.90 (dt, 1H, J ¼ 6.7, 1.8 Hz, oxaeAreH),
6.62 (t, 1H, J ¼ 5.2 Hz, eNHCOCH3), 6.39 (s, 1H, pyreH), 4.77e4.68
(m, 1H, oxaeCHe), 3.97 (dd, 1H, J ¼ 9.0, 6.1 Hz, oxaeCHHe), 3.87
(dd, 1H, J ¼ 9.1, 6.2 Hz, oxaeCHHe), 3.64e3.59 (m, 2H, oxaeCH2e),
3.47 (s, 2H, pyreCH2), 3.15e3.07 (t, 4H, piperazineeH), 2.74e2.63 (t,
4H, piperazineeH), 2.01 (s, 3H, NHCOCH3), 1.99 (s, 3H, pyreCH3);
The compound 4n was prepared according to the above-
described method using 11h (0.092 g, 0.6 mmol) (yield 0.074 g,
70%). 1H NMR (CDCl3, 500 MHz):
d 7.97 (s, 1H, triazoleeH), 7.66 (s,
1H, AreH), 7.61e7.59 (d, 1H, J ¼ 7.8 Hz, AreH), 7.33e7.29 (t, 1H,
J ¼ 7.8 Hz, AreH), 7.17e7.15 (d, 1H, J ¼ 7.8 Hz, AreH), 7.08e7.06 (m,
2H, AreH), 7.01e6.97 (m, 4H, AreH), 6.95e6.90 (m, 4H, AreH), 6.17
(s, 1H, pyreH), 5.10e5.04 (m, 1H, oxaeCHe), 4.84e4.73 (m, 2H,
oxaeCH2e), 4.17e4.12 (dd,1H, J ¼ 6.2 Hz, 3.1 Hz, oxaeCHHe), 3.93e
3.89 (dd, 1H, J ¼ 8.7 Hz, oxaeCHHe), 3.56 (s, 2H, pyreCH2), 3.12e
3.10 (t, 4H, piperazineeH), 2.74e2.72 (t, 4H, piperazineeH), 2.40 (s,
3H, AreCH3), 2.17 (s, 3H, AreCH3), 2.12 (s, 3H, pyreCH3); 13C NMR
13C NMR (CDCl3, 75 MHz):
d 171.2, 166.4, 154.3, 153.2, 134.4, 133.8,
132.5, 130.8, 130.7, 130.1, 129.2, 128.7, 127.1, 126.0, 125.1, 124.6, 119.1,
116.7, 116.5, 113.8, 111.8, 107.5, 107.2, 71.8, 53.9, 52.1, 49.9, 47.6, 46.3,
38.6, 22.9, 11.9. ESIMS: m/z 634 (M þ H)þ; HRMS: (ESI m/z) for
C34H35ClF2N5O3 calcd: 634.2396, found: 634.2425 (M þ H)þ.
(CDCl3, 75 MHz):
d 159.6, 156.9, 153.4, 148.6, 138.5, 137.3, 134.7,
132.7, 132.3, 131.4, 129.8, 129.6, 129.5, 129.2, 128.7, 127.2, 126.4,
125.0, 122.9, 121.0, 119.2, 115.6, 115.3, 114.2, 111.6, 107.8, 107.5, 70.5,
53.9, 52.2, 51.9, 49.6, 47.4, 31.3, 29.6, 21.3, 20.4, 11.3; ESIMS: m/z 714
(M þ H)þ; HRMS: (ESI m/z) for C42H42F2N7O2 calcd: 714.3362,
found: 714.3380 (M þ H)þ.
5.6.3. N-(((S)-3-(4-(4-((1-(2,4-Difluorophenyl)-5-(4-
isopropylphenyl)-2-methyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)-
3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (5c)
The compound 5c was prepared according to the above-
described method using 12c (0.092 g, 0.15 mmol) (yield 0.084 g,
85%). 1H NMR (CDCl3, 300 MHz):
d 7.40 (m, 1H, AreH and 1H, oxae
5.6. General procedure for the preparation of compounds 5aed
AreH), 7.12 (dd, 1H, J ¼ 3.0, 8.03 Hz, AreH), 7.05e6.99 (m, 3H, AreH
and 1H, oxaeAreH), 6.97e6.85 (m, 2H, AreH and 1H, oxaeAreH),
6.33 (s, 1H, pyreH), 6.22e6.19 (t, 1H, J ¼ 5.2, NH), 4.78e4.70 (m, 1H,
oxaeCHe), 4.00 (dd, 1H, J ¼ 6.1 Hz, 9.0 Hz, oxaeCHHe), 3.73 (dd,
1H, J ¼ 9.1, 6.2 Hz, oxaeCHHe), 3.67e3.62 (m, 2H, oxaeCH2e), 3.54
(s, 2H, pyreCH2), 3.09 (t, 4H, piperazineeH), 2.87e2.78 (m, 1H,
CH3eCHeCH3), 2.74e2.63 (t, 4H, piperazineeH), 2.06 (s, 3H,
NHCOCH3), 1.99 (s, 3H, pyreCH3), 1.20e1.18 (d, 6H, J ¼ 6.9 Hz,
The compounds (5aed) were prepared by acetylation of amino
compounds (12aed) in the presence of acetyl chloride. In detail, to
a stirred solution of appropriate amine (0.15 mmol) in dry
dichloromethane (5 mL) at 0 ꢀC, triethylamine (0.3 mmol) was
added. Then acetyl chloride (0.2 mmol) was added slowly drop
wise. After the addition was complete, the mixture was stirred at
room temperature for 1 h under nitrogen atmosphere. After
completion of reaction as indicated by TLC, reaction mixture was
poured on crushed ice and the product was extracted with
dichloromethane (2 ꢂ 5 mL). The organic layer was washed with
brine, dried (anhydrous Na2SO4), solvent was removed under
reduced pressure and the product was purified by column chro-
matography by using chloroform, methanol (10:1) system to give
the product.
CH(CH3)2); 13C NMR (CDCl3, 75 MHz):
d 171.2, 166.4, 154.3, 153.2,
152.2, 133.8, 132.5, 130.8, 130.7, 130.1, 128.2, 128.7, 127.5, 126.0,
125.1,124.6, 120.1,115.7,111.8, 107.5,107.2, 71.8, 53.9, 52.1, 49.9, 47.6,
46.3, 38.6, 30.2, 23.3, 22.9, 13.9. ESIMS: m/z 660 (M þ H)þ; HRMS:
(ESI m/z) for C37H41F3N5O3 calcd: 660.3161, found: 660.3145
(M þ H)þ.
5.6.4. N-(((S)-3-(3-Fluoro-4-(4-((1-(4-fluorophenyl)-2-methyl-5-
o-tolyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)phenyl)-2-
oxooxazolidin-5-yl)methyl)acetamide (5d)
5.6.1. N-(((S)-3-(4-(4-((1-(2-Bromo-5-fluorophenyl)-5-(2,4-
difluorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)piperazin-1-yl)-
3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (5a)
The compound 5a was prepared according to the above-
described method using 12a (0.100 g, 0.15 mmol) (yield 0.091 g,
The compound 5d was prepared according to the above-
described method using 12d (0.085 g, 0.15 mmol) (yield 0.081 g,
89%). 1H NMR (CDCl3, 300 MHz):
oxaeAreH), 7.06 (s, 2H, AreH), 7.01e6.98 (m, 4H, AreH and 1H,
oxaeAreH), 6.95e6.92 (m, 2H, AreH and 1H, oxaeAreH), 6.43e
d
7.43 (dd, 1H, J ¼ 14.5, 3.0 Hz,
85%). 1H NMR (CDCl3, 300 MHz):
d
7.50e7.47 (d, 1H, J ¼ 2.2 Hz, Are

250
A. Kamal et al. / European Journal of Medicinal Chemistry 64 (2013) 239e251
6.32 (bs, 1H, eNHCOCH3), 6.20 (s, 1H, pyreH), 4.78e4.72 (m, 1H,
oxaeCHe), 3.99 (dd, 1H, J ¼ 6.1, 9.0 Hz, oxaeCHHe), 3.76e3.73 (m,
3H, oxaeCH2e, oxaeCHHe), 3.67e3.59 (t, 4H, piperazineeH), 3.47
(s, 2H, pyreCH2), 3.26e3.24 (t, 4H, piperazineeH), 2.15 (s, 3H, e
NHCOCH3), 2.12 (s, 3H, AreCH3), 2.01 (s, 3H, pyreCH3); 13C NMR
Acknowledgments
We thank the Department of Science Technology (DST: SR/S1/
OC-42/2008), New Delhi for financial assistance. The authors PS,
RVCRNCS, ABS, MPNR and FS are thankful to CSIR, New Delhi and
UGC, New Delhi for the award of research fellowships.
(CDCl3, 75 MHz):
d 171.5, 166.4, 154.3, 153.2, 134.4, 133.8, 132.5,
130.8, 130.3, 129.2, 128.7, 127.1, 126.0, 125.1, 124.6, 119.0, 116.7, 113.8,
111.8, 107.5, 107.2, 71.7, 53.5, 52.3, 50.1, 47.6, 46.3, 38.6, 22.8, 22.0,
11.9; ESIMS: m/z 614 (M þ H)þ; HRMS: (ESI m/z) for C35H38F2N5O3
calcd: 614.2942, found: 614.2950 (M þ H)þ.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2013.03.027.
5.7. Antimycobacterial assay
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