Oxazolidinone: Search for highly potent antibacterial

Article abstract of DOI:10.1016/j.bmcl.2004.04.024

A number of substituted piperazinyl oxazolidinone derivatives have been synthesized and their antibacterial activities were evaluated by MIC determination. A systematic SAR was carried out to get highly potent oxazolidinone derivatives.

Full text of DOI:10.1016/j.bmcl.2004.04.024

Bioorganic& Medicinal Chemistry Letters 14 (2004) 3139–3142
Oxazolidinone: search for highly potent antibacterialq
a
a
Braj Bhushan Lohray,a,b, Vidya Bhushan Lohray, Brijesh Kumar Srivastava,
*
Sunil Gupta,a Manish Solanki,a Prashant Kapadnis,a Vijay Takalea and Purvi Pandyab
aMedicinal Chemistry Department, Zydus Research Centre, Cadila Healthcare Ltd, Sarkhej-Bavla N. H.8A, Moraiya,
Ahmedabad 382210, India
bCell Biology Department, Zydus Research Centre, Cadila Healthcare Ltd, Sarkhej-Bavla N. H.8A, Moraiya,
Ahmedabad 382210, India
Received 13 January 2004; revised 7 April 2004; accepted 8 April 2004
Abstract—A number of substituted piperazinyl oxazolidinone derivatives have been synthesized and their antibacterial activities
were evaluated by MIC determination. A systematicSAR was carried out to get highly potent oxazolidinone derivatives.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
O
6'
1'
5'
2
1
O
O
N
N
N
5
Oxazolidinone class of antibacterials has attracted con-
siderable interest from various research institutions1
including pharmaceutical industries2 especially after the
successful launch of linezolid by Upjohn and Pharmacia
in 1999. Linezolid 1 (Fig. 1) has been of great interest
due to growing resistance of bacteria to a number of
antibacterial therapies.3 Vancomycin and methicillin,
which were once considered the ultimate line of therapy
for Gram +ve infection, is no more sustainable due to
increasing number of reports of VRS, VRE and MRSA
organisms isolated from patients. Unfortunately, line-
zolid has poor efficacy; need multiple dosing and has
serious side effects. Therefore, search for superior
analogs of this class of antibacterials has been unawa-
ited during the last decade without notable success.4
4'
3
NHCOMe
HO
2'
4
3'
F
2
Figure 2.
In the present communication, we wish to report our
efforts in search of a novel and superior antibacterial
especially for Gram +ve organisms, which may be useful
for treating vancomycin and methicillin resistant
organisms. Eperezolid 2 (Fig. 2), which is not yet ap-
proved for treating antibacterial infection, has been the
main structural feature for modification to get superior
analogs by a number of research groups.5 We report
here synthesis of several substituted piperazine analogs
7–9 and their antibacterial activities (MIC) across
several Gram +ve organisms.
O
O
O
N
N
NHCOMe
2. Chemistry
F
1
A number of N-substituted piperazinyl derivatives 7–9
were prepared according to the pathways shown in
(Scheme 1). 40 Substituted piperazine derivative 4 or 5
can be prepared by literature method.6
Figure 1.
Keywords: Oxazolidinone; Antibacterial; Linezolid; Cinnamoyl
groups.
q ZRC communication no. 118.
The piperazine derivative 4 or 5 were coupled with
cinnamic acid derivative 3 using EDC/HOBT in the
presence of triethylamine at 27–28 °C (Scheme 1). The
* Corresponding author. Tel.: +91-02717-250801; fax: +91-02717-25-
0606; e-mail: braj.lohray@zyduscadila.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.04.024

3140
B. B. Lohray et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3139–3142
OH
R
O
3
O
O
O
O
HN
N
N
HN
N
N
NHR'
OH
(i)
(i)
O
F
F
4
5
O
O
(ii)
(iii, iv)
O
R
N
N
N
R
N
N
N
NHR'
OH
O
F
O
F
6-9
10
6 R' = H
(v)
(vii, viii)
7 R' = COCH3
8 R' = CSCH3
9 R' = CSNH2
(vi)
Scheme 1. Reagents and conditions: (i) EDC–HCl, HOBtÆH2O, TEA, CH2Cl2, 27–28 °C, 0.5–1 h; (ii) MeSO2Cl, TEA, CH2Cl, 0.5 °C, 1 h; (iii) NaN3,
DMF, 70–80 °C, 2–3 h; (iv) P(Ph)3, 1,4-dioxane, MeOH, NH3 (aq), 27–28 °C, 30 min; (v) (CH3CO2)2O, pyridine; (vi) Lawesson’s reagent, THF,
65–70 °C, 1 h; (vii) CS2 solution, ethyl chloroformate, TEA, 20–30 min; (viii) methanolic ammonia, 0–5 °C, 5–10 min.
piperazine derivative 4 gave 6, whereas compound 5
gave oxazolidinone 10, which was then converted into 6
by standard method (Scheme 1).
pounds showed good antibacterial activities. In fact,
when we substituted 4th position by bulky phenyl group
(7h), it led to the complete loss in antibacterial activities.
Thus, we synthesized compounds having 4-OH (7i) and
4-NH2 (7j) group on the phenyl group of cinnamoyl
moiety. Both the compounds 7i and 7j showed much
superior antibacterial activities, however, 7i is found to
be slightly superior to its amino counterpart.
A large number of compounds were synthesized (Table
1) and screened for antibacterial activities in a panel of
Gram +ve bacteria. Results of MIC assay carried out in
triplicate is summarized in Table 2. Some of the selected
compounds having MIC comparable to linezolid or
eperezolid were further screened in an extended panel of
bacteria having several strains of Gram +ve and Gram
)ve organisms, some of which are resistant to methi-
cillin and vancomycin (Table 3).
Further, we modified 4-OH group into 4-OSO2CH3 (7k),
4-OCOC (CH3)3 (7l), 3-OH (7m), 3,4-dihydroxy (7n) and
1,2-methylenedioxy (7o). From the results reported in the
Table 2, it is clear that any bulky substituent or modifi-
cation of electronic properties of 4-OH group is not
favourable (see 7k, 7l). However, replacement of 4-OH
group by 3-OH group (7m) did not destroy its antibac-
terial activity but compounds having both 3,4-dihydroxy
(7n) led to complete loss of antibacterial activity. In
contrast, when both –OH group at 3 and 4 position are
protected as 1,2-methylenedioxy group (7o), there is
considerable recovery of antibacterial activity. Similar
attempts to modify 4-NH2 group was made by substi-
tuting –NH2 by –NHCOCH3 (7p), as expected the
compound 7p was found to be inferior to 7j (4-NH2).
3. Results and discussion
Examination of Table 2 reveals that the parent com-
pound 7a containing the unsubstituted cinnamoyl group
is nearly as active as linezolid in in vitro MIC assay and
is superior to eperezolid in all the strains of bacteria.
Substitution of phenyl ring of cinnamoyl group showed
interesting structure–activity relationship. When 4-po-
sition of phenyl ring (in cinnamoyl moiety) is substituted
with –OMe group 7b, there is moderate decrease in the
antibacterial activity. Further replacement of –OMe by
–SMe (7c) led to further decrease in antibacterial
activity. This suggests that electron donating group on
cinnamoyl moiety is not preferred. Hence, we substi-
tuted 4th position of phenyl ring with electron with-
drawing groups such as –F (7d), –NO2 (7e), difluoro (7f)
and diacetyl (7g). From the results, it is clear that even
powerful electron withdrawing group is not preferred on
phenyl ring of cinnamoyl moiety and none of the com-
Thus, the compounds 7a, 7d, 7i, 7o, were taken for
further modification in order to get better antibacterial
compounds. In these compounds acetamide group 7
(R0 ¼ –COCH3) is replaced by thioacetamide group 8
(R0 ¼ –CSCH3) to yield 8a, 8d, 8i, 8o, respectively. From
the results shown in Table 2 it is clear that the com-
pounds 8a, 8d and 8i showed very potent antibacterial
activities. Compound 7a and 7o were further modified to
furnish 9a and 9o (R0 ¼ –CSNH2), respectively. Both
these analogs showed much superior antibacterial
activities than their acetamide analogs (7a and 7o).

B. B. Lohray et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3139–3142
Table 1. New oxazolidinones as antibacterial agents
3141
Compd
R
R0
% Yield
80
Compd
R
R0
% Yield
85
O
7a
COCH3
7l
COCH3
O
7b
7c
7d
COCH3
COCH3
COCH3
47
88
73
7m
7n
7o
COCH3
COCH3
COCH3
70
25
77
MeO
MeS
OH
HO
O
HO
O
F
7e
7f
COCH3
COCH3
55
64
7p
8a
COCH3
CSCH3
27
78
O2N
F
AcHN
F
7g
COCH3
81
8d
CSCH3
31
AcO
F
AcO
7h
7i
COCH3
COCH3
39
52
8i
CSCH3
CSCH3
49
79
HO
Ph
8o
HO
O
O
7j
COCH3
COCH3
6.9
9a
9o
CSNH2
CSNH2
67
45
H2N
7k
47
O
O
O
O
O
S
Thus, we selected compounds 7a, 7i, 7m, 7o, 8a, 8d, 8i,
8o, 9a and 9o for further screening in a wider panel of
Gram +ve bacteria, some of which are resistant to
methicillin and are also particularly resistant to vanco-
mycin and even linezolid and eperezolid. Table 3 sum-
marizes the results of the MIC assay carried out with
various strains of Gram +ve organisms.
This is remarkable in view of the fact that linezolid
resistant organisms have also started appearing in hos-
pital isolates of Gram +ve organisms, although very
very few cases have been reported.8
It is noteworthy that compounds 7a, 7i, 7m and 7o all of
which contain acetamide group (R0 ¼ COCH3) showed
nearly comparable antibacterial activity with that of
linezolid or eperezolid.
4. Conclusion
In summary, a series of N-phenyl piperazinyl derivatives
of oxazolidinone in which the nitrogen atom at 4-posi-
tion of piperazinyl ring is substituted by different cin-
namoyl groups resulted in a few good antibacterial
compounds against several Gram positive organisms.
Some groups are well tolerated on the phenyl ring of
cinnamoyl group; however, bulky substituents and
However, compounds having thioacetamide group (8a,
8d, 8i and 8o) showed superior antibacterial activities
even in MRSA, VRS as well as intrinsically resistant
Gram negative Klebsiella.

3142
B. B. Lohray et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3139–3142
Table 2. MIC [minimum inhibitory concentration in lg/mL] values of new oxazolidinones in various Gram positive bacteriaa
Compd B.p.
B.c.
S.p.
S.e.
0.5
E.f. 1
Sa 1
Compd
B.p.
B.c.
S.p.
S.e.
0.25
E.f. 1
Sa 1
7a
7b
7c
7d
7e
7f
1
2
1
2
2
4
2
4
4
4
7m
7n
0.5
8
0.5
16
1
2
16
2
1
2
1
1
4
8
8
2
2
16
8
2
16
16
4
7o
7p
1
1
4
1
2
4
4
2
4
8
4
8
4
8
2
1
1
4
4
8a
8d
0.5
0.5
0.25
0.25
1
0.5
0.5
0.5
2
0.25
0.5
6 0.12
1
0.5
0.5
1
2
16
2
4
4
>16
1
>16
2
>16
4
1
7g
7h
7i
2
>16
4
8i
8o
0.25
0.5
4
0.25
1
>16
1
>16
2
>16
>16
1
>16
2
0.25
0.25
1
8
0.5
0.25
9a
9o
0.25
1
0.5
0.25
2
1
7j
1
1
1
2
0.5
8
1
1
1
0.5
0.5
4
0.25
2
1
7k
7l
4
2
>16
4
8
>16
Linezolid
Eperezolid
1
2
4
ND
8
16
4
8
2
2
1
4
a MIC were determined by microbroth dilution technology7 and the values reported in the table represent the highest MIC value obtained in
triplicate.
Table 3. MIC [minimum inhibitory concentration in lg/mL] values of selected compounds in several Gram positive and Gram negative bacteria
Compd
B.p.
B.c.
S.p.
S.e.
E.f. 1
E.f. 2
Sa 1
Sa 2
Sa 3
Sa 4
K.p.
7a
1
1
2
0.5
0.25
2
1
4
4
2
4
>16
>16
>16
>16
>16
>16
4
7i
7m
1
0.5
0.5
1
2
1
2
2
2
1
2
0.5
1
2
0.25
1
1
2
4
4
1
7o
8a
2
1
0.25
0.5
6 0.12
1
1
2
2
2
4
4
0.5
0.5
0.25
0.25
1
0.5
0.5
0.25
0.25
0.25
1
0.5
2
0.5
0.5
1
0.5
2
2
2
1
1
8d
1
1
4
4
8i
8o
0.5
4
0.25
0.25
0.5
0.5
4
0.25
1
0.5
1
0.25
0.5
2
0.5
1
8
2
9a
9o
0.25
0.5
0.5
4
1
0.5
0.25
2
1
2
1
8
1
0.25
2
1
1
2
2
>16
>16
>16
Linezolid
Eperezolid
1
2
4
ND
4
4
4
2
2
1
4
2
4
4
4
B.p. ¼ Bacillus pumilus MTCC 1607, B.c. ¼ Bacillus cereus MTCC 430, S.p. ¼ Streptococcus pyogenes MTCC 442, S.e. ¼ Staphylococcus epidermidis
MTCC 155, E.f. 1 ¼ Enterococcus faecalis MTCC 439, E.f. 2 ¼ Enterococcus faecalis ATCC 14506, Sa 1 ¼ Staphylococcus aureus MTCC 96,
Sa 2 ¼ Staphylococcus aureus ATCC 14154, Sa 3 ¼ Staphylococcus aureus ATCC 25923, Sa 4 ¼ Staphylococcus aureus ATCC 29213, K.p. ¼ Klebsiella
pneumoniae ATCC 10031, ND ¼ not done.
Koh, H. Y.; Chung, B. Y.; Pae, A. N. Bioorg. Med. Chem.
Lett. 2003, 13, 4117.
electron withdrawing groups resulted in loss of activity.
One of the most potent compounds 8i is active against a
broader panel of Gram positive bacterial pathogens.
Our SAR study has also revealed that the antibacterial
activity is greatly affected by the conversion of 5-acetyl-
aminomethyl moiety to thioacetamide as well as 5-
thiourea group.
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Acknowledgements
We thank Mr. Pankaj R. Patel, CMD and the man-
agement of Zydus Group for encouragement and Mr.
Binu Phillip and Ms. Rina Soni for their help in pre-
paring the manuscript and the analytical department
for support.
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