Synthesis and antibacterial activity of oxazolidinone containing sulphonyl group

Article abstract of DOI:10.1016/S0960-894X(03)00430-X

A series of oxazolidinone derivatives carrying sulphonyl group was synthesized and their antibacterial activity was evaluated in vitro. Many of such compounds demonstrated potent antibacterial activity. The activity of a novel compound (YC-20) was 2-4-fol

Full text of DOI:10.1016/S0960-894X(03)00430-X

Bioorganic & Medicinal Chemistry Letters 13 (2003) 2311–2313
Synthesis and Antibacterial Activity of Oxazolidinone Containing
Sulphonyl Group
Yingjie Cui,a Yushe Yang,a,* Kaixian Chen,a Ruyun Jia and Shuhua Zhangb
aShanghai Institute of Materia Medica, Shanghai Institute for Biological Science, Chinese Academy of Sciences, Shanghai 200031, China
bSichuan Industrial Institute of Antibiotics, Chengdu 610051, China
Received 13 January 2003; revised 21 April 2003; accepted 23 April 2003
Abstract—A series of oxazolidinone derivatives carrying sulphonyl group was synthesized and their antibacterial activity was
evaluated in vitro. Many of such compounds demonstrated potent antibacterial activity. The activity of a novel compound (YC-20)
was 2–4-fold more potent than that of linezolid.
# 2003 Elsevier Science Ltd. All rights reserved.
The incidence of infections caused by Gram-positive
bacteria broadly resistant to current treatment is dra-
matically growing.1 Thus, the development of new broad
spectrum antibacterial agents aimed at methicillin-resis-
tant Staphylococcus aureus (MRSA), Staphylococcus
epidermidis (MRSE), vancomycin-resistant Enterococci
(VRE), and penicillin-and cephalosporin-resistant Strep-
tococci is the subject of current research.
Oxazolidinones, exemplified by linezolid (1), eperezolid
(2) and AZD2563 (3), represent an exciting new class of
totally synthetic antibacterial agents.2,3 Linezolid
(Zyvox1), approved by FDA, is the first agent of oxa-
zolidinone coming into market.4 Linezolid is a powerful
new tool to deal with described above Gram-positive
bacterial infections.5 It is believed that oxazolidinones
lack cross-resistance with any known antibiotics.6 Many
companies such as Pharmacia, Bayer, AstraZeneca et al.
are devoting to the development of oxazolidinones with
increased activity and expanded spectrum.7ꢀ9 Oxazoli-
dinones have a novel mechanism of action that shows to
selectively and uniquely bind to the 50S ribosomal sub-
unit, inhibiting bacterial translation at the initiation
phase of protein synthesis10 They inhibit protein synth-
esis by binding to the central loopof domain of 23S
rRNA of 50S ribosomal subunit, interfering with initia-
tor fMet-tRNA binding to the P-site of the ribosomal
peptidyltransferase center.11,12
Although resistance to oxazolidinone is difficult to gen-
erate, there are already reports in clinical isolates of
linezolid-resistance Enterococci13,14 and linezolid-resis-
tance S. aureus.15,16 So it is necessary to developnewer
and more effective antimicrobial agents. Eperezolid (2)
and other compounds possessing alkyl, aryl and acyl on
the piperazine of oxazolidinones exhibit potent anti-
bacterial activity, the pipeazine subclass become the
principal focus of ongoing chemical modification.17ꢀ19
Considering antibacterial activity of sulfa drugs, we
designed to link sulphonyl group to piperazine of oxa-
zolidinones. A new series of oxazolidinone containing
sulphonyl group was synthesized. We now report the
synthesis and antibacterial activity of these compounds.
Condensation of (S)-N-[3-[3-Fluoro-4-(N-1-piperazinyl)-
phenyl]-2-oxo- 5- oxazolidinyl]methyl]acetamide2 with
sulfonyl halide gave the product 4-12 after chromato-
graphic purification on silica gel (5%methanol-methyl-
ene chloride).20 Hydrogenation of 9–11 with 10% Pd/C
in methanol gave compounds 13, YC-20, 14. Com-
pounds 15–17 were obtained by acetylation of 13, YC-
20, 14 with acetic anhydride (Scheme 1). The structure
of Compounds 4–17, YC-20 is shown in Table 1.
*Corresponding author. Tel.: +86-21-50806600-3403; fax: +86-21-
50806786; e-mail: ysyang@shcnc.ac.cn
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00430-X

2312
Y. Cui et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2311–2313
Table 2. In vitro antibacterial activity of oxazolidinone derivatives
against 18 bacterial strains (MIC, mg/mL)
Microorganisma
Compd
S.a.
(8 strains) ( 4 strains) (2 strains) (1 strain) (3 strains)
S.e.
S.hom.
Str.p.
Str.
4
5
6
7
8
9
1–4
0.5–4
8–128
0.5–16
>128
1–8
0.25–4
4–128
0.25–16
1–8
0.25–0.5
0.25–16
>64
>128
1–32
0.5–2
0.5
0.25
2–4
0.25–0.5
128
2–4
0.25
4–8
0.25–4
0.125–4
0.25
0.25
>64
>128
0.5–1
0.25–0.5
2
2
2–4
2–4
64–128
2–16
>128
2–8
0.5–4
64–128
4
1–2
1
2–16
>64
>128
8–32
1–2
0.5–1
4–64
2
>128
8
>128
8
1
128
4
2
1
16
>64
>128
32
0.5–2
>128
N.T.b
0.25–0.5
16–32
N.T. b
N.T. b
0.25
0.25
>64
>128
1–4
0.25–1
10
11
12
13
YC-20
14
15
16
17
LZ
Scheme 1.
Table 1. Prepared compounds 4–17 and YC-20
No
R1
M.p. (ꢁC)
Yield (%)
2
4
5
6
7
8
9
Methyl
Phenyl
209.5–211
191–193
224–227
>230
203–205
158–162
175–178
188–190
202–205
>230
206–210
>230
156–158
222–225
228–230
24.2
82.9
69.0
83.0
75.7
52.4
63.0
56.6
85.0
43.5
80.7
91.0
30.0
27.7
66.0
LZ=linezolid
aStr.p.=Streptococcus pneumoniae, Str.=Streptococcus, S.hom.=-
Staphylococcus hominis, S.a.=Staphylococcus aureus, S.e.=Staphylo-
coccus epidermidis.
4-Methylphenyl
4-Methoxyphenyl
4-Bromophenyl
2-Nitrophenyl
3-Nitrophenyl
4-Nitrophenyl
2-Thiophenyl
2-Aminopheny
3-Aminophenyl
4-Aminophenyl
2-Acylaminophenyl
3-Acylaminopheny
4-Acylaminophenyl
bN.T.=No Tested.
10
11
12
13
YC-20
14
15
16
17
Based on above facts, potent activity of YC-20 may be
due to strong polarity of amine group. There may be
intense ‘binding action’ at the site of action between
YC-20 and receptor. Conversion of amino of YC-20 to
acylamino results in complete loss of antibacterial
activity. This observation may direct existence of
hydrogen bond between amino of YC-20 and receptor.
Furthermore, YC-20 demonstrates potent activity pos-
sibly because of hydrophilicity of amino. The position
of amino in YC-20 is similar to that of hydroxyl moiety
in Eperezolid and AZD2563, these three compounds
may have similar stereoelectronic action with receptor.
Antibacterial activity of compounds 4–17, YC-20 was
tested in vitro against a panel of clinical isolates of
Gram-positive pathogenic bacteria. Linezolid was
selected as reference compound. Minimum inhibitory
concentration (MIC) values were determined using agar
dilution or broth microdilution methodology.21 Com-
pounds were incorporated into MH (Mueller–Hinton)
agar medium at concentration of 128, 64, 32, 16, 8, 4, 2,
1, 0.5, 0.25, 0.125, 0.06, 0.03 mg/L. The test organism
was grown in MH broth medium at 35 ꢁC for 16–18 h,
the broths were adjusted to the turbidity of 0.5 McFar-
land standard; then the bacterial suspensions were
inoculated onto the drug-supplemented MH agar plates
at 35 ꢁC for 18–20 h. The MIC was defined as the lowest
concentration of drug that completely inhibited growth
of the organism. The results are shown in Table 2.
In conclusion, we have found that introduction of sul-
phonyl to oxazolidinones could enhance their anti-
bacterial activity. Compound YC-20 was 2–4-fold more
potent than linezolid and as drug candidate is now in
further studies.
Acknowledgements
The authors are thankful for the financial support from
the National Natural Science Foundation of China
(Project 20272067). We also thank Chinese Academy of
Sciences for funding (KSCX2-SW-220).
Most of analogues exhibited potent antibacterial activ-
ity against Gram-positive strains. The activity of com-
pound YC-20 was 2–4-fold more potent than that of
linezolid. By comparing activities of 10 with 9, 11, and
YC-20 with 13, 14, it could be found that position of
substituent had important effect on activity. Meta sub-
stituent in phenyl is more favorable for antibacterial
activity. The aminophenyl derivatives are more potent
than the corresponding nitrophenyl derivatives. On the
other hand, acetylation of aminophenyl derivative leads
to decrease activity.
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