Synthesis and antibacterial activity of arylpiperazinyl oxazolidinones with diversification of the N-substituents

Article abstract of DOI:10.1016/j.bmcl.2004.05.066

A series of 4-arylpiperazin-1-yl-3-phenyloxazolidin-2-one derivatives with diversification of the N-substituents such as methylene O-linked heterocycles, thioamide, dithiocarbamate, thiourea, and thiocarbamate were synthesized and evaluated as antibacteri

Full text of DOI:10.1016/j.bmcl.2004.05.066

Bioorganic & Medicinal Chemistry Letters 14(2004) 3881–3883
Synthesis and antibacterial activity of arylpiperazinyl
oxazolidinones with diversification of the N-substituents
Sun-Young Jang,a Young Hwan Ha,a Seung Whan Ko,a Wonku Lee,a Jongkook Lee,a
a,d,
Sunghoon Kim,a,b Yong Woo Kim,a,c Won Koo Leea,c, and Hyun-Joon Ha
*
*
aImagene Co. Ltd, Biotechnology Incubating Center, Seoul National University, Seoul 151-742, South Korea
bCenter for ARS Network, College of Pharmacy, Seoul National University, Seoul 151-741, South Korea
cDepartment of Chemistry, Sogang University, Seoul 121-742, South Korea
dDepartment of Chemistry, Hankuk University of Foreign Studies, Yongin 449-791, South Korea
Received 6 May 2004; revised 25 May 2004; accepted 25 May 2004
Available online 17 June 2004
Abstract—A series of 4-arylpiperazin-1-yl-3-phenyloxazolidin-2-one derivatives with diversification of the N-substituents such as
methylene O-linked heterocycles, thioamide, dithiocarbamate, thiourea, and thiocarbamate were synthesized and evaluated
as antibacterial agents. Their in vitro activities (MIC) were evaluated against MRSA and VRE resistant Gram-positive strains such
as Staphylococcus and Enterococcus. Most of the compounds were more potent in vitro but less active in vivo than linezolid.
Ó 2004Elsevier Ltd. All rights reserved.
Many strains of multidrug resistance of Gram-positive
pathogens cause clinical problems.1 These include
methicillin-resistant Staphylococcus aureus (MRSA),
penicillin-resistant Streptococcus pneumoniae (PRSP),
After a few years of introducing linezolid already re-
ported were linezolid-resistance Enterococci5 and
linezolid-resistance S. aureus.6 Therefore, continuous
efforts are necessary to develop more effective anti-
bacterial agent as a new chemical entity. Many different
approaches to alter the chemical structure of oxazoldi-
none antibiotic represented with linezolid and eperezolid
can be classified into three different strategies: (1)
modifying the core structure of oxazolin-2-one ring as
its surrogates, (2) changing the pendent structure at C-4
of the oxazolin-2-one ring, and (3) diversifying the
structure of N-acetylaminomethyl group. After the
observation of the antibacterial activity with the com-
pound bearing 4-(4-aryl)piperazinylphenyl group on the
nitrogen of the oxazolidin-2-one7 we tried to alter the
and
vancomycin-resistant
Enterococcus
faecium
(VREF). Since the first discovery of a new class of
purely synthetic antibiotics DuP 721 (1)2 was made,
linezolid (Zyvoxâ) (2)3 was introduced in the market for
the treatment of multidrug resistant Gram-positive
infections such as nosocomial and community-acquired
pneumonia and skin infections. It has novel action
mechanism to inhibit protein synthesis by binding to the
50S ribosomal subunit with interference of fMet-tRNA
binding to the P-site of the ribosomal peptidyltransfer-
ase center.4
O
O
O
O
O
O
O
N
N
N
R1
N
O
N
N
R3
NHAc
Z
NHAc
R2
F
3 R1 = O-2-Pyridine, R2 = F, R3= 2-Cl, Z = H
DuP 721 (1)
Linezolid (2)
4 R1 = O-2-Pyrazine, R2 = F, R3= 2-Cl, Z = H
5 R1 = O-2-Isoxazole, R2 = F, R3= 2-Cl, Z = H
6 R1 = N(C=S)CH3, R2 = F, R3= various substituents, Z = H or N
7 R1 = N(C=S)SCH3, R2 = H or F, R3= various substituents, Z = H or N
8 R1 = N(C=S)NH2, R2 = H or F, R3= various substituents, Z = H or N
9 R1 = N(C=S)OCH3, R2 = F, R3= various substituents, Z = H or N
Keywords: Antibacterial; Oxazolidinone; Thioamide.
* Corresponding authors. Tel.: +82-1-705-8449 (W.K.L.); tel.: +82-31-
3304369; fax: +82-31-3304566 (H.-J.H.); e-mail addresses:
wonkoo@sogang.ac.kr; hjha@hufs.ac.kr
0960-894X/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.05.066

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S.-Y. Jang et al. / Bioorg. Med. Chem. Lett. 14(2004) 3881–3883
structure of acetamide part with diversification of the N-
substituents such as methylene O-linked heterocycles,8
thioamide, dithiocarbamate, thiourea, and thiocarba-
mate.9 In this report is described the synthesis and
antibacterial activity of theses compounds (3–9).
droxypyridine, 2-chloropyrazine, and 3-hydroxyisoxaz-
ole, respectively. Azide displacement of the hydroxyl
group on compound 10 and the subsequent hydroge-
nation yielded amine 11 that was further reacted with
acetyl chloride to give acetamide. This was treated with
Lawesson’s reagents to give the corresponding thioam-
ide 6 in 65–89% yields. S-Methyldithiocarbamate 7 was
obtained from the corresponding amine by the reaction
with CS2 and iodomethane in good yield. Treatment of
the amines with 1.1 mol equivalent of 1,10-thio-
carbonyldi-2(1H)-pyridone yielded thiocyanate that was
At first the parent molecule 4-(4-aryl)piperazinylphenyl-
5-hydroxymethyloxazolidin-2-one 10 was synthesized by
the reported method.7 The substitution of 5-hydroxy-
methyl to C-5 methyleneoxoheterocylic compounds (3,
4, and 5) were achieved by the reaction with 2-hy-
O
O
O
O
(d)
N
N
N
N
N
N
R3
NH2
R3
OH
Z
Z
R2
11
R2
10
(e)
(h)
(c)
(b)
(a)
(g)
(f)
6
3
5
8
9
7
4
Scheme 1. Reagents and conditions: (a) 2-hydroxypyridine, PPh3, DEAD, DMF; (b) 2-chloropyrazine, NaH, DMF; (c) 3-hydroxyisoxazole, PPh3,
DEAD, DMF; (d) (i) MsCl, TEA, CH2Cl2, 0 °C; (ii) NaN3, DMF, 80 °C; (iii) Pd/C, H2, EtOAc/EtOH; (e) (i) acetyl chloride, TEA, CH2Cl2, 0 °C; (ii)
Lawesson’s reagent, dioxane, 110 °C; (f) CS2, TEA, EtOH, MeI; (g) (i) 1,10-thiocarbonyldi-2(1H)-pyridone, CH2Cl2; (ii) 2.0 M NH3 in MeOH, TEA,
0 °C; (h) (i) 1,1-thiocarbonyldi-2(1H)-pyridone, CH2Cl2; (ii) MeOH, reflux.
Table 1. Prepared compounds 3–9 and their in vitro antibacterial activity against four different bacterial strains (MIC, lg/mL)a
No.
Compound
R2
Microorganismb
S.a.2
R1
R3
Z
S.a.1
S.p.
E.f.
3
O-2-Pyridine
O-2-Piperazine
O-2-Isoxazole
N(C@S)CH3
N(C@S)CH3
N(C@S)CH3
N(C@S)CH3
N(C@S)CH3
N(C@S)CH3
N(C@S)CH3
N(C@S)SCH3
N(C@S)SCH3
N(C@S)SCH3
N(C@S)SCH3
N(C@S)NH2
N(C@S)NH2
N(C@S)NH2
N(C@S)NH2
N(C@S)NH2
N(C@S)NH2
N(C@S)NH2
N(C@S)NH2
N(C@S)NH2
N(C@S)NH2
N(C@S)NH2
N(C@S)OCH3
N(C@S)OCH3
N(C@S)OCH3
N(C@S)OCH3
F
F
F
F
F
F
F
F
F
F
F
F
H
F
H
F
F
F
H
F
F
F
F
F
F
F
F
F
F
2-Cl
2-Cl
2-Cl
H
H
H
H
H
N
H
H
H
H
H
N
H
H
H
H
H
H
N
H
H
H
H
H
H
H
H
N
H
H
>64>64>64>64
>64>64>64>64
>64>64>64>64
0.12
4
5
6a
6b
6c
6d
6d
6e
6f
0.06
0.12
0.12
0.12
0.03
0.25
0.12
0.12
0.25
1.00
0.25
0.12
0.25
0.06
0.25
0.12
0.06
0.12
0.25
0.25
>64
H
0.06
0.12
0.03
0.12
0.03
0.15
0.12
0.12
0.06
0.50
0.12
0.12
0.06
0.06
0.12
0.06
0.008
0.12
0.0040.008
0.06
0.12
0.06
0.12
0.12
0.06
0.06
0.06
0.50
2-Cl
3-Cl
4-Cl
2-Me
3-F
0.03
0.12
0.06
0.25
0.05
0.03
0.12
0.50
0.12
0.12
0.12
0.12
0.25
0.25
0.06
0.25
0.12
0.12
7a
7b
7c
7d
8a
8b
8c
8d
8e
8f
H
0.06
0.12
3-Cl
3-OMe
2-Me
H
0.12
0.12
0.12
0.06
H
2-OMe
H
0.25
0.12
2-Cl
2-Cl
3-Cl
3-OMe
4-Cl
2-Me
3-CF3
H
0.03
0.12
8g
8h
8i
0.02
0.03
0.06
0.06
0.12
0.12
0.12
0.12
0.06
0.12
0.12
0.50
0.06
0.50
0.25
0.25
0.25
0.12
0.12
0.12
1.00
0.12
0.12
8j
8k
9a
9b
9c
9d
Linezolid
0.25
0.25
H
0.12
0.12
3-Cl
3-OMe
0.12
0.25
a Agar dilution method, Mueller–Hinton agar, 104CFU/spot.
b S.a.1 ¼ Staphylococcus aureus ATCC 25923, S.p. ¼ Staphylococcus pyogenes ATCC 8668, S.a.2 ¼ Staphylococcus agalatiae ATCC 13813,
E.f. ¼ Enterococcus faecalis ATCC 29212.

S.-Y. Jang et al. / Bioorg. Med. Chem. Lett. 14(2004) 3881–3883
3883
served as the precursor for the synthesis of thiourea and
Acknowledgements
methylthiocarbamate. When this was treated with
ammonia in methanol or methanol only, thio-analogs of
thioureas 8 and methylthiocarbamates 9 were yielded,
respectively, in more than 85% yield in most cases
(Scheme 1).
The financial support from the Center for Bioactive
Molecular Hybrids is gratefully acknowledged.
References and notes
Antibacterial activity of compounds 4–9 were tested
in vitro against Gram-positive pathogenic bacteria with
linezolid as the reference compound. Minimum inhibi-
tory concentration (MIC) values were determined using
agar dilution or broth microdilution methodology.
Compounds were incorporated into MH (Mueller–
Hinton) agar medium at concentration of 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
McFarland standards, and then the bacterial suspen-
sions 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 and the results are
shown in Table 1.
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Most analogs exhibited excellent antibacterial activity
against the Gram-positive strains we tested except
compounds 4, 5, and 6 with methylene O-linked het-
erocycles. Thiocarbonyl compounds such as thioamide,
dithiocarbamate, thiourea, and thiocarbamate were
more active in vivo than linezolid tested as the internal
reference. Selected compounds 6d, 7a, 8g, and 9b rep-
resenting each group of compounds were also evaluated
for in vivo efficacy against S. aureus with lethally in-
fected mice. However, the activities of all three com-
pounds were less potent as >16 mg/kg than linezolid
4mg/kg in terms of ED 50s.
In summary, a series of 4-arylpiperazin-1-yl-3-phenyl-
oxazolidin-2-one derivatives with diversification of the
N-substituents such as methylene O-linked heterocycles,
thioamide, dithiocarbamate, thiourea, and thiocarba-
mate were synthesized efficiently and evaluated as anti-
bacterial agents in vitro. Most of the compounds were
more potent in vitro but less active in vivo than linezolid.