Synthesis and antibacterial activities of eperezolid analogs with glycinyl substitutions

Article abstract of DOI:10.1002/ardp.200800233

A series of eperezolid analogs with glycinyl substitutions were prepared and their antibacterial activities were studied against a panel of susceptible and resistant Gram-positive bacteria. The compounds with N-arylacyl or N-heteroarylacyl glycinyl struct

Full text of DOI:10.1002/ardp.200800233

Arch. Pharm. Chem. Life Sci. 2009, 342, 377–385
X. Wang et al.
377
Full Paper
Synthesis and Antibacterial Activities of Eperezolid Analogs
with Glycinyl Substitutions
Xiao-Jun Wang, Ning Wu, Guang-Jian Du, Shuang-Qi Zhao, Ming Yan, and Lian-Quan Gu
Industrial Institute of Fine Chemicals and Synthetic Drugs, School of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou, P.R. China
A series of eperezolid analogs with glycinyl substitutions were prepared and their antibacterial
activities were studied against a panel of susceptible and resistant Gram-positive bacteria. The
compounds with N-arylacyl or N-heteroarylacyl glycinyl structural units showed good antibacte-
rial activities. The compounds 11b, 11c, and 11e were twofold more active than linezolid against
Staphylococcus epidermidis and Enterococcus faecalis. Several pyridine analogs were also prepared
and found to have poor antibacterial activity against most of the tested Gram-positive bacteria,
however, one of the compounds 12e showed very high activity against Enterococcus faecalis.
Keywords: Antibacterial / Eperezolid analog / Glycinyl substitution / Oxazolidinone /
Received: December 23, 2008; accepted: March 16, 2009
DOI 10.1002/ardp.200800233
ity-acquired pneumonia, skin infections caused by MRSA,
and infections associated with VRE [4]. Oxazolidinone
antibacterials were reported to inhibit bacterial protein
synthesis through binding to the bacterial 23S ribosomal
RNA of the 50S subunit [5]. The mechanism is unique
compared with the present antibacterials. In recent
years, extensive structural modifications of linezolid
have been carried out to extend the antibacterial spec-
trum and to decrease the side effects [6]. We are especially
interested in eperezolid (1 in Scheme 1), which was
reported to possess excellent antibacterial activity com-
parable with linezolid [7]. However, its further develop-
ment was discontinued due to certain toxicity and side
effects. The piperazine ring of eperezolid provides a suit-
able motif for structural modifications. A lot of epere-
zolid analogs were prepared and screened against vari-
ous Gram-positive pathogens [8–11]. 3 (RBx7644), 4 (YC-
20), and 5 are the representative examples of these ana-
logs with potent antibacterial activities.
Introduction
In recent decades, the growing incidence of bacterial
resistance to the present antibacterials became a serious
medical problem worldwide [1]. Multidrug-resistant
Gram-positive pathogens, such as methicillin-resistant
Staphylococcus aureus (MRSA) and Staphylococcus epidermis
(MRSE), vancomycin-resistant Enterococci (VRE), cephalo-
sporin-resistant Streptococcus pneumonias have been iso-
lated clinically and are responsible for significant mor-
bidity and mortality of infected patients [2]. The develop-
ment of new antibacterials without cross-resistance with
the present antibacterials is an urgent task. Oxazolidi-
nones are a new class of synthetic antibacterials with
excellent activities against Gram-positive pathogens [3].
Linezolid, the first of the oxazolidinone antibacterials in
the market, is indicated for both hospital- and commun-
Correspondence: Ming Yan, Industrial Institute of Fine Chemicals and
Synthetic Drugs, School of Pharmaceutical Sciences, Sun Yat-sen Uni-
versity, Guangzhou 510006, P.R. China
E-mail: yanming@mail.sysu.edu.cn
Fax: +86 20 399-43049
Substitution of the 4-position of the piperazine ring is
important for antibacterial activity of eperezolid ana-
logs, since the unsubstituted compound 2 was found to
be ineffective (in-vitro antibacterial activity MIC A 16 lg/
mL against Staphylococcus aureus). Acyl, sulfonyl,and aryl
are suitable substitutents at this position. The volume of
the substitutents could be changed a lot as illustrated in
Abbreviations: Enterococcus faecalis (EF); E. coli (EC); methicillin-re-
sistant Staphylococcus aureus (MRSA); methicillin-resistant Staphylococ-
cus epidermis (MRSE); Staphylococcus aureus (SA); Staphylococcus ep-
idermidis (SE); vancomycin-resistant Enterococci (VRE)
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X. Wang et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 377–385
Scheme 1. Linezolid and eperezolid analogs.
Reagents and conditions: a) Piperazine, CH3CN, reflux (86%); b) H2, 10% Pd/C, THF; c) Cbz-Cl, NaHCO3, acetone-H2O
(79%); d) n-BuLi, THF, – 788C fi r. t. (42%); e) H2, 10% Pd/C, CH2Cl2 / CH3OH; f) DCC, DMF (10 – 53%).
Scheme 2. Synthesis of compounds 11a–11n.
several reported examples. Based on the analysis of the
structure-activity relationships of the eperezolid analogs,
Results and discussion
Synthesis
we speculate that a H-bond acceptor is the necessary
structure motif and a big pocket exists in this area. We
consider introducing glycinyl substitutents with N-acyl
or sulfonyl functional groups, so as to enhance the inter-
action of the target compounds with the bacterial riboso-
mal 50S subunit and to improve the physicochemical
properties. In this paper, we report the synthesis of a ser-
ies of eperezolid analogs with glycinyl substitutions and
their in-vitro antibacterial activities against Gram-posi-
tive pathogens.
The synthesis of compounds 11a–11n is illustrated in
Scheme 2 [12]. The SN reaction of 3,4-difluoro-1-nitroben-
zene with piperazine provided 6 in good yield. Hydroge-
nation of the nitro group with palladium / carbon and
benzyloxycarbonylation of the resulting amine fur-
nished the double Cbz-protected compound 8. Reaction
of the lithium anion of 8 with N-(((S)-oxiran-2-yl)methyl)a-
cetamide provided oxazolidinone 9 [13]. De-benzyloxycar-
bonylation with palladium / carbon gave key intermedi-
ate 10. The condensation of 10 with a series of glycine
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Arch. Pharm. Chem. Life Sci. 2009, 342, 377–385
Eperezolid Analogs with Glycinyl Substitutions
379
dinylacyl-glycinyl and furanylacyl-glycinyl respectively
substitutions also have a good activity against MRSA and
SA, but they have lower activity against SE and EF. Com-
pound 11i with thiophenylacyl-glycinyl substitution
showed lower activity than 11b, 11c, and 11e. The N-aryl-
sulfonylglycinyl derivatives 11j–11m showed inferior
antibacterial activities to the corresponding N-benzoyl-
glycinyl derivatives. N-Acetylglycinyl derivative 11n is far
less effective. The result suggests that the N-arylacyl or N-
heteroarylacyl glycinyl structural motif plays a key role
for good antibacterial activities. Compounds 11a–11n
showed very low inhibition activities against E. coli and
the similar results were observed for most of the reported
eperezolid analogs.
Reagents and conditions: a) Piperazine, CH3CN, r. t.; b) The procedure is similar to
that reported in Scheme 2.
Scheme 3. Synthesis of compounds 12a, 12c, and 12e.
derivatives in the presence of N,N9-dicyclohexylcarbodii-
mide (DCC) to provide target compounds 11a–11n.
The replacement of the phenyl ring (B-ring) of epere-
zolid with pyridine was reported to improve antibacte-
rial activities and to extend the antibacterial spectrum
[14]. Thus, compounds 11a, 11c, and 11e were taken for
further modifications. The pyridine analogs 12a, 12c, and
12e were prepared starting from 2-chloro-5-nitropyridine
(Scheme 3).
Compounds 12a, 12c, and 12e showed lower activities
than their phenyl analogs against most Gram-positive
bacteria, however, 12e showed potent antibacterial activ-
ity against EF (MIC is fourfold lower than linezolid). A rea-
sonable interpretation of this experimental observation
could not be achieved at the present stage.
Computational study
The experimental data were studied with the CoMFA
method (SYBYL7.3). Table 2 shows the cross-validated r2
(r2cv) values using CoMFA analyses at average antibacterial
activities. The CoMFA study, based on the selected lowest
energy conformer of template compound 11e, gave r2cv
values of 0.595. The noncross-validated PLS analysis
yielded an r2 of 0.944, and the estimated standard error
was 0.467 for COL1. Therefore, the CoMFA generated 3D-
QSAR models for the average antibacterial activities of
eperezolid analog against Gram-positive pathogens have
a reasonable cross-validated correlation.
Figure 1 shows the steric-electrostatic contour maps of
the CoMFA models for COL1. The individual contribu-
tions from the steric favored and disfavored levels are
fixed at 80% and 20%, while individual contributions
from the electrostatic favored and disfavored levels are
fixed at 90% and 10%. The CoMFA contours of the steric
maps are shown in yellow and green. Those of the electro-
static maps are shown in red and blue. Greater values of
“bioactive measurement” are collected, with more bulk
near the green-colored contours; less bulk near the yel-
low-colored contours; more positive charge near the
blue-colored contours; and more negative charge near
the red-colored contours.
Biological activities
The antibacterial activities of compounds 11a–11n, 12a,
12c, and 12e were examined against a panel of suscepti-
ble and resistant strains of Gram-positive bacteria,
including Staphylococcus aureus (SA), methicillin-resistant
Staphylococcus aureus (MRSA), Staphylococcus epidermidis
(SE), and Enterococcus faecalis (EF). E. coli (EC) was used as a
representative of Gram-negative bacteria. Linezolid was
used as the positive control in the experiments. The
experiment results of in-vitro evaluation of 11a–11n, 12a,
12c, and 12e are summarized in Table 1.
N-Benzoylglycine derivatives 11a–11e are highly active
against Gram-positive bacteria, especially for MRSA. 11b,
11c, and 11e showed comparable activity against MRSA
and SA with linezolid, however higher activity against SE
and EF. The substitutions at the 4-position of the phenyl
ring improve the antibacterial activities, since 11b, 11c,
and 11e possess superior activity to unsubstituted com-
pound 11a. The electronic property of the substitutents
seems to have a slight effect on the antibacterial activity.
Both electron-withdrawing group (NO2) and electron-
donating group (Me) afforded good antibacterial activ-
ities. The volume of substitutents also plays an important
role for the activity. Compound 11f with a bulk tert-butyl
group provided a lower antibacterial activity. It is inter-
esting to note that the N-4-fluoro-benzoylglycinyl deriv-
ative 11d is highly active against MRSA, but it is less effec-
tive against SA. Compounds 11g and 11h with N-pyri-
The computational study suggests that a highly elec-
tronegative amide group of the glycinyl substitution
decreases the antibacterial activity, for example, carboxa-
mide derivatives 11a–11e are generally more active than
sulfonamide derivatives 11j–11m. In addition, bulk
amide groups are proposed to be detrimental for the anti-
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X. Wang et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 377–385
Table 1. In-vitro antibacterial activities (MIC, lg/mL) of compounds 11a–11n, 12a, 12c, and 12e.a)
Compound
R
MRSAa)
SAb)
SEc)
EFd)
ECe)
Linezolid
1
1
4
8
2
2
2
2
A16
A16
11a
11b
11c
1
1
4
4
1
1
1
1
A16
A16
11d
11e
1
1
16
4
2
1
4
1
A16
A16
11f
2
8
4
2
A16
11g
11h
11i
1
1
2
4
4
1
2
2
2
2
4
A16
A16
A16
16
11j
2
2
16
8
4
2
4
4
A16
A16
11k
11l
2
2
8
8
2
2
4
2
A16
A16
11m
11n
12a
4
8
16
16
4
8
4
4
A16
–
12c
12e
4
4
8
8
4
4
2
–
–
0.5
a)
MRSA = methicillin-resistant Staphylococcus aureus (isolated clinically from Zhongshan III hospital, Guangzhou, China).
SA = Staphylococcus aureus (ATCC 25923).
SE = Staphylococcus epidermidis (ATCC 12228 ).
EF = Enterococcus faecalis (ATCC 29212).
EC = E. coli (ATCC 25922).
b)
c)
d)
e)
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Arch. Pharm. Chem. Life Sci. 2009, 342, 377–385
Eperezolid Analogs with Glycinyl Substitutions
381
Figure 1. Steric-electrostatic contour maps of the CoMFA models for COL1.
Table 2. Cross-validated analyses for the COL1 using the
CoMFA models, based on compound 11e as the template.
against most of the tested Gram-positive bacteria, how-
ever, 12e showed good activity against Enterococcus faeca-
lis. Further studies of in-vivo antibacterial activities and
toxicities of these compounds are currently under way.
CoMFA model
R2
0.944
0.000
Probability of r2
This work was supported by the National Natural Science Foun-
dation of China (No. 20772160), NCET plan of the Ministry of
Education of China, Guangzhou Bureau of Science and Tech-
nology, and Zhuhai Bureau of Science and Technology.
Standard error of estimate
F value (n1 = 2, n2 = 12)
Relative contributions of COL1/
steric/electrostatic/
0.467
101.626
0.675:0.253:0.144
The authors have declared no conflict of interest.
bacterial activity. In fact 4-tert-butylbenzoyl derivative
11f showed lower antibacterial activity. The arylacyl
groups are necessary for good antibacterial activity. The
acetyl derivative 11n is less active than its arylacyl ana-
logs. CoMFA contour maps also uncover a big green area
around the glycinyl substitution. The result implicates
that further introduction of a-alkyl groups at the glycinyl
substitution may increase the antibacterial activity.
Experimental
Chemistry
Melting points (m.p.) were determined on a WRS-2A microcom-
puter melting point apparatus (Shanghai, Ronbio Scientific Co,
Shanghai, China) and were uncorrected. IR spectra were recorded
on Bruker Tensor 37 spectrometer in KBr pellets (Bruker Bio-
science, USA). 1H-NMR and 13C-NMR spectra were recorded on a
Varian Mercury 300 spectrometer (Varian, Palo Alto, CA, USA).
Chemical shifts of protons are reported in parts per million
(ppm) downfield from tetramethylsilane or (DMSO-d6: d = 2.5).
Chemical shifts of carbon are referenced to the carbon resonan-
ces of the solvent (CHCl3: d = 77.0) or (DMSO-d6: d = 39.7). Coupling
constants (J) are reported in Hertz (Hz). Mass spectra were
recorded on a MAT95XP spectrometer. N-Carbobenzoxy-3-fluoro-
4-(N-carbobenzoxypiperazin-1-yl)aniline 8, (S)-N-[[3-[3-fluoro-4-[N-
1-(4-carbobenzoxy)piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]me-
thyl]acetamide 9, (S)-N-[[3-[3-fluoro-4-(1-piperazinyl)-phenyl]-2-
oxo-5-oxazolidinyl]methyl] acetamide 10, and N-(((S)-oxiran-2-
yl)methyl)acetamide were prepared according to reported proce-
dures [12–13].
Conclusion
In conclusion, a number of new eperezolid analogs with
glycinyl substitutions have been prepared. These com-
pounds showed good antibacterial activities against
Gram-positive pathogens. Compounds 11b, 11c, and 11e
are twofold more active than linezolid against Staphylo-
coccus Epidermitis and Enterococcus faecalis. The N-arylacyl
or N-heteroarylacyl glycinyl structural motifs are very
important for the antibacterial activity. The pyridine ana-
logs 12a, 12c, and 12e showed poor antibacterial activity
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Arch. Pharm. Chem. Life Sci. 2009, 342, 377–385
-NCH2CH(OCON)CH2NHAc), 4.28 (s, 2H, ArCONHCH2CON-), 4.75–
4.76 (m, 1H, -NCH2CH(OCON)CH2NHAc), 6.94 (t, J = 9.0 Hz, 1H, Ar-
H), 7.07-7.10 (m, 1H, Ar-H), 7.25 (d, 2H, J = 7.5 Hz, Ar-H), 7.45 (d,
1H, J = 14.7 Hz, Ar-H), 7.73 (d, 2H, J = 7.2 Hz, Ar-H);13C-NMR (CDCl3
+ CD3OD) d: 21.43, 23.06, 41.65, 42.00, 42.20, 44.62, 47.65, 50.42,
50.77, 71.89, 107.40, 107.66, 113.92, 119.64, 127.07, 129.22,
131.07, 133.72, 135.86, 142.12, 154.22, 166.74, 167.19, 171.01;
HRMS (EI+) calcd. for C26H30FN5O5 (M+): 511.2225, found:
511.2227.
General procedure for the synthesis of compounds 11a–
11n
To a solution of compound 10 (0.134 g, 0.4 mmol) and 2-benz-
amidoacetic acid (0.072 g, 0.4 mmol) in DMF (6 mL), was added
DCC (100 mg, 0.73 mmol) under stirring. The reaction mixture
was stirred at room temperature overnight. After evaporation of
the solvent under vacuum, the residue was purified by column
chromatography over silica gel (CH2Cl2 l CH2Cl2 / CH3OH =
20 : 1) to give compound 11a.
(S)-N-[[3-[3-Fluoro-4-[4-[2-(4-
fluorobenzamido)acetyl]piperazin-1-yl]phenyl]-2-oxo-5-
(S)-N-[[3-[3-Fluoro-4-[4-[2-(benzamido)acetyl]piperazin-
1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide 11a
White solid, yield: 19.1%; m.p.: 87–888C; IR (cm-1): 3413 (N-H),
1743 (C=O), 1639 (C=O), 1617 (C=C), 1550 (C=C), 1514(C=C), 1478
(C-H), 1442(C-H); MS (EI, 70 ev) m/z: 497 [M+], 453, 262, 208, 105,
77;1H-NMR (CDCl3 + CD3OD) d: 2.00 (s, 3H, CH3CO-), 3.07–3.12 (m,
4H, -CON(CH2CH2)2N-), 3.59–3.70 (m, 2H, -NCH2CH(OCON)CH2N-
HAc), 3.74-3.83 (m, 5H, -CON(CH2CH2)2N- and -NCH2CH(O-
CON)CH2NHAc), 4.02–4.08 (m, 1H, -NCH2CH(OCON)CH2NHAc),
4.30 (s, 2H, PhCONHCH2CON-), 4.75–4.77 (1H, m, -NCH2CH(O-
CON)CH2NHAc), 6.95–6.98 (1H, m, Ar-H), 7.07–7.10 (m, 1H, Ar-
H)), 7.44–7.53 (m, 4H, Ar-H), 7.83 (dd, J1 = 0.9 Hz, J2 = 6.9 Hz, 2H,
Ar-H); 13C-NMR (CDCl3 + CD3OD) d: 22.99, 41.67, 41.94, 42.19,
44.61, 47.63, 50.39, 50.71, 71.93, 107.39, 107.65, 113.94, 119.61,
127.06, 128.55, 131.66, 133.86, 135.82, 154.30, 166.65, 167.26,
171.17; HRMS (EI+) calcd. for C25H28FN5O5 (M+): 497.2069, found:
497.2058.
oxazolidinyl]methyl]acetamide 11d
The compound was prepared via a procedure similar to 11a with
2-(4-fluorobenzamido)acetic acid. White solid, yield: 20.8%; m.p.:
232–2348C; IR (cm– 1): 2924 (C-H), 2852 (C-H), 1721 (C=O), 1675
(C=O), 1642 (C=O), 1555 (C=C), 1516 (C=C), 1483 (C-H), 1442 (C-H),
1415 (C-H); MS (EI, 70 ev) m/z: 515 [M+], 471, 262, 208, 123, 95; 1H-
NMR (CDCl3 + CD3OD) d: 2.00 (s, 3H, CH3CO-), 3.07–3.12 (m, 4H,
-CON(CH2CH2)2N-), 3.55–3.69 (m, 2H, -NCH2CH(OCON)CH2NHAc),
3.73–3.84 (m, 5H, -CON(CH2CH2)2N- and -NCH2CH(OCON)CH2N-
HAc), 4.05 (m, 1H, -NCH2CH(OCON)CH2NHAc), 4.28 (s, 2H,
ArCONHCH2CON-), 4.75–4.78 (m, 1H, -NCH2CH(OCON)CH2NHAc),
6.95 (t, J = 9.0 Hz, 1H, Ar-H), 7.07–7.16 (m, 3H, Ar-H), 7.45 (dd, J1 =
1.8 Hz, J2 = 14.1 Hz, 1H, Ar-H), 7.87 (dd, J1 = 6.0 Hz, J2 = 9.0 Hz, 2H,
Ar-H); 13C-NMR (75 MHz, CDCl3 + CD3OD) d: 22.21, 41.31, 41.82,
42.09, 44.62, 47.72, 50.20, 50.52, 71.99, 107.21, 107.56, 113.91,
115.17, 115.46, 119.37, 129.17, 129.29, 135.57, 145.62, 154.71,
166.58,173.86; HRMS (EI+) calcd. for C25H27F2N5O5 (M+): 515.1975,
found: 515.1977.
(S)-N-[[3-[3-Fluoro-4-[4-[2-(4-
chlorobenzamido)acetyl]piperazin-1-yl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]acetamide 11b
(S)-N-[[3-[3-Fluoro-4-[4-[2-(4-
The compound was prepared via a procedure similar to 11a with
2-(4-chlorobenzamido)acetic acid. White solid, yield: 9.8%; m.p.:
239–2418C; IR (cm– 1): 3414 (N-H), 2920 (C-H), 1740 (C=O), 1722
(C=O), 1670 (C=O), 1645 (C=O), 1518 (C=C), 1476 (C-H), 1441 (C-H);
MS (EI, 70 ev) m/z: 531 [M+], 487, 262, 208, 139, 111; 1H-NMR
(CDCl3 + CD3OD) d: 1.99 (s, 3H, CH3CO-), 3.07-3.12 (m, 4H,
-CON(CH2CH2)2N-), 3.59–3.70 (m, 2H, -NCH2CH(OCON)CH2NHAc),
3.74–3.83 (m, 5H, -CON(CH2CH2)2N- and -NCH2CH(OCON)CH2N-
HAc), 4.05–4.06 (m, 1H, -NCH2CH(OCON)CH2NHAc), 4.28 (s, 2H,
ArCONHCH2CON-), 4.75–4.77 (m, 1H, -NCH2CH(OCON)CH2NHAc),
6.92–7.00 (m, 1H, Ar-H), 7.08–7.11 (m, 1H, Ar-H), 7.35–7.48 (m,
3H, Ar-H), 7.79–7.80 (m, 2H, Ar-H); 13C-NMR (CDCl3 + CD3OD) d:
22.09, 41.24, 41.80, 42.06, 44.60, 47.71, 50.15, 50.48, 71.93,
107.18, 107.52, 107.65, 109.59, 113.90, 119.35, 128.27, 128.46,
137.76, 154.70, 166.53, 166.65; HRMS (EI+) calcd. for
C25H27ClFN5O5 (M+): 531.1679, found: 531.1677.
nitrobenzamido)acetyl]piperazin-1-yl-phenyl]-2-oxo-5-
oxazolidinyl]methyl]acetamide 11e
The compound was prepared via a procedure similar to 11a with
2-(4-nitrobenzamido)acetic acid. Yellow solid, yield: 23.1%; m.p.:
234–2368C; IR (cm– 1): 3409 (N-H), 3074 (Ar-H), 2974 (C-H), 1735
(C=O), 1720 (C=O), 1666 (C=O), 1650 (C=O), 1617 (C=C), 1600
(C=C), 1519 (C=C), 1470 (C-H), 1442 (C-H); MS (EI, 70 ev) m/z: 542
[M+], 498, 262, 208, 150; 1H-NMR (DMSO-d6) d: 1.83 (s, 3H, CH3CO-),
2.94–3.01 (m, 4H, -CON(CH2CH2)2N-), 3.61–3.77 (m, 7H,
-NCH2CH(OCON)CH2NHAc, -CON(CH2CH2)2N- and -NCH2CH(O-
CON)CH2NHAc), 4.08 (m, 1H, -NCH2CH(OCON)CH2NHAc), 4.22 (d,
J = 5.7 Hz, 2H, ArCONHCH2CON-), 4.68–4.72 (m, 1H, -NCH2CH(O-
CON)CH2NHAc), 7.07 (t, J = 9.3 Hz, 1H, Ar-H), 7.17 (dd, J1 = 8.7 Hz,
J2 = 2.1 Hz, 1H, Ar-H), 7.49 (dd, J1 = 14.7 Hz, J2 = 2.4 Hz, 1H, Ar-H),
8.09 (d, J = 8.7 Hz, 2H, Ar-H), 8.32 (d, J = 8.7 Hz, 2H, Ar-H);13C-NMR
(DMSO-d6) d: 22.65, 41.23, 41.60, 41.73, 44.39, 47.47, 50.43, 50.83,
71.68, 106.52, 106.86, 114.17, 119.89, 123.63, 128.79, 135.31,
139.77, 149.08, 154.03, 164.83, 166.65, 169.97; HRMS (EI+) calcd.
for C25H27FN6O7 (M+): 542.1920, found: 542.1922.
(S)-N-[[3-[3-Fluoro-4-[4-[2-(4-
methylbenzamido)acetyl]piperazin-1-yl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]acetamide 11c
The compound was prepared via a procedure similar to 11a with
2-(4-methylbenzamido)acetic acid. White solid, yield: 14.7%;
m.p.: 225–2278C; IR (cm– 1): 3414 (N-H), 2919 (C-H), 1742 (C=O),
1721 (C=O), 1672 (C=O), 1640 (C=O), 1617 (C=C), 1554 (C=C), 1518
(C=C), 1475 (C-H), 1440 (C-H); MS (EI, 70 ev) m/z: 511 [M+], 467, 262,
208, 119, 91;1H-NMR (CDCl3 + CD3OD) d: 2.00 (s, 3H, CH3CO-), 2.40
(s, 3H, 4-CH3C6H4-), 3.07–3.11 (m, 4H, -CON(CH2CH2)2N-), 3.56–
3.70 (m, 2H, -NCH2CH(OCON)CH2NHAc), 3.74–3.82 (m, 5H,
-CON(CH2CH2)2N- and -NCH2CH(OCON)CH2NHAc), 4.05 (m, 1H,
(S)-N-[[3-[3-Fluoro-4-[4-[2-(4-tert-
butylbenzamido)acetyl]piperazin-1-yl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]acetamide 11f
The compound was prepared via a procedure similar to 11a with
2-(4-tert-butylbenzamido)acetic acid. White solid, yield: 44.3%;
m.p.: 199–2018C; IR (cm– 1): 3415 (N-H), 2929 (C-H), 2855 (C-H),
1747 (C=O), 1650 (C=O), 1618 (C=C), 1549 (C=C), 1521 (C=C), 1474
(C-H), 1441 (C-H), 1420 (C-H); MS (EI, 70 ev) m/z: 553 [M+], 509, 262,
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Arch. Pharm. Chem. Life Sci. 2009, 342, 377–385
Eperezolid Analogs with Glycinyl Substitutions
383
208, 161; 1H-NMR (CDCl3 + CD3OD) d: 1.34 (s, 9H, -C(CH3)3), 2.00 (s,
3H, CH3CO-), 3.05–3.11 (m, 4H, -CON(CH2CH2)2N-), 3.56–3.61 (m,
(S)-N-[[3-[3-Fluoro-4-[4-[2-(thiophene-2-
carboxamido)acetyl]piperazin-1-yl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]acetamide 11i
2H,
-NCH2CH(OCON)CH2NHAc),
3.65–3.82
(m,
2H,
-CON(CH2CH2)2N-), 3.75 (dd, J1 = 6.6 Hz, J2 = 8.0 Hz, 1H, -NCH2CH(O-
CON)CH2NHAc), 3.81–3.84 (m, 2H, -CON(CH2CH2)2N-), 4.03 (t, J =
9.0 Hz, 1H, -NCH2CH(OCON)CH2NHAc), 4.28 (s, 2H, ArCONHCH2-
CON-), 4.74–4.76 (m, 1H, -NCH2CH(OCON)CH2NHAc), 6.92 (t, J =
9.0 Hz, 1H, Ar-H), 7.07 (dd, J1 = 1.8 Hz, J2 = 8.7 Hz, 1H, Ar-H), 7.42-
7.44 (m, 1H, Ar-H), 7.47 (d, J = 8.4 Hz, 2H, Ar-H), 7.76 (d, J = 8.4 Hz,
2H, Ar-H); 13C-NMR (CDCl3 + CD3OD) d: 22.61, 31.06, 34.90, 41.45,
41.88, 42.17, 44.64, 47.72, 50.33, 50.64, 72.09, 107.30, 107.64,
113.94, 119.47, 125.37, 126.73, 130.48, 133.39, 135.59, 135.72,
154.62, 166.62, 167.41, 171.68; HRMS (EI+) calcd. for C29H36FN5O5
(M+): 553.2695, found: 553.2695.
The compound was prepared via a procedure similar to 11a with
2-(thiophene-2-carboxamido) acetic acid. White solid, yield:
53.2%; m.p.: 231–2338C; IR (cm– 1): 3414 (N-H), 3074 (Ar-H), 2923
(C-H), 2852 (C-H), 1732 (C=O), 1673 (C=O), 1645 (C=O), 1536 (C=C),
1517 (C=C), 1474 (C-H), 1444 (C-H), 1416 (C-H); MS (EI, 70 ev) m/z:
1
503 [M+], 459, 262, 208, 111; H-NMR (CDCl3 + CD3OD) d: 2.00 (s,
3H, CH3CO-), 2.40 (s, 3H, 4-CH3C6H4-), 3.07–3.11 (m, 4H,
-CON(CH2CH2)2N-), 3.56–3.65 (m, 2H, -NCH2CH(OCON)CH2NHAc),
3.69–3.73 (m, 2H, -CON(CH2CH2)2N-), 3.75–3.78 (m, 1H,
-NCH2CH(OCON)CH2NHAc), 3.79-3.83 (m, 2H, -CON(CH2CH2)2N-),
4.05 (m, 1H, -NCH2CH(OCON)CH2NHAc), 4.27 (s, 2H, ArCONHCH2-
CON-), 4.74–4.76 (m, 1H, -NCH2CH(OCON)CH2NHAc), 6.94 (t, J =
9.0 Hz, 1H, Ar-H), 7.07-7.10 (m, 2H, Ar-H), 7.44 (dd, J1 = 14.1 Hz, J2 =
2.7 Hz, 1H, Ar-H), 7.50 (d, J = 3.9 Hz, 1H, thiophene-H), 7.62 (dd, J1
= 3.6 Hz, J2 = 1.2 Hz, 1H, thiophene-H); 13C-NMR (CDCl3 + CD3OD)
d: 22.60, 41.32, 41.88, 42.21, 44.69, 47.72, 50.32, 50.65, 72.10,
107.31, 107.66, 113.92, 119.49, 127.59, 128.54, 130.30, 135.72,
137.83, 154.66, 166.44; HRMS (EI+) calcd. for C23H26FN5O5S (M+):
503.1633, found: 503.1632.
(S)-N-[[3-[3-Fluoro-4-[4-[2-
isonicotinamidoacetyl]piperazin-1-yl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]acetamide 11g
The compound was prepared via a procedure similar to 11a with
2-(isonicotinamido)acetic acid. White solid, yield: 24.6%; m.p.:
223–2258C; IR (cm– 1): 3414 (N-H), 3089 (Ar-H), 2925 (C-H), 1736
(C=O), 1679 (C=O), 1640 (C=O), 1551 (C=C), 1517 (C=C), 1481 (C-H),
1448 (C-H), 1419 (C-H); MS (EI, 70 ev) m/z: 498 [M+], 454, 262, 208,
106, 78; 1H-NMR (CDCl3 + CD3OD) d: 2.00 (s, 3H, CH3CO-), 3.05–
3.12 (m, 4H, -CON(CH2CH2)2N-), 3.57–3.61 (m, 2H, -NCH2CH(O-
CON)CH2NHAc), 3.65–3.68 (m, 2H, -CON(CH2CH2)2N-), 3.75 (dd, J1
= 6.6 Hz, J2 = 9.0 Hz, 1H, -NCH2CH(OCON)CH2NHAc), 3.83 (m, 2H,
-CON(CH2CH2)2N-), 4.03 (t, J = 9.0 Hz, 1H, -NCH2CH(OCON)CH2N-
HAc), 4.30 (s, 2H, ArCONHCH2CON-), 4.74–4.78 (m, 1H,
-NCH2CH(OCON)CH2NHAc), 6.92 (t, J = 9.0 Hz, 1H, Ar-H), 7.07 (dd,
J1 = 2.4 Hz, J2 = 9.0 Hz, 1H, Ar-H), 7.45 (dd, J1 = 2.4 Hz, J2 = 14.7 Hz,
1H, Ar-H), 7.72 (d, J = 6.0 Hz, 2H, Ar-H), 8.71 (d, J = 6.0 Hz, 2H, Ar-
H); 13C-NMR (CDCl3 + CD3OD) d: 22.61, 41.46, 41.86, 42.25, 44.71,
47.71, 50.28, 50.64, 72.11, 107.31, 107.65, 113.94, 119.50, 121.08,
133.33, 133.47, 135.62, 140.95, 150.02, 154.62, 166.11, 171.68;
HRMS (EI+) calcd. for C24H27FN6O5 (M+): 498.2021, found: 498.2023.
(S)-N-[[3-[3-Fluoro-4-[4-[2-
(phenylsulfonamido)acetyl]piperazin-1-yl]phenyl]-2-oxo-
5-oxazolidinyl]methyl]acetamide 11j
The compound was prepared via a procedure similar to 11a with
2-(phenylsulfonamido)acetic acid. White solid, yield: 24.4%;
m.p.: 72–738C; IR (cm– 1): 3413 (N-H), 2922 (C-H), 1752 (C=O),
1641 (C=O), 1548 (C=C), 1517 (C=C), 1481 (C-H), 1445 (C-H); MS (EI,
70 ev) m/z: 533 [M+], 489, 208, 77; 1H-NMR (CDCl3 + CD3OD) d: 2.00
(s, 3H, CH3CO-), 2.97–3.05 (m, 4H, -CON(CH2CH2)2N-), 3.46–3.49
(m, 2H, -CON(CH2CH2)2N-), 3.56–3.61 (m, 2H, -NCH2CH(O-
CON)CH2NHAc), 3.67–3.70 (m, 2H, -CON(CH2CH2)2N-), 3.74 (dd, J1
= 6.6 Hz, J2 = 9.0 Hz, 1H, -NCH2CH(OCON)CH2NHAc), 3.81 (s, 2H,
PhSO2NHCH2CON-), 4.02 (t, J = 9.0 Hz, 1H, -NCH2CH(OCON)CH2N-
HAc), 4.74-4.76 (m, 1H, -NCH2CH(OCON)CH2NHAc), 6.87 (t, J =
9.0 Hz, 1H, Ar-H), 7.04–7.08 (m, 1H, Ar-H), 7.42 (dd, J1 = 14.1 Hz, J2
= 2.7 Hz, 1H, Ar-H), 7.51–7.58 (m, 3H, Ar-H), 7.85–7.87 (m, 2H,
Ar-H); 13C-NMR (CDCl3 + CD3OD) d: 22.58, 41.84, 42.25, 43.53,
44.63, 47.71, 50.13, 50.48, 72.09, 107.26, 107.60, 113.93, 119.44,
126.91, 128.96, 132.68, 135.41, 135.53, 138.82, 154.61, 165.24,
171.71; HRMS (EI+) calcd. for C24H28FN5O6S (M+): 533.1739, found:
533.1734.
(S)-N-[[3-[3Ffluoro-4-[4-[2-(furan-2-
carboxamido)acetyl]piperazin-1-yl-phenyl]-2-oxo-5-
oxazolidinyl]methyl]acetamide 11h
The compound was prepared via a procedure similar to 11a with
2-(furan-2-carboxamido)acetic acid. White solid, yield: 34.9%;
m.p.: 231–2338C; IR (cm– 1): 2927 (C-H), 1748 (C=O), 1672 (C=O),
1642 (C=O), 1596 (C=C), 1545 (C=C), 1517 (C=C), 1470 (C-H), 1443
(C-H), 1427 (C-H); MS (EI, 70 ev) m/z: 487 [M+], 443, 306, 208, 95; 1H-
NMR (CDCl3 + CD3OD) d: 2.00 (s, 3H, CH3CO-), 3.07–3.11 (m, 4H,
-CON(CH2CH2)2N-), 3.56-3.61 (m, 2H, -NCH2CH(OCON)CH2NHAc),
3.64–3.75 (m, 2H, -CON(CH2CH2)2N-), 3.70–3.77 (m, 1H,
-NCH2CH(OCON)CH2NHAc), 3.82–3.90 (m, 2H, -CON(CH2CH2)2N-),
4.05 (m, 1H, -NCH2CH(OCON)CH2NHAc), 4.28 (s, 2H, ArCONHCH2-
CON-), 4.75–4.76 (m, 1H, -NCH2CH(OCON)CH2NHAc), 6.50 (dd, J1 =
3.6 Hz, J2 = 1.8 Hz, 1H, furan-H), 6.94 (t, J = 9.0 Hz, 1H, Ar-H), 7.07
(dd, J1 = 3.6 Hz, J2 = 0.9 Hz, 1H, Ar-H), 7.13 (d, J = 3.6 Hz, 1H, furan-
H), 7.45 (dd, J1 = 14.1 Hz, J2 = 2.4 Hz, 1H, Ar-H), 7.49 (d, J = 1.8 Hz,
1H, furan-H); 13C-NMR (CDCl3 + CD3OD) d: 22.62, 40.72, 41.90,
42.21, 44.67, 47.74, 50.31, 50.66, 72.12, 107.67, 109.66, 111.92,
113.92, 114.52, 119.49, 133.26, 133.41, 135.61, 144.37, 147.05,
154.65, 166.17, 171.68; HRMS (EI+) calcd. for C23H26FN5O6 (M+):
487.1862, found: 487.1863.
(S)-N-[[3-[3-Fluoro-4-[4-[2-(4-
methylphenylsulfonamido)acetyl]piperazin-1-yl]phenyl]-
2-oxo-5-oxazolidinyl]methyl]acetamide 11k
The compound was prepared via a procedure similar to 11a with
2-(4-methylphenylsulfonamido) acetic acid. White solid, yield:
49.5%; m.p.: 89–908C; IR (cm– 1): 3413 (N-H), 2923 (C-H), 1753
(C=O), 1658 (C=O), 1548 (C=C), 1516 (C=C), 1481 (C-H), 1441 (C-H);
MS (EI, 70 ev) m/z: 547 [M+], 503, 208, 91;1H-NMR (CDCl3 + CD3OD)
d: 2.00 (s, 3H, CH3CO-), 2.42 (s, 3H, CH3C6H4-), 2.94–3.00 (m, 4H,
-CON(CH2CH2)2N-), 3.46–3.49 (m, 2H, -CON(CH2CH2)2N-), 3.56–
3.62 (m, 2H, -NCH2CH(OCON)CH2NHAc), 3.65–3.72 (m, 2H,
-CON(CH2CH2)2N-), 3.74–3.78 (m, 1H, -NCH2CH(OCON)CH2NHAc),
3.78 (s, 2H, ArSO2NHCH2CON-), 4.02 (t, J = 9.0 Hz, 1H, -NCH2CH(O-
CON)CH2NHAc), 4.73–4.76 (m, 1H, -NCH2CH(OCON)CH2NHAc),
6.88 (t, J = 9.0 Hz, 1H, Ar-H), 7.04–7.08 (m, 1H, Ar-H), 7.32 (d, J =
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X. Wang et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 377–385
6.6 Hz, 2H, Ar-H), 7.43 (dd, J1 = 14.1 Hz, J2 = 2.7 Hz, 1H, Ar-H), 7.74
(dd, J1 = 6.6 Hz, J2 = 1.8 Hz, 2H, Ar-H); 13C-NMR (CDCl3 + CD3OD) d:
22.46, 24.83, 41.85, 42.22, 43.48, 44.62, 47.72, 50.11, 50.46,
72.06, 107.24, 107.59, 113.91, 119.38, 126.94, 129.54, 133.27,
133.40, 135.39, 135.51, 135.68, 143.56, 154.66, 165.30, 171.84;
HRMS (EI+) calcd. for C25H30FN5O6S (M+): 547.1895, found:
547.1898.
3.61 (m, 4H, -CON(CH2CH2)2N- and -NCH2CH(OCON)CH2NHAc),
3.72–3.76 (m, 1H, -NCH2CH(OCON)CH2NHAc), 3.77–3.83 (m, 2H,
-CON(CH2CH2)2N-), 4.03 (t, J = 9.0 Hz, 1H, -NCH2CH(OCON)CH2N-
HAc), 4.08 (s, 2H, CH3CONHCH2CON-), 4.73–4.77 (m, 1H,
-NCH2CH(OCON)CH2NHAc), 6.91 (t, J = 9.0 Hz, 1H, Ar-H), 7.07 (dd,
J1 = 8.7 Hz, J2 = 2.1 Hz, 1H, Ar-H), 7.44 (dd, J1 = 14.1 Hz, J2 = 2.4 Hz,
1H, Ar-H); 13C-NMR (CDCl3 + CD3OD) d: 22.57, 22.64, 41.07, 41.87,
42.10, 44.60, 47.72, 50.29, 50.61, 72.10, 107.29, 107.63, 113.93,
119.45, 133.39, 135.68, 154.63, 166.48, 170.65, 171.72; HRMS
(EI+) calcd. for C20H26FN5O5 (M+): 435.1912, found: 435.1913.
(S)-N-[[3-[3-Fluoro-4-[4-[2-(4-
fluorophenylsulfonamido)acetyl]piperazin-1-yl]phenyl]-2-
oxo-5-oxazolidinyl]methyl]acetamide 11l
(S)-N-[[3-[6-[4-[2-(Benzamido)acetyl]piperazin-1-yl]-
The compound was prepared via a procedure similar to 11a with
2-(4-fluorophenylsulfonamido) acetic acid. White solid, yield:
24.1%; m.p.: 96–988C; IR (cm– 1): 3414 (N-H), 2925 (C-H), 1754
(C=O), 1640 (C=O), 1618 (C=C), 1548 (C=C), 1516 (C=C), 1493 (C-H),
1442 (C-H); MS (EI, 70 ev) m/z: 551 [M+], 507, 208, 159; 1H-NMR
(CDCl3 + CD3OD) d: 2.00 (s, 3H, CH3CO-), 2.97–3.02 (m, 4H,
-CON(CH2CH2)2N-), 3.49–3.53 (m, 2H, -CON(CH2CH2)2N-), 3.57–
3.62 (m, 2H, -NCH2CH(OCON)CH2NHAc), 3.65–3.71 (m, 2H,
-CON(CH2CH2)2N-), 3.73–3.77 (m, 1H, -NCH2CH(OCON)CH2NHAc),
3.81 (s, 2H, ArSO2NHCH2CON-), 4.03 (t, J = 9.0 Hz, 1H, -NCH2CH(O-
CON)CH2NHAc), 4.75–4.79 (m, 1H, -NCH2CH(OCON)CH2NHAc),
6.89 (t, J = 9.0 Hz, 1H, Ar-H), 7.06 (d, J = 8.7 Hz, 1H, Ar-H), 7.19 (d, J
= 8.7 Hz, 2H, Ar-H), 7.44 (d, J = 14.1 Hz, 1H, Ar-H), 7.89 (dd, J1 =
8.7 Hz, J2 = 5.1 Hz, 2H, Ar-H); 13C-NMR (CDCl3 + CD3OD) d: 22.45,
41.83, 42.24, 43.49, 44.63, 47.70, 50.10, 50.49, 72.09, 107.25,
107.60, 113.92, 116.00, 116.30, 119.42, 129.62, 129.75, 133.44,
135.00, 135.38, 135.50, 154.68, 165.19, 171.86; HRMS (EI+) calcd.
for C24H27F2N5O6S (M+): 551.1645, found: 551.1642.
pyridine-3-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide 12a
To a solution of (S)-N-[[3-[6-(piperazin-1-yl)pyridine-3-yl]-2-oxo-5-
oxazolidinyl]methyl]acetamide (0.159 g, 0.5 mmol) and 2-benza-
midoacetic acid (0.095 g, 0.5 mmol) in DMF (10 mL), was added
DCC (150 mg, 0.73 mmol) under stirring. The reaction mixture
was stirred at room temperature overnight. After the solvent
was evaporated under vacuum, the residue was purified by col-
umn chromatography over silica gel (CH2Cl2 l CH2Cl2 / CH3OH =
20 : 1) to give 12a as a white solid (0.067 g, 17.1%). IR (cm– 1): 2924
(C-H), 2854 (C-H), 1743 (C=O), 1639 (C=O), 1619 (C=C), 1563 (C=C),
1549 (C=C), 1500 (C=C), 1431 (C-H); MS (EI, 70 ev) m/z: 480 [M+],
436, 245, 219, 191, 105, 77; 1H-NMR (CDCl3) d: 2.01 (s, 3H, CH3CO-
), 3.52–3.65 (m, 8H, -CON(CH2CH2)2N-, -NCH2CH(OCON)CH2NHAc
and -CON(CH2CH2)2N-), 3.66–3.81 (m, 3H, -CON(CH2CH2)2N- and
-NCH2CH(OCON)CH2NHAc), 4.02 (t, J = 9.0 Hz, 1H, -NCH2CH(O-
CON)CH2NHAc), 4.30 (d, J = 3.9 Hz, 2H, ArCONHCH2CON-), 4.76–
4.80 (m, 1H, -NCH2CH(OCON)CH2NHAc), 6.42 (t, J = 6.3 Hz, 1H, Ar-
H), 6.68 (d, J = 9.0 Hz, 1H, Ar-H), 7.38 (m, 1H, Ar-H), 7.42–7.50 (m,
2H, Ar-H), 7.82–7.90 (m, 2H, Ar-H), 8.15 (d, J = 2.7 Hz, 1H, Ar-H);
13C-NMR (CDCl3) d: 23.14, 41.68, 41.80, 42.06, 44.08, 45.33, 47.71,
72.29, 107.36, 126.29, 126.96, 128.48, 129.70, 131.60, 133.69,
138.24, 154.69, 155.74, 166.61, 167.09, 170.93; HRMS (EI+) calcd.
for C24H28N6O5 (M+): 480.2116, found: 480.2111.
(S)-N-[[3-[3-Fluoro-4-[4-[2-(thiophene-2-
sulfonamido)acetyl]piperazin-1-yl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]acetamide 11m
The compound was prepared via a procedure similar to 11a with
2-(thiophene-2-sulfonamido)acetic acid. White solid, yield:
29.7%; m.p.: 91–938C; IR (cm– 1): 3414 (N-H), 2922 (C-H), 1752
(C=O), 1640 (C=O), 1618 (C=C), 1548 (C=C), 1517 (C=C), 1482 (C-H),
1441 (C-H); MS (EI, 70 ev) m/z: 539 [M+], 495, 208, 147, 84; 1H-NMR
(CDCl3 + CD3OD) d: 2.00 (s, 3H, CH3CO-), 2.96–3.02 (m, 4H,
-CON(CH2CH2)2N-), 3.50–3.53 (m, 2H, -CON(CH2CH2)2N-), 3.56–
3.62 (m, 2H, -NCH2CH(OCON)CH2NHAc), 3.69–3.73 (m, 2H,
-CON(CH2CH2)2N-), 3.75–3.78 (m, 1H, -NCH2CH(OCON)CH2NHAc),
3.89 (s, 2H, ArSO2NHCH2CON-), 4.02 (t, J = 9.0 Hz, 1H, -NCH2CH(O-
CON)CH2NHAc), 4.73-4.77 (m, 1H, -NCH2CH(OCON)CH2NHAc),
6.89 (t, J = 9.0 Hz, 1H, Ar-H), 7.04 (d, J = 9.0 Hz, 1H, Ar-H), 7.09 (d, J
= 3.9 Hz, 1H, thiophene-H), 7.43 (dd, J1 = 14.1 Hz, J2 = 2.7 Hz, 1H,
Ar-H), 7.59–7.62 (m, 2H, Ar-H); 13C-NMR (CDCl3 + CD3OD) d: 22.62,
41.88, 42.33, 43.80, 44.69, 47.73, 50.20, 50.55, 72.12, 107.32,
107.66, 109.65, 113.96, 119.49, 127.37, 132.01, 132.21, 135.58,
139.69, 154.63, 165.09, 171.69; HRMS (EI+) calcd. for
C22H26FN5O6S2 (M+): 539.1303, found: 539.1300.
(S)-N-[[3-[6-[4-[2-(4-Methylbenzamido)acetyl]piperazin-
1-yl]pyridine-3-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide
12c
The compound was prepared via a procedure similar to 12a with
2-(4-methylbenzamido)acetic acid. White solid, yield: 17.2%; MS
(EI, 70 ev) m/z: 494 [M+], 450, 245, 219, 191, 119; 1H-NMR (CDCl3 +
CD3OD) d: 2.01 (s, 3H, CH3CO-), 2.41 (s, 3H, CH3C6H4-), 3.56–3.62
(m, 8H, -CON(CH2CH2)2N-, -NCH2CH(OCON)CH2NHAc and
-CON(CH2CH2)2N-), 3.63–3.70 (m, 1H, -NCH2CH(OCON)CH2NHAc),
3.78–3.80 (m, 2H, -CON(CH2CH2)2N-), 4.07 (t, J = 9.0 Hz, 1H,
-NCH2CH(OCON)CH2NHAc), 4.29 (s, 2H, ArCONHCH2CON-), 4.78–
4.80 (m, 1H, -NCH2CH(OCON)CH2NHAc), 6.79 (d, J = 9.3 Hz, 1H, Ar-
H), 7.26 (d, J = 8.1 Hz, 2H, Ar-H), 7.73 (d, J = 8.1 Hz, 2H, Ar-H), 7.86
(dd, J1 = 2.7 Hz, J2 = 9.3 Hz, 1H), 8.18 (d, J = 2.7 Hz, 1H); 13C-NMR
(CDCl3 + CD3OD) d: 21.00, 22.01, 41.21, 41.41, 41.80, 43.93, 45.04,
72.25, 107.59, 126.68, 128.86, 130.08, 130.20, 138.07, 142.10,
154.39, 166.91; HRMS (EI+) calcd. for C25H30N6O5 (M+): 494.2272,
found: 494.2275.
(S)-N-[[3-[3-Fluoro-4-[4-(2-acetamidoacetyl)piperazin-1-
yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide 11n
The compound was prepared via a procedure similar to 11a with
2-acetamidoacetic acid. White solid, yield: 35.1%; m.p.: 227–
2298C; IR (cm– 1): 3414 (N-H), 3075 (Ar-H), 2927 (C-H), 2853 (C-H),
1751 (C=O), 1675 (C=O), 1632 (C=O), 1554 (C=C), 1519 (C=C), 1481
(C-H), 1441 (C-H); MS (EI, 70 ev) m/z: 435 [M+], 391, 306, 262, 208,
(S)-N-[[3-[6-[4-[2-(4-Nitrobenzamido)acetyl]piperazin-1-
yl]pyridine-3-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide
12e
The compound was prepared via a procedure similar to 12a with
2-(4-nitrobenzamido)acetic acid. White solid, yield: 25.6%; m.p.:
1
43; H-NMR (CDCl3 + CD3OD) d: 2.00 (s, 3H, CH3CO-), 2.06 (s, 3H,
CH3CONHCH2CO-), 3.02–3.05 (m, 4H, -CON(CH2CH2)2N-), 3.56–
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2009, 342, 377–385
Eperezolid Analogs with Glycinyl Substitutions
385
231–2338C; IR (cm– 1): 3413 (N-H), 1743 (C=O), 1639 (C=O), 1617,
1550, 1514, 1478, 1442, 1229; MS (EI, 70 ev) m/z: 525 [M+], 481,
245, 219, 191, 150; 1H-NMR (DMSO-d6) d: 1.84 (s, 3H, CH3CO-),
3.46–3.62 (m, 4H, -CON(CH2CH2)2N-), 3.64-3.68 (m, 2H,
-NCH2CH(OCON)CH2NHAc), 3.70–3.75 (m, 4H, -CON(CH2CH2)2N-),
3.76-3.79 (m, 1H, NCH2CH(OCON)CH2NHAc), 4.07 (t, J = 9.0 Hz,
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1H, -NCH2CH(OCON)CH2NHAc), 4.22 (d,
J = 5.7 Hz, 2H,
ArCONHCH2CON-), 4.66–4.74 (m, 1H, -NCH2CH(OCON)CH2NHAc),
6.93 (d, J = 9.3 Hz, 1H, Ar-H), 7.80 (dd, J1 = 9.0 Hz, J2 = 2.7 Hz, 1H),
8.08 (d, J = 9.0 Hz, 2H, Ar-H), 8.21 (dd, J1 = 6.3 Hz, J2 = 3.0 Hz, 1H,
Ar-H), 8.32 (d, J = 9.0 Hz, 2H, Ar-H), 8.93–8.97 (m, ArCONHCH2-
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lowest concentration of a drug that inhibits the visible bacterial
growth after incubation at 378C for 24 h. MICs were determined
by broth microdilution method in accordance with the guide-
line of the Clinical and Laboratory Standards Institute (CLSI).
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medium with 96-well plate. The compound concentration was
diluted by double fold and was kept at 16, 8, 4, 2, 1, 0.5, 0.25,
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i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com