Effects of varied substituents on the antibacterial activity of triazolylmethyl oxazolidinones

Article abstract of DOI:10.1002/ardp.201100332

A number of 1,2,3-triazolylmethyl piperazino oxazolidinone derivatives with optionally varied substituents at the 4N-piperazine position were synthesized and their antibacterial activity evaluated against a panel of susceptible and resistant Gram-positive

Full text of DOI:10.1002/ardp.201100332

Arch. Pharm. Chem. Life Sci. 2012, 000, 1–14
1
Full Paper
Effects of Varied Substituents on the Antibacterial Activity
of Triazolylmethyl Oxazolidinones
Oludotun A. Phillips1, Edet E. Udo2, Mohammed E. Abdel-Hamid1, and Reny Varghese1
1 Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Kuwait University, Safat, Kuwait
2 Faculty of Medicine, Department of Microbiology, Kuwait University, Safat, Kuwait
A number of 1,2,3-triazolylmethyl piperazino oxzalidinone derivatives with optionally varied
substituents at the 4N-piperazine position were synthesized and their antibacterial activity
evaluated against a panel of susceptible and resistant Gram-positive and selected Gram-negative
bacteria. Substitution with 5-membered heteroaroyl and dinitrobenzoyl moieties potentiated activity
against staphylococci and enterococci strains. Furthermore, the compounds having dinitrobenzoyl
7n, 7o, and 5-nitrofuroyl 7t substitutions were four- to eightfold more potent than linezolid against
M. catarrahlis. However, substitution of guanidino and other water-solubilizing functionalities at the
4N-piperazine position resulted in compounds that are devoid of antibacterial activity.
Keywords: Antibacterial activity / Gram-positive bacteria / Guanidino-oxazolidinone / Linezolid / Triazolylmethyl-
oxazolidinone
Received: September 21, 2011; Revised: May 13, 2012; Accepted: June 19, 2012
DOI 10.1002/ardp.201100332
Introduction
and vancomycin-resistant enteroccoci (VRE) [3]. Oxazolidinones
including linezolid inhibit bacterial ribosomal protein bio-
synthesis and recent studies by Duffy and coworkers [4]
revealed that linezolid binds to the A-site of the 50S subunit.
The success of linezolid in the clinic and the demonstrated
efficacy of the oxazolidinone class of antibacterial agents
against Gram-positive resistant bacteria have impelled con-
siderable interest in the pursuit for development of newer
broad-spectrum oxazolidinone derivatives.
The World Health Organization (WHO) regards antibacterial
resistance as one of the three greatest threats to human
health. In addition, a House of Lords report blatantly con-
sidered bacterial resistance a ‘‘major threat to public health’’;
while the British Society for Antimicrobial Chemotherapy
(BSAC), the Infectious Diseases Society of America (IDSA) and
the European Union continue to voice their concerns [1]. This
growing incidence of bacterial resistance world-wide poses a
major threat to the treatment of infectious diseases that were
previously readily treated, and serves as impetus for the
development of new, more effective, and less toxic antibac-
terial agents. Although bacterial resistance continues to
spread like wildfire with devastating effects, the hope for
new agents remains very bleak [1, 2]. Linezolid (Lzd, Fig. 1), is
a prototypical oxazolidinone with demonstrated activity
against Gram-positive bacteria including multidrug-resistant
strains namely, methicillin-resistant Staphylococcus aureus
(MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP)
Consequently, significant efforts have been and continue
to be expended by several research groups on the structural
modifications around the phenyl-oxazolidinone ring in order
to combat bacterial resistance [5]. We and other investigators
have demonstrated that the 4-morpholinoaryl (PH027), 4-
thiopyranoaryl (1, Fig. 1) and 4-substitued-piperazinoaryl
(2, Fig. 1) oxazolidinones containing 5-triazolyl groups have
potent antibacterial activities against Gram-positive bacteria
including resistant strains [5–9]. Furthermore, derivatives
with 4-substituted-triazolyl moiety have been shown to pos-
sess diminished monoamine oxidase (MAO) inhibition [9],
identifying these derivatives as having potentially reduced
side-effects. Further observations have shown that the anti-
bacterial activities of the 4-substituted-piperazinoaryl oxazo-
lidinones varied significantly depending on the substituent
groups at the distal 4N-piperazine position. While structure-
activity relationships of selected piperazino analogs have
Correspondence: Oludotun A. Phillips, Faculty of Pharmacy, Department
of Pharmaceutical Chemistry, Kuwait University, P. O. Box 24923, Safat
13110, Kuwait.
E-mail: dphillips@hsc.edu.kw
Fax: þ965 2534 2807
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O. A. Phillips et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–14
Figure 1. Chemical structure of oxazolidinone antibiotics.
suggested the necessity of an H-bond acceptor group at the
4N-position [5, 10]. Hence, appropriate functional group sub-
stitutions at the 4N-piperazine position are highly significant
for predicting the antibacterial activity of 4-substituted-piper-
azinoaryl oxazolidinones. We herein report the synthesis of
new 5-(4-methyl-1H-1,2,3-triazol-1-yl)methyl oxazolidinones
with optionally varied substituents at the 4N-piperazine pos-
ition, which are anticipated to enhance binding at the active
site, and thus improve antibacterial activity against suscept-
ible and multidrug-resistant Gram-positive bacteria. These
new derivatives incorporate functionalized groups bearing
hydrogen bond acceptor and/or donor moieties at the termi-
nal N-piperazine position, which may enhance interactions at
the bacterial ribosomal binding sites and may result in
extended activity towards Gram-negative bacterial strains,
such as Haemophilus influenzae and Moraxella catarrhalis.
amido 8a and 3,5-dinitrobenzyl 8b–c derivatives were
prepared by reacting 2-iodoacetamide or 3,5-dinitrobenzyl
chloride with 6b and 6a, respectively, in DMF or CH3CN at
908C. The boc-protected guanidino derivatives 10a–b were
prepared by reacting N,N-(bis(tert-butoxycarbonyl)-S-methyl
isothiourea [13] with 6b and 6a, respectively. The compounds
10a–b were deprotected in TFA to give the final water-soluble
guanidinium derivatives 11a–b.
Antibacterial evaluation
The antibacterial activities of compound 7a–t, 8a–c, 9a–c,
10a–b, and 11a–b were examined against a panel of standard
and clinical isolates of Gram-positive and selected Gram-
negative bacteria encompassing susceptible and resistant
strains (n ¼ 46). The Gram-positive clinical isolates tested
include MRSA (n ¼ 9), methicillin-susceptible S. aureus
(MSSA, n ¼ 11), methicillin-resistant coagulase-negative
staphylococci (MR-CNS, n ¼ 4), methicillin-sensitive coagu-
lase-negative staphylococci (MS-CNS, n ¼ 6), S. pneumoniae
(n ¼ 3), vancomycin-sensitive enterococci (VSE, n ¼ 7) and
VRE (n ¼ 3). Reference Gram-positive strains S. aureus ATCC
25923, Staphylococcus epidermidis ATCC 12228 and Enterococcus
faecalis ATCC 29212; and Gram-negative strains, namely,
Escherichia coli ATCC 25922, H. influenzae ATCC 49247, and
M. catarrhalis ATCC8176 were used. Antibacterial suscepti-
bility testing was performed by the agar dilution method
according to the Clinical and Laboratory Standard Institute
(CSLI) [14] and reported as minimum inhibitory concen-
trations (MIC, mg/mL). The experimental results of this in vitro
antibacterial evaluation using linezolid and vancomycin as
positive controls are summarized in Tables 1 and 2. The
Clog P and MIC values of the compounds against S. aureus
ATCC25923 in the absence and presence of 50% human
plasma are shown in Table 1. From this result all the active
compounds with the exception of linezolid, PH027, vanco-
mycin, the monoethyl malonyl (7b), and 3,5-dinitrobenzoyl
(7n) derivatives showed fourfold or higher MIC values in the
Results and discussion
Chemistry
The syntheses of the target compounds 7a–t, 8a–c, 9a–c, 10a–
b, and 11a–b are outlined in Schemes 1 and 2. The chiral
methyl substituted and unsubstituted triazolylmethyl oxa-
zolidinone intermediates 5a and 5b were obtained from the
starting piperazine 3 and 3,4-difluoronitrobenzene 4, respect-
ively, according to established literature procedures [7, 9, 11].
These intermediates 5a and 5b were deprotected to give the
TFA-salts 6a [7] and 6b [8]; and were further reacted with a
series of optionally varied aroyl chlorides, substituted acyl
chlorides, activated carboxylic acids, and arylsulfonyl
chlorides to afford the target compounds 7a–d, 7f, 7i–t,
and 9a–c. Reaction of compound 7a with 1,2-dibromoethane
and CS2 in the presence of NaH gave the cyclic 1,3-dithian-2-
ylidene derivative 7e. The deprotection of 7f gave the TFA-salt
7g, which was further reacted with CS2 in the presence of
DIEA and p-toluenesulfonyl chloride to give the isothio-
cyanate 7h, according to a literature method [12]. The acet-
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–14
Antibacterial Activity of Triazolylmethyl Oxazolidinones
3
Scheme 1. Synthesis of 5-(4-methyl-1H-1,2,3-triazolyl)methyl oxazolidinone derivatives. i. TFA/DCM, 08C-r.t.; ii. CH3CN/acid chloride/
acid anhydride/TEA, r.t.; iii. DMF or CH3CN/benzyl halide or substituted alkyl halide/TEA/908C; (iv) TEA, arylsulfonyl chloride, CH3CN,
08C-rt.
presence of 50% human plasma, indicating potentially sig-
nificant plasma binding. Results from our previous studies of
some 4N-acyl- and 4N-aroyl-substituted piperazinyl analogs
have shown that these derivatives are relatively stable in
human plasma at the experimental temperature conditions
[15]. Generally, compounds with very low and very high Clog
P values tend to be relatively less active in this series.
M. catarrahlis strain with MICs of 1 and 2 mg/mL, respectively.
These compounds (7n, 7o, and 7t) showed potent anti-
bacterial activity against M. catarrahlis with MIC values four-
to eightfold lower than linezolid, and several-fold lower than
other compounds evaluated in this study, thus suggesting
the requirement for electron withdrawing groups to enhance
antibacterial activity. However, the boc-protected guanidino
10a and 10b and their respective water-soluble derivatives
11a and 11b were devoid of antibacterial activity against
Gram-positive bacteria. Similarly, the 1,3-dithian-2-ylidene
7e and isothiocyanate 7h derivatives were also devoid of
activity. All the compounds tested were inactive against
H. influenza and E. coli bacterial strains (Table 2).
The antibacterial activity of the new oxazolidinone deriva-
tives against a panel of susceptible and resistant Gram-
positive and selected Gram-negative bacteria are presented
on Table 2 as the MICs. Most of the compounds showed potent
activity against most Gram-positive organisms tested.
Overall, the 5-membered heteroaroyl and heteroarylsulfonyl
containing derivatives 7r–7t, and 9c had enhanced antibac-
terial activity against Gram-positive bacteria, especially Conclusions
staphylococci and enterococci. In addition, dinitro group
substitutions on the arylcarbonyl moiety as found in 7n
and 7o also resulted in improved activity against similar
Gram-positive bacteria strains including streptococci, while
the dinitrobenzyl derivatives 8b and 8c were less active
against Gram-positive bacteria particularly against strepto-
cocci (MIC, 4–8 mg/mL). Worthy of note are the activities
of the 3,5-dinitrobenzoyl 7n and 7o, and nitrofuroyl 7t
derivatives against the fastidious Gram-negative bacteria
In conclusion, a series of 5-(1,2,3-triazolylmethyl) containing
piperazino oxazolidinones having optionally varied substitu-
ent groups at the piperazine 4N-position were prepared.
Most of the compounds show potent antibacterial activities
against Gram-positive bacteria pathogens. The 5-membered
heteroaroyl and the dinitrobenzoyl containing derivatives
showed comparable activity to linezolid against Gram-
positive bacteria, but were four- to eightfold more active than
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O. A. Phillips et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–14
Scheme 2. Synthesis of 5-(4-methyl-1H-1,2,3-triazolyl)methyl oxazolidinone derivatives. i. DCM/CH3CN/DCC/1-HBT/mono ethyl mal-
onate; ii. DMF/NaH/1,2-dibromoethane/CS2, 08C; iii. DCM/CH3CN/DCC/1-HBT/N-tert-butoxycarbonylglycine; iv. TFA/DCM, 08C-r.t.; v.
DCM/DIEA/CS2/4-tolyl SO2Cl, S7 to 08C-r.t.; vi. DMF/N,N-(bis(tert-butoxycarbonyl)-S-methyl isothiourea/TEA, r.t.; vii. TFA/DCM, 08C-r.t.
8c, and 9c, were recorded on a Bruker Avance II 600 NMR
linezolid against the fastidious Gram-negative bacteria M.
spectrometer. The 13C NMR experiments performed included
catarrahlis. The highly hydrophilic guanidine derivatives were
13C NMR decoupled, 13C-DEPT-135 (distortionless enhancement
inactive against the Gram-positive and Gram-negative bac-
by polarization transfer-139) and 13C-APT (attached proton test).
teria strains tested in this study.
Chemical shifts of protons are reported in parts per million
(ppm) downfield from tetramethylsilane (TMS) as an internal
reference or DMSO-d6 (d ¼ 2.5; 39.7) as solvent. Mass spectra were
recorded on a Finnigan MAT INCOS XL mass spectrometer.
Infrared (IR) spectra were recorded on a Perkin Elmer System
2000 FT-IR spectrometer. Elemental analyses were performed on
a LECO elemental analyzer CHNS 932 apparatus, and analyses
indicated by the symbols of the elements were within ꢀ0.4% of
the theoretical values. Analyses were performed by the Science
Analytical Facilities (SAF), Faculty of Science, Kuwait University,
Kuwait. The structures of the oxazolidinones and their Clog P
values were sketched and estimated, respectively, using the
CambridgeSoft ChemDraw Ultra 8.0 software.
Experimental
Characterization
Column chromatography was carried out with silica gel
(Kieselgel 60, 70–230 mesh; Aldrich) and TLC was conducted
on 0.25 mm pre-coated silica gel plates (60F254, Merck).
Melting points were determined on a Stuart Scientific SMP1
melting point apparatus and were uncorrected. 1H NMR spectra
were recorded on a Bruker Avance II 600 NMR spectrometer. In
addition, the 13C NMR spectra of representative compounds, 7t,
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–14
Antibacterial Activity of Triazolylmethyl Oxazolidinones
5
Table 1. Clog P values and antibacterial activities of 5-(1H-1,2,3-triazolyl)methyl oxazolidinones against S. aureus standard strain
ATCC25923.
2
O
R
O
1
R
N
N
N
N
N
N
Compd
7a
R1
R2
Clog P values
MIC against ATCC 25923
Without plasma
þ50% plasma
O
O
O
CH3
0.1688
2
16
O
O
b
H
ꢁ0.1002
4
8
O
O
c
CH3
CH3
CH3
ꢁ0.1342
0.6208
2.6234
2
2
8
8
16
32
H3COOC
O
d
e
C2H5O2C
O
O
O
S
S
O
f
CH3
CH3
0.6456
4
16
Boc HN
O
g
ꢁ0.0982
64
>64
H3N+
-
CF3CO2
O
h
i
CH3
CH3
CH3
0.0670
1.1024
1.6724
16
32
16
32
S
C
N
O
F
1
O
j
1
Cl
continued
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O. A. Phillips et al.
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Table 1. (continued )
2
O
R
O
1
R
N
N
N
N
N
N
Compd
R1
R2
Clog P values
MIC against ATCC 25923
Without plasma
þ50% plasma
>64
O
k
CH3
0.7888
2
O2N
O
l
CH3
1.3828
2
>64
H3C
O
m
CH3
CH3
1.1037
0.5885
2
4
8
4
H3CO
O
n
O2
N
NO2
O
o
H
0.3195
1
8
O2
N
NO2
O
p
q
CH3
CH3
ꢁ0.2172
ꢁ0.2172
1
2
2
8
N
O
N
O
r
s
CH3
CH3
0.0598
0.8903
0.5
0.5
8
4
O
C
S
O
continued
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–14
Table 1. (continued )
Antibacterial Activity of Triazolylmethyl Oxazolidinones
7
2
O
R
O
1
R
N
N
N
N
N
N
Compd
t
R1
R2
Clog P values
ꢁ0.0352
MIC against ATCC 25923
Without plasma
þ50% plasma
O
CH3
0.5
4
O2
N
O
H2N
8a
b
CH3
CH3
ꢁ.06470
2
8
16
16
O
H2C
1.7388
O2N
NO2
H2C
c
H
1.4698
1.6138
2
4
16
16
O2N
NO2
O
S
9a
CH3
O
O
S
b
c
CH3
CH3
1.8438
1.5648
>64
>64
H3C
O
O
S
1
16
S
O
O
C
10a
b
CH3
H
3.6508
3.3818
16
16
>64
>64
O
HN
O
C
N
O
H2N
11a
CH3
ꢁ0.0899
32
64
. CF3 COOH
HN
continued
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Table 1. (continued )
2
O
R
O
1
R
N
N
N
N
N
N
Compd
R1
R2
Clog P values
ꢁ0.1791
MIC against ATCC 25923
Without plasma
þ50% plasma
>64
H2N
b
H
64
CF COOH
.
HN
3
O
PH027
0.631
0.532
n/d
1
2
2
1
2
2
O
O
N
N
N
N
N
F
O
Lzd
O
H
N
O
N
N
F
O
Van
(d, 2H, J ¼ 5.2 Hz, CH2), 4.18 (t, 1H, J ¼ 9.2 Hz, oxazolidinone H),
4.11 (q, 2H, J ¼ 7.1 Hz, CH3CH2), 3.83 (dd, 1H, J ¼ 5.9 Hz, 9.0 Hz,
oxazolidinone H), 3.57–3.62 (m, 6H, piperazine H overlapping
with the –CH2 signal), 2.93–2.98 (m, 4H, piperazine H), 2.28 (s, 3H,
triazole CH3), 1.19 (t, 3H, J ¼ 7.1 Hz, CH3). IR (KBr pellet, cmꢁ1):
n 2930, 1744, 1641, 1519, 1446, 1417, 1326, 1219, 1160, 1098,
1054. MS 474.4 (Mþ). Anal calcd for C22H27FN6O5: C: 55.69,
H: 5.74, N: 17.71; found C: 55.30, H: 6.00, N: 17.41.
Syntheses
General procedure for the synthesis of compounds 7a–d,
7f, 7i–s, and 9a–c
A solution of compound 6a (700 mg, 1.52 mmol) or 6b (1.0 g,
2.11 mmol) in CH3CN (20 mL) and TEA (1.0 mL) was treated with
1.1 equiv. of suitable activated acid (activated by reaction with
DCC, 1-hydroxybenzotriazole, or oxalyl chloride) or acid anhydride
or acid chloride or the arylsulfonyl chloride under stirring at 08C.
The reaction mixture was stirred to r.t. overnight. The reaction
mixture was concentrated on a rotovap to give a crude, which was
dissolved in DCM (30 mL), washed successively with water, dilute
aq. Na2CO3 solution (15 mL), water, dried (anhydrous Na2SO4),
filtered and concentrated to obtain a crude. The crude was purified
either by silica gel column chromatography and/or recrystallized
from a suitable organic solvent to give the respective products.
(R)-Ethyl 3-(4-(4-(5-((1H-1,2,3-triazol-1-yl)methyl)-2-
oxooxazolidin-3-yl)-2-fluorophenyl) piperazin-1-yl)-3-
oxopropanoate 7b
Prepared via the general procedure from compound 6a and mono-
ethyl malonate (2.31 mmol) activated by DCC and 1-HOBT. Silica
gel column chromatography (EtOAc/MeOH ¼ 9:1) gave a solid,
yield: 37%; m.p.: 168–1708C. 1H NMR (DMSO-d6): d 8.16 (s, 1H,
triazole H), 7.76 (s, 1H, triazole H), 7.42 (dd, 1H, J ¼ 2.5 Hz,
14.7 Hz, phenyl H), 7.13 (dd, 1H, J ¼ 2.0 Hz, 8.4 Hz, phenyl H),
7.06 (t, 1H, J ¼ 9.4 Hz, phenyl H), 5.11–5.13 (m, 1H, oxazolidinone
H), 4.82 (d, 2H, J ¼ 5.1 Hz, CH2), 4.20 (t, 1H, J ¼ 9.3 Hz, oxazoli-
dinone H), 4.10 (q, 2H, J ¼ 7.1, 14.2 Hz, CH3CH2), 3.85 (dd, 1H,
J ¼ 5.8, 9.4 Hz, oxazolidinone H), 3.54–3.62 (m, 6H, piperazine H
overlapping with the –CH2 signal), 2.92–2.98 (m, 4H, piperazine
H), 1.20 (t, 3H, J ¼ 7.1 Hz, CH3). IR (KBr pellet, cmꢁ1): n 2981, 2906,
1750, 1632, 1518, 1475, 1417, 1327, 1227, 1188, 1164, 1099, 1074,
1032. MS 460.4 (Mþ); Anal calcd for C21H25FN6O5: C: 54.78, H: 5.47,
N: 18.25; found C: 54.70, H: 4.99, N: 18.23.
(R)-Ethyl 3-(4-(2-fluoro-4-(5-((4-methyl-1H-1,2,
3-triazol-1-yl)methyl)-2-oxooxazolidin-3-yl)
phenyl)-piperazin-1-yl)-3-oxopropanoate 7a
Prepared via the general procedure from compound 6b and
mono-ethyl malonic acid (2.31 mmoL) activated by DCC and 1-
HOBT. Silica gel column chromatography (EtOAc/MeOH ¼ 9:1)
gave a solid, yield: 35%; m.p.: 164–1668C. 1H NMR (DMSO-d6): d
7.87 (s, 1H, triazole H), 7.44 (dd 1H, J ¼ 2.4, Hz, 14.9 Hz, phenyl
H), 7.15 (dd, 1H J ¼ 2.2 Hz, 9.0 Hz, phenyl H), 7.07 (t, 1H,
J ¼ 9.4 Hz, phenyl H), 5.05–5.08 (m, 1H, oxazolidinone H), 4.74
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–14
Antibacterial Activity of Triazolylmethyl Oxazolidinones
9
Table 2. Antibacterial activities of 5-(1H-1,2,3-triazolyl)methyl oxazolidinones against Gram-positive standard strains and clinical isolates.
Compd
Minimum inhibitory concentrations (MIC’s, mg/mL) against
S. aureus
Enterococci
E. coli
H. influ
S. pn
M. cat
(n ¼ 3)
MRSA
(n ¼ 9)
MSSA
(n ¼ 11)
MRCNS
(n ¼ 4)
MSCNS
(n ¼ 6)
VSE
(n ¼ 7)
VRE
(n ¼ 3)
7a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
t
8a
b
c
9a
b
c
10a
b
11a
b
PH027
Lzd
Van
2
2–4
1–2
2–4
4–8
8
32–64
8–16
1–2
1–2
1–2
2
1–2
4
1–2
2–4
4–8
4–8
32–64
8–16
1–2
1–2
1–2
1–2
2
0.5–4
0.5–1
1–2
1
2–4
1
2–4
4–8
4–8
32–64
8–16
1
1–2
1–2
1–2
1–2
0.5
0.5–1
1–2
1–2
0.5
0.5–1
0.5–1
2–4
1–4
1–2
4
>64
0.5–1
16
8–16
16–32
16–64
0.5–1
0.5–1
1
1–2
2–4
1–2
2–4
4–8
4–8
32–64
8–16
1
1–2
1–2
1–2
1–2
0.5–4
0.5–1
1–2
2
2–4
2
2
4
2
4
4–8
8
32
8
1–2
1–2
1
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
64
32
>64
16–32
64->64
>64
64->64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
64
2–4
1
2
8
16
16
16
64
16
>64
64
32
16
8
>64
64
1
2
64
8
4
4
4–8
4–8
32–64
8–16
1–2
1–2
1
1–2
1–2
4
4–8
4–8
8–16
8–16
1–2
4
2
4
8
1–2
0.5–1
4
1
1–2
8
1
2
4
1
1–2
1–4
1
1
1–2
1–2
0.5–1
0.5–1
0.5–1
2–4
8
1–2
1–2
0.5–1
0.5
0.5–1
4
1–4
1–2
4
>64
0.5
2
1–2
1–2
1–2
0.5–1
0.5–1
0.5
4
1–4
1
2–4
>64
0.5
16
8
16
16–64
1
0.5–1
>64
0.5–1
0.5–1
0.5–1
2–4
8
2
2–4
>64
0.5–1
16–32
8–16
16–32
64
0.5–1
0.5–1
1–2
0.5–1
0.5–1
0.5–1
2–4
4
1–2
64
>64
32
16
64
2
1–2
2
32
16
32
32
32
>64
>64
64
>64
>64
>64
>16
8
>64
>64
>64
>64
>64
>64
>64
>64
>64
32
4–8
4–8
4–8
>64
4
2
2–4
>64
1
16–32
8–16
32
16–64
0.5–1
0.5–1
0.5–1
2–4
>64
0.5–1
16
8–16
16
16–64
0.5–1
0.5–1
1–2
16
16
16
8–16
16–32
16–32
0.5–1
0.5–1
0.25–2
2–16
4–16
0.5
0.5
0.5
>64
>64
>64
n/d
8
n/d
n/d
MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus; MR-CNS, methicillin-resistant coagulase-negative S.
aureus; MS-CNS, methicillin-susceptible coagulase-negative S. aureus; VRE, vancomycin-susceptible enteroccoci; VRE, vancomycin-
resistance enteroccoci; E. coli, Escherichia coli; H. inf, H. influenzae; S. pn, S. pneumoniae; M. cat, M. catarrhalis.
J ¼ 4.7 Hz, piperazine H), 2.64 (t, 2H, J ¼ 5.8 Hz, CH2), 2.54 (t, 2H,
(R)-Methyl 4-(4-(2-fluoro-4-(5-((4-methyl-1H-1,2,3-triazol-
1-yl)methyl)-2-oxooxazolidin-3-yl) phenyl)piperazin-1-yl)-
J ¼ 5.8 Hz, CH2, overlaps with DMSO signal at 2.51 ppm), 2.23
(s, 3H, triazole CH3). IR (KBr pellet, cmꢁ1): n 2998, 2949, 2831,
1744, 1638, 1518, 1439, 1419, 1371, 1325, 1279, 1220, 1167,
4-oxobutanoate 7c
Prepared via the general procedure from compound 6b and
1137, 1100, 1054, 1033. MS 474.3 (Mþ). Anal calcd for
C22H27FN6O5: C: 55.69, H: 5.74, N: 17.71; found C: 55.69,
H: 5.90, N: 17.55.
methyl chloro-4-oxobutanoate (3.25 mmol). Recrystallization
(EtOAc/hexanes) gave a solid, yield: 90%; m.p.: 138–1408C.
1H NMR (DMSO-d6): d 7.87 (s, 1H, triazole H), 7.44 (dd, 1H,
J ¼ 2.3 Hz, 14.7 Hz, phenyl H) 7.13 (dd, 1H, J ¼ 2.3 Hz, 9.0 Hz,
(R)-Ethyl 5-(4-(2-fluoro-4-(5-((4-methyl-1H-1,2,-
3-triazol-1-yl)methyl)-2-oxooxazolidin-3-yl) phenyl)-
phenyl H), 7.05 (t, 1H, J ¼ 9.0 Hz, phenyl H), 5.06–5.11 (m, 1H,
oxazolidinone H), 4.74 (d, 2H, J ¼ 5.2 Hz, CH2) 4.20 (t. 1H,
J ¼ 9.0 Hz, oxazolidinone H), 3.84 (dd, 1H, J ¼ 5.9 Hz, 9.3 Hz,
piperazin-1-yl)-5-oxopentanoate 7d
oxazolidinone H), 3.56–3.67 (m, 7H, piperazine H, overlaps with
the CH3 signal), 2.98 (t, 2H, J ¼ 4.7 Hz, piperazine H), 2.91 (t, 2H,
Prepared via the general procedure from compound 6b
and glutaric acid monoethyl ester chloride (3.25 mmol).
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

10
O. A. Phillips et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–14
Recrystallization (EtOAc/hexanes) gave a solid, yield: 58%; m.p.:
125–1278C. 1H NMR (DMSO-d6): d 7.86 (s, 1H, triazole H), 7.44 (dd,
1H, J ¼ 2.5 Hz, 14.7 Hz, phenyl H), 7.14 (dd, 1H, J ¼ 2.5 Hz,
9.0 Hz, phenyl H), 7.11 (t, 1H, J ¼ 9.0 Hz, phenyl H), 5.06–5.10
(m, 1H, oxazolidinone H), 4.73 (d, 2H, J ¼ 5.2 Hz, CH2), 4.19 (t, 1H,
J ¼ 9.0 Hz, oxazolidinone H), 4.05 (q, 2H, J ¼ 7.1 Hz, CH3CH2),
3.83 (dd, 1H, J ¼ 5.9 Hz, 9.0 Hz, oxazolidinone H), 3.59 (m, 4H,
piperazine H), 2.96 (t, 2H, J ¼ 4.7 Hz, piperazine H), 2.91 (t, 2H,
J ¼ 4.7 Hz, piperazine H), 2.33–2.39 (m, 4H, CH2CH2), 2.22 (s, 3H,
triazole CH3), 1.76–1.78 (m, 2H, CH2), 1.18 (t, 3H, J ¼ 7.1 Hz
CH3CH2). IR (KBr pellet, cmꢁ1): n 2958, 2897, 2836, 1743, 1643,
1521, 1450, 1428, 1384, 1340, 1282, 1233, 1179, 1138, 1100,
1048, 1030. MS 502.4 (Mþ). Anal calcd for C24H31FN6O5: C:
57.36, H: 6.22, N: 16.72; found C: 57.00, H: 6.40, N: 16:45.
reaction mixture was concentrated and the residue triturated with
ether to give 7g as a solid in quantitative yield. 1H NMR (DMSO-d6):
d 7.70–7.82 (m, 3H, þNH3, exchangeable with D2O), 7.64 (s, 1H,
triazole H), 7.21 (dd, 1H, J ¼ 2.6 Hz, 14.7 Hz, phenyl H), 6.93 (dd,
1H, J ¼ 2.1 Hz, 8.6 Hz, phenyl H), 6.84 (t, 1H, J ¼ 9.5 Hz, phenyl H),
4.86–4.88 (m, 1H, oxazolidinone H), 4.52 (d, 2H, J ¼ 5.2 Hz, CH2),
3.97 (t, 1H, J ¼ 9.2 Hz, oxazolidinone H), 3.71 (q, 2H, J ¼ 5.7 Hz,
11.4 Hz, CH2), 3.61 (dd, 1H, J ¼ 5.9 Hz, 9.3 Hz, oxazolidinone H),
3.4–3.5 (m, 4H, piperazine H), 2.7–2.8 (m, 4H, piperazine H), 2.00
(s, 3H, triazole CH3). MS 418.75 (MþþH).
(R)-3-(3-Fluoro-4-(4-(2-isothiocyanatoacetyl)piperazin-1-yl)-
phenyl)-5-((4-methyl-1H-1,2,3-triazol-1-yl)methyl)-
oxazolidin-2-one 7h
To a solution of 7g (200 mg, 0.38 mmol) in DCM (anhyd.
15 mL), N,N-diisopropylethylamine (140 mL, 0.803 mmol) and
CS2 (150 mL, 2.55 mmol) were added with stirring. A solution
of p-toluenesulfonylchloride (75 mg, 1.04 mmol) in anhyd. DCM
(10 mL) was added dropwise at ꢁ78C. Slow effervescence was
observed and stirring was continued for 30 min at 08C to r.t.
overnight. The solvent was evaporated under vacuum to give a
residue, which was purified by column chromatography over
silica gel (EtOAc/MeOH ¼ 10:1) to give 7h as white crystals, yield:
(R)-Ethyl 2-(1,3-dithiolan-2-ylidene)-3-(4-(2-fluoro-4-
(5-((4-methyl-1H-1,2,3-triazol-1-yl) methyl)-2-
oxooxazolidin-3-yl)phenyl)piperazin-1-yl)-3-
oxopropanoate 7e
A solution of 7a (200 mg, 0.42 mmol) in DMF (anhyd. 10 mL) at
08C was treated with 1,2-dibromoethane (50 mL, 0.56 mmol),
CS2 (130 mL, 2.1 mmol), and NaH (60% in mineral oil, 58 mg,
1.42 mmol) and stirred for 1 h. Then diluted with EtOAc (30 mL),
washed with water, dried (Na2SO4), filtered and concentrated to
give a residue. Recrystallization (DCM/Et2O) gave a white solid,
yield: 41%; m.p.: 110–1128C. 1H NMR (DMSO-d6): d 7.87 (s, 1H,
triazole H), 7.44 (dd, 1H, J ¼ 2.3 Hz, 14.7 Hz, phenyl H), 7.08–7.13
(m, 2H, phenyl H), 5.08–5.1 (m, 1H, oxazolidinone H), 4.74 (d, 2H,
J ¼ 5.2 Hz, CH2), 4.12–4.22 (m, 3H, oxazolidinone H and CH2),
3.84 (dd, 1H, J ¼ 5.9 Hz, 9.4 Hz, oxazolidinone H), 3.68–3.72
(m, 2H, piperazine H), 3.45–3.51 (br, 2H, thiolane H), 3.37–3.41
(m, 4H, piperazine H), 2.90–3.10 (m, 4H, piperazine H), 2.22 (s, 3H,
triazole CH3). IR (KBr pellet, cmꢁ1): n 2951, 2921, 2858, 2835, 2071
1
75%; m.p.: 160–1618C. H NMR (DMSO-d6): d 7.86 (s, 1H, triazole
H), 7.43 (dd, 1H, J ¼ 2.5 Hz, 14.7 Hz, phenyl H), 7.13 (dd, 1H,
J ¼ 2.4 Hz, 9.0 Hz, phenyl H), 7.05 (t, 1H, J ¼ 9.1 Hz, phenyl H),
5.06–5.1 (m, 1H, oxazolidinone H), 4.77 (s, 2H, CH2), 4.73 (d, 2H,
J ¼ 5.5 Hz, –CH2), 4.19 (t, 1H, J ¼ 9.5 Hz, oxazolidinone H), 3.83
(dd, 1H, J ¼ 5.9 Hz, 9.4 Hz, oxazolidinone H), 3.62–3.64 (m, 2H,
piperazine H), 3.40–3.43 (m, 2H, piperazine H), 2.94–3.05 (m, 4H,
piperazine H), 2.22 (s, 3H, triazole CH3). IR (KBr pellet, cmꢁ1): n
–
–
2951, 2921, 2858, 2835, 2071 (S C N–), 1753, 1734, 1659, 1520,
–
–
1443, 1420, 1387, 1323, 1232, 1226, 1159, 1136, 1101, 1032.
MS 459.2 (Mþ). Anal calcd for C20H22FN7O3S: C: 52.28, H: 4.83,
N: 21.34; found C: 51.99, H: 4.87, N: 20.77.
–
–
(S C N–), 1753, 1734, 1659, 1520, 1443, 1420, 1387, 1323, 1232,
–
–
1226, 1159, 1136, 1101, 1032. MS 576.2 (Mþ). Anal calcd for
C25H29FN6O5S2: C: 52.07, H: 5.07, N: 14.57; found C: 52.10,
H: 5.27, N: 14.10.
(R)-3-(3-Fluoro-4-(4-(3-fluorobenzoyl)piperazin-1-yl)-
phenyl)-5-((4-methyl-1H-1,2,3-triazol-1-yl)methyl)-
oxazolidin-2-one 7i
(R)-2-(4-(2-Fluoro-4-(5-((4-methyl-1H-1,2,3-triazol-1-yl)-
methyl)-2-oxooxazolidin-3-yl)phenyl) piperazin-1-yl)-2-
oxoethanaminium 2,2,2-trifluoroacetate 7g
Compound 7i was prepared via the general procedure from
compound 6b and fluorobenzoyl chloride (1.50 mmol).
Recrystallization (EtOAc/hexanes) to give a solid, yield: 96%;
m.p.195–1978C. 1H NMR (DMSO-d6): d 7.87 (s, 1H, triazole H),
7.52 (m, 1H, phenyl H), 7.44 (dd, 1H, J ¼ 2.4 Hz, 14.7 Hz, phenyl
H), 7.26–7.36 (m, 3H, phenyl H), 7.15 (dd, 1H, J ¼ 2.3 Hz, 8.8 Hz,
phenyl H), 7.09 (t, 1H, J ¼ 9.20 Hz, phenyl H), 5.04–5.11 (m, 1H,
oxazolidinones H), 4.74 (d, 2H, J ¼ 5.2 Hz, CH2), 4.19 (t, 1H,
J ¼ 9.2 Hz, oxazolidinones H), 3.83 (dd, 1H, J ¼ 5.9 Hz, 9.4 Hz,
oxazolidinone H), 3.7–3.8 (m, 2H, piperazine H), 3.45–3.60
(m, 2H, piperazine H), 2.90–3.10 (m, 4H, piperazine H), 2.23
(s, 3H, triazole CH3). IR (KBr pellet, cmꢁ1): n 2992, 2907, 2836,
1740, 1629, 1524, 1440, 1417, 1329, 1288, 1217, 1162, 1021.
MS 482.1 (Mþ). Anal calcd for C24H24F2N6O3: C: 59.74, H: 5.01,
N: 17.42; found C: 59.85, H: 5.06, N: 17.63.
This compound was prepared from 7f, which was obtained via
the general procedure from compound 6b and N-tert-butoxycar-
bonylglycine (2.62 mmol) activated by DCC/1-HOBT. Silica gel
column chromatography (EtOAc/MeOH ¼ 9:1) gave (R)-tert-butyl
(2-(4-(2-fluoro-4-(5-((4-methyl-1H-1,2,3-triazol-1-yl)methyl)-2-oxooxazolidin-3-yl)-
phenyl)piperazin-1-yl)-2-oxoethyl) carbamate 7f as a solid, yield: 83%;
m.p.: 175–1778C. 1H NMR (DMSO-d6): d 7.86 (s, 1H, triazole H), 7.43
(dd, 1H, J ¼ 2.5 Hz, 14.7 Hz, phenyl H), 7.13 (dd, 1H J ¼ 2.5 Hz,
phenyl H), 7.06 (t, 1H, J ¼ 9.0 Hz, phenyl H), 6.77 (br. t, 1H,
NHBoc, exchangeable with D2O), 5.07–5.10 (m, 1H, oxazolidi-
none H), 4.74 (d, 2H, J ¼ 5.2 Hz, CH2), 4.19 (t, 1H, J ¼ 9.0 Hz,
oxazolidinone H), 3.82–3.85 (m, 3H, oxazolidinone H and CH2),
3.55–3.59 (m, 4H, piperazine H), 2.92–2.97 (m, 4H, piperazine H),
2.22 (s, 3H, triazole CH3), 1.39 (s, 9H, C(CH3)3). IR (KBr pellet,
cmꢁ1): n 3444, 2977, 2932, 1741, 1708, 1667.79, 1517, 1427, 1440,
1455, 1367, 1339, 1283, 1230, 1165, 1049, 1034. MS 517.4 (Mþ).
Anal calcd for C24H32FN7O5: C: 55.70, H: 6.23, N: 18.94; found C:
55.74, H: 6.52, N: 18.74. A solution of 7f (5.22 mmol) in DCM
(6 mL) and TFA (6 mL) at 08C was stirred to r.t. overnight. The
(R)-3-(4-(4-(4-Chlorobenzoyl)piperazin-1-yl)-
3-fluorophenyl)-5-((4-methyl-1H-1,2,3-triazol-1-yl)-
methyl)oxazolidin-2-one 7j
Compound 7j was prepared via the general procedure from
compound 6b and 4-chlorobenzoyl chloride (1.60 mmol).
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2012, 000, 1–14
Antibacterial Activity of Triazolylmethyl Oxazolidinones
11
1
Recrystallization (EtOAc/hexanes) to give a solid, yield: 84%; m.p.:
195–1978C. 1H NMR (DMSO-d6): d 7.87 (s, 1H, triazole H), 7.54
(m, 1H, phenyl H), 7.49 (dd, 1H, J ¼ 2.0 Hz, 14.7 Hz, phenyl H),
7.44 (dd, 1H, J ¼ 2.4 Hz, 14.7 Hz, phenyl H), 7.14 (dd, 1H,
J ¼ 2.3 Hz, 9.0 Hz, phenyl H), 7.08 (t, 1H, J ¼ 9.2 Hz, phenyl
H), 5.04–5.08 (m, 1H, oxazolidinone H), 4.74 (d, 2H, J ¼ 5.2 Hz,
CH2), 4.19 (t, 1H, J ¼ 9.2 Hz, oxazolidinone H), 3.84 (dd, 1H,
J ¼ 5.9 Hz, 9.4 Hz, oxazolidinone H), 3.72–3.80 (m, 2H, pipera-
zine H), 3.45–3.51 (m, 2H, piperazine H), 2.90–3.10 (m, 4H, piper-
azine H), 2.23 (s, 3H, triazole CH3). IR (KBr pellet, cmꢁ1): n 2912,
2837, 1740, 1627, 1523, 1489, 1438, 1418, 1380, 1329, 1286,
1219, 1159, 1096, 1014. Anal calcd for C24H24ClFN6O3: C:
57.78, H: 4.85, N: 16.84; found C: 57.91, H: 4.88, N: 17.09.
62%; m.p.: 155–1578C. H NMR (DMSO-d6): d 7.87 (s, 1H, triazole
H), 7.44 (dd, 1H, J ¼ 2.4 Hz, 14.6 Hz, phenyl H), 7.38 (t, 1H,
J ¼ 7.9 Hz, phenyl H), 7.15 (dd, 1H, J ¼ 2.3 Hz, 9.0 Hz, phenyl
H), 7.09 (t, 1H, J ¼ 9.2 Hz, phenyl H), 6.96–7.05 (m, 3H, phenyl H),
5.06–5.10 (m, 1H, oxazolidinone H), 4.74 (d, 2H, J ¼ 5.2 Hz, CH2),
4.19 (t, 1H, J ¼ 9.3 Hz, oxazolidinone H), 3.84 (dd, 1H, J ¼ 5.9 Hz,
9.5 Hz, oxazolidinone H), 3.79–3.84 (s, 5H, OCH3, and overlap-
ping piperazine H multiplet signal), 3.46–3.54 (m, 2H, piperazine
H), 2.90–3.08 (m, 4H, piperazine H), 2.23 (s, 3H, triazole CH3). IR
(KBr pellet, cmꢁ1): n 2996, 2836, 1741, 1631, 1524, 1422, 1323,
1289, 1230, 1102, 1042, 1021. Anal calcd for C25H27FN6O4: C:
60.72, H: 5.50, N: 16.99; found C: 61.00, H: 5.57, N: 17.23.
(R)-3-(4-(4-(3,5-Dinitrobenzoyl)piperazin-1-yl)-
3-fluorophenyl)-5-((4-methyl-1H-1,2,3-triazol-1-yl)methyl)-
oxazolidin-2-one 7n
(R)-3-(3-Fluoro-4-(4-(3-nitrobenzoyl)piperazin-1-yl)-
phenyl)-5-((4-methyl-1H-1,2,3-triazol-1-yl)methyl)-
oxazolidin-2-one 7k
Compound 7n was prepared via the general procedure from
compound 6b and 3,5-dinitro-benzoyl chloride (1.58 mmol).
Silica gel column chromatography (EtOAc) gave a yellow solid,
yield: 39%; m.p.: 105–1078C. 1H NMR (DMSO-d6): d 8.88 (t, 1H,
J ¼ 2.0 Hz, phenyl H), 8.69 (d, 2H, J ¼ 2.2 Hz, phenyl H), 7.86
(s, 1H, triazole H), 7.43 (dd, 1H, J ¼ 2.5 Hz, 14.7 Hz, phenyl H),
7.15 (dd, 1H, J ¼ 2.2 Hz, 8.7 Hz, phenyl H), 7.08 (t, 1H, J ¼ 9.4 Hz,
phenyl H), 5.06–5.09 (m, 1H, oxazolidinone H), 4.73 (d, 2H,
J ¼ 5.2 Hz, CH2), 4.19 (t, 1H, J ¼ 9.1 Hz, oxazolidinone H), 3.83
(m, 3H, oxazolidinone H and piperazine H), 3.45–3.55 (m, 2H,
piperazine H), 3.09–3.18 (m, 2H, piperazine H), 2.93–2.99 (m, 2H,
piperazine H), 2.22 (s, 3H, triazole H). IR (KBr pellet, cmꢁ1): n 2919,
2852, 1756, 1641, 1545, 1516, 1478, 1438, 1344, 1282, 1232,
1159, 1028. MS 554.2 (Mþ). Anal calcd for C24H23FN5O7: C:
51.99, H: 4.18, N: 20.21; found C: 51.82, H: 4.53, N: 19.94.
Compound 7k was prepared via the general procedure from
compound 6b and 3-nitrobenzoyl chloride (1.60 mmol).
Recrystallization (EtOAc/hexanes) to give a cream colored solid,
yield: 84%; m.p.: 183–1858C. 1H NMR (DMSO-d6): d 8.31–8.34
(m, 1H, phenyl H), 8.27 (t, 1H, J ¼ 1.75 Hz, phenyl H), 7.90–
7.93 (m, 1H, phenyl H), 7.87 (s, 1H, triazole H), 7.77 (t, 1H,
J ¼ 7.9 Hz, phenyl H), 7.44 (dd, 1H, J ¼ 2.4 Hz, 14.7 Hz, phenyl
H), 7.15 (dd, 1H, J ¼ 2.5 Hz, 9.0 Hz, phenyl H), 7.09 (t, 1H,
J ¼ 9.3 Hz, phenyl H), 5.06–5.10 (m, 1H, oxazolidinone H), 4.74
(d, 2H, J ¼ 5.2 Hz, CH2), 4.19 (t, 1H, J ¼ 9.3 Hz, oxazolidinone H),
3.84 (dd, 1H, J ¼ 5.9 Hz, 9.5 Hz, oxazolidinone H), 3.49 (m, 2H,
piperazine H), 3.08 (m, 2H, piperazine H), 2.97 (m, 2H, piperazine
H), 2.22 (m, 2H, piperazine H), 2.23 (s, 3H, triazole CH3). IR (KBr
pellet, cmꢁ1): n 2900, 2836, 1737, 1637, 1530, 1488, 1421, 1346,
1223, 1162, 1033. MS 509.5 (Mþ). Anal calcd for C24H24FN7O5: C:
56.58, H: 4.75, N: 19.24; found C: 56.66, H: 4.77, N: 19.44.
(R)-5-((1H-1,2,3-Triazol-1-yl)methyl)-3-(4-(4-(3,5-
dinitrobenzoyl)piperazin-1-yl)-3-fluorophenyl)oxazolidin-2-
one 7o
(R)-3-(3-Fluoro-4-(4-(3-methylbenzoyl)piperazin-1-yl)-
phenyl)-5-((4-methyl-1H-1,2,3-triazol-1-yl)methyl)-
oxazolidin-2-one 7l
Compound 7o was prepared via the general procedure from
compound 6a and 3,5-dinitro-benzoyl chloride (1.63 mmol).
Recrystallization (EtOAc/hexanes) to give a solid, yield: 53%;
m.p.: 240–2428C. 1H NMR (DMSO-d6): d 8.76 (t, 1H J ¼ 2.0 Hz,
phenyl), 8.61 (d, 2H, J ¼ 2.1 Hz, phenyl), 8.17 (s, 1H, triazole
H), 7.77 (s, 1H, triazole H), 7.40 (dd, 1H, J ¼ 2.5 Hz, 14.5 Hz,
phenyl), 7.11 (dd, 1H, J ¼ 2.9 Hz, 8.7 Hz, phemyl), 7.07 (t, 1H,
J ¼ 8.7 Hz, phenyl), 5.09–5.15 (m, 1H, oxazoldinone H) 4.82
(d, 2H, J ¼ 5.1 Hz, CH2), 4.20 (t, 1H, J ¼ 8.6, oxazolidinone H),
3.86 (t, 1H, J ¼ 5.4 Hz) oxazoldinone H), 3.00–3.02 (m, 4H,
piperazine H), 2.61–2.63 (m, 4H, piperazine H). IR (KBr pellet,
cmꢁ1): n 2921, 2845, 1746, 1640, 1546, 1516, 1482, 1435, 1342,
1285, 1236, 1192, 1027. MS 540.2 (Mþ). Anal calcd for
C23H21FN8O7: C: 51.10, H: 3.92, N: 20.72; found C: 50.86, H:
3.97, N: 20.64.
Compound 7l was prepared via the general procedure
from compound 6b and m-toluoyl chloride (1.50 mmol).
Recrystallization (EtOAc/hexanes) to give a solid, yield: 72%;
m.p.: 165–1678C. 1H NMR (DMSO-d6): d 7.86 (s, 1H, triazole H),
7.43 (dd, 1H, J ¼ 2.5 Hz, 14.6 Hz, phenyl H), 7.34 (t, 1H,
J ¼ 7.6 Hz, phenyl H), 7.28 (d, 1H, J ¼ 7.7 Hz) phenyl H), 7.24
(s, 1H, phenyl H), 7.21 (d, 1H, J ¼ 7.5 Hz, phenyl H), 7.14 (dd, 1H,
J ¼ 2.4 Hz, 8.8 Hz, phenyl H), 7.08 (t, 1H J ¼ 9.4 Hz, phenyl H),
5.05–5.09 (m, 1H, oxazolidinone H), 4.73 (d, 2H, J ¼ 5.3 Hz, CH2),
4.19 (t, 1H, J ¼ 9.2 Hz, oxazolidinone H), 3.83 (dd, 1H, J ¼ 6.0 Hz,
9.3 Hz, oxazolidinone H), 3.77 (m, 2H, piperazine H), 3.48 (m, 2H,
piperazine H), 2.94–3.02 (m, 4H, piperazine H), 2.35 (s, 3H, CH3),
2.22 (s, 3H, triazole CH3). IR (KBr pellet, cmꢁ1): n 2915, 2849, 1742,
1631, 1524, 1489, 1440, 1418, 1327, 1288, 1219, 1136, 1101. MS
478.0 (Mþ); Anal calcd for C25H27FN6O3: C: 62.75, H: 5.69, N: 17.56;
found C: 62.29, H: 5.4, N: 17.42.
(R)-3-(3-Fluoro-4-(4-isonicotinoylpiperazin-1-yl)phenyl)-5-
((4-methyl-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one
7p
Compound 7p was prepared via the general procedure from
compound 6b and isonicotinoyl chloride (2.10 mmol). Silica
gel column chromatography (EtOAc/MeOH ¼ 10:1) gave a white
solid, yield: 45%; m.p.: 194–1968C. 1H NMR (DMSO-d6): d 8.68–8.70
(m, 2H, pyridyl H), 7.86 (s, 1H, triazole H), 7.41–7.45 (m, 3H,
pyridyl and phenyl 1H), 7.15 (dd, 1H, J ¼ 2.4 Hz 9.0 Hz, phenyl
(R)-3-(3-Fluoro-4-(4-(3-methoxybenzoyl)piperazin-1-yl)-
phenyl)-5-((4-methyl-1H-1,2,3-triazol-1-yl)methyl)-
oxazolidin-2-one 7m
Compound 7m was prepared via the general procedure from
compound 6b and m-anisoyl chloride (1.50 mmol).
Recrystallization (EtOAc/hexanes) to give a white solid, yield:
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12
O. A. Phillips et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–14
H), 7.08 (t, 1H, J ¼ 9.4 Hz, phenyl H), 5.05–5.11 (m, 1H, oxazoli-
dinone H), 4.74 (d, 2H J ¼ 5.2 Hz, CH2), 4.19 (t, 1H J ¼ 9.2 Hz,
oxazolidinone H), 3.84 (dd, 1H, J ¼ 5.9 Hz, 9.4 Hz, oxazolidinone
H), 3.79–3.82 (m, 2H, piperazine H), 3.30–3.45 (m, 2H, piperazine
H), 3.05–3.08 (m, 2H, piperazine H), 2.92–2.96 (m, 2H, piperazine
H), 2.22 (s, 3H, triazole CH3). IR (KBr pellet, cmꢁ1): n 2898, 2851,
1743, 1633, 1517, 1440, 1413, 1334, 1285, 1217, 1160. MS 465.6
(Mþ). Anal calcd for C23H24FN7O3: C: 59.35, H: 5.20, N: 21.06;
found C: 58.98, H: 5.21, N: 20.77.
oxazolidinone H), 3.82 (t, 4H, J ¼ 5.5 Hz, piperazine H), 3.03
(t, 4H, J ¼ 5.5 Hz, piperazine H), 2.23 (s, 3H, triazole CH3).
IR (KBr pellet, cmꢁ1): n 2918, 1741, 1605, 1518, 1441, 1419,
1327, 1274, 1234, 1132, 1004. MS 469.7 (Mþ). Anal calcd for
C22H23FN6O3S: C: 56.16, H: 4.93, N: 17.86, S: 6.81; found C:
55.83, H: 4.97, N: 17.64, S: 6.64.
(R)-3-(3-Fluoro-4-(4-(5-nitrofuran-2-carbonyl)piperazin-1-
yl)phenyl)-5-((4-methyl-1H-1,2,3-triazol-1-yl)methyl)-
oxazolidin-2-one 7t
(R)-3-(3-Fluoro-4-(4-nicotinoylpiperazin-1-yl)phenyl)-5-
((4-methyl-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one
7q
Compound 7t was prepared via the general procedure from
compound 6b and 5-nitrofuran carboxylic acid (1.08 mmol) acti-
vated by oxalyl chloride. Recrystallization (EtOAc/hexanes) gave a
yellow crystalline solid, yield: 60%; m.p.: 178–1808C. 1H NMR
(DMSO-d6): d 7.86 (s, 1H, triazole H), 7.79 (d, 1H, J ¼ 3.8 Hz, furan
H), 7.45 (dd, 1H, J ¼ 2.5 Hz, 14.7 Hz, phenyl H), 7.32 (dd, 1H,
J ¼ 3.9 Hz, furan H), 7.15 (dd, 1H, J ¼ 2.3 Hz, 8.8 Hz, phenyl, H),
7.08 (t, 1H, J ¼ 9.4 Hz, phenyl H), 5.06–5.1 (m, 1H, oxazolidi-
none), 4.73 (d, 2H, J ¼ 5.2 Hz, CH2), 4.19 (t, 1H, J ¼ 9.2 Hz, oxa-
zolidinone), 3.86 (dd, 1H, J ¼ 5.9 Hz, 9.0 Hz, oxazolidinone,
overlaps with piperazine signal), 3.82–3.85 (m, 4H, piperazine),
3.02–3.05 (m, 4H, piperazine), 2.22 (s, 3H, triazole CH3). 13C NMR
(DMSO-d6): d 157.20, 155.85, 154.23, 153.98, 151.72, 147.95,
142.53, 135.69, 135.63, 133.94, 133.86, 123.69, 120.34, 117.59,
114.76, 113.33, 107.33, 107.16, 71.35, 66.59, 52.16, 47.60, 10.86.
IR (KBr pellet, cmꢁ1): n 2897, 1743, 1643, 1521, 1450, 1428, 1384,
1340, 1282, 1233, 1179, 1138, 1100, 1049, 1030. MS 499 (Mþ).
Anal calcd for C22H27FN7O6: C: 52.91, H: 4.44, N: 19.63; found C:
52.50, H: 4.52, N: 19.39.
Compound 7q was prepared via the general procedure from
compound 6b and nicotinoyl chloride (1.58 mmol).
Recrystallization (EtOAc/hexanes) gave crystalline needles, yield:
80%; m.p.: 186–1888C. 1H NMR (DMSO-d6): d 8.63–8.70 (m, 2H,
pyridyl H), 7.85–7.91 (m, 2H, pyridyl and triazole H), 7.49–7.52
(m, 1H, pyridyl H), 7.44 (dd, 1H, J ¼ 2.2 Hz, 14.6 Hz, phenyl H),
7.15 (dd, 1H, J ¼ 2.3 Hz, 9 Hz, phenyl H), 7.11 (t, 1H, J ¼ 9.3 Hz,
phenyl H), 5.05–5.10 (m, 1H, oxazolidinone H), 4.74 (dd, 2H,
J ¼ 5.2 Hz CH2), 4.19 (t, 1H, J ¼ 9.3 Hz, oxazolidinone H),
3.81–3.85 (m, 3H, oxazolidinone H overlaps with piperazine H
multiplet signals), 3.45–3.54 (m, 2H, piperazine H), 2.97–3.10 (m,
4H, piperazine H), 2.22 (s, 3H, triazole CH3). IR (KBr pellet, cmꢁ1):
n 2953, 2918, 1740, 1624, 1522, 1438, 1416, 1333, 1218, 1136. MS
464.7 (Mþ). Anal calcd for C23H24FN7O3: C: 59.35, H: 5.20, N: 21.06;
found C: 59.10, H: 5.26, N: 21:27.
(R)-3-(3-Fluoro-4-(4-(furan-2-carbonyl)piperazin-1-yl)-
phenyl)-5-((4-methyl-1H-1,2,3-triazol-1-yl)methyl)-
oxazolidin-2-one 7r
(R)-2-(4-(2-Fluoro-4-(5-((4-methyl-1H-1,2,3-triazol-1-yl)-
methyl)-2-oxooxazolidin-3-yl)phenyl)piperazin-1-yl)-
acetamide 8a
Compound 7r was prepared via the general procedure from
compound 6b and 2-furoyl chloride (1.61 mmol). Silica gel col-
umn chromatography (MeOH/EtOAc ¼ 20:0.5 ! 10:1) gave a
white solid, yield: 25%; m.p.: 191–1938C. 1H NMR (DMSO-d6): d
7.87 (br s, 2H, triazole and furan H), 7.45 (dd, 1H, J ¼ 2.8 Hz,
15.3 Hz, furan H), 7.15 (dd, 1H, J ¼ 2.8 Hz, 15.3 Hz, phenyl H),
7.09 (t, 2H, J ¼ 9.0 Hz, phenyl H), 7.04 (d, 1H, J ¼ 3.4 Hz, furan H),
6.60 (dd, 1H, J ¼ 1.8 Hz, 3.5 Hz, furan H), 5.05–5.10 (m, 1H,
oxazolidinone H), 4.74 (d, 2H, J ¼ 5.3 Hz, CH2), 4.19 (t, 1H,
J ¼ 9.1 Hz, oxzolidinone), 3.82–3.86 (m, 5H, oxazolidinone and
piperazine H), 3.03 (m, 4H, J ¼ 5 Hz, piperazine H), 2.23 (s, 3H,
triazole CH3). IR (KBr pellet, cmꢁ1): n 2918, 2825, 1740, 1622,
1518, 1481, 1422, 1341, 1281, 1229, 1196, 1155, 1106, 1029. MS
454.7 (Mþ). Anal calcd for C22H23FN6O4: C: 58.14, H: 5.10, N: 18.49;
found C: 58.23, H: 5.14, N: 18.46.
A solution of compound 6b (500 mg, 1.05 mmol) and iodoacet-
amide (600 mg, 3.24 mmol) in DMF (10 mL) and TEA (0.5 mL)
was heated at 908C overnight. The reaction mixture was diluted
with water and extracted with DCM. The organic layer was
washed with water, brine, dried (Na2SO4) and concentrated to
give a crude mass, which was purified by silica gel column
chromatography (EtOAc) to give a solid, which was recrystallized
from EtOAc/hexanes to give a solid, yield: 18%; m.p.: 212–2158C.
1H NMR (DMSO-d6): d 7.86 (d, 1H, triazole H), 7.40 (dd 1H, J ¼ 2.50,
Hz, 14.7 Hz, phenyl H), 7.21 (br, s, 1H, NH, exchangeable with
D2O), 7.13 (br, s, 1H, NH, exchangeable with D2O), 7.12 (dd, 1H,
J ¼ 2.5 Hz, 9.0 Hz, phenyl H overlapping with broad NH signal),
7.05 (t, 1H, J ¼ 9.0 Hz, phenyl H), 5.06–5.09 (m, 1H, oxazolidi-
none H), 4.73 (d, 2H, J ¼ 5.0 Hz, CH2), 4.18 (t, 1H, J ¼ 9.0 Hz,
oxazolidinone H), 3.83 (dd, 1H, J ¼ 5.9 Hz, 9.0 Hz, oxazolidinone
H), 3.01 (t, 4H, J ¼ 4.5 Hz, piperazine H), 2.92 (s, 2H, CH2), 2.59
(t, 4H, J ¼ 4.5 Hz, piperazine H), 2.22 (s, 3H, triazole CH3). IR (KBr
pellet, cmꢁ1): n 3431, 3354, 2828, 1744, 1659, 1519, 1450, 1409,
1331, 1240, 1134, 1102, 1053. MS 417.3 (Mþ). Anal calcd for
C19H24FN7O3: C: 54.67, H: 5.80, N: 23.49; found C: 54.13,
H: 5.94, N: 22.99.
(R)-3-(3-Fluoro-4-(4-(thiophene-2-carbonyl)piperazin-1-yl)-
phenyl)-5-((4-methyl-1H-1,2,3-triazol-1-yl)methyl)-
oxazolidin-2-one 7s
Compound 7s was prepared via the general procedure from
compound 6b and 2-thiophene-carbonyl chloride (1.58 mmol).
Recrystallization (EtOAc) gave a white solid, yield: 97%; m.p.:
183–1858C. 1H NMR (DMSO-d6, 600 MHz): d 7.87 (s, 1H, triazole
H), 7.79 (dd, 1H, J ¼ 0.9 Hz, 5.0 Hz, thiophene H), 7.43–7.47 (m,
2H, thiophene and phenyl H), 7.13–7.16 (m, 2H, thiophene and
phenyl H), 7.09 (t, 1H, J ¼ 9.3 Hz, phenyl H), 5.06–5.10 (m, 1H,
oxazolidinone H), 4.74 (d, 2H, J ¼ 5.2 Hz, CH2), 4.19 (t, 1H
J ¼ 9.2 Hz, oxazolidinone H), 3.84 (dd, 1H, J ¼ 5.9 Hz, 9.4 Hz,
(R)-3-(4-(4-(3,5-Dinitrobenzyl)piperazin-1-yl)-
3-fluorophenyl)-5-((4-methyl-1H-1,2,3-triazol-1-yl)methyl)-
oxazolidin-2-one 8b
Compound 8b was prepared via a similar procedure to 8a from 6b
and 3,5-dinitrobenzyl chloride (340 mg, 1.57 mmol) in CH3CN
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–14
Antibacterial Activity of Triazolylmethyl Oxazolidinones
13
(20 mL); to give a yellow solid, yield: 40%; m.p.: 192–1948C.
1H NMR (DMSO-d6): d 8.75 (t, 1H, J ¼ 2.1 Hz phenyl H), 8.60
(d, 2H, J ¼ 2.1 Hz phenyl H), 7.86 (s, 1H, triazole H), 7.40
(dd, 1H, J ¼ 2.5 Hz, 14.8 Hz phenyl H), 7.12 (dd, 1H, J ¼ 2.4 Hz
and 8.8 Hz, phenyl H), 7.07 (t, 1H, J ¼ 9.4 Hz, phenyl H), 5.05–
5.09 (m, 1H, oxazolidinone H), 4.73 (d, 2H, J ¼ 5.08 Hz, CH2), 4.18
(t, 1H, J ¼ 9.2 Hz oxazolidinone H), 3.80–3.83 (m, 3H, oxazolidi-
none H and CH2), 2.95–3.05 (m, 4H, piperazine H), 2.60–2.68
(m, 4H, piperazine H), 2.22 (s, 3H, triazole CH3). IR (KBr pellet,
cmꢁ1): n 2938, 2829, 1739, 1541, 1517, 1448, 1410, 1344, 1236,
1128, 1048. MS 540.2 (Mþ). Anal calcd for CHFNO: C: 53.33, H:
4.66, N: 20.73; found C: 53.67, H: 4.63, N: 20.96.
(dd, 1H, J ¼ 2.5 Hz, 14.7 Hz, phenyl H), 7.11 (dd, 1H, J ¼ 2.3 Hz,
8.8 Hz, phenyl H), 7.05 (t, 1H, J ¼ 9.5 Hz, phenyl H), 5.04–5.08
(m, 1H, oxazolidinone H), 4.72 (d, 2H, J ¼ 4.8 Hz, CH2), 4.17 (t, 1H,
J ¼ 9.2 Hz, oxazolidinone H), 3.81 (dd, 1H, J ¼ 5.9 Hz, oxazolidi-
none H), 3.03 (m, 8H, piperazine H), 2.43 (s, 3H, tolyl CH3), 2.21
(s, 3H, triazole CH3). IR (KBr pellet, cmꢁ1): n 2920, 2855, 1740,
1520, 1448, 1420, 1335, 1225, 1157, 1115, 1050. MS 514.2 (Mþ).
Anal calcd for C24H27FN6O4S: C: 56.02, H: 5.29, N: 16.33, S: 6.23;
found C: 56.30, H: 5.19, N: 16.19, S: 6.20.
(R)-3-(3-Fluoro-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)-
phenyl)-5-((4-methyl-1H-1,2,3-triazol-1-yl)methyl)-
oxazolidin-2-one 9c
(R)-5-((1H-1,2,3-Triazol-1-yl)methyl)-3-(4-(4-(3,5-
dinitrobenzyl)piperazin-1-yl)-3-fluorophenyl)oxazolidin-
2-one 8c
Prepared from compound 6b and 2-thiophenesulfonyl chloride
via the general procedure. Purification by silica gel column
chromatography (EtOAc/MeOH ¼ 9:1) afforded a white solid,
yield: 81%; m.p.: 183–1858C. 1H NMR (DMSO-d6): d 8.11 (dd, 1H,
J ¼ 1.3 Hz, 5.0 Hz, thiophene H), 7.86 (s, 1H, triazole H), 7.70 (dd,
1H, J ¼ 1.2 Hz, 3.8 Hz, thiophene H), 7.40 (dd, 1H, J ¼ 2.5 Hz,
14.6 Hz, phenyl), 7.34 (dd, 1H, J ¼ 3.8 Hz, 5.0 Hz, thiophene H),
7.13 (dd, 1H, J ¼ 2.4 Hz, 9.0 Hz, phenyl H), 7.07 (t, 1H, J ¼ 9.3 Hz,
phenyl H), 5.04–5.10 (m, 1H, oxazolidinone H), 4.73 (d, 2H,
J ¼ 5.2 Hz, CH2), 4.18 (t, 1H, J ¼ 9.2 Hz, oxazolidinone H), 3.82
(dd, 1H, J ¼ 5.9 Hz, 9.4 Hz, oxazolidinone H), 3.33 (m, 4H, piper-
Compound 8c was prepared via a similar procedure to 8a from 6a
and 3,5-dinitrobenzyl chloride (340 mg, 1.57 mmol) in CH3CN
(20 mL) to give an orange powder, yield: 67%; m.p.: 150–1528C.
1H NMR (DMSO-d6): d 8.88 (t, 1H, J ¼ 2.1 Hz, benzyl H), 8.69 (d, 2H,
J ¼ 2.1 Hz, benzyl H), 8.17 (s, 1H, triazole H), 7.77 (s, 1H, triazole
H), 7.43 (dd, 1H, J ¼ 2.43 Hz, 14.61 Hz, phenyl H), 7.14 (dd, 1H,
J ¼ 2.8 Hz, 8.9 Hz, phenyl H), 7.08 (t, 1H, J ¼ 9.4 Hz, phenyl H),
5.09–5.15 (m, 1H, oxazolidinone H), 4.82 (d, 2H, J ¼ 5.04 Hz,
CH2), 4.21 (t, 1H, J ¼ 9.3 Hz, oxazolidinone H), 3.83–3.88 (m,
3H, oxazolidinone and piperazine H), 3.40–3.60 (m, 4H, piper-
azine H and CH2), 2.97–3.11 (m, 4H, piperazine H). 13C NMR
(DMSO-d6): d 164.81, 155.33, 153.71, 153.44, 148.15, 138.77,
135.32, 135.26, 133.35, 133.26, 127.57, 125.83, 119.85, 119.83,
119.15, 114.22, 106.80, 106.63, 70.75, 51.67, 47.05. IR (KBr pellet,
cmꢁ1): n 2927, 2812, 1751, 1625, 1538, 1515, 1447, 1419, 1342,
1226, 1146, 1109, 1078. MS 526.2 (Mþ). Anal calcd for
C23H23FN8O6: C: 52.47, H: 4.40, N: 21.28; found C: 52.13, H:
4.58, N:21.18.
azine H), 3.08 (m, 4H, piperazine H), 2.21 (s, 3H, triazole CH3). 13
C
NMR (DMSO-d6): d 155.28, 153.66, 153.46, 142.01, 134.84, 134.35,
134.10, 133.52, 133.34, 128.42, 123.18, 119.90, 114.20, 106.76,
106.59, 70.85, 51.65, 49.40, 47.08, 45.99, 10.37. IR (KBr pellet,
cmꢁ1): n 3101, 1740, 1519, 1447, 1419, 1347, 1224, 1156, 1052.
MS 506.0 (Mþ). Anal calcd for C21H23FN6O4S2: C: 49.79, H: 4.58, N:
16.59, S: 12.66; found C: 49.89, H: 4.62, N: 16.81, S: 12.38.
(R)-Amino(4-(2-fluoro-4-(5-((4-methyl-1H-1,2,3-triazol-1-
yl)methyl)-2-oxooxazolidin-3-yl)phenyl)piperazin-1-
yl)methaniminium 2,2,2-trifluoroacetate 11a
(R)-3-(3-Fluoro-4-(4-(phenylsulfonyl)piperazin-1-yl)-
phenyl)-5-((4-methyl-1H-1,2,3-triazol-1-yl)methyl)-
oxazolidin-2-one 9a
To a solution of (R)-4-(2-fluoro-4-(5-((4-methyl-1H-1,2,3-triazol-1-
yl)methyl)-2-oxooxazolidin-3-yl)phenyl)piperazin-1-ium 2,2,2-tri-
fluoroacetate 6b (400 mg, 0.84 mmol) salt in DMF (anhyd.
4 mL), TEA (3 mL) was added N,N-(bis(tert-butoxy-carbonyl) S-
methyl isothiourea [13] (370 mg, 1.27 mmol). The mixture was
stirred at r.t. for 5 days, treated with water (30 mL) and extracted
with EtOAc. The EtOAc layer was separated, washed with water,
dried (Na2SO4), filtered and concentrated to give a crude mass.
Silica gel column chromatography (EtOAc/hexane ¼ 2:1 !
EtOAc) afforded (R)-tert-butyl (((tert-butoxycarbonyl) amino)(4-(2-fluoro-
4-(5-((4-methyl-1H-1,2,3-triazol-1-yl)methyl)-2-oxooxazolidin-3-yl)phenyl)pi-
perazin-1-yl)methylene)carbamate 10a as a solid, yield: 63%; m.p.:
170–1728C. 1H NMR (DMSO-d6): d 9.67 (s, 1H, NH, exchangeable
with D2O), 7.86 (s, 1H, triazole H), 7.43 (dd, 1H, J ¼ 2.4 Hz,
14.6 Hz, phenyl H), 7.13 (dd, 1H, J ¼ 6.6 Hz, 8.8 Hz, phenyl H),
7.07 (t, 1H, J ¼ 9.3 Hz, phenyl H), 5.06–5.09 (m, 1H, oxazolidi-
none H), 4.74 (d, 2H, J ¼ 5.2 Hz, CH2), 4.19 (t, 1H, J ¼ 9.2 Hz,
oxazolidonone H), 3.83 (dd, 1H, J ¼ 5.9 Hz, 9.4 Hz, oxazolidinone
H), 3.50–3.51 (m, 4H, piperazine H), 2.91–3.0 (m, 4H, piperazine
H), 2.22 (s, 3H, triazole CH3), 1.42 (s, 9H (CH3)3), 1.36 (s, 9H (CH3)3).
IR (KBr pellet, cmꢁ1): n 3435, 2977, 2931, 1746, 1615, 1517, 1484,
1427, 1365, 1299, 1231, 1148, 1136, 1051. Anal calcd for
C28H39FN8O6: C: 55.80, H: 6.52, N: 18.59; found C: 55.61, H:
6.56, N: 18.38. A solution of compound 10a (400 mg, 0.66 mmol)
in DCM (1 mL) and TFA (1 mL) was stirred at 08C to r.t. overnight.
The reaction mixture was concentrated on a rotavapor to give a
Prepared from compound 6b and benzenesulfonyl chloride via
the general procedure. Purification by silica gel column chroma-
tography (EtOAc/MeOH ¼ 9:1) gave a white solid, yield: 67%;
m.p.: 208–2108C. 1H NMR (DMSO-d6): d 7.85 (s, 1H, triazole H),
7.46–7.79 (m, 3H, phenyl H), 7.69 (t, 2H, J ¼ 7.8 Hz, phenyl H),
7.39 (dd, 1H, J ¼ 2.5 Hz, 14.7 Hz, phenyl H), 7.11 (dd, 1H,
J ¼ 2.4 Hz, 8.9 Hz, phenyl H), 7.05 (t, 1H, J ¼ 9.4, phenyl H),
5.04–5.08 (m, 1H, oxazolidinone H), 4.72 (d, 2H, J ¼ 5.0 Hz,
–CH2), 4.16 (t, 1H, J ¼ 9.2 Hz, oxazolidinone H), 3.18 (dd, 1H,
J ¼ 6.0 Hz, oxazolidinone H), 3.03 (m, 8H, piperazine H), 2.21 (s,
3H, triazole CH3). IR (KBr pellet, cmꢁ1): n 2974, 2916, 2840, 1750,
1519, 1479, 1447, 1424, 1330, 1271, 1234, 1200, 1109, 1067,
1044. MS 500.2 (Mþ). Anal calcd for C22H27FN6O5: C: 55.19, H:
5.03 N: 16.79; found C: 55.31, H: 5.27, N: 16.90.
(R)-3-(3-Fluoro-4-(4-tosylpiperazin-1-yl)phenyl)-5-((4-
methyl-1H-1,2,3-triazol-1-yl) methyl)oxazolidin-2-one 9b
Prepared from compound 6b and p-toluenesulfonyl chloride via
the general procedure. Purification by silica gel column chroma-
tography (EtOAc/MeOH ¼ 9:1) gave a white solid yield: 88%; m.p.:
206–2088C. 1H NMR (DMSO-d6): d 7.85 (s, 1H, triazole H), 7.66 (d,
2H, J ¼ 8.3 Hz, phenyl H), 7.49 (d, 2H, J ¼ 8.1 Hz, phenyl H), 7.39
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14
O. A. Phillips et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–14
mass, which was triturated with diethyl ether to afford 11a as a
white solid in quantitative yield; m.p.: 241–2438C. 1H NMR
(DMSO-d6): d 7.86 (s, 1H, triazole H), 7.44 (m, 5H, phenyl H and
guanidine H), 7.15 (dd, 1H, J ¼ 2.3 Hz, 8.9 Hz, phenyl H), 7.08 (t,
1H, J ¼ 9.4 Hz, phenyl H), 5.07–5.15 (m, 1H, oxazolidinone H),
4.74 (d, 2H, J ¼ 6.1 Hz, CH2), 4.19 (t, 1H, J ¼ 9.2 Hz, oxazolidi-
none H), 3.83 (dd, 1H, J ¼ 5.7 Hz, 9.4 Hz, oxazolidinone H), 3.57
(t, 4H, J ¼ 4.7 Hz, piperazine H), 3.04 (t, 4H, J ¼ 4.7 Hz, piper-
azine H), 2.22 (s, 3H, triazole CH3). IR (KBr pellet, cmꢁ1): n 3375,
3168, 2923, 1749, 1672, 1615, 1519, 1485, 1447, 1230, 1189. MS
403.75 (MþþH).
25923, S. epidermidis ATCC 12228 and E. faecalis ATCC 29212,
E. coli ATCC 25922, H. influenzae ATCC 49247, and M. catarrhalis
ATCC8176 were used. The final bacterial concentration for inoc-
ula was 107 CFU/mL, and incubation was at 358C for 18 h. To
assess the extent of plasma binding and/or plasma instability,
test compounds were evaluated against S. aureus ATTC 25923 in
MH broth supplemented with 50% human plasma. Linezolid and
PH-027 [6, 11] and vancomycin (Sigma–Aldrich, Germany) were
used as reference antibacterial agents.
This work was supported by the Research Administration, Kuwait
University Research Grant PC01/05 (OAP), and the Instrument Grants
GS01/01, GS01/03 and GS01/05 awarded to the Science Analytical
Facilities (SAF).
(R)-(4-(4-(5-((1H-1,2,3-Triazol-1-yl)methyl)-2-
oxooxazolidin-3-yl)-2-fluorophenyl)piperazin-1-yl)-
(amino)methaniminium 2,2,2-trifluoroacetate 11b
The authors have declared no conflict of interest.
Compound 10b was prepared via a similar procedure to 10a from
compound 6a to afford a white solid, yield: 34%; m.p.: 191–1938C.
1H NMR (DMSO-d6): d 9.49 (br s, 1H, NH), 8.00 (s, 1H, triazole H),
7.59 (s, 1H, triazole H), 7.25 (dd, 1H, J ¼ 2.6 Hz, 14.7 Hz, phenyl
H), 6.96 (dd, 1H, J ¼ 2.1 Hz, 8.6 Hz, phenyl H), 6.89 (t, 1H,
J ¼ 9.5 Hz, phenyl H), 5.08–5.10 (m, 1H, oxazolidinone H), 4.66
(d, 2H, J ¼ 5.1 Hz, CH2), 4.04 (t, 1H, J ¼ 9.3 Hz, oxazolidonone H),
3.69 (dd, 1H, J ¼ 5.7 Hz, 9.4 Hz, oxazolidinone H), 3.36–3.38 (m,
4H, piperazine H), 2.80–2.81(m, 4H, piperazine H), 1.20–1.25 (2br
s, 18H, [C(CH3)3]2). IR (KBr pellet, cmꢁ1): n 3392, 2980, 2821, 1741,
1689, 1619, 1518, 1488, 1453, 1367, 1298, 1223, 1157, 1120. MS
590.21 (MþþH). Anal calcd for C27H37FN8O6: C: 55.09, H: 6.34, N:
19.04; found C: 55.00, H: 5.99, N: 18.93. Compound 11b was
prepared via a similar procedure to 11a from 10b (100 mg,
0.17 mmoL) to afford a white solid yield: 88%; m.p.: 253–
2558C. 1H NMR (DMSO-d6): d 8.16 (s, 1H, triazole H), 7.76 (s, 1H,
triazole H), 7.43 (m, 5H, phenyl H and guanidine H), 7.14 (dd, 1H,
J ¼ 2.3 Hz, 9.4 Hz, phenyl H), 7.08 (t, 1H, J ¼ 9.4 Hz, phenyl H),
5.07–5.15 (m, 1H, oxazolidinone H), 4.82 (d, 2H, J ¼ 5.0 Hz, CH2),
4.20 (t, 1H, J ¼ 9.2 Hz, oxazolidinone H), 3.85 (dd, 1H, J ¼ 5.7 Hz,
9.4 Hz, oxazolidinone H), 3.57 (t, 4H, J ¼ 4.8 Hz, piperazine H),
3.03 (t, 4H, J ¼ 4.6 Hz, piperazine H). IR (KBr pellet, cmꢁ1): n 3347,
3162, 2917, 2849, 1750, 1669, 1595, 1519, 1486, 1447, 1330,
1281, 1240, 1201, 1140, 1111. MS 389.75 (MþþH).
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