Synthesis and antibacterial activity of some aryloxy/thioaryloxy oxazolidinone derivatives

Article abstract of DOI:10.1016/j.bmcl.2004.06.096

A series of aryloxy/thioaryloxy oxazolidinones has been synthesized and their antibacterial activity in vitro were evaluated and compared with linezolid. A series of aryloxy/thioaryloxy oxazolidinone derivatives has been synthesized and tested for in vitro antibacterial activity by MIC determination against a panel of susceptible and resistant Gram-positive and Gram-negative microorganisms, some of which are resistant to methicillin and vancomycin. Compounds 12a, 12b, 14a, and 14b from this series were found to be equipotent or more potent than linezolid in vitro.

Full text of DOI:10.1016/j.bmcl.2004.06.096

Bioorganic & Medicinal Chemistry Letters 14 (2004) 4647–4650
Synthesis and antibacterial activity of some
aryloxy/thioaryloxy oxazolidinone derivatives
Vishal Arora,a Manikrao M. Salunkhe,a Neelima Sinha,b
Rakesh K. Sinhac and Sanjay Jainb,
*
aDepartment of Chemistry, The Institute of Science, 15 Madam Cama Road, Mumbai 400 032, Maharashtra, India
bMedicinalChemistry Division, New ChemicalEntity Research, Lupin Research Park,
46/47A,Village Nande, Taluka Mulshi, Pune 411 042, Maharashtra, India
cMicrobiology Division, New Chemical Entity Research, Lupin Research Park,
46/47A, Village Nande, Taluka Mulshi, Pune 411 042, Maharashtra, India
Received 24 May 2004; revised 29 June 2004; accepted 30 June 2004
Available online 24 July 2004
Abstract—A series of aryloxy/thioaryloxy oxazolidinone derivatives has been synthesized and tested for in vitro antibacterial activity
by MIC determination against a panel of susceptible and resistant Gram-positive and Gram-negative microorganisms, some of
which are resistant to methicillin and vancomycin. Compounds 12a, 12b, 14a, and 14b from this series were found to be equipotent
or more potent than linezolid in vitro.
Ó 2004 Elsevier Ltd. All rights reserved.
O
O
The oxazolidinones, a new class of synthetic antimicro-
bial agents, are active against numerous multi-
drug-resistant Gram-positive organisms.1 Particularly,
problematic pathogens include methicillin-resistant
Staphylococcus aureus (MRSA), vancomycin-resistant
enterococci (VRE), penicillin- and cephalosporin-resist-
ant Streptococcus pneumoniae. Their mode of action
has been found to inhibit protein synthesis in the initial
stage.2 Due to this novel mechanism of action, oxazolid-
inones are not cross resistant with other types of antibi-
otics. This class was discovered through broad screening
and is exemplified by the erstwhile clinical candi- date DuP
721 (1, Fig. 1).3–5
O
O
O
N
O
N
N
H3C
NHAc
NHAc
F
1
2
DuP 721
Linezolid
Figure 1.
The potential of this new antibacterial class has stimu-
lated an exploratory chemical analog program in our
discovery research laboratories. In the present commu-
nication, we wish to report the synthesis and microbio-
logical evaluation of a series of hitherto unknown
substituted aryloxy/thioaryloxy oxazolidinone deriva-
tives 12, 14–18.
Early studies of DuP 721 revealed a number of attractive
features but despite these attractive features, the devel-
opment of DuP 721 was terminated.6 Pharmacia group
found Linezolid (2, Fig. 1),7,8 which is well known as
the first promising candidate of oxazolidinone and
works effectively against numerous serious Gram-posi-
tive human pathogens caused by MRSA and VRE.
Compounds 12, 14–18 were synthesized in various steps
as shown in Scheme 1. Compound 7 was synthesized
starting from 1,2-difluoro-4-nitrobenzene (3). Com-
pound 3 on condensation with 4-acetamidophenol/thio-
phenol in the presence of K2CO3 in DMF at 80°C gave
N-(4-[2-fluoro-4-nitro-phenoxy/phenylthio]phenyl)acet-
amide (5) in excellent yields, which on reduction by
Pd–C/H2 followed by condensation with benzyl chloro-
formate gave benzyl 4-(4-[acetylamino]phenoxy/
phenylthio)-3-fluorophenyl-carbamate (7). Conversion
Keywords: Antibacterial; Oxazolidinone; Aryloxy/thioaryloxy deriva-
tives; Resistant bacteria.
*
Corresponding author. Tel.: +91-20-25126689; fax: +91-20-
25863630; e-mail addresses: sanjayjain@lupinpharma.com; sanjayjain_
ran@hotmail.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.06.096

4648
V. Arora et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4647–4650
X
NH2
X
NO2
(ii)
(i)
+
F
NO2
XH
F
F
NHCOCH3
F
NHCOCH3
NHCOCH3
3
5
6
4
X = O, S
O
(iii)
(iv)(v)
O
X
NH
O
X
N
OH
O
F
Ph
F
NHCOCH3
NHCOCH3
7
8
O
O
O
N
(vii)
(vi)
O
O
O
X
N
X
N
X
OMs
N3
R
F
F
F
NHCOCH3
NHCOCH3
NHCOCH3
9
10
11-18
11a,b: R = NH2
12a-d: R = NHCOCH3
13a,b: R = NCS
(viii)
(ix)
(x)
14a,b: R = NHCSNH2
(xi)
15a,b: R = NHCSOCH3
16a,b: R = NHCSNMe2
17a,b: R = NHCSNHNH2
(xii)
(xiii, xiv)
(xv)
NHCSHN
18a,b: R =
Scheme 1. Reagents and conditions: (i) K2CO3, DMF, 75–80°C, 3–4h; (ii) 10% Pd–C, HCO2NH4, MeOH, reflux, 0.5–1h; (iii) Cbz-Cl, Na2CO3,
acetone–H2O (2:1), 0!25°C, 3h; (iv) n-BuLi, (R)-glycidyl butyrate, THF, ꢀ78!25°C, 12h; (v) MsCl, TEA, DCM, 0–25°C, 3–4h; (vi) NaN3,
DMF, 80°C, 5–6h; (vii) PPh3, acetonitrile, 45°C, 1h, H2O, 65–70°C, 3–4h; (viii) Ac2O, pyridine, 25°C, 3–4h; (ix) CS2 solution, ClCO2Et, TEA,
THF, 0!25°C, 12–14h; (x) MeOH–NH3, 0 –5°C, 4–6h; (xi) NaH, MeOH, 0–5°C, 2–3h; (xii) Me2NHÆHCl, TEA, DCM, 0!25°C, 2–3h; (xiii)
phenyl chlorothionoformate, pyridine, PhH, 25°C, 2–4h; (xiv) NH2NH2ÆH2O, dioxane, reflux, 0.5–1h; (xv) cyclopropylamine, DCM, 0!25°C,
4–5h.
of compound 7 to N-(4-{2-fluoro-4-[(5R)-5-(hydroxy-
methyl)-2-oxo-1,3-oxazolidin-3-yl]phenoxy/phenylthio}-
phenyl)acetamide (8) was accomplished by use of n-bu-
tyl lithium and (R)-glycidyl butyrate in THF at
ꢀ78°C. The alcohol 8 was reacted with methanesulfonyl
chloride, followed by treatment with sodium azide to yield
N-(4-{4-[(5S)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-
1). All new compounds reported here were fully charac-
terized on the basis of complementary spectroscopic (1H
NMR and MS) and analytical data.9
A large number of compounds were synthesized (Table
1) and evaluated for antibacterial activity by agar diffu-
sion and agar dilution method as per NCCLS recom-
mendations.10 Among them, 12 compounds exhibited
mild to good activity in the preliminary screen (agar dif-
fusion assay) at 50and 25 lg concentrations. All these
compounds were then tested for determination of mini-
mal inhibitory concentration (MIC) against a panel of
Gram-positive and Gram-negative organisms, some of
which are resistant to methicillin and vancomycin. Their
MIC (lg/mL) are shown in Table 1. Linezolid was used
as reference compound.
2-fluoro-phenoxy/phenylthio}phenyl)acetamide
(10).
Reduction of azide 10 using PPh3 gave the key
intermediate N-(4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-
oxazolidin-3-yl]-2-fluoro-phenoxy/phenylthio}phenyl)-
acetamide (11a and 11b). Acetylation of 11 with acetic
anhydride in pyridine gave N-(4-{4-[(5S)-5-[(acetylami-
no)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-fluoro-phenoxy/
phenylthio}phenyl)acetamide (12a and 12b) in quantita-
tive yields. Thiourea derivatives 14a and 14b were
obtained from the isothiocyanate 13a and 13b, which
were easily derived from key intermediate 11 by treat-
ment with carbon disulfide solution and ethyl chlorofor-
mate. The thiocarbamate derivatives 15a and 15b were
prepared from 13a and 13b by treatment with NaH
and methanol. Compounds 16–17a and 16–17b were
prepared by reacting isothiocyanate 13 with dimethyl-
amine and cyclopropylamine, respectively. Compounds
18a and 18b were also prepared by the condensation
of 11 with phenyl chlorothionoformate followed by its
reaction with hydrazine hydrate in dioxane (Scheme
The antibacterial data in Table 1 clearly show that com-
pounds 12a and 14a containing p-acetamido phenol are
nearly as active as linezolid in vitro MIC assay against
sensitive and drug resistant gram-positive bacteria
though both the compounds have different substitution
at the other end of oxazolidinone ring (12a: R=NHC-
OCH3, 14a: R=NHCSNH2). Further, the replacement
of phenol by thiophenol (12b and 14b) led to increase
in antibacterial activity. This suggests that the thio-
phenol moiety is more preferable as compared to phenol.

V. Arora et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4647–4650
4649
Further, we also modified the thiourea group into thio-
carbamate (15a and 15b) and found a decrease in anti-
bacterial activity, however, 15b is found to be slightly
superior to its phenolic analog 15a. The data given in
Table 1 reveal that any bulky substituent (16–18a,b)
led to the significant loss in antibacterial activities,
which suggests that bulky substituents are not favorable.
It is worth mentioning that compounds 12b and 14b
containing p-acetamido thiophenol group showed com-
parable antibacterial activity against MRSA and VRE
with that of linezolid.
In summary, a number of aryloxy/thioaryloxy oxazolid-
inone derivatives were synthesized and evaluated for
microbiological activity against resistant and susceptible
Gram-positive organisms were found to have activity
comparable to linezolid. These findings clearly indicate
that small groups are well tolerated on the methylamino
moiety of oxazolidinone ring; however, bulky substitu-
ent at this end resulted in loss of activity.
Acknowledgements
We wish to express our thanks to Dr. Sudershan K.
Arora, President R&D of Lupin Research Park for
encouragement of this work and the analytical chemis-
1
try department for H NMR, mass spectroscopy, ele-
mental analyses of compounds synthesized.
References and notes
1. Gregory, W. A.; Brittelli, D. R.; Wang, C.-L. J.; Wuonola,
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2. Eustice, D. C.; Feldman, P. A.; Zajac, I.; Slee, A. M.
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3. Slee, A. M.; Wuonola, M. A.; McRipley, R. J.; Zajac, I.;
Zawada, M. J.; Bartholomew, P. T.; Gregory, W. A.;
Forbes, M. Antimicrob. Agents Chemother. 1987, 31, 1791.
4. Gregory, W. A.; Brittelli, D. R.; Wang, C.-L. J.; Kezar, H.
S.; Carlson, R. K.; Park, C.-H.; Corless, P. F.; Miller, S.
J.; Rajagopalan, P.; Wuonola, M. A.; McRipley, R. J.;
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33, 2569.
5. Park, C.-H.; Brittelli, D. R.; Wang, C.-L. J.; Marsh, F. D.;
Gregory, W. A.; Wuonola, M. A.; McRipley, R. J.;
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35, 1156.
6. Scrip World Pharmaceutical News, October 13, 1987; 1250,
p 25. Pharmaprojects, April 12, 1995, PJB Publications
Ltd., Richmond, Surrey, U.K. Pharmcast-International,
February 1995; 7-1-484, 487.
7. Brickner, S. J.; Hutchinson, D. K.; Barbachyn, M. R.;
Garmon, S. A.; Grega, K. C.; Hendges, S. K.; Manninen,
P. R.; Toops, D. S.; Ulanowicz, D. A.; Kilburn, J. O.;
Glickman, S.; Zurenko, G. E.; Ford, C. W. 35th
Interscience Conference on Antimicrobial Agents and
Chemotherapy, San Francisco, September 1995; F 208, p
149.
8. Brickner, S. J.; Hutchinson, D. K.; Barbachyn, M. R.;
Manninen, P. R.; Ulanowicz, D. A.; Garmon, S. A.;

4650
V. Arora et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4647–4650
Grega, G. E.; Hendges, S. K.; Toops, D. S.; Ford, C. W.;
Zurenko, G. E. J. Med. Chem. 1996, 39, 673.
Found: C, 55.87; H, 4.89; N, 9.77. 15b: 1H NMR: d 10.05
(br s, 1H), 7.85–7.90(m, 2H), 7.70–7.80(br s, 1H), 7.15–
7.25 (m, 1H), 7.00–7.10 (m, 2H), 6.40–6.75 (m, 2H), 4.35–
4.50(m, 1H), 3.85–4.25 (m, 4H), 3.80(s, 3H), 2.10(s, 3H).
MS: m/z 450(M+1). Anal. Calcd for C 20H20FN3O4S2: C,
53.44; H, 4.48; N, 9.35. Found: C, 53.23; H, 4.39; N, 9.04.
16a: 1H NMR: d 10.00 (br s, 1H), 7.55–7.65 (m, 2H), 6.75–
7.00 (m, 4H), 6.30–6.60 (m, 2H), 4.30–4.45 (m, 1H), 3.85–
4.25 (m, 4H), 3.25 (s, 6H), 2.10(s, 3H). MS: m/z 447
(M+1). Anal. Calcd for C21H23FN4O4S: C, 56.49; H, 5.19;
N, 12.55. Found: C, 56.31; H, 4.96; N, 12.29. 16b: 1H
NMR: d 9.95 (br s, 1H), 7.80–7.90 (m, 2H), 7.05–7.25 (m,
3H), 6.75–6.80(br s, 1H), 6.45–6.75 (m, 2H), 4.30–4.45 (m,
1H), 3.80–4.30 (m, 4H), 3.30 (s, 6H), 2.15 (s, 3H). MS: m/z
463 (M+1). Anal. Calcd for C21H23FN4O3S2: C, 54.53; H,
5.01; N, 12.11. Found: C, 54.78; H, 5.27; N, 12.44. 17a: 1H
NMR: d 10.10 (br s, 1H), 7.55–7.65 (m, 2H), 6.95–7.00 (m,
1H), 6.80–6.85 (m, 2H), 6.30–6.60 (m, 2H), 5.55–5.65 (br s,
4H), 4.55–4.65 (m, 1H), 3.90–4.30 (m, 4H), 2.15 (s, 3H).
MS: m/z 434 (M+1). Anal. Calcd for C19H20FN5O4S: C,
52.65; H, 4.65; N, 16.16. Found: C, 52.96; H, 4.87; N,
16.22. 17b: 1H NMR: d 10.05 (br s, 1H), 7.85–7.95 (m,
2H), 7.10–7.25 (m, 3H), 6.40–6.75 (m, 2H), 6.60–6.65 (br s,
4H), 4.55–4.65 (m, 1H), 3.90–4.35 (m, 4H), 2.10 (s, 3H).
MS: m/z 450(M+1). Anal. Calcd for C 19H20FN5O3S2: C,
50.77; H, 4.48; N, 15.58. Found: C, 50.45; H, 4.29; N,
15.37. 18a: 1H NMR: d 9.95 (br s, 1H), 7.60–7.70 (m, 2H),
6.80–7.00 (m, 5H), 6.25–6.60 (m, 2H), 4.40–4.50 (m, 1H),
3.85–4.25 (m, 4H), 2.10(s, 3H), 1.70–1.75 (m, 1H), 1.35–
1.55 (m, 4H). MS: m/z 459 (M+1). Anal. Calcd for
C22H23FN4O4S: C, 57.63; H, 5.06; N, 12.22. Found: C,
57.47; H, 4.85; N, 12.01. 18b: 1H NMR: d 9.90(br s, 1H),
7.85–7.95 (m, 2H), 7.10–7.25 (m, 3H), 6.90–6.95 (br s, 2H),
6.45–6.80(m, 2H), 4.40–4.50(m, 1H), 3.85–4.30(m, 4H),
2.05 (s, 3H), 1.40–1.75 (m, 5H). MS: m/z 475 (M+1). Anal.
Calcd for C22H23FN4O3S2: C, 55.68; H, 4.88; N, 11.81.
Found: C, 55.96; H, 5.04; N, 11.95.
9. Analytical data for compounds 12, 14–18. 1H NMR
spectra were recorded on Bruker Advance DRX 200MHz
instrument as solutions in CDCl3 otherwise mentioned.
12a: 1H NMR: d 7.85 (br s, 1H), 7.80(br s, 1H), 7.60–7.65
(m, 2H), 6.95–7.00 (m, 1H), 6.80–6.85 (m, 2H), 6.50–6.60
(m, 1H), 6.30–6.35 (m, 1H), 3.95–4.50 (m, 3H), 3.40–3.65
(m, 2H), 2.00 (s, 3H), 1.75 (s, 3H). MS: m/z 402 (M+1).
Anal. Calcd for C20H20FN3O5: C, 59.85; H, 5.02; N, 10.47.
Found: C, 59.54; H, 4.83; N, 10.25. 12b: 1H NMR: d 7.85–
7.90 (m, 3H), 7.75 (br s, 1H), 7.20–7.25 (m, 1H), 7.10–7.15
(m, 2H), 6.45–6.75 (m, 2H), 3.95–4.25 (m, 3H), 3.45–3.65
(m, 2H), 2.05 (s, 3H), 1.75 (s, 3H). MS: m/z 418 (M+1).
Anal. Calcd for C20H20FN3O4S: C, 57.54; H, 4.83; N,
10.07. Found: C, 57.69; H, 4.99; N, 10.32. 12c: 1H NMR: d
12.00 (br s, 1H), 7.40–7.45 (m, 1H), 7.10–7.20 (m, 2H),
6.65–6.85 (m, 2H), 6.25–6.35 (m, 2H), 5.85–5.95 (br s, 1H),
3.95–4.20(m, 3H), 3.40–3.70(m, 2H), 2.10(s, 3H), 1.85 (s,
3H). MS: m/z 402 (M+1). Anal. Calcd for C20H20FN3O5:
C, 59.85; H, 5.02; N, 10.47. Found: C, 60.07; H, 5.24; N,
10.71. 12d: 1H NMR: d 9.35 (br s, 1H), 7.00–7.20 (m, 3H),
6.90–6.95 (m, 1H), 6.70–6.65 (m, 1H), 6.55–6.50 (m, 1H),
6.30–6.35 (m, 1H), 5.80–5.90 (br s, 1H), 3.90–4.25 (m, 3H),
3.45–3.65 (m, 2H), 2.15 (s, 3H), 1.90(s, 3H). MS: m/z 402
(M+1). Anal. Calcd for C20H20FN3O5: C, 59.85; H, 5.02;
N, 10.47. Found: C, 59.99; H, 5.33; N, 10.62. 14a: 1H
NMR: d 9.95 (br s, 1H), 7.55–7.65 (m, 2H), 6.90–6.95 (m,
1H), 6.75–6.85 (m, 2H), 6.55–6.60(m, 1H), 6.30–6.35 (br s,
3H), 6.25–6.35 (m, 1H), 4.45–4.65 (m, 1H), 3.90–4.20 (m,
4H), 2.10(s, 3H). MS: m/z 419 (M+1). Anal. Calcd for
C19H19FN4O4S: C, 54.54; H, 4.58; N, 13.39. Found: C,
54.91; H, 4.84; N, 13.70. 14b: 1H NMR: d 10.00 (br s, 1H),
7.85–7.95 (m, 2H), 7.15–7.25 (m, 1H), 7.00–7.10 (m, 2H),
6.75–6.70(m, 1H), 6.45–6.40(m, 1H), 6.25–6.35 (br s, 3H),
4.55–4.65 (m, 1H), 3.90–4.25 (m, 4H), 2.15 (s, 3H). MS:
m/z 435 (M+1). Anal. Calcd for C19H19FN4O3S2: C,
52.52; H, 4.41; N, 12.89. Found: C, 52.76; H, 4.63; N,
10. National Committee for Clinical Laboratory Standards
(NCCLS), 1997. Methods for dilution antimicrobial sus-
ceptibility tests for bacteria that grow aerobically, 4th ed.
Approved standard. NCCLS Document M7-A4. National
Committee for Clinical Laboratory Standards, Villanova,
PA.
1
13.08. 15a: H NMR: d 9.95 (br s, 1H), 7.70–7.75 (br s,
1H), 7.55–7.65 (m, 2H), 6.95–7.00 (m, 1H), 6.80–6.85 (m,
2H), 6.30–6.60 (m, 2H), 4.40–4.50 (m, 1H), 3.90–4.25 (m,
4H), 3.85 (s, 3H), 2.05 (s, 3H). MS: m/z 434 (M+1). Anal.
Calcd for C20H20FN3O5S: C, 55.42; H, 4.65; N, 9.69.