Synthesis and antibacterial activity of novel oxazolidinones with methylene oxygen- and methylene sulfur-linked substituents at C5-position

Article abstract of DOI:10.1016/j.bmcl.2007.06.056

Novel oxazolidinone derivatives of the lead compound RBx 8700, containing methylene oxygen- and methylene sulfur-linked substituents at the C5-position, were synthesized. Antibacterial screening of these compounds against a panel of resistant and susceptible Gram-positive and fastidious Gram-negative bacteria gave compounds 2 and 4 as new antibacterial agents.

Full text of DOI:10.1016/j.bmcl.2007.06.056

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4778–4783
Synthesis and antibacterial activity of novel oxazolidinones
with methylene oxygen- and methylene sulfur-linked
substituents at C5-position
Sonali Rudra,a,* Fnu Sangita,a Arti Gujrati,a Manisha Pandya,b Pragya Bhateja,b
Tarun Mathur,b Smita Singhal,b Ashok Rattan,b Mohammed Salmana and Biswajit Dasa
aDepartment of Medicinal Chemistry, New Drug Discovery Research, Ranbaxy Laboratories Limited,
Plot-20, Sector-18, Udyog Vihar, Gurgaon 122001, India
bDepartment of Infectious Diseases, New Drug Discovery Research, Ranbaxy Laboratories Limited, Plot-20,
Sector-18, Udyog Vihar, Gurgaon 122001, India
Received 30 January 2007; revised 28 May 2007; accepted 20 June 2007
Available online 26 June 2007
Abstract—Novel oxazolidinone derivatives of the lead compound RBx 8700, containing methylene oxygen- and methylene sulfur-
linked substituents at the C5-position, were synthesized. Antibacterial screening of these compounds against a panel of resistant and
susceptible Gram-positive and fastidious Gram-negative bacteria gave compounds 2 and 4 as new antibacterial agents.
Ó 2007 Elsevier Ltd. All rights reserved.
O
Oxazolidinone antibacterial agents represented by linezo-
lid1 (ZyvoxTM), approved for use in humans in April 2000,
C-5 acyl-amino group
2
O
1
O
N
N
3
emerged as the first totally synthetic, structurally distinct,
and mechanistically novel class of antibacterial agents
since the discovery of trimethoprim in 1968. Linezolid is
active against Gram-positive pathogens such as
methicillin-resistant Staphylococcus aureus (MRSA),
methicillin-resistant Staphylococcus epidermidis (MRSE),
vancomycin-resistant Enterococcus faecium (VRE),
Streptococcus pneumoniae (S.pn), and Streptococcus
pyogenes (S.py), which cause various nosocomial and
community-acquired infections, including bacteremia,
pneumonia, and skin infections.2,3 Linezolid exhibits its
antibacterial activity by inhibiting bacterial protein
synthesis via binding to the 50S ribosomal subunit and
interfering with the fMet-tRNA binding to the P-site of
the ribosomal peptidyltransferase center.4 The therapy
profile of linezolid is less than ideal5 because it is inactive
against Gram-negative bacilli, requires a twice daily
dosing regimen, and may cause bone marrow toxicity
on usage of more than two weeks. Thus, an oxazolidinone
antibiotic with a broader antibacterial spectrum, and a
better pharmacokinetic and safety profile than linezolid,
may be a useful addition in the armamentarium of anti-
biotics for treating infections.
NHCOCH3
5
4
F
Linezolid (ZyvoxTM, Pharmacia/Pfizer)
Early SAR emerging from work of Barbachyn et al. on
oxazolidinones indicated that the C5-acylamino group
was essential for good activity.6 However, it has now been
shown that compounds bearing thio-amides, thio-ureas,
halogen-substituted methyl-amides, ureas, N-carba-
mates, etc. have superior or similar activity to linezo-
lid,5,7–9 and indeed a radical modification involving the
introduction of O-linked and N-linked heterocycles at
the C5-position led to the discovery of a clinical com-
pound AZD-2563.10–12 The replacement of the C5 N-acet-
amido group with thiocarbonyl functional groups has
provided compounds with enhanced spectra of antibacte-
rial activity such as activity against fastidious Gram-neg-
ative bacteria Haemophilus influenzae and Moraxella
catarrhalis.5
F
O
OH
O
HO
N
N
O
O
F
O
N
AZD 2563
Keywords: Antibacterial; Oxazolidinone; RBx 8700; Nitro-thiophene.
*
From our in-house oxazolidinone discovery program,
we previously obtained RBx 8700 (1) as a potent
Corresponding author. Tel.: +91 1242342001 10x5156; fax: +91
1242343544; e-mail: sonali.rudra@ranbaxy.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.06.056

S. Rudra et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4778–4783
4779
Table 1. Synthesized compounds 2–21
Table 1 (continued)
Compounda
R
%Yieldb
O
O
S
S
20
22
N
N
N
S
R
O2N
F
Compounda
R
%Yieldb
21
45
2
3
–OH
–OCH3
55
32
a The compounds were characterized by 400 MHz NMR (Bruker)
spectroscopy and Mass spectroscopy (ESI, Micro mass ZQ2000).
The qualitative purity of the compounds was P85% as observed by
NMR spectroscopy.
O
CH3
4
40
O
b %Yield is the chemical yield in the final step of the synthetic sequence.
H
O
O
N
5
40
O
O
antibacterial compound active against Gram-positive
bacteria and mycobacteria, and modestly active against
fastidious Gram-negative bacteria such as H. influenzae
and M. catarrhalis.13–16 With the opportunities offered
by C5-substitution in mind, we wished to explore the
effect of various methylene oxygen- and methylene
sulfur-linked substituents at the C5-position of RBx
8700. As shown in Table 1, various O-linked carbamates
and thiocarbamates (5–12), O-linked heterocycles (13
and 14, 16–18), and S-linked alkyl and aryl derivatives
(19–21) were synthesized.17
H
N
F
6
7
84
59
H
N
O
O
O
O
CF3
O
H
N
8
9
42
40
S
S
S
H
N
O
Cl
O
N
N
N
S
O2N
NHCOCH3
H
N
F
F
10
11
37
65
1 (RBx 8700)
F
O
S
For the synthesis of the target compounds, the oxazo-
lidinone-methanol derivative 2218 was acylated with
acetic anhydride in pyridine to give compound 23
(Scheme 1). Boc-deprotection, followed by aromatic
substitution of 2-bromo-5-nitro-thiophene, led to com-
pound 4. Hydrolysis of the acetate group of 4 by heat-
ing in 3 N HCl produced compound 2. The alcohol 2
was alkylated with methyliodide using sodium hydride
as base to give 3. Mitsunobu reaction of 2 with
2-hydroxy-6-methylpyridine led to the ether-linked
derivative 17. Treatment of 2 with sodium hydride in
THF at 0 °C followed by substituted isocyanates
produced the carbamate derivatives 5–7 and 11 and
12. Similarly, the thiocarbamate derivatives 8–10 were
obtained by treatment of compound 2 with the corre-
sponding isothiocyanates.
H
N
O
O
O
O
O
S
H
N
O
O
O
12
62
O
H3C
13
14
13
27
N
O
N
N
15
16
41
47
O
O
The synthesis of compounds 13 and 18 is given in
Scheme 2. Mitsunobu reaction of the alcohol 22 with
3-hydroxyisoxazole produced the ether-linked heterocy-
clic intermediate 24a. Heating 22 with sodium hydride
and 2-chloropyrazine led to the ether-linked intermedi-
ate 24b. Boc-deprotection of 24a,b followed by aromatic
substitution as described earlier led to compounds 13
and 18.19
N
O
N
17
48
CH3
N
O
S
18
19
22
57
For the synthesis of compounds 14–16 (Scheme 3), the
alcohol 22 was converted to the methanesulfonate
derivative 25, which on heating with sodium hydride
and 2-pyridone gave the ether-inked intermediate 26a
N

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S. Rudra et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4778–4783
O
O
O
(a)
O
(b)
O
boc
N
N
N
O
boc
N
N
N
N
N
N
OH
S
O2N
O
O
CH3
F
CH3
F
F
22
O
23
4
O
O
O
(c)
O
N
N
N
(d)
O
N
N
N
S
O2N
OH
S
O2N
F
OMe
F
3
2
(e)
(f)
(g)
O
O
O
O
O
O
N
N
N
N
N
N
N
N
N
S
O2N
S
S
O2N
O2N
O
O
NHR'
O
NHR'
N
F
F
F
S
O
17
8-10
5-7, 11-12
Scheme 1. Reagents and conditions: (a) acetic anhydride, pyridine, rt, 17 h; (b) 0.3 N HCl in ethanol, 0 °C ! rt, 2 h; 2-bromo-5-nitro-thiophene,
N-ethyldiisopropyl amine, acetonitrile, 60 °C, 30 h; (c) 3 N HCl, 100 °C, 2 h; (d) MeI, NaH, THF, 0 °C ! rt, 55 h; (e) 2-hydroxy-6-methylpyridine,
DEAD, PPh3, THF, rt 17 h; (f) NaH, THF, 0 °C, 10 min, then suitably substituted isocyanates, rt, 25 h (for 5), 9 h (for 6 and 7), 1 h (for 11 and 12);
(g) NaH, THF, 0 °C, 10 min, then suitably substituted isothiocyanates, rt, 1 h (for 8), 17 h (for 10), 12 h (for 9).
O
O
O
(a)
O
O
(c)
boc
N
N
N
O
boc
N
N
N
N
N
N
OH
or (b)
OR'
O
S
OR'
O2N
F
F
F
13, 18
22
24a: R' =
N
N
24b: R' =
N
Scheme 2. Reagents and conditions: (a) compound 24a: 3-hydroxyisoxazole, DIAD, PPh3, THF, rt, 18 h; (b) compound 24b: NaH, DMF,
2-chloropyrazine, 80 °C, 4 h; (c) TFA, dichloromethane, 0 °C ! rt, 2 h; 2-bromo-5-nitro-thiophene, N-ethyldiisopropylamine, acetonitrile, 60 °C,
17–24 h.
along with the N-alkylated product 26b. Similarly, on
using 4-hydroxypyridine the intermediate 27 was
obtained. Compounds 26a,b were differentiated by IR:
compound 26b showed a strong conjugated amide peak
at 1661 cmꢀ1. The intermediates 26a,b and 27 were con-
verted to the compounds 14–16 by methods described
earlier.
determined as per NCCLS guidelines (Table 2). The
potencies of the hydroxyl compound 2 and its acetate
derivative 4 were comparable to RBx 8700 against
Staphylococci and Enterococci, and superior to linezo-
lid. The o-tosyl derivative 12 was weakly active. The
in vivo activity of compound 2 against MRSA 33 was
weaker than RBx 8700. The in vivo activity of com-
pound 4 was not evaluated because its in vitro activity
against fastidious Gram-negative organisms was weaker
than RBx 8700.
The sulfur-linked compounds 19–21 were prepared by
the methods shown in Scheme 4. The methanesulfonate
derivative 25 was converted to the thio-ether com-
pounds 28a–c by heating with substituted thiols. Trans-
formation of the intermediates 28a–c to compounds
19–21 was carried out by the methods described earlier.
In general, with the exception of compounds 2 and 4, the
compounds in Table 1 containing methylene oxygen-
linked substituents and isosteric methylene sulfur-linked
substituent, were weaker in antibacterial activity than
the C5-acetamido analog RBx 8700. The calculated log P
value22 of RBx 8700 was 2.82 whilst that of linezolid was
0.43. The calculated log P values of AZD 2563 and its
direct congener compound 13 were 1.60 and 4.36, respec-
tively. Indeed, the calculated log P values of compounds
2–21 were found to be in the range 3.16–7.84, with many
being toward the higher side (>5). Tokuyama et al. have
Compounds 1–21 were screened for their antibacterial
activity against S. pneumoniae, S. aureus, Enterococcus
faecalis, E. facium, and H. influenzae using an agar
diffusion assay.20 Compounds 1, 2, 4, and 12 showed
comparable or better zone of inhibition sizes than the
standards linezolid and vancomycin, and so their
minimum inhibitory concentrations (MIC)21 were

S. Rudra et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4778–4783
4781
O
N
O
(a)
O
O
boc
N
N
boc
N
N
N
OH
OSO2CH3
F
F
22
25
(b)
O
O
O
O
O
O
boc
N
N
N
boc
N
N
N
boc
N
N
N
N
O
O
O
F
F
F
N
N
27
26b
26a
(c)
(c)
(c)
O
O
O
O
O
O
N
N
N
N
N
N
N
N
N
S
S
S
O
O
N
O
O2N
O2N
O2N
F
F
F
N
N
14
16
15
Scheme 3. Reagents and conditions: (a) CH3SO2Cl, Et3N, CH2Cl2, 0 °C, 30 min; (b) 2-pyridone (for 26a,b), 4-hydroxypyridine (for 27), NaH (60%
w/w), DMF, 80 °C, 2 h; (c) 20% TFA/CH2Cl2; 2-bromo-5-nitro-thiophene, N-ethyldiisopropylamine, acetonitrile, 60 °C, 17–24 h.
O
O
O
(a)
O
O
(b)
O
boc
N
N
N
boc
N
N
N
N
N
N
S
OSO2CH3
SR'
O2N
SR'
F
F
F
25
19-21
28a: R' = Et;
28b: R' = n-heptyl;
28c: R' = 2-naphthyl
Scheme 4. Reagents and conditions: (a) NaH (60% w/w), R0SH, DMF, 55 °C, 5 h (for 28a), 6 h (for 28b); 80 °C, 15 min (for 28c);
(b) 2-bromo-5-nitro-thiophene, N-ethyldiisopropylamine, acetonitrile, 60 °C, 17 h (for 19, 20), 2 h (for 21).
reported9 that a log P of ꢀ1 to +2 is favored for strong
in vitro MRSA and VRE activity in a series of thiocarbon-
yl oxazolidinones. However, other authors have reported
no direct correlation between log P and MIC values23 and
that activities were more dependent on the appendages at
the para position of the phenyl ring.23,24 In our case,
Table 2. In vitro and In vivo activity
Microorganismsa
Minimum inhibitory concentrations (MIC) lg/mL
Compound 2
Compound 4
Compound 12
Compound 1 (RBx 8700)
Linezolid
Vancomycin
S.au 25923
S.au 15187
MRSA 562
MRSA 33
E.fa 29212
VRE 6A
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
0.5
0.5
0.5
0.5
0.5
1
16
16
16
16
8
0.25
0.25
0.25
0.25
0.25
0.25
0.125
0.125
0.25
8
2
1
2
0.5
0.5
0.5
4
2
2
2
1
2
>16
0.5
0.5
>16
>64
S.py 19615
S.pn 6303
M.cat M2
H.flu 49247
0.25
1
0.5
1
2
2
2
>16
>16
>8
>16
>4
4
8
ED50 (MRSA 33) mg/kg po
>25
ND
ND
11.15
5.6
ND
a Microorganisms: S.au 25923, Staphylococcus aureus ATCC 25923; S.au 15187, Staphylococcus aureus 15187; MRSA 562, methicillin-resistant
Staphylococcus aureus 562; MRSA 33, methicillin-resistant Staphylococcus aureus 33; E.fa 29212, Enterococcus faecalis ATCC 29212; VRE 6A,
vancomycin-resistant Enterococcus faecium 6A; S.py 19615, Streptococcus pyogenes ATCC 19615; S.pn 6303, Streptococcus pneumoniae ATCC
6303; M.cat M2, Moraxella catarrhalis M2; H.flu 49247, Haemophilus influenzae ATCC 49247.

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S. Rudra et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4778–4783
9. Tokuyama, R.; Takahashi, Y.; Tomita, Y.; Tsubou-
chi, M.; Yoshida, T.; Iwasaki, N.; Kado, N.;
Okezaki, E.; Nagato, O. Chem. Pharm. Bull. 2001,
49, 361.
10. Gravestock, M. B.; Acton, D. G.; Betts, M. J.; Dennis, M.;
Hatter, G.; McGregor, A.; Swain, M. C.; Wilson, R. G.;
Woods, L.; Wookey, A. Bioorg. Med. Chem. Lett. 2003, 13,
4179.
compounds 2 and 4 with calculated log P values of 3.16
and 4.05, respectively, were active in vitro, whereas
compounds 3, 13, and 15 with log P values 3.79, 4.36,
and 3.68, respectively, were less active. Hence, a direct
correlation between MIC values and physicochemical
properties could not be made.
C5 substituted N-carbamates in the tetrahydroquinoline
series of oxazolidinones are reported to have good anti-
bacterial activities against S. aureus and S. pneumoniae
strains.5 In a tricyclic imidazolyl-oxazolidinone series
N-thiocarbamates have 4- to 8-fold more antibacterial
activities than N-carbamates.5 The N-thiocarbamate
analogs of thiomorpholine-phenyl oxazolidinones also
have potent antibacterial activities against Staphylo-
cocci and Enterococcci.9 In our series of compounds,
reversing the N-carbamates and N-thiocarbamates to
O-carbamates and O-thiocarbamates (compounds
5–12) led to weaker antibacterial compounds. These
compounds have bulky hydrophobic groups on the
O-carbamates and O-thiocarbamates and so steric con-
straints may be a limiting factor to their biological
activities. RBx 8700 and compound 2 are the most po-
tent compounds in this series, both containing hydrogen
bond donor substituents at C5-position, which too may
be an important feature in this series of compounds.
11. Reck, F.; Zhou, F.; Girardot, M.; Kern, G.; Eyermann, C.
J.; Hales, N. J.; Ramsar, R. R.; Gravestock, M. B. J. Med.
Chem. 2005, 48, 499.
12. Gravestock, M. B.; Roberts, D. A.; Betts, M. J.; Mills, S.
D.; Hatter, G. PCT WO 00/21960, 2000.
13. Mehta, A.; Rudra, S.; Rajarao, A. V. S.; Yadav, A. S.;
Rattan, A. PCT WO 04/014392, 2004.
14. Sood, R.; Bhaduria, T.; Rao, M.; Gautam, R.; Malhotra,
S.; Barman, T. K.; Upadhyay, D.; Rattan, A. Infect.
Disord. Drug Targets 2006, 6, 343.
15. Sood, R.; Rao, M.; Singhal, S.; Rattan, A. Int. J.
Antimicrob. Agents 2005, 25, 464.
16. Rao, M.; Sood, R.; Malhotra, S.; Fatma, T.; Upadhyay,
D. J.; Rattan, A. J. Chemother. 2006, 18, 144.
17. Mehta, A.; Das, B.; Rudra, S.; Yadav, A.;
Sangita, Salman, M.; Rattan, A. PCT WO 06/
043121, 2006.
18. Hutchinson, D. K.; Brickner, S. J.; Gammill, R. V.; Patel,
M. V. U.S. Patent 5700799, 1997.
19. Analytical data of compound 18: 1H NMR (CDCl3,
300 MHz): d 8.28 (s, 1H, pyrazinyl-H), 8.21 (d, 1H,
J = 2.4 Hz, pyrazinyl-H), 8.09 (d, 1H, pyrazinyl-H), 7.81
(d, 1H, J = 4.8 Hz, thienyl-H), 7.51 (dd, 1H, J = 14.1 Hz,
1.8 Hz, phenyl-H), 7.18 (d, 1H, J = 7.8 Hz, phenyl-H),
6.97 (t, 1H, J = 9 Hz, phenyl-H), 6.02 (d, 1H, J = 4.8 Hz
thienyl-H), 5.06 (m, 1H, oxazolidinyl C5-H), 4.62 (m, 2H,
–CH2–O), 4.17 (t, 1H, oxazolidinyl C4-H), 3.55 (m, 4H,
piperazinyl-H), 3.22 (m, 4H, piperazinyl-H); Mass m/z
(rel. int.): 501.3 (100%, M++H), 523 (45%, M++Na), 455.1
(25%, M+ꢀNO2).
In conclusion, in the RBx 8700 series of compounds,
which contain a thienyl-piperazine group, only small
O-linked groups can be tolerated at the C5-position,
and SAR is more closely aligned with that of linezolid
than that of other O-linked compounds.10
Acknowledgments
20. Agar diffusion assay was performed against fastidious
and facultative bacteria. For fastidious bacteria,
S. pneumoniae—Mueller Hinton agar with 5% sheep
blood was used and for Haemophilus—Haemophilus test
medium with supplements was used. For facultative
bacteria, S. aureus and Enterococci—Mueller Hinton
agar was used. Standard antibiotics used were linezolid
and vancomycin. Bacterial cultures (500 lL of 0.5–0.8
Mc Farland per 50 mL of molten agar) were added into
agar plates. Plates were allowed to settle. Wells of 6 mm
size were punched into the agar. Compounds and
standard antibiotics were subjected to serial 2-fold
dilutions in DMSO and sterile distilled water, respec-
tively. Fifty microliters of each dilution was added into
the wells. The plates were incubated at 37 °C for 18–
24 h. For fastidious organisms CO2 incubator was used
for incubation. Zone of inhibition sizes were measured
using vernier caliper.
21. MIC’s were determined by agar dilution method
(NCCLS) using doubling dilutions in Mueller Hinton
agar. Stock solutions of the compounds and standard
antibiotics were prepared (1 mg/mL) in DMSO and
respective solvents, respectively. Serial 2-fold dilutions
were prepared in respective diluents to get a concentra-
tion range of 16–0.015 lg/mL. Two hundred and ninety
microliters of respective drug dilution was added in
20 mL of molten agar to get the required concentration
range. Direct colony suspensions of bacterial cultures
were made in saline and were adjusted to 0.5 McFar-
land turbidity standard. The inoculum was diluted
10-fold in normal saline. Thirty cultures were replicated
The authors are grateful to Dr. Pradip Bhatnagar, Dr.
Ian Cliffe, and Dr. Dharam Vir, Ranbaxy Laboratories
Limited, for their valuable suggestions. The authors are
also thankful to the Analytical Department, Ranbaxy
Laboratories Limited, for the spectral data.
References and notes
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S. Rudra et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4778–4783
4783
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