Synthesis and biological activity of novel oxazolidinones

Article abstract of DOI:10.1016/j.bmcl.2009.09.054

A number of 5-substituted derivatives of Ranbezolid, a novel oxazolidinone were synthesized. Antibacterial activity of the compounds against a number of sensitive and resistant bacteria showed promising results.

Full text of DOI:10.1016/j.bmcl.2009.09.054

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6424–6428
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological activity of novel oxazolidinones
a
a
a
a
b
Biswajit Das a, , A. V. S. Rajarao , Sonali Rudra , Ajay Yadav , Abhijit Ray , Manisha Pandya ,
*
Ashok Rattan b, Anita Mehta a
a Department of Medicinal Chemistry, New Drug Discovery Research, Ranbaxy Research Laboratories, Plot-20, Sector-18, Udyog Vihar, Gurgaon 122001, India
b Department of Infectious Diseases, New Drug Discovery Research, Ranbaxy Research Laboratories, Plot-20, Sector-18, Udyog Vihar, Gurgaon 122001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A number of 5-substituted derivatives of Ranbezolid, a novel oxazolidinone were synthesized. Antibacte-
Received 29 August 2008
Revised 7 January 2009
Accepted 14 September 2009
Available online 17 September 2009
rial activity of the compounds against a number of sensitive and resistant bacteria showed promising
results.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Antibacterial
Oxazolidinone
Nitro-furan
Ranbezolid
Oxazolidinones were first discovered in the late 1970s at
DuPont and were of great interest in view of their activity against
methicillin-resistant Staphylococcus aureus (MRSA) and methicil-
lin-resistant Staphylococcus epidermidis (MRSE). These strains
were becoming increasingly problematic in clinical settings. As
the scenario of infectious diseases changed in the 1990s, oxazolid-
inones were also found to exhibit potent activity against more re-
cently problematic penicillin-resistant Streptococcus pneumoniae
(PRSP) strains and the vancomycin-resistant Enterococcus faecium
(VRE) and vancomycin-intermediate Staphylococcus aureus
(VISA).1,2 The oxazolidinone class also exhibits activity against
multi-drug resistant mycobacterium tuberculosis strains. Oxazo-
lidinones are orally active synthetic antibacterial agents that act
by inhibiting protein synthesis at the ribosomal level. Their unique
mode of action offers a potential for low cross resistance with
existing antimicrobial protein synthesis inhibitors.3,4
O
O
O
N
N
NHCOCH3
F
Linezolid
O
O
N
N
N
O
NHCOCH3
O2N
F
.HCl
Ranbezolid
Linezolid,5 the first member of the oxazolidinone class to be
introduced by Pharmacia in 2000 was approved for the treatment
of multi-drug resistant gram-positive infections such as nosoco-
mial and community acquired pneumonia and skin infections.
Recently, linezolid-resistant isolates6 have been reported and
the development of resistance necessitates the urgent exploration
of new oxazolidinone series with greater potency and a broader
spectrum of activity.
was found that minor variations in the acetamidomethyl group
at C-5 position led to a decrease in activity. In other studies, Bayer
and Versicor showed that sulfur isosteres of the acetamidomethyl
side chain such as thioamides, thioureas or thiocarbamates could
also give highly potent compounds, often better than the acetam-
ido derivatives.8 Phillips et al.9,10 reported the synthesis and anti-
bacterial activity of 5-substituted oxazolidinones with various
substituents at the 5-position of the oxazolidinone ring. Gravestock
et al. from AstraZeneca reported on a new class of antibacterial
oxazolidinone with C-5 methylene O-linked and N-linked hetero-
cyclic side chains.11
The SAR of the oxazolidinone C-5 side chain has been exten-
sively explored by the DuPont group in their early studies.7 It
As part of the Ranbaxy oxazolidinone discovery program, RBx
* Corresponding author. Tel.: +91 124 2342001–10x5172; fax: +91 124 234544.
E-mail address: biswajit.das@ranbaxy.com (B. Das).
7644 (Ranbezolid) was developed as a clinical candidate.12 In the
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.09.054

B. Das et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6424–6428
6425
Table 1
Chemical yield and in-vitro activity of compounds 1–26
O
O
N
N
N
O
O2N
R
F
Compd
R
% Yielda
MIC (
l
g/mL) (organisms)b
S.au 25923
S.au 15187
MRSA 562
MRSA 33
E.fa 29212
VRE 6A
S.py 19615
S.pn 6303
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
NH2
61
50
22
38
50
48
54
45
20
24
50
53
50
56
25
23
50
>16
4
2
>16
2
1
>16
2
2
>16
4
2
>16
4
2
>16
4
2
>16
0.5
0.5
0.5
>16
>16
>16
>16
0.5
1
0.25
>16
>16
0.5
1
>16
1
NHCOCH2F
NHCOCHF2
NHCOCH2Cl
NHCOCHCl2
NHCOCHClCH3
NCS
NHCSSCH3
NHCSCH3
NHCSOCH3
NHCSNH2
NHCSN(CH3)2
NHCOCH2OCH3
NHCHO
NHCOOCH3
NHCOOC2H5
NHCOCH@CHPh
0.5
0.5
>16
>16
>16
>16
0.25
0.5
<0.06
>16
>16
1
2
2
2
2
2
2
>16
>16
>16
>16
1
2
1
>16
>16
4
>16
>16
>16
>16
1
2
1
>16
>16
2
>16
>16
>16
>16
1
2
1
>16
>16
2
>16
>16
>16
>16
1
2
1
>16
>16
2
>16
>16
>16
>16
1
>16
>16
>16
>16
1
1
1
>16
>16
4
1
0.5
>16
>16
2
8
>16
>16
8
>16
>16
8
>16
>16
2
>16
>16
8
>16
>16
8
>16
>16
1
>16
>16
>16
>16
O
O
F
18
19
50
18
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
O
H
H
N
O
N
H
N
20
21
22
23
25
12
14
17
>16
>16
8
>16
>16
2
>16
>16
1
>16
>16
2
>16
>16
4
>16
>16
>8
>16
>16
>8
>16
>16
8
O
O
H
N
NO2
S
O
O
O
O
O
H
N
NO2
Br
H
N
>16
>16
>16
>16
>16
>16
>16
>16
H
N
24
25
26
50
22
50
2
2
2
2
2
2
1
1
N
O
OH
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
O
N
O
Linezolid
Ranbezolid
2
1
2
2
2
2
2
2
2
2
2
2
0.125
0.125
a
% Yield: chemical yield in the final step of the synthetic sequence.
Organisms: S.au 25923, Staphylococcus aureus ATCC 25923; S.au 15187, Staphylococcus aureus 15187; MRSA 562, methicillin-resistant Staphylococcus aureus 562; MRSA
b
33, methicillin-resistant Staphylococcus aureus 33; E.fa 29212, Enterococcus faecalis ATCC 29212; VRE 6A, vancomycin-resistant Enterococcus faecium 6A; S.py 19615, Strep-
tococcus pyogenes ATCC 19615; S.pn 6303, Streptococcus pneumoniae ATCC 6303.

6426
B. Das et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6424–6428
O
O
O
a
O
O
O
O
N
N
N
H
N
N
N
O
N
O
NH2
R
F
F
28
27
b
O
O
c
O
O
O
O
H
N
N
N
N
N
N
H
H
N
O2N
N
O
R
R
F
F
29
2: R= CH2F
3: R= CHF2
4: R= CH2Cl
5: R= CHCl2
6: R= CHClCH3
Scheme 1. Reagents and conditions: for compounds 2–6 (a) HOBT, NMM, EDC, DMF, carboxylic acid, 0 °C to rt for 24 h; (b) TFA, DCM, 0 °C to 10 °C, 2 h; (c) 5-nitrofuran-2-
carboxaldehyde, sodium triacetoxyborohydride, THF, molecular sieve (4 Å), rt, 24 h.
present Letter we wish to report the synthesis and antibacterial
activity of novel C-5 substituted derivatives of Ranbezolid. The
different types of substituents that are incorporated are mentioned
in Table 1 (compds 1–26). Compounds 2–6 consist of derivatives
wherein the acetamido methyl group was replaced by haloalkyl
derivatives. Compounds bearing formamide (14), carbamate (15,
16), thioamide (9), thiocyanide (7), thioester (8), thioketone (9),
thiourea (11, 12), methoxymethylacetamide (13) and cinnamoyl
(17–19) groups were also synthesized. In another set of compounds,
the heterocyclic derivatives (20–22, 24, 26) were synthesized.
A number of halomethyl and cinnamoyl derivatives of Ranbezo-
lid were synthesized (Scheme 1). The amine 2713 on treatment
O
O
O
H
N
O
a
O
H
N
N
N
N
O2N
O
N
N
N
O2N
O
H
CH3
F
F
Ranbezolid
1
b
c
O
O
O
N
N
N
O2N
O
H
N
S
O
N
N
N
O2N
R
O
F
CH3
F
8,13-16,19-23
9
O
8: R= NHCSSMe
13: R= NHCOCH2OCH3
14: R= NHCHO
15: R= NHCOOCH3
NH
O
17: R=
19: R=
O
NH
O
F
NH
18: R=
O
16: R= NHCOOC2H5
NH
NH
22: R=
NH
20: R=
23: R=
21: R=
NO2
NO2
S
O
O
O
O
O
NH
Br
O
O
Scheme 2. Reagents and conditions: (a) 1 N HCl (aq), reflux, 8 h; (b) for 8: TEA, dichloromethane, CS2, 0 °C to rt, 7 h, then CH3I, rt, 30 min; for 13: TEA, dichloromethane,
methoxyacetyl chloride, 0 °C to rt, 18 h; for 14: ethyl formate, 80 °C, 18 h; for 15, 16: TEA, dichloromethane, then methyl chloroformate for or ethyl chloroformate, 0 °C to rt,
18 h; for 17–23: HOBT, NMM, EDC, DMF, cinnamic acid, 3,4-methylenedioxycinnamic acid, 4-fluorocinnamic acid, benzofuran-2-carboxylic acid, 5-nitro-2-thiophene
carboxylic acid, 5-nitro-2-furoic acid, 5-bromo-2-furoic acid respectively, at 0 °C to rt, 24 h; (c) Lawesson’s reagent, toluene, 90 °C.

B. Das et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6424–6428
6427
O
O
a
O
O
H
N
N
N
7
N
O2N
N
N
N
O
O2N
O
NCS
H
F
F
1
b
O
O
N
N
N
O2N
O
R
F
10: R= NHCSOCH3
11: R= NHCSNH2
12: R= NHCSN(CH3)2
Scheme 3. Reagents and conditions: (a) CS2, TEA, THF, rt, 5 h, 0 °C, ethylchloroformate, 2 h; (b) 10: MeOH, TEA, diethylamine hydrochloride, rt, 2 h; for 11: MeOH, methanolic
ammonia, 0 °C, 3 h; for 12: dimethylamine, MeOH, 0 °C to rt, 3 h.
with different carboxylic acids or acyl chlorides gave the respective
amides (28). The Boc-group was removed under acidic conditions
and the subsequent compounds subjected to a reductive amination
reaction to give nitrofuran compounds (2–6, 17, 18).
A number of other amides in which the methyl group was re-
placed by different heteroaroyl groups is mentioned in Scheme 2.
According to this procedure, the acetamido group of Ranbezolid
was hydrolyzed by hydrochloric acid to give the corresponding
amino compound (1). The desired amide derivatives (8, 13–16,
19–23) were made from amine 1 using alkyl and acyl chlorides
in the presence of base in dichloromethane. Treatment of Ranbezo-
lid with Lawesson’s reagent produced the thioamide derivative 9.
In Scheme 3, a number of thiocarbamates (10), and thioureas
(11, 12) were prepared from thiocyanide derivative (7) using
methanol, ammoniacal methanol and dimethylamine. Compound
(7) was synthesized from amine (1) using carbondisulphide and
triethylamine.
In Scheme 4, the O-substituted derivative (26) and the N-substi-
tuted derivative (24) at the C-5 position were made from the hy-
droxyl methyl derivative (30). When this hydoxymethyl
compound (30) was treated with 2-hydroxy isoxazole and DIAD
compound 33 was formed. Compound 33 was treated with trifluo-
O
O
O
O
a
O
O
N
N
N
N
N
N
O
OMs
O
OH
F
F
31
30
b
c
e
O
O
O
O
O
O
boc
N
O
O
N
N
N
N
N
N
N
N
N
O2N
O
O
O
OH
O
N
O
F
N
O
F
F
33
32
25
c, d
c, d
O
O
O
H
N
O
N
N
N
O2N
N
N
N
O2N
O
O
O
N
O
F
N
O
F
24
26
Scheme 4. Reagents and conditions: TEA, MsCl, DCM, 0 °C to rt, 4 h; (b) NaH, N-boc-2-aminoisoxazole, DMF, 80 °C, 2 h; (c) TFA, DCM, 0 °C, 2 h, THF, molecular sieves (4 Å); (d)
5-nitro-furan-2-carboxaldehyde, sodium triacetoxyborohydride, rt, 24 h; (e) 2-hydroxyisoxazole, diisopropylazadicarboxylate, PPh3, THF, 5 °C to rt, 2 h.

6428
B. Das et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6424–6428
roacetic acid in dichloromethane to remove Boc-group, this NH
compound was then subjected to reductive amination to give com-
pound 26. By using similar method compound 25 was obtained
from compound 30. Similarly N-isoxazole derivative (24) was ob-
tained from mesylderivative (31) by treatment with Boc protected
aminoisoxazole followed by Boc deprotection in acidic condition.
Compounds were tested in-vitro against a panel of gram-posi-
tive bacteria. MIC values were determined using the NCCLS meth-
od and Ranbezolid and Linezolid were used as reference standards.
When the 5-acetamido methyl group of Ranbezolid was replaced
by difluoromethyl and chloromethyl, the resulting compounds (3, 4)
showed comparable activity to Ranbezolid and Linezolid against S.
au sensitive and resistant strains but their activity against S. pyoge-
nes and S. pneum were four fold superior to Linezolid and four fold
inferior to Ranbezolid. Compound 2, in which the methyl group
was replaced by fluoromethyl showed slightly inferior activity
against different gram-positive strains compared to Ranbezolid.
When the group was replaced by a dichloromethyl, chloromethyl
or methoxymethyl group (5, 6, 13), a significant decrease in activity
was observed. When the methyl group was replaced by aryl substit-
uents (20–23), reasonable activity was only observed for nitrofuran
compound22. Substitutedcinnamoylderivatives (17–19) uniformly
led to weakly active compounds. Among the sulfur containing com-
pounds (7–12) only the thioamide and thiourea derivatives (9, 11)
showed better activity than Ranbezolid. The methyl and ethyl carba-
mate derivatives (15, 16) and the formamide showed inferior activ-
ity to Ranbezolid. When the acetamide group was replaced with an
N-linked 3-substitued oxazole, the compound (24) showed compa-
rable activity to Ranbezolid and Linezolid. The 5-hydroxymethyl
derivative (25) and its O-linked oxazole derivative (26) showed
weak activity against target pathogens.
ring (compare 4 with 5, 6, 13; 9 with 8; 11 with 12; and 15 with
16b 17, 18, 19).
Acknowledgments
We would like to thank Drs Pradip Bhatnagar, Ian A. Cliffe and
Dharam Vir for their valuable comments; and the Analytical Dept.
for the spectral data.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.09.054.
References and notes
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In summary, only a very few 5-substituted derivatives were tol-
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and these were the thioamide, thiourea, and difluoromethyl deriv-
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