Novel and potent oxazolidinone antibacterials featuring 3-indolylglyoxamide substituents

Article abstract of DOI:10.1016/j.bmcl.2008.03.043

Novel oxazolidinone antibacterials bearing a variety of 3-indolylglyoxamide substituents have been explored in an effort to improve the spectrum and potency of this class of agents. A subclass of this series was also made with the diversity at C-5 terminus. These derivatives have been screened against a panel of clinically relevant Gram-positive pathogens and fastidious Gram-negative organisms. Several analogs in this series were identified with in vitro activity superior to linezolid (MIC = 0.25-2 μg/mL). Compounds 10a, 10c, 10e and 10f displayed activity against linezolid resistant Gram-positive organisms (MIC = 2-4 μg/mL). Selected oxazolidinones were evaluated for in vivo efficacy against a mouse systemic infection model.

Full text of DOI:10.1016/j.bmcl.2008.03.043

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 5150–5155
Novel and potent oxazolidinone antibacterials featuring
3-indolylglyoxamide substituentsq
Mohamed Takhi,* Gurpreet Singh, C. Murugan, Nirvesh Thaplyyal, Soma Maitra,
K. M. Bhaskarreddy, P. V. S. Amarnath, Arundhuti Mallik, T. Harisudan,
Ravi Kumar Trivedi, K. Sreenivas, N. Selvakumar and Javed Iqbal
Discovery Research, Dr. Reddy’s Laboratories Ltd, Miyapur, Hyderabad 500 049, India
Received 12 October 2007; revised 15 February 2008; accepted 17 March 2008
Available online 20 March 2008
Abstract—Novel oxazolidinone antibacterials bearing a variety of 3-indolylglyoxamide substituents have been explored in an effort
to improve the spectrum and potency of this class of agents. A subclass of this series was also made with the diversity at C-5 ter-
minus. These derivatives have been screened against a panel of clinically relevant Gram-positive pathogens and fastidious Gram-
negative organisms. Several analogs in this series were identified with in vitro activity superior to linezolid (MIC = 0.25–2 lg/
mL). Compounds 10a, 10c, 10e and 10f displayed activity against linezolid resistant Gram-positive organisms (MIC = 2–4 lg/
mL). Selected oxazolidinones were evaluated for in vivo efficacy against a mouse systemic infection model.
ꢀ 2008 Elsevier Ltd. All rights reserved.
The oxazolidinones, exemplified by linezolid 1 and eper-
ezolid 2, are a group of promising antibacterials active
against a variety of susceptible and resistant Gram-posi-
tive organisms such as methicillin-resistant Staphylococ-
cus aureus (MRSA), vancomycin-resistant enterococci
(VRE), and penicillin-resistant Streptococcus pneumo-
niae (PRSP).1 This class is known to inhibit the bacterial
protein synthesis by binding to the 50S ribosomal sub-
unit and prevents the formation of a functional 70S ini-
tiation complex.2 Due to this unique mechanism of
action, no cross-resistance is expected between the oxa-
zolidinones and the other families of antibacterials. Lin-
ezolid, the first oxazolidinone to receive FDA approval,
has become an important clinical option for the treat-
ment of nosocomial resistant Gram-positive bacterial
infections. However, a few cases of linezolid-resistant
pathogens in clinical isolates have been reported.3 The
emergence of early resistance and safety concerns in
terms of myelosupression emphasize the need for the
development of more effective oxazolidinones.4 (see
Fig. 1).
In the course of research to enhance the spectrum and
potency of oxazolidinones,5 we embarked on relatively
less explored glyoxamide derivatives. There are only
two examples reported in the literature carrying 3-thie-
nyl and methyl glyoxamide substituents on piperazine
scaffold of eperezolid analogs.6 This type of modifica-
tion resulted in compounds with improved antibacterial
activity against Gram-positive pathogens. For example,
MIC values are in the range of 0.25–0.5 lg/mL and 0.5–
2 lg/mL against S. aureus organisms for 3-thienyl and
methyl glyoxamide derivatives, respectively. On the
other hand, indole ring provides instant access to a vari-
ety of 3-indolylglyoxamides. The synthetic ease and
diversity of indole derivatives as well as the reported po-
tency of glyoxamides prompted us to investigate the ef-
fect of indolylglyoxamides 3 on the antibacterial activity
of oxazolidinones. Thus, a focused library was made
wherein hydroxyacetamido group in eperezolid has been
replaced initially with various substituted 3-indolylgly-
oxamides. In the second variation, acetamide at C-5 ter-
minus has been modified with various N-and O-linked
substituents keeping 5-bromoindole fixed on the left
hand side. The synthesis and antibacterial activity of
these compounds are reported herein.
Keywords: Linezolid; Oxazolidinones; Indole; Antibacterials.
q
DRL Publication No. 656.
The advanced intermediates 4, 5, 6, and 7 were prepared
conveniently following the reported procedure as de-
picted in Scheme 1.7 The 3-indolylglyoxalyl chlorides
*
Corresponding author. Tel.: +91 40 23045439; fax: +91 40
23045438; e-mail addresses: takhi@drreddys.com; takhi@hotmail.
com
0960-894X/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.03.043

M. Takhi et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5150–5155
5151
F
F
O
O
O
HO
O
O
N
N
O
N
O
N
N
H
N
H
N
O
O
Eperezolid (2)
Linezolid (1)
R1
F
O
O
N
N
N
R4
X
O
N
R2
R3
Indolylglyoxamide series (3)
R1 = CN, Br, OMe, NO2; R2 =R3 = alkyl, H
R4 = N or O-linkage; X = CH or N
Figure 1.
F
F
O
O
a
O
O
t-BocN
N
N
t-BocN
N
N
OH
N3
5
4
7
b
F
O
F
O
c, d
O
O
HN
N
N
t-BocN
N
N
H
N
NH2
6
O
Scheme 1. Reagents and conditions: (a) i—MsCl, Et3N, CH2Cl2, rt, ii—NaN3, DMF, 90 ꢁC, 80%; (b) PPh3, THF–H2O, 78%; (c) Ac2O, Et3N,
CH2Cl2, 82%; (d) TFA, CH2Cl2, rt, 86%.
have been made by the treatment of corresponding in-
doles 8a–h with oxalyl chloride. Subsequently, the reac-
tion of these 3-indolylglyoxalyl chlorides with 7 in the
presence of Hunig’s base produced targeted oxazolidi-
nones 9a–h in good yields.8
and N-methylindole 9g were onefold better than
linezolid against two enterococcal strains. However,
none of these molecules showed antibacterial activity
against
a
representative
Gram-negative
CAP
(community acquired pneumonia) pathogen such as H.
influenzae. The preliminary SAR indicates that the posi-
tion and electronic nature of substituents on indole ring
have little influence on the antibacterial activity. Thus,
the in vitro activities of simple indole analog 9a and
the rest of the molecules in Table 2 are comparable
(see Scheme 2).
A series of C-5 acetamide compounds was screened
against a panel of susceptible and resistant Gram-posi-
tive and fastidious Gram-negative strains.9 As per the
data summarized in Table 1, most of the analogs exhib-
ited superior activity compared to linezolid against
MSSA, MRSA, E. faecalis and E. faecium. The simple
indole analog 9a exhibited onefold better activity
compared to linezolid against most of the organisms.
Among the 5-substituted indole derivatives (9b, 9c, 9e,
and 9h), 5-bromoindole 9h displayed 1-2-fold superior
potency compared to linezolid across the panel of
organisms. The MIC values of this derivative against
S. aureus, E. faecalis and E. faecium are in the range
of 0.5–1 lg/mL. The antibacterial activity was minimally
impacted when indole moiety in 9a was substituted by
azaindole 9d. In vitro activities of 2-methylindole 9f
In the next phase, SAR on a relatively potent compound
9h from the above series was undertaken at C-5 side
chain of oxazolidinone pharmacophore. Previous stud-
ies had identified various cyclic and acyclic surrogates
for the privileged acetamidomethyl side chain.10–13
Accordingly, acetamide group in 9h has been replaced
with a variety of substituents including amides, carba-
mates and azoles. As illustrated in Scheme 3, primary
amine 6 was reacted with ethyl dithioacetate to yield
the corresponding thioacetamide. Subsequently, trifluo-

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M. Takhi et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5150–5155
Table 1. In vitro antibacterial activity (MIC (lg/mL)) of oxazolidinone derivatives 9a–h
Compound
Saa
Sab
Efc
Efd
Efe
Hif
9a
9b
9c
1
1
2
2
2
2
2
1
2
1
1
1
1
1
1
1
1
1
2
1
1
1
2
1
1
2
2
1
2
16
1
0.5
1
>32
>32
>32
>32
>32
>32
>32
8
1
9d
9e
1
0.5
0.5
1
1
9f
1
9g
9h
LNZ
1
1
0.5
1
0.5
2
LNZ—linezolid.
MIC—minimum inhibitory concentration.
a S.a., Staphylococcus aureus DRCC 035 (methicillin-susceptible S. aureus).
b S.a., Staphylococcus aureus DRCC 019 (methicillin-resistant S. aureus).
c E.f., Enterococcus faecalis DRCC 034 (vancomycin susceptible E. faecalis).
d E.f., Enterococcus faecalis DRCC 153 (vancomycin-resistant E. faecalis).
e E.f., Enterococcus faecium DRCC154 (vancomycin-resistant E. faecium).
f H.i., Haemophilus influenzae DRCC 433 (b-lactamase –ve).
Table 2. In vitro antibacterial activity (MIC (lg/mL)) of oxazolidinone derivatives 10a–h
Compound
Saa
Sab
Sac
Efd
Efe
Eff
Efg
Mch
Hii
9h
1
0.5
0.25
0.5
1
8
1
0.5
0.12
0.5
0.5
1
1
8
2
2
>32
>32
>32
>32
>32
>32
>32
>32
>32
8
10a
10b
10c
10d
10e
10f
0.5
1
2
0.5
1
0.25
1
2
16
2
32
2
2
1
1
1
1
1
2
8
2
2
8
4
2
1
4
1
0.25
0.25
0.5
32
0.5
0.5
0.5
>32
2
4
2
1
1
4
1
4
2
10g
10h
LNZ
2
0.5
32
1
8
1
16
32
32
4
>32
2
32
32
32
2
32
4
2
a S.a., Staphylococcus aureus DRCC 035 (methicillin-susceptible S. aureus).
b S.a., Staphylococcus aureus DRCC 019 (methicillin-resistant S. aureus).
c S.a., Staphylococcus aureus DRCC 564 (linezolid resistant S. aureus).
d E.f., Enterococcus faecalis DRCC 034 (vancomycin susceptible E. faecalis).
e E.f., Enterococcus faecalis DRCC 153 (vancomycin-resistant E. faecalis).
f E.f., Enterococcus faecium DRCC154 (vancomycin-resistant E. faecium).
g E.f., Enterococcus faecalis DRCC 632 (linezolid resistant E. faecalis).
h M.c., Moraxella catarrhalis DRCC 300 (b-lactamase –ve).
i H.i., Haemophilus influenzae DRCC 433 (b-lactamase –ve).
R1
F
O
R1
a) Oxalyl chloride, THF
r.t
O
R3
O
N
N
N
H
N
N
X
b) 7, Hunig's base, THF
X
R2
O
r.t
N
R2
R3
O
8a-h
9a-h
8a: R1=R2=R3=H, X=CH; 8b: R1=CN, R2=R3=H, X=CH
8c: R1=NO2, R2=R3=H, X=CH; 8d: R1=R2=R3=H, X=N
8e: R1=OMe, R2=R3=H, X=CH; 8f: R1=R2=H, R3=Me, X=CH
8g: R1=R3=H, R2=Me, X=CH; 8h: R1=Br, R2=R3=H, X=CH
Yields: 9a (40%), 9b (65%),
9c (24%), 9d ((55%)
9e (83%), 9f (40%)
9g (39%), 9h (45%)
Scheme 2.
roacetic acid treatment followed by the reaction of 3-
indolylglyoxalyl chloride derived from 5-bromoindole
8h furnished the desired oxazolidinone 10a. Amine 6
was treated with methyl chloroformate in the presence
of Hunig’s base to furnish methylcarbamate 10b. Thio-
carbamate 10c was prepared by the reaction of amine

M. Takhi et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5150–5155
5153
10a: A, B, C (29%); 10b: D, B, C (31%)
F
O
Br
10c: E, B, C (30%); 10d: F, B, C (32%)
10e: G, B, C (30%); 10f: H, B, C (32%)
O
O
N
N
N
6
Y
O
N
H
10a-f
10a: Y=NHC(S)Me; 10b: Y=NHC(O)OMe
10c: Y=NHC(S)OMe; 10d: Y= NHC(O)cyclopropyl
10e: Y=NHC(O)CHF2; 10f: Y=NHC(O)CHCl2
F
O
Br
10g: I, B, C (22%)
10h: J, B, C (25%)
O
O
5
4
N
N
N
N
N
N
O
N
H
10g
F
O
Br
O
O
N
N
N
N
O
O
O
N
H
10h
Scheme 3. Reagents and conditions: (A) CH3C(S)SC2H5, Et3N, THF, rt, 80%; (B) TFA, CH2Cl2, rt; (C) 5-bromo-3-indolylglyoxalyl chloride, N-
diisopropyl ethylamine, THF; (D) ClC(O)OMe, N-diisopropyl ethylamine, CH2Cl2, rt, 72%; (E) C(S)Cl2, NaHCO3, CH2Cl2 then MeOH, reflux,
67%; (F) cyclopropyl carboxylic acid, EDCÆHCl, NMM, CH2Cl2, rt, 65%; (G) CHF2COOH, EDCÆHCl, NMM, CH2Cl2, rt, 55%; (H) CHCl2COOH,
EDCÆHCl, NMM, CH2Cl2, rt, 52%; (I) bicyclo[2.2.1] hepta-2,5-diene, dioxane, 100 ꢁC, sealed tube, 94%; (J) PPh3, DEAD, 3-hydroxy isooxazole,
THF, rt, 70%.
6 with thiophosgene to produce the corresponding iso-
thiocyanate, which in turn reacted with excess of meth-
anol under reflux. The cyclopropyl amide 10d was
fashioned by the sequential treatment of 6 with cyclo-
propyl carboxylic acid in the presence of EDCÆHCl, tri-
fluoroacetic acid and then 5-bromo 3-indolylglyoxalyl
chloride obtained from 8h. Similarly, difluoroacetamide
10e and dichloroacetamide 10f have been accessed by
using difluoroacetic acid and dichloroacetic acid, respec-
tively. The triazole derivative 10g was made by the reac-
tion of azide 5 with bicyclo[2.2.1] hepta-2,5-diene at
100 ꢁC in a closed vial.
be the result of subtle changes in electronic character
and lipophilicity of the molecules.10a–c The dihaloaceta-
mides 10e and 10f have shown improved potency com-
pared to simple acetamide 9h. This characteristic is
reminiscent to the C-5 modifications reported by Vicu-
ron and Pfizer groups using various haloaceta-
mides.11The noteworthy feature of thioacetamide 10a,
thiocarbamate 10c, difluoroacetamide 10e and dichloro-
acetamide 10f analogs is their activity against linezolid-
resistant S. aureus and E. faecalis (MICs = 2–4 lg/mL).
This result exemplifies that appropriate substitution
around oxazolidinone would result in compounds active
against linezolid-resistant organisms. Though the ra-
tional behind this activity feature is not very clear, it
can be attributed to distinct binding mode to oxazolidi-
The isooxazole ring was appended at C-5 position by
exposing alcohol 4 to Mitsunobu conditions. The t-
Boc group was cleaved by acid treatment and the result-
ing amine was derivatized with 5-bromo 3-indolylglyox-
alyl chloride to afford ether derivative 10h.
Table 3. In vivo efficacy in a murine systemic infection model by oral
route13
All of the analogs were tested in vitro against a broader
panel of Gram-positive bacteria including linezolid-
resistant organisms14 and fastidious Gram-negative bac-
teria such as M. catarrhallis and H. influenzae. The re-
sults are presented in Table 2. In general, C-5
modifications based on N-linkage were well tolerated
and furnished potent molecules. The analogs 10a, 10b,
10c, 10e, 10f and 10g showed excellent in vitro activity
against key Gram-positive pathogens (MICs = 0.25–
2 lg/mL). The thiocarbonyl compounds 10a and 10c
were more potent than the corresponding oxocarbonyl
compounds 9h and 10b as observed in many other oxa-
zolidinone series.10 The enhancement in potency could
Compound
ED50 (mg/kg/day)
9a
9b
19.4 (5.3–70.5)a
>30
>30
9d
9h
27.0 (18.0–40.4)
>30
>30
10a
10c
10d
10e
10f
18.9 (9.4–37.9)
>30
>30
10g
Linezolid
28.9 (19.3–43.3)
5.3 (2.6–9.0)
a Numbers in parentheses are 95% confidence ranges.

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M. Takhi et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5150–5155
Table 4. Pharmacokinetic parameters of selected compounds in Swiss Albino micea
Parameters
9b
9d
9h
10d
Linezolid
AUC(0–t) (lg h/mL)
Tmax (h)
1.90
3.00
0.43
1.19
0.58
3.36
0.50
1.05
0.87
0.79
2.25
2.00
0.68
2.17
0.32
1.26
2.00
0.30
1.13
0.61
10.98
0.25
6.31
1.37
0.51
Cmax (lg/mL)
t1/2 (h)
Kel (hÀ1)
a Pharmacokinetic experiments were performed by single dose (10 mg/kg) using oral route of administration.
none site and/or binding to additional site on ribosome.
Cyclopropyl amide 10d derivative showed 1-2-fold less
potency than acetamide congener 9h. Among the C-5-
linked azoles, the activity of triazole derivative 10g
was comparable to acetamide 9h and superior to stan-
dard. The result is in accordance with the early work
on C-5 heterocyclic groups.12 However, the O-isooxaz-
ole substitution at C-5 terminus in 10h proved to be det-
rimental to the antibacterial activity. This observation is
in contrast to the report disclosing tetrahydropyranyl
and tetrahydropyridyl series where O-linked isooxazole
was found to be optimal.13 Most of the analogs exhib-
ited respectable activity against fastidious Gram-nega-
tive bacterium M. catarhalis (MIC = 2–4 lg/mL).
However, these molecules were devoid of antibacterial
activity against other Gram-negative organism H. influ-
enzae. The lack of activity against this Gram-negative
organism in both series could be due in part to active ef-
flux, effectively lowering the intracellular concentration
of the test compound.15 In general the SAR at C-5 ter-
minus followed the trend as reported earlier in most of
the cases and showed improvement in in vitro activity
except for the O-isooxazole analog 10h. These results
once again prove that C-5 side chain can accommodate
diverse functionalities depending upon the nature of
other substituents in the molecule.
found to be 1-2-fold more potent compared to linezolid
against the tested organisms. Notable improvements in
terms of potency and spectrum have been made through
the introduction of halogenated amides, thioamides and
1,2,3-triazole at C-5 side chain. Compounds 10a, 10c,
10e and 10f exhibited excellent activity against Gram-
positive organisms such as MSSA, MRSA, E. faecalis
and E. faecium. The activity of these four molecules
against linezolid-resistant S. aureus and E. faecalis is
an additional trait of the present series (MIC = 2–4 lg/
mL). A few members of this series also showed in vivo
efficacy in a lethal murine infection model at higher
doses.
Acknowledgments
We thank Dr. Rajinder Kumar, President, Discovery
Research, Dr. Reddy’s Laboratories Limited for his sup-
port and constant encouragement. We would also like to
thank Analytical Department for spectral data.
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10e, 10f, and 10g from both the series have been tested
in vivo against S. aureus DRCC 035 organism in a mur-
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analogs with acetamide moiety at C-5 position were

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8. Preparation of compound 9a. To a solution of indole
(80 mg, 0.68 mmol) in THF was added oxalyl chloride
(0.065 mL, 0.75 mmol) dropwise at 0 ꢁC and the reaction
mixture was stirred at rt for 4 h. The solvent was removed
under reduced pressure to obtain indole-3-glyoxalyl chlo-
ride as a yellow solid. To a suspension of 7 (150 mg,
0.44 mmol) and above-prepared indole-3-glyoxalyl chlo-
ride (140 mg, 0.66 mmol) in THF, N,N-diisopropylethyl-
amine (0.155 mL, 0.89 mmol) was added dropwise and
stirred at rt overnight. Finally it was quenched with 10%
aq NaHCO3 (20 mL) and extracted with ethyl acetate (2·
20 mL). The combined organic layers were washed with
water followed by brine and dried over anhydrous
Na2SO4. The solvent was evaporated under vacuum and
the residue was purified by column chromatography on
silica gel (eluent: 4% MeOH/CHCl3) to obtain oxazolid-
inone 9a as light green solid (90 mg, 40%). 1H NMR
(DMSO-d6): d12.31 (d, J = 2.9 Hz, 1H), 8.24–8.18 (m,
2H), 8.16–8.11 (m, 1H), 7.57–7.52 (m, 1H), 7.48 (dd,
J = 2.4 Hz, 14.6 Hz, 1H), 7.32–7.24 (m, 2H), 7.18 (dd,
J = 2.4 Hz, 8.8 Hz, 1H), 7.08 (t, J = 9.2 Hz, 1H), 4.73–4.66
(m, 1H), 4.07 (t, J = 8.8 Hz, 1H), 3.78 (t, J = 4.8 Hz, 2H),
3.69 (dd, J = 6.3 Hz, 9.2 Hz, 1H), 3.50 (t, J = 3.9 Hz, 2H),
3.42–3.37 (m, 2H), 3.10 (t, J = 4.8 Hz, 2H), 2.94 (t,
J = 4.3 Hz, 2H), 1.82 (s, 3H); IR (KBr): 3284, 2924,
1751, 1630, 1518, 1425, 1377, 1325, 1281, 1236, 1155, 1034,
953, 840, 773, 754, 640 cmÀ1; MS: (m/z) 508 (M+1).
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