Design, Synthesis, and Identification of Silicon Incorporated Oxazolidinone Antibiotics with Improved Brain Exposure

Article abstract of DOI:10.1021/acsmedchemlett.5b00213

Therapeutic options for brain infections caused by pathogens with a reduced sensitivity to drugs are limited. Recent reports on the potential use of linezolid in treating brain infections prompted us to design novel compounds around this scaffold. Herein, we describe the design and synthesis of various oxazolidinone antibiotics with the incorporation of silicon. Our findings in preclinical species suggest that silicon incorporation is highly useful in improving brain exposures. Interestingly, three compounds from this series demonstrated up to a 30-fold higher brain/plasma ratio when compared to linezolid thereby indicating their therapeutic potential in brain associated disorders.

Full text of DOI:10.1021/acsmedchemlett.5b00213

Letter
pubs.acs.org/acsmedchemlett
Design, Synthesis, and Identification of Silicon Incorporated
Oxazolidinone Antibiotics with Improved Brain Exposure
B. Seetharamsingh,† Remya Ramesh,† Santoshkumar S. Dange,† Pankaj V. Khairnar,† Smita Singhal,‡
Dilip Upadhyay,‡ Sridhar Veeraraghavan,§ Srikant Viswanadha,§ Swaroop Vakkalanka,§
and D. Srinivasa Reddy*,†
†CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
‡Daiichi Sankyo India Pharma Pvt. Ltd., Gurgaon, Haryana 122015, India
§Incozen Therapeutics Pvt. Ltd., Alexandria Knowledge Park, Turkapally, Rangareddy 500078, India
S
* Supporting Information
ABSTRACT: Therapeutic options for brain infections caused
by pathogens with a reduced sensitivity to drugs are limited.
Recent reports on the potential use of linezolid in treating
brain infections prompted us to design novel compounds
around this scaffold. Herein, we describe the design and
synthesis of various oxazolidinone antibiotics with the
incorporation of silicon. Our findings in preclinical species
suggest that silicon incorporation is highly useful in improving
brain exposures. Interestingly, three compounds from this
series demonstrated up to a 30-fold higher brain/plasma ratio when compared to linezolid thereby indicating their therapeutic
potential in brain associated disorders.
KEYWORDS: Antibacterial, linezolid, oxazolidinone, brain exposure, sila analogue
acterial meningitis is a very severe condition with sudden
Linezolid5,6 is the first oxazolidinone antibiotic to be
Bonset of symptoms and death within hours. According to marketed for clinical use that suppresses bacterial growth via
inhibition of ribosomal protein synthesis. Linezolid binds to a
site on the 50S ribosomal subunit near its interface with the 30S
unit and thus prevents the formation of a 70S initiation
complex.7 Linezolid’s broad spectrum of activity against
virtually all Gram-positive bacteria, including methicillin
resistant and vancomycin resistant bacteria, led to an increased
usage of the drug and resulted in significant worldwide sales
ever since its approval in 2000. However, only limited
information has been established with respect to linezolid’s
efficacy in treating infections of the central nervous system
(CNS). The cerebrospinal fluid (CSF) penetration of linezolid,
a limitation observed with other frontline antibiotics in the
treatment of CNS infections, is relatively better. Although, it
was not evaluated in a large number of patients suffering from
CNS infections, positive clinical experience with linezolid was
documented in the literature by a few groups.8,9 To increase the
utility of linezolid in CNS infections, synthesis of novel
compounds is necessary; in particular, by improving B/P ratios
of drug concentrations. Sutezolid (PNU-100480)10 is another
closely related molecule that falls in the oxazolidinone category
and is currently in phase II clinical trials for the treatment of
both drug resistant and sensitive tuberculosis. While
WHO statistics, bacterial meningitis affects more than 400
million people per year in the “African meningitis belt”. Of the
22 831 cases diagnosed in 2010 across 14 African countries,
2415 deaths were reported with a case-fatality ratio of 10.6%.1
The diagnosis is done by investigating the cerebrospinal fluid of
patients obtained by a lumbar puncture. Since meningitis is
fatal, wide spectrum antibiotics are given even before the
disease is actually confirmed. The choice of antibiotics depends
on the pathogen that causes meningitis, the most common ones
being Streptococcus pneumoniae and Neisseria meningitidis.
Cephalosporin, ampicillin, vancomycin, and rifampin are
some of the commonly used antibiotics for treating bacterial
meningitis.2 The central nervous system (CNS) is protected by
the highly selective blood−brain barrier (BBB) that controls
the entry of compounds into the brain. In a normal individual,
the BBB efficiently protects the brain from pathogens that can
easily cause infections in other parts of the body. While brain
infections are not common, they can be difficult to treat in
affected individuals due to the inability of drugs to cross the
BBB. The BBB, therefore, makes drug delivery to the CNS a
challenging task for medicinal chemists.3,4 In addition to
permeability, development of resistance to existing antibiotics is
yet another problem encountered in treatment of brain
infections. Hence, a global demand and medical need exists
to develop novel lipophilic antibiotics with better BBB
penetration for treating brain infections.
Received: June 15, 2015
Accepted: October 26, 2015
© XXXX American Chemical Society
A
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oxazolidinone antibiotics are typically bacteriostatic, their
clinical activity is governed by the clinical dose as well as the
pharmacokinetics. Other bacteriostatic agents such as tetracy-
cline and chloramphenicol also possess good CSF penetration
and are used in the treatment of bacterial meningitis.11
silapiperidines 3a and 3b. These important intermediates were
synthesized on multigram scale, which helped us to generate a
library of silicon analogues of linezolid without much difficulty.
The silapiperidines 3a and 3b on treatment with 3,4-
difluoronitrobenzene and 3,4,5-trifluoronitrobenzene, resulted
in compounds 4a−4c by a simple nucleophilic aromatic
substitution. The nitro group was reduced with H2−Pd/C in
THF followed by Cbz protection of the resulting amine in one
pot to give the intermediates 5a−5c. Compounds 5a−5c were
treated with chiral building block A29 in the presence of LiOtBu
in dimethylformamide (DMF) to furnish the oxazolidinone
core. Boc deprotection was achieved with trifluoroacetic acid
(TFA) in CH2Cl2, and the salts were neutralized to afford the
free amines 6a−6c (Scheme 1).
Bioisosterism is one of the widely used methods for the
efficient optimization of pharmacokinetic (PK) properties of a
lead molecule.12−14 The incorporation of silicon into known
drug scaffolds called the “silicon switch approach” has gained
momentum in recent times.15−22 It is worth highlighting the
efforts of Tacke’s group for their work on this interesting
approach. In general, silicon analogues are more lipophilic than
their carbon counterparts. Hence this strategy would be
beneficial in CNS drug discovery wherein siliconized
compounds could potentially display better blood−brain barrier
(BBB) penetration. In our group, we are interested in
synthesizing novel bioactive molecules with the incorporation
of silicon.23 Along these lines, we have designed and
synthesized silicon analogues of the oxazolidinone antibiotics
linezolid/sutezolid. We reasoned that the incorporation of
silicon instead of an oxygen atom or sulfur atom in the
morpholine/thiomorpholine ring can lead to a more lipophilic
molecule, which was further supported by simple clogP
calculations (Figure 1).24,25 Since the morpholine/thiomorpho-
Scheme 1. Synthesis of Oxazolidinone Amines with Silicon
Incorporation
Figure 1. Design of silicon incorporated oxazolidinones.
line ring is not essential for activity and is amenable to different
sterics around this moiety while retaining potency, we
anticipated that the newly designed compounds would show
similar activity to that of the parent. The details of experimental
results are disclosed herein.26
The chemical synthesis commenced with the preparation of
1,4-azasilinanes 3a27 and 3b28 from commercially available
divinylsilanes 1a and 1b. The treatment of HBr gas to
vinylsilanes in heptane in the presence of a catalytic amount of
dibenzoyl peroxide (DBP) gave bis(bromoethyl)silanes, which
on reaction with benzylamine in CHCl3 resulted in
silapiperidines with benzyl protection 2a and 2b, respectively.
The compounds 2a and 2b were debenzylated to give the key
These oxazolidinone amines 6a−6c were treated with acetyl
chloride and propionyl chloride to give the corresponding
amides 7a−7f. Treatment of amines 6a and 6b with
carbonyldiimidazole (CDI) followed by addition of methanol
produced two methylcarbamate derivatives 8a and 8b.29 The
reaction of amines 6a and 6b with thiophosgene followed by
methanol yielded the thiocarbamates 9a and 9b. Similarly,
quenching with aqueous ammonia resulted in the thiourea
derivatives 9c and 9d (Scheme 2).
For the generation of compounds with varying structural
features, compounds 5a−5c were treated with n-BuLi and (R)-
glycidyl butyrate to furnish the hydroxyl derivatives 10a−10c.
The alcohols 10a and 10b were converted to the corresponding
B
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After synthesizing several silicon analogues, the antibacterial
activity was assessed against various strains. MIC (minimum
inhibitory concentration) of NCEs were determined by
microbroth dilution method against facultative bacteria. The
screening results of all compounds are provided in the
Supporting Information. Among the screened oxazolidinones,
the compounds 7a, 7c, 7d, 9a, and 9d were more active against
a majority of the bacterial strains tested. Compound 7a, which
is the closest linezolid analogue of all the compounds
synthesized, showed good potency, but 4−8-fold less potent
compared to linezolid across the strains. Introduction of
additional fluorine atom on to aromatic ring (7c) resulted in a
modest improvement in the potency. The compound with
thiocarbamate functionality 9a was the most potent compound
in the series with activity comparable to that of linezolid. The
presence of phenyl group on silicon resulted in a loss of
potency (see Supporting Information). The alcohols 10a−10c
were found to be less potent. In general the addition of fluorine
atom in the aromatic ring enhanced the antibacterial activity.
However, addition of a fluorine atom onto the aromatic ring
resulted in a marked decrease in potency (9a vs 9b, see
Supporting Information) in compounds belonging to the
thiocarbamate series. After analysis of the structural features
present in some of the potent oxazolidinones reported in
literature, compounds 11a and 11b were prepared with triazole
moieties in place of N-acyl group.30 However, we did not
observe significant activity with these compounds.
Scheme 2. Synthesis of Target Oxazolidinones with Silicon
Incorporation
Upon completion of in vitro testing of antibacterial activities,
three out of the five best compounds (7a, 7c, and 9a) from this
series were selected for ADME and physicochemical property
studies. Specifically, solubility across the pH range, stability in
plasma, stability in microsomes, and plasma protein binding
were evaluated (results compiled in Table 1). Compound 7a
was soluble across the pH range tested with values being similar
to that of linezolid. The solubility of compounds 7c and 9a was
also comparable to linezolid at acidic pH; however, it was
decreased at higher pH conditions. All silicon compounds
demonstrated very good plasma stability profile similar to that
of linezolid. All three compounds (7a, 7c, and 9a), along with
linezolid, were screened for their microsomal metabolic stability
in three different species (mouse, rat, and human). Compounds
7a and 7c were moderately stable in both mouse and human
liver microsomes with 7c being superior among the two.
Compound 9a showed poor stability in rodent liver micro-
somes, but it showed better stability in human microsomes. In
the case of plasma protein binding studies, we found striking
difference between linezolid and sila compounds. All three
compounds, 7a, 7c, and 9a, were strongly bound to the plasma
proteins. Hence, this can be an advantage for the improvement
in BBB penetration. Although free drug concentrations are
generally associated with greater antimicrobial activity, the
success of telavancin and daptomycin reflect the benefit
associated with high protein binding (lower clearance, longer
half-life, and longer duration of action). The discrepancy in
findings can be attributed to the difference in the static in vitro
mesylates and the mesylate group was displaced with azide. The
azide on heating with norbornadiene underwent a 1,3-dipolar
cycloaddition followed by retro Diels−Alder reaction to furnish
the triazoles 11a and 11b, respectively (Scheme 3).
Scheme 3. Synthesis of Triazole-Based Oxazolidinones
̀
test systems vis-a-vis the dynamic nature in an in vivo setting
wherein several factors such as binding affinity of the drug to
the proteins, transport across barriers, physiological conditions,
and metabolism play a major role.31 Based on the overall in
vitro profile, compound 7a was selected for detailed in vivo
pharmacokinetic studies in mice (results are compiled in the
table provided in the Supporting Information). Although
compound 7a demonstrated 100% bioavailability and similar
C
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Table 1. In Vitro PhysChem and ADME Data
% metabolic stability in liver
microsomes (after 30 min)
solubility (μM) at pH
% plasma stability
compd
1.2
2.2
4.5
7.4
10.2
rat
human
mouse
rat
human
% human PPB
LZD
7a
50
50
48
48
50
50
43
47
50
41
20
9
49
40
17
2
50
41
20
2
100.0
97.3
100.0
100.0
100.0
100.0
100.0
40.8
68.4
15.2
88.3
10.8
9.6
100.0
48.9
69.8
43.0
26.04
94.33
99.60
100.00
7c
94.7
9a
100.0
5.7
a
Table 2. Brain PK Comparison of 7a, 7c, 9a, and LZD
7a
7c
9a
LZD
route
dose
brain
plasma
B/P ratio
brain
plasma
B/P ratio
brain
plasma
B/P ratio
brain
plasma
B/P ratio
10
10
10
10
10
10
10
10
N
2
2
2
2
2
2
2
2
Cmax
AUC
AUC
1.33
3.01
3.05
1.05
1.78
1.80
1.27
1.69
1.69
5.58
14.74
16.44
2.02
5.80
6.21
2.76
2.54
2.65
1.47
3.11
3.24
0.37
0.87
0.93
3.96
3.57
3.49
0.45
0.83
0.90
3.65
7.58
7.70
0.12
0.11
0.12
0‑t
0‑inf
a
Units for brain: Cmax = μg/g, AUC0‑t = μg·h/g, AUC0‑inf = μg·h/g. Units for plasma: Cmax = μg/mL, AUC0‑t = μg·h/mL, AUC0‑inf = μg·h/mL.
Table 3. Antibacterial Activity of Selected Compounds against S. pneumoniae and N. meningitidis
b
b
b
b
strain
7a
7c
9a
LZD
S.pneumoniae ATCC 49619
8
4
16
8
4
4
0.5
0.5
32
1
S.pneumoniae ATCC 6303
S.pneumoniae 6303 LZDR
>32
4
>32
16
32
4
S.pneumoniae ATCC 700904 PenR, erm+ve
a
N.meningitidis E-63
32
>32
>32
>32
>32
>32
32
32
32
32
32
8
a
N.meningitidis M-1
>32
>32
>32
>32
8
a
N.meningitidis 306
8
a
N.meningitidis E-95
8
a
N.meningitidis 184
8
a
b
Clinical isolates. MIC values are measured in μg/mL.
half-life as compared to linezolid, it was inferior in terms of
max, AUC, and clearance. However, the volume of distribution
μg/mL. Although the antibacterial potencies are less when
compared to the marketed drug linezolid, the higher B/P ratio
of silicon compounds suggest that incorporation of silicon is
beneficial in terms of BBB penetration.
C
(Vz) of 7a was twice that of linezolid, which can be attributed
to its high plasma protein binding. Next, we decided to
understand BBB penetrating potential of the silicon com-
pounds, which was the main objective of this project. Toward
this goal, all three selected compounds, i.e., 7a, 7c, and 9a were
administered through oral route and various parameters were
measured. The details of experimental protocol and all the
measurements are placed in the Supporting Information.
Interestingly, all the three compounds displayed significant
brain penetration. Compounds 7a, 7c, and 9a had a 14-, 22-,
and 29-fold higher B/P ratios compared to linezolid (see Table
2). These ratios were calculated using AUC measurements.
Calculations using Cmax also gave similar ratios. It is worth
highlighting that actual brain concentrations of the sila
compounds 7a, 7c, and 9a are much superior with respect to
linezolid. Out of the three compounds, 7c was the best in terms
of actual drug concentration (Cmax = 5.58 μg/g and AUC =
16.44 μg·h/g). As the siliconized linezolid analogues displayed
impressive B/P ratio, we became interested in testing these
compounds against selected bacterial strains (S. pneumoniae and
N. meningitidis) that cause brain infections.2 The MIC values
generated using various strains suggest that all three
compounds possess comparable activity with respect to S.
pneumoniae (Table 3).32 However, in the case of N. meningitidis
strains, only compound 9a showed significant activity and other
two compounds 7a and 7c did not show the activity up to 32
In conclusion, we have designed and synthesized various
oxazolidinones with the incorporation of silicon. Three
compounds 7a, 7c, and 9a were identified as potential lead
molecules from the present series, demonstrating up to 30-fold
higher B/P ratio as compared to the marketed antibiotic drug,
linezolid. These results can be considered as an initial step
toward the development of brain penetrant oxazolidinone
antibiotics. The demonstrated concept with the incorporation
of silicon into known drug scaffold to improve CNS exposures
can also be applied to other classes of compounds. Profiling of
selected compounds in brain infected preclinical models is the
future course of action and the goal is to further optimize the
identified compounds toward the development of an antibiotic
that can be useful in treating CNS infections.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.5b00213.
Experimental details; compound characterization details;
screening details; antibacterial data for all the com-
pounds; protocols for pharmacokinetic studies including
brain PK; data from mice PK experiments (PDF)
D
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ds.reddy@ncl.res.in.
Author Contributions
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Funding
BIRAC (Biotechnology Industry Research Assistance Council),
New Delhi for the support through CRS Scheme (BT/
CRS0046/CRS-02/12). Initially, this project was supported by
NCL-IGIB joint collaborative project (BSC-0124) and NCL in-
house grants. B.S.R. and R.R. thank CSIR, New Delhi for the
award of fellowship.
Notes
The authors declare no competing financial interest.
DEDICATION
■
This work is dedicated to Professor Sourav Pal, Indian Institute
of Technology, Bombay and former Director, CSIR-NCL, Pune
on the occasion of his 60th birthday.
ABBREVIATIONS
■
NCE, new chemical entity; brsm, based on recovered starting
material; LZD, linezolid; ADME, absorption, distribution,
metabolism, excretion; N, number of subjects; AUC, area
under the curve; t1/2, half-life; Kel, elimination rate constant;
Clz, clearance; BA, bioavailability; B/P ratio, brain to plasma
ratio; PPB, plasma protein binding
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(32) We have also determined the cytotoxicity of compounds 7a, 7c,
and 9a following 24 h incubation with human hepatoma (HepG2) and
tracheal epithelial cells (HTEpiC). Compounds 7c and 9a were
nontoxic at >10 μM concentration in both HepG2 and HTEpiC cells.
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cells and 5 μM in HTEpiC cells. Details are provided in the
Supporting Information.
F
DOI: 10.1021/acsmedchemlett.5b00213
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX