Oxazolidina

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Expert Opinion on Therapeutic Patents
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Oxazolidinone antimicrobials: a patent review
(2012-2015)
Oludotun A. Phillips & Leyla H. Sharaf
To cite this article: Oludotun A. Phillips & Leyla H. Sharaf (2016): Oxazolidinone
antimicrobials: a patent review (2012-2015), Expert Opinion on Therapeutic Patents, DOI:
10.1517/13543776.2016.1168807
To link to this article: http://dx.doi.org/10.1517/13543776.2016.1168807
Accepted author version posted online: 21
Mar 2016.
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Publisher: Taylor & Francis
Journal: Expert Opinion on Therapeutic Patents
DOI: 10.1517/13543776.2016.1168807
Review
Oxazolidinone antimicrobials: a patent review (2012-2015)
Oludotun A. Phillips1
*, Leyla H. Sharaf1
1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University,
P. O. Box 24923, Safat 13110, Kuwait
* Corresponding author
Oludotun A. Phillips
Department of Pharmaceutical Chemistry
Faculty of Pharmacy, Kuwait University
P.O. Box 24923, Safat 13110, Kuwait
Tel: +965-2463-6070
Fax: +965-2463-6841
E-mail: dphillips@hsc.edu.kw
Downloadedby[UniversityofCaliforniaSantaBarbara]at22:2222March2016

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Abstract
Introduction: Antimicrobial resistance in Gram-positive bacteria is a major health care
issue. This review summarizes patent publications from 2012 to 2015 that divulged novel
oxazolidinones as antibacterial agents.
Areas covered: A total of 25 patents obtained from Espacenet, WIPO Patentscope and
FreePatentsOnline, and AcclaimIP search engines were reviewed. The patents were
scrutinized based on the novelty of the compounds, their antibacterial activity (MIC,
µg/mL), and the process of preparation. The oxazolidinones with promising antibacterial
activity were classified according to the following structural diversities, as biaryl
heterocyclic, fused heteroaryl rings containing oxazolidinones, and others. The biaryl
heterocyclic, fused heteroaryl, benzoxazine, and the 1H-pyrazol-1-yl containing
oxazolidinone derivatives demonstrated potent antibacterial activities superior to
linezolid against Gram-positive bacteria. Some derivatives were effective against
standard strains of Gram-negative bacteria, namely Moraxella catarrhalis ATCC A894,
and Escherichia coli ATCC 25922. In addition, a patent disclosed a structural isomer of
linezolid with marginal activity against the aerobic Gram-negative bacteria MDR
Stenotrophomonas (Xanthomonas) maltophilia, while linezolid and vancomycin did not
inhibit growth. Finally, some derivatives showed activity against respiratory infectious
diseases’ causative agents, such as B. anthracis, B. mallei, Y. pestis, and M.
pneumoniae.
Expert opinion: Overall, there is limited in vivo data to support the potential clinical
advancement of the currently reported novel derivatives.
Keywords: Antibacterial agents, antimicrobials, bacterial-resistance, fluoroquinolone-
oxazolidinone hybrids, Gram-negative bacteria, Gram-positive bacteria, linezolid,
oxazolidinone, tedizolid.

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List of abbreviations
B. anthracis = Bacillus anthracis
B. mallei = Burkholderia mallei
Compd # =Compound number
ED50= 50% Effective Dose
E= Enterococcus
IC50 = 50% inhibitory concentration
S= Streptococcus, Staphylococcus
MDR= multi drug resistant
MRSA= Methicillin resistant Staphylococcus aureus
MSSA= Methicillin sensitive Staphylococcus aureus
MRSE= Methicillin resistant Streptococcus epidermidis
MSSE= Methicillin sensitive Streptococcus epidermidis
Y. pestis = Yersinia pestis
M. pneumoniae = Mycoplasma pneumoniae
PRSP = Penicillin-resistant Streptococcus pneumoniae
VRE = Vancomycin resistant enterococcus
MIC = Minimum inhibitory concentration
MAO = Monoamine oxidase
M. catarrhalis = Moraxella catarrhalis
PK= pharmacokinetics

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Article Highlights:
• Twenty five patents publications from 2012 to 2015 were selected for review.
• The patents were obtained from free patent search engines such as
Espacenet and WIPO patentscope.
• Heteroaryl containing oxazolidinones showed potent in vitro antibacterial
activities superior to linezolid against Gram-positive bacteria.
• Some derivatives showed activity against selected Gram-negative bacteria
strains, M. catarrhalis and E. coli.
• There was limited in vivo antimicrobial data to affirm potential clinical
effectiveness of the compounds.
• No in vivo data are presented confirm the safety profiles of reported
oxazolidinone derivatives.

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1. Introduction
The breakthrough discoveries of the sulfonamide and the beta-lactam antibiotics
in the 1930s contributed to the prevention of significant loss of lives due to bacterial
infections [1 *]. Although the treatment of various human infectious diseases with these
agents have enjoyed a great success in the clinic, nonetheless, significant antimicrobial-
resistance continues to pose a major threat to the usefulness of these agents [2 **, 3]. In
recent years, resistance to antimicrobial agents continues to emerge and increase at an
alarming rate, while the number of new antimicrobial approvals continue to decline [4 **,
5, 6]. In 2013, Britain’s top health officials [7 **] and the Center for Disease Control and
Prevention (CDC) [8 **] independently reported the rising and lethal threat of
antimicrobial-resistance and stressed the catastrophic threat posed by this development
on patients’ health care in Britain and the United States, respectively. Several factors
including non-prescription use and overuse of antimicrobial drugs, and use of
counterfeits and substandard antimicrobial drugs have been suggested as contributors
to the development of antimicrobial resistance [9-11]. In the United States, about 2
million people are stricken annually with antimicrobial-resistant infections with an
estimated 23,000 deaths per year. Gram-positive organisms including methicillin-
resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae
(PRSP), methicillin-resistant Staphylococcus epidermidis (MRSE) and vancomycin-
resistant enterococci (VRE) are a worldwide threat to hospitalized patients and continue
to pose serious threats [12-13].
The oxazolidinone class of antibiotics, exemplified by linezolid (1 in Figure 1),
and more recently, tedizolid (2 in Figure 1) and its pro-drug tedizolid phosphate (3;
TR201 in Figure 1) represent a novel class of antibacterial agents with potent activity
against multidrug-resistant (MDR) Gram-positive pathogenic bacterial strains. Linezolid,
the first oxazolidinone approved for clinical use, is characterized by excellent oral

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bioavailability, tissue and organ penetration, with demonstrated effectiveness against
MDR Gram-positive bacterial pathogens, including MRSA, PRSP, VRE and
Streptococcus spp [14-16]. Furthermore, it is also active against Mycobacterium
tuberculosis hence may be useful for treating multidrug-resistant tuberculosis (MDR-TB)
[14-18]. However, linezolid is plagued with a number of limitations, firstly, the twice daily
dosing may complicate compliance in outpatients. It has also been associated with other
undesirable side-effects, such as lactic acidosis, myelosuppression, thrombocytopenia
and neuropathies during prolonged administration. In addition, treatment with linezolid
may lead to unfavorable interactions with serotonergic and adrenergic agents which may
result in severe hypertensive crisis in patients [19-21]. This serotonin toxicity has been
associated with its inhibitory effects on monoamine oxidases (MAO) [20, 22], due to the
structural similarity to the MAO inhibitor toloxatone (4 in Figure 1). More recently, an
incidence of linezolid-induced black hairy tongue (BHT) was reported in a 10 year old
boy after two-week postsurgical treatment [23].
Oxazolidinones exhibit their antibacterial effects by inhibiting bacterial protein
biosynthesis by binding to sites on the bacterial ribosomes, thus preventing formation of
a functional 70S initiation complex [14, 22, 24]. Duffy et.al. [25 **] have shown that
linezolid binds to the A-site of the 50S subunit, thus preventing binding of the aminoacyl-
tRNA. While resistance was soon observed after linezolid’s clinical introduction, results
from post-FDA approval surveillance study groups have shown the rate of linezolid-
resistance development to be relatively low and stable since its clinical approval 16
years ago [26-28]. The two most common linezolid resistance mechanisms are mutation
(G2576T) to the 23S rRNA and the presence of a transmissible cfr ribosomal
methyltransferase [26]. The plasmid-mediated staphylococcal cfr gene confers a
multidrug-resistance phenotype to oxazolidinones and other protein inhibitor
antimicrobials such as phenicols, licosamides, pleuromutilins and streptogramin A [29].

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Furthermore, it has been shown that the presence of the cfr gene, encoding the RNA
methyltransferase targeting an rRNA nucleotide located in the linezolid binding site, may
account for significant resistance [30]. Finally, mutations in the ribosomal proteins L3
and L4 are potential additional modes of linezolid resistance [22]. Overall, a combination
of these events may limit the future clinical effectiveness of linezolid.
Tedizolid phosphate (3 in Figure 1), an inactive pro-drug that is readily
hydrolyzed in vivo by plasma phosphatases to the active drug tedizolid (2 in Figure 1) is
a second generation agent and the most recent addition to the synthetic oxazolidinone
class of antimicrobial agents [15-16, 31 **-32]. Structurally, tedizolid (TR-700) formerly
torezolid [33] contains a 5-hydroxymethyl moiety at the C-5 position of the oxazolidinone
ring, replacing the linezolid acetamidomethyl group. The advantages of tedizolid over
linezolid include, improved pharmacokinetics (PK) facilitating once daily dosing and
enhanced effectiveness against linezolid-resistant strains [32, 33-34]. The comparative
minimum inhibitory concentrations (MIC) of tedizolid versus linezolid when evaluated
against 169 linezolid-resistant staphylococci isolates, showed that tedizolid MIC was 0.5
µg/mL for all S. aureus isolates, in comparison to linezolid with MIC range of 8-16
µg/mL. Moreover, some in vitro studies have demonstrated that tedizolid MIC for
linezolid-resistant isolates falls within the range for the proposed susceptible
breakpoints, while others have shown higher MICs in the intermediate or resistant range
[32]. Also, tedizolid was superior to linezolid when evaluated against linezolid-resistant
enterococci with MICs of 1-16 µg/mL compared to 4-64 µg/mL for linezolid. In this light,
tedizolid is particularly active against linezolid-resistant MRSA and VRE [35 **-36 **].
Tedizolid has superior in vitro antimicrobial potency up to 16 times and is particularly
active against bacterial strains harboring mutation in the 50S L3 and L4 ribosomal
proteins (G2576T mutation to the 23S rRNA) and the transmissible cfr ribosomal
methyltransferase [22, 36 **-36 **, 37]. Like linezolid, tedizolid also inhibits protein

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synthesis by binding to the 50S ribosomal subunit. Generally, linezolid-resistance has
been associated with mutations in the 23S rRNA with the four main sites of mutations at
G2576T, T2500A, G2505A and G2447T [32, 34]. However, development of spontaneous
resistance to linezolid in S. aureus isolates involved both G2576T and T2500A mutations
but spontaneous tedizolid-resistance involved only T2500A mutation [32, 35]. However,
tedizolid, like linezolid reversibly inhibits human MAO-A and MAO-B with 50% inhibitory
concentration (IC50) for tedizolid 8.7 µM / 5.7 µM (MAO-A/MAO-B) and for linezolid 46.0
µM / 2.1 µM (MAO-A/MAO-B), respectively. To date, animal model studies have
indicated the lack of potential serotonergic toxicity with tedizolid in comparison to
linezolid [16,32, 38 **-39].
With regards to structure-activity relationships studies (SAR), linezolid and most
recently tedizolid, continue to serve as the reference compounds since their approval for
clinical use, with focus on structural modifications around the phenyl-oxazolidinone ring
systems (A- and B-ring, Figure 1). Several research investigators have performed
extensive structural modifications along with SAR studies around the phenyl-
oxazolidinone pharmacophoric group (A-, B-, C- and D-rings, Figure 1) with the intention
of identifying newer derivatives with improved potency, extended antibacterial spectrum
and / or improved safety profiles such as reduced MAO inhibitory activity and
myelosuppression and thrombocytopenia, without much success [22, 34, 40 **-43].
Stokes et al. [44] and Keating et al. [45] have reviewed new antibacterial agents patents
published in 2010 and 2011, respectively. In order to find and gain free access to
relevant patent documentation we used Espacenet, WIPO Patentscope and
FreePatentsOnline and AcclaimIP, as search engines. The current review will focus on
composition-of-matter patent applications published from 2012 to 2015 that contain
novel oxazolidinone derivatives with claimed antibacterial activity. It will highlight
significant antibacterial activity data of at least one or more compounds for SAR studies

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and elaborate on their therapeutic future. It also describes a method of use and a
method of synthesis.
2. Biaryl oxazolidinones containing heterocyclic groups
During this patent period, Rib-X Pharmaceuticals (US) disclosed several biaryl
(biphenyl rings) oxazolidinone derivatives having at least one heterocyclic moiety,
methods of making them and their therapeutic uses, including uses as antibacterial
agents in four separate patents [ 46-49]. This series of compounds are derived from the
biaryl ring-system found in tedizolid and radezolid, which have been demonstrated to
enhance binding at the ribosomal RNA site due to the presence of the aromatic ring
spacers [22]. The first patent [46] divulged a series of biaryl derivatives containing a
variety of aromatic and non-aromatic heterocyclic groups, namely, 1H-1,2,3-triazolyl, 1H-
1,2,3-triazolyl, imidazolyl, pyridinyl, morpholinyl and piperazinyl among others. The
specifically claimed compounds are exemplified by 5a (Figure 2), which is structurally
similar to radezolid 5b (Figure 2), with regards to the presence of the biaryl ring and the
C5-methylacetamido moiety. However, compound 5a contains an 1H-1,3,4-triazol-5-yl
propylthio substituent while radezolid 5b has an 1H-1,2,3-triazol-5-yl substituent. The
compounds were claimed as effective anti-infectious agents among other therapeutic
uses, however, no antibacterial activity data were reported for the compounds.
The second invention also synthesized a vast number of biaryl oxazolidinones
containing varied substituted heterocyclic moieties but no compound was specifically
claimed and no biological data was presented [47]. Two exemplary compounds among
the large numbers synthesized were the 1H-1,2,4-triazol-3-yl propylthio 6 and the
pyridine-3-yl sulphonamide 7 (Figure 2) derivatives. Finally, the third and fourth patent
disclosures by Rib-X further reported a large number of biaryl oxazolidinones closely

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related to compounds 6 and 7, but with varied optional substitution patterns. Again, no
specific compounds were claimed and no biological and / or antibacterial activity data
was presented [48-49]. Among the exemplary compounds synthesized was the 1H-
1,2,4-triazol-3-ylthio 8 and the D-cycloserine 9 derivatives, which contain the 1H-1,2,3-
triazol-1-yl and an acetamido functional group at the C5-oxazolidinone positions,
respectively. Melinta Therapeutics Inc. [50] also filed a patent which disclosed a series of
biaryl heterocyclic oxazolidinones of similar structural diversity to compounds 5a, b and
8 [46, 48]. Although the compounds were claimed to be useful as anti-infective agents
among other therapeutic uses, no antibacterial activity data were presented.
Three patent publications by Dong-A of South Korea [51-53], describe the
synthesis and antibacterial activities of a large number of heterocyclic-substituted biaryl
(phenyl-pyridinyl system as B- and C-rings) oxazolidinones exemplified by compounds
10, 11 and 12 (Figure 2). The compounds bear structural similarities to tedizolid with
regards to rings B and C, but differ in the structure of ring D and the C5 substitution on
the oxazolidinone ring A. Compounds 10 and 11 demonstrated potent antibacterial
activity against MRSA (MIC: 0.5 µg/mL) and VRE (MIC: 0.25 and 1 µg/mL), which are
superior to linezolid but comparable to tedizolid. Compound 12 is a 5-glycyloxymethyl
pro-drug derivative, with the prodrug charged amine making the compound highly water-
soluble. This compound also showed potent antibacterial activity, with MIC of 0.5 µg/mL
and 0.25 µg/mL against MRSA and VRE, respectively. Compounds bearing 2-methyl-
2H-tetrazol-5-yl substituents and a 5-glycyloxymethyl group at the C5-position of the
oxazolidinone ring having structural resemblance to compound 12 have been reported
previously [40].
Xuanzhu Pharma of China further published a patent detailing structurally
diversified biaryl (phenyl-pyridinyl system as B- and C-rings) heterocycle containing
oxazolidinone derivatives as potent antibacterial agents [54]. The compounds have

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structural resemblance to tedizolid, but contain a nitrogen atom linker between the
pyridinyl and tetrazolyl rings. Detailed in vitro antibacterial activity and in vivo
pharmacokinetic data are presented in the patent. The exemplified compounds 13, 14,
15, 16, 17 and 18 (Figure 3) demonstrated potent antibacterial activity that was superior
to linezolid against all the Gram-positive bacterial strains reported. Compound 15, the 1-
methyl-1H-tetrazol-5-yl 5-hydroxymethyl derivative demonstrated the most potent activity
with MIC value range of 0.125 to 1 µg/mL against MRSA, MRSE, MSSA, MSSE, E.
faecalis, E. faecium and S. pneumoniae (Table 1). On the other hand, the 1-methyl-1H-
1,2,3-triazol-4-yl 2-hydroxymethyl derivative 18 was less active than the methyl-1H-
tetrazol-5-yl substituted derivatives.
Trius Therapeutics disclosed the in vivo efficacy and PK data for the two pro-drug
phosphate dimers 19 and 20 (Figure 3) of tedizolid [55]. These dimers were previously
isolated as impurities during the synthesis of tedizolid. Formulations containing both the
mono-phosphate and di-phosphate administered intravenously showed that dimer 19
was highly effective as an antibacterial agent protecting 10 out of 10 Balb/c mice (100%
protection) S. aureus Smith strain ATCC13709 in mouse septicemia infection model
after 24 and 48 hr at concentrations of 5 and 10mg/kg. In contrast, mono-phosphate
dimer 20 showed only 10% protection rate at these concentrations after 48 hr. This
showed that the di-phosphate dimer is more readily hydrolyzed by plasma phosphatases
to the active 5-hydroxymethyl monomers [22, 44].
3. Oxazolidinone antibacterial agents containing fused heteroaryl rings
In two separate patents, Actelion Pharmaceuticals disclosed a very large number
of novel oxazolidinone derivatives, containing optionally substituted quinolinyl,
naphthyridinyl, quinoxalinyl, 2,3-dihydrobenzo [1,4]dioxinyl and other heterocyclic

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moieties, notably on the aminomethyl oxazolidinone substituent where most other
oxazolidinone substituents are unsubstituted [56-57]. The compounds were claimed to
be useful antimicrobial agents effective against a variety of human and veterinary
pathogens including Gram-positive and Gram-negative aerobic and anaerobic bacteria
and mycobacteria. In the first patent, the synthesized compounds were tested against
several Gram-positive and Gram-negative bacterial strains, but, only detailed
antibacterial activity data against S. aureus ATCC 29213 were presented in the patent
publication. The compounds showed moderate to potent antibacterial activity against
Gram-positive bacteria S. aureus ATCC 29213, E. faecalis ATCC 29212 and S.
pneumoniae ATCC 49619, with MIC value ranges of 0.015 to 16 µg/mL, 0.031 to 32
µg/mL and 0.015 to 32 µg/mL, respectively. Against the standard strain of the fastidious,
Gram-negative respiratory disease causative bacteria Moraxella catarrhalis ATCC A894,
and Escherichia coli ATCC 25922 the evaluated compounds showed MIC ranges of
0.015 to 32 µg/mL and 0.031 to 32 µg/mL, respectively. Compounds 21 and 22 (Figure
4) exemplified the series and constitute two of the most active examples with MIC values
of ≤ 0.063 µg/ml. Compound 21 and 22 are oxazolidinone derivatives containing 2-
fluoro-6-methoxy-[1,5]naphthyridin-4-yl and 3-methoxy-quinoxalin-5-yl on the
aminomethyl or aminopropyl oxazolidinone substituent and 4 H-benzo [1,4]oxazin-3-one
and 3(2,3-dihydrobenzo [1,4]dioxin-6-yl moieties, respectively at the N-1 position of the
oxazolidinone ring. The second patent disclosed over 180 optionally substituted
oxazolidinone derivatives containing fused heteroaryl rings. The authors reported that
the compounds were tested against Gram-positive and Gram-negative bacterial strains,
however, only antibacterial activity against S. aureus A798 strain was reported. For
example, the exemplified azetindin-3-yl containing [1,5]-naphthyridin-4-yl derivatives 23
and 24 (Figure 4) showed potent antibacterial activity against S.aureus A789 with MIC
value of ≤ 0.031 µg/mL. Similarly, the piperazin-4-ylmethoxy derivative 25 (Figure 4),

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containing 3N-benzothiazol-6-yl, also showed potent activity(MIC ≤ 0.031µg/mL), while
the 3N-fluoro-phenyl oxazolidinone derivative 26 (Figure 4) was relatively less active
(MIC of 0.125 µg/mL against similar bacterial strains) [57].
Actelion Pharmaceutica
ls in another patent publication disclosed oxazolidinone compounds with complex
tricyclic substituents on the oxazolidinone aminoethyl substituent as antibacterial agents
evaluated against Gram-positive and Gram-negative bacterial strains such as S. aureus,
S. pneumoniae, fastidious respiratory causative bacteria M. catarrhalis A894, E. coli, and
Pseudomonas aeruginosa. However, only typical antibacterial test results against M.
catarrhalis A894, were presented with MIC values in the range of ≤ 0.031 - 16 µg/mL. A
representative compound 27 (Figure 4), showed potent antibacterial activity with MIC of
≤ 0.031µg/mL against the M. catarrhalis A894 bacterial strain [58].
Xuanzhu Pharma disclosed a series of fused heteroaryl-spacer containing
oxazolidinones as potent antibacterial agents to meet the urgent clinical needs for
additional antimicrobials for the treatment of more aggressive bacterial infections [59].
The examples covered in this patent publication are typified by the N-substituted
isoindolin-5-yl containing compounds 28-33 (Figure 5), which were tested against a
panel of Gram-positive bacterial strains including MRSA, MRSE, MSSA, MSSE, E.
faecalis, E. faecium and S. pneumoniae, and compared to linezolid and a previously
reported compound 34 (Figure 5), which is a 2-(2-methyl-2H-tetrazol-5-yl)imidazo[1,2-
a]pyridine derivative [60]. From the MIC data (Table 2), compounds 30 and 31
demonstrated the most potent activity against all the Gram-positive bacteria tested with
an MIC range of 0.125-0.5 µg/mL in comparison to linezolid and compound 34, with MIC
ranges of 1-2 µg/mL and 0.25-0.5 µg/mL, respectively against similar strains.

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Entasis Therapeutics [61] in a patent publication disclosed the synthesis and the
antibacterial activity of a complex fused, spirocyclic heteroaromatic oxazolidinone
containing compound against a variety of bacterial strains. The specifically claimed
compound 35 (Figure 5), showed antibacterial activity against a variety of selected
bacteria, including Bacillus anthracis (n=30; MIC: 0.12-4 µg/mL), Brucella suis (n=10;
MIC: 1-2 µg/mL), Burkholderia mallei (n=10; MIC: 0.25-64 µg/mL) and Yersinia pestis
(n=10; MIC: 1-64 µg/mL), Chlamydia trachomatis and Mycoplasma pneumoniae (n=12;
MIC: 0.5-1 µg/mL) compared with levofloxacin MIC range of ≤ 0.25-1 µg/mL. This
compound showed effectiveness against respiratory infectious diseases causative
agents, such as B. anthracis, B. mallei, Y. pestis and M. pneumoniae.
4. Other new oxazolidinone antibacterial agents
The South Korean company Legochem Biosciences Inc published a patent
describing the methods for the synthesis of two oxazolidinone derivatives having a cyclic
amidrazone group at the C-4 position of the phenyl-oxazolidinone pharmacophore [62]
as antibacterial agents. An efficient 8 steps synthetic method was claimed starting from
3,4-difluoronitrobenzene to give the compounds exemplified by 36 and 37 (Figure 6),
containing a 5-acetamido and 5-carbamato moieties at the oxazolidinone C-5 positions,
respectively. These compounds are derivatives of the LCB01-0371 (38, Figure 6), a 5-
hydroxymethyl oxazolidinone currently under Phase I clinical trials [63-64]. It was stated
that the compounds could be formulated as water-soluble salts with improved water-
solubility due to the presence of the cyclic amidrazone, which could be useful as orally
effective agents against antibiotic-susceptible and resistant strains. No antibacterial data
are presented in support of this claim.

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Lee Pharma [65] disclosed the synthesis and antibacterial activity of compound
39 (Figure 6) against selected Gram-positive and Gram-negative bacteria in comparison
to linezolid and vancomycin. Compound 39, a structural isomer of linezolid with the
fluoro and morpholino aryl substituents interchanged, was disclosed in Indian Patent
Applications 5063/CHE/2013 and PCT/IN2014/000018. The current patent publication
disclosed its antibacterial activity against MDR Stenotrophomonas (Xanthomonas)
maltophilia, which is an aerobic Gram-negative bacteria that causes nosocomial
infections in humans. Although the compound did not exhibit significant activity,
however, it showed a marginal zone of growth inhibition at 10 µg against S. maltophilia
and completely inhibited the growth of the bacteria at 500 µg/mL, while linezolid and
vancomycin were unable to inhibit.
Morphochem [66] disclosed a previously reported oxazolidinone-quinolone hybrid
pro-drug [22] antibacterial agent for the parenteral treatment or prophylaxis of bacterial
infections. The specifically claimed compound 40 (Figure 6), a pro-drug readily
converted to the active form 41 [WO2005/058888] was indicated to have improved
methods of administration for the treatment of Gram-positive bacteria especially Gram-
positive anaerobes such as Clostridium spp. particularly Clostridium difficile and
Clostridium perfringes. This patent publication highlighted the usefulness of compound
41 for the treatment of intestinal diseases. This compound reduced the viable counts of
Clostridium spp. from pre-dose to Day 5 by 3.0 log10, in healthy volunteers after 6 mg/kg
body weight administration over 12 hours for 5 days. Furthermore, against 144 C.
difficile strains compound 41 showed MIC90 and MIC50 ranges of 0.064 and 0.008-0.5
µg/mL. Compounds 40 and 41 have been previously reported, and 41 is currently in
clinical trial studies as cadazolid (ACT-179811) for the treatment of C. difficile in humans
[64,67,68].

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The University of South Florida, disclosed a patent publication on the discovery,
synthesis and antibacterial activity of a series of N-thiolated non-traditional class of
oxazolidinone antibacterial agents [69]. This series, exemplified by compounds 42 - 46
(Figure 6), was tested for their ability to inhibit growth of MRSA and S. aureus 849
strains. Non-N-thiol Compound 42 did not show any zone of growth inhibition, while
compounds 43 - 46 inhibited the bacterial strains with zones of growth inhibition in the
range of 19-30 mm, with 43 being the most active compound with zones of 29 and 30
mm against MRSA and S. aureus, respectively and 46 being the least active.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Nanjing
Changao Pharmaceutical Science and Technology, disclosed a novel series of pyridine
containing benzoxazine oxazolidinone derivatives as antimicrobial agents [70]. These
compounds, exemplified by 47-51 (Figure 6) showed moderate to potent antimicrobial
activity against selected Gram-positive bacteria including susceptible and resistant
strains of S. aureus, S. epidermidis and S. pneumoniae with MIC values in the range of
0.125 – 16 µg/mL. Furthermore, compounds 47 and 48 demonstrated slightly improved
antimicrobial activity against linezolid-resistant strains of S. aureus, S. epidermidis and
E. fecalis and E. faecium with MIC values in the range of 4 - 8 µg/mL, and linezolid with
MIC range of 8 - >32 µg/mL. The disodium phosphate pro-drug compound 50 was
metabolized by plasma phosphatases to 51 after intravenous administration in rats.
Compound 50 showed superior activity to linezolid in a S. aureus systemic infection mice
model with 50% effective dose (ED50) of 5.00 mg/Kg in comparison to 9.87 mg/Kg for
linezolid.
Sichuan University and Sichuan Gooddoctor Pharmaceutical divulge novel 1H-
pyrazol-1-yl containing 5-acetamido oxazolidinone derivatives exemplified by compound
52 (Figure 6) as potent antimicrobial agents [71]. Against E. faecalis (n=7), S. aureus
(n=12), S. pneumoniae (n=10) and S. agalactiae (n=5) strains, compound 52 had MIC

18
ranges of 0.5-2, 0.25-2, 0.25-1 and 0.25-2 µg/mL. Compared to linezolid with MIC
ranges of 4-32, and 2-32 µg/mL against similar strains. The author disclosed that
compound 52 had better in vivo efficacy and protection effects in a mouse model of
systemic S. aureus ATCC 25923 bacterial infection than linezolid at 5 mg/Kg and 10
mg/Kg doses. In addition, at 50 µM concentration, compound 52 was claimed to show
less cytotoxicity against normal cells HEK-293 and L02 in comparison to linezolid.
Council of Scientific and Industrial Research, divulge novel 1,4-aza-silinan-1-yl
oxazolidinone derivatives as antimicrobial agents among other biological activities [72].
The exemplified compounds 53-55 (Figure 6) demonstrated moderate to weak
antimicrobial activity against selected Gram-positive bacterial strains including E.
faecalis, E. faecium, S. aureus, S. epidermidis and MRSA with MIC range of 1->32
µg/mL. In this series, compounds 53 was most active with MIC range of 1-32 µg/mL, no
in vivo activity data was presented.
5. Novel process for preparation of linezolid
At present, several methods for the synthesis of linezolid as the first example of
the oxazolidinone class of antibacterial agents have been published, with the major
focus on the key synthetic step of constructing the oxazolidinone ring, compound 60 [73-
76]. Among the many methods reported for the formation of the 5-membered
heterocyclic oxazolidinone ring, Brickner et al [76] used stringent cryogenic reaction
conditions (-78 °C) and air sensitive n-BuLi. From this method the reaction of an N-
lithiated carbamate derivative of aniline with (R)-glycidyl butyrate under cryogenic
conditions led to the construction of the oxazolidinone ring. Other reported methods are
limited for large-scale production of linezolid due to high cost or lack of availability of raw
materials, stringent reaction conditions, multiple number of steps, low yields and / or

19
contamination with impurities that are difficult to eliminate during purification steps. Lee
Pharma disclosed a novel process for the preparation of linezolid in three separately
published patents [77-79], which claimed specific intermediates and the process leading
to the synthesis of linezolid as outlined in Scheme 1. This 9 step process starting from
commercially available 56 and 57, avoided the use of the moisture-sensitive and highly
reactive n-BuLi, instead constructing the oxazolidinone ring by carbonylation using
carbonyl di-imidazole in dichloromethane. This claimed method from the patent
publication is similar to a recently published method by Reddy et al. [80].
6. Conclusion
The review of selected patent applications published between 2012 to 2015
revealed that there is a limited number of patent disclosures describing novel
oxazolidinones as antibacterial agents. The majority of new derivatives reported during
this patent period focused on the incorporation of the biaryl ring systems found in
tedizolid and radezolid since the addition of such ring system has been reported to
extend binding at the bacterial ribosomal binding site. In the case of tedizolid, the
presence of rings C and D (Figure 1) have been shown to significantly enhance its
antibacterial activity against MDR strains and in particular against linezolid-resistant
Gram-positive bacteria including MRSA and VRE. In general, tedizolid has been shown
to overcome linezolid-resistance in bacterial strains harboring mutation in the 50S L3
and L4 ribosomal proteins and the transmissible cfr ribosomal methyltransferase, while
radezolid has been shown to offer coverage to fastidious Gram-negative organisms.
Although some of the compounds disclosed during this patent period showed
antibacterial activities superior to linezolid, there were no detailed antibacterial data
affirming improved activity particularly, against linezolid-resistant bacterial strains, which
is one of the major current issues facing the oxazolidinone antibacterial class of

20
compounds. Among the newly reported oxazolidinone derivatives, the differences in
antimicrobial activity do not depend on whether the C-5 substitution is a hydroxymethyl,
an aminomethyl or a substituted aminoalkyl moiety, since the substituents on the B and
C rings also play significant roles in modifying the antimicrobial activity. In addition, none
of the newly disclosed compounds reported any in vivo biological data in support of
improved safety profiles of the new oxazolidinones with regards to undesirable side-
effects, namely, MAO-A and -B inhibitory activity, myelosuppression, thrombocytopenia
and/or neuropathies. Finally, no in vivo biological data are presented to suggest any
improvement in pharmacokinetic profiles of the newer derivatives over linezolid or
tedizolid. The outcome of such data would help predict the future potential development
of the newer oxazolidinone antibacterial agents as a third generation.
7. Expert opinion
The clinical success of linezolid over the past 16 years after its FDA approval
have been celebrated due to its effectiveness in treating nosocomial MDR pathogenic
Gram-positive bacterial strains infecting humans. Development of resistance to linezolid
has been reported as limited and associated with invasive procedures, deep organ
involvement and mainly prolonged therapy. Linezolid-resistant enterococci,
staphylococci and streptococci have been described, with most isolates harboring 23S
rRNA mutations and cfr-mediated resistance, which often result in elevated linezolid MIC
values [14, 22, 27-28]. In addition, linezolid has to be administered twice daily and is
also plagued with unwanted side-effects including, myelosuppression, meuropathies,
thrombocytopenia and MAO inhibition, which may lead to serotonergic activity that
results in severe hypertensive crisis in patients. The recent introduction of tedizolid has
addressed some of the drawbacks of linezolid, with improved effectiveness against

21
linezolid-resistant Gram-positive bacteria and reduced potential for serotonergic and
adrenergic toxicity. Among the aims for the search for new oxazolidinones are to: (i)
extend the activity spectrum to include linezolid-resistant strains and community-
acquired respiratory pathogens Haemophilus influenza, M. catarrhalis and other atypical
bacteria, and (ii) eliminate or reduce potential unwanted side-effect issues that are
intrinsic to this class of compounds. To achieve these goals, relentless efforts by several
investigators have carried out extensive structural modifications around the phenyl-
oxazolidinone pharmacophoric group leading to the clinical advancement of several
oxazolidinones [22, 34-35, 39-45,63]. Unfortunately, only a few oxazolidinones, including
cadazolid (oxazolidinone-quinolone hybrid 41, Figure 6), radezolid and MRX-1 and
LCB01-0371 (38, Figure 6), are currently in different stages of clinical development [64].
A few others have been terminated from clinical trials due to several reasons, which vary
from inadequate pharmacokinetic properties and poor coverage of targeted pathogens to
solubility and formulation difficulties, among other issues [22]. The major challenges in
the oxazolidinone antibacterial research are to circumvent or minimize myelosupression,
thrombocytopenia, mitochondrial protein synthesis inhibition and MAO inhibition safety
issues and to maintain extended potent antibacterial activity.
During this reviewed duration, patent applications from Asia and United States
were dominant. The newly reported biaryl (biphenyl, B and C ring) heterocyclic
containing oxazolidinones having structural similarities to radezolid are claimed to have
potent antibacterial activity, but no detailed antibacterial activity and studies evaluating
their safety and PK profiles are reported. Therefore, it is rather difficult to predict their
potential future development and therapeutic uses. The future of these new compounds
will depend on the success and outcome of the clinical studies on radezolid, which is
currently awaiting phase 3 clinical trial study results [22, 64]. For the biaryl (containing
phenyl-pyridinyl B and C rings system) heterocyclic containing oxazolidinones, which

22
bear structural resemblance to tedizolid, their low MIC value range (0.125 – 1 µg/mL) for
most Gram-positive bacterial strains tested is supportive of the potency of these
compounds. Moreover, no detailed in vivo infectious animal model studies, activity
against linezolid-resistant strains, and PK and safety profile studies are presented to
permit critical evaluation of the potential future clinical developments of these
compounds. Of significant interest during this patent period are the novel oxazolidinones
containing fused heteroaromatic ring systems from Actelion Pharmaceuticals. These
derivatives showed significant activity against Gram-positive and Gram-negative
bacterial strains, including M. catarrhalis and E. coli, ascribing superior advantages to
this class over linezolid and tedizolid, which only possess limited activity against Gram-
negative bacteria. These fused heteroaromatic oxazolidinones showed MIC values in the
range of 0.015 - 32 mg/L for all bacterial strains tested. Similarly, the tricyclic heteroaryl
oxazolidinone derivatives from Actelion with potent antibacterial activity against Gram-
positive and Gram-negative bacterial strains, including M. catarrhalis (MIC: ≤
0.031µg/mL), might have advantages with regards to newer oxazolidinones for clinical
development. Furthermore, both the novel pyridine containing benzoxazine
oxazolidinone and the novel 1H-pyrazol-1-yl containing 5-acetamido oxazolidinone
derivatives demonstrated improved activity against selected Gram-positive bacterial
strains, while the benzoxazine derivatives had moderately improved activity against
linezolid-resistant strains. Overall, the antimicrobial activity of the newly reported
oxazolidinone are dependent on both the C-5 substitution and the substitutions on the B
and C rings. Further detailed in vivo pharmacokinetics and safety profile studies are
warranted.
However, for some of these reported derivatives no sufficient in vivo data are
presented to affirm their efficacy in infectious disease animal models against linezolid-

23
susceptible and -resistant strains, safety and PK profiles to justify their clinical
usefulness further for future clinical studies.
Since one of the major aims in oxazolidinone research is to extend the activity
spectrum of newer derivatives to include linezolid-resistant strains and respiratory
pathogens Haemophilus influenza, M. catarrhalis and other atypical bacteria, the
complex fused spirocyclic heteroaromatic derivatives from Entasis Therapeutics could
be of clinical importance. The compounds showed potency against respiratory infectious
diseases causative agents, such as B. anthracis, B. mallei, Y. pestis and M.
pneumoniae, although further studies are warranted. Although some of the compounds
in the patent applications discussed showed excellent antimicrobial activity, it remains
unclear at this point to predict with any certainty whether a compound will advance to
clinical trials or not. This is because of a lack of reported in vivo biological data to
support efficacy in disease models, PK and safety profiles in comparison to linezolid and
tedizolid. Overall, any oxazolidinone that would deserve advancement to clinical
development stages must satisfy all the deficiencies currently identified in linezolid and
those that might surface with the clinical usage of tedizolid. Furthermore, it must have
significant advantages over other classes of Gram-positive active antimicrobial agents,
namely ceftaroline, ceftobiprole, dalbavancin and oritavancin [15-16], with regards to
efficacy, PK and pharmacodynamics and safety profiles and overall treatment costs. The
establishment of the PK profiles of potential clinically useful novel oxazolidinones will
provide information on the dosing and frequency of administration.
The discovery and development of novel oxazolidinones will complement the
fight against treatment of resistant Gram-positive bacteria by joining the list of recently
approved antimicrobial agents and those still in clinical trials, including tedizolid,
ceftaroline, ceftobiprole, dalbavancin and telavancin [2, 15-16]. Moreover, the
introduction of additional antimicrobial agents does not eliminate the development of

24
antimicrobial-resistance. Finally, to truly combat the growing problems of antimicrobial
resistance, relentless combinations of efforts are needed from big Pharmaceutical
companies, Academia and Government establishments to support discovery and
development of more effective agents. To this effect, the recently drafted and signed
Declaration on Combating Antimicrobial Resistance by 85 companies and 9 industrial
associations from 18 countries at the World Economic forum in Davos Switzerland is a
major and significant step forward in establishing a properly global response to the
challenges of drug resistance [81].
Declaration of interest
The author has no relevant affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with the subject matter or materials
discussed in the manuscript. This includes employment, consultancies, honoraria, stock
ownership or options, expert testimony, grants or patents received or pending, or
royalties.
Acknowledgments
The authors would like to thank the Faculty of Pharmacy, Kuwait University for providing
the facilities during the preparation of this manuscript.

25
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Table 1. Antibacterial activity of biaryl heterocyclic oxazolidinones
Compd.
Antibacterial activity (MIC; µg/mL) against
MRSAa
MRSEb
MSSAc
MSSEd
E. faecalis E. faecium S. pneumoniae
Linezolid 4 2 2 2 4 4 2
13 1 0.5 1 0.5 1 1 0.5
14 1 0.25 0.5 0.25 0.25 0.25 0.25
15 0.25 0.125 0.25 0.125 0.25 0.25 1
16 0.5 0.5 0.5 0.5 1 1 0.5
17 1 0.5 1 0.5 1 1 0.5
18 1 1 1 0.5 2 2 1
a
MRSA = methicillin-resistant Staphylococcus aureus
b
MRSE = methicillin-resistant Staphylococcus epidermidis
c
MSSA = methicillin-susceptible Staphylococcus aureus
a
MSSE = methicillin-susceptible Staphylococcus epidermidis

35
Table 2. Antibacterial activity of oxazolidinones containing fused heteroaryl rings
Compd #
Antibacterial activity (MIC; µg/mL) against
MRSAa
MRSEb
MSSAc
MSSEd
E. faecalis E. faecium S. pneumoniae
28 1 0.5 1 0.5 1 0.5 0.25
29 0.25 0.25 0.5 0.5 0.5 0.5 0.5
30 0.5 0.25 0.5 0.125 0.5 0.5 0.5
31 0.25 0.25 0.25 0.125 0.25 0.25 0.5
32 1 1 1 0.5 2 2 1
33 2 0.5 1 0.5 8 8 n/d
34 0.5 0.25 0.5 0.5 0.25 0.5 0.5
Linezolid 2 1 2 2 2 2 2
a
MRSA = methicillin-resistant Staphylococcus aureus
b
MRSE = methicillin-resistant Staphylococcus epidermidis
c
MSSA = methicillin-susceptible Staphylococcus aureus
d
MSSE = methicillin-susceptible Staphylococcus epidermidis

36
N N
O
F
O
H
N
N
O
O
OH
H3C
CH3
O
O
N
O
F
O
O
N
N
N
N
N
1. Linezolid
R
1
2
3
4
5
2. Tedizolid: R = H
3. Tedizolid phosphate: R = PO3
2- 2Na+
A
AB
BC
D C
4. Toloxatone
Figure 1. Chemical structures of clinically used oxazolidinone derivatives

37
N
O
F
O
H
N CH3
O
5a. R =
H
N
R
N
O
F
O
H
N CH3
O
6.
N
H
OH
S
N
H
N
N
N
O
F
O
H
N CH3
O7.
S
H
N
O
ON
N
O
F
O
N
8.
N
H
S
N
H
N
N
.HCl
NN
N
O
F
O
H
N CH3
O
9.
H
N
HN
O
O
N
O
F
O
OHN
10.
N
N
O
N
O
F
O
H
NN
11.
S
N
O
NC
N
O
F
O
ON
N
N
N
N
O
12. NH3
+
Cl
-
N
N
N
H
5b. R =
S
NN
N
H
Figure 2. Biaryl oxazolidinones containing heterocyclic groups

38
N
O
F
O
XN
N
N
N
N
13. R = 2-methyl-1H-tetrazol-5-yl; X = OH
14. R = 2-methyl-1H-tetrazol-5-yl; X = NHCOCH3
15. R = 1-methyl-1H-tetrazol-5-yl; X = OH
HN
N
O
F
O
ON
N
N
N
N
16. R = 1-methyl-1H-tetrazol-5-yl
17. R = 2-methyl-1H-tetrazol-5-yl
N
H
R
N
O
F
O
OHN
N
N
N
18.
HN
R
N
O
F
O
ON
N
N
N
N
P
O
O
19.
OH
P
OH
o
O
O
N
O
N
N
N
NN
N
O
F
O
ON
N
N
N
N
P
O
O
OH
O
N
O
N
N
N
NN
20.
F
F
Figure 3. Biaryl oxazolidinones containing heterocyclic groups

39
O
HN
O
O
N
O
N
CH2OH
N
N
O
F
O
H
N
N
N
O
O
N
O
O
O
21.
22.
25.
O
H
N O
O
N
O
H
N
N
N
N
O
23.
S
H
N O
O
N
O
H
N
N
N
N
O
24.
O
N
O
N
N
N
N
O
S
N
O
N
O
N
N
N
N
O
F26.
NO
NH
O N
S
N
H O
O
F
27.
Figure 4. Oxazolidinone antibacterial agents containing fused heteroaryl rings

40
N
O
F
O
OH
28.
N
NN
N
N
H3C
N
O
F
O
H
N
N
NN
N
N
H3C
CH3
O
29.
N
O
F
O
OH
30.
N
N
N
N
H
N
O
F
O
H
N
N
N
N
N
H
CH3
O
31.
N
O
F
O
OH
32.
N
NN
N
N
N
O
F
O
OH
N
N
N
H
33.
H3C
N
O
F
O
H
N
N
N
NN
N
N
H3C
CH3
O
34.
F O
N
N
OO
NO
NH
HN O
O
O H
35.
Figure 5. Oxazolidinone antibacterial agents containing fused heteroaryl rings

41
N N
O
F
O
R
36. R = NHCOCH3
37. R = NHCO2CH3
38. (LCB01-0371): R = OH
N
N
N
N
O
O
H
N CH3
O
3
9
.O
F
O
N
O
F
O
N
F
O
OH
O
HN
O
N
RO
40. R = PO3H2
41. R = OH
XN
O
O
42. R = (S)-Phenyl; X = H
43. R = (S)-Phenyl; X = SCH3
44. R = (R)-Phenyl; X = SCH3
45. R = (S)-iPropyl; X = SCH3
46. R = (R)-iPropyl; X = SCH3
R
N
O
N
O
O
OH
O
OH
47.
N
O
N
O
N
O
OH
48.
N
N
N
O
N
ON
O
OH
49.
O
O
N
O
N
O
O
OR
50. R = PO3
2- 2Na+
51. R = H
O
N
O
N
O
N
O
NHCOCH3
52.
N
N F
Si
N
N O
O
R53. X = H; R = NHCSOCH3
54. X = H; R = 1H-1,2,3-triazol-1-yl
55. X = F; R = NHCOCH3
F
X
Figure 6. Other new oxazolidinones

42
Cl
O
O NH + F
F
NO2 N
F
NH2O
N
F
H
NO
OH
N
F
NO
Cl
O
CH2Cl
O
N
F
NO
O
CH2OAc
O
N
F
NO
O
CH2OH
O
N
F
NO
O
CH2NH2
O
N
F
NO
O
CH2NHCOCH3
O
CDI
56.
57. 58.
59. 60.
61. 62.
63. 1.
Ac2O
Scheme 1. Novel synthesis of linezolid

Oxazolidina

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