Discovery of Fluorine-Containing Benzoxazinyl-oxazolidinones for the Treatment of Multidrug Resistant Tuberculosis

Article abstract of DOI:10.1021/acsmedchemlett.7b00068

A novel series of fluorine-containing benzoxazinyl-oxazolidinones were designed and synthesized as antidrug-resistant tuberculosis agents possessing good activity and improved pharmacokinetic profiles. Compound 21 exhibited not only outstanding in vitro a

Full text of DOI:10.1021/acsmedchemlett.7b00068

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Letter
Discovery of Fluorine-Containing Benzoxazinyl-Oxazolidinones
for the Treatment of Multidrug Resistant Tuberculosis
Hongyi Zhao, Yu Lu, Li Sheng, Zishuo Yuan, Bin Wang, Weiping Wang,
Yan Li, Chen Ma, Xiaoliang Wang, Dongfeng Zhang, and Haihong Huang
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00068 • Publication Date (Web): 12 Apr 2017
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ACS Medicinal Chemistry Letters
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Discovery of Fluorine-Containing Benzoxazinyl-Oxazolidinones for
the Treatment of Multidrug Resistant Tuberculosis
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⊥
⊥
Hongyi Zhao,†,‡, Yu Lu,§, Li Sheng,† ZishuoYuan,† Bin Wang,§ Weiping Wang,† Yan Li,† Chen Ma,†
Xiaoliang Wang,† Dongfeng Zhang* ,†,‡ and Haihong Huang* ,†, ‡
†State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking Union
Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China
‡Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking
Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China
§Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and
Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
KEYWORDS Antitubercular agents, fluoro-benzoxazinyl-oxazolidinones, structure-activity relationships, drug-resistant tu-
berculosis (DR-TB)
ABSTRACT: A novel series of fluorineꢀcontaining benzoxazinylꢀoxazolidinones were designed and synthesized as antiꢀdrugꢀ
resistant tuberculosis agents possessing good activity and improved pharmacokinetic profiles. Compound 21 exhibited not only
outstanding in vitro activity with a MIC value of 0.25−0.50 ꢁg/mL against drugꢀsusceptible H37Rv strain and two clinically isolated
drugꢀresistant mycobacterium tuberculosis strains, but also acceptable in vitro ADME/T properties. Moreover, this compound disꢀ
played excellent mouse pharmacokinetic profiles with an oral bioavailability of 102% and a longer elimination halfꢀlife of 4.22 h,
thereby supporting further optimization and development of this promising lead series.
Tuberculosis (TB), one of the top 10 causes of death
worldwide in 20151, is caused by the infection of Mycobacte-
rium tuberculosis (MTB). In recent years, the emergence of
multidrugꢀresistant tuberculosis (MDRꢀTB), extensively drugꢀ
resistant tuberculosis (XDRꢀTB), totally drugꢀresistant tuberꢀ
culosis (TDRꢀTB) and even coꢀinfections with HIV create a
serious global challenge for treatment of this fatal disease2,3.
The prolonged treatment of TB, adverse drug reactions and
drugꢀdrug interactions are commonly encountered, especially
to the secondꢀline medicines and in HIV coꢀinfected individuꢀ
als on antiretroviral treatment. Consequently, there is a pressꢀ
ing need for new antiꢀtuberculosis agents effective against
drugꢀresistant TB4,5. The current situation even necessitates the
reꢀengineering and repositioning of some old drug families to
achieve effective control.
it is still needed to develop new oxazolidinones with acceptaꢀ
ble safety margins through enhancing efficacy and reducing
toxicity.
Figure 1. Structures of representative oxazolidinones for TB
treatment.
The oxazolidinones is a new class of antibacterial protein
synthesis inhibitors that block translation through a unique
mechanism by binding to 23S RNA in the 50S ribosomal subꢀ
unit of bacteria6,7. Linezolid8,9 (Figure 1), the first marketed
oxazolidinone developed to treat gramꢀpositive bacterial infecꢀ
tion with a dose of 600 mg twice daily in adults, has an offꢀ
label use to treat complicated MDRꢀTB and XDRꢀTB with
improved outcome10,11. In addition, sutezolid12 (Figure 1) is
undergoing clinical studies for tuberculosis treatment, making
the oxazolidinones a class likely to play a key role in future
TB treatment regimens. However, prolonged treatment with
linezolid is associated with serious neuropathies and myeloꢀ
suppression which is mediated by doseꢀ and timeꢀdependent
inhibition of mitochondrial protein synthesis (MPS)13,14. Hence
Considering the very short halfꢀlife (less than one hour) of
linezolid after oral administration in mouse15, the drugꢀlike
scaffoldꢀtricyclic fused benzoxazinylꢀoxazolidinone developed
by Yang and coꢀworkers16,17 has attracted our great interest,
due to its benefits regarding pharmacokinetics profile. Addiꢀ
tionally, the tetrahydropyridine moiety of AZD584718 (Figure
1) provided a possibility to reduce molecular planarity and
increase molecular hydrophilicity19. To our delight, our first
fluoroꢀbenzoxazinylꢀoxazolidinone compound 4 containing
acetylaminomethyl side chain from linezolid and dihydroxyꢀ
propinoyl tetrahydropyridine moiety from AZD5847 demonꢀ
strated good antiꢀTB activity with MIC 0.48 ꢁg/mL against
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MTB H37Rv and very low Vero cytotoxicity with an IC50 of antibacterial activity and improve pharmacokinetic properꢀ
ties16, compound 4 was prepared to investigate the effect of
this scaffold on antiꢀtuberculosis activity. To our delight, as
shown in Table 1, compound 4 displayed the same antiꢀTB
activity as linezolid but superior to that of AZD5847. In addiꢀ
tion, this compound exhibited low toxicity. With the encouragꢀ
ing observation, a preliminary structureꢀactivity relationship
(SAR) investigation was carried out to seek the optimal R2 and
R1 substituents in this new fluorineꢀcontaining benzoxazinylꢀ
oxazolidinone scaffold.
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more than 64 ꢁg/mL. Herein, we disclose the synthesis, bioꢀ
logical evaluation and preliminary structureꢀactivity relationꢀ
ship (SAR) studies from the hitꢀtoꢀlead optimization of these
novel fluorineꢀcontaining benzoxazinylꢀoxazolidinones bearꢀ
ing a tetrahydropyridine moiety.
As shown in Scheme 1, the synthetic routes for target comꢀ
pounds 4, 17-41 were outlined. The synthesis of the key inꢀ
termediates Iaꢀf, IIa and IIIa-c is summarized in Scheme S1
and Scheme S2 (Supporting Information). The desired comꢀ
pounds 24, 26, 28, and 36-41 were obtained through nucleoꢀ
philic substitution reaction of respective intermediates with 2ꢀ
bromoethanol. The intermediate Ia reacted with cycloproꢀ
panecarbonyl chloride to give compound 18. The remaining
acylated target compounds were prepared by condensation
reaction of respective intermediates with different carboxylic
acids. Among them, compounds 22 and 23 were obtained as a
hydrochloride form by the deprotection of Boc group using
HCl in EtOAc.
9
Keeping the tricyclic fused scaffold (section B) and the traꢀ
ditional Cꢀ5 acetylaminomethyl side chain (section C), which
plays a very important role in linezolid and sutezolid21, our
initial exploration of the hit compound 4 was focused on the
modification of section A (Table 1) to identify the optimum R2
substituent. A variety of different substituents including acyꢀ
clic and cyclic alkylated acyl with or without hetero atoms
were evaluated at this position. Unfortunately, the results reꢀ
vealed that R2 without polar substituent like hydroxyl or amino
(17-19) or with a bulkier group (20, 23) caused a more than
10ꢀfold loss of potency. However, replacement of the chiral
(S)ꢀ2,3ꢀdihydroxypropanoyl group with simple achiral 2ꢀ
hydroxyacetyl group (21) or even 2ꢀhydroxyethyl group (24)
displayed equipotent activity compared to the hit compound 4.
Compound 22 bearing glycyl group also displayed good acꢀ
tivity. From results described above, it appeared that a small
flexible hydrophilic group is beneficial for the antiꢀ
tuberculosis activity.
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All the target compounds were evaluated for their activity
against MTB H37Rv using the microplate alamar blue assay
(MABA)20. The MIC was defined as the lowest concentration
effecting a reduction in fluorescence of ≥90% relative to the
mean of replicate bacteriumꢀonly controls. The compounds
with MIC less than 5 ꢁg/mL were further tested for mammaliꢀ
an cell cytotoxicity using Vero cells measured as a concentraꢀ
tion inhibiting 50% growth (IC50) as compared to a noꢀ
treatment control. Table 1 summarizes the biological data for
26 new benzoxazinylꢀoxazolidinones derivatives. Linezolid
and AZD5847 were used as reference compounds.
As such, the 2ꢀhydroxyacetyl group or 2ꢀhydroxyethyl
group in section A and acetylamino group in section C were
selected as optimized fragments to probe the impact of the
fluorine on the benzene ring and the double bond in the
Inspired by the observation that the privileged scaffold of
tricyclic fused benzoxazinylꢀoxazolidinone could increase the
Scheme 1. Synthesis of the Target Compounds 4 and 17-41.
Reagents and conditions: (i) cyclopropanecarbonyl chloride, Et3N, DCM, rt for 18; carboxylic acids, EDCI, HOBt, Et3N, DMF, rt
for the others; (ii) HCl/H2O, 0 oC to rt for 4; HCl/EtOAc, 0 oC to rt for 22ꢀ23; (iii) 2ꢀbromoethanol, Et3N, DMF, 100 oC.
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Table 1. Structures, Anti-tuberculosis Activity, Cytotoxicity, and Selectivity Index (SI) Values for Target Compounds
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4
5
6
7
8
9
Double MIC
bond (ꢁg/mL) (ꢁg/mL)
IC50
Double MIC
Bond (ꢁg/mL) (ꢁg/mL)
IC50
Compd
R2
R1
X
F
SIa Compd
R2
R1
X
F
SIa
34
4
Y
0.483
>64
133
30
Y
1.868
>64
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17
18
19
20
21
22b
23b
24
25
26
F
F
F
F
F
F
F
F
H
H
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
6.357
6.404
7.940
5.525
0.391
0.732
7.125
0.578
0.725
2.645
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32
33
34
35
36
37
38
39
40
F
F
F
F
F
F
F
F
F
F
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
1.680
0.999
1.044
10.900
>32
>64
>64
>64
39
64
61
>64
>64
164
87
1.916
0.473
1.104
2.223
0.980
>64
>64
33
135
58
>64
111
19
>64
13.76
26.77
57.43
>64
26
10
65
27
28
29
F
F
F
N
N
Y
3.814
14.602
1.159
>64
17
41
F
Y
7.956
1.023
0.304
AZD5847
>64
>64
62
>64
55 Linezolid
197
aSelectivity index (SI) = IC50(Vero)/MIC. bUsing in the form of hydrochloride.
tetrahydropyridine ring on potency and cytotoxicity. As exhibꢀ
ited in Table 1, compound 26 bearing 2ꢀhydroxyethyl group
displayed 5ꢀfold less potency than compound 24. Although
compound 25 still exhibited moderate antiꢀTB activity with
MIC 0.725 ꢁg/mL compared to compound 21 (MIC 0.391
ꢁg/mL), these two fluorineꢀfree compounds 25 and 26 showed
higher cytotoxicity (25 vs 21, 26 vs 24). Interestingly, almost
all compounds listed in Table 1 with fluorine on the benzene
ring exhibited very low cytotoxicity, no matter what the MIC
values are. The advantage of fluorine on the benzene ring in
this tricyclic scaffold was confirmed, consistent with the genꢀ
eral SAR studies results of oxazolidinone. Replacement of the
4ꢀtetrahydropyridine with 4ꢀpiperidine caused a significant
loss of activity (27 vs 21, 28 vs 24). This result demonstrated
that the double bond is required for potency.
(31 and 38), had been introduced to replace the acetylamino
group in section C. Most compounds showed good to moderꢀ
ate potency with MIC values 0.473ꢀ2.223 ꢁg/mL. However,
analogues with [1,2,3]tirazole (34 and 41), hydroxyisoxazole
(35) completely lost the antiꢀTB activity. The results revealed
Table 2. In Vitro Activity of the Selected Compounds
against Drug Resistant Tuberculosis
MIC (ꢁg/mL) MIC (ꢁg/mL) MIC (ꢁg/mL)
Compd
(H37Rv)
0.483
(16892a)
0.25
(16802b)
1.00
4
21
0.391
0.732
0.578
0.473
0.037
0.057
0.25
0.25
0.50
0.50
>40
>40
0.50
2.00
2.00
1.00
2.50
20.0
22
24
Although it is wellꢀestablished that Cꢀ5 acetylaminomethyl
group in linezolid is essential for good antibacterial activity,
further explorations on the Cꢀ5 side chain (section C) in this
new tricyclic fused oxazolidinone were also undertaken. Difꢀ
ferent Cꢀ5 side chain moieties like trifluoroacetamino (29 and
36), methyl carbamate (32 and 39), aminoisoxazole (33 and
40), hydroxyisoxazole (35), [1,2,3]tirazole (34 and 41), cycloꢀ
propanecarboxamide (30 and 37) and cyclobutanecarboxamide
37
INH
RFP
aResistance to isoniazid (INH) and rifampicin (RFP). Reꢀ
sistance to isoniazid, rifampicin, streptomycin, ethambutol,
and levofloxacin.
b
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Table 3. Representative Properties of Compound 21
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4
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8
MLMb
HLMc
HepG2
Cytotoxicity inhibition inhibition
hERG K+
MPSa
Cacoꢀ2
Papp
Substrate
Substrate
remaining Stabilitye
remaining Stabilitye
IC50(ꢁg/mL) IC50(ꢁM) IC50(ꢁM) (×10ꢀ6cm/s)
(%)d
(%)d
> 64
> 30
9.19
4.14±0.57
102.0
stable
103.0
stable
aMitochondrial protein synthesis. bMouse liver microsome. cHuman liver microsome. dSubstrate concentrations were determined in
e
incubations with NADPH after 30 min and normalized to concentrations at time zero. Stability was determined without the
NADPH cofactor.
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Table 4. Mouse Pharmacokinetic Properties of Compound 21
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21
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a
b
Dose
(mg/kg) (ꢁg/ml)
100
10
Cmax
Tmax t1/2
(h)
2
AUC0ꢀ∞
MRT(0ꢀ∞)
(h)
4.12
Clearance
(mL/h/kg) (%)
Fc
Compd
Route
(h) (ꢁg·h/mL)
4.22
0.03 8.23
po
iv
30.0
11.4
122
12
102
836
21
2.54
aPlasma elimination halfꢀlife. bMean residence time. cBioavailability.
that NꢀH is essential for the maintenance of activity.
promising antiꢀtuberculosis potential lead compound, warrantꢀ
ing further evaluation, will be reported in due course.
As a result of their high potency against H37Rv strain and
superior selectivity index values, five compounds including 4,
21, 22, 24 and 37 were selected to investigate their antiꢀDRꢀ
TB activity. As summarized in Table 2, all tested compounds
displayed high in vitro potency to 16892 strain (MDRꢀTB).
More importantly, compound 21 also exhibited good activity
against 16802 strain (XDRꢀTB), supporting it to move forward
for further evaluation.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: .
Experimental procedures, compounds characterization,
minimum inhibitory concentration assay, in vitro
ADME/T and PK evaluation. (PDF)
To develop a deeper understanding of compound 21’s drugꢀ
gability, more profiling was performed. As depicted in Table 3,
compound 21 exhibited high IC50 value against HepG2 cell,
indicating a lack of toxicity to hepatic cells. Notably, this
compound showed almost no inhibition of the hERG K+ chanꢀ
nel using the patch clamp technique. Due to the main adverse
effect of myelosuppression during the longꢀterm use of lineꢀ
zolid, likely related to inhibition of mitochondrial protein synꢀ
thesis (MPS)13, the in vitro MPS inhibition activity was conꢀ
ducted to predict myelosuppression risk. Compound 21
showed a comparable inhibition activity (IC50 9.19 ꢁM) with
linezolid (IC50 8.71 ꢁM). This outcome suggested that 21 and
linezolid have a similar safety profile in terms of myelosupꢀ
pression risk. Regarding the in vitro physicochemical properꢀ
ties, compound 21 showed good membrane permeability and
excellent metabolic stability against mouse and human liver
microsomes. These data therefore indicate that compound 21
may exhibit favorable in vivo PK performance. Indeed the PK
of 21 in Balb/c mouse was outstanding (Table 4), with high
maximal plasma concentration (Cmax = 30.0 ꢁg/mL), high
plasma exposure (AUC0−∞ = 122 ꢁg·h /mL), long elimination
halfꢀlife (t1/2 = 4.22 h) and excellent oral bioavailability (F =
102%) after oral administration.
AUTHOR INFORMATION
Corresponding Author
*(D.F.) Eꢀmail: zdf@imm.ac.cn;
*(H.H.) Eꢀmail: joyce@imm.ac.cn.
ORICD
Dongfeng Zhang: 0000ꢀ0003ꢀ0870ꢀ3782
Haihong Huang: 0000ꢀ0003ꢀ1641ꢀ1309
Author Contributions
⊥These authors contributed equally.
Funding Sources
The research is supported in part by the National Science &
Technology Major Project of China (Grant 2015ZX09102007ꢀ
013), the National Natural Science Foundation of China (Grant
81502917), and the Fundamental Scientific Research Fund of
Institute of Materia Medica (Grant 2014CX15).
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
In summary, a new series of fluorineꢀcontaining benzoxaziꢀ
nylꢀoxazolidinones were prepared and characterized. Prelimiꢀ
nary exploration of structureꢀactivity relationships on the scafꢀ
fold revealed that the fluorine atom on the benzene ring has
dual function in improving activity and reducing toxicity.
Compound 21 displayed promising antiꢀtuberculosis activity
against drugꢀsensitivity H37Rv and drugꢀresistant strains (MIC
= 0.25~0.50 ꢁg/mL) and an adequate preliminary in vitro safeꢀ
ty profiles with negligible cytotoxicity and cardiotoxicity.
Importantly, compound 21 exhibited notable oral bioavailabilꢀ
ity (102%) in mouse as well as relatively long halfꢀlife, which
may help to reduce the dosage and frequency of medication
and improve patient compliance. Hence, compound 21 as a
ADME/T, absorption, distribution, metabolism, excretion, and
toxicity; Boc, tertꢀbutoxycarbonyl; DCM, dichloromethane; DMF,
N,Nꢀdimethylforamide; EDCI, 1ꢀ(3ꢀ(dimethylamino)propyl)ꢀ3ꢀ
ethylcarbodiimide hydrochloride; HOBt, 1ꢀhydroxybenzotriazole;
PK, pharmacokinetic
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Discovery of Fluorine-Containing Benzoxazinyl-Oxazolidinones for the Treatment of Multidrug Resistant Tuberculo-
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Hongyi Zhao, Yu Lu, Li Sheng, ZishuoYuan, Bin Wang, Weiping Wang, Yan Li, Chen Ma, Xiaoliang Wang, Dongfeng
Zhang, Haihong Huang
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