Identification of Pyrazolo[1,5- a]pyridine-3-carboxamide Diaryl Derivatives as Drug Resistant Antituberculosis Agents

Article abstract of DOI:10.1021/acsmedchemlett.8b00410

A series of pyrazolo[1,5-a]pyridine-3-carboxamide (PPA) derivatives bearing diaryl side chain was designed and synthesized as new antituberculosis agents, aiming to improve the efficacy toward drug resistant Mycobacterium tuberculosis (Mtb) strains. Most

Full text of DOI:10.1021/acsmedchemlett.8b00410

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Letter
Identification of Pyrazolo[1,5-a]pyridine-3-carboxamide Diaryl
Derivatives as Drug Resistant Anti-tuberculosis Agents
Xianglong Hu, Baojie Wan, yang Liu, Jiayi Shen, Scott G. Franzblau, Tianyu Zhang, Ke Ding, and Xiaoyun Lu
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.8b00410 • Publication Date (Web): 21 Feb 2019
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Identification of Pyrazolo[1,5-a]pyridine-3-carboxamide Diaryl
Derivatives as Drug Resistant Anti-tuberculosis Agents
Xianglong Hua#, Baojie Wanb#,Yang Liuc#, Jiayi Shena, Scott G. Franzblaub, Tianyu Zhangc*, Ke Ding
a*, Xiaoyun Lu a*
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a International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of
Chinese Ministry of Education (MOE), School of pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou
510632, China.
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b
Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street,
Chicago, Illinois60612, United States.
c
State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory,
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190, Kai Yuan Avenue, Guangzhou
510530, China.
KEYWORDS. Anti-tuberculosis agents, INH-resistant Mtb strain, RMP-resistant Mtb strains, Structure activity relationship.
ABSTRACT: A series of pyrazolo[1,5-a]pyridine-3-carboxamide (PPA) derivatives bearing diaryl side chain were designed and
synthesized as new anti-tuberculosis agents, aiming to improve the efficacy toward drug resistant Mycobacterium tuberculosis
(Mtb) strains. Most of the substituted diphenyl and heterodiaryl PPAs exhibited excellent in vitro potency against the drug
susceptive H37Rv strain (MIC: <0.002-0.381 µg/mL) and drug resistant Mtb strains (INH-resistant (rINH), MIC: < 0.002-0.465
µg/mL; RMP-resistant (rRMP), MIC: <0.002-0.004 µg/mL). Noticeably, some compounds also showed very low cytotoxicity
against Vero cells. Further, compound 6j displayed good pharmacokinetic profiles with oral bioavailability (F) of 41%, and
significantly reduced the bacterial burden in an autoluminescent H37Ra infected mouse model.
Tuberculosis (TB), caused by Mycobacterium tuberculosis
(Mtb), remains the leading infectious cause of death
worldwide. It was estimated that nearly 10.4 million people
fell ill with TB and 1.7 million died of TB in 2016.1 A
standard 6-9 months regimen recommended by World Health
Organization (WHO) results in multidrug-resistant TB (MDR-
TB) and extensively drug-resistant TB (XDR-TB) due to lack
of patient adherence.2,3 At present, MDR-TB usually has to be
treated with a combination of five to seven drugs lasting up to
18-24 months.4 Therefore, new drugs with the potential to
shorten the duration of treatment or overcome drug-resistant
TB are urgently needed. Encouragingly, bedaquiline
(TMC207, 1)5,6 and delamanid (OPC67683, 2)7 were approved
for the treatment of MDR-TB by FDA in 2012 and by EMA in
2014, respectively (Figure 1), even though the wide-scale use
of 1 is restricted for safety risks.8 It is still imperative to
identify new molecules with alternative scaffolds as effective
agents to banish the scourge of TB.
properties.11 Our previous studies had identified a series of
pyrazolo[1,5-a]pyridine-3-carboxamides (PPAs) as anti-
tuberculosis agents (Figure 2), which exhibited good activities
with low nanomolar MIC values against H37Rv strain (Figure
2).12,13 Considering PPAs linked with the N-benzylic moiety as
crucial for the anti-tubercular activity, we firstly envisioned to
make structural modifications on the side chain of lead 5 by
introducing substituted diaryl (diphenyl or heterodiaryl)
groups, which was similar to the optimization strategy of
TBA354 and would possibly target drug resistant Mtb strains
(Figure 2). In addition, our previous SAR study had suggested
that the 2-methyl-5-methoxy-pyrazolo[1,5-a]pyridine scaffold-
based compound displayed better potency than the related 2-
methyl-5-methyl-pyrazolo[1,5-a]pyridine
against
drug
resistant clinical Mtb isolates.12 Thus, a series of 2-methyl-5-
methoxy-pyrazolo[1,5-a]pyridine-3-carboxamide
derivatives were designed and synthesized.
diaryl
O
O
NH
NH
Substituted Diphenyl
O
OCF3
OCF3
Ar or Het
4
1
N
3
N
N
2
or Heterodiaryl chain
N
N
O
PPA diaryl, 6
PPA, 5
OH
O2
N
O
Br
N
N
OCF3
N
N
O
Figure 2. Design of pyrazolo[1,5-a]pyridine-3-carboxamide
O
diaryl derivatives.
1
Bedaquiline ( ,TMC207)
2
Delamanid ( ,OPC67683)
O
N
Compounds 6a-6l and 6o-6p were readily synthesized using a
straightforward amidation of pyrazolo[1,5-a]pyridine-3-
carboxylic acid 1012 with different self-prepared primary
amines 9, 13, 16 and 19 (Scheme 1). Different strategies were
used to synthesize these amines. Briefly, the amines 8 were
synthesized by Suzuki coupling bromo-substituted materials 7
and (4-(trifluoromethoxy)phenyl)boronic acid followed by
nitrile reduction with lithium aluminium hydride (supporting
O
N
O2
N
N
O2
N
O
N
O
N
OCF3
OCF3
3
PA-824 (
)
4
TBA-354 (
)
Figure 1. The chemical structures of anti-tubercular drugs
bedaquiline, delamanid, PA-824, and TBA-354.
The other two nitroimidazole drugs PA-824 (3) and TBA-354
(4) are currently in clinical studies for drug-sensitive and drug-
resistant TB (Figure 1).9,10 TBA-354, only with a 4-
trifluoromethoxyphenyl-pyridine group to replace the 4-
trifluoromethoxyphenyl in PA-824, is promising to shorten TB
treatment as part of a regimen superior to that of PA-824 in
terms of anti-TB potency and improved pharmacokinetic
information).
The
synthesis
of
(5-(4-
(trifluoromethoxy)phenyl)thiophen-2-yl)methanamine 13 was
started by Boc protection and bromination of thiophen-2-
ylmethanamine 11 to give bromothiophene 12, which was
followed by Suzuki coupling and deprotection reactions. The
(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-4-
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yl)methanamine 16 was obtained by diazo and click reactions
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O
OH
O
H
O
O
H
O
O
N
1
2
3
4
5
6
7
8
starting from 4-(trifluoromethoxy)aniline 14. The (5-(4-
(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)methanamine
19 was synthesized starting from 17 that was condensed with
BOC-glycine, then followed by cyclization and deprotection
reactions based on the published procedures.14
N
N
N
O
O
OH
10
O
O
H2
N
O
N
a
b
N
20
N
N
22
21
H
N
O
HN
O
O
OCF3
N
Br
O
F
H
F
F
O
N
OCF3
OCF3
OCF3
N
O
O
N
d
6m
23
O
Br
R
O
c
N
N
a
b
NC
24
H
N
O
R
R
O
e
CN
8
NH2
O
N
7
9
OCF3
9
OCF3
N
Br
N
6n
S
10
11
12
13
14
15
16
17
18
19
20
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22
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S
d
e
O
OH
O
H2
N
S
BocHN
12
Scheme 2. Synthesis of compounds 6m and 6n. Reagents and
conditions: (a) HATU, DIEA, DCM, rt, overnight, 70%; (b) TFA,
DCM, rt, 2h, 98%; (c) Cs2CO3, EtOH, DMF, rt, overnight, 46%,
(d) Ammonium acetate, xylene, 140℃, 6h, 56 %; (e) Acetamide,
xylene, 140℃, 3h, 45 %.
N
10
O
N
NH
NH2
13
11
O
OCF3
Ar or Het
OCF3
c
N
OCF3
N
OCF3
6a-6l, 6o-6p
i
N
N
h
NH2
N3
N
H2
N
k
15
16
14
The first round of modifications was to investigate the role of
the substituents at 3 position of the phenyl group (Figure 2).
Therefore, keeping intact the diphenyl chain, small functional
groups (CH3, OCH3, CF3, F) were introduced at the 3 position
of the phenyl group. The resulting compounds 6a-6d exhibited
strong anti-tubercular activity against Mtb H37Rv with all
MICs values of < 0.02 µg/mL at the first round assay with
concentrations ranged from 0.02 to 5 µg/mL (Table 1). This
prompted us to gain further insights into the exact MICs at
lower concentrations. Under the second screening
concentrations (0.002-0.5 µg/mL), the MICs values of
compounds 6a-6d were 0.013, 0.007, 0.029 and < 0.002
µg/mL, respectively, which were comparable to that of RMP,
TMC207, and the lead compound 5 (MIC = 0.006 µg/mL)
(Table 2).12 These results suggested that this position is
tolerated for substitution, especially for the OCH3 and F
groups. Switching these substituents from the 3 to 2 position
of the phenyl group, an almost 43- and 40-fold reduction in
activity was noticed for compounds 6e (MIC = 0.57 µg/mL)
and 6f (MIC = 0.28 µg/mL), whereas the anti-tubercular
activity of compound 6g was completely lost when the CF3
was introduced at the 2 position. Interestingly, introduction of
F atom in the 2 position led to compound 6h (MIC = 0.007
µg/mL), which kept potent anti-tubercular activity compared
to compound 6d. A plausible explanation of this result maybe
that F atom does not affect the activity due to its relatively
small size (similar to that of H atom).
OCF3
OCF3
OCF3
j
O
O
N
O
O
NHNH
18
NHNH2
17
NHBoc
N
NH2
19
Scheme 1. Synthesis of compounds 6a-6l and 6o-6p. Reagents
and conditions: (a) (4-(Trifluoromethoxy)phenyl)boronic acid,
Pd(PPh3)4, Na2CO3, toluene, 110 ℃ , overnight, 83-92%; (b)
LiAlH4, THF, -40℃, 3h, 48-53%; (c) HATU, DIPEA, DCM, rt,
overnight, 49-53%; (d) i. NaHCO3, Boc2O, THF, rt, 3h, 97%; ii.
NBS,
DMF,
rt,
5h,
82%;
(e)
i.
4-
(Trifluoromethoxy)phenylboronic acid, K2CO3, Pd(PPh3)4, DME,
80℃, 4h, 87%; ii. TFA, DCM, rt, 5h, 82%; (h) Hydrochloric acid,
NaNO2, NaN3, H2O, 0℃→rt, 2.5h, 92%; (i) 2-propynylamine,
CuI, THF, DIPEA, rt, overnight, 70%; (j) BOC-glycine, HATU,
DIPEA, DMF, rt, overnight, 85%; (k) i. Et3N, PPh3, CCl4, DMF,
rt, overnight, 68%; ii TFA, DCM, rt, 2h, 98%.
The other two compounds 6m and 6n were synthesized in
Scheme 2. The procedure was started by condensation of tert-
butyl glycinate 20 and pyrazolo[1,5-a]pyridine-3-carboxylic
acid 10, followed by hydrolysis in TFA to give intermediate
22. The intermediate 22 was then reacted with 2-bromo-1-(4-
(trifluoromethoxy)phenyl)ethan-1-one 23 to give the ester 24,
and followed by cycloaddition with ammonium acetate and
acetamide to produce the compounds 6m and 6n, respectively.
The minimum inhibitory concentration (MIC) values of all the
new compounds were preliminarily screened against Mtb
H37Rv strain in microplate alamar blue assay (MABA) and
low oxygen recovery assay (LORA) with the assay
concentrations ranged from 0.02 to 5 µg/mL (Table 1).15
Compounds showing encouraging MICs (< 0.02 µg/mL) in
MABA were further tested against Mtb H37Rv, rRMP and
rINH with the assay concentrations ranged from 0.002 to 0.5
µg/mL, and were also tested against Vero Cells to assess the
compounds’ potential cytotoxicity (Table 2). Rifampicin
(RMP), isoniazid (INH), linezolid (LIZ), and TMC207 were
used as positive control drugs to support the reliability of our
screening results.
Table 1 In vitro anti-tubercular activity of compounds 6a-6p
against the Mtb strains H37Rv in MABA and LORA with the
assay concentrations ranged from 0.02 to 5 µg/mL.
O
NH
O
OCF3
Ar or Het
N
N
Compds Ar Or Het H37Rv MIC (µg/mL)
ClogPa
5.87
MABA
LORA
6a
6b
<0.02
2.28
<0.02
<0.02
>5
>5
5.20
OCH3
6c
6.23
CF3
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6d
<0.02
>5
5.50
Encouraged by their strong potencies against the drug
1
2
3
4
5
6
7
8
sensitive H37Rv strain, compounds 6a-6d, 6h-6j and 6l were
further evaluated against rRMP and rINH strains. It was
shown that all of the compounds displayed excellent potencies
against rRMP and rINH strains with MIC values < 0.002-
0.465 and <0.002-0.004 µg/mL (Table 2). Moreover, the in
vitro Vero cell toxicity of these compounds was further
determined. As it was shown in Table 2, the compounds had
low or no cytotoxicity against VERO cells with IC50 values
from 3.15 to > 50 µg/mL. Particularly, compounds 6d, 6j and
6l had no cytotoxicity against VERO cells, with all of the IC50
values of > 50 µg/mL and the selectivity index (SI) values of >
25000.
F
6e
6f
0.57
0.28
>5
5.87
5.20
2.25
H3CO
F3C
F
6g
6h
>5
>5
>5
6.23
5.50
<0.02
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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45
46
47
48
49
50
51
52
53
54
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57
58
59
60
6i
6j
<0.02
<0.02
0.53
4.36
>5
4.52
4.22
4.52
N
Table 2. In vitro anti-tubercular activity of compounds 6a-6d,
6h-6j and 6l against the Mtb strains H37Rv, rRMP and rINH
with the assay concentrations ranged from 0.002 to 0.5 µg/mL,
and Vero cellular toxicity.
N
S
6k
>5
N
S
6l
<0.02
>5
>5
>5
5.26
3.23
Compds
MIC (µg/mL)
VERO
cell
IC50
Selectivity
index
H
N
(SI) a
H37Rv
rRMP
rINH
6m
6n
(µg/mL)
N
6a
0.013
<0.002
<0.002
3.15
242
O
1.96
2.84
3.29
6b
6c
0.007
0.029
<0.002
<0.002
0.003
0.003
11.8
11.6
1685
402
N
O
6o
6p
>5
>5
>5
>5
2.79
3.49
6d
6h
6i
6j
6l
<0.002
0.007
0.053
<0.002
<0.002
<0.008
0.239
<0.002
<0.002
0.458
<0.002
0.465
>2
0.438
1.870
<0.016
0.004
0.004
0.004
0.002
0.002
<0.008
>8
>50
>50
28.4
>50
>50
>100
-
>25000
>7142
535
>25000
>25000
>12500
-
N
N
N
N
N
RMP
INH
LIZ
-
-
-
-
0.02
0.48
3.27
0.03
2.95
＞128
5.98
-
-
-
-
-
RMP
INH
LIZ
TMC207
1.254
0.020
0.953
<0.016
-
-
>10
>500
TMC207
aSI: IC50/ MIC for H37Rv
a: calculated by MarvinSketch 5.4.1.1 version
Combined with other factors such as ClogP, we selected
compound 6j for further study. The pharmacokinetic (PK)
properties of compound 6j were evaluated in rats by single
intravenous injection (i.v. 2.5 mg/kg) and oral administration
(p.o. 10 mg/kg). As shown in Table 3, 6j exhibited a half-life
of 5.1 h and a relative high optimal plasma exposure with
AUC value of 15638 h*μg/L. It also displayed a good oral
bioavailability of 41%, suggesting its good absorption in rats.
Like TBA-354, the pyridine ring was used to replace the
phenyl group. The yielded compound 6i showed an MIC value
of 0.053 µg/mL, which was better than that of the control drug
INH and LIZ, and comparable to TMC207 (Table 2). Moving
the N atom from the 3 to 2 position led to compound 6j, with
improved anti-tubercular activity against H37Rv to <0.002
µg/mL. Inspirited by the activities of compounds 6i and 6j, we
further investigated five-membered heterocyclic ring instead
of the phenyl group. However, only the thiophene derivative
6l (MIC < 0.002 µg/mL) had the MIC value comparable to 6j.
The thiazole 6k (MIC = 0.53 µg/mL) and oxazole 6n (MIC =
1.96 µg/mL) had almost 265- and 980-fold reduction in
activities compared to 6j (Table 1). The imidazole 6m,
oxadiazole 6o and triazole 6p completely lost the activities
with all of MICs values of > 5 µg/mL. Briefly, it was
suggested that five-membered heterocyclic ring such as
thiophene can substitute the phenyl, but others led to loss of
activity in varying degrees.
Table 3 The pharmacokinetic profile of compound 6j in rats.
Pharmacokinetics parameters of 6j
Route Dose
(mg/kg)
10
2.5
Cmax
(μg/L)
1428
4152
Tmax
(h)
4.67
0.08
T1/2
(h)
5.10
3.49
MRT0
-∞(h)
8.21
4.02
F
(%)
41
AUC0-
(h*μg/L)
15638
oral
iv
9002
Given the promising anti-tubercular activity against H37Rv
and good PK properties in rats, 6j was evaluated for its in vivo
anti-tubercular efficacy by using the mouse model infected
with the selectable marker-free autoluminescent Mtb strain
H37Ra.12,16 The animals were infected with log-phase
autoluminescent Mtb H37Ra via intravenous injection (2 ×106
CFU per mouse) and then were repeatedly administered with
6j once daily via oral gavage for 5 consecutive days. The
bacterial burden was measured by monitoring the
bioluminescence intensity (relative light unit, RLU) from the
same batch of live mice every day. As shown in Figure 3, with
the two tested doses of 10 and 50 mg/kg/day, compound 6j
exhibited dose-dependent in vivo anti-tubercular activity. The
6j 50 mg/kg/day group showed a significant reduction in lung
The compounds were also tested in LORA, which is an in
vitro model for the assessment of activity against persistent
Mtb. Among the current anti-tubercular drugs, only RMP and
PZA have been reported to possess activity against dormant
strain. From the results (Table 1), it was very remarkable that
compounds 6a (MIC = 2.28 µg/mL), 6f (MIC = 2.25 µg/mL)
and 6n (MIC = 2.84 µg/mL) exhibited good LORA MICs
values comparable to that of RMP (MIC = 2.95 µg/mL).
However, most of the other compounds were not very active
in LORA with MIC values of > 5 µg/mL.
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RLU by ～ 1.0 log10 compared with the untreated CMC-Na
group (Figure 3A). The 6j 50 mg/kg/day group also reduced
the spleen bacterial burdens by ～0.61 log10 RLU relative to
that of CMC-Na group. The RMP treated group showed the
decrease by ～1.42 log10 RLU and ～1.34 log10 RLU in lung
and spleen, respectively. These results strongly suggest the
promising potential of compound 6j to serve as a lead
compound for further anti-tubercular drug discovery.
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Figure 3. Mean RLU count (±SD) assessed at day 0 and the day
after treatment completition. A) for lung, B) for spleen. y-axis:
corresponding Log10RLU/lung; x-axis: different treatment groups.
(ns, not significant; *P < 0.05; ** P < 0.01; *** P < 0.001.)
A series of PPA diaryl derivatives have been synthesized and
evaluated for the anti-tubercular activity. Most of the
derivatives exhibited excellent in vitro potency against the
drug susceptive H37Rv strain (MIC: < 0.002-0.381 µg/mL)
and two rINH (MIC: < 0.002-0.465 µg/mL) and rRMP (MIC:
< 0.002-0.004 µg/mL) Mtb strains. The representative
compound 6j exhibited promising in vitro activities against
Mtb H37Rv, rRMP and rINH with MIC values ≤ 0.002
µg/mL, and no toxicity against Vero cells. Further in vivo
studies indicated that compound 6j displayed good
pharmacokinetic profiles with an oral bioavilability of 41 %
and significantly reduced the mycobacterial burden in an
H37Ra infected mouse model.
ABBREVIATIONS
TB,
tuberculosis;
PPA,
pyrazolo[1,5-a]pyridine-3-
carboxamide;
Mtb, Mycobacterium tuberculosis; WHO,
World Health Organization; MDR-TB, multidrug-resistant TB;
XDR-TB, extensively drug-resistant TB; MIC, minimum
inhibitory concentration; MABA, microplate alamar blue
assay; MRT, mean residence time; LORA, low oxygen
recovery assay; RMP, rifampicin; INH, isoniazid; LIZ,
linezolid; RLU, relative light unit; rINH, INH-resistant; rRMP,
RMP-resistant; DIPEA, N,N-Diisopropylethylamine; HATU,
2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate; EMA, European Medicines Agency;
FDA, Food and Drug Administration.
ASSOCIATED CONTENT
REFERENCES
Electronic supplementary information (ESI) available:
Chemistry procedures and analytical data for title
compounds, and biological assay. See DOI:
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AUTHOR INFORMATION
Corresponding Author
* Tel: 020-85223259. Fax: 020-85224766. E-mail addresses:
zhang_tianyu@gibh.ac.cn, dingke@jnu.edu.cn,
luxy2016@jnu.edu.cn.
Author Contributions
# These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We
thank
Guangdong
Natural
Science
Funds
(2016A030313106, 2015A030306042), National Natural
Science Foundation of China (81673285), Guangzhou City
Key Laboratory of Precision Chemical Drug and Chinese
Academy of Sciences Grants (154144KYSB20150045,
YJKYYQ20170036) and Guangzhou Municipal Industry and
Research Collaborative Innovation Program (201508020248,
201604020019) for the financial support.
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Insert Table of Contents artwork here
O
O
NH
Substituted Diphenyl
or Heterodiaryl
NH
OCF3
O
OCF3
4
Ar or Het
1
3
N
2
N
N
N
5
6
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