Design, synthesis, and antitubercular activity of 3-amidophenols with 5-heteroatomic substitutions

Article abstract of DOI:10.1002/ardp.201800277

A series of novel 3-amidophenols with 5-heteroatomic substitutions were designed and synthesized. Several compounds showed potent antitubercular activity against Mycobacterium tuberculosis H37Ra (MIC = 0.25–5 μg/mL). Compounds 12j and 14i also displayed good inhibitory activity against M. tuberculosis H37Rv and two clinically isolated multidrug-resistant M. tuberculosis strains (MIC = 0.39–3.12 μg/mL). The privileged compound 14i showed certain oral efficacy on a mouse infection model. The compounds are non-cytotoxic against L-O2 hepatocytes and RAW264.7 macrophagocytes. They did not exert inhibitory activity against representative Gram-positive and Gram-negative bacteria.

Full text of DOI:10.1002/ardp.201800277

Received: 19 September 2018
DOI: 10.1002/ardp.201800277
Revised: 1 January 2019
Accepted: 3 January 2019
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FULL PAPER
Design, synthesis, and antitubercular activity of
3-amidophenols with 5-heteroatomic substitutions
1
2,3
1
2,4
|
|
|
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Niu-niu Zhang
Yun-xiang Tang
Lu Qian
Ya-min Gao
2
1
2,4
1
|
|
|
Zhi-yong Liu
Zhi-liang Zou
Tian-yu Zhang
Ming Yan
1
Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, Guangzhou, China
Institute of Physical Science and Information Technology, Anhui University, Hefei, China
2
3
4
University of Chinese Academy of Sciences (UCAS), Beijing, China
Correspondence
Abstract
Prof. Ming Yan, Guangdong Provincial Key
Laboratory of New Drug Design and Evaluation,
School of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou 510006, China.
Email: yanming@mail.sysu.edu.cn
A series of novel 3-amidophenols with 5-heteroatomic substitutions were designed
and synthesized. Several compounds showed potent antitubercular activity against
Mycobacterium tuberculosis H37Ra (MIC = 0.25–5 μg/mL). Compounds 12j and 14i
also displayed good inhibitory activity against M. tuberculosis H37Rv and two
clinically isolated multidrug-resistant M. tuberculosis strains (MIC = 0.39–3.12 μg/
mL). The privileged compound 14i showed certain oral efficacy on a mouse infection
model. The compounds are non-cytotoxic against L-O2 hepatocytes and RAW264.7
macrophagocytes. They did not exert inhibitory activity against representative Gram-
positive and Gram-negative bacteria.
Dr. Tian-yu Zhang, State Key Laboratory of
Respiratory Disease, Guangzhou Institutes of
Biomedicine and Health, Chinese Academy of
Science, Guangzhou 510530, China.
Email: zhang_tianyu@gibh.ac.cn
Funding information
Natural Science Foundation of China,
Grant number: 21772240; Ministry of Science
and Technology of China, Grant number:
K E Y W O R D S
2
017ZX10302301-003-002; Chinese Academy
of Sciences, Grant numbers:
54144KYSB20150045, KFZD-SW-207,
3-amidophenol derivative, antitubercular activity, Mycobacterium tuberculosis
1
YJKYYQ20170036; Guangdong Science and
Technology Department, Grant number:
2017B030314030
[
2]
1
|
INTRODUCTION
for these patients. The cure rates are less than 50%. In the past
[3]
four decades, only two new anti-TB drugs, delamanide
and
[
4]
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), still
poses a huge threat to the human health. According to the report of
the World Health Organization (WHO), in 2016 there were 10.4
bedaquiline, were added to clinical practice for the treatment of
MDR-TB and XDR-TB as second-line drugs. A number of drug
[
5]
[6]
candidates with good potentials including PA-824,
[7]
SQ109,
[1]
million new cases and 1.7 million deaths caused by TB. The current
standard therapy for the drug-susceptible TB requires a combination
of several first-line antitubercular agents such as isoniazid (INH),
rifampicin (RIF), pyrazinamide (PZA), and ethambutol (EMB) for 6–9
months. Moreover, the treatment period is extended up to
Q203 are still under the investigation. However, the Mtb strains
[
8]
resistant to these new candidates have been reported. Therefore
the discovery of anti-TB drugs with new chemical structures and
[
9]
mechanisms of action is still an urgent task.
Recently, we identified 3-amidophenol derivatives as a new class
[10]
2
4 months for multidrug-resistant (MDR) and extensive drug-
of anti-TB agents.
The compounds YZ-6 and YZ-7 showed potent in
resistant (XDR) TB. In addition, rather limited drugs are applicable
vitro inhibitory activity against Mtb H37Ra, Mtb H37Rv and several
clinically isolated MDR-TB strains (MIC = 0.39–5 μg/mL). However,
the compounds did not show in vivo efficacy in a mouse infection
Niu-niu Zhang and Yun-xiang Tang contributed equally to this work.
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Arch Pharm Chem Life Sci. 2019;e1800277.
wileyonlinelibrary.com/journal/ardp
© 2019 Deutsche Pharmazeutische Gesellschaft
1 of 13
https://doi.org/10.1002/ardp.201800277

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ZHANG ET AL.
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model, probably due to poor solubility and ADME properties. The
-benzyl group in the compounds was suspected to be the
bacteria growth was determined using relative light unit (RLU) by a
[14]
5
luminometer.
The minimal inhibitory concentration (MIC) was
metabolically liable moiety. The quick oxidization was expected to
occur at the diphenylmethylene position. We speculated that the
replacement of the methylene group with heteroatoms (O, S, N) can
improve the pharmacokinetic properties and exhibit in vivo antituber-
cular activity (Scheme 1). In this paper, we report the synthesis and
antitubercular evaluation of 3-amidophenols with 5-heteroatomic
substitutions.
defined as the lowest concentration that can inhibit 90% growth
compared with the drug-free control. Isoniazid (INH) was used as the
positive control and DMSO was used as the negative control. The
results are listed in Tables 1–3.
Firstly, antitubercular activities of 3-amidophenols 3, 5a–h, and 7
with 5-alkoxyl and 5-phenoxyl groups were investigated (Table 1). The
compounds 3, 5a–c with short 5-alkoxyl groups did not show
antitubercular activity (Table 1, entries 1–4). The extension of
5
-alkoxyl chain (such as 5-butoxyl and 5-pentoxyl) increased
2
2
|
RESULTS AND DISCUSSION
Chemistry
antitubercular activity (MIC = 10 μg/mL), however, the introduction
of longer alkoxyl chain (hexoxyl) resulted in the decreased inhibitory
activity (MIC = 25 μg/mL) (Table 1, entries 5–7). In addition, the
substitution with bulkier alkoxyls (c-pentoxyl or benzyloxyl) also led to
the loss of the antitubercular activity (Table 1, entries 8–9).
5-Phenoxyl-3-amidophenol 7 showed good antitubercular activity
(MIC = 5 μg/mL), which is comparable with that of 5-benzyl-3-
amidophenol (YZ-7). The LogP value of compound 7 is lower than
that of YZ-7 (4.06 vs. 4.54). The result confirmed that the introduction
of oxygen atom helps to improve the hydrophilicity.
.1
|
The synthesis of 3-amidophenol derivatives 3, 5a–h, 7 with 5-alkoxyl
or 5-phenoxyl substitutions is illustrated in Scheme 2. Firstly,
3
,5-dimethoxyaniline 1 reacted with benzoyl chloride to give N-(3,5-
dimethoxyphenyl)benzamide 2. The double-demethylation of 2 with
BBr afforded the compound 4. The alkylation of 4 with iodoalkanes
gave compounds 5a–h. On the other hand, the mono-demethylation of
with BBr afforded the compound 3. The phenylation of 3 with
diphenyliodonium triflate afforded the compound 6. The demethyla-
tion of 6 with BBr provided the compound 7.
3
2
3
Furthermore, 3-amidophenols 12a–o with 5-N- or S-substituents
were evaluated and the results are listed in Table 2. 5-Phenylthio-3-
benzamidophenol 12a showed good antitubercular activity
(MIC = 6.25 μg/mL). Lower activity was observed for 5-phenyl-
amino-3-benzamidophenol 12b (MIC = 10 μg/mL). The substitution
at the phenylamino group with methyl or fluoro decreased the activity
3
The synthesis of compounds 12a–o is shown in Scheme 3. The
Buchwald–Hartwig cross-coupling of 1-bromo-3-methoxy-5-nitro-
[11,12]
benzene 8 with amines or thiophenol provided compounds 9a–o.
The reduction of the nitro group via the catalytic hydrogenation gave
compounds 10a–o. The subsequent acylation and the demethylation
provided compounds 12a–o.
3
(Table 2, entries 3–7). The introduction of t-butyl or CF resulted in the
loss of the antitubercular activity (Table 2, entries 8–9). The results
demonstrated that the increase of steric hindrance on the phenyl ring
has a detrimental impact on the activity. Furthermore, the substitu-
tions at the 5-nitrogen were examined. 5-N-Methylphenylamino-3-
benzamidophenol (12j) is fourfold more active (MIC = 2.5 μg/mL) than
The synthesis of compounds 14a–j is illustrated in Scheme 4. The
acylation of 10k with acyl chlorides provided compounds 13a–j. The
3
demethylation with BBr afforded the compounds 14a–j.
1
2b. However, the introduction of bulkier alkyl group such as ethyl,
2
.2
|
Biological evaluation
In vitro inhibitory activity against Mtb H37Ra
benzyl led to the loss of the activity (Table 2, entries 11–12). The fact
indicated again the existence of a small binding pocket for the
2
.2.1
|
5
-substituent. The replacement of N-phenyl with N-2-pyridinyl
In vitro antitubercular activities of the compounds were evaluated
resulted in the loss of activity, but 2-pyrimidiyl and 2-pyrazinyl
[13]
against an unmarked autoluminescent Mtb H37Ra strain.
The
analogs showed good activity (MIC = 6.25 and 12.5 μg/mL,
SCHEME 1 Design of 3-amidophenols with 5-heteroatomic substitutions

ZHANG ET AL.
| 3 of 13
3 3
SCHEME 2 Synthesis of products 3, 5a–h, 7. Reagents and conditions: (a) benzoyl chloride, Et N, THF, 0°C to rt, 1 h, 92%; (b) BBr ,
CH
2
Cl
2
, −40 to 0°C, 12 h, 21–68%; (c) R-I, K
2
CO
3
, Me
2
CO, reflux, 6 h, 30–50%; (d) diphenyliodonium triflate, t-BuOK, THF, 0°C to rt, 1 h,
6
3%
respectively) (Table 2, entries 13–15). Based on the results,
N-methylphenylamino was identified as the best 5-substituent.
Keeping 5-methylphenylamino substitution, the different 3-amido
groups were examined and the results are summarized in Table 3. In
14e (MIC = 0.5 μg/mL). Several cycloalkylcarboxamido derivatives
were examined and good inhibitory activities were observed (Table 3,
entries 6–9). Among them, 3-cyclohexanecarboxamido derivative 14i
is most potent (MIC = 0.25 μg/mL). The introduction of oxygen atom to
the cyclohexyl ring exerted the detrimental effect on the activity
(Table 3, entry 10).
3
general, the size and lipophilicity of R group have strong effect on the
antitubercular activity. The replacements of phenyl with furanyl (14a),
thiophenyl (14b), and 2-chloronicotinyl (14c) are applicable. Good
inhibitory activities (MIC = 1.25–5 μg/mL) were observed (Table 3,
entries 1–3). The replacements of phenyl with alkyl groups are also
acceptable. 3-Isobutyramido derivative 14d showed comparable
activity (MIC = 2.5 μg/mL) with 12j. Further increase of antitubercular
activity was observed for more lipophilic 3-tert-valeramido derivative
2
.2.2 In vitro inhibitory activity against Mtb H37Rv
|
and MDR-TB strains
Compounds 12j and 14i were selected for the further evaluation of the
inhibitory activity against Mtb H37Rv and five clinically isolated MDR-
SCHEME 3 Synthesis of products 12a–o. Reagents and conditions: (a) Pd(OAc)
2
, BINAP, Cs
2
CO
3
, toluene, 120°C, 6 h, 60–90%; (b) H
Cl , −40 to 0°C, 12 h, 65–88%
2
,
1
0% Pd/C, CH OH, 4 h, 45–87%; (c) benzoyl chloride, Et N, THF, 0°C − rt, 1 h, 73–95%; (d) BBr
3
3
3
, CH
2
2

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ZHANG ET AL.
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3
SCHEME 4 Synthesis of products 14a–j. Reagents and conditions: (a) R COCl, Et
°C, 12 h, 65–88%
3 3 2 2
N, THF, 0°C to rt, 1 h, 73–95%; (b) BBr , CH Cl , −40 to
0
TB strains. The results are summarized in Table 4. Two compounds
showed the similar activity against H37Rv (MIC = 1.56 µg/mL). They
were also effective against MDR-TB strains P105 and P136
faecalis, and Gram-negative bacteria Escherichia coli. Amoxicillin and
ofloxacin were used as the positive controls. The results are
summarized in Table 5. All compounds did not show antibacterial
activity (MIC90 > 50 μg/mL). The results indicated that 3-amidophenol
derivatives can exclusively inhibit Mtb.
(
MIC = 0.39–3.12 µg/mL). Low inhibitory activities were observed
against MDR-TB strains P76 and Z23. The compounds 12j and 14i
were almost inactive against MDR-TB strain L18.
2
.2.4 Evaluation of cytotoxicity
|
2
.2.3 Evaluation of antibacterial activity
|
The cytotoxicity of six 3-amidophenol derivatives was evaluated
against hepatocyte L-O2 and macrophagocyte RAW264.7. The IC50
values are listed in Table 6. All compounds showed low cytotoxicity
against RAW264.7, but most of them showed moderate cytotoxicity
The antibacterial activity of several selected compounds was examined
against Gram-positive bacteria Staphylococcus aureus, Enterococcus
against L-O
2
. To our delight, the privileged compound 14i was non-
cytotoxic against both two cell lines.
TABLE 1 Inhibitory activities of 3-amidophenols 3, 5a–h, 7 with 5-
alkoxyl and 5-phenoxyl groups
2
.2.5 Evaluation of solubility and metabolic stability
|
The solubility and metabolic stability of compounds 14i and YZ-6
were examined and the results are listed in Table 7. Lower solubility
of 14i in Tris/BSA (0.1%) solution was observed in comparison with
YZ-6. The half-life of compounds 14i and YZ-6 in mouse liver
microsome were determined as 5.43 and 6.60 min (CLint = 387 and
3
18 mL/min/gprot, respectively). The result implicated a faster
clearance of compound 14i than YZ-6 in the liver. The reason
a
Entry
Comp.
3
R
LogP
2.32
2.66
3.15
3.02
3.57
3.98
4.40
3.45
4.06
3.99
4.54
–
MIClux (μg/mL)
remains to be investigated.
1
2
3
4
5
6
7
8
9
Me
>100
>50
>50
>50
10
5a
Et
2
.2.6 In vivo inhibitory activity against Mtb H37a
|
5b
n-Pr
Allyl
n-Bu
n-Pent
n-Hex
c-Pent
Bn
5c
In vivo efficacy of compound 14i was investigated on a mouse model
infected with Mtb H37Ra. Treatment was initiated 1 day after
infection: the compound 14i at 200 mg/kg as treatment group, 0.5%
CMC-Na as an untreated control group, and RIF at 10 mg/kg as a
positive control group. The treatment was administrated once daily
by oral gavage. After 5 days treatment, mice were sacrificed by
cervical dislocation. The lungs and spleens were removed and
homogenized under sterile conditions. Finally RLU was detected
from each homogenate. The results are summarized in Figure 1. The
certain reduction of RLU (0.3–0.4 log) was achieved in the lung and
the spleen compared with the untreated control group. However,
5d
5e
10
5f
25
5g
>50
>50
5
5h
10
11
12
7
Ph
YZ-7
INH
–
5
–
0.1
a
LogP was calculated with ChemBioDraw Ultra 12.0.

ZHANG ET AL.
| 5 of 13
TABLE 2 Inhibitory activities of 3-amidophenols with 5-S- and 5-N-substituents
1
2
a
Entry
Comp.
12a
X
R
R
LogP
MIClux (μg/mL)
1
S
–
4.55
6.25
2
3
12b
12c
N
N
H
H
3.91
4.40
10
25
4
5
12d
12e
N
N
H
H
4.40
4.07
25
12.5
6
7
12f
N
N
H
H
4.07
4.23
25
25
12g
8
9
12h
12i
N
N
H
H
5.62
4.84
>50
>50
1
1
0
1
12j
N
N
Me
4.15
4.49
2.5
12k
Ethyl
>50
1
1
2
3
12l
N
N
Benzyl
Me
5.81
3.53
>50
12m
>100
1
1
1
4
5
6
12n
12o
INH
N
N
–
Me
Me
–
2.73
2.19
6.25
12.5
0.1
–
a
LogP was calculated with ChemBioDraw Ultra 12.0.
the inhibitory activity is weak and the further improvement is
required.
In addition, the compound 14i showed in vivo antitubercular activity
on the mouse infection model via the oral administration. The further
improvement of in vivo efficacy via the structural modifications is
currently underway.
3
|
CONCLUSION
4
4
|
EXPERIMENTAL
Chemistry
In summary, we designed and synthetized a series of 3-amidophe-
nols with 5-heteroatomic substitutions. Their antitubercular activi-
ties were evaluated against Mtb H37Ra, H37Rv and clinically
.1
|
isolated MDR-TB strains.
A number of compounds with 5-
4
.1.1 General
|
methylphenylamino group showed potent inhibitory activity against
H37Ra. The selected compounds 12j and 14i also displayed good
inhibitory activity against H37Rv and two MDR-TB strains. The
privileged compound 14i was non-cytotoxic against tested cell lines.
1
13
H and C NMR spectra were recorded on Bruker AVANCE 400 or
500 MHz spectrometers with TMS as the internal standard. Chemical
shifts are expressed in parts per million (δ ppm). The coupling constants

6
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ZHANG ET AL.
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TABLE 3 Inhibitory activities of 3-amidophenols 14a–j
open capillary tubes on a MPA100 Optimelt automated melting point
system. The chemicals were purchased from the Energy chemical
company and were used without further purification.
The original spectra of the investigated compounds are provided
as Supporting Information, as are their InChI codes together with some
biological activity data.
4
.1.2 Synthesis of compounds 3 and 4
|
To a solution of compound 1 (306 mg, 2 mmol) and triethylamine
3
a
Entry
Comp.
14a
R
LogP
MIClux (μg/mL)
(
(
0.554 mL, 4 mmol) in THF (20 mL) was added slowly benzoyl chloride
0.253 mL, 2.2 mmol) at 0°C. After the reaction mixture was stirred for
1
2.77
5
3
h at room temperature, the reaction was quenched with water
10 mL). The mixture was extracted with EtOAc (15 mL × 2). The
combined organic layer was dried over anhydrous Na SO and filtered.
2
3
14b
14c
4.13
3.71
2.5
(
2
4
1.25
After the solvent was removed in vacuum, the crude product was
purified by column chromatography (petroleum ether/EtOAc = 5:1) to
afford 2 as a white solid (473 mg, 92% yield).
4
5
6
14d
14e
14f
3.47
4.18
2.97
2.5
0.5
5
To a solution of compound 2 (257 mg, 1 mmol) in dichloro-
methane (10 mL) was added slowly a solution of BBr
3
in dichloro-
methane (2 mL, 1.0 M in CH Cl , 2 mmol) at −40°C. The resulting
2
2
7
8
9
14g
14h
3.39
3.81
4.23
2.54
10
solution was warmed to 0°C and stirred for 12 h. Saturated
aqueous sodium bicarbonate (10 mL) was added at 0°C. The
solution was extracted with dichloromethane (10 mL × 3). The
combined organic layer was dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuum. The residue was
purified by flash chromatography on silica gel (petroleum ether/
EtOAc = 2:1) to afford 3 (44 mg, 18% yield) and 4 (119 mg, 52%
yield) as white solids.
2.5
14i
14j
INH
0.25
2.5
1
1
0
1
–
0.1
a
LogP was calculated with ChemBioDraw Ultra 12.0.
N-(3-Hydroxy-5-methoxyphenyl)benzamide (3)
1
Yield 18%, white solid, mp 188.4–189.8°C. H NMR (500 MHz,
(
J) are given in Hz. Peaks are labeled as single (s), broad singlet (br),
DMSO-d
6
) δ 10.07 (s, 1H), 9.44 (s, 1H), 7.92 (d, J = 7.4 Hz, 2H), 7.60–
doublet (d), triplet (t), double doublet (dd), doublet of triplets (dt),
multiplet (m). The products were purified by column chromatography
on silica gel (60–120 mesh) using petroleum ether/ethyl acetate as the
eluent. The high-resolution mass spectra were analyzed on a Shimadzu
LCMS-IT-TOF mass spectrometer. Melting points were determined in
7
1
1
9
.56 (m, 1H), 7.52 (t, J = 7.3 Hz, 2H), 6.99 (s, 1H), 6.89 (s, 1H), 6.10 (s,
1
3
6
H), 3.69 (s, 3H). C NMR (126 MHz, DMSO-d ) δ 165.98, 160.75,
58.86, 141.17, 135.58, 131.95, 128.81, 128.10, 100.59, 97.64,
+
7.31, 55.35. HRMS (ESI) calcd. for C14
H
14NO
3
[M+H] : 244.0941,
found: 244.0946.
N-(3,5-Dihydroxyphenyl)benzamide (4)
1
TABLE 4 Inhibitory activities of 12j and 14i against H37Rv and
Yield 52%, white solid, mp 212.5–214.3°C. H NMR (500 MHz,
clinical isolated MDR-TB strains
DMSO-d
6
) δ 9.96 (s, 1H), 9.21 (s, 2H), 7.90 (d, J = 7.8 Hz, 2H), 7.59–
13
MIC90 μg/mL)
7
.55 (m, 1H), 7.51 (t, J = 7.1 Hz, 2H), 6.76 (s, 2H), 5.96 (s, 1H). C NMR
Mtb strain
12j
14i
1.56
0.39
3.12
25
INH
RIF
(126 MHz, DMSO-d
6
) δ 165.90, 158.70, 141.00, 135.76, 131.83,
1
28.76, 128.11, 99.30, 98.84. HRMS (ESI) calcd. for C13H12NO
3
H37Rv
1.56
1.56
3.12
12.5
25
0.41
0.003
+
a
[M+H] : 230.0788, found: 230.0794.
P105
/
/
/
/
/
/
/
/
/
/
a
P136
b
|
P76
4.1.3 General procedure for the synthesis of 5a–h
b
Z23
50
To a solution of 4 (229 mg, 1 mmol) and potassium carbonate (276 mg,
mmol) in acetone (10 mL) was added iodoalkane (1.3 mmol) dropwise
b
L18
>100
50
2
a
at room temperature. The mixture was refluxed and stirred for 6 h.
After the solvent was removed in vacuum, the residue was purified by
Resistant to rifampicin (RIF), isoniazid (INH), and pyrazinamide.
b
Resistant to RIF and INH.

ZHANG ET AL.
| 7 of 13
TABLE 5 Antibacterial activities of selected compounds
MIC90 (μg/mL)
Bacteria
S. aureus
E. faecalis
E. coli
12a
>50
>50
>50
12j
12n
>50
>50
>50
14c
>50
>50
>50
14i
14j
Amoxicillin
0.78
Ofloxacin
>50
>50
>50
>50
>50
>50
>50
>50
>50
0.31
1.25
/
6.25
1.25
column chromatography on silica gel (petroleum ether/EtOAc = 2:1) to
J = 7.2 Hz, 1H), 7.52 (t, J = 7.4 Hz, 2H), 6.97 (s, 1H), 6.89 (s, 1H), 6.08 (s,
1H), 3.96–3.79 (m, 2H), 1.78–1.58 (m, 2H), 1.50–1.35 (m, 2H), 0.94 (t,
provide 5a–h.
1
3
J = 7.4 Hz, 3H). C NMR (126 MHz, DMSO-d
6
) δ 165.95, 160.17,
N-(3-Ethoxy-5-hydroxyphenyl)benzamide (5a)
158.82, 141.13, 135.60, 131.93, 128.80, 128.09, 100.51, 98.16,
1
Yield 35%, white solid, mp 140.5–142°C. H NMR (500 MHz,
97.88, 67.41, 31.23, 19.23, 14.18. HRMS (ESI) calcd. for C17H20NO
3
+
DMSO-d
6
) δ 10.05 (s, 1H), 9.41 (s, 1H), 7.92 (d, J = 7.3 Hz, 2H), 7.58
[M+H] : 286.1438, found: 286.1442.
(
t, J = 7.3 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 6.97 (s, 1H), 6.88 (s, 1H),
6
.08 (s, 1H), 3.95 (q, J = 6.9 Hz, 2H), 1.31 (t, J = 6.9 Hz, 3H).
N-(3-Hydroxy-5-(pentyloxy)phenyl)benzamide (5e)
1
3
1
C NMR (126 MHz, DMSO-d
6
) δ 165.97, 159.99, 158.82, 141.14,
Yield 32%, white solid, mp 126.2–127.7°C. H NMR (500 MHz,
1
1
2
35.62, 131.93, 128.80, 128.09, 100.52, 98.12, 97.83, 63.25,
6
DMSO-d ) δ 10.05 (s, 1H), 9.42 (s, 1H), 7.92 (d, J = 7.3 Hz, 2H), 7.57 (t,
+
5.18. HRMS (ESI) calcd. for C15
58.1131.
H
16NO
3
[M+H] : 258.1125, found:
J = 7.7 Hz, 1H), 7.52 (t, J = 7.0 Hz, 2H), 6.98 (s, 1H), 6.90 (s, 1H), 6.08 (s,
1H), 3.88 (s, 2H), 1.69 (d, J = 5.8 Hz, 2H), 1.35 (m, 4H), 0.91 (t,
1
3
6
J = 6.1 Hz, 3H). C NMR (126 MHz, DMSO-d ) δ 165.95, 160.16,
N-(3-Hydroxy-5-propoxyphenyl)benzamide (5b)
158.82, 141.13, 135.59, 131.93, 128.80, 128.09, 100.49, 98.14,
1
Yield 32%, white solid, mp 133.5–134.9°C. H NMR (500 MHz,
97.84, 67.69, 28.86, 28.22, 22.39, 14.41. HRMS (ESI) calcd. for
+
DMSO-d
6
) δ 10.04 (s, 1H), 9.41 (s, 1H), 7.91 (d, J = 6.1 Hz, 2H), 7.57 (d,
C
18
H22NO
3
[M+H] : 300.1594, found: 300.1589.
J = 6.5 Hz, 1H), 7.53 (d, J = 6.3 Hz, 2H), 6.96 (s, 1H), 6.89 (s, 1H), 6.07 (s,
1
3
1
H), 3.84 (s, 2H), 1.71 (d, J = 6.3 Hz, 2H), 0.97 (s, 3H). C NMR
N-(3-(Hexyloxy)-5-hydroxyphenyl)benzamide (5f)
1
(
126 MHz, DMSO-d ) δ 165.95, 160.14, 158.81, 141.12, 135.58,
6
Yield 33%, white solid, mp 119.3–120.6°C. H NMR (500 MHz,
1
31.92, 128.79, 128.08, 100.48, 98.12, 97.85, 69.20, 22.52, 10.89.
6
DMSO-d ) δ 10.05 (s, 1H), 9.41 (s, 1H), 7.92 (d, J = 7.1 Hz, 2H), 7.58 (d,
+
HRMS (ESI) calcd. for
72.1274.
C
16
H
18NO
3
[M+H] : 272.1281, found:
J = 7.0 Hz, 1H), 7.52 (t, J = 7.2 Hz, 2H), 6.97 (s, 1H), 6.89 (s, 1H), 6.08 (s,
1H), 3.88 (s, 2H), 1.75–1.62 (m, 2H), 1.40 (s, 2H), 1.31 (d, J = 2.2 Hz,
2
1
3
4
6
H), 0.88 (s, 3H). C NMR (126 MHz, DMSO-d ) δ 165.93, 160.14,
N-(3-Allyloxy-5-hydroxyphenyl)benzamide (5c)
158.80, 141.11, 135.57, 131.92, 128.79, 128.08, 100.47, 98.13,
1
Yield 37%, white solid, mp 135.6–137.2°C. H NMR (500 MHz,
97.83, 67.69, 31.48, 25.68, 22.57, 14.40. HRMS (ESI) calcd. for
+
DMSO-d
J = 7.0 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 6.98 (s, 1H), 6.91 (s, 1H), 6.11 (s,
H), 6.04 (ddd, J = 16.0, 10.3, 5.1 Hz, 1H), 5.39 (d, J = 17.3 Hz, 1H), 5.26
6
) δ 10.07 (s, 1H), 9.46 (s, 1H), 7.91 (d, J = 7.9 Hz, 2H), 7.58 (t,
C
19
H24NO
3
[M+H] : 314.1751, found: 314.1747.
1
N-(3-(Cyclopentyloxy)-5-hydroxyphenyl)benzamide (5g)
1
3
1
(
d, J = 10.5 Hz, 1H), 4.49 (d, J = 4.5 Hz, 2H). C NMR (126 MHz,
DMSO-d ) δ 166.00, 159.68, 158.85, 141.16, 135.60, 134.25, 131.94,
28.80, 128.10, 117.72, 100.75, 98.42, 98.03, 68.50. HRMS (ESI)
Yield 28%, white solid, mp 154.5–156.3°C. H NMR (500 MHz,
6
DMSO-d ) δ 10.03 (s, 1H), 9.38 (s, 1H), 7.91 (dd, J = 5.2, 3.3 Hz, 2H),
6
1
7.62–7.54 (m, 1H), 7.56–7.48 (m, 2H), 6.95 (t, J = 1.9 Hz, 1H), 6.86 (t,
+
3
calcd. for C16H16NO [M+H] : 270.1125, found: 270.1122.
J = 1.9 Hz, 1H), 6.05 (t, J = 2.2 Hz, 1H), 4.72–4.64 (m, 1H), 1.96–1.83
1
3
(
m, 2H), 1.77–1.64 (m, 4H), 1.63–1.51 (m, 2H). C NMR (126 MHz,
N-(3-Butoxy-5-hydroxyphenyl)benzamide (5d)
DMSO-d ) δ 165.96, 159.11, 158.77, 141.10, 135.64, 131.92, 128.80,
6
1
Yield 31%, white solid, mp 132.0–133.5°C. H NMR (500 MHz,
128.09, 100.33, 99.14, 98.79, 78.98, 32.84, 24.06. HRMS (ESI) calcd.
+
DMSO-d
6
) δ 10.04 (s, 1H), 9.41 (s, 1H), 7.92 (d, J = 7.5 Hz, 2H), 7.58 (t,
for C18
H20NO
3
[M+H] : 298.1438, found: 298.1432.
N-(3-(Benzyloxy)-5-hydroxyphenyl)benzamide (5h)
1
TABLE 6 Cytotoxicities of selected compounds
IC50 (μM)
Yield 39%, white solid, mp 159.3–160.8°C. H NMR (500 MHz,
DMSO-d
.56 (m, 1H), 7.53 (t, J = 7.3 Hz, 2H), 7.45 (d, J = 7.4 Hz, 2H), 7.40 (t,
J = 7.2 Hz, 2H), 7.34 (t, J = 6.9 Hz, 1H), 6.99 (s, 2H), 6.17 (s, 1H), 5.04 (s,
6
) δ 10.08 (s, 1H), 9.47 (s, 1H), 7.92 (d, J = 7.5 Hz, 2H), 7.62–
7
Cell line
12a
233
30
12j
157
63
12n
312
65
14c
283
65
14i
14j
273
32
Raw264.7
231
308
1
3
2
H). C NMR (126 MHz, DMSO-d
6
) δ 166.01, 159.86, 158.87,
L-O
2
1
41.18, 137.67, 135.60, 131.92, 128.87, 128.79, 128.21, 128.09,

8
of 13
ZHANG ET AL.
|
TABLE 7 Metabolic stability of compounds 14i and YZ-6 in mouse liver microsome
Solubility (μM)
CLint in vitro
CLint in vivo
CLint Hep in vivo
Compound
4i
YZ-6
Tris/BSA (0.1%)
T
1/2 (min)
(mL/min/gprot)
Extpl (mL/min)
Extpl (mL/min)
MF (%)
10.3
1
10
50
5.43
6.60
387
318
26.1
21.5
2.69
2.63
12.3
1
28.00, 100.92, 98.68, 98.24, 69.55. HRMS (ESI) calcd. for C20
H
18NO
3
7.16 (dd, J = 9.0, 4.7 Hz, 2H), 7.05 (d, J = 7.7 Hz, 2H), 6.95 (t, J = 1.9 Hz,
13
+
[M+H] : 320.1281, found: 320.1285.
6
1H), 6.14 (t, J = 2.1 Hz, 1H). C NMR (126 MHz, DMSO-d ) δ 166.10,
1
1
59.17, 158.35, 156.89, 141.62, 135.45, 131.99, 130.43, 128.78,
28.12, 123.99, 119.55, 102.94, 101.68, 101.58. HRMS (ESI) calcd. for
4
.1.4
|
Synthesis of N-(3-hydroxy-5-phenoxyphenyl)
C
19
H16NO
3
benzamide (7)
+
[M+H] : 306.1125, found: 306.1117.
To a suspension of t-BuOK (123.2 mg, 1.1 mmol) in THF (5 mL) was
added compound 3 (243 mg, 1.0 mmol) at 0°C. The reaction mixture
was stirred at 0°C for 15 min. After diphenyliodonium triflate (516 mg,
4
.1.5 General procedure for the synthesis of 12a–o
|
1
.2 mmol) was added in one portion, the reaction mixture was stirred at
2 3
A mixture of compound 8 (928 mg, 4 mmol), Cs CO (1.95 g, 6 mmol),
room temperature until the complete consumption of 3 as indicated by
TLC analysis. The reaction was quenched with water (10 mL) at 0°C.
The organic phase was separated, and the aqueous phase was
rac-BINAP (199 mg, 0.32 mmol), Pd(OAc) (44 mg, 0.2 mmol), aryl-
2
amine or thiophenol (4 mmol), and toluene (30 mL) was stirred at
120°C for 12 h. The reaction mixture was cooled to room temperature
and filtered over a layer of Celite. The filter cake was washed with
dichloromethane. After the solvent was evaporated in vacuum, the
residue was purified by flash chromatography on silica gel (petroleum
ether/EtOAc = 5:1) to give compounds 9a–o.
extracted with Et
2
O (10 mL × 3). The combined organic phase was
dried over anhydrous Na
2
SO and concentrated in vacuum. The
4
residue was purified by flash chromatography to give compound 6 as a
white solid (201 mg, 63% yield).
To a solution of compound 6 (160 mg, 0.5 mmol) in dichloro-
A solution of compounds 9a–o (2 mmol) and 10% Pd/C (60 mg) in
methane (5 mL) was added slowly a solution of BBr
3
in dichloro-
CH
3
2
OH (10 mL) was purged with H three times. The reaction mixture
methane (1 mL, 1.0 M in CH Cl , 1 mmol) at −40°C. The resulting
2
2
was stirred with a balloon of H
2
at room temperature for 4 h. The
solution was warmed to 0°C and stirred for 12 h. Saturated aqueous
sodium bicarbonate (5 mL) was added at 0°C. The solution was
extracted with dichloromethane (5 mL × 3). The combined organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated in vacuum. The residue was purified by flash chroma-
tography on silica gel (petroleum ether/EtOAc = 2:1) to afford 7 as a
reaction mixture was filtered and the filtrate was concentrated in
vacuum. The residue was purified by flash chromatography on silica gel
(petroleum ether/EtOAc = 3:1) to give compounds 10a–o.
To a solution of compounds 10a–o (1 mmol) and triethylamine
(202 mg, 2 mmol) in THF (10 mL) was added slowly a solution of
benzoyl chloride (154 mg, 1.1 mmol) in THF (10 mL) at 0°C. After the
reaction mixture was stirred at room temperature for 3 h, the reaction
was quenched with water (10 mL). The mixture was extracted with
EtOAc (15 mL × 2). The combined organic layer was dried over
1
white solid (104 mg, 68%). Mp 178.2–189.8°C. H NMR (500 MHz,
DMSO-d
6
) δ 10.16 (s, 1H), 9.66 (s, 1H), 7.92–7.88 (m, 2H), 7.58 (t,
J = 7.3 Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 7.41 (dd, J = 8.3, 7.6 Hz, 2H),
FIGURE 1 In vivo inhibitory activity of 14i against Mtb H37Ra on a mouse infection model. Four mice per group were treated for 6 days.
Data were presented as mean ± SD. ns: not significant. *: p < 0.05; **: p < 0.01; ***: p < 0.001

ZHANG ET AL.
| 9 of 13
anhydrous Na
2
SO
4
, filtered and concentrated in vacuum. Compounds
N-(3-((2-Fluorophenyl)amino)-5-hydroxyphenyl)benzamide
(12e)
Yield 85%, white solid, mp 180.1–181.4°C. H NMR (500 MHz,
DMSO-d ) δ 10.00 (s, 1H), 9.24 (s, 1H), 8.03 (s, 1H), 7.90 (d, J = 7.8 Hz,
2H), 7.57 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.4 Hz, 2H), 7.09 (d, J = 6.8 Hz,
1
1a–o were obtained and directly used in the next step without further
purification.
To a solution of compounds 11a–o (0.75 mmol) in dichloro-
methane (10 mL) was added slowly a solution of BBr in dichloro-
methane (2 mL, 1.0 M in CH Cl , 2 mmol) at −40°C. The resulting
1
6
3
1
3
2
2
4H), 7.02 (s, 1H), 6.82 (s, 1H), 6.19 (s, 1H). C NMR (126 MHz, DMSO-
1
solution was warmed to 0°C and stirred for 12 h. Saturated aqueous
sodium bicarbonate (5 mL) was added at 0°C. The solution was
extracted with dichloromethane (10 mL × 3). The combined organic
layer was dried over anhydrous magnesium sulfate, filtered and
concentrated in vacuum. The residue was purified by flash chroma-
tography on silica gel (petroleum ether/EtOAc = 2:1) to give 12a–o.
d
6
) δ 165.87, 158.48, 154.33 (d,
J
CF = 242.0 Hz), 145.04, 140.92,
2
135.68, 131.83, 131.50 (d, JCF = 11.4 Hz), 128.74, 128.10, 125.03 (d,
3
3
4
J
CF = 3.2 Hz), 122.01 (d,
J
CF = 7.1 Hz), 121.19 (d,
JCF = 2.2 Hz),
2
116.29 (d, JCF = 19.3 Hz), 100.34, 100.27, 100.14. HRMS (ESI) calcd.
+
for C19
H16FN
2
O
2
[M+H] : 323.1190, found: 323.1182.
N-(3-((4-Fluorophenyl)amino)-5-hydroxyphenyl)benzamide (12f)
1
N-(3-Hydroxy-5-(phenylthio)phenyl)benzamide (12a)
Yield 83%, white solid, mp 182.1–183.7°C. H NMR (500 MHz,
1
Yield 78%, white solid, mp 157.8–158.9°C. H NMR (500 MHz,
6
DMSO-d ) δ 10.02 (s, 1H), 9.26 (s, 1H), 7.91 (d, J = 7.5 Hz, 2H), 7.83 (s,
DMSO-d
6
) δ 10.19 (s, 1H), 9.70 (s, 1H), 7.91 (d, J = 7.3 Hz, 2H), 7.59 (t,
1H), 7.57 (t, J = 7.1 Hz, 1H), 7.51 (t, J = 7.3 Hz, 2H), 7.33 (t, J = 8.2 Hz,
J = 7.3 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.43–7.36 (m, 4H), 7.35–7.31
1H), 7.25–7.17 (m, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 6.9 Hz, 1H),
13
1
3
(
m, 2H), 7.28 (s, 1H), 6.42 (t, J = 1.7 Hz, 1H). C NMR (126 MHz,
DMSO-d ) δ 166.12, 158.63, 141.47, 136.08, 135.33, 135.05, 132.07,
31.40, 130.01, 128.82, 128.15, 127.93, 113.36, 112.93, 106.91.
6.97–6.90 (m, 1H), 6.88 (s, 1H), 6.19 (s, 1H). C NMR (126 MHz,
1
6
DMSO-d
6
) δ 165.90, 158.62, 156.80 (d,
JCF = 236.0 Hz), 145.41,
4
1
141.13, 140.22 (d,
JCF = 1.7 Hz), 135.72, 131.84, 128.76, 128.11,
+
3
2
HRMS (ESI) calcd. for C19
22.0889.
H
16NO
2
S [M+H] : 322.0896, found:
119.81 (d,
J
CF = 7.8 Hz), 116.01 (d,
16FN
J
CF = 22.7 Hz), 99.90, 99.62,
+
3
99.30. HRMS (ESI) calcd. for C19
H
2
O
2
[M+H] : 323.1190, found:
3
23.1183.
N-(3-Hydroxy-5-(phenylamino)phenyl)benzamide (12b)
1
Yield 72%, white solid, mp 192.2–193.5°C. H NMR (400 MHz,
N-(3-((2,4-Difluorophenyl)amino)-5-hydroxyphenyl)benzamide
DMSO-d
6
) δ 10.01 (s, 1H), 9.24 (s, 1H), 8.07 (s, 1H), 7.97–7.87 (m, 2H),
.61–7.54 (m, 1H), 7.51 (t, J = 7.3 Hz, 2H), 7.24 (t, J = 7.8 Hz, 2H), 7.16–
.05 (m, 3H), 6.85 (d, J = 5.9 Hz, 1H), 6.82 (t, J = 7.3 Hz, 1H), 6.27 (t,
(12g)
1
7
7
Yield 88%, white solid, mp 184.5–186.3°C. H NMR (500 MHz,
DMSO-d
6
) δ 9.97 (s, 1H), 9.21 (s, 1H), 7.90 (d, J = 7.2 Hz, 2H), 7.73 (s,
1
3
J = 1.8 Hz, 1H). C NMR (101 MHz, DMSO-d
6
) δ 165.89, 158.55,
1H), 7.60–7.54 (m, 1H), 7.50 (t, J = 7.1 Hz, 2H), 7.30 (m,2H), 7.02 (t,
13
1
1
44.89, 143.90, 141.05, 135.73, 131.82, 129.49, 128.74, 128.10,
J = 7.1 Hz, 1H), 6.84 (d, J = 7.3 Hz, 2H), 6.07 (s, 1H). C NMR
(126 MHz, DMSO-d ) δ 165.88, 158.55, 145.93, 141.01, 135.71,
131.83, 128.74, 128.10, 123.85, 111.83, 111.64, 105.19, 104.99,
20.01, 117.69, 100.34, 100.18, 99.98. HRMS (ESI) calcd. for
6
+
C
19
H
17
N
2
O
2
[M+H] : 305.1285, found: 305.1279.
1
15 2 2 2
04.78, 99.89, 99.33, 99.14. HRMS (ESI) calcd. for C19H F N O
+
N-(3-Hydroxy-5-(o-tolylamino)phenyl)benzamide (12c)
[M+H] : 341.1096, found: 341.1088.
1
Yield 82%, white solid, mp 157.1–158.2°C. H NMR (500 MHz,
DMSO-d
6
) δ 9.94 (s, 1H), 9.13 (s, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.59–
.52 (m, 1H), 7.49 (t, J = 7.1 Hz, 2H), 7.31 (s, 1H), 7.19 (d, J = 7.6 Hz,
H), 7.12 (t, J = 7.4 Hz, 1H), 6.91 (t, J = 7.2 Hz, 1H), 6.84 (s, 1H), 6.76 (s,
N-(3-((4-(tert-Butyl)phenyl)amino)-5-hydroxyphenyl)benzamide
7
2
1
1
1
(12h)
1
Yield 87%, white solid, mp 144.4–146.2°C. H NMR (500 MHz,
1
3
H), 6.06 (s, 1H), 2.20 (s, 3H). C NMR (126 MHz, DMSO-d
6
) δ 165.82,
6
DMSO-d ) δ 9.99 (s, 1H), 9.19 (s, 1H), 7.97 (s, 1H), 7.91 (d, J = 7.0 Hz,
58.48, 146.81, 141.75, 140.92, 135.76, 131.78, 131.23, 130.67,
2H), 7.57 (d, J = 6.9 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.26 (d, J = 8.1 Hz,
13
28.72, 128.10, 126.84, 122.57, 121.64, 99.75, 99.34, 99.18, 18.51.
2H), 7.05 (s, 3H), 6.82 (s, 1H), 6.22 (s, 1H), 1.27 (s, 9H). C NMR
(126 MHz, DMSO-d ) δ 165.87, 158.55, 145.44, 142.55, 141.11,
141.03, 135.75, 131.82, 128.74, 128.11, 126.10, 118.02, 99.65,
+
HRMS (ESI) calcd. for
19.1436.
C
20
H
19
N
2
O
2
[M+H] : 319.1441, found:
6
3
9
25 2 2
9.56, 99.34, 34.26, 31.82. HRMS (ESI) calcd. for C23H N O
+
N-(3-Hydroxy-5-(p-tolylamino)phenyl)benzamide (12d)
[M+H] : 361.1911, found: 361.1905.
1
Yield 81%, white solid, mp 158.4–160.3°C. H NMR (500 MHz,
DMSO-d
6
) δ 9.98 (s, 1H), 9.20 (s, 1H), 8.04–7.85 (m, 3H), 7.57 (t,
N-(3-Hydroxy-5-((4-(trifluoromethyl)phenyl)amino)phenyl)
J = 7.1 Hz, 1H), 7.51 (t, J = 7.3 Hz, 2H), 7.05 (t, J = 7.5 Hz, 2H), 7.01 (t,
benzamide (12i)
1
3
1
J = 7.4 Hz, 3H), 6.80 (s, 1H), 6.20 (s, 1H), 2.24 (s, 3H). C NMR
Yield 85%, white solid, mp 200.1–201.9°C. H NMR (500 MHz,
(
126 MHz, DMSO-d
6
) δ 165.84, 158.51, 145.58, 141.15, 141.01,
6
DMSO-d ) δ 10.08 (s, 1H), 9.42 (s, 1H), 8.63 (s, 1H), 7.92 (d, J = 7.4 Hz,
1
9
35.74, 131.80, 129.91, 129.09, 128.73, 128.10, 118.55, 99.60,
2H), 7.58 (t, J = 7.3 Hz, 1H), 7.52 (t, J = 7.6 Hz, 4H), 7.19 (d, J = 5.6 Hz,
13
+
9.24, 20.77. HRMS (ESI) calcd. for C20
H
19
N
2
O
2
[M+H] : 319.1441,
2H), 7.17 (s, 1H), 6.99 (s, 1H), 6.33 (s, 1H). C NMR (126 MHz, DMSO-
found: 319.1434.
6
d ) δ 166.01, 158.69, 147.94, 142.97, 141.22, 135.63, 131.93, 128.79,

10 of 13
ZHANG ET AL.
|
1
28.12, 126.89, 115.65, 102.11, 101.96, 101.75. HRMS (ESI) calcd. for
111.54, 109.89, 109.81, 105.35, 38.75. HRMS (ESI) calcd. for
+
+
C
20
H
16
F
3
N
2
O
2
[M+H] : 373.1158, found: 373.1153.
C
18
H
17
N
4
O
2
[M+H] : 321.1364, found: 321.1358.
N-(3-Hydroxy-5-(methyl(phenyl)amino)phenyl)benzamide (12j)
N-(3-Hydroxy-5-(methyl(pyrazin-2-yl)amino)phenyl)benzamide
1
Yield 57%, white solid, mp 171.6–173.5°C. H NMR (500 MHz,
(12o)
1
DMSO-d
6
) δ 10.03 (s, 1H), 9.32 (s, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.56 (t,
Yield 47%, white solid, mp 193.1–194.4°C. H NMR (500 MHz,
J = 7.2 Hz, 1H), 7.50 (t, J = 7.4 Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.05 (d,
6
DMSO-d ) δ 10.23 (s, 1H), 9.76 (s, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.93 (d,
J = 8.2 Hz, 3H), 6.96 (t, J = 7.2 Hz, 1H), 6.90 (s, 1H), 6.14 (s, 1H), 3.21 (s,
J = 7.5 Hz, 2H), 7.87 (d, J = 2.0 Hz, 1H), 7.59 (t, J = 7.1 Hz, 1H), 7.53 (t,
1
3
3
1
1
6
H). C NMR (101 MHz, DMSO-d ) δ 165.88, 158.54, 150.16,
J = 7.4 Hz, 2H), 7.33 (s, 1H), 7.24 (s, 1H), 6.49 (s, 1H), 3.37 (s, 3H).
1
3
49.11, 141.11, 135.60, 131.86, 129.62, 128.74, 128.08, 121.88,
C NMR (126 MHz, DMSO-d
6
) δ 166.09, 159.24, 154.65, 146.24,
21.44, 103.38, 102.89, 101.30, 40.56. HRMS (ESI) calcd. for
142.00, 141.73, 135.35, 133.17, 133.04, 132.08, 128.84, 128.13,
+
C
20
H
18
N
2
O
2
Na [M+Na] : 341.1260, found: 341.1251.
17 4 2
108.70, 108.46, 105.71, 38.22. HRMS (ESI) calcd. for C18H N O
+
[
M+H] : 321.1346, found: 321.1353.
N-(3-(Ethyl(phenyl)amino)-5-hydroxyphenyl)benzamide (12k)
1
Yield 53%, white solid, mp 175.3–176.5°C. H NMR (500 MHz,
4
.1.6 General procedure for the synthesis of 14a–k
|
DMSO-d
6
) δ 10.01 (s, 1H), 9.27 (s, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.57 (t,
J = 7.3 Hz, 1H), 7.50 (t, J = 7.4 Hz, 2H), 7.28 (t, J = 7.6 Hz, 2H), 7.02
To solution of compound 10k (228 mg, 1 mmol) and triethylamine
(202 mg, 2 mmol) in THF (10 mL) was added slowly a solution of acyl
chloride (1.1 mmol) in THF (10 mL) at 0°C. After the reaction mixture
was stirred for 3 h at room temperature, the reaction was quenched
with water (10 mL). The mixture was extracted with EtOAc
(15 mL × 2). The combined organic layer was dried over anhydrous
(
d, J = 6.5 Hz, 3H), 6.94 (t, J = 7.3 Hz, 1H), 6.88 (s, 1H), 6.09 (s, 1H), 3.70
1
3
(
q, J = 6.9 Hz, 2H), 1.14 (t, J = 6.9 Hz, 3H). C NMR (126 MHz, DMSO-
) δ 165.88, 158.58, 148.79, 147.66, 141.23, 135.63, 131.87, 129.72,
28.75, 128.09, 121.92, 121.76, 103.52, 103.14, 101.09, 46.39,
d
6
1
1
3
+
3.00. HRMS (ESI) calcd. for C21
33.1589.
21 2 2
H N O [M+H] : 333.1598, found:
2 4
Na SO , filtered and concentrated in vacuum. Compounds 13a–k
was obtained and directly used in next step without further
purification.
N-(3-(Diphenylamino)-5-hydroxyphenyl)benzamide (12l)
1
Yield 52%, white solid, mp 213.4–214.9°C. H NMR (500 MHz,
To a solution of compounds 13a–k (0.75 mmol) in dichloro-
DMSO-d
6
) δ 10.07 (s, 1H), 9.40 (s, 1H), 7.88 (s, 2H), 7.55 (s, 1H), 7.49 (s,
methane (10 mL) was added slowly a solution of BBr
3
(2 mL, 1.0 M in
2
H), 7.30 (s, 4H), 7.17 (s, 1H), 7.03 (s, 6H), 6.96 (s, 1H), 6.14 (s, 1H).
CH Cl , 2 mmol) at −40°C. The resulting solution was warmed to
2
2
1
3
C NMR (126 MHz, DMSO-d
6
) δ 165.90, 158.63, 148.74, 147.75,
0°C and stirred for 12 h. Saturated aqueous sodium bicarbonate (5 mL)
was added at 0°C. The solution was extracted with dichloromethane
(10 mL × 3). The combined organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated in vacuum. The residue
was purified by flash chromatography on silica gel (petroleum ether/
EtOAc = 2:1) to give compounds 14a–k.
1
1
3
41.38, 135.44, 131.91, 129.88, 128.72, 128.10, 124.48, 123.28,
+
07.02, 106.67, 102.91. HRMS (ESI) calcd. for C25
81.1598, found: 381.1590.
H
21
N
2
O
2
[M+H] :
N-(3-Hydroxy-5-(methyl(pyridin-2-yl)amino)phenyl)benzamide
12m)
Yield 44%, white solid, mp 223.5–224.7°C. H NMR (500 MHz,
DMSO-d ) δ 10.14 (s, 1H), 9.59 (s, 1H), 8.16 (m, 1H), 7.95–7.88 (m, 1H),
.58 (m, 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 6.9 Hz, 1H), 7.26 (t,
J = 1.9 Hz, 1H), 7.17 (s, 1H), 6.70–6.65 (m, 1H), 6.63 (d, J = 8.6 Hz, 1H),
(
1
N-(3-Hydroxy-5-(methyl(phenyl)amino)phenyl)furan-2-
6
carboxamide (14a)
1
7
Yield 89%, white solid, mp 190.6–192.3°C. H NMR (500 MHz,
6
DMSO-d ) δ 9.92 (s, 1H), 9.31 (s, 1H), 7.90 (s, 1H), 7.30 (t, J = 7.4 Hz,
1
3
6
1
1
3
3
6
.41 (t, J = 2.0 Hz, 1H), 3.35 (s, 1H). C NMR (126 MHz, DMSO-d ) δ
3H), 7.05 (d, J = 7.8 Hz, 2H), 7.01–6.92 (m, 2H), 6.84 (s, 1H), 6.67 (s,
1
3
66.02, 158.95, 158.62, 148.03, 147.80, 141.51, 137.31, 135.43,
6
1H), 6.11 (s, 1H), 3.21 (s, 3H). C NMR (126 MHz, DMSO-d ) δ 158.53,
32.03, 128.82, 128.12, 113.77, 109.70, 108.77, 108.46, 104.94,
156.53, 150.17, 149.06, 148.05, 146.05, 140.45, 129.65, 122.04,
+
8.41. HRMS (ESI) calcd. for C19
20.1387.
H
18
N
3
O
2
[M+H] : 320.1394, found:
121.67, 114.92, 112.50, 103.14, 102.71, 101.16, 40.54. HRMS (ESI)
+
calcd. for C18
H
17
N
2
O
3
[M+H] : 309.1234, found: 309.1228.
N-(3-Hydroxy-5-(methyl(pyrimidin-2-yl)amino)phenyl)
N-(3-Hydroxy-5-(methyl(phenyl)amino)phenyl)thiophene-2-
benzamide (12n)
carboxamide (14b)
1
1
Yield 51%, white solid, mp 220.2–221.5°C. H NMR (500 MHz,
Yield 87%, white solid, mp 156.6–158.2°C. H NMR (500 MHz,
DMSO-d
J = 7.7 Hz, 2H), 7.58 (m, 1H), 7.52 (t, J = 7.0 Hz, 2H), 7.26 (d, J = 1.5 Hz,
H), 7.19 (s, 1H), 6.78–6.67 (m, 1H), 6.47 (d, J = 1.7 Hz, 1H), 3.41 (d,
6
) δ 10.15 (s, 1H), 9.53 (d, J = 1.0 Hz, 1H), 8.37 (m 2H), 7.93 (d,
DMSO-d
6
) δ 9.98 (s, 1H), 9.32 (s, 1H), 7.98 (s, 1H), 7.82 (d, J = 4.5 Hz,
1H), 7.30 (t, J = 7.5 Hz, 2H), 7.19 (s, 1H), 7.06 (d, J = 7.9 Hz, 2H), 7.01–
1
3
1
6.93 (m, 2H), 6.83 (s, 1H), 6.13 (s, 1H), 3.22 (s, 3H). C NMR (126 MHz,
DMSO-d ) δ 160.18, 158.58, 150.21, 149.08, 140.78, 140.64, 132.20,
129.67, 129.41, 128.46, 122.06, 121.69, 103.09, 102.73, 101.14,
13
J = 1.5 Hz, 3H). C NMR (126 MHz, DMSO-d
6
) δ 165.96, 161.92,
6
1
58.26, 158.19, 146.78, 140.83, 135.48, 131.98, 128.82, 128.10,

ZHANG ET AL.
11 of 13
|
+
4
0.58. HRMS (ESI) calcd. for C18
25.1012.
H
17
N
2
O
2
S [M+H] : 325.1005, found:
N-(3-Hydroxy-5-(methyl(phenyl)amino)phenyl)
3
cyclopentanecarboxamide (14h)
1
Yield 75%, white solid, mp 187.2–189.1°C. H NMR (500 MHz,
2
-Chloro-N-(3-hydroxy-5-(methyl(phenyl)amino)phenyl)
6
DMSO-d ) δ 9.59 (s, 1H), 9.19 (s, 1H), 7.28 (t, J = 7.0 Hz, 2H), 7.01 (d,
nicotinamide (14c)
J = 7.4 Hz, 2H), 6.95 (t, J = 6.7 Hz, 1H), 6.83 (s, 1H), 6.69 (s, 1H), 6.06 (s,
1
Yield 81%, white solid, mp 169.7–171.2°C. H NMR (500 MHz,
1H), 3.18 (s, 3H), 2.70 (d, J = 6.8 Hz, 1H), 1.79 (s, 2H), 1.66 (s, 4H), 1.53
1
3
DMSO-d
6
) δ 10.36 (s, 1H), 9.32 (s, 1H), 8.50 (d, J = 2.9 Hz, 1H), 8.01 (d,
6
(s, 2H). C NMR (126 MHz, DMSO-d ) δ 158.59, 150.23, 149.17,
J = 7.4 Hz, 1H), 7.56–7.48 (m, 1H), 7.30 (t, J = 7.3 Hz, 2H), 7.06 (d,
141.39, 129.58, 121.78, 121.34, 102.32, 102.30, 100.28, 45.77,
+
J = 7.7 Hz, 2H), 6.99 (t, J = 7.1 Hz, 1H), 6.92 (s, 1H), 6.72 (s, 1H), 6.13 (s,
40.52, 30.53, 26.13. HRMS (ESI) calcd. for C19
311.1754, found: 311.1748.
H
23
N
2
O
2
[M+H] :
13
1
1
1
6
H), 3.20 (s, 3H). C NMR (126 MHz, DMSO-d ) δ 163.81, 158.73,
50.78, 150.44, 148.96, 146.87, 140.56, 138.55, 133.79, 129.68,
23.54, 122.39, 122.15, 102.57, 101.98, 100.21, 40.51. HRMS (ESI)
N-(3-Hydroxy-5-(methyl(phenyl)amino)phenyl)
+
calcd. for C19
H
3
17ClN O
2
[M+H] : 354.1044, found: 354.1036.
cyclohexanecarboxamide (14i)
1
Yield 63%, white solid, mp 194.5–195.8°C. H NMR (500 MHz,
N-(3-Hydroxy-5-(methyl(phenyl)amino)phenyl)isobutyramide
14d)
Yield 77%, white solid, mp 167.8–169.5°C. H NMR (500 MHz,
DMSO-d ) δ 9.55 (s, 1H), 9.19 (s, 1H), 7.28 (t, J = 7.5 Hz, 2H), 7.01 (d,
J = 7.9 Hz, 2H), 6.95 (t, J = 7.2 Hz, 1H), 6.84 (s, 1H), 6.69 (s, 1H), 6.07 (s,
6
DMSO-d ) δ 9.54 (s, 1H), 9.19 (s, 1H), 7.32–7.23 (m, 2H), 7.03–6.98 (m,
(
2H), 6.95 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 1.8 Hz, 1H), 6.69 (t, J = 1.8 Hz,
1
1H), 6.05 (t, J = 2.1 Hz, 1H), 3.18 (s, 3H), 2.30–2.20 (m, 1H), 1.74 (m,
1
3
6
4H), 1.64 (m,1H), 1.36 (m, 2H), 1.28–1.14 (m, 3H). C NMR (126 MHz,
DMSO-d ) δ 174.60, 158.58, 150.22, 149.16, 141.43, 129.59, 121.80,
6
13
1
H), 3.18 (s, 3H), 2.54 (m, 1H), 1.06 (d, J = 6.7 Hz, 6H). C NMR
121.37, 102.24, 100.19, 45.36, 40.51, 29.60, 25.88, 25.72. HRMS (ESI)
+
(
126 MHz, DMSO-d ) δ 175.47, 158.58, 150.24, 149.17, 141.36,
6
calcd. for C20
H
25
N
2
O
2
[M+H] : 325.1911, found: 325.1904.
1
29.59, 121.81, 121.39, 102.32, 100.30, 40.36, 35.36, 19.97. HRMS
+
(
ESI) calcd. for C17
H
21
N
2
O
2
[M+H] : 285.1598, found: 285.1590.
N-(3-Hydroxy-5-(methyl(phenyl)amino)phenyl)tetrahydro-2H-
pyran-4-carboxamide (14j)
1
N-(3-Hydroxy-5-(methyl(phenyl)amino)phenyl)pivalamide (14e)
Yield 73%, white solid, mp 207.4–208.8°C. H NMR (500 MHz,
1
Yield 73%, white solid, mp 181.0–182.9°C. H NMR (500 MHz,
6
DMSO-d ) δ 9.65 (s, 1H), 9.25 (s, 1H), 7.29 (d, J = 4.8 Hz, 2H), 7.02 (s,
DMSO-d
6
) δ 9.21 (s, 1H), 8.97 (s, 1H), 7.27 (t, J = 7.4 Hz, 2H), 7.00 (d,
2H), 6.96 (s, 1H), 6.82 (s, 1H), 6.68 (s, 1H), 6.06 (s, 1H), 6.06 (s, 1H), 3.89
J = 7.6 Hz, 2H), 6.97–6.90 (m, 2H), 6.79 (s, 1H), 6.09 (s, 1H), 3.19 (s, 3H),
(d, J = 9.8 Hz, 2H), 3.31 (s, 2H), 3.18 (s, 3H), 1.63 (s, 4H), 1.24 (s, 1H).
13
1
3
1
1
4
.19 (s, 9H). C NMR (126 MHz, DMSO-d
6
) δ 176.69, 158.37, 149.99,
6
C NMR (126 MHz, DMSO-d ) δ 173.26, 158.58, 150.24, 141.23,
49.22, 141.41, 129.56, 121.47, 120.86, 103.65, 102.93, 101.47,
129.61, 121.93, 121.55, 102.19, 102.06, 100.08, 66.86, 42.24, 40.52,
+
+
0.47, 27.66. HRMS (ESI) calcd. for C18
H
23
N
2
O
2
[M+H] : 299.1754,
29.31. HRMS (ESI) calcd. for C19
327.1695.
H
23
N
2
O
3
[M+H] : 327.1703, found:
found: 299.1748.
N-(3-Hydroxy-5-(methyl(phenyl)amino)phenyl)
4
.2
|
Biological assays
Determination of MIC against Mtb
cyclopropanecarboxamide (14f)
1
Yield 78%, white solid, mp 160.9–162.4°C. H NMR (500 MHz,
4
.2.1
H37Ra
|
DMSO-d
6
) δ 9.96 (s, 1H), 9.26 (s, 1H), 7.28 (d, J = 5.2 Hz, 2H), 7.03 (s,
[
13,14]
2
H), 6.96 (d, J = 5.1 Hz, 1H), 6.81 (s, 1H), 6.68 (s, 1H), 6.07 (s, 1H), 3.19
1
3
(
s, 3H), 1.73 (d, J = 2.0 Hz, 1H), 0.75 (s, 4H). C NMR (126 MHz,
The assay was conducted over a range of fourfold increasing
concentrations prepared in 1 mL of 7H9 broth containing 0.2 mL of
a 1/100 dilution of autoluminescent Mtb H37Ra broth culture
(OD600 = 0.8) grown in 7H9 broth. The tested compound was prepared
as 10-point twofold serial dilutions in DMSO and diluted into
7H9 + Tween80 + OADC medium in 96-well plates with a final
DMSO concentration of 2%. The highest concentration of compound
was 100 μg/mL. To each well, 196 μL of a 1/100 dilution of
autoluminescent Mtb H37Ra broth culture (OD600 = 0.8, grown in
7H9 broth) and 4 μL of the solution of the tested compound were
added. For potent compounds, assays were repeated at a lower
starting concentration.
DMSO-d
6
) δ 171.85, 158.64, 150.26, 149.10, 141.24, 129.61, 121.94,
1
21.57, 102.06, 101.92, 99.99, 40.51, 14.99, 7.50. HRMS (ESI) calcd.
+
for C17
19 2 2
H N O [M+H] : 283.1441, found: 283.1437.
N-(3-Hydroxy-5-(methyl(phenyl)amino)phenyl)
cyclobutanecarboxamide (14g)
1
Yield 75%, white solid, mp 165.5–167.2°C. H NMR (500 MHz,
DMSO-d
6
) δ 9.48 (s, 1H), 9.24 (s, 1H), 7.28 (t, J = 7.6 Hz, 2H), 7.02 (d,
J = 7.8 Hz, 2H), 6.96 (t, J = 7.2 Hz, 1H), 6.85 (s, 1H), 6.67 (s, 1H), 6.06 (s,
1
1
1
1
H), 3.36 (s, 1H), 3.18 (s, 3H), 2.22–2.13 (m, 2H), 2.03 (m, 2H), 1.96–
1
3
6
.86 (m, 1H), 1.77 (d, J = 9.5 Hz, 1H). C NMR (126 MHz, DMSO-d ) δ
73.12, 158.59, 150.21, 149.12, 141.26, 129.60, 121.86, 121.46,
Each plate included a control for zero growth (INH, 1 μg/mL), a
maximum growth (DMSO only), as well as INH dose response curve. A
total of 200 μL medium was added into each well on the inside edge of
02.18, 100.16, 40.52, 40.09, 25.02, 18.16. HRMS (ESI) calcd. for
+
C
18
H
21
N
2
O
2
[M+H] : 297.1598, found: 297.1590.

12 of 13
ZHANG ET AL.
|
[
15]
the plate to prevent evaporation. RLU counts were determined daily in
triplicate for 0–5 days. Growth was measured by fluorescence using
the Glomax reader. For MIC, the 10-point dose response curve was
plotted as percentage (%) of growth and fitted to the Gompertz model
using GraphPad Prism 5. The MIC was defined as the minimum
inhibitory concentration that can inhibit 90% growth compared with
the drug-free control.
4.2.5 Evaluation of in vivo antitubercular activity
|
Mtb H37Ra isolated on plates were homogenized with sterile glass
beads in a 250 mL flask containing 50 mL 7H9 with Tween-80. When
RLU reached 2 million/mL, the broth culture was used to infect 4- to
6
-week-old male BALB/c mice by tail vein injection. The day after
infection (day 0), RLU counts were determined. The mice were first
anesthetized by isoflurane inhalation and the RLU count was deter-
mined by laying the breast of mouse on the detection hole of the
luminometer and measuring light production twice for 3 s. Mice with
similar RLU readings were randomly allocated to treatment groups (four
mice/group) and individually marked. The treatment groups received:
0.5% CMC-Na alone as negative control; RIF (10 mg/kg) as positive
control;14i(200 mg/kg). The treatment wasadministrated once daily by
oral gavage for 6 days. On the final day of treatment, animals were
sacrificed by cervical dislocation. The removed lungs and spleens were
homogenized under sterile conditions in a 2 mL volume of PBS. Finally,
RLU was detected for each homogenate.
4
.2.2
|
Determination of MIC against Mtb H37Rv and
[15]
MDR-TB
MICs of the tested compounds were determined by a well-established
microplate Alamar Blue assay (MABA) against H37Rv and clinically
isolated MDR-TB strains (provided by Guangzhou Chest Hospital). Mtb
H37Rv strain and MDR-TB strains in 7H9 + OADC were cultured in a
5
2
0 mL tube at 37°C with shaking. The strains were transferred into a
50 mL flask containing 50 mL 7H9 + Tween80 + OADC while OD600
reached 0.3–0.8. The tested compounds were prepared as 4.3.1. Each
well contained 196 μL broth culture of a 1/100 dilution of Mtb H37Rv
or MDR-TB (OD600 = 0.8, grown in 7H9 broth) and 4 μL of the solution
of tested compound. For potent compounds, assays were repeated at
lower starting concentrations. INH and RIF were used as the positive
controls. The plates were incubated at 37°C. On the seventh day,
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (No.
2
1772240), National Science and Technology Major Project of the
Ministry of Science and Technology of China (2017ZX10302301-003-
02), the Chinese Academy of Sciences Grants (154144KYSB20150045,
0
1
2.5 µL of 20% Tween-80 and 20 µL of Alamar Blue were added to
KFZD-SW-207, YJKYYQ20170036), the National Mega-project of China
for Innovative Drugs (2018ZX09721001-003-003), Guangdong Provin-
cial Key Laboratory of Construction Foundation (2017B030314030), and
Science and Technology Innovation Leader of Guangdong Province
each well of the testing plate. A change in color from blue (oxidized
state) to pink (reduced state) indicated the growth of bacteria after
incubation at 37°C for 16–24 h. The MIC was defined as the lowest
drug concentration that prevented this change in color.
(2016TX03R095) for the financial support of this study.
4
.2.3 Determination of antibacterial activity
|
CONFLICT OF INTEREST
MIC was defined as the lowest concentration (the highest dilution) of
each compound that 99% inhibited the growth of bacteria after
incubation at 37°C for 18–24 h, by means of standard twofolds serial
dilution method in 96-well microtest plates. Amoxicillin and ofloxacin
were used as positive controls. The bacterial suspension was adjusted
There are no conflicts of interest to declare.
ORCID
Tian-yu Zhang
http://orcid.org/0000-0001-5647-6014
http://orcid.org/0000-0001-9888-0744
5
with sterile saline to a concentration of 1 × 10 CFU. Initially the tested
Ming Yan
compounds were dissolved in DMSO to prepare the stock solutions
(
10 mg/mL), and then the tested compounds and reference drugs were
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