Design, synthesis, and biological evaluation of m-amidophenol derivatives as a new class of antitubercular agents

Article abstract of DOI:10.1039/c8md00212f

A series of m-amidophenol derivatives (6a-6l, 7a-7q, 9a, 9b, 12a-12c, 14 and 15) were designed and synthesized. Their antitubercular activities were evaluated in vitro against M. tuberculosis strains H37Ra and H37Rv and clinically isolated multidrug-resistant M. tuberculosis strains. Ten compounds displayed minimal inhibitory concentrations (MICs) against M. tuberculosis H37Ra below 2.5 μg mL^?1 and 6g was the most active compound (MIC = 0.625 μg mL^?1). Compounds 6g and 7a also showed potent inhibitory activity against M. tuberculosis H37Rv (MIC = 0.39 μg mL^?1) and several clinically isolated multidrug-resistant M. tuberculosis strains (MIC = 0.39-3.125 μg mL^?1). The compounds did not show inhibitory activity against normal Gram-positive and Gram-negative bacteria. They exhibited low cytotoxicity against HepG2 and RAW264.7 cell lines. The results demonstrated m-amidophenol as an attractive scaffold for the development of new antitubercular agents.

Full text of DOI:10.1039/c8md00212f

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ARTICLE
Design, synthesis, and biological evaluation of m-amidophenol
derivatives as a new class of antitubercular agents
Niu-niu Zhanga#, Zhi-yong Liub#, Jie-Lianga, Yun-xiang Tangb,c, Lu Qiana, Ya-min Gaob,d, Tian-yu
Received 00th January 20xx,
Accepted 00th January 20xx
Zhangb,d*, Ming Yana*
DOI: 10.1039/x0xx00000x
A series of m-amidophenol derivatives (6a-6l, 7a-7q, 9a-9b, 12a-12c, 14 and 15) were designed and synthesized. Their
antitubercular activities were evaluated in vitro against M. tuberculosis H37Ra, H37Rv and clinically isolated multidrug-
resistant M. tuberculosis strains. Ten compounds displayed minimal inhibitory concentrations (MICs) against M.
tuberculosis H37Ra below 2.5 ꢀg/mL and 6g was the most active compound (MIC = 0.625 ꢀg/mL). The compounds 6g and
7a also showed potent inhibitory activities against M. tuberculosis H37Rv (MIC = 0.39 ꢀg/mL) and several clinically isolated
multidrug-resistant M. tuberculosis strains (MIC = 0.39 - 3.125 ꢀg/mL). The compounds did not show inhibitory activity
against normal Gram-positive and Gram-negative bacteria. They exhibited low cytotoxicity against HepG2 and RAW264.7
cell lines. The results demonstrated m-amidophenol as an attractive scaffold for the development of new antitubercular
agents.
www.rsc.org/
Mycobacterial enoyl-ACP reductase (InhA) is a validated drug
target against Mtb.7 Isoniazid (INH), an inhibitor of InhA, is a
powerful first-line antitubercular drugs.8-9 INH is a prodrug that
Introduction
Tuberculosis (TB) is a highly infected disease caused by
Mycobacterium tuberculosis (Mtb). Today tuberculosis still
remains one of the leading causes of human death in
developing countries. According to the World Health
Organization (WHO) report, there were estimated 10.4 million
new TB cases worldwide and over 1.3 million people died from
TB in 2016. Moreover, the resistance of Mtb to clinical
antitubercular agents is a continuing threat. As reported, in
2016 there were 600,000 new cases with resistance to
rifampicin, one of the most effective first-line drugs. Among
the cases, 490,000 were multidrug-resistant TB (MDR-TB).1
This situation brought big challenge for clinical treatment. In
the past four decades, only bedaquiline and delamanid had
been approved by the Food and Drug Administration (FDA) of
United States and the European Medicines Agency (EMA) to
treat MDR-TB.2-3 Bedaquiline is an ATP synthase inhibitor.
Delamanid inhibits mycolic acid synthesis of Mtb. The two
drugs are still beset by the side effects.4-5 Therefore, the
antitubercular agents with innovative action mechanisms and
structural scaffolds are urgently desired.6
is activated by the catalase-peroxidase KatG to form an
isonicotinoyl radical which reacts with NAD to produce an INH-
NAD adduct. Unfortunately, the majority of INH-resistant M.
tuberculosis clinical isolates have mutations in KatG.10 Thus,
the direct InhA inhibitors were developed to avoid of the
resistance.11-12 In 2015, Manjunatha, Diagana and co-workers
found a new class of direct InhA inhibitors, 4-hydroxy-2-
pyridones, through unbiased phenotypic screening. Several
compounds showed potent bactericidal activity against INH-
resistant Mtb strains.13 The lead compound NITD-916 (Scheme
1) displayed good oral bioavailability and in vivo efficacy in
mouse models of Mtb infection. Based on the co-crystal
structure, key interactions of 4-hydroxy-2-pyridones with InhA-
NADH complex were identified as H-bonds, π-stacks and
hydrophobic interactions. Inspired by the proposed interaction
model of NITD-916, we designed and synthesized a class of m-
amidophenol derivatives (Scheme 1). A number of compounds
were found to exert potent inhibitory activities against Mtb
H37Ra, Mtb H37Rv and clinically isolated MDR-Mtb strains. In
addition, the compounds showed low cytotoxicity and did not
inhibit normal Gram-positive and Gram-negative bacteria.
a.
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical
Sciences,
Sun
Yat-sen
University,
Guangzhou,
China.
E-mail:
yanming@mail.sysu.edu.cn.
b.State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine
and Health, Chinese Academy of Science, Guangzhou, China.
c. Institute of Physical Science and Information Technology, Anhui University, Hefei,
China.
d.University of Chinese Academy of Sciences (UCAS), Beijing, China.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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compound
3
was achieved using hexafluoroisopropanol (HFIP)
N
O2N
as the solvent and trifluoromethanesulfonic acid (TfOH) as the
catalyst.14 The compounds 8a
8b were obtained in excellent
O
N
O
OH
-
Br
N
yields. After the demethylation, the reduction of nitro group
and the acylation with cyclohexanecarboxyl chloride, the
N
N
O
OCF3
O
products 9a-9b were obtained.
bedaquiline
OH
delamanid
H
N
HO
R
1
3
O
5
N
H
O
m-amidophenols
NITD-916
Scheme 1. Structures of antitubercular agents.
Scheme 3. Reagents and conditions: a) p-xylene or mesitylene, HFIP, TfOH, 100°C, 24 h,
90%-96%; b) BBr3, CH2Cl2, -40°C - 0°C, 12 h, 40%-50%; c) H2, 10% Pd/C, CH2Cl2/CH3OH, 4
h, 99%; d) cyclohexanecarbonyl chloride, Et3N, THF, 0°C - rt, 50%-80%.
Results and discussion
Chemistry
Antitubercular activity against Mtb H37Ra
The synthetic pathways of m-amidophenol derivatives 6a
7a 7q are illustrated in Scheme 2. The synthesis started from 3,
5-dinitrobenzoic acid . The compound was transformed to
-6l,
Antitubercular activities of the compounds were preliminarily
screened and evaluated by using a cost-efficient in vitro assay
against a selectable marker-free avirulent autoluminescent
Mtb H37Ra strain.15 The bacteria growth was conveniently
monitored by the bioluminescence intensity.
-
1
1
its methyl ester with thionylchloride in methanol. Then the
nucleophilic substitution of nitro group with lithium methoxide
afforded methyl 3-methoxy-5-nitro-benzoate
methoxy-5-nitrobenzoic acid was obtained by basic hydrolysis
of . The reduction of the acid with sodium borohydride
yielded (3-methoxy-5-nitrophenyl)-methanol . Friedel-Crafts
alkylation of benzene with gave 1-benzyl-3-methoxy-5-
nitrobenzene Demethylation with boron tribromide
provided 3-benzyl-5-nitrophenol, which was hydrogenated
over Pd/C to provide 3-amino-5-benzylphenol . The m-
amidophenol derivatives 6a 6l and 7a 7q were obtained by the
reaction of with different acyl chloride or by the coupling of
with the corresponding carboxylic acids.
2. The 3-
The effect of 3-amido group
2
The antitubercular activities of compounds 6a
evaluated against Mtb H37Ra and the MIC values are
summarized in Table 1 INH was used as the positive control
-6l, 7a-7q were
3
3
.
4.
and DMSO was used as the negative control.
5
Table 1 In vitro antitubercular activity of compounds 6a-6l, 7a -7q against
Mtb H37Ra
-
-
5
5
Compound
R
ClogPa
MIClux
(ꢀg/mL)
>100
>50
6a
6b
6c
6d
Me
CF3
i-Pr
2.56
3.67
3.39
3.14
5
5
6e
6f
t-Bu
3.79
4.03
2.5
2.5
Scheme 2. Reagents and conditions: a) SOCl2, CH3OH, reflux, 4 h, 60%; b) lithium
methoxide , anhydrous methanol, reflux, 12 h, 35%; c) NaOH, CH2Cl2, CH3OH, rt, 3 h,
98%; d) NaBH4, BF3.OEt2, THF, 0°C - rt, 1 h, 99% ; e) benzene, CH2Cl2, AlCl3, reflux, 5 h,
52.6%; f) BBr3, CH2Cl2, -40°C - 0°C, 12 h, 60%; g) H2, 10% Pd/C, CH2Cl2/CH3OH, 4 h, 99%;
h) RCOCl, Et3N, THF, 0°C - rt, 50%-80%; or RCOOH, triphenyl phosphite, toluene. For R
group, see Table 1.
4.59
0.625
6g
The synthesis of compounds 9a-9b is shown in Scheme 3.
Friedel–Crafts reaction of p-xylene and mesitylene with
2 | J. Name., 2012, 00, 1-3
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5.64
2.5
4.22
>50
6h
7m
3.88
3.22
2.5
10
6.43
5.22
2.19
>50
7n
6i
6j
>50
7o
6.25
2.61
3.26
10
5
6k
7p
2.20
4.05
4.54
12.5
6l
7a
7b
7q
5
INH
0.1
-
DMSO
a CLogP was calculated with ChemBioDraw Ultra 12.0.
1.25
2.5
5.87
6.67
The size and lipophilicity of R group exert strong effect on the
antitubercular activity. Acetamide derivative 6a and
trifluoroacetamide derivative 6b did not show obvious
activities. However, the increase of the lipophilicity of amido
group improved significantly the inhibitory activity.
Compounds 6c and 6d (R = i-Pr and c-Pr respectively) showed
7c
7d
>50
good inhibitory activity (MIC = 5 ꢀg/mL). The further increase
of antitubercular activity was achieved via the introduction of
more lipophilic substitutents such as t-Bu, cyclopentyl, and
cyclohexyl. The compound 6g with cyclohexyl substitution
7e
7f
5.28
6.29
5
showed the most potent activity (MIC = 0.625 ꢀg/mL). Further
>25
increase of lipophilicity and the volume of the substitutent led
to the gradual loss of the inhibitory activity. The compound 6h
with 4-ethyl-cyclohexyl substitution afforded lower activity
(MIC = 2.5 ꢀg/mL). The compounds 6i and 6j with more bulk 4-
7g
5.36
10
t-butyl-cyclohexyl and adamantanyl almost lost the inhibitory
activity completely. The incorporation of O (6k) and N (6l) to
the cyclohexyl ring resulted in lower activities. These results
indicated a hydrophobic pocket binding with the amido group.
The size of the pocket can accommodate best a cyclohexyl
group or the similar groups.
7h
7i
4.13
4.96
4.96
2.5
2.5
2.5
We also found benzoamide derivative 7a showed good
inhibitory activity (MIC = 5
ꢀ
7b) afforded a 4-fold increase of the activity (MIC = 1.25
g/mL). The 4-methyl substitution
(
ꢀ
activity (MIC = 2.5
g/mL). 4-t-butyl substitution (7c) showed a slightly lower
g/mL). The introduction of more bulk 4-
ꢀ
cyclohexyl (7d) led to the loss of the activity. The results are
7j
7k
7l
commendably consistent with the above observation. The
4.92
5.17
5
5
substitution with CF3
detrimental effect on the activity. Chloro substitution at 2-, or
3-, or 4-position of the phenyl ring (7h 7i 7j) exhibited the
(7e, 7f) and CF3O (7g) exerted the
,
,
similar efficiency. A 2-fold increase of the activity was achieved
in comparison with 7a. The introduction of more than one
halogen atom at the phenyl ring (7k, 7l) did not afford the
beneficial result. The 4-nitro substitution (7m) resulted in the
loss of the inhibitory activity. The replacement of the benzene
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ring with heteroaryl rings is applicable. Thiophene-2- both compounds did not show antitubercular activity. The 1-
carboxamide 7n, furan-2-carboxamide 7o, 1, 2, 3-thiadiazole- hydroxyl group is also imperative. The methylation of 1-
5-carboxamide 7p and 2-chloronicotinamide 7q are all active hydroxy (18) led to the loss of the activity. Similarly, the
against Mtb H37Ra. Among them, thiophene-2-carboxamide replacement of 1-hydroxyl with carboxylic group (19) and
7n showed the best activity (MIC = 2.5
ꢀ
g/mL).
amino group (20) resulted in the complete loss or decreased
activities.
The effect of 5-substitutent
The effect of 5-substitutent was examined and the results are
summarized in Table The introduction of methyl
substitution to the benzyl group (9a 9b) resulted in the loss of
2.
,
the activity. The replacement of 5-benzyl with methyl (12a), n-
Pr (12b) and i-pr (12c) also led to the loss of antitubercular
activity.16 The results implicated that the existence of 5-benzyl
group is important for antitubercular activity. A π-π interaction
is possibly required. However, the binding pocket is relatively
small. Even the methyl substitution also hampers the insertion
of benzyl group to the pocket. In addition, benzyl oxidation
products 14 showed lower antitubercular activity compared to
compound 7a. The reduction of 14 provided compound 15
which is completely inactive.17
,
Scheme 4. The effect of other structural modifications.
Table 2 In vitro antitubercular activity of compounds 9a-9b, 12a-12c, 14, 15
against Mtb H37Ra
Structure-activity relationship (SAR) of m-amidophenol derivatives
The structure-activity relationship of m-amidophenol
derivatives is summarized in Scheme 5. The crucial H-bonding
interaction of 1-hydroxyl group with the target is expected.
The methylation or the replacement with carboxylic group
resulted in the loss of the antitubercular activity. 5-Benzyl
group is rather conservative. The replacement with alkyl group
or the introduction of substitutents exerted detrimental effect
on the activity. A small binding pocket and an important π-π
interaction are suggested. 3-Amido group is involved in a
crucial hydrophobic interaction with the target. The size of the
binding pocket is best suitable for a cyclohexyl group.
Comp
ound
R1
Clog
Pa
MIClux
(ꢀg/m
L)
Compou
nd
R2
Clog
Pa
MIClux
(ꢀg/m
L)
Scheme 5. SAR of m-amidophenol derivatives.
9a
9b
14
2,4-
dimethyl
2,4,6-
trimethyl
/
5.54
5.98
>50
12a
12b
12c
INH
M
e
4.08
5.14
5.01
>50
In vitro inhibitive activity against Mtb H37Rv and MDR-Mtb strains
Compounds 6g, 7a with potent inhibitory activities against
>50
n-
Pr
i-
>50
>50
H37Ra were selected for further evaluation against Mtb H37Rv
and six clinically isolated MDR-Mtb strains. The results are
6.25
summarized in Table 3. Compound 6g, 7a showed the similar
Pr
activity against H37Rv and MDR-Mtb strains P103, P91 (0.39
μg/mL). Compound 7a exhibited better inhibitory activity
against MDR-Mtb strain R7 than 6g (MIC 0.78 μg/mL vs 3.125
μg/mL). However, both compounds 6g and 7a did not inhibit
MDR-Mtb strains P71, P90 and P98. The reason of the selective
inhibition against different MDR-Mtb strains is unclear at
present.
15
/
>50
-
0.1
-
DMSO
a CLogP was calculated with ChemBioDraw Ultra 12.0.
The effect of other structural modifications
To verify the importance of 3-amido and 5-benzyl group, we
prepared compounds 16 and 17 (
Scheme 4).18-19 As expected,
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Table 3 Inhibitive activity against H37Rv and clinically isolated MDR-Mtb Table 5 Cytotoxicity of compounds 6g, 7a
strains
Entry
IC50 (μM)
RAW264.7
>323
H
H
HO
N
HO
N
HepG2
>161
O
O
6g
7a
(SI > 80)
(SI > 160)
>330
6g
7a
>330
MIC (μg/mL)
(SI > 20)
(SI > 20)
Strains
H37Rv
P103a
P91a
6g
7a
INH
RIF
DMSO
0.39
0.39
0.39
3.125
>100
>100
>100
0.39
0.39
0.39
0.78
0.41
0.003
-
-
-
-
-
-
-
/
/
/
/
/
/
/
/
/
/
/
/
3D-QSAR study
For further exploration of the structure-activity relationship,
CoMFA approach was employed on the tested compounds to
establish 3D-QSAR models. Their conformations were first
generated by molecular mechanism-based structural
optimization embedded in Tripos Sybyl X2.0 software.
Compound 6g was selected as the template for alignment
R7a
P71b
>100
>100
>100
P90a
P98a
(
Figure 1).
a
b
Resistant to rifampicin and INH; Resistant to rifampicin, INH and
pyrazinamide.
Evaluation of antibacterial activity
The antibacterial activity of compounds 6g and 7a was
examined against the representative Gram-positive bacteria
Staphylococcus aureus, Enterococcus faecalis and Gram-
negative bacteria Escherichia coli. Amoxicillin and ofloxacin
were used as the positive controls and DMSO was used as the
negative control. The results are summarized in Table 4. Both
6g and 7a did not show antibacterial activity (MIC > 50 ꢀg/mL)
against the tested bacteria. The fact confirmed that the
inhibition activity of 6g and 7a against Mtb are highly exclusive
The property is favorable considering the long treatment
.
course for tuberculosis (typically 12-24 months). The avoid of
the inhibition against the normal intestinal bacteria is
advantageous for antitubercular agents.
Table 4 Evaluation of antibacterial activity of compounds 6g and 7a
Figure 1. 3D-QSAR structure alignment using compound 6g as the template
.
MIC
(ꢀg/mL)
Based on these conformations with the local minimum
energies and partial charges assigned by MMFF94 forcefield,
CoMFA model was performed with 33 molecules as the
training set and 2 molecules as the test set. The best model
(CoMFA) yielded q2 of 0.616, r2 of 0.950 and F value of 102.537
with the optimum number of components (PC) 5 (Table 6).
6g
7a
Amoxicillin
0.78
Ofloxacin
0.31
DMSO
-
Staphylococcus
aureus
> 50
> 50
Escherichia coli.
Enterococcus
faecalis
> 50
> 50
> 50
> 50
6.25
1.25
1.25
/
-
-
Table 6 The parameters derived from CoMFA model
Parameters
COMFA model
0.616
q2
Evaluation of cytotoxicity
r2
0.950
5
The cytotoxicity of compounds 6g and 7a was evaluated
against HepG2 and RAW264.7 cell lines. The IC50 values are
listed in Table 5. Compound 6g and 7a are almost non-
cytotoxic against two cell lines. Both compounds have a
selectivity index (SI = IC50/MIC) above 20.
PC
F
102.537
contributions (%)
Steric
67.6
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Electrostatics
32.4
Conclusion
The Figure 2 showed the scattered plot of predicted pMIC
versus experimental pMIC value of the training set and test set.
Contour map with rpred2 = 0.6758 provided visual and spatial
information for future design and optimization of new
compounds with enhanced activities.
We have discovered m-amidophenol derivatives as a new class
of antitubercular agents. Several compounds showed potent
inhibitory activities against Mtb H37Ra, Mtb H37Rv and
clinically isolated MDR-Mtb strains. The compounds did not
inhibit normal Gram-positive and Gram-negative bacteria.
Their inhibition against Mtb is highly exclusive. The compounds
showed low cytotoxicity and the selectivity indexes are
acceptable. The further studies toward the elucidation of the
inhibition mechanism and the development of more potent
candidates are currently underway.20
Experimental
Chemistry
1H NMR and 13C NMR spectra were recorded on Bruker
AVANCE 400 or 500 spectrometer. Chemical shifts of protons
are reported in parts per million downfield from
tetramethylsilane. Peaks are labeled as single (s), broad singlet
(br), doublet (d), triplet (t), double doublet (dd), doublet of
triplets (dt), multiplet (m). The high-resolution mass spectra
Figure 2. A graph of predicted versus experimental pMIC values of the
were analyzed on
a
SHIMADZU LCMS-IT-TOF mass
molecules.
spectrometer. The purity of the synthesized compounds was
determined by high-performance liquid chromatography
(HPLC) with a TC-C18 column (250 mm × 4.6 mm, 5 μm) using
methanol/water mobile phase (0.50 mL/min). Melting points
were determined in open capillary tubes on a MPA100
Optimelt automated melting point system. All chemicals were
purchased from Sigma-Aldrich and Alfa Aesar chemical
companies and were used without further purification.
The CoMFA contour map of steric field and electrostatic field is
shown in Figure 3. The steric contour is shown in green (more
bulk favored) and yellow (less bulk favored), while suggested
that the sterically bulky group is disfavored at the 5-position of
the phenyl. For example, the compound 9a and 9b containing
methyl groups led to the complete loss of the inhibitory
activity. The green contour in the o-position of cyclohexyl
indicates that this space is in favor of accommodating sterically
Synthesis of N-(3-benzyl-5-hydroxyphenyl)acetamide (6a)
bulky group (for example, compound 7h with
a 4-Cl
To a solution of 3-amino-5-benzylphenol 5 (99.5 mg, 0.5 mmol)
substitution). The electrostatic contour was colored red and
blue. A red contour near the 1-position of the phenyl ring
showed that the electron-withdrawing groups were favored at
this position. The compound 7a with 1-OH and the compound
20 with 1-NH2 exhibited good anti-TB activity. The compound
7b with 4-CH3 lies near blue contour and exhibited good anti-
TB activity, while compound 7m with 4-NO2 near blue contour
hence lost the inhibitory activity.
and triethylamine (76.3 μL, 0.55 mmol) in THF (2 mL) was
added slowly a solution of acetyl chloride (40 μL, 0.55 mmol) in
THF (1 mL) at 0
room temperature. The reaction was quenched with water (10
mL) and the mixture was extracted with EtOAc (15 mL 2).
°C. The reaction mixture was stirred for 3 h at
×
The combined organic layer was dried over anhydrous Na2SO4
and filtered. After the solvent was removed in vacuo, the
crude product was purified by column chromatography
(petroleum/EtOAc=20:1∼5:1) to afford 6a as a colorless solid
(72 mg, 60%). m.p. 158.5–160.2°C; 1H NMR (400 MHz, DMSO-
d6) δ 9.72 (bs, 1H, NH), 9.26 (bs, 1H, OH), 7.28 (m, 2H, ArH),
7.19 (m, 3H, ArH), 7.06 (s, 1H, ArH), 6.76 (s, 1H, ArH), 6.29 (s,
1H, ArH), 3.78 (s, 2H, CH2), 1.98 (s, 3H, CH3); 13C NMR (101
MHz, DMSO-d6) δ 168.59 (CONH), 158.01, 143.00, 141.58,
140.73, 129.20, 128.83, 126.41, 111.12, 110.65, 104.48, 41.75
(CH2), 24.50 (CH3); HRMS (ESI) calculated for C15H16NO2
[M+H]+: 242.1176, found: 242.1173. Purity: 98.1% (by HPLC).
Synthesis of N-(3-benzyl-5-hydroxyphenyl)-2, 2, 2-
trifluoroacetamide (6b)
To a solution of
(137 mg, 1.2 mmol) in 4 mL toluene was added P(OPh)3 (314
μL 1.2 mmol). The reaction mixture was stirred at 110°C for
5 (160 mg，0.8 mmol), trifluoroacetic acid
，
Figure 3. The steric and electrostatic field distribution around 6g.
12 h. After being cooled to room temperature, water (20 mL)
was added. The reaction mixture was extracted with ethyl
6 | J. Name., 2012, 00, 1-3
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acetate (20 mL 2). The combined organic layer was dried
N-(3-benzyl-5-hydroxyphenyl)cyclohexanecarboxamide (6g)
The compound was synthesized via a similar procedure of 6a
×
over anhydrous Na2SO4, filtered and evaporated under
reduced pressure. The residue was purified by column
chromatography over silica gel (petroleum/EtOAc=4:1) to yield
6b as a red solid (94 mg, 40%). m.p. 95.8–98.7°C; 1H NMR (400
MHz, CD3OD) δ 7.25 (m, 2H, ArH), 7.16 (m, 3H, ArH), 7.10 (m,
1H, ArH), 6.91 (m, 1H, ArH), 6.50 (m, 1H, ArH), 3.87 (s, 2H,
CH2); 13C NMR (101 MHz, CD3OD) δ 157.68, 155.26 (q, 2J = 37.2
Hz, CONH), 143.63, 140.71, 137.19, 128.58, 128.08, 116.04 (q,
1J = 286 Hz), 125.78, 113.11, 112.44, 105.77, 41.33 (CH2);
HRMS (ESI) calculated for C15H12NO2F3 [M-H]-: 294.0747,
found: 294.0746. Purity: 98.9% (by HPLC).
.
White solid, yield 49%, m.p. 200.9–202.8°C; 1H NMR (400 MHz,
DMSO-d6) δ 9.59 (bs, 1H, NH), 9.24 (bs, 1H, OH), 7.28 (m, 2H),
7.19 (m, 3H), 7.04 (m, 1H), 6.84 (m, 1H), 6.28 (m, 1H), 3.77 (s,
2H,ArCH2Ar), 2.27 (t, J = 11.4 Hz, 1H), 1.73 (d, J = 9.2 Hz, 4H),
1.63 (d, J = 9.6 Hz, 1H), 1.37 (m, 2H), 1.30 – 1.14 (m, 3H); 13C
NMR (101MHz, DMSO-d6) δ 174.62 (CONH), 157.96, 142.93,
141.62, 140.91, 129.18, 128.82, 126.39, 111.02, 110.82,
104.55, 45.31 (cyclohexyl-CH), 41.80 (ArCH2Ar), 29.61
(cyclohexyl-CH2), 25.88 (cyclohexyl-CH2), 25.71 (cyclohexyl-
CH2); HRMS (ESI) calculated for C20H24NO2 [M+H]+: 310.1802,
found: 310.1800. Purity: 97.1% (by HPLC).
N-(3-benzyl-5-hydroxyphenyl)-isobutyramide (6c)
N-(3-benzyl-5-hydroxyphenyl)-4-ethylcyclohexanecarboxamide
The compound was synthesized via a similar procedure of 6a
.
Orange solid, yield 86%, m.p. 169.8–171.6°C; 1H NMR (400
MHz, DMSO-d6) δ 9.59 (bs, 1H, NH), 9.23 (bs, 1H, OH), 7.31 –
7.24 (m, 2H), 7.22 – 7.12 (m, 3H), 7.04 (m, 1H), 6.84 (m, 1H),
6.29 (m, 1H), 3.78 (m, 2H, CH2), 2.54 (m, 1H, CH), 1.06 (s, 3H,
CH3), 1.05 (s, 3H, CH3); 13C NMR (101MHz, DMSO-d6) δ: 175.50
(CONH), 157.98, 142.93, 141.60, 140.85, 129.18, 128.82,
126.40, 111.10, 110.92, 104.69, 41.81 (CH2), 35.33 (CH), 19.97
(CH3); HRMS (ESI) calculated for C17H19NO2 [M+H]+: 270.1489,
found: 270.1491. Purity: 96.2% (by HPLC).
(6h)
The compound was prepared via a similar procedure of 6b
.
White solid, yield 69%, m.p. 201.4–203.3°C; 1H NMR (400 MHz,
DMSO-d6) δ 9.57 (bs, 1H, NH), 9.21 (bs, 1H, OH), 7.28 (m, 2H),
7.17 (m, 3H), 7.03 (m, 1H), 6.84 (m, 1H), 6.28 (m, 1H), 3.77 (s,
2H, ArCH2Ar), 2.21 (dd, J = 16.5, 7.7 Hz, 1H), 1.78 (d, J = 11.2
Hz, 4H), 1.45 – 1.31 (m, 2H), 1.20 (dt, J = 14.2, 7.3 Hz, 2H), 1.11
(m, 1H), 0.86 (m, 5H); 13C NMR (101 MHz, DMSO-d6) δ 174.64
(CONH), 157.96, 142.91, 141.61, 140.90, 129.18, 128.81,
126.39, 111.04, 110.86, 104.61, 45.51 (cyclohexyl-CH), 41.81
(ArCH2Ar), 38.72 (-CH2CH3), 32.09 (cyclohexyl-CH2), 29.91
(cyclohexyl-CH2), 29.55 (cyclohexyl-CH2), 11.74 (CH3); HRMS
(ESI) calculated for C22H27NO2 [M+H]+: 338.2115, found:
338.2117. Purity: 98.8% (by HPLC).
N-(3-benzyl-5-hydroxyphenyl)cyclopropanecarboxamide (6d)
The compound was synthesized via a similar procedure of 6a
.
Orange solid, yield 63%, m.p. 163.8–165.3°C; 1H NMR (400
MHz, DMSO-d6) δ 9.95 (bs, 1H, NH), 9.24 (bs, 1H, OH), 7.28 (m,
2H), 7.23 – 7.14 (m, 3H), 7.01 (m, 1H), 6.82 (m, 1H), 6.29 (m,
1H), 3.78 (s, 2H, CH2), 1.73 (dq, J = 7.6, 5.0 Hz, 1H, CH), 0.82 –
N-(3-benzyl-5-hydroxyphenyl)-4-(tert-
0.64 (m, 4H); 13C NMR (101 MHz, DMSO-d6) δ 171.86 (CONH), butyl)cyclohexanecarboxamide (6i)
158.02, 143.01, 141.58, 140.76, 129.19, 128.82, 126.40,
111.09, 110.74, 104.55, 41.79 (ArCH2Ar), 14.94 (cyclopropanyl-
CH), 7.47 (2CH2); HRMS (ESI) calculated for C17H17NO2 [M+H]+:
268.1332, found: 268.1332. Purity: 98.456% (by HPLC).
N-(3-benzyl-5-hydroxyphenyl)pivalamide (6e)
This compound was prepared via a similar procedure of 6b
.
White solid, yield 76%, m.p. 227.2–229.0°C; 1H NMR (400 MHz,
DMSO-d6) δ 9.56 (bs, 1H, NH), 9.21 (bs, 1H, OH), 7.32 – 7.23
(m, 2H), 7.17 (m, 3H), 7.02 (m, 1H), 6.84 (m, 1H), 6.27 (m, 1H),
3.77 (s, 2H, ArCH2Ar), 2.29 – 2.11 (m, 1H), 1.80 (m, 4H), 1.37
(m, 2H), 1.05 – 0.91 (m, 3H), 0.84 (s, 9H, t-Bu); 13C NMR (101
MHz, DMSO-d6) δ 174.67 (CONH), 157.96, 142.91, 141.61,
140.88, 129.17, 128.81, 126.38, 111.05, 110.87, 104.61, 47.30,
45.47, 41.82 (ArCH2Ar), 32.62, 30.00, 27.80, 26.66; HRMS (ESI)
calculated for C24 H31NO2 [M+H]+: 366.2428, found: 366.2445.
Purity: 98.6% (by HPLC).
The compound was synthesized via a similar procedure of 6b
.
Yellow solid, yield 52%, m.p. 142.6–144.3°C; 1H NMR (400
MHz, DMSO-d6) δ 9.20 (bs, 1H, NH), 8.98 (bs, 1H, OH), 7.35 –
7.25 (m, 2H), 7.21 (d, J = 5.1 Hz, 3H), 7.09 (m, 1H), 6.93 (m,
1H), 6.32 (m, 1H), 3.80 (s, 2H, CH2), 1.19 (s, 9H, CH3); 13C NMR
(101 MHz, CD3OD) δ 178.41 (CONH), 157.33, 142.91, 141.06,
139.34, 128.55, 128.00, 125.65, 113.01, 111.68, 106.23, 41.47
(CH2), 39.11(CMe3), 26.39 (CH3); HRMS (ESI) calculated for
C18H21NO2 [M+H]+: 284.1645, found: 284.1649. Purity: 98.8%
(by HPLC).
N-(3-benzyl-5-hydroxyphenyl)adamantane-1-carboxamide (6j)
The compound was prepared via a similar procedure of 6a
.
White solid, yield 31%, m.p.183.5–185.4°C; 1H NMR (400 MHz,
CD3OD) δ 7.23 (m, 2H), 7.15 (m, 3H), 7.00 (m, 1H), 6.83 (m,
1H), 6.37 (m, 1H), 3.79 (m, 2H, ArCH2Ar), 2.01 (s, 3H), 1.94 (m,
6H), 1.75 (s, 6H); 13C NMR (101 MHz, CD3OD) δ 177.88 (CONH),
157.31, 142.89, 141.07, 139.28, 128.55, 128.01, 125.65,
112.99, 111.64, 106.18, 41.48 (ArCH2Ar), 41.26, 38.56, 36.13,
28.31; HRMS (ESI) calculated for C24H27NO2 [M+H]+: 362.2115,
found: 362.2118. Purity: 96.6% (by HPLC).
N-(3-benzyl-5-hydroxyphenyl)cyclopentanecarboxamide (6f)
The compound was synthesized via a similar procedure of 6a
.
Orange solid, yield 70%, m.p. 182.4–184.3°C; 1H NMR (400
MHz, DMSO-d6) δ 9.62 (bs, 1H, NH), 9.22 (bs, 1H, OH), 7.34 –
7.24 (m, 2H), 7.18 (m, 3H), 7.04 (s, 1H), 6.84 (m, 1H), 6.28 (m,
1H), 3.78 (s, 2H, ArCH2Ar), 2.78 – 2.65 (m, 1H, cyclopentyl-CH),
1.86 – 1.71 (m, 2H), 1.73 – 1.58 (m, 4H), 1.52 (m, 2H); 13C NMR N-(3-benzyl-5-hydroxyphenyl)tetrahydro-2H-pyran-4-carboxamide
(101 MHz, DMSO-d6) δ 174.67 (CONH), 157.98, 142.93, 141.61,
140.88, 129.18, 128.82, 126.39, 111.07, 110.88, 104.65, 45.72
(cyclopentyl-CH), 41.81 (ArCH2Ar), 30.54 (cyclopentyl-CH2),
26.14 (cyclopentyl-CH2); HRMS (ESI) calculated for C19H21NO2
[M+H]+: 296.1645, found: 296.1648. Purity: 97.9% (by HPLC).
(6k)
The compound was synthesized via a similar procedure of 6a
White solid, yield 63%, m.p. 151.2–152.6°C; 1H NMR (400 MHz,
.
CD3OD) δ 7.30 – 7.21 (m, 1H), 7.16 (m, 1H), 7.02 (m, 1H), 6.79
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(m, 1H), 6.38 (m, 1H), 3.98 (dd, J = 11.4, 2.6 Hz, 2H), 3.84 (s, 2H, (m, 4H), 7.05 (s, 1H), 6.35 (s, 1H), 3.82 (s, 2H, ArCH2Ar), 2.58
ArCH2Ar), 3.45 (td, J = 11.7, 2.1 Hz, 2H), 2.57 (tt, J = 11.4, 4.0 (m, 1H, cyclohexyl-CH), 1.80 (m, 4H), 1.71 (m, 1H), 1.42 (m,
Hz, 1H), 1.89 – 1.67 (m, 4H); 13C NMR (101 MHz, DMSO-d6) δ 4H), 1.25 (m, 1H); 13C NMR (101 MHz, DMSO-d6) δ 165.83
173.29 (CONH), 157.98, 142.99, 141.58, 140.73, 129.19, (CONH), 157.93, 151.67, 142.88, 141.62, 140.70, 133.23,
128.83, 126.40, 111.20, 110.91, 104.66, 66.87 (CH2O-), 42.19, 129.20, 128.84, 128.21, 127.05, 126.42, 112.01, 111.67,
41.79, 29.33 (CHCO); HRMS (ESI) calculated for C19H21NO3 105.71, 44.16, 41.84 (ArCH2Ar), 34.18, 26.73, 26.00; HRMS
[M+H]+: 312.1594, found: 312.1602. Purity: 97.3% (by HPLC).
N-(3-benzyl-5-hydroxyphenyl)morpholine-4-carboxamide (6l)
(ESI) calculated for C26H27NO2 [M+H]+: 386.2115, found:
386.2120. Purity: 99.8% (by HPLC).
N-(3-benzyl-5-hydroxyphenyl)-4-(trifluoromethyl)benzamide (7e)
White solid, yield 39%, m.p. 155.6–157.0°C; 1H NMR (400 MHz, The compound was synthesized via a similar procedure of 6a
The compound was synthesized via a similar procedure of 6a
.
.
DMSO-d6) δ 9.11 (bs, 1H, NH), 8.32 (bs, 1H, OH), 7.28 (m, 2H), White solid, yield 86%, m.p. 177.6–178.5°C; 1H NMR (400 MHz,
7.22 – 7.15 (m, 3H), 6.87 (m, 1H), 6.72 (m, 1H), 6.21 (m, 1H), DMSO-d6) δ 10.26 (bs, 1H, NH), 9.36 (bs, 1H, OH), 8.10 (d, J =
3.76 (s, 2H, ArCH2Ar), 3.59 – 3.55 (t, J = 4 Hz, 4H, CH2), 3.40 – 8.1 Hz, 2H), 7.88 (d, J = 8.3 Hz, 2H), 7.30 (m, 2H), 7.20 (m, 4H),
3.35 (t, J = 1 Hz ,4H, CH2); 13C NMR (101 MHz, DMSO-d6) δ 7.05 (m, 1H), 6.40 (m, 1H), 3.84 (s, 2H, ArCH2Ar); 13C NMR (101
157.82, 155.56, 142.49, 141.80, 141.74, 129.16, 128.79, MHz, DMSO-d6) δ 164.73, 158.00, 143.08, 141.55, 140.24,
126.35, 111.40, 110.08, 105.09, 66.48 (CH2O), 44.68 (CH2N), 139.37, 131.71 (q, 2J = 31.8 Hz), 129.21, 129.04, 128.86,
3
1
41.89 (ArCH2Ar); HRMS (ESI) calculated for C18H20N2O3 [M+H]+: 126.44, 125.76 (q, J = 3.4 Hz), 124.40 (q, J = 270 Hz), 112.16,
313.1547, found: 313.1549. Purity: 97.1% (by HPLC).
N-(3-benzyl-5-hydroxyphenyl)benzamide (7a)
112.11, 105.84, 41.79 (ArCH2Ar); HRMS (ESI) calculated for
C21H16NO2F3 [M+H]+: 372.1206, found: 372.1208. Purity: 98.5%
(by HPLC).
The compound was synthesized via a similar procedure of 6a
White solid, yield 52%, m.p. 215.8–217.6°C; 1H NMR (400 MHz,
DMSO-d6) δ 10.02 (bs, 1H, NH), 9.29 (bs, 1H, OH), 7.94 – 7.88
(m, 1H), 7.59 – 7.53 (m, 1H), 7.50 (m, 1H), 7.29 (m, 1H), 7.20
(m, 2H), 7.06 (m, 1H), 6.37 (m, 1H), 3.83 (s, 2H, ArCH2Ar); 13C
NMR (101 MHz, DMSO-d6) 165.90 (CONH) , 157.97, 142.91 ,
141.60 , 140.59 , 135.60 , 131.86 , 129.20, 128.84 , 128.75 ,
128.09 , 126.42 , 112.18 , 111.85 , 105.90 , 41.86 (ArCH2Ar);
HRMS (ESI) calculated for C20H17NO2 [M+H]+: 304.1332, found:
304.1332. Purity: 98.7% (by HPLC).
.
N-(3-benzyl-5-hydroxyphenyl)-3, 5-bis(trifluoromethyl)benzamide
(7f)
The compound was synthesized via a similar procedure of 6a
.
White solid, yield 48%, m.p. 167.9–169.8°C; 1H NMR (400 MHz,
DMSO-d6) δ 10.48 (bs, 1H, NH), 9.46 (bs, 1H, OH), 8.58 (s, 1H),
8.34 (s, 1H), 7.30 (m, 1H), 7.21 (m, 4H), 7.02 (s, 1H), 6.45 (s,
1H), 3.86 (s, 1H, ArCH2Ar); 13C NMR (101 MHz, DMSO-d6) δ
162.82 (CONH), 158.05, 143.16, 141.51, 139.89, 137.69, 130.86
2
4
(q, J = 33.4 Hz), 129.21, 129.01 (q, J = 1 Hz), 128.88, 126.47,
3
125.44 (q, J = 3 Hz), 123.60 (q,1 J = 272 Hz), 112.50, 112.26,
N-(3-benzyl-5-hydroxyphenyl)-4-methylbenzamide (7b)
The compound was synthesized via a similar procedure of 6a
.
106.08, 41.76 (ArCH2Ar); HRMS (ESI) calculated for
Light red solid, yield 64%, m.p. 184.5–186.7°C; 1H NMR (400 C22H16NO2F6 [M+H]+: 440.1080, found: 440.1092. Purity: 96.6%
MHz, DMSO-d6) δ 9.96 (bs, 1H, NH), 9.32 (bs, 1H, OH), 7.83 (d, (by HPLC).
N-(3-benzyl-5-hydroxyphenyl)-4-(trifluoromethoxy)benzamide (7g)
J = 8.1 Hz, 2H), 7.30 (t, J = 7.7 Hz, 4H), 7.20 (m, 4H), 7.05 (s,
1H), 6.36 (s, 1H), 3.82 (s, 2H, ArCH2Ar), 2.37 (s, 3H, CH3); 13C
NMR (101 MHz, DMSO-d6) δ 165.69 (CONH), 157.93, 142.89,
141.89, 141.63, 140.66, 132.66, 129.29, 129.20, 128.85,
128.14, 126.42, 112.10, 111.70, 105.80, 41.85 (ArCH2Ar), 21.46
(CH3); HRMS (ESI) calculated for C21H19NO2 [M+H]+: 318.1489,
found: 318.1488. Purity: 99.2% (by HPLC).
The compound was synthesized via a similar procedure of 6a
.
White solid, yield 80%, m.p. 129.3–131.3°C; 1H NMR (400 MHz,
DMSO-d6) δ 10.15 (bs, 1H, NH), 9.34 (bs, 1H, OH), 8.08 – 7.96
(m, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.30 (t, J = 7.4 Hz, 2H), 7.25 –
7.15 (m, 4H), 7.04 (s, 1H), 6.39 (s, 1H), 3.84 (s, 2H, ArCH2Ar);
13C NMR (101 MHz, DMSO-d6) δ 164.82 (CONH), 157.91,
150.84, 143.11, 141.53, 140.28, 134.61, 130.46, 129.17,
128.87, 126.46, 121.09, 120.43(q, 1J = 256 Hz), 112.14, 112.03,
N-(3-benzyl-5-hydroxyphenyl)-4-(tert-butyl)benzamide (7c)
The compound was synthesized via a similar procedure of 6a
.
White solid, yield 81%, m.p. 178.3–179.3°C; 1H NMR (400 MHz, 105.83, 41.77 (ArCH2Ar); HRMS (ESI) calculated for
DMSO-d6) δ: 9.99 (bs, 1H, NH), 9.33 (bs, 1H, OH), 7.85 (d, J = C21H16NO3F3 [M-H]-: 386.1010, found: 386.1015. Purity: 99.6%
7.9 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.30 (by HPLC).
N-(3-benzyl-5-hydroxyphenyl)-2-chlorobenzamide (7h)
(m, 2H), 7.20 (m, 4H), 7.07 (m, 1H), 6.36 (m, 1H), 3.83 (s, 2H,
ArCH2Ar), 1.31 (s, 9H, t-Bu); 13C NMR (101 MHz, DMSO-d6) δ
165.83 (CONH), 157.93, 154.72, 142.90, 141.63, 140.68,
132.87, 129.20, 128.85, 127.97, 126.42, 125.54, 112.03,
111.69, 105.72, 41.84 (ArCH2Ar), 35.12, 31.41 (CH3); HRMS
(ESI) calculated for C24H25NO2 [M+H]+: 360.1958, found:
360.1954. Purity: 99.5% (by HPLC).
The compound was synthesized via a similar procedure of 6a
.
White solid, yield 52%, m.p. 159.2–161.3°C; 1H NMR (400 MHz,
DMSO-d6) δ 10.29 (bs, 1H, NH), 9.34 (bs, 1H, OH), 7.57 – 7.45
(m, 3H), 7.42 (m, 1H), 7.29 (m, 2H), 7.19 (m, 3H), 7.15 (m, 1H),
6.98 (m, 1H), 6.98 (m, 1H), 6.37 (m, 1H), 3.82 (s, 1H, ArCH2Ar);
13C NMR (101 MHz, DMSO-d6) δ 163.87 (CONH), 158.12,
150.82, 146.89, 143.35, 141.46, 140.08, 138.59, 133.79,
129.23, 128.87, 126.46, 123.57, 112.20, 111.27, 105.05, 41.72
N-(3-benzyl-5-hydroxyphenyl)-4-cyclohexylbenzamide (7d)
The compound was synthesized via a similar procedure of 6b
.
Yellow solid, yield 49%, m.p. 243.8–245.6°C; 1H NMR (400 (ArCH2Ar); HRMS (ESI) calculated for C20H17NO2Cl [M+H]+:
MHz, DMSO-d6) δ :9.97 (bs, 1H, NH), 9.31 (bs, 1H, OH), 7.83 (d, 338.0942, found: 338.0942. Purity: 99.9% (by HPLC).
N-(3-benzyl-5-hydroxyphenyl)-4-chlorobenzamide (7i)
J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 7.29 (m, 2H), 7.24 – 7.16
8 | J. Name., 2012, 00, 1-3
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The compound was synthesized via a similar procedure of 6a
.
The compound was synthesized via a similar procedure of 6a.
Red solid, yield 62%, m.p. 191.6–192.8°C; 1H NMR (500 MHz, White solid, yield 61%, m.p. 180.6–182.3°C; 1H NMR (400 MHz,
DMSO-d6) δ 10.12 (bs, 1H, NH), 9.36 (bs, 1H, OH), 7.94 (d, J = DMSO-d6) δ 10.01 (bs, 1H, NH), 9.34 (bs, 1H, OH), 7.99 (d, J =
8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.30 (m, 2H), 7.25 – 7.16 3.3 Hz, 1H), 7.82 (d, J = 4.8 Hz, 1H), 7.36 – 7.25 (m, 2H), 7.20
(m, 4H), 7.04 (s, 1H), 6.38 (s, 1H), 3.83 (s, 2H, ArCH2Ar); 13C (m, 4H), 7.16 (s, 1H), 6.99 (s, 1H), 6.38 (s, 1H), 3.83 (s, 2H,
NMR (101 MHz, DMSO-d6) δ 164.77 (CONH), 157.97, 142.98, ArCH2Ar); 13C NMR (101 MHz, DMSO-d6) δ 160.21 (CONH),
141.56, 140.38, 136.74, 134.25, 130.06, 129.20, 128.85, 157.99, 143.02, 141.56, 140.74, 140.12, 132.15, 129.42,
128.83, 126.43, 112.17, 112.00, 105.91, 41.83 (ArCH2Ar); 129.20, 128.86, 128.45, 126.44, 112.10, 111.93, 105.87, 41.81
HRMS (ESI) calculated for C20H16NO2Cl [M+H]+: 338.0942, (ArCH2Ar); HRMS (ESI) calculated for C18H15NO2S [M+H]+:
found: 338.0940. Purity: 99.3% (by HPLC).
N-(3-benzyl-5-hydroxyphenyl)-3-chlorobenzamide (7j)
310.0896, found: 310.0892. Purity: 97.2% (by HPLC).
N-(3-benzyl-5-hydroxyphenyl)furan-2-carboxamide (7o)
The compound was synthesized via a similar procedure of 6a
.
The compound was synthesized via a similar procedure of 6a.
Red solid, yield 74%, m.p. 167.2–169.1°C; 1H NMR (500 MHz, White solid, yield 46%, m.p. 193.9–195.5°C; 1H NMR (400 MHz,
DMSO-d6) δ 10.16 (bs, 1H, NH), 9.37 (bs, 1H, OH), 7.96 (s, 1H), CD3OD) δ 7.70 (s, 1H), 7.30 – 7.23 (m, 2H), 7.21 (m, 3H), 7.19 –
7.87 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.54 (m, 1H), 7.12 (m, 2H), 6.95 (s, 1H), 6.61 (m, 1H), 6.43 (s, 1H), 3.88 (s, 2H,
7.33 – 7.25 (m, 2H), 7.20 (m, 4H), 7.04 (s, 1H), 6.39 (s, 1H), 3.83 ArCH2Ar); 13C NMR (126 MHz, DMSO-d6) δ 157.95 (CONH),
(s, 2H, ArCH2Ar); 13C NMR (101 MHz, DMSO-d6) δ 164.38 156.55, 148.03, 146.08, 142.99, 141.55, 139.92, 129.21,
(CONH), 157.98, 143.00, 141.56, 140.29, 137.51, 133.62, 128.85, 126.43, 114.93, 112.49, 112.07, 111.87, 105.80, 41.80
131.71, 130.77, 129.20, 128.85, 127.86, 126.92, 126.44, (ArCH2Ar); HRMS (ESI) calculated for C18H15NO3 [M+H]+:
112.18, 112.10, 105.92, 41.82 (ArCH2Ar); HRMS (ESI) 294.1125, found: 294.1118. Purity: 97.8% (by HPLC).
calculated for C20H16NO2Cl [M-H]-: 336.0797, found: 336.0797.
N-(3-benzyl-5-hydroxyphenyl)-4-methyl-1, 2, 3-thiadiazole-5-
carboxamide (7p)
Purity: 98.7% (by HPLC).
N-(3-benzyl-5-hydroxyphenyl)-2, 4-dichlorobenzamide (7k)
The compound was synthesized via a similar procedure of 6b
.
Yellow solid, yield 44%, m.p. 134.1–135.9°C; 1H NMR (400
MHz, DMSO-d6) δ 10.52 (bs, 1H, NH), 9.43 (bs, 1H, OH), 7.29
(m, 2H), 7.22 (m, 3H), 7.11 (s, 1H), 6.93 (s, 1H), 6.43 (s, 1H),
3.84 (s, 2H, ArCH2Ar), 2.78 (s, 3H, CH3); 13C NMR (101 MHz,
CD3OD) δ 159.28 (CONH), 158.18, 157.64, 144.18, 143.49,
140.84, 138.69, 128.58, 128.07, 125.75, 112.49, 112.09,
105.40, 41.40 (ArCH2Ar), 12.01 (CH3); HRMS (ESI) calculated for
C17H15N3O2S [M+H]+: 326.0958, found: 326.0956. Purity: 98.5%
(by HPLC).
The compound was synthesized via a similar procedure of 6a
White solid, yield 55%, m.p. 130.2–132.0°C; 1H NMR (400 MHz,
CD3OD) δ 7.55 (d, J = 1.9 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.41
(dd, J = 8.2, 1.9 Hz, 1H), 7.29 – 7.22 (m, 2H), 7.22 – 7.12 (m,
5H), 6.92 (s, 1H), 3.87 (s, 2H, ArCH2Ar); 13C NMR (101 MHz,
CD3OD) δ 165.70 (CONH), 157.48, 143.41, 140.91, 139.02
135.95, 135.26, 131.76, 129.69, 129.37, 128.57, 128.08,
127.14, 125.75, 112.12, 111.96, 105.11, 41.43 (ArCH2Ar);
HRMS (ESI) calculated for C20H15NO2Cl2 [M+H]+: 372.0553,
found: 372.0561. Purity: 991% (by HPLC).
.
N-(3-benzyl-5-hydroxyphenyl)-2-chloronicotinamide (7q)
N-(3-benzyl-5-hydroxyphenyl)-3-chloro-4-fluorobenzamide (7l)
The compound was synthesized via a similar procedure of 6a
.
White solid, yield 48%, m.p. 157.6–159.3°C; 1H NMR (400 MHz,
DMSO-d6) δ :10.42 (bs, 1H, NH), 9.39 (bs, 1H, OH), 8.51 (d, J =
4.7 Hz, 1H), 8.02 (d, J = 7.4 Hz, 1H), 7.54 (dd, J = 7.3, 4.9 Hz,
1H), 7.30(m, 1H), 7.21 (m,1H), 7.14 (s, 1H), 6.94 (s, 1H), 6.40 (s,
1H), 3.84 (s, 1H, ArCH2Ar); 13C NMR (101 MHz, DMSO-d6) δ
163.87 (CONH), 158.12, 150.82, 146.89, 143.35, 141.46,
140.08, 138.59, 133.79, 129.23, 128.87, 126.46, 123.57,
112.20, 111.27, 105.05, 41.72 (ArCH2Ar); HRMS (ESI)
calculated for C19H16N2O2Cl [M+H]+: 339.0895, found:
339.0896. Purity: 98.9% (by HPLC).
The compound was synthesized via a similar procedure of 6a
.
White solid, yield 43%, m.p. 159.3–160.9°C; 1H NMR (400 MHz,
CD3OD) δ 8.02 (d, J = 7.0 Hz, 1H), 7.92 – 7.80 (m, 1H), 7.33 (t, J
= 8.8 Hz, 1H), 7.25 (m, 2H), 7.21 – 7.10 (m, 4H), 6.95 (s, 1H),
6.44 (s, 1H), 3.86 (s, 2H, ArCH2Ar); 13C NMR (101 MHz, CD3OD)
δ 164.79 (CONH), 159.93 (d, 1J = 253.0 Hz), 157.51, 143.22,
140.96, 139.17, 132.49 (d, 4J = 3.7 Hz), 130.10, 128.58, 128.11,
128.03, 125.69, 120.73 (d, 2J = 18.2 Hz), 116.35 (d, 2J = 21.9 Hz),
112.65, 112.06, 105.86, 41.45 (ArCH2Ar); HRMS (ESI)
calculated for C20H15NO2FCl [M+H]+: 356.0848, found:
356.0845. Purity: 99.3% (by HPLC).
Synthesis of N-(3-(2, 5-dimethylbenzyl)-5-
N-(3-benzyl-5-hydroxyphenyl)-4-nitrobenzamide (7m)
hydroxyphenyl)cyclohexanecarboxamide (9a)
The compound was synthesized via a similar procedure of 6a
.
A solution of (3-methoxy-5-nitrophenyl) methanol
3 (460 mg,
Yellow solid, yield 82%, m.p. 205.9–207.6°C; 1H NMR (400
MHz, DMSO-d6) δ 10.38 (bs, 1H, NH), 9.42 (bs, 1H, OH), 8.34
(d, J = 8.8 Hz, 2H), 8.14 (d, J = 8.8 Hz, 2H), 7.30 (m, 2H), 7.21
(m, 4H), 7.05 (s, 1H), 6.41 (s, 1H), 3.84 (s, 2H, ArCH2Ar ); 13C
NMR (101 MHz, DMSO-d6) δ 164.24 (CONH), 158.01, 149.52,
143.13, 141.52, 141.22, 140.12, 129.66, 129.21, 128.87,
126.46, 123.93, 112.31, 112.12, 105.86, 41.78 (ArCH2Ar);
HRMS (ESI) calculated for C20H16N2O4 [M+H]+: 349.1183, found:
349.1190. Purity: 98.3% (by HPLC).
2.5 mmol), p-xylene (1.5 mL, 12.5 mmol), TfOH (38 mg, 0.25
mmol) and hexafluoroisopropanol (5 mL) in a 10 mL glass
pressure tube was stirred at 100 °C for 24 h. After being cooled
to room temperature, water (50 mL) was added. The reaction
mixture was extracted with EtOAc (50 mL
× 2). The combined
organic layer was dried over anhydrous Na2SO4, filtered and
evaporated under the reduced pressure. The residue was
purified by flash column chromatography over silica
(petroleum ether/EtOAc=50:1) to give (2-(3-methoxy-5-
N-(3-benzyl-5-hydroxyphenyl)thiophene-2-carboxamide (7n)
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Journal Name
nitrobenzyl)-1,4-dimethylbenzene 8a.
1H NMR (400 MHz, 2H), 6.60 (s, 1H), 6.06 (s, 1H), 3.80 (s, 2H, ArCH2Ar), 2.32 – 2.19
CDCl3) δ 7.60 (s, 1H), 7.54 (s, 1H), 7.04 (m, 1H), 6.98 (m, 2H), (m, 4H), 2.15 (s, 6H), 1.72 (m, 3H), 1.63 (m, 1H), 1.36 (m, 2H),
6.91 (s, 1H), 3.97 (s, 2H, ArCH2Ar), 3.82 (s, 3H,CH3O), 2.29 (s, 1.28 – 1.10 (m, 3H); 13C NMR (101 MHz, DMSO-d6) δ 174.56
3H), 2.17 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 160.13, 149.34, (CONH), 158.28, 141.65, 140.83, 136.84, 135.17, 134.24,
143.76, 136.89, 135.81, 133.30, 130.76, 130.56, 127.84, 129.09, 110.13, 109.61, 104.58, 45.28 (cyclohexyl-CH), 34.74
121.80, 116.19, 105.52, 55.79 (CH3O), 39.21 (ArCH2Ar), 20.99, (ArCH2Ar), 29.61, 25.88, 25.72, 20.99, 20.25; HRMS (EI)
19.21.
calculated for C23H29NO2 [M+H]+: 352.2271, found: 352.2261.
To a solution of compound 8a (271 mg, 1 mmol) in methylene Purity: 96.4% (by HPLC).
chloride (2 mL) was added slowly a solution of BBr3 in
dichloromethane (1.0 M, 5 mL, 5 mmol) at -80°C. The resulting Biological assays
red solution was warmed to 0°C and stirred for 12 h. Saturated
Determination of minimum inhibitory concentration (MIC)
against Mtb H37Ra21
aqueous sodium bicarbonate (5 mL) was added at 0°C. The
solution was extracted with dichloromethane (5 mL 3). The
×
The assay was conducted over a range of 4-fold 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 two-fold serial dilutions in DMSO
and diluted into 7H9-Tw-OADC medium in 96-well plates with
a final DMSO concentration of 2%. The highest concentration
combined organic layer was dried over anhydrous magnesium
sulfate, filtered and concentrated in vacuo. The residue was
purified by flash chromatography over silica gel
(petroleum/EtOAc=20:1∼5:1) to give 3-(2,5-dimethylbenzyl)-5-
nitrophenol (141 mg, 55%). 1H NMR (400 MHz, CD3OD) δ 7.40
(m, 2H), 7.02 (m, 1H), 6.95 (m, 2H), 6.88 – 6.84 (m, 1H), 3.93 (s,
2H, ArCH2Ar), 2.26 (s, 3H), 2.12 (s, 3H).
of compound was 100
dilution of autoluminescent Mtb H37Ra broth culture (OD600
0.8, grown in 7H9 broth) and 4 L of the solution of the tested
ꢀg/mL. To each well, 196 ꢀL of a 1/100
A solution of 3-(2, 5-dimethylbenzyl)-5-nitrophenol (141 mg,
0.55 mmol) and 10% Pd/C (28 mg) in a mixed solvent
(CH3OH/CH2Cl2 = 1:1(V/V), 5 mL) was purged with H2 three
times. The reaction mixture was stirred with a balloon of H2 at
room temperature for 4 h. The reaction mixture was filtered
and concentrated in vacuo. The 3-amino-5-(2, 5-
dimethylbenzyl)phenol was obtained and directly used in next
step without further purification. 1H NMR (400 MHz, CDCl3) δ
7.04 (m, 1H), 7.00 – 6.91 (m, 2H), 6.04 (m, 1H), 6.01 (t, J = 2.1
Hz, 1H), 5.98 (m, 1H), 3.79 (s, 2H, ArCH2Ar), 2.29 (s, 3H, CH3),
2.19 (s, 3H, CH3).
=
ꢀ
compound were added. For potent compounds, assays were
repeated at a lower starting concentration.
Each plate was included a control for zero growth (INH, 1
ꢀg/mL), a maximum growth (DMSO only), as well as INH dose
response curve. 200 L medium was added into holes on the
ꢀ
inside edge of 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
concentration at which growth was completely inhibited and
was calculated from the inflection point of the fitted curve to
the lower asymptote (zero growth).
A solution of cyclohexanecarbonyl chloride (73.3 μL, 0.55
mmol) in THF (1 mL) was slowly added at 0 °C to solution of 3-
amino-5-(2, 5-dimethylbenzyl)phenol (113.5 mg, 0.5 mmol)
and triethylamine (76.3 μL, 0.55 mmol) in THF (2 mL). After the
reaction mixture was stirred for 3h at room temperature, the
reaction was quenched with water (10 mL) and the mixture
Determination of minimum inhibitory concentration (MIC) against
Mtb H37Rv and MDR-Mtb
was extracted with EtOAc (15 mL
× 2). The combined organic
phase was dried over anhydrous Na2SO4 and filtered. After the
solvent was removed under reduced pressure, the crude
product was purified by column chromatography
(petroleum/EtOAc=20:1-2:1) to afford 9a as a white solid. m.p.
179.5–181.7°C; 1H NMR (400 MHz, DMSO-d6) δ 9.56 (bs, 1H,
NH), 9.19 (bs, 1H, OH), 7.09 – 7.00 (m, 2H), 6.93 (m, 2H), 6.72
(s, 1H), 6.18 (s, 1H), 3.75 (s, 2H, ArCH2Ar), 2.25 (m, 4H), 2.14 (s,
3H), 1.73 (m, 4H), 1.63 (m, 1H), 1.36 (m, 2H), 1.26 – 1.12 (m,
3H); 13C NMR (101 MHz, CD3OD) δ 176.27 (CONH), 157.34,
142.53, 139.56, 138.33, 134.94, 133.17, 130.51, 129.78,
126.70, 111.38, 110.97, 104.75, 45.78 (cyclohexyl-CH), 38.99
(ArCH2Ar), 29.27, 25.49, 25.38, 19.65, 17.91; HRMS (ESI)
calculated for C22H27NO2 [M-H]-: 336.1969, found: 336.1955.
Purity: 99.4% (by HPLC).
MICs of the tested compounds were determined by a well-
established microplate alamar blue assay (MABA) against
H37Rv and clinically isolated MDR-Mtb strains (provided by
Guangzhou Chest Hospital).22 Mtb H37Rv strain and MDR-Mtb
strains in 7H9-Tw-OADC were cultivated in a 50 mL tube
containing glass beads at 37°C. The strains were transferred
into a 250 mL flask containing 50 mL 7H9-Tw-OADC while
OD600 reached 0.3-0.8. The tested compounds were prepared
as 4.2.1. Each well contained 196
dilution of Mtb H37Rv or MDR-Mtb (OD600 = 0.8, grown in 7H9
broth) and 4 L of the solution of tested compound. For
ꢀL broth culture of a 1/100
ꢀ
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 7th day, 12.5 μL of
20% Tween80 and 20 μL of Alamar Blue (Bio-Red) were added
to the test plate. A change in color from blue (oxidized state)
to pink (reduced) indicated the growth of bacteria after
incubation at 37°C for 16-24 h. The MIC was defined as the
N-(3-hydroxy-5-(2, 4, 6-
trimethylbenzyl)phenyl)cyclohexanecarboxamide (9b)
This compound was synthesized via a similar procedure of 9a
.
Yellow solid, yield 44%, m.p. 248.5–249.7°C; 1H NMR (400
MHz, DMSO-d6) δ 9.49 (bs, 1H, NH), 6.96 (bs, 1H, OH), 6.84 (s,
10 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C8MD00212F
Journal Name ARTICLE
lowest concentration of drug that prevented this change in 5 S. K. Field, Clin. Med. Insights: Ther. 2013,
5, 137−149.
color.
6 For the reviews of antitubercular agents, see: (a) Beena, D. S.
Rawat, Med. Res. Rev. 2013, 33, 693-764; (b) Gf. D. S.
Fernandes, D. H. Jornada, P. C. De Souza, C. M. Chin, F. R.
Pavan, J. L. Dos Santos, Curr. Med. Chem. 2015, 22, 3133-
3161; (c) R. Mehra, I. A. Khan, A. Nargotra, Eur. J. Pharm. Sci.
2017, 104, 1-15; (d) L. R. Chiarelli, G. Mori, M. Esposito, B. S.
Orena, M. R. Pasca, Curr. Med. Chem. 2016, 23, 3813-3846.
7 K. Rožman, I. Sosič, R. Fernandez, R. J. Young, A Mendoza, S.
Gobec, L. Encinas, Drug. Discov. Today 2017, 22, 492-502.
8 J. Bernstei, W. A. Lott, B. A. Steinberg, H. L. Yale, Am. Rev.
Tuberc. 1952, 65, 357–364.
Determination of the antibacterial activity
Minimum inhibitory concentration (MIC) of compounds 6g and
7a were defined as the lowest concentration (the highest
dilution) of each compound that completely inhibit the growth
of bacteria after incubation at 37 °C for 18−24 h, by means of
standard two folds serial dilution method in 96–well microtest
plates. Amoxicillin and Ofloxacin were used as the positive
control. The bacterial and fungal suspension was adjusted with
sterile saline to a concentration of 1 ×
105 CFU. Initially the
compounds were dissolved in DMSO to prepare the stock
solutions (10 mg/mL), and then the tested compounds and
reference drugs were prepared in BHI broth to obtain the
required concentrations 50 ug/mL - 1.5125 ug/mL. These
dilutions were inoculated and incubated at 37 °C for 24 h.
Cytotoxicity studies
9 A. Dessen, A. Quémard, J. S. Blanchard, W. R. Jacobs, J. C.
Sacchettini, Science 1995, 267, 1638–1641.
10 S. V. Ramaswamy, R. Reich, S. J. Dou, L. Jasperse, X. Pan, A.
Wanger, T. Quitugua, E. A. Graviss, Antimicrob. Agents
Chemother. 2003, 47, 1241–1250.
11 For the reviews of InhA inhibitors, see: (a) X. Y. Lu, Q. D. You,
Y. D. Chen, Mini Rev. Med. Chem. 2010, 10, 182-193; (b) M.
AlMatar, E. A. Makky, I. Var, B. Kayar, F. Köksal, Pharmacol.
Rep. 2018, 70, 217-226.
The cytotoxicities of compound 6g and 7a were assayed
against RAW 264.7 and HepG2 cell lines at concentrations
from 100 to 6.25 μg/mL. The cells were seeded in the 96-well
plate and then allowed to recover for 24 h. Different
concentrations of the tested compound were added to the
plate and each experiment was repeated three times. After
being incubated for 72 h, cells were harvested and cell viability
was assessed by MTT assay. The cytotoxicity was showed as
IC50 values, which were calculated by GraphPad Prism
Software version 5.23
12 For the recent studies of InhA inhibitors as the
antitubercular agents, see: (a) L. A. Spagnuolo, S. Eltschkner,
W. X. Yu, F. Daryaee, S. Davoodi, S. E. Knudson, E. K. H.
Allen, J. Merino, A. Pschibul, B. Moree, N.Thivalapill, J. J.
Truglio, J. Salafsky, R. A. Slayden, C. Kisker, P. J. Tonge, J.
Am. Chem. Soc. 2017, 139, 3417-3429; (b) T. Štular, S. Lešnik,
K. Rožman, J. Schink, M. Zdouc, A. Ghysels, F. Liu, C. C.
Aldrich, V. J. Haupt, S. Salentin, S. Daminelli, M. Schroeder,
T. Langer, S. Gobec, D. Janežič , J. Konc, J. Med. Chem. 2016,
59, 11069-11078; (c) A. Chollet, J. L. Stigliani, M. R. Pasca, G.
Mori, C. Lherbet, P. Constant, A. Quémard, J. Bernadou, G.
Pratviel, V. Bernardes-Génisson, Chem. Bio. Drug Design
2016, 88, 740-755; (d ) A. Chollet, G. Mori, C. Menendez, F.
Rodriguez, I. Fabing, M. R. Pasca, J. Madacki, J. Korduláková,
P. Constant, A. Quémard, V. Bernardes-Génisson, C. Lherbet,
M. Baltas, Eur. J. Med. Chem. 2015, 101, 218-235.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank National Science and Technology Major Project of
the Ministry of Science and Technology of China
(2018ZX09735010, 2017ZX10302301-003-002), the Chinese
Academy of Sciences Grants (154144KYSB20150045, KFZD-SW-
207, YJKYYQ20170036), the National Mega-project of China for
Innovative Drugs (2018ZX09721001-003-003), Science and
Technology Innovation Leader of Guangdong Provenience
(2016TX03R095), Guangzhou Science Technology and
Innovation Commission (201707010210, 201604020019) for
the financial support of this study.
13 (a) U. H. Manjunatha, S. P. S. Rao, R. R. Kondreddi, C. G.
Noble, L. R. Camacho, B. H. Tan, S. H. Ng, P. S. Ng, N. L. Ma,
S. B. Lakshminarayana, M. Herve, S. W. Barnes, W. Yu, K.
Kuhen, F. Blasco, D. Beer, J. R. Walker, P. J. Tonge, R. Glynne,
P. W. Smith, T. T. Diagana, Sci. Transl. Med. 2015, 7, 269ra3;
(b) P. S. Ng, U. H. Manjunatha, S. P.S. Rao, L. R. Camacho, N.
L. Ma, M. Herve, C. G. Noble, A. Goh, S. Peukert, T. T.
Diagana, P. W. Smith, R. R. Kondreddi. Eur. J. Med. Chem.
2015, 106, 144-156.
14 V. D. Vuković, E. Richmond, E. Wolf, J. Moran, Angew.
Chem. Int. Ed. 2017, 56, 3085–3089.
15 T. Y. Zhang, S. Y. Li, E. L. Nuermberger, PLoS One 2012, 7,
Notes and references
e29774.
1 World Health Organization. Global tuberculosis report 2017.
16 For the synthesis of compounds 12a
-12c, See SI for the
2 J. C. Palomino, A. Martin, Future Microbiol. 2013,
1080.
8, 1071-
details.
17 For the synthesis of compounds 14
, 15, See SI for the
3 N. J. Ryan, J. H. Lo, Drugs 2014, 74, 1041-1045.
details.
4 D. T. Hoagland, J. Liu, R. B. Lee, R. E. Lee, Adv. Drug Deliv.
18 P. O. Brendan, T. E. Justin, D. H. Andrew, J. Am. Chem. Soc.
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This journal is © The Royal Society of Chemistry 20xx
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Journal Name
19 S. Ueda, N. H. Nagasawa, J. Org. Chem. 2009, 74, 4272–
4277.
20. The inhibitive activity of compound 6g against Mtb-InhA
was examined. Unexpectedly, 6g did not exert inhibitive
activity against InhA. The result indicated that Mtb-InhA is
not the target of m-amidophenol derivatives. The action
mechanism remains to be investigated. See SI for the
experiment details.
21 F. Yang, M. M. Njire, J. Liu, T. Wu; B. X. Wang, T. Z. Liu, Y. Y.
Cao, Z. Y. Liu, J. T. Wan, Z. C. Tu, Y. J. Tan, S. Y. Tan, T. Y.
Zhang, PLoS One 2015, 10, e0119341.
22 J. Tang, B. X. Wang, T. Wu, J. T. Wan, Z. C. Tu, M. Njire, B. J.
Wan, S. G. Franzblauc, T. Y. Zhang, X. Y. Lu, K. Ding, ACS Med
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12 | J. Name., 2012, 00, 1-3
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Contents entry
m-Amidophenol derivatives were found to potently inhibit the growth of M. tuberculosis H37Ra, H37Rv and clinically isolated
multidrug-resistant M. tuberculosis strains.
Compound
MIC（μg/mL）
Cytotoxicity (IC50, μM)
H37Ra
0.625
5
H37Rv
0.39
P103
P91
0.39
0.39
HepG2
>161
>330
RAW264.7
6g
7a
0.39
0.39
>323
>330
0.39