Pyrazole–coumarin and pyrazole–quinoline chalcones as potential antitubercular agents

Article abstract of DOI:10.1002/ardp.202000077

Pyrazole, coumarin, and quinoline are medicinally important moieties. In this study, two series of novel pyrazole–coumarin chalcones and pyrazole–quinoline chalcones were synthesized using multiple-step reactions. All the synthesized compounds were well c

Full text of DOI:10.1002/ardp.202000077

Received: 12 March 2020
Revised: 18 April 2020
Accepted: 6 May 2020
|
|
DOI: 10.1002/ardp.202000077
F U L L P A P E R
Pyrazole–coumarin and pyrazole–quinoline chalcones as
potential antitubercular agents
1
2
2
1
Gautam Kumar
| Vagolu Siva Krishna | Dharmarajan Sriram | Sanjay M. Jachak
1
Department of Natural Products, National
Institute of Pharmaceutical Education and
Research (NIPER), Mohali, Punjab, India
Abstract
Pyrazole, coumarin, and quinoline are medicinally important moieties. In this study,
two series of novel pyrazole–coumarin chalcones and pyrazole–quinoline chalcones
were synthesized using multiple‐step reactions. All the synthesized compounds were
2
Medicinal Chemistry and Antimycobacterial
Research Laboratory, Pharmacy Group, Birla
Institute of Technology & Science–Pilani,
Hyderabad, Andhra Pradesh, India
1
13
well characterized using different spectroscopic techniques including H and
C
Correspondence
nuclear magnetic resonance, high‐resolution mass spectroscopy, and electrospray
ionization–mass spectrometry. The compounds were evaluated for their anti-
tubercular activity against the Mycobacterium tuberculosis H37Rv strain using the
microplate Alamar Blue assay, and the minimal inhibitory concentrations (MIC) of
the compounds were determined. Among the 32 tested compounds, compounds 3e,
Sanjay M. Jachak, Department of Natural
Products, National Institute of Pharmaceutical
Education and Research (NIPER), S.A.S Nagar,
Sec‐67, Mohali, Punjab 160062, India.
Email: sanjayjachak@niper.ac.in and
sjachak11@gmail.com
3
u, and 7h showed an MIC value of 3.125 µg/ml, and they were found to be non-
toxic. Molecular docking studies of the compounds with the enzyme DprE1 revealed
the probable mechanism of action. The chalcone derivatives exhibited binding affi-
nity values between −7.047 and −9.353 kcal/mol. ADME parameters were predicted
using the QikProp module of the Schrödinger software, and these compounds ex-
hibited good pharmacological and oral absorption properties.
K E Y W O R D S
antimycobacterial activity, cytotoxic activity, pyrazole, synthesis
1
| INTRODUCTION
(+)‐Calanolide A is active against a variety of M. tuberculosis strains,
[
8]
including those resistant to the standard antitubercular drugs.
Tuberculosis (TB) is caused by Mycobacterium tuberculosis, and it is
Ferulenol showed an antimycobacterial effect against different spe-
the ninth leading cause of death worldwide from a single infectious
cies of Mycobacterium fortuitum, Mycobacterium phlei, Mycobacterium
[9]
[
1,2]
agent, ranking above HIV/AIDS.
The most common regimen for
aurum, and Mycobacterium smegmatis. Quinoline‐based compound,
the treatment of drug‐sensitive TB consists of an initial 2‐month
phase of treatment with isoniazid, rifampicin, pyrazinamide, and
ethambutol followed by a treatment lasting 4 months with isoniazid
bedaquiline is effective against resistant and nonresistant strains of
[
10]
mycobacteria.
Mefloquine is a well‐known antimalarial drug,
[
11–13]
which also showed antibacterial and antitubercular activities
(Figure 1).
[
3]
and rifampicin. The emergence of resistance in M. tuberculosis has
given rise to new virulent forms of mycobacteria such as multidrug‐
Chalcones (1,3‐diaryl‐2‐propen‐1‐one) belong to flavonoids class.
In open‐chain flavonoids, two aromatic rings are linked by three
carbons having α,β‐unsaturated or saturated carbonyl systems. The
most widely used method for the synthesis of chalcones is the
[
1,4]
resistant (MDR‐TB) and extremely drug‐resistant (XDR‐TB).
Heterocyclic compounds possess diverse biological activities.
Pyrazole‐based bioactive compounds are pyrazofurin, possessing an
antitumor activity as well as an antiviral activity, and 3‐n‐
[
14]
Claisen–Schmidt condensation.
A vast number of naturally oc-
[5]
nonylpyrazole, possessing an antimicrobial activity.
Coumarin‐
curring chalcones, namely licochalcone A and licochalcone C have
based naturally occurring compounds, (+)‐calanolide A and ferulenol,
exhibited an antibacterial activity against Bacillus subtilis, Staphylo-
[15]
[
6,7]
have been reported to possess an antitubercular activity.
coccus aureus, and Micrococcus luteus.
A number of synthetic and
Arch Pharm. 2020;e2000077.
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https://doi.org/10.1002/ardp.202000077

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KUMAR ET AL.
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FIGURE 1 Biologically active compounds
that possess a pyrazole/quinoline/coumarin
scaffold
natural chalcones possessing an antitubercular activity are widely
NMR showed a signal at δ 184.6 ppm, assigned to carbonyl –CHO.
The electrospray ionization–mass spectrometry (ESI–MS) of 1c
[
16–24]
reported in the literature.
The cell wall of the mycobacterial
+
cell is the primary interface to protect the cell from the surrounding
atmosphere. Drugs such as isoniazid and ethambutol act by inter-
showed an [M+H] peak of 277.27, corresponding to the molecular
+
formula C18
H
17
N
2
O . Thus, based on the above spectral data, the
[
25]
1
rupting the biosynthesis of vital components of the cell wall.
structure of 1c was confirmed. H NMR of compound 3b showed a
singlet at δ 8.50, 8.46, and 2.45 ppm due to coumarin –CH, pyrazole
Decaprenylphosphoryl‐D‐ribose oxidase (DprE1) catalyzes the oxi-
dation of decaprenylphosphoryl‐D‐ribose to decaprenylphosphoryl‐
–CH, and –CH
3
protons, respectively. The doublet signals at δ
[
26]
2
‐keto‐ribose (DPX).
The intermediate formed from DPX is
7.98 ppm with J = 15.64 Hz were observed due to the trans alkene
reduced by decaprenylphosphoryl‐2‐keto‐ribose reductase to
decaprenylphosphoryl‐D‐arabinose (DPA). The inhibition of enzyme
DprE1 will arrest the synthesis of DPA. DPA acts as a substrate for
arabinosyltransferase and plays an important role in the synthesis of
protons. Twelve aromatic protons and one trans alkene proton were
1
3
present between δ 7.82 and 7.30 ppm. Further C NMR showed
signals at δ 185.4 and 158.8 ppm, assigned to carbonyl carbon of
chalcone and coumarin, respectively, and signal at δ 21.4 ppm due to
[
27]
+
polysaccharides, that is, arabinogalactan and lipoarabinomannan.
−CH
3
. The ESI–MS of 3b showed the [M+Na] peak of 533.04, cor-
+
Previous studies have confirmed the chalcones probable mode of
responding to the molecular formula C28
H19BrN
2
NaO
3
. Thus, based
[
22]
1
action by inhibition of DprE1 enzyme.
Molecular hybridization is
on the above spectral data, the structure of 3b was confirmed.
H
the rational design of hybrid molecules, with pharmacophoric subu-
nities of two or more bioactive derivatives. The joining of two dif-
ferent molecules with the help of linkers can lead to the formation of
a new hybrid scaffold. The designed hybrid compounds would exhibit
an improved efficacy, potency, and selectivity, and lesser toxicity
NMR of compound 4 showed a singlet at δ 10.60, 8.95, and 7.22 ppm
due to –NH (protonated), –NH, and –NH of sulfonamide moiety,
respectively, and four aromatic protons were present between δ 7.70
2
2
1
3
and 7.06 ppm. Further C NMR showed a signal at δ 148.9, 136.5,
127.4, and 113.8 ppm, assigned to aromatic carbons. The ESI–MS of 4
[28–31]
+
than the parent molecules.
Keeping this in view, the designed
showed an [M] peak of 187.12, corresponding to the molecular
hybrid compounds would exhibit antitubercular activities. Herein, we
report pyrazole–coumarins and pyrazole–quinolines chalcone deri-
vatives as antitubercular agents.
formula C
6
H
9
N
3
O
2
S. Thus, based on the above spectral data, the
1
structure of 4 was confirmed. H NMR of compound 5 showed a
singlet at δ 9.99, 9.46, and 8.27 ppm due to –CHO, pyrazole –CH
proton, and imine –CH protons, respectively, and a singlet at δ 3.17
and 2.93 ppm due to two –N‐methyl groups. Eight aromatic protons
13
2
| RESULTS AND DISCUSSION
were present between δ 8.15 and 7.58 ppm. Further C NMR
showed a signal at δ 185.0 ppm, assigned to carbonyl –CHO, and
signals at δ 41.5 and 35.6 ppm were due to two –N‐methyl groups.
1
The synthesized compounds were characterized using H nuclear
1
3
+
magnetic resonance (NMR), C NMR, and mass spectrometry tech-
The ESI–MS of 5 showed an [M+Na] peak of 439.12, corresponding
1
+
niques. H NMR of compound 1c showed a singlet at δ 9.98 and
4
to the molecular formula C19H17ClN NaO
3
S . Thus, based on the
1
9
.31 ppm due to –CHO and pyrazole –CH protons, respectively, a
quartet at δ 2.68 ppm with J = 7.56 Hz, and a triplet at δ 1.23 ppm
with J = 7.6 Hz due to –CH and –CH , respectively. Nine aromatic
protons were present between δ 7.99 and 7.35 ppm. Further
above spectral data, the structure of 5 was confirmed. H NMR of
compound 6a showed a singlet at δ 2.72 and 2.02 ppm due to –CH
(acetyl) and –CH protons, respectively. Nine aromatic protons were
present between δ 8.09 and 7.36 ppm. Further C NMR showed a
3
2
3
3
1
3
13
C

KUMAR ET AL.
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|
signal at δ 205.8 ppm, assigned to the carbonyl carbon, and signals at
piperidine to give acrylic pyrazole–coumarin derivatives (3a–v). The
synthesis of 4‐hydrazinylbenzenesulfonamide hydrochloride was
done from sulfonamide.
δ 31.9 and 23.9 ppm were due to –CH
3
3
(acetyl) and –CH , respec-
+
tively. The ESI–MS of 6a showed an [M+H] peak of 261.12, corre-
+
sponding to the molecular formula C18
H
16NO . Thus, based on the
The sulfonamide was dissolved in HCl, followed by diazotization
in the presence of sodium nitrite at 0–5°C to give a diazonium salt of
sulfonamide. The diazonium salt of sulfonamide was converted into
hydrazine. In situ reduction of the diazonium salt in the presence
of stannous chloride (dissolved in HCl at 0–5°C) afforded
4‐hydrazinylbenzenesulfonamide hydrochloride (4), which was stored
in the refrigerator till further use. 4‐Hydrazinylbenzenesulfonamide
hydrochloride reacted with p‐chloroacetophenone, converting into
hydrazone. The obtained hydrazones were cyclized and formylated
with the help of Vilsmeier–Haack reaction to give N′‐((4‐(3‐
(4‐chlorophenyl)‐4‐formyl‐1H‐pyrazol‐1‐yl)phenyl)sulfonyl)‐N,N‐dim-
ethylformimidamide (5). The Friedländer annulation reaction was
used to synthesize substituted 3‐acetyl quinoline derivatives. Sub-
stituted 2‐aminobenzophenone and acetylacetone were refluxed in
the presence of 10 mol% of sodium trifluoromethanesulfonate to give
1
above spectral data, the structure of 6a was confirmed. H NMR of
compound 7a showed a singlet at δ 8.05 ppm due to pyrazole –CH
3
and a singlet at 2.74 and 2.36 ppm due to –CH protons. The doublet
signal at δ 6.45 ppm with J = 16.16 Hz was due to the trans alkene
protons. Also, 19 aromatic protons and 1 trans alkene proton were
1
3
observed between δ 8.13 and 6.45 ppm. Further C NMR showed
signals at δ 197.2 ppm, assigned to the carbonyl carbon, and signal at
+
δ 21.3 ppm due to –CH
3
. The ESI–MS of 7a showed an [M+H] peak
+
of 506.27, corresponding to the molecular formula C35
H
28
N
3
O .
Thus, based on the above spectral data, the structure of 7a was
1
confirmed. From H NMR data and values of coupling constants, it
was found that chalcones were present in a trans form (the spectra
showed protons only for a trans isomer), but a slight shoulder ob-
served in ultra‐performance liquid chromatography (UPLC) chroma-
togram in some of the compounds indicated that a cis isomer could
have been formed in minor quantities in addition to the trans isomer.
[
32]
substituted 3‐acetyl quinoline derivatives (6a–c).
The substituted
pyrazole carbaldehyde reacted with substituted 3‐acetyl quinoline to
give acrylic pyrazole–quinoline derivatives (7a–j).
2
.1 | Chemistry
2
.2 | Biology
The synthesis of respective compounds was achieved, as outlined in
Schemes 1 and 2. The substituted acetophenones were reacted with
aromatic hydrazines in methanol and glacial acetic acid to give a
substituted hydrazone. The obtained hydrazones were cyclized and
formylated with the help of the Vilsmeier–Haack reaction. The syn-
thesized hydrazones were dissolved in dimethylformamide (DMF)
and added to Vilsmeier–Haack reagent generated in situ (using
2.2.1 | Antitubercular activity
All the synthesized acrylic pyrazole–coumarin derivatives (3a–v) and
acrylic pyrazole–quinoline derivatives (7a–j) were evaluated for their
antitubercular activity against M. tuberculosis H37Rv strain using the
MABA (microplate Alamar Blue assay) method. The minimal inhibitory
concentration (MIC) values of the test compounds and positive con-
trols (isoniazid, rifampicin, and ethambutol) are shown in Table 1. The
compounds were dissolved in dimethyl sulfoxide (DMSO) to achieve a
concentration of 25–0.78 μg/ml, and the analysis of the activity of
the compounds was performed in triplicate. Among 32 tested com-
pounds, three compounds (3e, 3u, and 7h) showed an MIC value of
3.125 µg/ml, three compounds, 3b, 3o, and 3q, showed an MIC value
of 6.25 μg/ml, and two compounds, 3c and 3r, showed an MIC value
3
POCl and DMF) and stirred at 75°C to give substituted pyrazole
carbaldehydes (1a–e). The Knoevenagel condensation reaction was
used to synthesize 3‐acetyl coumarin derivatives. The substituted
salicylaldehyde reacted with the ethyl acetoacetate in the presence
of piperidine to give substituted 3‐acetyl coumarin derivatives
(2a–h). The Claisen–Schmidt condensation reaction was used to
synthesize chalcones. The substituted pyrazole carbaldehydes re-
acted with substituted 3‐acetyl coumarin in the presence of
1
a–1e
3
a–3v
2
a–2h
SCHEME 1 The synthesis of acrylic pyrazole–coumarins

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4
5
1
a–1e
6
a–6c
1
a–1e
6
a–6c
7
a–7j
5
SCHEME 2 The synthesis of acrylic pyrazole–quinolines
of 12.5 μg/ml against M. tuberculosis H37Rv strain. The remaining
compounds were found to be inactive against M. tuberculosis H37Rv
strain.
compounds 3i and 3h led to a loss of accommodation of compounds
in the cavity; thus, no antitubercular activity was observed. The
modification was carried out in compounds 3o, 3q, 3r, and 3u; hy-
droxyl was replaced with ethyl to give compounds such as 3h, 3f, 3i,
and 3l. It can be inferred that the activities exhibited by compounds
3o, 3q, 3r, and 3u were mainly due to a hydrogen bond interaction
with protein; the replacement of hydroxyl by ethyl leads to a loss in
activity of compounds 3h, 3f, 3i, and 3l. It was further confirmed by
replacing hydroxyl in compound 3u by bromine, which led to the
formation of 3n; a complete loss in antitubercular activity was ob-
served. In pyrazole–coumarin series, it can be summarized as follows:
Substituents like methyl and hydroxy group at para position of the
phenyl ring and substituents like –Cl and –Br at the sixth position of
coumarin ring were the most acceptable substituents for anti-
tubercular activity, which can be seen in the compounds such as 3b,
3c, 3o, 3q, and 3r. To find potent antitubercular compounds, cou-
marin was replaced by quinoline to give acrylic pyrazole–quinolines.
In this series, substitution was carried out in both the phenyl and
quinoline ring. Keeping this in view, the importance of para
2
.2.2 | Structure–activity relationship (SAR)
In this study, two series of compounds were synthesized and
tested for their antitubercular activity. In series of acrylic
a
pyrazole–coumarin, substitutions were carried out in coumarin and
phenyl linked to the third position of pyrazole, and no changes were
made in the phenyl linked to the first position of pyrazole. The
substitution at the para position of phenyl was responsible for the
antitubercular activity. The substitution like methyl and hydroxyl at
the para position was well tolerated in compounds (3b, 3c, 3e, 3o, 3q,
3
r, and 3u), whereas para substitution with ethyl and bromine led to a
drastic decrease in antitubercular activity in compounds (3f, 3g, 3h,
i, 3k, 3l, 3m, and 3n). In compounds 3b and 3c, methyl was replaced
by ethyl to form compounds 3i and 3h. The increase of one carbon in
3

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|
TABLE 1 Biological activities of the
compounds in Scheme 1
MIC
Cytotoxicity at 25 μg/ XP G score
b
a
Compounds
R
1
R
2
R
3
(μg/ml)
ml (% inhibition)
(kcal/mol)
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
H
–H
–H
>25
6.25
12.5
>25
3.125
>25
>25
>25
>25
>25
>25
>25
>25
>25
6.25
>25
6.25
12.5
>25
>25
3.125
>25
ND
ND
–CH
–CH
–CH
–CH
–CH
–CH
–CH
–CH
–CH
–CH
–CH
–Br
3
3
3
3
2
2
2
2
2
2
2
–H
–Br
–Cl
–H
24.65
ND
−8.620
−8.588
ND
–H
–CH
3
ND
–OCH
3
–H
26.32
ND
−8.448
ND
–CH
–CH
–CH
–CH
–CH
–CH
–CH
3
3
3
3
3
3
3
–CH
–H
–H
–H
–H
–H
–H
–H
–H
–H
–H
–CH
–H
–H
–H
–H
3
–H
g
h
i
–OH
–Cl
–Br
–NO
ND
ND
ND
ND
ND
ND
j
2
ND
ND
k
l
–OCH
3
3
ND
ND
–H
ND
ND
m
n
o
p
q
r
–OCH
–H
ND
ND
–Br
ND
ND
–OH
–OH
–OH
–OH
–OH
–OH
–OH
–OH
–Cl
21.80
ND
−8.899
ND
–OH
–H
3
19.86
ND
−8.992
−9.069
ND
–Br
s
–NO
2
ND
t
–OCH
3
ND
ND
u
v
–H
20.02
ND
−8.771
ND
–OCH
3
–H
Abbreviations: MABA, microplate Alamar Blue assay; MIC, minimal inhibitory concentration; ND, not
determined.
a
The MIC values of the compounds were determined using the MABA assay.
b
RAW 264.7 (murine macrophage) cell line.
substitution with methyl and hydroxyl group is responsible for the
antitubercular activity. In acrylic pyrazole–coumarin series, the
change of coumarin to quinoline led to a loss in the antitubercular
activity of compounds such as 7a, 7b, 7c, 7e, 7f, and 7g. The mod-
ification with the sulfonamide group in phenyl linked to the third
position of pyrazole in compounds 7i and 7j does not lead to any
significant change in activity.
were found to be nontoxic in a cell viability assay at 25 µg/ml
concentration.
2.3 | In silico studies
2.3.1 | Docking studies
In an effort to rationalize the observed result and to find out the
probable binding mode of the compounds, molecular docking studies
of the active compounds were performed against M. tuberculosis DprE1
with Protein Data Bank (PDB) ID: 4P8N. The target enzyme is con-
firmed from X‐ray with a resolution of 1.62 Å, and it has been used for
2
.2.3 | Cell cytotoxicity studies
The compounds showing antitubercular activity up to 6.25 µg/ml
were examined for the cell toxicity by the MTT (3‐(4,5‐
dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay
against RAW 264.7 (murine macrophages) cells, and their % in-
hibition is shown in Table 1. After 48 hr of exposure, the viability
of these cells was assessed on the basis of the conversion of MTT
into the formazan product. The results showed that compounds
[22]
docking studies in the reported literature.
The docking results are
depicted in Tables 1 and 2. In silico studies reveal that active mole-
cules showed a good binding energy to the target enzyme, ranging
from −7.047 to −9.353 kcal/mol. The active molecules, 3b, 3c, 3e, 3o,
3q, 3r, 3u, 7g, 7h, and 7i, showed a good binding energy to the target

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TABLE 2 Biological activities of the compounds in Scheme 2
MIC
Cytotoxicity at 25 μg/
ml (% inhibition)
XP G score
(kcal/mol)
a
b
Compounds
R
1
R
2
R
3
R
4
(μg/ml)
7
7
7
7
7
7
7
7
7
7
a
b
c
d
e
f
–CH
–CH
–CH
–CH
3
3
3
2
–H
–H
–H
–H
–H
–H
–H
–H
–SO
–SO
–H
–H
–H
–F
>25
>25
>25
>25
>25
>25
25
ND
ND
ND
ND
ND
ND
ND
30.25
ND
ND
ND
ND
ND
ND
–Cl
–Cl
–Cl
–H
ND
ND
CH
3
–H
–H
–H
–F
ND
–OH
–OH
–OH
–Br
ND
–Cl
–Cl
–Cl
–Cl
–Cl
ND
g
h
i
−7.047
−7.626
−9.353
ND
–F
3.125
25
–Cl
2
NH
NH
2
2
–H
–F
j
–Cl
2
>25
0.1
Isoniazid
ND
Rifampicin
Ethambutol
0.2
ND
1.56
ND
Abbreviations: MABA, microplate Alamar Blue assay; MIC, minimal inhibitory concentration; ND, not determined.
a
The MIC value of compounds was determined using the MABA assay.
b
RAW 264.7 (murine macrophage) cell line.
enzyme DprE1, ranging from −8.620, −8.588, −8.448, −8.899, −8.992,
9.069, −8.771, −7.047, −7.626, and −9.353 kcal/mol, respectively. The
module of Schrödinger software. Lipinski's rule is most commonly used
to determine the drug‐likeness. According to the rule of five by Lipinski
and colleagues at Pfizer, physicochemical parameters should be within
the following range: MW ≤ 500, log P ≤ 5, H‐bond donors ≤5, and
H‐bond acceptor ≤10. Furthermore, a compound is more likely to ex-
hibit a poor absorption or poor permeation when two or more of the
−
docking results were drawn on the basis of the docking score, hy-
drogen bonding, π–π interaction, and the van der Waals interactions of
the ligand with the enzyme (Figure 2). Based on the docking results, it
appears that the mechanism of antitubercular activity of the studied
compounds could be due to the DprE1 enzyme inhibition.
[33,34]
criteria are not satisfied.
When all the 32 compounds were stu-
died for Lipinski's rule of five, it was observed that 7 compounds did
not violate any parameters, whereas 11 compounds violated one
parameter and 14 compounds violated two parameters. QPPCaco
predicts Caco‐2 cells permeability model for the gut–blood barrier for
2
.3.2 | Prediction of ADME (absorption, distribution,
metabolism, and excretion) properties of pyrazole
containing coumarin and quinoline derivatives
[35]
nonactive transport of human absorption process.
All the com-
pounds showed a better‐predicted gut permeability. The compounds
having logBB > 0.3 cross the blood–brain barrier (BBB), whereas those
with logBB < −1.0 are only poorly distributed into the brain. For the
compounds to be central nervous system (CNS)‐active, its value must
The ADME properties of compounds are one of the most important
requisites for a drug to be a successful candidate. Drug‐likeness and
ADME properties of the synthesized acrylic pyrazole–coumarin/acrylic
pyrazole–quinoline derivatives were predicted using the QikProp
[35,36]
be ≥2.
Out of the 32 tested compounds, only 7h was able to cross
FIGURE 2 (a) Compound 3e docking confirmation at the same active site. (b) Compound 7h docking confirmation at the same active site

KUMAR ET AL.
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the BBB and none of the compounds exhibited CNS activity. Further-
more, these compounds also exhibited good predicted pharmacological
techniques. Melting points were measured in open capillaries using
Veego LX‐300 melting point apparatus and are uncorrected. The syn-
+
+
1
13
properties like HERG K (HERG K channel), QPlogKhsa (human serum
albumin), QPPMDCK (MDCK cell permeability), and skin permeability
thesized compounds were characterized using H and C NMR and
mass spectrometry. The purity of the final compounds was determined
using Waters ACQUITY UPLC H‐Class System, equipped with a binary
pump, autosampler, photodiode array detector, and Empower™ 3 soft-
ware. All the final compounds were found to have more than 95%
(Table S1).
1
13
3
| CONCLUSION
purity. H and C NMR spectra were recorded using Bruker Avance
DPX 400 spectrometer, Bruker (Germany) at 400 and 100 MHz, re-
spectively, using tetramethylsilane (TMS) as an internal standard. The
chemical shift values (δ) are expressed in ppm relative to internal
standard TMS and the coupling constant (J) is expressed in Hz. Spin
multiplicities are given as s (singlet), d (doublet), dd (doublet of doub-
lets), and m (multiplet). The mass spectra were recorded on Bruker
Maxis High‐Resolution LCMS/MS, and Thermo LTQ‐XL LCMS/MS.
The InChI codes of the investigated compounds, together with
some biological activity data, are provided as Supporting Informa-
tion Data.
The molecular hybridization approach was used to design the hybrid
scaffold containing pyrazole–coumarin and pyrazole–quinoline. The syn-
thetic strategy described in this paper includes the Vilsmeier–Haack
reaction (to synthesize pyrazole carbaldehyde derivatives), the Knoeve-
nagel condensation reaction (to synthesize 3‐acetyl coumarin derivatives),
the Friedländer annulation reaction (to synthesize 3‐acetyl quinoline
derivatives), and the Claisen–Schmidt condensation reaction (to synthe-
size chalcones). The synthetic methods can be used to synthesize other
biologically active compounds having acrylic pyrazole–coumarin and ac-
rylic pyrazole–quinoline derivatives. The synthesized compounds were
purified by recrystallization. A total of 32 compounds were synthesized in
this series and evaluated for their anti‐TB activity against M. tuberculosis
H37Rv. Among the 32 tested compounds, three compounds (3e, 3u, and
4.1.2 | General procedure for the synthesis of
substituted 1,3‐diphenyl‐1H‐pyrazole‐4‐
carbaldehydes (1a–e)
7h) showed an MIC value of 3.125 µg/ml. The SAR of acrylic
pyrazole–coumarin series revealed that substituents like methyl and
hydroxy group at para position of phenyl ring and substituents like –Cl
and –Br at the sixth position of the coumarin ring were the most ac-
ceptable substituents for antitubercular activity, which can be seen in
compounds 3b, 3c, 3o, 3q, and 3r. The change of coumarin to quinoline
led to a loss in activity of compounds. Molecular docking studies of these
compounds with enzyme DprE1 revealed the antitubercular activity of
the active compounds due to the inhibition of the DprE1 enzyme. The
potent compounds having activity ≤6.25 µg/ml were evaluated for their
toxicity against RAW 264.7 (murine macrophage) cells. The results
showed that the compounds were nontoxic at 25‐µg/ml concentration.
The ADME properties of the compounds were determined by QikProp
software, and their values were found to be within an appreciable range.
Hence, it is concluded that pharmacophoric features of the most active
compounds can be considered as lead fragments to design and develop
novel antitubercular agents.
Equimolar substituted acetophenone and phenylhydrazine were
dissolved in methanol followed by the addition of a catalytic amount
of glacial acetic acid. The reaction mixture was refluxed at 80°C for
1 hr. After the completion of reaction, the solvent was evaporated
under vacuum to give crude hydrazone. Simultaneously,
3
Vilsmeier–Haack reagent was prepared. POCl (0.075 mol) was ad-
ded dropwise to DMF (0.075 mol) maintained at 0–5°C and it was
stirred for 20 min. To this mixture, hydrazone (0.025 mol) dissolved
in sufficient DMF was added to the reaction mixture maintained at
temperature 0–5°C, and it was stirred for 30 min. The reaction
mixture was allowed to reach room temperature. The reaction mix-
ture was refluxed at 75°C for 8–12 hr. After completion of the re-
action, the reaction mixture was quenched with a cold saturated
solution of sodium bicarbonate solution. The obtained precipitate
was filtered and washed with water to remove excess sodium bi-
carbonate, and the crude product was recrystallized using ethanol to
give the desired product in the yield of 63–86%.
4
4
4
| EXPERIMENTAL
.1 | Chemistry
1
,3‐Diphenyl‐1H‐pyrazole‐4‐carbaldehyde (1a)
1
Yield 79%; white solid; mp: 144–146°C; H NMR (400 MHz, DMSO‐d
6
) δ
ppm: 9.99 (s, 1H), 9.34 (s, 1H), 8.00 (d, J = 8.12 Hz, 2H), 7.93 (d, J = 6.8 Hz,
.1.1 | General
2H), 7.58 (t, J = 7.76 Hz, 2H), 7.56–7.47 (m, 3H), 7.43 (t, J = 7.36 Hz, 1H);
13
6
C NMR (100 MHz, DMSO‐d ) δ ppm: 185.1, 153.2, 139.1, 135.3, 131.7,
All chemicals and reagents for synthesis were purchased from Sigma
Aldrich (St. Louis, MO) and Alfa Aesar (Johnson Matthey Company,
Ward Hill, MA) and were used without purification. Thin‐layer chro-
matography (TLC) precoated with silica gel 60 F254 was used for
monitoring the reactions, and visualization of TLC was accomplished in
a UV chamber. The compounds were purified by recrystallization
130.2, 129.7, 129.2, 129.0, 128.20, 122.6, 119.7; ESI–MS m/z; calcd for
+
+
16 12 2
C H N NaO [M+Na] 271.08, found 271.10.
3‐(4‐Bromophenyl)‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde (1b)
1
Yield 86%; white solid; mp: 139–141°C; H NMR (400 MHz, DMSO‐d
6
)
δ ppm: 9.98 (s, 1H), 9.36 (s, 1H), 7.99 (d, J = 7.88 Hz, 2H), 7.93

8
of 14
KUMAR ET AL.
|
(
d, J = 8.24 Hz, 2H), 7.71 (d, J = 8.36 Hz, 2H), 7.58 (t, J = 7.56 Hz, 2H),
the presence of 15 mol% piperidine, till the reaction got com-
pleted. After completion of the reaction, the solvent was evapo-
rated under vacuum, and the crude solid product was poured in
crushed ice. The piperidine present in the reaction mixture was
neutralized with dil. HCl, to obtain solid precipitate. The solid
precipitate was filtered under vacuum to give crude product. The
crude product was recrystallized using ethanol and chloroform in
the ratio of 8:2 to give the desired compound with yield in the
range 62–87%.
1
3
7
1
1
3
.44 (t, J = 7.24 Hz, 1H); C NMR (100 MHz, DMSO‐d
6
) δ ppm: 184.2,
51.2, 138.5, 135.7, 131.5, 130.6, 130.5, 129.7, 127.8, 122.7, 122.1,
+
+
2
19.2; ESI–MS m/z; calcd for C16H12BrN O [M+H] 327.01, found
27.07.
3
‐(4‐Ethylphenyl)‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde (1c)
1
Yield 81%; white solid; mp: 117–120°C; H NMR (400 MHz, DMSO‐
d
6
) δ ppm: 9.98 (s, 1H), 9.31 (s, 1H), 7.99 (d, J = 8.28 Hz, 2H), 7.84
(d, J = 7.92 Hz, 2H), 7.57 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 7.44 Hz, 1H),
7
.35 (d, J = 7.92 Hz, 2H), 2.68 (q, J = 7.56 Hz, 2H), 1.23 (t, J = 7.6 Hz,
3‐[(2E)‐3‐(1,3‐Diphenyl‐1H‐pyrazol‐4‐yl)prop‐2‐enoyl]‐2H‐chromen‐
13
3H); C NMR (100 MHz, DMSO‐d
6
) δ ppm: 184.6, 152.8, 144.9,
2‐one (3a)
1
1
38.6, 134.7, 129.7, 128.7, 127.9, 127.6, 122.1, 119.2, 27.9, 15.5;
Yield 74%; yellow solid; mp: 237–240°C; H NMR (400 MHz, CDCl
3
)
+
+
ESI–MS m/z; calcd for C18
H
17
2
N O
[M+H] 277.13, found 277.27.
δ ppm: 8.61 (s, 1H), 8.48 (s, 1H), 7.99 (d, J = 15.72 Hz, 1H), 7.86–785
13
(m, 3H), 7.74–7.65 (m, 4H), 7.55–7.47 (m, 5H), 7.43–7.35 (m, 3H);
C
3
‐(4‐Hydroxyphenyl)‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde (1d)
3
NMR (100 MHz, CDCl ) δ ppm: 185.9, 159.5, 155.2, 154.4, 148.2,
1
Yield 63%; white solid; mp: 222–225°C; H NMR (400 MHz, DMSO‐
) δ ppm: 9.96 (s, 1H), 9.82 (s, 1H), 9.27 (s, 1H), 7.98 (d, J = 7.88 Hz,
H), 7.79 (d, J = 8.6 Hz, 2H), 7.56 (t, J = 7.68 Hz, 2H), 7.41
139.4, 135.9, 134.2, 132.1, 130.1, 129.6, 128.9, 128.8, 128.7, 127.4,
127.1, 125.2, 125.0, 123.1, 119.5, 118.6, 118.4, 116.7; high‐
resolution mass spectroscopy (HRMS) (ESI) m/z; calcd for
d
6
2
1
3
+
+
(
t, J = 7.36 Hz, 1H), 6.89 (d, J = 8.6 Hz, 2H); C NMR (100 MHz,
DMSO‐d ) δ ppm: 185.2, 158.9, 153.4, 139.1, 135.1, 130.6, 130.2,
28.0, 122.5, 122.3, 119.6, 115.8; ESI–MS m/z; calcd for
27 18 2 3
C H N NaO [M+Na] , 441.12096, found 441.1216.
6
1
6‐Bromo‐3‐[(2E)‐3‐[3‐(4‐methylphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
prop‐2‐enoyl]‐2H‐chromen‐2‐one (3b)
+
+
16 12 2 2
C H N NaO [M+Na] , 287.08, found 287.10.
1
Yield 66%; orange solid; mp: 249–251°C; H NMR (400 MHz, CDCl
3
)
3
‐(4‐Methylphenyl)‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde (1e)
δ ppm: 8.50 (s, 1H), 8.46 (s, 1H), 7.98 (d, J = 15.64 Hz, 1H), 7.82 (t,
J = 7.56 Hz, 3H), 7.75 (dd, J = 8.6 Hz, 2.04 Hz, 1H), 7.62 (d, J = 8.0 Hz,
1
Yield 73%; white solid; mp: 121–123°C; H NMR (400 MHz, DMSO‐
13
d
6
) δ ppm: 9.98 (s, 1H), 9.31 (s, 1H), 7.99 (d, J = 7.84 Hz, 2H), 7.83
2H), 7.52 (t, J = 7.56 Hz, 2H), 7.39–7.30 (m, 5H), 2.45 (s, 3H);
C
(d, J = 8.04 Hz, 2H), 7.57 (t, J = 7.68 Hz, 2H), 7.43 (t, J = 7.36 Hz, 1H),
NMR (100 MHz, CDCl ) δ ppm: 185.4, 158.8, 154.6, 153.9, 146.6,
3
1
3
7
.32 (d, J = 7.96 Hz, 2H), 2.38 (s, 3H); C NMR (100 MHz, DMSO‐d
6
) δ
139.4, 138.7, 136.8, 136.6, 131.9, 129.6, 129.5, 129.1, 128.7, 127.3,
127.0, 126.3, 122.6, 120.10, 119.5, 118.4, 118.3, 117.5, 21.4; HRMS
ppm: 185.1, 153.2, 139.2, 139.1, 135.2, 130.2, 129.6, 129.1, 128.9,
+
+
+
3
+
1
2
28.1, 122.6, 119.7, 21.4. ESI–MS m/z; calcd for C17
H
15
N
2
O [M+H] ,
(ESI) m/z; calcd for C28
H
19BrN
2
NaO
[M+Na] , 533.0471, found
63.12, found 263.10.
533.0480.
6
‐Chloro‐3‐[(2E)‐3‐[3‐(4‐methylphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
prop‐2‐enoyl]‐2H‐chromen‐2‐one (3c)
Yield 81%; orange solid; mp: 241–243°C; H NMR (400 MHz, CDCl
4
.1.3 | Synthesis of the substituted 3‐acetyl‐2H‐
1
chromen‐2‐ones (2a–h)
3
)
δ ppm: 8.50 (s, 1H), 8.46 (s, 1H), 7.99 (d, J = 15.64 Hz, 1H), 7.83
(t, J = 7.68 Hz, 2H), 7.78 (d, J = 15.64 Hz, 1H), 7.66–7.59 (m, 4H), 7.52
Salicylaldehyde (0.0035 mol) and ethyl acetoacetate (0.0035 mol)
were stirred in ethanol (5 ml), in the presence of 5 mol% of piperidine
at room temperature for 3–8 hr. After completion of reaction, the
resultant mixture was neutralized with dil. HCl, and the obtained
precipitate was dried under vacuum to give crude product. This crude
product was recrystallized using methanol to give coumarin deriva-
tives in the yield of 68–83%.
13
(t, J = 7.68 Hz, 2H), 7.39–7.32 (m, 4H), 2.45 (s, 3H);
C NMR
(100 MHz, CDCl ) δ ppm: 185.5, 158.9, 154.6, 153.5, 146.7, 139.4,
3
138.7, 136.6, 134.0, 130.3, 129.6, 129.5, 129.1, 128.9, 128.7, 127.3,
127.0, 126.3, 122.6, 119.6, 119.5, 118.3, 118.2, 21.4; HRMS (ESI) m/z;
+
+
2 3
calcd for C28H19ClN NaO [M+Na] , 489.0976, found 489.0985.
7
‐Methyl‐3‐[(2E)‐3‐[3‐(4‐methylphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
prop‐2‐enoyl]‐2H‐chromen‐2‐one (3d)
3
Yield 83%; yellow solid; mp: 262–264°C; H NMR (400 MHz, CDCl )
1
4
.1.4 | Synthesis of the substituted 3‐[(2E)‐3‐(1,3‐
diphenyl‐1H‐pyrazol‐4‐yl)prop‐2‐enoyl]‐2H‐chromen‐
‐ones (3a–v)
δ ppm: 8.59 (s, 1H), 8.46 (s, 1H), 7.98 (d, J = 15.68 Hz, 1H), 7.84
(t, J = 7.24 Hz, 3H), 7.62 (d, J = 8.0 Hz, 2H), 7.57–7.49 (m, 3H),
2
7.38–7.32 (m, 3H), 7.19 (t, J = 7.96 Hz, 2H), 2.51 (s, 3H), 2.45 (s, 3H);
1
3
Equimolar amount of pyrazole carbaldehyde and 3‐acetyl cou-
3
C NMR (100 MHz, CDCl ) δ ppm: 186.0, 159.8, 155.4, 154.4, 148.3,
marin were dissolved in ethanol (10 ml) and refluxed at 80°C in
146.2, 139.4, 138.6, 135.8, 129.8, 129.6, 129.5, 129.2, 128.7, 127.2,

KUMAR ET AL.
9 of 14
|
1
26.9, 126.4, 124.0, 123.1, 119.5, 118.4, 116.8, 116.3, 22.2, 21.4;
6‐Bromo‐3‐[(2E)‐3‐[3‐(4‐ethylphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
prop‐2‐enoyl]‐2H‐chromen‐2‐one (3i)
+
3
+
HRMS (ESI) m/z; calcd for C29
H
22
2
N NaO
[M+Na] , 469.1523,
1
found 469.1523.
Yield 81%; orange solid; mp: 222–224°C; H NMR (400 MHz, DMSO‐
d
6
) δ ppm: 9.29 (s, 1H), 8.59 (s, 1H), 8.21 (d, J = 2.28 Hz, 1H), 7.97
7
‐Methoxy‐3‐[(2E)‐3‐[3‐(4‐methylphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐
(d, J = 7.96 Hz, 2H), 7.89 (d, = 8.84 Hz, = 2.32, 1H), 7.74
J
L
J
S
yl]‐prop‐2‐enoyl]‐2H‐chromen‐2‐one (3e)
(d, J = 15.76 Hz, 1H), 7.58–7.53 (m, 5H), 7.48 (t, J = 4.44 Hz, 1H),
1
Yield 79%; yellow solid; mp: 272–274°C; H NMR (400 MHz, CDCl
3
) δ
7.41–7.36 (m, 3H), 2.68 (q, J = 7.52 Hz, 2H), 1.22 (t, J = 7.60 Hz, 3H);
1
3
ppm: 8.61 (s, 1H), 8.47 (s, 1H), 7.98 (d, J = 15.68 Hz, 1H), 7.90
d, J = 15.68 Hz, 1H), 7.83 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.04 Hz, 2H),
6
C NMR (100 MHz, DMSO‐d ) δ ppm: 186.8, 157.8, 153.4, 153.2,
(
145.4, 144.6, 138.9, 136.3, 135.5, 132.1, 129.7, 129.1, 128.8, 128.5,
7
.59 (d, J = 8.68 Hz, 1H), 7.52 (t, J = 8.4 Hz, 2H), 7.38–7.32 (m, 3H),
.93 (dd, J = 8.68 Hz, J = 2.4 Hz, 1H), 6.88 (d, J = 2.32 Hz, 1H), 3.94
) δ ppm: 185.9, 165.1,
59.9, 157.6, 154.4, 148.6, 139.5, 138.6, 135.5, 131.3, 129.6, 129.5,
29.3, 128.7, 127.2, 126.9, 123.3, 121.4, 119.5, 118.5, 113.9, 112.5,
128.3, 127.2, 126.3, 120.2, 118.8, 118.5, 117.3, 27.9, 15.5; HRMS
+
3
+
6
L
S
(ESI) m/z; calcd for C29
H
21BrN
2
NaO
[M+Na] , 547.0628, found
13
(s, 3H), 2.45 (s, 3H); C NMR (100 MHz, CDCl
3
547.0627.
1
1
1
4
3‐[(2E)‐3‐[3‐(4‐Ethylphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
prop‐2‐enoyl]‐6‐nitro‐2H‐chromen‐2‐one (3j)
+
+
22 2 4
00.3, 56.1, 21.4; HRMS (ESI) m/z; calcd for C29H N NaO [M+Na] ,
1
85.1472, found 485.1467.
Yield 73%; yellow solid; mp: 214–216°C; H NMR (400 MHz,
DMSO‐d
6
) δ ppm: 9.29 (s, 1H), 8.94 (d, J = 2.72 Hz, 1H), 8.79
= 9.16 Hz, = 2.72 Hz, 1H), 7.97
3
‐[(2E)‐3‐[3‐(4‐Ethylphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
(s, 1H), 8.51 (dd,
J
L
J
S
prop‐2‐enoyl]‐7‐methyl‐2H‐chromen‐2‐one (3f)
(d, J = 7.92 Hz, 2H), 7.72 (d, J = 15.76 Hz, 1H), 7.70 (d, J = 9.16 Hz,
1H), 7.56 (t, J = 7.92 Hz, 4H), 7.49 (d, J = 15.76 Hz, 1H), 7.41–7.36
1
Yield 77%; yellow solid; mp: 224–228°C; H NMR (400 MHz, CDCl
3
) δ
1
3
ppm: 8.56 (s, 1H), 8.45 (s, 1H), 7.96 (d, J = 15.64 Hz, 1H), 7.86–7.80
m, 3H), 7.62 (d, J = 7.92 Hz, 2H), 7.55–7.47 (m, 3H), 7.36–7.32 (m, 3H),
(m, 3H), 2.67 (q, J = 7.52 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H); C NMR
(100 MHz, DMSO‐d ) δ ppm: 187.1, 158.4, 157.8, 153.7, 146.0,
(
6
7
3
1
1
1
.19–7.14 (m, 2H), 2.72 (q, J = 7.6 Hz, 2H), 2.49 (s, 3H), 1.29 (t, J = 7.6 Hz,
145.1, 144.2, 139.3, 136.4, 130.1, 129.6, 129.4, 128.9, 128.7,
13
3
H); C NMR (100 MHz, CDCl ) δ ppm: 186.0, 159.8, 155.4, 154.5,
128.7, 127.7, 127.5, 126.5, 124.0, 119.3, 118.3, 117.8, 28.4, 15.9;
+
+
48.3, 146.3, 144.9, 139.4, 135.9, 129.8, 129.6, 129.5, 128.8, 128.4,
HRMS (ESI) m/z; calcd for C29
H
21
N
3
NaO
5
[M+Na] , 514.1373,
27.2, 126.9, 126.4, 124.0, 123.1, 119.4, 118.4, 116.8, 116.3, 28.8, 22.2,
found 514.1379.
+
+
24 2 3
5.6; HRMS (ESI) m/z; calcd for C30H N NaO [M+Na] , 483.1679,
found 483.1671.
3‐[(2E)‐3‐[3‐(4‐Ethylphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
prop‐2‐enoyl]‐6‐methoxy‐2H‐chromen‐2‐one (3k)
1
3
‐[(2E)‐3‐[3‐(4‐Ethylphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
Yield 73%; yellow solid; mp: 187–189°C; H NMR (400 MHz,
prop‐2‐enoyl]‐6‐hydroxy‐2H‐chromen‐2‐one (3g)
3
CDCl ) δ ppm: 8.56 (s, 1H), 8.47 (s, 1H), 7.99 (d, J = 15.68 Hz, 1H),
1
Yield 79%; dark green solid; mp: 261–264°C; H NMR (400 MHz,
DMSO‐d ) δ ppm: 11.24 (s, 1H), 9.30 (s, 1H), 8.66 (s, 1H), 8.03
d, J = 8.08 Hz, 2H), 7.84 (d, J = 8.6 Hz, 1H), 7.75 (d, J = 15.68 Hz, 1H),
7.85 (d, J = 15.68 Hz, 1H), 7.83 (d, J = 7.76 Hz, 2H), 7.64
(d, J = 8.04 Hz, 2H), 7.52 (t, J = 7.6 Hz, 2H), 7.38–7.33 (m, 4H),
6
(
7.25 (dd, J
3.89 (s, 3H), 2.74 (q, J = 7.64 Hz, 2H), 1.31 (t, J = 7.6 Hz, 3H);
NMR (100 MHz, CDCl ) δ ppm: 186.0, 159.7, 156.4, 154.6, 149.8,
L S
= 9.08 Hz, J = 2.88 Hz, 1H), 7.07 (d, J = 2.88 Hz, 1H),
1
3
7
3
.70 (d, J = 15.68 Hz, 1H), 7.60 (t, J = 7.8 Hz, 4H), 7.43 (d, J = 7.68 Hz,
C
H), 6.92 (d, J = 8.6 Hz, 1H), 6.84 (s, 1H), 2.73 (q, J = 7.56 Hz, 2H), 1.28
3
13
(
t, J = 7.56 Hz, 3H); C NMR (100 MHz, DMSO‐d
6
) δ ppm: 186.6,
147.9, 144.9, 139.4, 136.1, 129.6, 129.4, 128.8, 128.4, 127.3,
1
1
1
64.5, 159.5, 157.5, 153.6, 148.7, 144.9, 139.4, 134.3, 132.9, 130.1,
126.9, 125.4, 123.0, 122.7, 119.4, 118.9, 118.4, 117.8, 110.9,
+
29.8, 128.9, 128.8, 127.6, 124.3, 120.5, 119.2, 118.0, 114.7, 111.6,
24 2 4
55.9, 28.8, 15.6; HRMS (ESI) m/z; calcd for C30H N NaO
+
4
+
02.3, 28.5, 15.9; HRMS (ESI) m/z; calcd for C29
H
22
2
N NaO
[M+Na] , 499.1628, found 499.1619.
+
[
M+Na] , 485.147, found 485.147.
3
‐[(2E)‐3‐[3‐(4‐Ethylphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
prop‐2‐enoyl]‐2H‐chromen‐2‐one (3l)
3
Yield 67%; yellow solid; mp: 190–192°C; H NMR (400 MHz, CDCl )
6
‐Chloro‐3‐[(2E)‐3‐[3‐(4‐ethylphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
1
prop‐2‐enoyl]‐2H‐chromen‐2‐one (3h)
Yield 87%; orange solid; mp: 215–217°C; H NMR (400 MHz, CDCl
δ ppm: 8.49 (s, 1H), 8.46 (s, 1H), 7.99 (d, J = 15.64 Hz, 1H), 7.82
1
3
)
δ ppm: 8.60 (s, 1H), 8.47 (s, 1H), 8.00 (d, J = 15.64 Hz, 1H), 7.84
(t, J = 8.68 Hz, 3H), 7.69–7.64 (m, 4H), 7.51 (t, J = 7.56 Hz, 2H),
13
(d, J = 8.04 Hz, 2H), 7.78 (d, J = 15.64 Hz, 1H), 7.65–7.61 (m, 4H), 7.51
7.42–7.34 (m, 5H), 2.74 (q, J = 7.6 Hz, 2H), 1.31 (t, J = 7.6 Hz, 3H);
C
(t, J = 7.72 Hz, 2H), 7.36 (t, J = 8.04 Hz, 4H), 2.74 (q, J = 7.6 Hz, 2H),
NMR (100 MHz, CDCl ) δ ppm: 185.9, 159.5, 155.2, 154.6, 148.1,
3
1
3
1
1
1
1
.31 (t, J = 7.6 Hz, 3H); C NMR (100 MHz, CDCl
3
) δ ppm: 185.4,
144.9, 139.4, 136.2, 134.2, 130.1, 129.6, 129.4, 128.8, 128.4, 127.3,
126.9, 125.3, 125.0, 122.9, 119.4, 118.6, 118.4, 116.7, 28.8, 15.6;
58.9, 154.6, 153.5, 146.7, 145.0, 139.4, 136.7, 133.9, 130.3, 129.6,
+
3
+
29.3, 128.9, 128.8, 128.4, 127.3, 126.9, 126.3, 122.6, 119.6, 119.4,
HRMS (ESI) m/z; calcd for C29
H
22 2
N NaO
[M+Na] , 469.1523,
+
3
18.3, 118.1, 28.8, 15.6; HRMS (ESI) m/z; calcd for C29
2
H21ClN NaO
found 469.1521.
+
[
M+Na] , 503.1132, found 503.1130.

10 of 14
KUMAR ET AL.
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3
‐[(2E)‐3‐[3‐(4‐Bromophenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
7.81 (d, J = 7.92 Hz, 1H), 7.66 (d, J = 15.72 Hz, 1H), 7.59–7.53 (m, 3H),
7.47 (d, J = 8.44 Hz, 2H), 7.37 (t, J = 7.36 Hz, 1H), 7.32 (s, 1H), 7.25
13
prop‐2‐enoyl]‐6‐methoxy‐2H‐chromen‐2‐one (3m)
1
Yield 84%; yellow solid; mp: 232–235°C; H NMR (400 MHz, CDCl
3
)
(d, J = 7.88 Hz, 1H), 6.92 (d, J = 8.44 Hz, 2H), 2.44 (s, 3H); C NMR
δ ppm: 8.56 (s, 1H), 8.45 (s, 1H), 7.91 (d, J = 15.64 Hz, 1H), 7.87
6
(100 MHz, DMSO‐d ) δ ppm: 187.2, 158.9, 158.5, 155.1, 153.8, 147.6,
(
s, 1H), 7.81 (d, J = 8.08 Hz, 2H), 7.63 (q, J = 8.4 Hz, 4H), 7.52
t, J = 7.72 Hz, 2H), 7.39–7.33 (m, 2H), 7.25 (dd, J = 9.08 Hz, J
.76Hz, 1H), 7.07 (d, J = 2.72 Hz, 1H), 3.88 (s, 3H);
100 MHz, CDCl ) δ ppm: 185.9, 159.7, 156.4, 153.1, 149.9, 139.3,
146.3, 139.4, 135.4, 130.6, 130.3, 130.1, 129.1, 127.5, 126.7, 124.6,
(
L
S
=
123.9, 122.9, 119.1, 117.7, 116.7, 116.5, 116.1, 21.9; HRMS (ESI) m/z;
13
+
+
2
C NMR
20 2 4
calcd for C28H N NaO [M+Na] , 471.1315, found 471.2694.
(
3
1
35.1, 131.9, 131.1, 130.4, 129.6, 127.5, 127.2, 125.2, 123.6, 123.1,
6‐Bromo‐3‐[(2E)‐3‐[3‐(4‐hydroxyphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
prop‐2‐enoyl]‐2H‐chromen‐2‐one (3r)
122.9, 119.5, 118.9, 118.4, 117.8, 110.9, 55.9; HRMS (ESI) m/z; calcd
+
4
+
1
for C28
H19BrN
2
NaO
[M+Na] , 549.0420, found 549.0419.
Yield 80%; brick red solid; mp: 278–281°C; H NMR (400 MHz, DMSO‐
6
d ) δ ppm: 9.85 (s, 1H), 9.24 (s, 1H), 8.58 (s, 1H), 8.19 (s, 1H), 7.95
3
‐[(2E)‐3‐[3‐(4‐Bromophenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
prop‐2‐enoyl]‐2H‐chromen‐2‐one (3n)
Yield 85%; yellow solid; mp: 223–226°C; H NMR (400 MHz, CDCl
δ ppm: 8.62 (s, 1H), 8.46 (s, 1H), 7.93 (d, J = 15.68 Hz, 1H), 7.83
(d, J = 8.04 Hz, 2H), 7.88 (d, J = 8.72 Hz, 1H), 7.69 (d, J = 15.72 Hz, 1H),
13
7.57–7.46 (m, 6H), 7.37 (t, J = 7.32 Hz, 1H), 6.91 (d, J = 8.36 Hz, 2H);
C
1
3
)
NMR (100 MHz, DMSO‐d ) δ ppm: 187.1, 158.6, 158.3, 153.9, 145.9,
6
139.4, 136.8, 136.1, 132.6, 130.3, 130.1, 129.2, 127.5, 126.9, 123.8,
(t, J = 7.64 Hz, 3H), 7.71–7.60 (m, 6H), 7.53 (t, J = 7.68 Hz, 2H),
122.9, 120.7, 119.2, 118.9, 117.6, 116.9, 116.1; HRMS (ESI) m/z; calcd
13
+
+
7
.43–7.36 (m, 3H); C NMR (100 MHz, CDCl
3
) δ ppm: 185.9, 159.5,
2 4
for C27H17BrN NaO [M+Na] , 535.0263, found 535.0258.
155.2, 153.1, 148.4, 139.3, 135.2, 134.3, 132.0, 131.1, 130.4, 130.1,
1
29.7, 127.5, 127.2, 125.1, 123.5, 123.1, 119.5, 118.6, 118.3, 116.7;
3‐[(2E)‐3‐[3‐(4‐Hydroxyphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
prop‐2‐enoyl]‐6‐nitro‐2H‐chromen‐2‐one (3s)
+
3
+
HRMS (ESI) m/z; calcd for C27
H
17BrN
2
NaO
[M+Na] , 519.03148,
1
found 519.0320.
Yield 69%; yellow solid; mp: 275–277°C; H NMR (400 MHz, DMSO‐
d
6
) δ ppm: 9.83 (s, 1H), 9.24 (s, 1H), 8.93 (s, 1H), 8.78 (d, J = 4.76 Hz,
6
‐Chloro‐3‐[(2E)‐3‐[3‐(4‐hydroxyphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
1H), 8.50 (dd, J = 9.04 Hz, J = 1.92 Hz, 1H), 7.95 (d, J = 8.08 Hz, 2H),
L
S
prop‐2‐enoyl]‐2H‐chromen‐2‐one (3o)
7.73–7.68 (m, 2H), 7.57 (t, J = 7.6 Hz, 2H), 7.49–7.45 (m, 3H), 7.39
13
1
Yield 71%; brick red solid; mp: 251–254°C; H NMR (400 MHz,
(t, J = 7.44 Hz, 1H), 6.90 (d, J = 8.52 Hz, 2H); C NMR (100 MHz,
DMSO‐d
6
) δ ppm: 9.84 (s, 1H), 9.24 (s, 1H), 8.59 (s, 1H), 8.07
d, J = 2.4 Hz, 1H), 7.96 (d, J = 7.84 Hz, 2H), 7.78 (dd, J = 8.88 Hz,
= 2.44 Hz, 1H), 7.69 (d, J = 15.72 Hz, 1H), 7.57–7.46 (m, 6H), 7.38
6
DMSO‐d ) δ ppm: 186.9, 158.6, 158.3, 157.8, 153.9, 145.9, 144.2,
(
L
139.4, 136.7, 130.4, 130.1, 129.3, 128.6, 127.5, 126.4, 123.7, 122.9,
J
S
119.2, 119.2, 118.2, 117.5, 116.1; HRMS (ESI) m/z; calcd for
1
3
+
+
(
t, J = 7.36 Hz, 1H), 6.92 (d, J = 8.48 Hz, 2H); C NMR (100 MHz,
DMSO‐d ) δ ppm: 187.1, 158.6, 158.4, 153.9, 153.5, 146.0, 139.4,
36.1, 133.9, 130.3, 130.1, 129.6, 129.2, 129.1, 127.5, 126.9, 123.8,
27 17 3 6
C H N NaO [M+Na] , 502.1009, found 502.1005.
6
1
1
C
3‐[(2E)‐3‐[3‐(4‐Hydroxyphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
prop‐2‐enoyl]‐6‐methoxy‐2H‐chromen‐2‐one (3t)
22.9, 120.2, 119.2, 118.7, 117.6, 116.1; HRMS (ESI) m/z; calcd for
+
4
+
1
27
H17ClN
2
NaO
[M+Na] , 491.0769, found 491.0776.
Yield 62%; yellow solid; mp: 254–256°C; H NMR (400 MHz, DMSO‐
d
6
) δ ppm: 9.85 (s, 1H), 9.24 (s, 1H), 8.59 (s, 1H), 7.95 (d, J = 8 Hz, 2H),
6
‐Hydroxy‐3‐[(2E)‐3‐[3‐(4‐hydroxyphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐
7.67 (d, J = 15.76 Hz, 1H), 7.55 (t, J = 8.44 Hz, 3H), 7.50–7.42 (m, 4H),
13
yl]prop‐2‐enoyl]‐2H‐chromen‐2‐one (3p)
7.39–7.31 (m, 2H), 6.92 (d, J = 8.48 Hz, 2H), 3.82 (s, 3H); C NMR
(100 MHz, DMSO‐d ) δ ppm: 187.3, 158.9, 158.5, 156.3, 153.9, 149.4,
1
Yield 64%; black solid; mp: 287–289°C; H NMR (400 MHz, DMSO‐
) δ ppm: 9.83 (s, 1H), 9.21 (s, 1H), 8.61 (s, 1H), 7.96 (d, J = 7.8 Hz,
H), 7.79 (d, J = 8.64 Hz, 1H), 7.66 (t, J = 15.92 Hz, 2H), 7.54
t, J = 7.72 Hz, 2H), 7.47 (d, J = 8.56 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H),
.93 (d, J = 8.56 Hz, 2H), 6.87 (dd, J = 8.52 Hz, J = 2.04 Hz, 1H), 6.79
d, J = 1.92 Hz, 1H); C NMR (100 MHz, DMSO‐d ) δ ppm: 186.7,
64.5, 159.4, 158.5, 157.5, 153.8, 148.6, 139.4, 134.6, 132.9, 130.3,
30.1, 128.9, 127.4, 124.1, 123.1, 120.6, 119.1, 117.8, 116.1, 114.7,
6
d
6
147.2, 139.4, 135.7, 130.3, 130.1, 129.1, 127.5, 126.0, 123.9, 122.9,
2
122.6, 119.2, 119.2, 117.8, 117.6, 116.1, 112.3, 56.3; HRMS (ESI) m/z;
+
+
(
20 2 5
calcd for C28H N NaO [M+Na] , 487.1264, found 487.1251.
6
L
S
13
(
6
3‐[(2E)‐3‐[3‐(4‐Hydroxyphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
prop‐2‐enoyl]‐2H‐chromen‐2‐one (3u)
1
1
1
4
1
Yield 70%; light green solid; mp: 279–281°C; H NMR (400 MHz,
+
5
+
11.5, 102.4; HRMS (ESI) m/z; calcd for C27
H
18
2
N NaO
[M+Na] ,
DMSO‐d
6
) δ ppm: 9.83 (s, 1H), 9.24 (s, 1H), 8.65 (s, 1H), 7.95
73.1107, found 473.3938.
(t, J = 7.72 Hz, 3H), 7.76–7.66 (m, 2H), 7.55 (t, J = 8.4 Hz, 3H),
1
3
7
.50–7.35 (m, 5H), 6.92 (d, J = 8.52 Hz, 2H); C NMR (100 MHz,
3
‐[(2E)‐3‐[3‐(4‐Hydroxyphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
DMSO‐d ) δ ppm: 187.3, 158.8, 158.6, 154.9, 153.9, 147.4, 139.4,
6
prop‐2‐enoyl]‐7‐methyl‐2H‐chromen‐2‐one (3q)
135.7, 134.7, 130.8, 130.3, 130.1, 129.2, 127.5, 125.8, 125.5, 123.9,
1
Yield 68%; yellow solid; mp: 264–266°C; H NMR (400 MHz, DMSO‐d
6
)
122.9, 119.2, 118.8, 117.6, 116.7, 116.1, 115.8; HRMS (ESI) m/z;
+
+
δ ppm: 9.85 (s, 1H), 9.23 (s, 1H), 8.62 (s, 1H), 7.95 (d, J = 8.08 Hz, 2H),
18 2 4
calcd for C27H N NaO [M+Na] , 457.1158, found 457.1160.

KUMAR ET AL.
11 of 14
|
3
‐[(2E)‐3‐[3‐(4‐Hydroxyphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐
completion of the reaction, the reaction mixture was quenched with a
cold saturated solution of sodium bicarbonate solution. The obtained
precipitate was filtered and washed with sufficient water to remove ex-
cess sodium bicarbonate, and the crude product was recrystallized using
ethanol to give the desired product in the yield of 54%.
prop‐2‐enoyl]‐7‐methoxy‐2H‐chromen‐2‐one (3v)
1
Yield 64%; yellow solid; mp: 275–277°C; H NMR (400 MHz, DMSO‐d
6
)
δ ppm: 9.83 (s, 1H), 9.21 (s, 1H), 8.64 (s, 1H), 7.96 (d, J = 7.92 Hz, 2H),
.86 (d, J = 8.72 Hz, 1H), 7.66 (s, 2H), 7.54 (t, J = 7.76 Hz, 2H), 7.43
d, J = 8.56 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.08 (s, 1H), 7.02
7
(
1
3
(
d, J = 8.68 Hz, 1H), 6.92 (d, J = 8.56 Hz, 2H), 3.89 (s, 3H); C NMR
100 MHz, DMSO‐d ) δ ppm: 186.68, 165.1, 159.2, 158.2, 157.4, 153.8,
48.3, 139.4, 134.9, 132.3, 130.3, 130.1, 128.9, 127.4, 123.9, 123.0,
21.7, 119.1, 117.8, 116.1, 113.9, 112.5, 100.8, 56.7; HRMS (ESI) m/z;
(E)‐N'‐{4‐[3‐(4‐Chlorophenyl)‐4‐formyl‐1H‐pyrazol‐1‐yl]‐
(
6
benzenesulfonyl}‐N,N‐dimethylmethanimidamide (5)
1
1
Yield 54%; gray solid; mp: 212–214°C; H NMR (400 MHz, DMSO‐d
6
) δ
1
ppm: 9.99 (s, 1H), 9.46 (s, 1H), 8.27 (s, 1H), 8.15 (d, J = 8.20 Hz, 2H),
13
+
5
+
calcd for C28
H N
20 2
NaO
[M+Na] , 487.1264, found 487.1271.
8.00–7.95 (m, 4H), 7.58 (d, J = 7.92 Hz, 2H), 3.17 (s, 3H), 2.93 (s, 3H);
NMR (100 MHz, DMSO‐d
C
6
) δ ppm: 185.0, 160.4, 152.1, 142.4, 140.9,
136.8, 134.6, 130.9, 130.3, 129.1, 128.2, 123.1, 119.9, 41.5, 35.6; ESI–MS
+
+
4
1
.1.5 | Synthesis of 4‐hydrazinylbenzene‐
‐sulfonamide hydrochloride (4)
4 3
m/z; calcd for C19H17ClN NaO S [M+Na] , 439.06, found 439.12.
4
‐Aminobenzenesulfonamide (0.029 mol) was added to 10 ml of HCl
maintained at 0–5°C and was stirred for 20 min. Sodium nitrite
0.0725 mol) dissolved in 5 ml water was added dropwise to the above
4.1.7 | Synthesis of substituted 1‐(2‐methyl‐
4‐phenylquinolin‐3‐yl)ethan‐1‐ones (6a–c)
(
reaction mixture and was stirred for 30 min. Simultaneously, stannous
chloride (0.0725 mol) was dissolved in 10 ml HCl maintained at tem-
perature 0°C. Then, cold diazonium salt solution was added dropwise
to a solution of stannous chloride and the resulting mixture was stirred
for 10 hr at 0°C. After completion of the reaction, the reaction mixture
was filtered through a Büchner funnel, washed with cold methanol to
remove traces of HCl and stannous chloride. The obtained precipitate
of 4‐hydrazinylbenzenesulfonamide hydrochloride was filtered, dried,
and stored in the refrigerator till further use.
Substituted benzophenone (0.0019 mol) and acetylacetone
(0.0022 mol) were refluxed at 110°C in the presence of 10 mol%
sodium trifluoromethanesulfonate, till the reaction got completed.
The crude product was recrystallized with a mixture of methanol and
dichloromethane in the ratio of 9:1 to give the desired compounds in
the yield of 74–87%.
1‐(2‐Methyl‐4‐phenylquinolin‐3‐yl)ethan‐1‐one (6a)
1
Yield 81%; white solid; mp: 113–115°C; H NMR (400 MHz, CDCl
3
) δ
ppm: 8.09 (d, J = 8.44 Hz, 1H), 7.74 (t, J = 7.28 Hz, 1H), 7.64
(d, J = 8.32 Hz, 1H), 7.54–7.52 (m, 3H), 7.46 (t, J = 7.68 Hz, 1H),
13
4
‐Hydrazinylbenzene‐1‐sulfonamide hydrochloride (4)
1
Yield 59%; white solid; mp: 223–227°C; H NMR (400 MHz, DMSO‐
7.39–7.36 (m, 2H), 2.72 (s, 3H), 2.02 (s, 3H); C NMR (100 MHz,
d
6
) δ ppm: 10.60 (s, 3H), 8.95 (s, 1H), 7.70 (d, J = 8.68 Hz, 2H), 7.22
3
CDCl ) δ ppm: 205.8, 153.6, 147.5, 143.9, 135.2, 134.8, 130.2, 130.1,
1
3
(
6
s, 2H), 7.06 (d, J = 8.68 Hz, 2H); C NMR (100 MHz, DMSO‐d ) δ
128.9, 128.7, 126.6, 126.2, 125.0, 31.9, 23.9; ESI–MS m/z; calcd for
+
+
ppm: 148.9, 136.5, 127.4, 113.8; ESI–MS m/z; calcd for C
H N
6 9 3
2
O S
18
C H16NO [M+H] , 261.12, found 262.12.
+
[
M] , 187.04, found 187.12.
1
‐(6‐Chloro‐2‐methyl‐4‐phenylquinolin‐3‐yl)ethan‐1‐one (6b)
1
Yield 87%; white solid; mp: 156–158°C; H NMR (400 MHz, CDCl
3
) δ
= 2.20 Hz, 1H),
7.57 (d, J = 2.20 Hz, 1H), 7.54–7.53 (m, 3H), 7.36–7.32 (m, 2H), 2.68
4
.1.6 | Synthesis of (E)‐N'‐{4‐[3‐(4‐chlorophenyl)‐4‐
L S
ppm: 8.01 (d, J = 8.96 Hz, 1H), 7.65 (dd, J = 8.96 Hz, J
formyl‐1H‐pyrazol‐1‐yl]benzenesulfonyl}‐N,N‐
1
3
dimethylmethanimidamide (5)
(s, 3H), 2.00 (s, 3H); C NMR (100 MHz, CDCl
3
) δ ppm: 205.4, 135.9,
145.9, 143.1, 135.5, 134.5, 132.5, 131.0, 130.6, 129.9, 129.3, 128.9,
+
+
Equimolar p‐chloro acetophenone and 4‐hydrazinylbenzenesulfonamide
hydrochloride were dissolved in methanol followed by the addition of a
catalytic amount of glacial acetic acid. The reaction mixture was refluxed
at 80°C for 1 hr. After the completion of the reaction, the solvent was
evaporated under vacuum to give crude hydrazone. Simultaneously,
125.9, 124.9, 31.9, 23.9; ESI–MS m/z; calcd for C18H15ClNO [M+H]
296.08, found 296.12.
1‐[6‐Chloro‐4‐(2‐fluorophenyl)‐2‐methylquinolin‐3‐yl]ethan‐1‐one (6c)
1
Yield 74%; white solid; mp: 123–125°C; H NMR (400 MHz, CDCl
3
) δ
Vilsmeier–Haack reagent was prepared. POCl
dropwise to DMF (0.075 mol) maintained at 0–5°C and it was stirred for
0 min. To this mixture, hydrazone (0.025 mol) dissolved in sufficient
3
(0.075 mol) was added
ppm: 8.04 (d, J = 8.96 Hz, 1H), 7.68 (d, J = 9.00 Hz, 1H), 7.59–7.54
13
(m, 1H), 7.41 (s, 1H), 7.35–7.24 (m, 3H), 2.71 (s, 3H), 2.15 (s, 3H);
C
2
NMR (100 MHz, CDCl ) δ ppm: 204.5, 160.6, 158.1, 153.9, 145.7,
3
DMF, was added and the reaction mixture was stirred for 30 min main-
tained at temperature 0–5°C. The reaction mixture was allowed to reach
room temperature and then it was refluxed at 70°C for 12 hr. After
137.4, 136.3, 132.8, 132.1, 131.7, 131.2, 130.6, 125.8, 124.9, 124.5,
122.1, 121.9, 116.3, 116.1, 31.5, 23.8; ESI–MS m/z; calcd for
+
+
18
C H14ClFNO [M+H] , 314.07, found 314.12.

12 of 14
KUMAR ET AL.
|
4
4
.1.8 | Synthesis of the substituted (2E)‐1‐(2‐methyl‐
(2E)‐1‐(6‐Chloro‐2‐methyl‐4‐phenylquinolin‐3‐yl)‐3‐[3‐(4‐
‐phenylquinolin‐3‐yl)‐3‐[3‐(4‐methylphenyl)‐1‐
ethylphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]prop‐2‐en‐1‐one (7d)
1
phenyl‐1H‐pyrazol‐4‐yl]prop‐2‐en‐1‐ones (7a–j)
Yield 69%; white solid; mp: 119–121°C; H NMR (400 MHz,
3
CDCl ) δ ppm: 8.07–8.05 (m, 2H), 7.72–7.67 (m, 3H), 7.58
Equimolar amount of pyrazole carbaldehyde and substituted 1‐
(d, J = 2.24 Hz, 1H), 7.50–7.43 (m, 5H), 7.36–7.33 (m, 3H),
(
2‐methyl‐4‐phenylquinolin‐3‐yl)ethanone was dissolved in ethanol
7.25–7.23 (m, 2H), 7.20–7.16 (m, 3H), 6.44 (d, J = 16.20 Hz, 1H),
1
3
(10 ml) and refluxed at 80°C in presence of 10 mol% NaOH, till the
2.72 (s, 3H), 2.67 (q, J = 7.64 Hz, 2H), 1.23 (t, J = 7.60 Hz, 3H);
C
reaction got completed. After completion of the reaction, the solvent
was evaporated under vacuum, and the crude solid product was
poured in crushed ice and was neutralized with dil. HCl, to obtain
solid precipitate that was filtered under vacuum to give crude pro-
duct. The crude product was recrystallized using ethanol and
chloroform in the ratio of 8:2 to give the desired compound in the
yield of 48–93%.
NMR (100 MHz, CDCl ) δ ppm: 196.9, 155.3, 153.8, 146.0, 145.2,
3
144.3, 139.2, 137.9, 134.6, 133.4, 132.4, 130.9, 130.5, 130.0,
129.6, 129.1, 128.9, 128.6, 128.5, 128.2, 127.4, 126.9, 126.0,
125.0, 119.3, 117.3, 28.7, 23.9, 15.5; ESI–MS m/z; calcd for
+
+
36 3
C H29ClN O [M+H] , 554.20, found 554.21.
(2E)‐3‐[3‐(4‐Hydroxyphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐1‐
(
2‐methyl‐4‐phenylquinolin‐3‐yl)prop‐2‐en‐1‐one (7e)
1
(
2E)‐1‐(2‐Methyl‐4‐phenylquinolin‐3‐yl)‐3‐[3‐(4‐methylphenyl)‐1‐
Yield 64%; white solid; mp: 262–265°C; H NMR (400 MHz, DMSO‐
phenyl‐1H‐pyrazol‐4‐yl]prop‐2‐en‐1‐one (7a)
6
d ) δ ppm: 9.74 (s, 1H), 9.04 (s, 1H), 8.07 (d, J = 8.36 Hz, 1H),
1
Yield 93%; white solid; mp: 206–209°C; H NMR (400 MHz, CDCl
3
) δ
7.84–7.80 (m, 3H), 7.58–7.43 (m, 7H), 7.35 (t, J = 7.40 Hz, 1H),
ppm: 8.13 (d, J = 8.40 Hz, 1H), 8.05 (s, 1H), 7.78–7.74 (m, 1H), 7.71
d, J = 7.68 Hz, 2H), 7.63 (d, J = 8.24 Hz, 1H), 7.50–7.43 (m, 6H),
7.28–7.24 (m, 2H), 7.20 (d, J = 8.48 Hz, 2H), 7.07 (d, J = 16.16 Hz, 1H),
13
(
6.75 (d, J = 8.48 Hz, 2H), 6.65 (d, J = 16.16 Hz, 1H), 2.60 (s, 3H);
C
7
2
1
1
1
C
.36–7.28 (m, 5H), 7.17 (t, J = 7.68 Hz, 3H), 6.45 (d, J = 16.16 Hz, 1H),
NMR (100 MHz, DMSO‐d ) δ ppm: 196.9, 158.5, 154.6, 153.3, 147.4,
6
1
3
.74 (s, 3H), 2.36 (s, 3H); C NMR (100 MHz, CDCl
3
) δ ppm: 197.2,
144.8, 139.3, 138.3, 135.2, 132.9, 130.7, 130.2, 130.1, 130.0, 129.7,
129.1, 128.8, 127.5, 127.4, 127.2, 126.2, 125.0, 122.8, 119.0, 117.0,
54.9, 153.7, 147.7, 145.1, 139.3, 138.8, 137.6, 135.3, 132.6, 130.2,
30.0, 129.6, 129.4, 128.9, 128.6, 128.4, 128.3, 127.3, 126.9, 126.4,
26.3, 125.2, 119.3, 117.4, 23.9, 21.3; ESI–MS m/z; calcd for
+
2
+
115.9, 23.9; ESI–MS m/z; calcd for C34
H N
26 3
O
[M+H] , 508.20,
found 508.24.
+
+
35
28 3
H N O [M+H] , 506.22, found 506.30.
(2E)‐1‐(6‐Chloro‐2‐methyl‐4‐phenylquinolin‐3‐yl)‐3‐[3‐
(
2E)‐1‐(6‐Chloro‐2‐methyl‐4‐phenylquinolin‐3‐yl)‐3‐[3‐(4‐
(4‐hydroxyphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]prop‐2‐en‐1‐one (7f)
1
methylphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]prop‐2‐en‐1‐one (7b)
Yield 59%; white solid; mp: 249–251°C; H NMR (400 MHz,
1
Yield 82%; white solid; mp: 165–167°C; H NMR (400 MHz, CDCl
3
) δ
6
DMSO‐d ) δ ppm: 9.75 (s, 1H), 9.04 (s, 1H), 8.09 (d, J = 8.96 Hz,
ppm: 8.06 (t, J = 3.56 Hz, 1H), 7.72–7.68 (m, 3H), 7.58 (d, J = 2.28 Hz,
1H), 7.84–7.81 (m, 3H), 7.53–7.44 (m, 5H), 7.40 (d, J = 2.28 Hz,
1H), 7.35 (t, J = 7.36 Hz, 1H), 7.26–7.24 (m, 2H), 7.19
(d, J = 8.52 Hz, 2H), 7.08 (d, J = 16.16 Hz, 1H), 6.76 (d, J = 8.56 Hz,
1
7
H), 7.50–7.45 (m, 5H), 7.36–7.32 (m, 3H), 7.28–7.24 (m, 2H),
.19–7.15 (m, 3H), 6.44 (d, J = 16.20 Hz, 1H), 2.72 (s, 3H), 2.37 (s, 3H);
1
3
13
C NMR (100 MHz, CDCl
3
) δ ppm: 196.9, 155.3, 153.7, 146.1, 144.3,
2H), 6.64 (d, J = 16.16 Hz, 1H), 2.59 (s, 3H); C NMR (100 MHz,
1
1
2
39.2, 138.9, 137.8, 134.6, 133.4, 132.4, 130.9, 130.6, 130.0, 129.6,
6
DMSO‐d ) δ ppm: 196.5, 158.5, 155.4, 153.3, 145.9, 144.0, 139.3,
29.4, 128.9, 128.6, 128.4, 127.4, 126.9, 126.0, 125.0, 119.3, 117.3,
138.7, 134.5, 133.7, 131.8, 131.4, 131.4, 131.2, 130.2, 130.1,
+
+
3
3.9, 21.3; ESI–MS m/z; calcd for C35H27ClN O [M+H] , 540.18,
129.4, 129.0, 127.6, 126.9, 124.7, 122.7, 119.1, 117.0, 115.9,
+
+
found 540.26.
23.9; ESI–MS m/z; calcd for C34
H
25ClN
3
O
2
[M+H] , 542.16,
found 542.20.
(
2E)‐1‐[6‐Chloro‐4‐(2‐fluorophenyl)‐2‐methylquinolin‐3‐yl]‐3‐[3‐(4‐
methylphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]prop‐2‐en‐1‐one (7c)
(2E)‐1‐[6‐Chloro‐4‐(2‐fluorophenyl)‐2‐methylquinolin‐3‐yl]‐3‐[3‐
(4‐hydroxyphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]prop‐2‐en‐1‐one (7g)
1
Yield 48%; white solid; mp: 179–182°C; H NMR (400 MHz,
1
CDCl
3
) δ ppm: 8.11 (s, 1H), 8.07 (d, J = 8.96 Hz, 1H), 7.74–7.69
m, 3H), 7.51–7.45 (m, 3H), 7.42 (t, J = 1.84 Hz, 1H), 7.37–7.33
m, 3H), 7.29–7.16 (m, 6H), 6.51 (d, J = 16.24 Hz, 1H), 2.72 (s, 3H),
Yield 74%; yellow solid; mp: 143–146°C; H NMR (400 MHz, CDCl
3
)
(
δ ppm: 8.11 (s, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.72–7.68 (m, 3H),
7.50–7.42 (m, 4H), 7.37–7.24 (m, 7H), 7.18 (t, J = 8.88 Hz, 1H), 6.81
13
(
1
3
2
1
1
1
1
.36 (s, 3H); C NMR (100 MHz, CDCl
3
) δ ppm: 196.4, 160.6,
(d, J = 8.56 Hz, 2H), 6.53 (d, J = 16.24 Hz, 1H), 2.73 (s, 3H); C NMR
58.1, 155.3, 153.8, 145.8, 139.2, 138.9, 138.8, 138.3, 134.3,
32.7, 132.2, 131.3, 131.1, 130.6, 129.6, 129.5, 128.9, 128.4,
3
(100 MHz, CDCl ) δ ppm: 196.4, 160.6, 158.1, 157.1, 155.3, 153.9,
145.4, 139.3, 139.1, 138.6, 134.4, 132.9, 132.2, 131.4, 130.2, 130.0,
27.4, 127.3, 126.5, 125.9, 124.6, 122.3, 122.1, 119.3, 117.2,
129.6, 127.5, 127.4, 126.3, 126.1, 124.7, 123.6, 122.1, 121.9, 119.4,
+
+
15.9, 115.7, 23.9, 21.3; ESI–MS m/z; calcd for C35
H
26ClFN
3
O
3 2
117.1, 115.9, 115.8, 23.57; ESI–MS m/z; calcd for C34H24ClFN O
+
+
[
M+H] , 558.17, found 558.21.
[M+H] , 560.15, found 560.24.

KUMAR ET AL.
13 of 14
|
(
(
2E)‐3‐[3‐(4‐Bromophenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐1‐[6‐chloro‐4‐
sterile 96‐well microtiter plate using 100‐µl Middlebrook 7H9 broth.
All the samples was tested in triplicates. Isoniazid, rifampicin, and
ethambutol were used as positive controls, and a growth control
containing no antibiotic as a negative control was also tested. Sterile
water was added to all perimeter wells to maintain humidity and
prevent evaporation during incubation. The plates were incubated at
37°C for a period of 7 days. After an incubation period, 30 µl of
Alamar Blue solution was added to each well, and the plates were
reincubated for 12 hr. The growth is indicated by the change of color
from blue to pink. The lowest concentration of the sample at which
2‐fluorophenyl)‐2‐methylquinolin‐3‐yl]prop‐2‐en‐1‐one (7h)
1
Yield 56%; white solid; mp: 205–207°C; H NMR (400 MHz, CDCl
3
) δ
ppm: 8.12 (s, 1H), 8.08 (d, J = 8.96 Hz, 1H), 7.73–7.71 (m, 3H),
7
.51–7.46 (m, 5H), 7.42 (t, J = 1.88 Hz, 1H), 7.39–7.31 (m, 3H),
7
.29–7.23 (m, 2H), 7.19 (t, J = 7.20 Hz, 2H), 6.51 (d, J = 16.24 Hz, 1H),
13
2
3
.72 (s, 3H); C NMR (100 MHz, CDCl ) δ ppm: 196.3, 160.6, 158.1,
1
55.2, 152.5, 145.8, 139.1, 138.9, 137.4, 134.1, 132.8, 132.3, 131.9,
31.4, 131.3, 130.7, 130.0, 129.7, 127.7, 127.5, 126.9, 125.9, 124.7,
24.6, 123.2, 122.3, 122.1, 119.4, 117.2, 115.9, 115.7, 23.9; ESI–MS
1
1
+
+
[37,38]
m/z; calcd for C34H23BrClFN
3
O
[M+H] , 622.07, found 622.15.
there was no change in color was noted as its MIC.
4
1
‐{4‐[(1E)‐3‐(6‐Chloro‐2‐methyl‐4‐phenylquinolin‐3‐yl)‐3‐oxoprop‐
‐en‐1‐yl]‐3‐(4‐chlorophenyl)‐1H‐pyrazol‐1‐yl}benzene‐1‐
4.2.2 | In vitro cytotoxicity study
sulfonamide (7i)
Yield 75%; gray solid; mp: 246–249°C; H NMR (400 MHz, DMSO‐d
δ ppm: 9.20 (s, 1H), 8.44 (d, J = 8.44 Hz, 1H), 8.06 (d, J = 8.80 Hz, 3H),
1
6
)
The active compounds were evaluated for cell toxicity by the MTT
assay. The compounds were tested against HEK 293 (human em-
bryonic kidney) cell line at 25 μg/ml concentration. The cell line
7
1
7
.97 (d, J = 8.76 Hz, 2H), 7.78 (t, J = 7.96 Hz, 1H), 7.67 (d, J = 8.36 Hz,
H), 7.54–7.50 (m, 6H), 7.44 (d, J = 8.48 Hz, 2H), 7.32–7.29 (m, 2H),
2
cultures were maintained at 37°C in a humidified 5% CO incubator
1
3
.25 (d, J = 16.16 Hz, 1H), 6.66 (d, J = 16.20 Hz, 1H), 2.80 (s, 3H);
) δ ppm: 194.7, 154.8, 152.3, 142.9, 141.1,
38.7, 134.4, 134.1, 133.4, 130.9, 130.7, 130.5, 130.1, 129.9, 129.1,
C
(Thermo Fisher Scientific). The adhered cells were detached and
centrifuged to get the cell pellet. To the cell pellet, fresh medium was
added to make the volume 100 μl in a 96‐well plate. A cell count, as
determined by a hemocytometer, should range from 5,000 to
NMR (100 MHz, DMSO‐d
6
1
1
C
27.9, 127.8, 127.1, 125.8, 119.3, 118.1, 21.3; ESI–MS m/z; calcd for
+
+
34
H25Cl
2
4 3
N O S
[M+H] , 639.10, found 639.08.
2
6,000 cells/well. Then the plate was incubated in a CO incubator
overnight, so that the cells could adhere and regain their shape. After
24 hr, cells were treated with the test compounds at 25 μg/ml and
diluted using the medium to deduce the percentage inhibition on
normal cells. The cells were incubated for 48 hr to assay the effect of
the test compounds on cell lines. A zero‐hour reading was noted
down with untreated cells and also control with 1% DMSO, to sub-
tract further from the 48‐hr reading. After 48‐hr incubation, cells
were treated with MTT at a concentration of 5 mg/ml, dissolved in
phosphate‐buffered saline, and incubated for 3–4 hr at 37°C. The
formazan crystals thus formed were dissolved in 100 μl of DMSO,
and the viability was measured at 540 nm on a multimode reader
(SpectraMax). The assay was performed in triplicates for each con-
centration. The cytotoxicity values were expressed as a percentage
4
‐{4‐[(1E)‐3‐[6‐Chloro‐4‐(2‐fluorophenyl)‐2‐methylquinolin‐3‐yl]‐3‐
oxoprop‐1‐en‐1‐yl]‐3‐(4‐chlorophenyl)‐1H‐pyrazol‐1‐yl}benzene‐1‐
sulfonamide (7j)
1
Yield 67%; white solid; mp: 199–202°C; H NMR (400 MHz, DMSO‐
d
6
) δ ppm: 9.30 (s, 1H), 8.20 (d, J = 9.00 Hz, 1H), 8.07 (d, J = 8.84 Hz,
H), 7.98 (d, J = 8.84 Hz, 2H), 7.92 (dd, J = 8.96 Hz, J = 2.12, 1H),
.62–7.56 (m, 1H), 7.49–7.44 (m, 6H), 7.39–7.34 (m, 2H), 7.32–7.28
2
7
L
S
(
(
m, 2H), 7.16 (d, J = 16.16 Hz, 1H), 6.75 (d, J = 16.20 Hz, 1H), 2.67
13
s, 3H); C NMR (100 MHz, DMSO‐d
6
) δ ppm: 195.4, 160.5, 158.0,
1
1
1
55.6, 152.5, 142.9, 141.1, 137.8, 134.7, 134.3, 132.6, 132.3, 131.9,
30.8, 130.6, 130.4, 129.3, 127.9, 127.7, 126.0, 125.4, 124.4, 119.3,
+
2 4 3
17.9, 116.5, 116.3, 23.5; ESI–MS m/z; calcd for C34H24Cl FN O S
+
[32,39]
[
M+H] , 657.09, found 657.08.
inhibition at a particular concentration of the compound.
4
.2 | Biological assays
4.3 | Molecular docking studies in silico
4
.2.1 | In vitro MTB MABA assay
The structures of ligands were drawn in ChemDraw Ultra 6.0. The
target protein crystal structure was retrieved from PDB. Molecular
docking studies were performed against M. tuberculosis enzyme
DprE1 with PDB ID: 4P8N. The protein was prepared with the help
of Protein Preparation Wizard of Schrödinger Suite 9.8. The prepared
protein was optimized and minimized using algorithm OPLS_2005
(optimized potential for liquid simulations) force field, and the grid
was generated using the Glide Grid Generation panel in Glide. The
minimized test compounds were docked using Glide XP docking
calculations. XP descriptor and root mean square deviation calculator
were enabled. The XP Glide scoring function was used to get the best
Synthesized compounds were evaluated for their antitubercular ac-
tivity using the MABA method. The inoculum was prepared using
active M. tuberculosis H37Rv culture in Middlebrook 7H9 broth with
1
0% OADC (0.1% casitone, 0.5% glycerol, supplemented with oleic
acid, albumin, dextrose, and catalase; HiMedia). The broth having
OD590 = 1.0 was diluted in 1:20, of which 100‐µl culture was used as
an inoculum for screening. Each test sample stock solution was
diluted in Middlebrook 7H9 broth at fourfold the final highest
concentration to be tested. The compounds were diluted serially in a

14 of 14
KUMAR ET AL.
|
ranked compounds, and the specific interactions like H‐bonds,
π–cation, π–π stacking, and the van der Waals were analyzed using
XP visualizer in a Glide module.
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ACKNOWLEDGMENTS
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We thank the Director, NIPER for providing necessary facilities re-
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CONFLICT OF INTEREST
The authors declare that there are no conflicts of interests.
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