Green approach for the synthesis of 3-methyl-1-phenyl-4-((2-phenyl-1H-indol 3-yl)methylene)-1H-pyrazole-5(4H)-ones and their DNA Cleavage, antioxidant, and antimicrobial activities

Article abstract of DOI:10.1002/jhet.3726

3-Methyl-1-phenyl-4-((2-phenyl-1H-indol-3-yl)methylene)-1H-pyrazol-5(4H)-ones (5a-i) was prepared by the condensation reaction of different 3-formyl-2-phenylindole derivatives (2a-i) and 3-methyl-1-phenyl-2-pyrazoline-5-one in quantitative yield by applying various green synthetic methods as grinding, microwave irradiation using different catalysts under solvent-free mild reaction conditions with high product yields. The structures of the synthesized compounds were characterized on the basis of elemental analysis, infrared, ¹HNMR, ¹³C NMR, and mass spectral data. The synthesized compounds were screened for free radical scavenging, antimicrobial, and DNA cleavage activities. Most of the tested compounds belonging to the 3-methyl-1-phenyl-4-((2-phenyl-1H-indol-3-yl)methylene)-1H-pyrazol-5(4H)-ones series exhibited promising activities.

Full text of DOI:10.1002/jhet.3726

Received: 11 June 2019
DOI: 10.1002/jhet.3726
Revised: 14 August 2019
Accepted: 17 August 2019
A R T I C L E
Green approach for the synthesis of 3‐methyl‐1‐phenyl‐4‐((2‐
phenyl‐1H‐indol 3‐yl)methylene)‐1H‐pyrazole‐5(4H)‐ones
and their DNA Cleavage, antioxidant, and antimicrobial
activities
Madhuri Modi
| Meenakshi Jain
Center of advance studies, Department of
chemistry, University of Rajasthan, Jaipur,
India
Abstract
3‐Methyl‐1‐phenyl‐4‐((2‐phenyl‐1H‐indol‐3‐yl)methylene)‐1H‐pyrazol‐5(4H)‐
ones (5a‐i) was prepared by the condensation reaction of different 3‐formyl‐2‐
phenylindole derivatives (2a‐i) and 3‐methyl‐1‐phenyl‐2‐pyrazoline‐5‐one in
quantitative yield by applying various green synthetic methods as grinding,
microwave irradiation using different catalysts under solvent‐free mild reac-
tion conditions with high product yields. The structures of the synthesized
compounds were characterized on the basis of elemental analysis, infrared,
1HNMR, 13C NMR, and mass spectral data. The synthesized compounds were
screened for free radical scavenging, antimicrobial, and DNA cleavage activ-
ities. Most of the tested compounds belonging to the 3‐methyl‐1‐phenyl‐4‐
((2‐phenyl‐1H‐indol‐3‐yl)methylene)‐1H‐pyrazol‐5(4H)‐ones series exhibited
promising activities.
Correspondence
Meenakshi Jain, Center of advance
studies, Department of chemistry,
University of Rajasthan, Jaipur, India.
Email: minimaharani@yahoo.co.in
1 | INTRODUCTION
HIV,[12] anti‐inflammatory,[13] antidiabetic,[14] antihista-
minic,[15] anticonvulsant,[16] antihelminthic,[17] antihy-
Heterocycles are useful due to their combination of com-
pact and robust molecular structure with a high degree of
molecular diversity that results in properties, which can
be finely adjusted to needs of sophisticated application.[1,2]
The heterocycles possessing indole, pyrazole, and
isoxaline moiety deserve a special mention due to their ver-
satile use in pharmacological and biochemical studies.[3,4]
The important role of Indole nucleus in the field of phar-
maceutical chemistry and biochemistry is well‐established
form last many decades.[5] Chemical studies reveal that
the naturally occurring as well as synthetic hallucinogenic
drugs such as LSD, harmine, psilocin, psilocybin,
and DMT, most of them are derivatives of tryptamine,
β‐[(3‐indolyl)ethyl]amin.[6] The importance of serotonin
(5‐hydroxytryptamine) has been recognized as a modula-
tor of CNS neurohormonal activity.[7,8] Various biological
activities like anticancer,[9,10] antirheumatoidal,[11] anti‐
pertensive,[18] antioxidant,[19] and antimicrobial[20] have
been attributed to indole derivatives. Phenyl group at 2‐
position of indole moiety enhances biological activities like
antimicrobial, monoamine oxidase inhibition.[21] The
derivatives of 2‐phenylindoles exhibits have shown potent
CNS depressant activity[22] and cytotoxic activity.[23]
Pyrazole is an important pharmacophore, which
exhibits a wide spectrum of biological activities, such as
antitumor,[24]
antidepressant,[25]
antidiabetic,[26]
antiamoebic,[27] and COX‐2 inhibitor.[28] Incorporation of
pyrazoline in indole framework enhances pharmacologi-
cal importance, according to the review of literature indole
derivatives bearing pyrazoline moiety possess diverse bio-
logical activities like antitumor,[29] antioxidant,[30] anti-
cancer,[31] antimicrobial,[32] and anti‐inflammatory.[33]
DNA cleavage studies have been of great interest for
biologists and chemists. The cleaved DNA under
J Heterocyclic Chem. 2019;1–10.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

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MODI AND JAIN
physiological conditions has been developed as artificial
nucleases; these synthetic nucleases have provided
important tools in the hand of chemists to manipulate
DNA and cooperate with molecular biologists.[34] The
nature of substituents and interaction of the compound
with DNA molecule would help in the design of newer
drugs and develop new selective, efficient DNA recogni-
tion and cleaving agent.
adsorbent, and the spots were visualized using ultraviolet
1
light and iodine. H NMR and 13C NMR spectra were
recorded on BRUKER AVENE II 400‐MHz NMR
spectrometer using tetramethylsilane as an internal
standard and DMSO‐d6/CDCl3 as a solvent. The mass
spectral data were obtained on a JEOLD‐300 spectrometer.
Microwave‐assisted reactions were carried out in a domes-
tic MW oven (LG MS‐194A) operating at 2450 MHz.
Free radicals have been implicated in several human
diseases such as diabetic's Mellitus, stroke, diabetes,
Alzheimer's diseases, atherosclerosis, arthritis, and neuro-
degenerative Parkinson's disease.[35] Melatonin and sero-
tonin are good free radical scavengers and antioxidant
that shows an important role in the immune system. N‐
substituted indole‐2/3‐carboxamide and ester derivatives
are also showed excellent antioxidant activity against
superoxide free radicals.[36]
Reactions in Grindstone Chemistry have initiated itself
by grinding crystals of substrate and reagent with the gen-
eration of the small amount of energy in the form of heat
through friction.[37] Such reactions are easy to handle,
comparatively cheaper to operate, and ecologically more
favorable. Silica‐supported catalysts have great interest
and special attention of chemists due to high reactivity,
more efficient, eco‐friendly nature, recyclable, and easy
to handling.[38]
Another solvent‐free popular technique is Microwave
Chemistry since microwave irradiation is a well‐known,
eco‐friendly, and convenient synthetic method.[39] Mont-
morillonite KSF showed catalytic activity for this conden-
sation reaction and has many advantages over catalysts
like NaOH, KOH such as easy to handle, low cost, and
elimination of metal waste. Keeping in view these obser-
vations and continuation of our studies towards the syn-
thesis of a variety of bioactive heterocycles,[40] herein,
we have designed various strategies to synthesize some
noble indolyl pyrazoline derivatives. To make the effi-
ciency and comparative study of these synthetic routes,
we have used conventional and solvent‐free methods
(Grindstone and microwave irradiation). An inexpensive
catalyst likes Mg (HSO4)2/SiO2 and KSF are used to
obtain the target molecule. All the synthesized compound
screened for DNA cleavage, free radical scavenging, and
antimicrobial activity.
2.1 | Biological activities
2.1.1 | Free radical scavenging assays
Free radical scavenging activity was done by α, α‐
diphenyl‐β‐picry‐hydrazyl radical scavenging (DDPH)
assay. The DPPH is a stable free radical and is widely
used to assess the free radical scavenging activity of anti-
oxidant compounds. This method is based on the reduc-
tion of DPPH in methanol solution in the presence of
hydrogen‐donating antioxidant due to the formation of
the nonradical form DPPH‐H (Blois, 1958). This transfor-
mation results in a color change from purple to yellow,
which was measured by spectrophotometrically. The dis-
appearance of the purple color monitored at 517 nm. The
free radical scavenging activity can be measured by using
2, 2‐diphenyl‐1‐picryl‐hydrazyl or 2, 2‐diphenyl‐2‐picryl‐
hydrazyl by the method of McCune and Johns (2002).
The reaction mixture (3.0 mL) consists of 1.0 mL of DPPH
in methanol (0.3 mM), 1.0 mL of various concentrations
of test compounds (50, 75, and 100 μg mL−1), and 1.0
mL of methanol. It incubated for 10 minutes in dark,
and then the absorbance was measured at 517 nm. In this
assay, the positive controls can be ascorbic acid used as
standard; the percentage of inhibition can be calculated
using the formula.
Inhibition ð%Þ ¼ ðA0 − A1=A0Þ × 100;
where A0 is the absorbance of the control and A1 is the
absorbance of the sample. The test was carried out in
triplicate.
2.2 | DNA cleavage analysis
2.2.1 | Preparation of culture media
2 | MATERIALS AND METHODS
DNA cleavage experiments were done according to the
literature method.[41] Nutrient broth [Peptone, 10; yeast
extract, 5; NaCl, 10; in (g/L) was used for culturing of
Escherichia coli. About 50‐mL media was prepared,
autoclaved for 15 minutes at 121°C under 15‐lb pressures.
The autoclaved media were inoculated for 24 h at 37°C.
Melting points of all the synthesized compounds are
determined in open capillary tubes and are uncorrected.
The infrared (IR) spectra (υ
in cm−1) were recorded
max
on a Perkin Elmer‐557 model. Reactions are monitored
by thin‐layer chromatography (TLC) using silica gel‐G as

MODI AND JAIN
3
antibacterial plates were kept for incubation at 37°C for
24 hours. The zone of inhibition was measured and com-
pared with the controls.
2.2.2 | Isolation of DNA
The fresh bacterial culture (1.5 mL) was centrifuged to
obtain the pellet, which was then dissolved in 0.5 mL of
lysis buffer (100 mM tris pH 8.0, 50 mM EDTA, and 10 %
SDS). To this, 0.5 mL of saturated phenol was added and
incubated at 55°C for 10 minutes, then centrifuged at 10
000 rpm for 10 minutes and to the supernatant, an equal
volume of chloroform: isoamyl alcohol (24:1) and 1/20th
volume of 3 M sodium acetate (pH 4.8) was added. This
was further centrifuged at 10 000 rpm for 10 minutes, and
to the supernatant, three volumes of chilled absolute alco-
hol was added. The precipitated DNA was separated by
centrifugation, and the pellet was dried and dissolved in
TAE buffer (10 mM tris pH 8.0, 1 mM EDTA) and stored
in cold condition.
2.4 | Antifungal assay
Antifungal activity was also done by the disk diffusion
method. Sabouraud Dextrose Agar plates were prepared
for antifungal activity. Cultures of the fungal strain of
Candida albicans and Aspergillus niger were inoculated
in Peptone water and were kept for incubation for 24
hours at 37°C. Fungal cultures were swabbed onto the
Sabouraud Dextrose Agar surface. About 50 μl of dilution
of sample (5a‐i), the positive control Itraconazole (5mg/
well) and the negative control (DMSO), was loaded into
the respective wells. The antifungal plates were kept for
incubation at 37°C for 24 hours. The antifungal activity
of each compound was compared with Itraconazole as
standard drug. Inhibition zones were measured and com-
pared with the controls.
2.2.3 | Agarose gel electrophoresis
The cleavage products were analyzed by agarose gel elec-
trophoresis method [41]. Test samples (1 mg/mL) were
prepared in dimethylformamide (DMF). The samples (25
mg) were added to the isolated DNA of E coli. The samples
were incubated for 2 hours at 37°C, and then 20 mL of
DNA sample (Mixed with bromophenol blue dye at 1:1
ratio) was loaded carefully into the electrophoresis cham-
ber wells along with standard DNA marker containing
TAE buffer (4.84 g tris base, pH 8.0, 0.5 M EDTA/1 L)
and finally loaded on agarose gel and passed the constant
50 V of electricity for 30 minutes. Removing the gel and
stained with 10.0‐mg/mL ethidium bromide for 10e 15
minutes, the bands were observed under Vilber Lourmat
Gel documentation system and then photographed to
determine the extent of DNA cleavage. The results are
compared with standard DNA marker. DNA ladder was
used 100 to 1000bp (100 bp step up ladder, Merck).
2.5 | Preparation of silica‐supported
magnesium hydrogen sulfate
Anhydrous magnesium chloride (5.0 g, 50 mmol) was
charged in the 50‐mL suction flask equipped with dropping
funnel; concentrated sulfuric acid (98 %, 9.43 g, 50 mmol)
was added drop wise over the period of 45 minutes with
stirring at room temperature. HCl evolved immediately
through a funnel and adsorbed by the solution of water
and alkali, while the residual HCl eliminated by suction.
The Mg (HSO4)2 (8.36 g) was obtained as white gel and
mixed by silica gel (7.65 g) to get the desired catalyst.
2.3 | Antibacterial assay
2.6 | Synthesis of 2‐phenyl‐1H‐indole‐3‐
carbaldehyde (2a‐i)
Antibacterial bacterial activity is done by Kirby‐Bauer
well diffusion method. Mueller‐Hinton Agar plates were
prepared for the antibacterial activity. ATCC Cultures of
E coli (ATCC 25922) and Staphylococcus aureus (ATCC
29213) were inoculated in Peptone water and were kept
for incubation for 24 hours at 37°C. Inoculum size of bac-
teria was adjusted using McFarland Turbidity Standard as
reference. The bacterial suspensions were compared with
0.5 McFarland Turbidity Standard. Bacterial cultures
were swabbed onto the Mueller Hinton Agar surface.
About 50 μL of dilution of sample (5a‐i), the positive con-
trol (Streptomycin (5mg/mL (w/v)) and the negative con-
trol (DMSO) was loaded into the respective wells. The
Phosphorus oxychloride (6.0 mmol) was added slowly,
with stirring to dimethylformamide (DMF; 5 mL) at 10 to
15°C. The solution was further stirred for 15 minutes at
the same temperature until an orange‐colored syrupy liq-
uid was formed; to this, 2‐phenylindoles (5 mmol) was
added in portions with stirring at 40–50°C. The solution
was further stirred for 45 minutes and then poured into
ice water (100 mL). Sodium hydroxide solution (2 N, 10
mL) was added to it and the mixture was heated on a water
bath for 1 hour. It was cooled, filtered, and recrystallized
from acetone (80%) to obtain pure compounds (2a‐i).

4
MODI AND JAIN
NaOH solution (40 mL) was added to it, and the whole
reaction mixture was further stirred for half an hour, neu-
tralized with 2N HCl (3 mL) diluted with water, and left
overnight to get solid compound, which was filtered and
recrystallized from ethanol to obtain pure compound.
Result and conditions of the synthesis of 3‐methyl‐1‐phe-
nyl‐4‐((2‐phenyl‐1H‐indol‐3‐yl)methylene)‐1H‐pyrazol‐
5(4H)‐ones (5a‐i) are tabulated in Table 1. The compounds
of the series (5a‐i) also synthesized by the above method.
2.7 | Synthesis of 3‐methyl‐1‐phenyl‐4‐((2‐
phenyl‐1H‐indol‐3‐yl)methylene)‐1H‐
pyrazole‐5(4H)‐ones. (5a‐i)
2.7.1 | General method (i): Solvent‐free
synthesis of (5a‐i)
A mixture of 2‐phenyl‐1H‐indole‐3‐carbaldehyde (2a‐i) (3
mmol) and Mg (HSO4)2/SiO2(0.5 g) was grinded at room
temperature for 2 to 5 minutes in mortar and pestle to gen-
erate yellow colored enolate. Then 3‐methyl‐1‐phenyl‐2‐
pyrazoline‐5‐one (3 mmol) was added to it and grinding
continues further to give orange‐red colored tacky solid
within 10 to 20 minutes. The reaction proceeds exothermi-
cally indicated by the rise in temperature (5‐10°C). After
completion of the reaction (checked by TLC), the mixture
was dissolved in CH2Cl2 and catalyst was filtered; the resi-
due washed many times with CH2Cl2. After evaporation of
the solvent under reduced pressure, almost pure com-
pound was obtained. Further purification was achieved
by recrystallization from ethanol. The catalyst was washed
with diethyl ether, dried at 70°C for 50 minutes, and reused
in another reaction. The compounds of the series (5a‐i) also
synthesized by the above method.
3 | RESULT AND DISCUSSIONS
3.1 | Synthesis
p‐Fluorophenylhydrazine was prepared by the method
of Chattaway et al.[42] 2‐Phenylindole derivatives, which
have been prepared by the Fischer indole synthesis
and by the method of Joshi et al, were subjected to
formylation with phosphorous oxychloride (POCl3) and
DMF under Vilsmeier‐Haack Formylation reaction. We
carried out condensation reaction between various 3‐for-
myl‐2‐phenylindole derivatives (2a‐i) and 3‐methyl‐1‐
phenyl‐2‐pyrazoline‐5‐one and get desired product 3‐
methyl‐1‐phenyl‐4‐((2‐phenyl‐1H‐indol‐3‐yl)methylene)‐
1H‐pyrazol‐5(4H)‐ones (5a‐i) (Scheme 1). The reaction
was conducted by employing various reaction condi-
tions. In the traditional conventional method, the reac-
tants (compounds 2a‐i and appropriate 3‐methyl‐1‐
phenyl‐4‐((2‐phenyl‐1H‐indol‐3‐yl)methylene)‐1H‐
2.7.2 | General method (ii):
Microwave‐assisted solvent‐free synthesis
of (5a‐i)
The reaction was carried out in domestic microwave
(800 W, 2450 MHz). A mixture of 2‐phenyl‐1H‐indole‐
3‐carbaldehyde (2a‐i) (3 mmol), 3‐methyl‐1‐phenyl‐2‐
pyrazoline‐5‐one (3 mmol), and montmorillonite KSF
(0.4 g) was mixed thoroughly in a pestle mortar. This
mixture was then transferred into a conical flask (100
cm3) and irradiated with microwaves for 5 to 11
minutes. After completion of the reaction (checked by
TLC), ethanol was added and the mixture was filtered;
the filtrate was concentrated and then the crude product
so obtained was recrystallized from ethanol to obtain
pure compound (5a‐i). The catalyst left as the residue
was washed 2 to 3 times with ethanol and dried in vac-
uum for reuse. The compounds of the series (5a‐i) also
synthesized by the above method.
pyrazol‐5(4H)‐ones) were dissolved in ethanol and then
aqueous NaOH was added dropwise with continuous
stirring. In contrast under solvent‐free conditions, the
condensation reaction of the same reactants can be car-
ried out by adding and 0.5g amount of Mg (HSO4)2/SiO2
under grinded conditions using mortar and pestle to
afford target compound (5a‐i) in higher yield and lesser
time. Grinding together the solid reagents without the
addition of catalyst reveals that in some cases, liquid
melt is observed, while in others, the discrete crystalline
phase of solid reagents remains. More important, upon
addition of the catalyst, a rise in temperature (5‐10°C)
occurs only those systems that exhibit a phase change
to a melt. Thus, the existence of a liquid phase is a pre-
requisite for reaction in these systems. The microwave‐
assisted reaction using a catalytic amount of KSF clay
and solvent‐free environment proceeds efficiently and
completed within 5 to 11 minutes with excellent yield
(78‐90%). The result obtained is presented in [Table 1].
The IR spectra of 2‐Phenyl‐1H‐indole (1a‐i), N─H
stretching absorption appears as a strong absorption band
in the range of 3460 to 3420 cm−1. The C─N frequencies
have been assigned to the 1275 to 970 cm−1 region. In 1H
2.7.3 | Method (iii) conventional proce-
dure of synthesis (5a‐i)
2‐Phenyl‐1H‐indole‐3‐carbaldehyde (2a‐i) (3 mmol) and 3‐
methyl‐1‐phenyl‐2‐pyrazoline‐5‐one (3 mmol) were dis-
solved in a minimum amount of ethanol (25 mL) and then
stirred at room temperature for 5 minutes. Sufficient 2N

MODI AND JAIN
5
TABLE 1 Result and conditions of the synthesis of 3‐methyl‐1‐phenyl‐4‐((2‐phenyl‐1H‐indol‐3‐yl)methylene)‐1H‐pyrazol‐5(4H)‐ones (5a‐i)
% Yield
i
Time required
Temp, °C
II
Compound
X
Y
ii
iii
I, min
II, min
III, min
5a
5b
5c
5d
5e
5f
H
H
H
H
H
H
H
H
F
H
87.8
92.0
89.2
93.4
88.7
87.6
84.7
91.0
92.0
82.1
89.3
82.3
90.1
84.5
84.4
78.5
83.0
87.0
68.2
78.5
75.6
67.5
77.6
65.0
70.5
71.3
72.4
10
10
14
10
11
10
13
12
9
5
7
30
30
40
45
30
50
30
40
30
70
60
50
65
60
75
55
60
60
4‐F
4‐Cl
8
4‐Br
11
9
4‐CH3
4‐OCH3
3‐Cl, 4‐F
2‐Cl, 4‐F
4‐F
6
5g
5h
5i
5
8
6
Note. (i) By grinding with Mg (HSO4)2/SiO2. (ii) By microwave irradiation with Montmorillonite KSF; reaction was carried out in an LG MS‐194A household
microwave even with maximum 800W power. (iii) By conventional method.
3150 cm−1 due to the presence of –CHO group at position
3‐ of the indole ring, The strong absorption band in the
range 1230‐1060 cm−1 has been attributed to Ar‐F
stretching mode. The characteristic absorption due to–
CHO group appears 1675 to 1625 cm−1. Analysis of IR spec-
tra of 2‐phenyl‐1H‐indole‐3‐carbaldehyde shows one spe-
cial feature that the appearance of two broad strong
peaks in –NH stretching region. This may be due to the
intermolecular hydrogen bonding between the N─H
group of one molecule and the –CHO group of the second
1
molecule. In H NMR spectra of 2‐phenyl‐1H‐indole‐3‐
carbaldehyde derivatives, the N─H resonance signal is
observed in the region of δ 10.2 to 11.6 ppm as a broad sin-
glet. Aromatic protons are observed as multiplet from δ 7.2
to 7.9 ppm. Singlet due to –CHO proton appears in the
region δ 9 to 10.0 ppm.
SCHEME 1 Schematic representation for the synthesis the
synthesis of 3‐methyl‐1‐phenyl‐4‐((2‐phenyl‐1H‐indol‐3‐yl)
methylene)‐1H‐pyrazol‐5(4H)‐ones
In the IR spectra of 3‐methyl‐1‐phenyl‐4‐((2‐phenyl‐1H‐
indol‐3‐yl)methylene)‐1H‐pyrazol‐5(4H)‐ones (5a‐i), the
N─H absorption appears as a broad band 3170 to 3010
NMR spectra of 2‐phenyl‐1H‐indole, methine proton at
C‐3 of indole moiety shows a resonance signal at δ 6.6
ppm, N─H resonance signal appears at δ 8.2 to 8.4 ppm
as a broad singlet. Aromatic protons are observed at mul-
tiplet from δ 7.8 to 8.0 ppm.
In the IR spectra of 2‐phenyl‐1H‐indole‐3‐carbaldehyde
derivatives (2a‐i), the absorption band of the N─H
stretching is shifted towards lower wave number 3300 to
cm−1. Characteristic absorption due to carbonyl group
appears in the range of 1625 to 1605 cm−1. The downfield
shift is due to conjugation of the carbonyl group with the
olefinic double bond, which results in delocalization of
electrons of carbonyl group giving ionic resonance struc-
tures. The olefinic double bond (C═C) appears between
1
the range of 1600 to 1525 cm−1. The H NMR spectra of
3‐methyl‐1‐phenyl‐4‐((2‐phenyl‐1H‐indol‐3‐yl)

6
MODI AND JAIN
Ar‐H),7.6−7.2 (m, 13H, Ar‐H), 2.3(s, 3H, CH3)13C NMR
(DMSO‐d6) in δ (ppm): 182.2 (C═O), 149.8, 140.1, 136.4,
130.1, 127.4, 126.0, 124.8, 122.2, 120.5, 113.9, 112.3 and
21.4; ESI‐MS: m/z = 378 [M + 1]+ . Anal. Calcd. for
C25H19N3O (377): C, 79.55; H, 5.07; N, 11.13%. Found: C,
79.53; H, 5.09; N, 11.11%
4‐((2‐(4‐fluorophenyl)‐1H‐indol‐3‐yl)methylene)‐
3‐methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐one (5b). Yield
75% (ethanol): mp 283−285°C; IR (υ max, cm−1, KBr):
3232, 3164, 2870, 1620, 1540; 1H NMR (400MHz,
DMSO‐d6, δ ppm): 12.02 (s, 1 H indole NH), 9.24 (s, 1H,
−CH=), 8.22(d, 1H, indole Ar‐H),7.9−7. 3(m, 12H, Ar‐
H), 2.27(s, 3H, CH3)13C NMR (DMSO‐d6) in δ (ppm):
182.5 (C═O), 144.4, 142.1, 133.4, 129.1, 126.3, 124.7,
123.1, 120.6, 118.3, 115.3, 112.5 and 20.3; ESI‐MS: m/z =
396[M + 1]+ , 397 [M + 2]+ Anal. Calcd. for C25H18FN3O
(395): C, 75.93; H, 4.59; N, 10.63%. Found: C, 75.95; H,
4.43; N, 10.67%
TABLE 2 Free radical scavenging activity of synthesized com-
pounds (5a‐i)
Concentration, μg mL−1
Compound 50 Mean SD 75 Mean SD 100 Mean SD
5a
5b
5c
5d
5e
5f
63.46 0.14
37.45 0.35
40.43 0.26
38.36 0.15
74.26 0.10
78.72 0.43
65.25 0.32
67.34 0.65
63.50 0.17
64.73 0.19
39.67 0.39
42.68 0.22
40.53 0.34
76.43 0.18
80.45 0.12
67.67 0.23
69.26 0.14
65.72 0.14
78.48 0.12
66.96 0.16
41.48 0.87
43.96 0.27
42.73 0.16
78.54 0.25
82.27 0.21
68.98 0.13
70.67 0.34
67.56 0.37
80.26 0.17
5g
5h
5i
Ascorbic acid 76.24 0.10
methylene)‐1H‐pyrazol‐5(4H)‐ones (5a‐i) exhibit a com-
plex splitting pattern. N─H resonance signal appears as a
broad singlet from δ 11.24 to 12.30 ppm. A singlet at δ
9.9−8.7 ppm assigned for the vicinal proton. Aromatic pro-
ton appears as a complex multiplet in the region δ 7.3 to 8.2
ppm. 13C NMR Spectrum of 3‐methyl‐1‐phenyl‐4‐((2‐phe-
nyl‐1H‐indol‐3‐yl)methylene)‐1H‐pyrazol‐5(4H)‐ones has
displayed a downfield signal at δ182‐169for carbonyl car-
bon and δ 23 and 20 integrated for methyl carbon. The
mass spectrum of compound 5a has shown ion peak at
m/z 378 [M+1] +
4‐((2‐(4‐chlorophenyl)‐1H‐indol‐3‐yl)methylene)‐
3‐methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐one (5c). Yield
79% (ethanol): mp 245−248°C; IR (υ max, cm−1, KBr):
3152, 3054, 2896, 1634, 1552; 1H NMR (400MHz,
DMSO‐d6, δ ppm): 11.89 (s, 1 H indole NH), 9.84 (s, 1H,
−CH=), 8.3(d, 1H, indole Ar‐H),7.8−7.2 (m, 12H, Ar‐
H), 2.33(s, 3H, CH3)13C NMR (DMSO‐d6) in δ (ppm):
172.8 (C═O), 145.4, 140.1, 137.4, 129.1, 127.3, 125.4,
123.4, 121.6, 120.3, 113.3, 111.5 and 21.3; ESI‐MS: m/z =
413 [M + 2]+ , 415 [M + 4]+ Anal. Calcd. for
C25H18ClN3O (411): C, 72.90; H, 4.40; N, 10.20%. Found:
C, 72.94; H, 4.43; N, 10.24%
4‐((2‐(4‐bromophenyl)‐1H‐indol‐3‐yl)methylene)‐
3‐methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐one (5d). Yield
89% (ethanol): mp 305−307°C; IR (υ max, cm−1, KBr):
3187, 3068, 2817, 16, 1557; 1H NMR (400MHz,
DMSO‐d6, δ ppm): 11.87 (s, 1 H indole NH), 8.98 (s, 1H,
−CH=), 8.22(d, 1H, indole Ar‐H),7.8−7. 2(m, 12H, Ar‐
H), 2.24(s, 3H, CH3)13C NMR (DMSO‐d6) in δ (ppm):
172.5 (C═O), 143.4, 142.1, 137.7, 128.1, 126.2, 124.7,
3.2 | Spectral data of compound
3‐methyl‐1‐phenyl‐4‐((2‐phenyl‐1H‐indol‐3‐yl)meth-
ylene)‐1H‐pyrazol‐5(4H)‐one (5a). Yield 82% (ethanol):
mp 235−237°C; IR (υ max, cm−1, KBr): 3150, 3053, 2895,
1
1630, 1550; H NMR (400MHz, DMSO‐d6,δ ppm): 12.32
(s, 1 H indole NH), 9.94 (s, 1H,−CH=), 8.2(d, 1H, indole
FIGURE 1 Free radical scavenging
activity of synthesized compounds (5a‐i)
[Color figure can be viewed at
wileyonlinelibrary.com]

MODI AND JAIN
7
TABLE 3 Zone of inhibition (mm) of compounds (5a‐i) against
tested bacterial strains
Bacterial strains
S. aureus (ATCC
Escherichia coli
Entry
Compound
29213)
(ATCC 25922)
1
2
3
4
5
6
7
8
9
10
5a
17.2 0.6
18.2 0.4
19.4 0.5
18.9 0.2
21.3 0.2
22.1 0.3
20.0 0.2
20.7 0.4
19.5 0.4
27.5 0.6
16.4 0.3
16.8 0.4
18.3 0.2
17.7 0.3
22.0 0.6
22.1 0.4
19.4 0.3
20.4 0.2
18.6 0.3
24.4 0.3
5b
5c
5d
5e
FIGURE 2 DNA cleavage activity of synthesized compounds (5a‐
i) [Color figure can be viewed at wileyonlinelibrary.com]
5f
5g
123.3, 121.4, 118.2, 115.0, 112.8 and 22.2; ESI‐MS: m/z =
456 [M + 1]+ , 458 [M + 2]+ Anal. Calcd. for C25H18FN3O
(455): C, 65.80; H, 3.98; N, 9.21%. Found: C, 65.76; H,
3.95; N, 9.23%
5h
5i
Standard
3‐methyl‐1‐phenyl‐4‐((2‐p‐tolyl‐1H‐indole‐3‐yl)
methylene)‐1H‐pyrazol‐5(4H)‐one (5e). Yield 87%
(ethanol): mp 270−272°C; IR (υ max, cm−1, KBr): 3145,
Note. Streptomycin was used as a standard. About 50 μl/mL of the compound
in each well.
1
3050, 2890, 1632, 1545; H NMR (400MHz, DMSO‐d6, δ
ppm): 12.26 (s, 1 H indole NH), 9.92 (s, 1H,−CH=),
8.1(d, 1H, indole Ar‐H),7.4−7.1 (m, 12H, Ar‐H), 2.3(s,
3H, CH3), 2.2(s, 3H, CH3)13C NMR (DMSO‐d6) in δ
(ppm): 173.3 (C═O), 148.5, 139.4, 135.2, 130.0, 127.3,
125.7, 123.6, 122.1, 121.4, 113.8, 112.2, 22.1, ; ESI‐MS:
m/z = 392 [M + 1]+ . Anal. Calcd. For C26H21N3O
(391): C, 79.77; H, 5.41; N, 10.73%. Found: C, 79.75; H,
5.39; N, 10.71%
4‐((2‐(2‐chloro‐4‐fluorophenyl)‐1H‐indol‐3‐yl)
methylene)‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐
one (5h). Yield 93% (ethanol): mp 300−302°C; IR (υ max,
cm−1, KBr): 3182, 3074, 2860, 1650, 1560; 1H NMR
(400MHz, DMSO‐d6, δ ppm): 12.30 (s, 1 H indole NH),
9.25 (s, 1H,−CH=), 8.80(d, 1H, indole Ar‐H),8.4−7. 4(m,
10H, Ar‐H), 2.23(s, 3H, CH3)13C NMR (DMSO‐d6) in δ
(ppm): 178.5 (C═O), 145.4, 143.1, 132.7, 129.6, 126.6,
125.7, 123.4, 120.4, 118.2, 114.3, 112.9, and 21.3; ESI‐MS:
m/z = 431[M + 2]+ , 433[M + 4]+ Anal. Calcd. for
C25H17ClFN3O (429): C, 69.85; H, 3.99; N, 8.25%. Found:
C, 69.88; H, 3.98; N, 8.23
4‐((2‐(4‐methoxyphenyl)‐1H‐indol‐3‐yl)methy-
lene)‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐one (5f).
Yield 89% (ethanol): mp 278−280°C; IR (υ max, cm−1
,
1
KBr): 3167, 3064, 2824, 1630, 1560; H NMR (400MHz,
DMSO‐d6, δ ppm): 12.56 (s, 1 H indole NH), 8.79 (s, 1H,
−CH=), 8.34(d, 1H, indole Ar‐H),7.7−7. 15(m, 12H, Ar‐
H), 3.4(s, 3H, CH3), 2.24(s, 3H, CH3)13C NMR (DMSO‐
d6) in δ (ppm): 177.5 (C═O), 146.4, 143.8, 136.9, 130.1,
128.8, 128.2, 124.4, 123.1, 120.4, 118.2, 115.0, 55.4, and
22.2; ESI‐MS: m/z = 408 [M + 1]+ , Anal. Calcd. for
C26H21N3O2 (407): C, 76.64; H, 5.19; N, 10.31%. Found:
C, 76.62; H, 5.16; N, 10.29%
4‐((5‐fluoro‐2‐(4‐fluorophenyl)‐1H‐indol‐3‐yl)
methylene)‐5‐methyl‐2‐phenyl‐2,4‐dihydro‐3H‐
pyrazol‐3‐one (5i). Yield 92% (ethanol): mp 149‐150°C;
1
IR (υ max, cm−1, KBr): 3240, 3165, 2860, 1620, 1540; H
NMR (400MHz, DMSO‐d6, δ ppm): 11.97 (s, 1 H indole
NH), 9.20 (s, 1H,−CH=), 8.20(d, 1H, indole Ar‐H),7.9−7.
3(m, 11H, Ar‐H), 2.26(s, 3H, CH3)13C NMR (DMSO‐d6) in
δ (ppm): 182.4 (C═O), 144.0, 142.0, 133.2, 128.4, 126.4,
125.7, 124.1, 120.4, 118.4, 115.5, 112.3 and 20.4; ESI‐MS:
m/z = 413 [M]+ , 414 [M + 1]+ Anal. Calcd. for
C25H17F2N3O (413): C, 72.63; H, 4.14; N, 10.16 %. Found:
C, 72.61; H, 4.16; N, 10.14 %
4‐((2‐(3‐chloro‐4‐fluorophenyl)‐1H‐indol‐3‐yl)
methylene)‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐
one (5g). Yield 82% (ethanol): mp 292−294°C; IR (υ max,
cm−1, KBr): 3170, 3065, 2870, 1620, 1547; 1H NMR
(400MHz, DMSO‐d6, δ ppm): 12.27 (s, 1 H indole NH),
9.14 (s, 1H,−CH=), 8.72(d, 1H, indole Ar‐H),7.9−7. 1(m,
11H, Ar‐H), 2.23(s, 3H, CH3)13C NMR (DMSO‐d6) in δ
(ppm): 178.5 (C═O), 147.4, 145.1, 136.7, 126.6, 124.6,
123.7, 122.4, 120.4, 117.2, 113.8, 111.9, and 21.7; ESI‐MS:
m/z = 431[M + 2]+ , 433[M + 4]+ Anal. Calcd. for
C25H17ClFN3O (429): C, 69.85; H, 3.99; N, 8.25%. Found:
C, 69.81; H, 3.94; N, 8.28%
3.3 | Biological activities
3.3.1 | Free radical scavenging assay
The free radical scavenging activity of synthesized com-
pounds was done by α, α‐diphenyl‐β‐picry‐hydrazyl radical

8
MODI AND JAIN
FIGURE 3 Zone of inhibition (mm) of
compounds 5a‐i against tested bacterial
strains [Color figure can be viewed at
wileyonlinelibrary.com]
scavenging (DDPH) method. Samples were prepared at
concentrations of 50, 75, and 100 μg/mL, and ascorbic acid
is taken as standard. The experimental data on the antiox-
idant activity of the compounds (5a‐i) and control drug are
presented in Table 2. Among synthesized ‐CH3‐ and ‐
OCH3‐ substituted indole derivatives (5e) and (5f) have
very good scavenging activity, simple indole derivative
(5a) and Di‐halogen‐substituted indole derivatives (5g),
(5h), and (5i) have shown moderate activities and mono‐
halogen‐substituted derivatives (5b), (5c), and (5d) have
shown least activity compare with the standard. Therefore,
such compounds containing substitutions ‐CH3 and ‐
OCH3 on 2‐phenyl indole moiety enhance the free radical
scavenging activity. Further, the synthesized compounds
scavenged the DDPH radicals in a concentration‐
dependent manner. The bar graph representation of the
percentage of mean free radical scavenging activity is
shown in Figure 1.
TABLE 4 Zone of inhibition (mm) of compounds 5a‐i against
tested fungal strains
Fungal strains
Entry Compound Candida albicans Aspergillus niger
1
2
3
4
5
6
7
8
9
10
5a
18.2 0.6
19.2 0.2
21.6 0.3
20.2 0.5
22.6 0.2
23.3 0.4
20.2 0.5
21.4 0.3
21.4 0.5
27.4 0.6
15.6 0.5
16.5 0.2
20.2 0.7
18.8 0.6
21.7 0.2
22.2 0.2
19.3 0.8
20.4 0.9
20.3 0.3
23.4 0.2
5b
5c
5d
5e
5f
5g
5h
5i
Standard
Note. Itraconazole was used as the standard. About 50 μl/mL of the com-
pound in each well.
3.4 | DNA cleavage analysis
efficiency shown in the (Figure 2); the super coiled DNA
was completely converted to form II and form III, and well
defined. The significant activity was shown by simple
indole derivative (5a) and Di‐halogen‐substituted indole
derivatives (5g), (5h), and (5i); least activity was shown
by mono‐halogen‐substituted indole derivative (5b), (5c),
and (5d). Therefore, compounds having ‐CH3 and ‐OCH3
substitutions on 2‐phenylindole moiety were more capable
of abstract hydrogen from deoxyribose sugar to cleave
DNA compare than other substituted indole derivative
The DNA cleavage activity of 3‐methyl‐1‐phenyl‐4‐((2‐
phenyl‐1H‐indol‐3‐yl)methylene)‐1H‐pyrazol‐5(4H)‐ones
(5a‐i) was studied by agarose gel electrophoresis method.
The pictures of gels are presented in Figure 2. DNA cleav-
age study is considered by observing the conversion of
super coiled DNA (form I) to nicked DNA (form II) and lin-
ear DNA (form III) under anaerobic condition. DNA cleav-
age was not observed in (lane 1) in which the compound
was absent. All the compounds (5a‐i) can induce the
observable cleavage of the DNA plasmid at the100‐μM con-
centration. At this concentration, all synthesized com-
pounds can promote 70 to 90% conversion of super coiled
DNA to nicked and linear DNA. It was observed that
DNA cleavage not effective at lower concentrations. The
studies revealed that ‐CH3‐ and ‐OCH3‐substituted indole
derivatives (5e) and (5f) exhibit much higher cleaving
3.5 | Antibacterial studies
All the synthesized compounds (5a‐i) were screened for
their antibacterial activity against Escherichia coli (ATCC
25922) and Staphylococcus aureus (ATCC 29213) by

MODI AND JAIN
9
FIGURE 4 Zone of inhibition (mm) of
compounds 5a‐i against tested fungal
strains [Color figure can be viewed at
wileyonlinelibrary.com]
Kirby‐Bauer well diffusion method with reference to Strep-
tomycin. The observation of antibacterial screening data
revealed that all the tested compounds (5a‐i) showed
promising antibacterial activities. Compound 5e and 5f
showed more potent antibacterial activity with the zone
of inhibition more than 22 mm; this is due to that the
electron‐donating methyl and methoxy substituents on
indole nucleus have enhanced binding interactions with
biological targets. The bacterial zones of inhibition values
are summarized in (Table 3). The bar graph representation
zone of inhibition (mm) of compounds (5a‐i) against tested
bacterial strains is shown in Figure 3.
targets and enhanced interactions with binding sites. Con-
sequently, there is a good scope to develop a synthetic less
harmful drug to reduce oxidative stress and good antioxi-
dant and also capable to inhibit the growth of the patho-
gens by cleaving their genome.
ACKNOWLEDGMENT
One of the authors, Madhuri Modi, is thankful to CSIR
New Delhi for providing Junior Research Fellowship. The
authors thank University of Rajasthan for providing the
necessary facility; MNIT (MRC), Jaipur, for spectral analy-
sis; and Dr. B. Lal Institute of Biotechnology, Jaipur, for
biological activities.
3.6 | Antifungal studies
The antifungal activity of tested compounds (5a‐i) was
compared with Itraconazole (standard), and results are
tabulated in Table 4. The antifungal screening of the com-
pounds revealed good to moderate activity. Compound
(5e) and (5f) were showed good inhibitory activity against
Candida albicans and Aspergillus niger. The bar graph
representation zone of inhibition (mm) of compounds
(5a‐i) against tested fungal strains is shown in Figure 4.
ORCID
Madhuri Modi https://orcid.org/0000-0003-3929-3026
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How to cite this article: Modi M, Jain M. Green
approach for the synthesis of 3‐methyl‐1‐phenyl‐4‐
((2‐phenyl‐1H‐indol 3‐yl)methylene)‐1H‐pyrazole‐
5(4H)‐ones and their DNA Cleavage, antioxidant,
and antimicrobial activities. J Heterocyclic Chem.
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