Synthesis and Antibacterial Activity

Estin Nofiyanti, et al.

Articles

MOLEKUL

eISSN: 2503-0310

https://doi.org/10.20884/1.jm.2025.20.2.5618

Synthesis and Antibacterial Activity of N-phenyl-3-(4-chlorophenyl)-5-(3,4-dimethoxy-phenyl)
pyrazoline
Estin Nofiyanti1*, Tutik Dwi Wahyuningsih3, Noer Laelly BTAG2, Chairil Anwar3, Novi Nurjanah1,
Nurcholis Salman1, Yoga Priastomo3
1

Environmental Engineering Department, Universitas Muhammadiyah Tasikmalaya, 46196 Indonesia
2
Electronichal Engineering Department, Universitas Muhammadiyah Tasikmalaya, 46196 Indonesia
3
Chemical Organic Laboratory, Chemistry Department, Universitas Gadjah Mada,
Yogyakarta 55281, Indonesia
*Correspondence author email: estin.nofi@umtas.ac.id

Received May 13, 2022; Accepted June 15, 2025; Available online July 20, 2025
ABSTRACT. Compound of N-phenyl-3-(4-chlorophenyl)-5-(3,4-dimethoxy-phenyl) pyrazoline was synthesized by
cycloaddition reaction. The structure of the product was chracterized by FTIR, 1H-NMR and 13C-NMR spectrometers. The
pyrazoline was screened for antibacterial activity using agar diffusion method against Staphylococcus aureus, Bacillus cereus,
Bacillus subtillis, Shigella flexnerri, and Escherichia coli. The pyrazoline had been synthesized from chalcone with
phenylhydrazine to give 52.90% yield. Antibacterial screening showed that pyrazoline was active against selected gram
positive bacteria. The pyrazoline was found to exhibits an antibacterial activity and its zone of inhibition/concentration against
S. aureus (8.75/300), B. cereus (7.75/1000), B. subtillis (6.50/1000), and E. coli (3.50/300). The result showed that
pyrazoline which was subtituted with chloro and methoxy, was able to posse broad spectrum of the tested pathogenic
bacteria.
Keywords: chalcone, pyrazoline, antibacterial

INTRODUCTION
Infectious diseases which caused by pathogenic
bacteria are still a public health problem. WHO
reported that infectious diseases are diseases with a
high incidence rate and one of the biggest causes of
death (World Health Organization, 2014). Antibiotics
are the choice in dealing infectious diseases,
especially caused by bacteria. Bacterial resistance to
antibiotics was currently increasing and has become
a major problem in overcoming infectious diseases in
addition to the problems of toxicity and side effects
(Murray et al., 2022). The development of new types
of antibacterial agent needs to be done to solve this
resistance problem. Indonesia is one country which
has many natural products. Vanillin and its derivate
is one of natural product that can used as basic
material aldehyde source.
As a tropical country with numerous natural
resources, Indonesia may be able to develop natural
resources such as vanillin, fennel oil, clove oil, and
patchouli oil as natural igredients that can be
employed as basic materials in the production of
chalcone compound intermediates. One of the raw
materials that can be used is a natural component.
Vanillin is used to make chalcone intermediates.
Vanillin is a naturally occurring substance found in
the Vanilla planifolia plant's fruit (Arya et al., 2021).

Electron-rich nitrogen containing heterocycles
such as pyrazolines have been gaining considerable
amount of attention due to their important role in
drug discovery. Pyrazolines possess a broad spectrum
of microbial activities (Matiadis & Sagnou, 2020;
Matiadis & Sagnou, 2020; Saroja et al., 2021),
antidepressant activity (Popova et al., 2021;
Sharma et al., 2021; Fatmayanti et al., 2024;
Bhakare et al., 2025), anti-inflammatory and
analgesic agents (Cuartas et al., 2020; Ouyang et
al., 2021; Yasar & Zaheer, 2021; Shalaby et al.,
2023; Stessel et al., 2023), anticancer activity
(Matiadis & Sagnou, 2020; Tjitda et al., 2022;
Fatmayanti et al., 2024), antitubercular activity
(Vaddiraju et al., 2021; Gurav et al., 2022; Kumar et
al., 2022; Zala et al., 2025), antioxidant activity
(Lakshminarayanan et al., 2020; Mantzanidou et al.,
2021; Cahyono et al., 2022; Balamon et al., 2023),
anticonvulsant activity (Ray et al., 2023; Chauhan
et al., 2024), antimalarial (Tiwari et al., 2021;
Andhare et al., 2022), antidiabetic activity (R. S.
Kumar et al., 2023; Kafali et al., 2024) and
antihepatotoxic activity (Sathiya et al., 2020).
Antibiotics are the first line of defense in the fight
against infectious diseases, particularly those caused
by bacteria. In addition to the difficulties of toxicity
and side effects, Muteeb et al. (2023) says that
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Molekul, Vol. 20. No. 2, July 2025: 197 – 202
bacterial resistance to antibiotics is currently
increasing and is a serious difficulty in combating
infectious diseases. To combat the problem of
antibacterial resistance, new forms of antibacterials
must be developed.
Some of pyrazoline derivatives which were
subtitued with para chloro, para nitro and hydroxy
in pyrazoline ring C3 position had role increase
antimicrobial (Farooq & Ngaini, 2022). The most
popular method to synthesize pyrazolines is carried
out by under acidic solvent such as using acetic acid
(Saleh et al., 2020; Matiadis, 2023; Anita et al.,
2024; Novaković et al., 2024). The synthesis of Nphenyl pyrazoline of veratradehyde through
cyclization reaction from phenylhydazine and α,βunsaturated ketones in acidic solvent (Mironov et
al., 2021; Annes et al., 2023). The electron-donating
substituents obtained from veratraldehyde were
introduced to evaluate antibacterial activity by invitro assay.
The reaction of chalcone molecules with 2phenylhydrazine can be used to make pyrazoline
compounds, according to the retrosynthetic strategy.
The Claisen-Schmidt condensation reaction can
produce chalcone compounds as intermediates from
aryl aldehyde compounds with aryl ketones. The
Claisen-Schmidt condensation process follows a
simple procedure that involves alkaline stirring.

CDCl3, TMS) δ: 56.14 (OCH3), 56.17 (OCH3),
123.50 & 145.71 (C=C trans), 189.4 (C=O),
110.26, 111.29, 119.59, 127.82, 128.57, 130.01,
136.92, 139.12, 149.44, 151.78 (Ar).

General procedure
pyrazoline (4)

synthesis

of

N-Phenyl

A solution of intermediate product (chalcone) 0.76
mmol in acetic acid glacial and phenylhydrazine (0.76
mmol) was refluxed for 4 h. The mixture was poured
in crushed ice and cooled in refrigerator for 24 h. The
precipitated was filtrated off, washed with aquadest
and ethanol, respectively. No further purification was
required.

N-phenyl-3phenyl) (4)

EXPERIMENTAL SECTION
General remarks
All starting materials and solvents were
commercially available without further purification.
Melting points were measured on a Electrothermal
9100 and are uncorrected. The 1H and 13C-NMR
spectra of the obtained compounds were analyzed by
JEOL JNMECA 500 MHz (1H) and 125 MHz (13C)
spectrometers use internal standard tetramethylsilane.
IR spectra (KBr pellets) were recorded by Shimadzu
prestige-21 spectrophotometer.
Synthetic procedure and characterization data

Procedure synthesis of chalcones

for

The aqueous sodium hydroxide (5 mL, 30%)
was added into mixture of 5 mmol 4chholoroacetophenone and 5 mmol veratraldehyde
in ethanol and the resulting stirred for 4 h under
room temperature. The precipitation was collected
and crystallized by from the appropriate solvents.
1-(4-chlorophenyl)-3-(3,4dimetoxyphenyl)-1propenon (3). Yield: 79.07%; mp: 99 oC; νmax
(KBr)/cm-1: 987 (C=C trans); 2731&2839 (C-H
aldehyde), 1658 (C=O), 1157&1026 (Ar-Cl). 1HNMR (500 MHz, CDCl3, TMS) δ: 3.93 (3H, s, -OCH3),
3.94 (3H, s, -OCH3), 6.89 (1H, d, J = 8.40 Hz, Ar-H),
7.14 (1H, d, J = 1.95 Hz, Ar-H), 7.23 (1H, dd, J =
8.45 & 1.95 Hz, Ar-H), 7.33 (1H, d, J = 15.5 Hz,
C=C trans), 7.46 (2H, dd, J = 8.75 & 2.00 Hz, Ar-H),
7.76 (1H, d, J = 15.5 Hz, C=C trans), 7.95 (2H, dd,
J = 6.50 & 1.95 Hz, Ar-H). 13C-NMR (125 MHz,

(4-chlorophenyl)

-5-(3,4-dimethoxy-

Yield 52.9%; as a yellow solid; m.p. 143-144 C.
IR: νmax (KBr)/cm-1: 1597 (C=N), 1242 (C-N), 1465 &
1496 (aromatic C=C), 1381 (C-O-C Methoxy). 1HNMR (500 MHz, CDCl3, TMS) δ: 3.10 (1H, dd, J =
17.00, 7.80 Hz, CH2), 3.78 (1H, dd, J = 17.25, 12.35
Hz, CH2), 3.81 (3H, s, OCH3), 3.85 (3H, s, OCH3),
5.20 (1H, dd, J = 12.32, 7.80 Hz, CH), 6.81 (1H, m,
ArH), 6.87 (1H, dd, J = 8.45, 1.95 Hz, ArH), 7.08
(2H, d, J = 7.75 Hz, ArH), 7.18 (2H, t, ArH), 7.35,
7.64 (4H, d, ArH). 13C-NMR (125 MHz, CDCl3, TMS)
δ: 29.53 (CH2), 29.87 (CH), 55.83 & 56.04 (CH3-O),
104.60, 111.52, 121.62, 122.85, 125.70, 127.49,
129.01, 129.16, 131.56, 133.99, 140.07, 144.79,
148.72, 149.30 (Ar), 150.78 (C=N).
Antibacterial activity
The pyrazoline 4 was in vitro assayed by cup plate
method for antibacterial activity against Bacillus
Subtillis FNCC 0041, Bacillus Cerreus FNCC 0040,
Staphylococcus Aureus FNCC 0047, Escherichia Coli
FNCC 0091, Shigella Flexnerrii ATCC 12022
obtained from Biotechnology laboratory, Universitas
Gadjah Mada Yogyakarta, Indonesia. The tested
solutions were prepared by dissolving the compound
in DMSO at 100, 300, 500, 1000 µg/mL
concentrations. DMSO used as a control test to be
inactive. The tested solution series were added into cup
of plate and incubated at 37 ºC for 24 h. The
inhibition zones were measured.
RESULTS AND DISCUSSION
Chemistry
The synthesis of N-phenyl-3-(4-chlorophenyl)-5(3,4-dimethoxy-phenyl) (4) was accomplished by
cyclo-condensation of chalcones 3 (Figure1). The
chalcones 3 has been synthesized from the
halogenated acetophenone and veratraldehyde by
Claisen-Schmidt condensation. The structures of
chalcones were supported by several spectral. Thus, IR
spectra showed the appearing band at 972 cm-1
indicated C=C trans. The absence bands at 2746 and
2846 cm-1 indicated the vibration of C-H aldehyde.
1
H-NMR spectra indicated the appearance of
duplets signals (~7.20-7.70 ppm). New signals

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Synthesis and Antibacterial Activity

Estin Nofiyanti, et al.

corresponded to the allylic trans hydrogens by
calculating coupling constant (J = 15.5 Hz);
corresponding signals were also observed in 13C-NMR
spectra.
The compound 4 has been achieved by hetero
cyclo-condensation between chalcone 3 and Phenyl
hydrazine. The reactions was performed using
acetic acid glacial. Cyclization of chalcone to NPhenyl
pyrazoline was
proved by important
spectral changes. Thus, IR spectroscopy showed
the absence of the carbonyl adsorption bands
(~1600 cm-1) and of the double bond allylic trans
(~972cm-1) and the presence of new adsorption
band (~1597 cm-1) of heterocyclic ring. In the
1
HNMR spectra, the presence of new signals
corresponded to the methylene and methine of
hetero ring (~3.80 & ~5.12 ppm). 13CNMR spectra
confirmed the absence signals of the carbonyl
and allylic trans (~189.5 and ~123.7 & ~ 145.9
ppm) and showed new signals at ~ 43.80 &
~56.48 ppm corresponding to the methylene and
methine of hetero ring.

CH3

OCH3

O

O
Cl

Biology
The compound was tested against Gram-Positive
bacteria: B. cereus FNCC 0040, B. Subtillis FNCC
0041 and S. Aureus FNCC 0047 and against GramNegative bacteria: E. Coli FNCC 0091 and S. Flexnerii
ATCC 12022 using agar diffusion method. The
inhibitor zone values of these compounds against
these bacteria are presented in Table 1 tetracycline as
known commercially antibiotic was also tested. The
result showed that the compound exhibited
antibacterial activities. The best of inhibition zone
value was obtained against Gram-Positive bacteria
S. aureus at 300 µg mL-1. Antibacterial screening
showed that chloropyrazoline was active against
selected gram positive bacteria. The pyrazoline was
found to exhibits an antibacterial activity and its zone
of inhibition/concentratio n against S. aureus
(8.75/300), B. cereus (7.75/1000), B. subtillis
(6.50/1000), and E. coli (3.50/300). The result
showed that the pyrazoline which was subtituted with
chloro and methoxy, was found to exhibits an
antibacterial activity.

OCH3

+

1

Cl

OCH3

ii

OCH3

O

2

3
+

HN
H2N
iii
Cl
OCH3
OCH3

N N

4

Figure 1. Cyclization of the chalcone (3) with phenylhydrazine in acetic acid glacial form N-phenyl
pyrazoline (4). Reagents and conditions: (ii) ethanol, NaOH 30%, room temperature. (iii)
CH3COOH, PhNHNH2, refluxed, 4 h.
Table 1. Antibacterial activity of the compound 4
Compound

Concentration (µg
mL-1)

S.

B.

aureus

cereus

Inhibition zone (mm)
B.
E.
S. flexnerrii

subtilis

coli

100
7.50
3.75
2.25
4
300
8.75
2.75
3.50
500
6.25
5.50
3.75
2.75
1000
3.75
7.75
6.50
3.25
Tetracycline
100
20.75
20.25
20.25
12.25
14.25
DMSO
99.9%
0.75
Zone of Inhibition: -: < 1mm (no activity); +:1-4 (weak activity); ++:5-9 (moderate activity); +++:1015 (strong activity), ++++: > 16 (Very strong activity)
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CONCLUSIONS
The product of N-phenyl-3-(4-chlorophenyl)-5(3,4-dimethoxy-phenyl) pyrazoline 4 was synthesized
by cycloaddition reaction. The pyrazoline had been
synthesized from derivate vanillin (veratraldehyde) to
give 52.90% yield. Antibacterial screening showed
that pyrazoline was active against selected gram
positive bacteria. The pyrazoline was found to
exhibits an antibacterial activity and its zone of
inhibition/concentration against S. aureus (8.75/300),
B. cereus (7.75/1000), B. subtillis (6.50/1000), and E.
coli (3.50/300). The result showed that pyrazoline 4
which was subtituted with chloro and methoxy, was
able to posse broad spectrum of the tested pathogenic
bacteria. of the tested pathogenic bacteria.
ACKNOWLEDGMENTS
The author wishes to express his gratitude to
UMTAS for funding this research through internal
basic research funds, as well as the Gadjah Mada
University Chemistry Laboratory for allowing us to
conduct sample testing.
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