Synthesis, crystal structure, Hirshfeld surface analysis, biological evaluation, DFT calculations, and in silico ADME analysis of 4-arylidene pyrazolone derivatives as promising antibacterial agents

Article abstract of DOI:10.1016/j.molstruc.2020.129586

The present paper describes an ultrasound-assisted synthesis of a series of 4-arylidene-1H-pyrazol-5(4H)-one derivatives (3a-i) catalyzed by sulfamic acid. The prepared compounds were characterized by physical and spectroscopic techniques and for compound

Full text of DOI:10.1016/j.molstruc.2020.129586

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Synthesis, crystal structure, Hirshfeld surface analysis, biological
evaluation, DFT calculations, and in silico ADME analysis of
4-arylidene pyrazolone derivatives as promising antibacterial agents
Imene Sehout , Houssem Boulebd , Raouf Boulcina ,
Sara Nemouchi , Lamia Bendjeddou , Amina Bramki ,
Hocine Merazig , Abdelmadjid Debache
PII:
S0022-2860(20)31900-1
DOI:
Reference:
https://doi.org/10.1016/j.molstruc.2020.129586
MOLSTR 129586
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Journal of Molecular Structure
Received date:
Revised date:
Accepted date:
20 September 2020
21 October 2020
3 November 2020
Please cite this article as: Imene Sehout , Houssem Boulebd , Raouf Boulcina , Sara Nemouchi ,
Lamia Bendjeddou , Amina Bramki , Hocine Merazig , Abdelmadjid Debache , Synthesis, crystal
structure, Hirshfeld surface analysis, biological evaluation, DFT calculations, and in silico ADME analy-
sis of 4-arylidene pyrazolone derivatives as promising antibacterial agents, Journal of Molecular Struc-
ture (2020), doi: https://doi.org/10.1016/j.molstruc.2020.129586
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Highlights

An ultrasound-assisted synthesis of a series of pyrazolone derivatives has been
described.




Single crystal X-Ray diffraction analysis of compound 3i has been reported.
Theoretical calculations using DFT/B3LYP method have been performed.
The antibacterial activity of all the synthesized compounds was evaluated.
In silico ADME parameters have been studied.
1

Synthesis, crystal structure, Hirshfeld surface analysis, biological evaluation, DFT
calculations, and in silico ADME analysis of 4-arylidene pyrazolone derivatives as
promising antibacterial agents
1
1,*
1
1
2
Imene Sehout , Houssem Boulebd , Raouf Boulcina , Sara Nemouchi , Lamia Bendjeddou ,
3
2
1,*
Amina Bramki , Hocine Merazig , Abdelmadjid Debache
1
Laboratory of Synthesis of Molecules with Biological Interest, University of Frères Mentouri
Constantine 1, Constantine, Algeria.
2
Unité de Recherche Chimie de l’Environnement et Moléculaire Structurale, Université
Frères Mentouri Constantine 1, 25000, Constantine, Algeria
3
Laboratory of Mycology, Biotechnology and Microbial Activity, Mentouri Constantine 1
University, 25000 Constantine, Algeria.
*
Corresponding authors: boulebd.houssem@umc.edu.dz (H. Boulebd); a_debache@yahoo.fr
(A. Debache)
Abstract
The present paper describes an ultrasound-assisted synthesis of a series of 4-arylidene-1H-
pyrazol-5(4H)-one derivatives (3a-i) catalyzed by sulfamic acid. The prepared compounds
were characterized by physical and spectroscopic techniques and for compound 3i by single
crystal X-ray diffraction analysis. Theoretical calculations such as molecular structure
optimization, frontier molecular orbitals, molecular electrostatic potential, and molecular
descriptors have been performed in order to get insight into the molecular structure and
chemical reactivity of the synthesized compounds. The antibacterial activity of all compounds
was assessed against six bacterial strains, and it was found that these compounds are good
inhibitors of Gram-positive bacteria rather than Gram-negative. In addition, good oral
bioavailability was predicted for all compounds by in silico calculations of ADME
(absorption, distribution, metabolism, and elimination) and pharmacokinetic parameters.
Keywords: Pyrazolone; crystal structure; DFT calculations; antibacterial activity; ADME
parameters.
2

1
. Introduction
Heterocycles constitute the basic skeleton for a large variety of compounds with chemical,
biological, pharmacological, and industrial interests [1]. Consequently, heterocyclic chemistry
became the center of interest of a great community of experimental chemists and theorists.
Also, a large number of biologically active natural substances are heterocyclic compounds [2,
3
]. Among them, pyrazole is an integral part in several biologically active natural products, in
particular alkaloids [4]. These derivatives attracted much attention in recent years, because of
their numerous applications as pharmaceutical agents, photographic couplers, chelating agents
in coordination chemistry, and agrochemical products [5-8].
Pyrazolones are a very important class of the pyrazole family, they are known since
more than one century [9]. This scaffold is present in a number of commercial drugs. For
example (Figure 1), phenazone is a pyrazolone derivative with analgesic and anti-
inflammatory properties [10]. Metamizole is a pyrazolone derivative that acts as an
antipyretic and has modest analgesic and spasmolytic properties [11]. Propyphenazone has
anti-inflammatory, analgesic, and antipyretic activities [12]. Also, benzpiperylone is used as
an anti-inflammatory agent [13]. Other pyrazolone derivatives have been reported to exhibit
several biological activities such as antioxidant [14], antitumor [15], anti-tuberculosis [16],
anti-cancer [17], anti-inflammatory [18], and antimicrobial [19-21]. Their analogues were
also employed as fluorescent herbicide [22], dyes and pigments [23], chelating agents [24],
and polymers [25]. The various applications of these compounds aroused a great interest on
behalf of chemists by searching for new biologically active molecules and by the
development of new methods leading to this kind of compounds. In this context, ultrasonic
organic synthesis is considered as green approach towards organic synthesis as it offers
simple, clean, fast, efficient and economic technique for organic synthesis [26, 27].
3

Figure 1. Some commercialized drugs based on pyrazolone scaffold.
As part of an ongoing program in search of new methods of organic synthesis [28-31],
as well as the development of new biologically active compounds [31, 32], we present in this
paper a simple, rapid, and high yielding ultrasonic synthesis of a series of 4-arylidene
pyrazolone derivatives 3a-i. Molecular structures of these compounds were fully
characterized by various physical and spectroscopic techniques, and also, in the case of
compound 3i, by X-ray crystal structure analysis. Theoretical calculations based on
DFT/B3LYP method were performed in order to get insight into the molecular structure and
chemical reactivity of compound 3i as representative molecule. Antibacterial activity of the
synthesized compounds was evaluated against six bacterial strains; Staphylococcus aureus,
Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, and
Klebsiella pneumoniae. Finally, in silico ADME calculations were carried out in order to
investigate the pharmacokinetic profile of the prepared compounds.
4

2
2
. Experimental section
.1. Materials and instrumentation
All reagents as well as the solvents were acquired from Sigma Aldrich and employed without
1
13
further purification. H NMR and C NMR spectra were determined using Brucker 250 and
4
00 MHz spectrometers. J values are in hertz (Hz). Chemical shifts are expressed in parts per
million downfield from internal standard TMS. Ultrasonication was performed in a Bandelin
SONOREX Digital 10 P ultrasonic bath with a frequency of 35 kHz (Built-in heating, 30−80
°
C thermostatically adjustable). The reaction flask was located at the maximum energy area in
the cleaner, and the surface of the reactants was placed slightly lower than the level of the
water. Observation of the surface of the reaction solution during vertical adjustment of vessel
depth will show the optimum position by the point at which maximum surface disturbance
occurs. Crystal suitable for single crystal X-ray diffraction was selected using a polarizing
microscope. The crystal was coated with Paratone oil and mounted on a loop for data
collection and the lattice parameters were determined using a Bruker APEX II CCD
diffractometer (SADABS; Sheldrick, 2002).
2
.2. Synthesis
4
-Arylidene pyrazolone derivatives were prepared as follows: to a mixture of aldehyde
derivatives and 3-methyl-1-phenyl-pyrazol-5-one in the proportions (1:1) molar in the
presence of 5 mL of ethanol, was added a catalytic amount of sulfamic acid (10 mol %). The
reaction was carried out under ultrasonic irradiation (100 %: 35 kHz) at 35 °C. The reaction is
monitored by TLC using ethyl acetate/hexane as eluent. After completion, the reaction
mixture was allowed to cool to room temperature. Then 5 mL of petroleum ether was added.
The precipitate formed is recovered by filtration and recrystallized from ethanol to give pure
products in good to excellent yields.
5

(E)-4-(2,3,4-Trimethoxybenzylidene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (3a): Yellow
1
crystals, yield 61%, M.p = 213-215 ºC. H NMR (250 MHz, DMSO-d ): δ 7.60 (d, J = 8.1 Hz,
6
2
2
6
3
H, Ar-H), 7.30 (s, 1H, H-CSp ), 7.25 (d, J = 8.2 Hz, 2H, Ar-H), 7.03-7.09 (m, 1H, Ar-H),
.50 (d, J = 8.5 Hz, 1H, H-Ar), 6.15 (d, J = 8.4 Hz, 1H, Ar-H), 3.68 (s, 9H, OCH ), 2.34 (s ,
3
13
3
H, CH ). C NMR (62.5 MHz, DMSO-d ): δ 164.3 (CO), 149.1 (C-Ar), 148.8 ( C), 147.3
3
6
2
4
(
Csp ), 142.6 (C-Ar), 139.0 (C-Ar), 136.7 (C-Ar), 128.0 ( C), 126.6 (C-Ar), 124.8 (C-Ar),
22.1 (C-Ar), 119.4 (C-Ar), 108.2 (C-Ar), 107.2 (C-Ar), 50.1 (OCH ), 13.6 (CH ).
1
3
3
(E)-4-(2,4-Dimethylbenzylidene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (3b): Yellow
1
crystals, yield 61%, M.p =193-195 ºC. H NMR (400 MHz, DMSO-d ): δ 8.66 (d, J = 12 Hz,
6
1
7
H, Ar-H), 7.94-7.99 (m, 2H, Ar-H), 7.30 (s, 1H, H-Sp2), 7.41 (t, J = 12 Hz, 2H, Ar-H), 7.10-
.13 (m, 1H, Ar-H), 6.85 (d, J = 8.0 Hz, 2H, Ar-H), 3.13 (s, 6H, 2CH ), 2.30 (s, 3H, CH ).
3
3
1
3
3
2
C NMR (100 MHz, DMSO-d ): δ 162.9 (CO), 154.3 ( C), 152.0 (Csp ), 148.6 (C-Ar), 139.4
6
4
(
C-Ar), 137.9 (C-Ar), 129.2 ( C), 124.4 (C-Ar), 121.7 (C-Ar), 119.5 (C-Ar), 118.6 (C-Ar),
4
2
1
11.8 (C-Ar), 40.4 ( CH ), 39.8 (CH ), 13.7 ( CH ).
3 3 3
(E)-4-(3-Hydroxy-4-methoxybenzylidene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one
(3c):
1
Yellow crystals, yield 85%, M.p =224-226 ºC. H NMR (400 MHz, DMSO-d ): δ 8.46 (m,
6
3
4
1
H, Ar-H), 8.03 (dd, J =12.0 Hz , J =4.0 Hz, 1H, Ar-H), 7.93 (d, J =8.0 Hz, 2H, Ar-H), 7.65
2
(
s, 1H, H-CSp ), 7.43 (t, J =12 Hz, 2H, Ar-H), 7.18 (t, J = 8.0 Hz, 1H, Ar-H), 7.12 (d, J =
1
3
1
1
2.0 Hz, 1H, Ar-H), 3.91 (s, 3H, CH ), 2.32 (s, 3H, CH ). C NMR (100 MHz, DMSO-d ): δ
3 3 6
3
2
62.2 (CO), 153.4 (C-Ar), 152.2 ( C), 149.2 (Csp ), 146.5 (C-Ar), 138.8 (C-Ar), 129.7 (C-
4
Ar), 129.2 ( C), 126.9 (C-Ar), 124.8 (C-Ar), 123.8 (C-Ar), 120.4 (C-Ar), 118.7 (C-Ar), 112.0
(
C-Ar), 56.2 (OCH ), 13.6 (CH ).
3 3
(E)-3-Methyl-1-phenyl-4-(thiophen-2-ylmethylene)-1H-pyrazol-5(4H)-one
(3d):
Yellow
1
crystals, yield 75%, M.p = 121-123 ºC. H NMR (250 MHz, DMSO-d ): δ 7.64 (d , J = 8.7
6
2
Hz, 1H, Ar-H), 7.60 (d, J = 8.5 Hz, 1H, Ar-H), 7.32 (s, 1H, H-CSp ), 7.30 (d, J = 8.1Hz, 2H,
6

Ar-H), 7.25-7.29 (m, 1H, H-Ar), 7.14-7.19 (m, 1H, Ar-H), 6.90 (d, J=8.5 Hz, 2H, Ar-H), 2.31
13
3
2
(
s, 3H, CH ). C NMR (62.5 MHz, DMSO-d ): δ 164.1 (CO), 146.8 ( C), 140.2 (Csp ), 137.5
3 6
4
(
C-Ar), 137.2 ( C), 130.1 (C-Ar), 129.9 (C-Ar), 129.0 (C-Ar), 128.5 (C-Ar), 126.8 (C-Ar),
1
24.1 (C-Ar), 120.8 (C-Ar), 13.4 (CH3).
(E)-4-(4-methoxybenzylidene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one)
(3e):
Yellow
1
crystals, yield 75%, M.p = 135-137 ºC. H NMR (250 MHz, DMSO-d ): δ 8.54 (d, J = 8.9 Hz,
6
2
2
H, Ar-H), 7.89 (d, J = 8.2 Hz, 2H, Ar-H), 7.34 (s, 1H, H-CSp ), 7.32 (d, J = 8.1Hz , 2H, Ar-
H), 7.10 (t , J = 14.8 Hz, 1H, Ar-H), 6.94 (d, J = 8.8 Hz, 2H, Ar-H), 3.84 (s, 3H, OCH ), 2.24
3
1
3
3
(
s, 3H, CH ). C NMR (62.5 MHz, DMSO-d ): δ 163.2 (CO), 161.6 (C-Ar), 150.6 ( C),
3
6
2
4
1
46.5 (Csp ), 138.0 (C-Ar), 136.2 (C-Ar), 128.1 ( C), 125.7 (C-Ar), 124.0 (C-Ar), 119.3 (C-
Ar), 118.3 (C-Ar), 113.6 (C-Ar), 55.0 (OCH ), 12.8 (CH ).
3
3
(Z)-4-((1H-indol-2-yl)methylene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (3f): Yellow
1
crystals, yield 78%, M.p = 241-243 ºC. H NMR (400 MHz, DMSO-d ): δ 12.06 (s, 1H, NH),
6
2
9
7
.86 (s, 1H, H-Ind), 8.00-7.97 (m, 2H, Ar-H), 7.90-7.82 (m, 2H, Ar-H), 7.25 (s, 1H, H-CSp ),
1
3
.48-7.23 (m, 4H, Ar-H), 7.14-7.08 (m, 1H, Ar-H), 2.36 (s, 3H, CH ). C NMR (100 MHz,
3
3
4
DMSO-d ): δ 162.8 (CO), 150.5 ( C), 138.6 (C-Ar), 138.2 (C-Ar), 136.3 ( C), 135.9 (C-Ar),
6
2
1
32.9 (C-Ar), 128.2 (Csp ), 128.0 (C-Ar), 123.7 (C-Ar), 123.5 (C-Ar), 121.8 (C-Ar), 118.4
(C-Ar), 117.2 (C-Ar), 112.4 (C-Ar), 112.1 (C-Ar), 12.7(CH3).
(E)-4-(4-hydroxybenzylidene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one
(3g):
Yellow
1
crystals, yield 82%, M.p = 231-233 ºC. H NMR (250 MHz, DMSO-d ): δ 10.45 (s, 1H, OH),
6
2
8
.48 (d, J = 8.7 Hz, 2H, Ar-H), 7.88 (d , J = 8.6 Hz, 2H, Ar-H), 7.37 (s, 1H, H-CSp ), 7.31 (d,
J = 8.3 Hz, 2H, Ar-H), 7.12-7.06 (m, 1H, Ar-H), 6.87 (d, J = 8.7 Hz, 2H, Ar-H), 2.27 (s, 3H,
1
3
3
CH3). C NMR (62.5 MHz, DMSO-d ): δ 162.8 (CO), 161.8 (C-Ar), 150.9 ( C), 147.5
6
2
4
(
Csp ), 136.9 (C-Ar), 128.2 ( C), 124.0 (C-Ar), 122.8 (C-Ar), 119.6 (C-Ar), 115.6 (C-Ar),
1
2.9 (CH3).
7

(E)-4-(4-(dimethylamino)benzylidene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (3h): Yellow
1
crystals, yield 84%, M.p = 191-193 ºC. H NMR (250 MHz, DMSO-d ) : δ 8.57-8.53 (m, 2H,
6
2
H-Ar), 7.91 (d, J = 7.8 Hz , 2H, Ar-H), 7.28-7.34 (m, 2H, Ar-H), 7.26 (s, 1H, H-Sp ), 7.07 (t ,
1
3
J = 7.4 Hz, 1H, Ar-H), 6.67 (d, 2H, Ar-H), 3.09 (s, 6H, 2CH ), 2.26 (s, 3H, CH ). C NMR
3
3
3
2
(
62.5 MHz, DMSO-d ): δ 162.2 (CO), 153.2 (C-Ar), 150.8 ( C), 147.2 (Csp ), 138.5 (C-Ar),
6
4
1
36.9 (C-Ar), 128.1 ( C), 123.6 (C-Ar), 121.0 (C-Ar), 119.7 (C-Ar), 118.3 (C-Ar), 110.7 (C-
Ar), 39.5 (N(CH ) ), 12.9 (CH ).
3
2
3
(E)-4-(3,5-dimethoxybenzylidene)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one
(3i):
Red
1
crystals, Yield 87%, M.p = 133-135 ºC. H NMR (400 MHz, DMSO-d ) : δ 7.87-7.93 (m, 3H,
6
Harom), 7.41-7.48 (m , 2H, Ar-H), 7.73 (s, 1H, H-Cethylenic), 7.17-7.23 (m, 2H, Ar-H), 6.76-6.75
1
3
(
m, 1H, Ar-H), 3.82 (s, 6H, OCH ), 2.31 (s, 3H, CH ). C NMR (100 MHz, DMSO-d ): δ
3 3 6
3
2
1
61.8 (CO), 160.7 (C-Ar), 160.6 (C-Ar), 152.2 ( C), 148.9 (Csp ), 138.5 (C-Ar), 135.0 (C-
4
Ar), 129.4 (C-Ar), 127.4 (C-Ar), 125.1 ( C), 118.9 (C-Ar), 118.3 (C-Ar), 111.8 (C-Ar), 109.0
(
C-Ar), 106.3 (C-Ar), 55.9 (OCH ), 13.5 (CH ).
3 3
2
.3. Crystal structure analysis
X-ray diffraction data were acquired at 293 K on a Bruker APEX II CCD diffractometer
employing graphite crystal monochromatized MoKα radiation source (0.71073A). Data
collection, indexing with reduction and absorption corrections were carried out using APEX2,
SAINT and SADABS programs, respectively. The structure was solved using direct methods
(SIR92) [33] and refined by full-matrix least-squares techniques on F2 with SHELXL-2014
[
34] operating within WinGX [35]. All H atoms were positioned geometrically and refined as
riding atoms, with C-H = 0.93 and 0.96 aromatic and methyl respectively; and constrained to
ride on their parent atoms, with U iso (H) = 1.2U eq. General crystallographic details for the
3
i are provided in Table 1. The figures were made using the Mercury program [36]. CCDC
number 2012606 contains the supplementary crystallographic data for this paper. These data
8

can be obtained free of charge from The Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk/data_request/cif.
Table 1. Single-crystal X-ray data and structure refinement details for 3i.
Compound
Formula
3i
C H N O
1 3
9
18
2
M r
322.35
296
Temperature/K
Wavelength/Å
Crystal system
Space group, N°
a/Å
0.71073
Triclinic
̅
P1, 2
7.4058(7)
10.0747(8)
11.644(1)
71.265(4)
78.205(5)
83.181(4)
804.05(12)
2
b/Å
c/Å

/ °


/ °
/ °
3
V/Å
Z
-1
μ(mm )
0.09
-3
D (g cm Å )
1.331
c
Diffractometer
Bruker APEX-II CCD
-
Absorption correction
No. of measured, independent and
observed
14493/4015/2991
[
I> 2σ(I)] reflections
Rint
0.047
Data/restraints/parameters
4015/0/217
0.059 / 0.203
1.07
R /wR [I > 2(I) ]
1
2
2
Goodness-of-fit on F
−
3
Δρmax, Δρmin (e Å )
0.27 / - 0.19
9

2
.4. Computational details
Density functional theory (DFT) calculations have been carried out using Gaussian09
software [37]. The B3LYP functional [38, 39] and the 6-311G(d,p) basis set have been used
for all calculations [40, 41]. All of the ground states were confirmed by vibrational frequency
analysis (no imaginary frequency). Electronegativity, chemical softness, chemical hardness,
and electrophilic index were calculated from HOMO/LUMO energies method as reported in
our previous studies [42-45].
2
2
.5. Antibacterial activity evaluation
.5.1. Preparation of microorganism tests
Microbial support is composed of six bacterial strains: four ATCC strains (American Type
Culture Collection), which are: Staphylococcus aureus (ATCC 25923), Bacillus subtilis
(ATCC 6633), Escherichia coli (ATCC, 25922), Pseudomonas aeruginosa (ATCC, 27853),
and two clinical strains namely Enterococcus faecalis and Klebsiella pneumoniae.
Antibacterial tests were performed from young cultures (18 to 24 h), in the exponential
growth phase. The opacity of the bacterial suspensions in sterile physiological water was
6
equivalent to 0.5 McFarland (a bacterial concentration estimated at 10 CFU/mL) [46].
2
.5.2. Discs technique
To evaluate the antibacterial activity of the prepared compounds, they were dissolved in
dimethylsulfoxide (DMSO) in order to obtain a concentration of 10 mg/mL. Then, sterile
discs of 6 mm diameter were prepared from Whatman paper No. 1, containing 10 μL of the
products. After drying, the discs were carefully placed on Petri dishes containing Mueller-
Hinton medium previously seeded by the tested bacteria. Before incubation at 37°C, the
dishes were left for 2h at 4°C to allow the diffusion of the bioactive substances [47, 48].
Results’ reading was done after 18 to 24 h. The antibacterial activity was evaluated by
measuring the zone of growth inhibition of bacteria surrounding the wells. Ciprofloxacin
1
0

served as the positive control. DMSO was taken as the negative control which did not produce
any significant zone of inhibition. Any extending of inhibition zone around discs, even a
small diameter, was considered as a positive result. It should be noted that three repetitions
were performed, and the diameters of the inhibition zones were measured in millimeter.
3
3
. Results and discussion
.1. Synthesis
In order to optimize the reaction conditions, the condensation of 3-methyl-1-phenyl-5-
pyrazolone with 4-hydroxybenzaldehyde was chosen as a reaction model. Initial study on
Knoevenagel condensation was tested in EtOH at room temperature in the presence of
sulfamic acid (10 mol%) as catalyst, but the reaction rate decreased and did not complete even
after 3 h (Table 2, entry 1). The same reaction was then conducted at reflux (Table 2, entry 2)
then at 35 ºC under ultrasound irradiations (Table 2, entry 3). According to the obtained
results, the reaction works better with ultrasonic irradiations.
In the next step, a number of solvents such as EtOH, EtOH/H O, THF, and ethyl
2
acetate were also tested while fixing the catalytic amount of sulfamic acid (10 mol%), the
temperature at 35 ºC, and the ultra-sound frequency (Table 2, entries 4-6). It was found that
the use of ethanol as a solvent dramatically reduces the reaction time with improved product
yield.
After that, we evaluated the required amount of the catalyst for this condensation. In
the presence of 5 mol% of the catalyst, the reaction proceeded efficiently after 4.5 h (Table 2,
entry 7). By further increasing the catalyst amount, no appreciable improvement in the
product yield and reaction time was observed (Table 2, entries 8 and 9).
To determine the appropriate temperature of this condensation, we investigated the
model reaction using 10 mol% of the catalyst at different temperatures: 25, 45, and 65 ºC
1
1

(Table 2, entries 10-12), however, the product yield diminished to 34, 10, and 51%
respectively, indicating that a 35 ºC was adequate for optimal results considering the reaction
time and product yield (Table 2, entry 3).
In continuation of this method, to further improve the yield and decrease the reaction
time, the effect of various amplitude of ultrasonic irradiation on the reaction was studied
(Table 2, entries 13-15). As shown in Table 2, the best result was found with an amplitude of
1
00% with 83% isolated yield after 0.5 h (Table 2, entry 3). Therefore, the optimal conditions
for the synthesis of pyrazolone derivatives are the use of 10 mol% of sulfamic acid in ethanol
at 35°C under ultrasonic irradiation (100% of amplitude).
Table 2. Optimization of the operating conditions for the synthesis of arylidene pyrazolone 3g
(equimolar reaction of 3-methyl-5-phenyl-pyrazol-5-one and 4-hydroxybenzaldehydes in the
presence of sulfamic acid as catalyst).
Ultrasound
amplitude
Cat.
T
Time
(h)
Yield
Entry
1
Solvent
EtOH
*
(
mol %)
(°C)
(%)
(
-
-
%)
Ref
lux
R.T
35
35
35
35
35
35
35
25
45
65
10
3
80
2
3
4
5
6
7
8
9
EtOH
EtOH
10
10
10
10
10
5
3
0.5
2
49
83
87
51
59
82
30
73
34
10
51
100
100
100
100
100
100
100
100
100
100
THF
Aqueous EtOH
Ethyl acetate
EtOH
6
6
4.5
5
EtOH
20
30
10
10
10
EtOH
6
1
1
1
0
1
2
EtOH
2
EtOH
1
EtOH
1
1
2

1
1
1
3
4
5
EtOH
EtOH
EtOH
10
10
10
35
35
35
80
50
30
0.75
0.5
52
72
32
0.5
*
Yield of the isolated product
Using the optimized reaction conditions, a series of pyrazolone derivatives was
synthesized as shown in Table 3. As can be seen from Table 3, the reaction was found to be
general and applicable to the aromatic aldehydes bearing various substituents such as nitro,
chloro, methyl, methoxyl, hydroxyl, and N,N-dimethylamino, etc. Furthermore, in the case of
heteroaromatic aldehydes such as 2-thiophenecarboxaldehyde (compound 3d) and 3-
indolcarboxaldehyde (compound 3f), the reactions also could proceed smoothly under the
reaction conditions led to the formation of the corresponding compounds in good yields. The
experimental results show that both aromatic aldehydes bearing electron-withdrawing or
electron-donating groups reacted easily to afford the desired products in high yields. The
1
proposed molecular structures of the synthesized compounds were confirmed by H NMR and
1
3
C NMR, spectroscopy techniques and, for compound 3i, by single crystal X-ray diffraction
analysis.
1
3

Table 3. Sulfamic acid–catalyzed synthesis of arylidene pyrazolones 3a-i under ultrasonic
irradiation.
Compound
R
Times (min)
Tfus(°C)
Yields (%)
3
a
3,4,5-(OCH
3
)
3
-C
6
H
2
60
180
45
213-215
193-195
224-226
121-122
135-137
241-243
231-233
191-193
133-135
61
61
85
75
75
78
83
84
87
3
b
2,4-(CH
3-OH-4-CH
Thiophen-2-yl
4-OCH -C
1H-indol-2-yl
4-OH-C
4-N(CH
3,5-(OCH
3
)
2
-C
6
H
3
3
c
-C H
3 6 3
3
d
130
40
3
e
3
H
6 4
3
f
90
3
g
6
H
4
30
3
h
3
)
2
-C
6
H
4
150
120
3
i
3
)
2
-C
6
H
3
We propose a plausible mechanism for the formation of the synthesized pyrazolones
Scheme 2). In the first step, sulfamic acid plays two roles: that of protonating the aldehyde
(
function, which thus promotes the nucleophilic attack on the electropositive center of the
carbonyl, while the second is the removal of hydrogen from the active methylene of
pyrazolone. The hydroxypyrazolone intermediate which is rapidly formed gives rise to the
formation of the desired products after dehydration.
1
4

Scheme 2. Proposed mechanism for the synthesis of pyrazolone derivatives 3a-i.
3
.2. Crystal structure
Single-crystal structure analysis shows that compound 3i crystallizes in the triclinic space
̅
group P1, with one symmetry-independent molecule in the asymmetric unit (Figure 2). All
bond lengths and angles in this compound have regular values [49]. For example, the C7—O1
bond length of 1.2148(1) Å is in good agreement with that for a C=O double bond. The C9-
N2 bond length of 1.2906 (1) Å is consistent with that for a normal C=N double bond, which
indicates that the compound exists in the keto form. The phenyl, benzene and pyrazolone
rings systems are essentially planar with maximum deviations from the mean plane of 0.0011,
0
.0117, 0.0025 respectively. The mean plane of the phenyl ring system subtends a dihedral
angle of 5.20 (7)Å with the pyrazolone ring, which is close to the value of 6.2 (2) and 7.58
12) Å reported for a related compound, 4-isopropylidene-3-methyl-1-(3-nitrophenyl)-1H-
pyrazol-5(4H)-one and 1-(3-Methyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazol-4-ylidene)
propyl] benzene sulfonohydrazide respectively which also exist in the keto form [50, 51];
(
1
5

while the dihedral angle between the benzene ring system and the pyrazolone ring system is
.38(8) Å.
3
Figure 2. ORTEP view of the asymmetric unit of title compound, showing the atom
numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.
The structure of title compound contains two distinct intramolecular hydrogen bonds
between the oxo group of pyrazolone and the carbon atoms from phenyl and benzene
respectively. These interactions are observed between C6-H6…O1 and C13-H13…O1
(Figure 3, Table. 4). The crystal structure of compound 3i can be described as a three-
2
dimensional network, the molecules are interconnected to inversion dimers of the R (10)
2
i
motif [52]; by C5-H5…O1 (i: –x+1, -y, -z+1) intermolecular hydrogen bonds. These dimers
are interconnected into three-dimensional structure via C-H… hydrogen bonds, connecting
one of the methyl group of methoxy fragment and the centroid of phenyl ring, with a distance
of 2.79 Å and an angle of 143°. The three-dimensional structure is also stabilized by two
… interactions involving two centroids of pyrazolone and benzene rings [ring centroid
i
ii
separation Cg1··· Cg3 = 3.7238(4) Å and Cg1··· Cg3 = 3.7960(4) Å, where Cg1 and Cg3 are
the centroid of the N1-N2-C9-C8-C7 and C12-C17 ring, respectively; symmetry codes: (i)
x,1-y,1-z; (ii) 1-x,1-y,1-z] (Figure 4).
1
6

Figure 3. Intra and inter molecular hydrogen bonds in compound 3i.
Figure 4. A view of the three-dimensional network of the compound 3i, showing the
C- H···π hydrogen bonds and π… π interactions.
Table 4. Hydrogen-bond geometry (Å, ° ). Cg2 is the centroid of the C1–C6 ring.
D-H…A
D-H
H…A
2.5800
2.2900
2.1500
2.7900
D…A
D-H…A
i
C5-H5…O1
C6-H6…O1
0.9300
0.9300
0.9300
0.9300
3.4317(3) 152.00
2.9094(3) 124.00
2.9882(3) 149.00
3.5997(3) 60.000
C13H13…O1
ii
C19-H19C…Cg2
Symmetry codes : (i) –x+1, -y, -z+1; (ii) –x, -y+1, -z+1
1
7

3
.3. Hirshfeld surface analysis
Hirshfeld surface mapped over dnorm, and its related two-dimensional fingerprints have been
computed in order to quantify the intermolecular contacts of the crystal structure of
compound 3i using Crystal Explorer 17.5 software [53]. The obtained results are shown in
Figures 5 and 6. As can be seen from the 3D Hirshfeld surface represented in Figure 5, two
intermolecular hydrogen bonds between O1 and H5 are present for compound 3i with
distances shorter than Van der waals (Vdw) radii (red spots on the Hirshfeld surface). It was
revealed also the presence of two H…H bonds, H10–H4 and H2–H2 with distances nearly
equal to the sum of Vdw radii (white areas on the Hirshfeld surface). The 2D fingerprint plots
depicted in Figure 6 show the contribution of the different types of intermolecular
interactions. It was found that the H…H interaction has the highest interatomic contact
contributions (53.0%), followed by C…H (16.2%), and O…H (13.4%) interactions.
Figure 5. The three-dimensional Hirshfeld surface of compound 3i mapped over dnorm in the
range –0.1121 to 1.2526 a. u.
1
8

Figure 6. Two-dimensional fingerprints of compound 3i resolved into H…O/O…H,
H…H/H…H, and H…C/C…H contacts (blue areas).
3
.4. Theoretical investigations
DFT calculations at B3LYP/6-311G(d,p) level of theory have been carried out in order to gain
more insights into the molecular structure and chemical reactivity of compound 3i as an
example molecule. Firstly, the molecular geometry of compound 3i has been optimized and
the most stable structure was compared with that obtained from the crystal structure analysis.
Figure 7 shows the DFT-optimized molecular structure of compound 3i, and Table S1
represents some selected experimental and theoretical geometry parameters. As shown, good
correlations are observed between the experimental and theoretical structures. The bond
lengths and angles have nearly the same values, while the dihedral angles are slightly deviated
by 3.40° to 3.47°. This result confirms the accuracy of B3LYP/6-311G(d,p) method for
geometry optimization. In this geometry, compound 3i adopts a planar structure due to
1
9

conjugation of -electrons over the whole structure of the molecule, which is an indication of
its stability.
Figure 7. Molecular geometry (A), molecular electrostatic potential (B), and atomic polar
tensor charges (C) of compound 3i obtained in the gas-phase at B3LYP/6-311G(d,p) level of
theory.
Using the optimized molecular geometry of compound 3i, we have calculated at the
same level of theory some molecular properties such as frontier molecular orbitals (FMO),
atomic charge distributions, and molecular electrostatic potential mapping. FMO are
important properties that characterize the chemical reactivity of organic compounds [41, 54,
5
5]. LUMO (lowest unoccupied molecular orbital) is the easiest orbital to accept electrons
and determines the sites for electrophilic attacks, while HOMO is the easiest orbital to donate
electrons and determines the sites for nucleophilic attacks. The calculated FMO energies and
distributions of compound 3i are shown in Figure 8. As can be seen, the HOMO is distributed
mainly on the pyrazolone and the N-phenyl moieties, whereas the LUMO is located on the
pyrazolone, C8-C11 double bond, and the substituted phenyl. These results clearly enlighten
the transfer of electron density from the non-substituted phenyl to substituted phenyl moieties.
The calculated gap energies (3.05 eV) indicates the high kinetic stability and low chemical
reactivity of compound 3i [56, 57].
2
0

Figure 8. Frontier molecular orbitals of compound 3i obtained in the gas-phase at B3LYP/6-
3
11G(d,p) level of theory.
The distribution of electrons (charges distribution) in organic compounds is a crucial
property, because it determines several physicochemical properties such as solubility,
stability, dipole moment, electrostatic potential, vibrational spectroscopy, chemical reactivity,
and others [58-60]. The distribution of electrons of compound 3i has been characterized by
computing molecular electrostatic potential (ESP) and the atomic polar tensor charges (APT).
The obtained results are presented in Figure 7 and tabulated in Table S2 in supporting
information. ESP revealed that the highest positive regions are around the H11 and H17,
suggesting that these regions must be the most favorable sites for the attack of nucleophiles.
With the APT charges, the highest positive atoms were found to be C9, C12, and C15 with
partial charges of 1.05, 0.63, and 0.62, respectively. On the other hand, the highest negative
charges are found around the oxygens O1 and O2 with both ESP and APT (-0.94 and -0.69,
2
1

respectively). This indicates that these atoms should be the most nucleophilic sites of
compound 3i.
Electronegativity (), chemical hardness (), chemical softness (S), and electrophilic
index () are also useful quantitative properties of organic compounds that could be used to
predict the chemical stability and reactivity [61-63]. Electronegativity characterizes the
capacity of a molecule to attract electrons. The chemical hardness () and softness (S)
measure the resistance to charge transfer. The electrophilic index is defined as a measure of
energy lowering associated with a maximum amount of electron flow between a donor and an
acceptor [61-63]. Using HOMO/LUMO energy method, we have calculated all of the
mentioned parameters for compound 3i, and the obtained values are reported in Table S3.
From the obtained data, it was found that compound 3i has a relatively high  value (2.31 and
2
.39 eV) and low S value (0.33 eV), indicating high kinetic stability and low chemical
reactivity. It presents also high values of  and  which reflects that this compound prefers to
act as electron acceptor rather than electron donor [42].
3
.5. Antibacterial activity
The antibacterial activity of the synthesized pyrazolones 3a-i was evaluated against six
bacterial strains, four ATCC strains namely: Staphylococcus aureus (ATCC 25923), Bacillus
subtilis (ATCC 6633), Escherichia coli (ATCC, 25922), Pseudomonas aeruginosa (ATCC,
2
7853), and two clinical strains namely: Enterococcus faecalis and Klebsiella pneumoniae.
Ciprofloxacin was used as the reference drug. The obtained results are shown in Table 5. The
results showed that the majority of the products have shown an antibacterial activity against
the test bacteria; S. aureus, B subtilis, and E. faecalis, where the averages of the inhibition
zones diameters went from 7.0 to 12.5 mm. Furthermore, no inhibition zone was observed
with the three tested strains E. coli, P. aeruginosa, and K. pneumoniae (Table 5). Overall, the
2
2

most considerable effects are observed with compounds 3a, 3c, 3d, and 3i which have shown
an activity against the three sensitive strains, comparable to the reference drug Ciprofloxacin
with a zone of inhibition of 18 mm, followed by compounds 3g and 3h against two strains
only. However, the two compounds 3b and 3f make the exception and they could not inhibit
the development of any bacteria. Gram-positive bacteria appear to be more sensitive to the
synthesized pyrazolones in comparison with Gram-negative ones. Against Gam-positive
bacteria (S. aureus and E. faecalis), compound 3i showed the best antibacterial activity with a
zone of inhibition of 12.5 mm and 11 mm, respectively. Compound 3d showed also the best
activity among the other derivatives with a zone of inhibition of 11mm against Gam-positive
bacteria B. subtilis. These results can be explained by the fact that these two groups of
microorganisms differ morphologically, because Gram negative bacteria have an outer
membrane which is a polysaccharide membrane carrying the lipopolysaccharide structural
components [64, 65]. This makes the cell wall impermeable to lipophilic compounds, unlike
Gram-positive bacteria, which will be more sensitive because they only have an outer
peptidoglycan layer, which is not an effective permeability barrier [64]. As can be concluded
from the obtained results, the pyrazolone derivatives 3a-i are promising antibacterial agents,
in particular against Gram-positive bacteria. This result is close to the study reported by P.
Khloya et al. on the in vitro antibacterial activity of pyrazolone derivatives[66].
2
3

Table 5. Demonstration of the antibacterial activity of the synthesized pyrazolone derivatives
a-i by disks technic.
3
Diameter of zone of inhibition in mm
S. aureus B. subtilis E. faecalis E. coli P. aeruginosa
Compound
K. pneumoniae
3
a
11.0± 1.4 10.5±0.7
8.5±0.7
-
-
-
-
3
b
-
-
-
-
-
3
c
9.5±0.7
7.0±0.0
11.0±0.0
-
10.0±0.0
11.0±2.8
9.5±0.7
-
9.0±0.0
9.0±0.0
10.0±0.0
-
-
-
-
3
d
-
-
-
3
e
-
-
-
3
f
-
-
-
3
g
8.0±0.0
-
9.5±0.7
10.0±0.0
-
-
-
-
3
h
7.0±0.0
11.0±0.0
18±0.2
-
-
-
-
-
-
3
i
12.5±0.7 10.5±0.7
18±0.1 18±0.3
Ciprofloxacine
16±0.2
20±0.3
22±0.3
(-) : Diameter of the inhibition zone <6 mm
3
.6. In silico ADME analysis
ADME (absorption, distribution, metabolism and excretion) properties of the synthesized
pyrazolones 3a-i have been estimated using Molinspiration software. Based on Lipinski's rule
[
67], molecules with good ADME properties should have no more than one violation of the
following criteria: number of hydrogen bond donors (n-OHNH) < 5, number of hydrogen
bond acceptors (n-ON) < 10, molecular weight < 500 daltons, an octanol-water partition
coefficient (milogP) < 5. As indicated in Table 6, all of the studied compounds showed no
violation of the mentioned criteria. Thus, these compounds perfectly respect the Lipinski rule.
In addition, the calculated percentage of absorption of compounds 3a-i (80.43–96.65%)
suggests that these compounds should be easily absorbed by the human body [68]. These
2
4

results indicate that the synthesized pyrazolones 3a-i have good ADME properties and could
be considered as drug candidates.
Table 6. ADME properties of compounds 3a-i.
TPSA
nOHN
Comp.
miLogP
MW
nON
n-rotb
MV
vio. %Abs
o
(
A)
H
<5
0
<
5
<500
<10
6
<1
3
a
2.48
3.00
2.75
3.68
2.91
3.68
2.38
2.96
2.90
62.60 352.39
50.69 301.35
34.90 268.34
34.90 290.37
44.13 292.34
34.90 290.37
55.12 278.31
38.13 303.38
53.37 322.36
5
2
0
2
3
2
2
3
0
320.25
272.59
234.33
276.74
269.16
276.74
251.63
289.52
294.71
0
0
0
0
0
0
0
0
0
86.84
91.06
96.65
96.65
93.38
96.65
89.49
95.50
90.11
3
b
4
1
3
c
3
0
3
d
3
0
3
e
4
0
3f
3
0
3
g
4
1
3
h
4
0
3
i
5
0
Logarithm of partition coefficient between n-octanol and water (miLogP); Topological polar
surface area (TPSA); Molecular weight (MW); Number of hydrogen bond acceptors (n-ON);
Number of hydrogen bond donors (n-OHNH); Number of rotatable bonds (n-rotb); Molecular
volume (MV); Lipinski’s violation (vio.); Percentage of absorption (%Abs).
4
. Conclusion
A green and efficient ultrasound-assisted synthesis of a series of 4-arylidene-1H-pyrazol-
(4H)-one derivatives (3a-i) has been reported. All the compounds were fully characterized
5
by spectroscopy techniques and for compound 3i by single crystal X-ray diffraction analysis.
Molecular geometry, electronic properties, and physicochemical descriptors have been
investigated using DFT calculations in order to understand the chemical reactivity and
2
5

stability of the studied pyrazolones. The study of the antibacterial activity was revealed that
the synthesized compounds are promising inhibitors of tested Gam-positive bacterial strains S.
aureus, B. subtilis, and E. faecalis. However, none of the compounds were found to be as
effective as the standard drug Ciprofloxacin. The results revealed also that the synthesized
compounds are not effective against the tested Gam-negative bacterial strains E. coli, P.
aeruginosa, and K. pneumonia. This result is in line with reported studies on pyrazolone
derivatives. In addition, in silico ADME calculations suggested that these compounds have a
good pharmacokinetic profile.
Acknowledgements
We would like to thank MESRS (Ministère de l’Enseignement Supérieur et de la Recherche
Scientifique, Algeria) and DGRSDT (Direction Générale de la Recherche Scientifique et du
développement Technologique, Algeria) for financial support.
CRediT author statement
Imen Sehout: Investigation; Houssem Boulebd: Theoretical calculations, Formal
analysis, Writing – original draft, Visualization, Writing – review and editing; Raouf
Boulcina: Writing – original draft; Sara Nemouchi: Investigation; Amina Bramki:
Investigation; Lamia Bendjeddou: Investigation; Hocine Merazig: Resources;
Abdelmadjid Debache: Conceptualization, Supervision.
Declaration of interests
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
2
6

References
[
1] R. Dua, S. Shrivastava, S.K. Sonwane, S.K. Srivastava, Pharmacological significance of
synthetic heterocycles scaffold: a review, Advances in Biological Research 5(3) (2011) 120-
44.
2] K. Chand, A. Hiremathad, M. Singh, M.A. Santos, R.S. Keri, A review on antioxidant
1
[
potential of bioactive heterocycle benzofuran: Natural and synthetic derivatives,
Pharmacological Reports 69(2) (2017) 281-295.
[
3] A.E. Goetz, T.K. Shah, N.K. Garg, Pyridynes and indolynes as building blocks for
functionalized heterocycles and natural products, Chemical Communications 51(1) (2015)
4-45.
4] V. Kumar, K. Kaur, G.K. Gupta, A.K. Sharma, Pyrazole containing natural products:
synthetic preview and biological significance, European journal of medicinal chemistry 69
3
[
(2013) 735-753.
[
5] M.F. Khan, M.M. Alam, G. Verma, W. Akhtar, M. Akhter, M. Shaquiquzzaman, The
therapeutic voyage of pyrazole and its analogs: a review, European journal of medicinal
chemistry 120 (2016) 170-201.
[
6] K. Karrouchi, S. Radi, Y. Ramli, J. Taoufik, Y.N. Mabkhot, F.A. Al-aizari, Synthesis and
pharmacological activities of pyrazole derivatives: a review, Molecules 23(1) (2018) 134.
7] A. Chauhan, P.K. Sharma, N. Kaushik, Pyrazole: a versatile moiety, Int. J. ChemTech Res
(1) (2011) 11-17.
8] R. Mukherjee, Coordination chemistry with pyrazole-based chelating ligands: molecular
structural aspects, Coordination Chemistry Reviews 203(1) (2000) 151-218.
9] D.A. Horton, G.T. Bourne, M.L. Smythe, The combinatorial synthesis of bicyclic privileged
structures or privileged substructures, Chemical reviews 103(3) (2003) 893-930.
10] M. Verleye, I. Heulard, J.-M. Gillardin, Phenazone potentiates the local anaesthetic
effect of lidocaine in mice, Pharmacological research 41(5) (2000) 539-542.
11] F. Arellano, J.A. Sacristán, Metamizole: reassessment of its therapeutic role, European
journal of clinical pharmacology 38(6) (1990) 617-619.
12] H.G. Kraetsch, T. Hummel, J. Lötsch, R. Kussat, G. Kobal, Analgesic effects of
[
3
[
[
[
[
[
propyphenazone in comparison to its combination with caffeine, European journal of clinical
pharmacology 49(5) (1996) 377-382.
[
13] A.G. Lipman, MARTINDALE: ‘Martindale — the Extra Pharmacopoeia’ (30th ed), edited
by J. E. F. Reynolds, International Journal of Pharmacy Practice 2(2) (1993) 124-124.
14] G. Mariappan, B.P. Saha, N.R. Bhuyan, P.R. Bharti, D. Kumar, Evaluation of antioxidant
[
potential of pyrazolone derivatives, Journal of advanced pharmaceutical technology &
research 1(2) (2010) 260.
[
15] H.-J. Park, K. Lee, S.-J. Park, B. Ahn, J.-C. Lee, H. Cho, K.-I. Lee, Identification of antitumor
activity of pyrazole oxime ethers, Bioorganic & medicinal chemistry letters 15(13) (2005)
307-3312.
16] Z. Xu, C. Gao, Q.-C. Ren, X.-F. Song, L.-S. Feng, Z.-S. Lv, Recent advances of pyrazole-
containing derivatives as anti-tubercular agents, European journal of medicinal chemistry
39 (2017) 429-440.
17] R. Thomas, Y.S. Mary, K.S. Resmi, B. Narayana, B.K. Sarojini, G. Vijayakumar, C. Van
3
[
1
[
Alsenoy, Two neoteric pyrazole compounds as potential anti-cancer agents: Synthesis,
electronic structure, physico-chemical properties and docking analysis, Journal of Molecular
Structure 1181 (2019) 455-466.
2
7

[
18] A.A. Bekhit, H.M.A. Ashour, A.A. Guemei, Novel Pyrazole Derivatives as Potential
Promising Anti‐inflammatory Antimicrobial Agents, Archiv der Pharmazie: An International
Journal Pharmaceutical and Medicinal Chemistry 338(4) (2005) 167-174.
[
19] G.H. Sayed, M.E. Azab, K.E. Anwer, M.A. Raouf, N.A. Negm, Pyrazole, pyrazolone and
enaminonitrile pyrazole derivatives: Synthesis, characterization and potential in corrosion
inhibition and antimicrobial applications, Journal of Molecular Liquids 252 (2018) 329-338.
[
20] F. Marchetti, J. Palmucci, C. Pettinari, R. Pettinari, M. Marangoni, S. Ferraro, R.
Giovannetti, S. Scuri, I. Grappasonni, M. Cocchioni, F.J. Maldonado Hodar, R. Gunnella,
Preparation of Polyethylene Composites Containing Silver(I) Acylpyrazolonato Additives and
SAR Investigation of their Antibacterial Activity, ACS Applied Materials & Interfaces 8(43)
(
[
2016) 29676-29687.
21] S. Scuri, F. Petrelli, I. Grappasonni, L. Idemudia, F. Marchetti, C. Di Nicola, Evaluation of
the antimicrobial activity of novel composite plastics containing two silver (I) additives, acyl
pyrazolonate and acyl pyrazolone, Acta Bio Medica Atenei Parmensis 90(3) (2019) 370-377.
[
22] F. Karcı, N. Ertan, Hetarylazo disperse dyes derived from 3-methyl-1-(3′, 5′-dipiperidino-
s-triazinyl)-5-pyrazolone as coupling component, Dyes and pigments 55(2-3) (2002) 99-108.
23] F. Karcı, F. Karcı, Synthesis and absorption spectra of some novel heterocyclic disazo
dyes derived from pyridone and pyrazolone derivatives, Dyes and pigments 76(1) (2008)
47-157.
[
1
[
(
24] N.J. Parmar, H.A. Barad, B.R. Pansuriya, R.A. Patel, Chelation and extraction of copper
II) with 5-pyrazolone-based Schiff bases, Journal of Coordination Chemistry 64(4) (2011)
6
88-698.
25] J.-W. Byun, D.-H. Lee, Y.-S. Lee, Preparation of polymer-bound pyrazolone active esters
for combinatorial chemistry, Tetrahedron letters 44(44) (2003) 8063-8067.
26] C. Leonelli, T.J. Mason, Microwave and ultrasonic processing: now a realistic option for
industry, Chemical Engineering and Processing: Process Intensification 49(9) (2010) 885-900.
27] B. Banerjee, Recent developments on ultrasound assisted catalyst-free organic
synthesis, Ultrasonics sonochemistry 35 (2017) 1-14.
28] A. Ziadi Chibane, R. Boulcina, H. Boulebd, C. Bensouici, M. Yildirim, A. Debache, Green
[
[
[
[
one-pot multicomponent synthesis, biological evaluation and theoretical investigations of
some novel β-acetamido ketone derivatives as potent cholinesterase inhibitors, Tetrahedron
7
6(25) (2020) 131260.
[
29] K. Boudebbous, H. Boulebd, R. Boulcina, L. Bendjeddou, C. Bensouici, H. Merazig, A.
Debache, Synthesis, crystal structure, biological evaluation, docking study, and DFT
calculations of 1-amidoalkyl-2-naphthol derivative, Journal of Molecular Structure 1212
(
[
2020) 128179.
30] K. Boudebbous, H. Boulebd, C. Bensouici, D. Harakat, R. Boulcina, A. Debache, Synthesis,
Docking Study and Biological Activities Evaluation of 1-Amidoalkyl-2-naphthol Derivatives as
Dual Inhibitors of Cholinesterase and α-Glucosidase, ChemistrySelect 5(19) (2020) 5515-
5
520.
[
31] M.I. Chouiter, H. Boulebd, D.M. Pereira, P. Valentão, P.B. Andrade, A. Belfaitah, A.M.S.
Silva, New chalcone-type compounds and 2-pyrazoline derivatives: synthesis and caspase-
dependent anticancer activity, Future Medicinal Chemistry 12(6) (2020) 493-509.
[
32] C. Derabli, H. Boulebd, A.B. Abdelwahab, C. Boucheraine, S. Zerrouki, C. Bensouici, G.
Kirsch, R. Boulcina, A. Debache, Synthesis, biological evaluation and molecular docking
studies of novel 2-alkylthiopyrimidino-tacrines as anticholinesterase agents and their DFT
calculations, Journal of Molecular Structure 1209 (2020) 127902.
2
8

[
33] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, Completion and refinement of
crystal structures with SIR92, Journal of Applied Crystallography 26(3) (1993) 343-350.
34] G.M. Sheldrick, SHELXT–Integrated space-group and crystal-structure determination,
Acta Crystallographica Section A: Foundations and Advances 71(1) (2015) 3-8.
35] L.J. Farrugia, WinGX and ORTEP for Windows: an update, Journal of Applied
Crystallography 45(4) (2012) 849-854.
36] C.F. Macrae, P.R. Edgington, P. McCabe, E. Pidcock, G.P. Shields, R. Taylor, M. Towler,
[
[
[
J.V.D. Streek, Mercury: visualization and analysis of crystal structures, Journal of Applied
Crystallography 39(3) (2006) 453-457.
[
37] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G.
Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, A.F.I. H. P.
Hratchian, J. Bloino, G. Zheng,, M.H. J. L. Sonnenberg, M. Ehara, K. Toyota,, J.H. R. Fukuda,
M. Ishida, T. Nakajima, Y. Honda,, H.N. O. Kitao, T. Vreven, J. A. Montgomery Jr,, F.O. J. E.
Peralta, M. J. Bearpark, J. Heyd,, K.N.K. E. N. Brothers, V. N. Staroverov, R. Kobayashi,, K.R. J.
Normand, A. P. Rendell, J. C. Burant,, J.T. S. S. Iyengar, M. Cossi, N. Rega, N. J. Millam,, J.E.K.
M. Klene, J. B. Cross, V. Bakken, C. Adamo,, R.G. J. Jaramillo, R. E. Stratmann, O. Yazyev,, R.C.
A. J. Austin, C. Pomelli, J. W. Ochterski,, K.M. R. L. Martin, V. G. Zakrzewski, G. A. Voth,, J.J.D.
P. Salvador, S. Dapprich, A. D. Daniels,, J.B.F. ¨ O. Farkas, J. V. Ortiz, J. Cioslowski,, D. J. Fox,
Gaussian 09, Gaussian, Inc., Wallingford CT, (2009).
[
38] A.D. Becke, Density-functional exchange-energy approximation with correct asymptotic
behavior, Physical review A 38(6) (1988) 3098.
39] P.C. Hariharan, J.A. Pople, The influence of polarization functions on molecular orbital
hydrogenation energies, Theoretica chimica acta 28(3) (1973) 213-222.
40] A. Benhassine, H. Boulebd, B. Anak, M.K. Ali, A. Bouraiou, H. Merazig, N. Kacem-
[
[
Chaouche, A. Belfaitah, Co (II) complexes derived from (1-methyl-1H-imidazol-2-yl)
methanol: Synthesis, characterization, spectroscopic study, DFT/TD-DFT calculations and
biological evaluation, Inorganica Chimica Acta (2019) 119073.
[
41] H. Boulebd, Y.D. Lahneche, I.A. Khodja, M. Benslimane, A. Belfaitah, New Schiff bases
derived from benzimidazole as efficient mercury-complexing agents in aqueous medium,
Journal of Molecular Structure 1196 (2019) 58-65.
[
42] H. Boulebd, Comparative study of the radical scavenging behavior of ascorbic acid, BHT,
BHA and Trolox: Experimental and theoretical study, Journal of Molecular Structure 1201
(
[
2020) 127210.
43] H. Boulebd, DFT study of the antiradical properties of some aromatic compounds
derived from antioxidant essential oils: C–H bond vs. O–H bond, Free Radical Research
3(11-12) (2019) 1125-1134.
44] H. Boulebd, I. Amine Khodja, M.V. Bay, N.T. Hoa, A. Mechler, Q.V. Vo, Thermodynamic
5
[
and Kinetic Studies of the Radical Scavenging Behavior of Hydralazine and Dihydralazine:
Theoretical Insights, The Journal of Physical Chemistry B 124(20) (2020) 4123-4131.
[
45] H. Boulebd, The role of benzylic-allylic hydrogen atoms on the antiradical activity of
prenylated natural chalcones: a thermodynamic and kinetic study, Journal of Biomolecular
Structure and Dynamics (2020) 1-10.
[
46] F.D. Gonelimali, J. Lin, W. Miao, J. Xuan, F. Charles, M. Chen, S.R. Hatab, Antimicrobial
properties and mechanism of action of some plant extracts against food pathogens and
spoilage microorganisms, Frontiers in microbiology 9 (2018) 1639.
[
47] M. Yamaç, F. Bilgili, Antimicrobial activities of fruit bodies and/or mycelial cultures of
some mushroom isolates, Pharmaceutical biology 44(9) (2006) 660-667.
2
9