Synthesis, characterization, and molecular docking of benzodiazepines in the presence of SrFe12O19 magnetic nanocatalyst

Article abstract of DOI:10.1007/s13738-021-02163-6

Abstract: An efficient and concise method for the synthesis of 1,5-benzodiazepine derivatives was developed using o-phenylenediamine derivatives, 4,4-dimethyl cyclohexane-1,3-dione, and different aldehydes through a rapid three-component domino reaction i

Full text of DOI:10.1007/s13738-021-02163-6

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-021-02163-6
ORIGINAL PAPER
Synthesis, characterization, and molecular docking
of benzodiazepines in the presence of SrFe12O19 magnetic
nanocatalyst
Tahereh Ahmadi1 · Ghodsi Mohammadi Ziarani1 · Seyed Mohsen Masoumian Hoseini2 · Alireza Badiei3 ·
Mohammad Mehdi Ranjbar4
Received: 26 August 2020 / Accepted: 2 January 2021
© Iranian Chemical Society 2021
Abstract
An efcient and concise method for the synthesis of 1,5-benzodiazepine derivatives was developed using o-phenylenedi-
amine derivatives, 4,4-dimethyl cyclohexane-1,3-dione, and diferent aldehydes through a rapid three-component domino
reaction in the presence of the SrFe12O19 magnetic nanocatalyst under solvent-free conditions.The SrFe12O19 nanoparticles
were synthesized using the sol–gel auto-combustion technique. The main advantages of using this nanocatalyst are its easy
handling and removal from the reaction mixture, by the use of an external magnet, and reusing it several times without any
loss of activity. Some parameters such as the bond length and bond strength between the obtained products and the GABA
receptor were evaluated to have an insight on the interactions involved. The electrostatic energy, ligand efciency, log P, and
the total binding energy of the compounds with the receptor were also calculated.
Graphic abstract
Keywords Domino reaction · 1,5-Benzodiazepine derivatives · Nanomagnethiccatalyst · Docking study · GABA receptor
* Ghodsi Mohammadi Ziarani
gmohammadi@alzahra.ac.ir
Introduction
1
Department of Chemistry, Alzahra University, Vanak
Square, P.O. Box 1993893973, Tehran, Iran
Benzodiazepines and their derivatives have been known as
2
an important class of heterocyclic compounds because of
their diverse therapeutic and pharmacological properties.
They are a group of sedative/hypnotic agents which have
been introduced to clinical practice over 50 years ago [1].
In addition to their applications on medicinal chemistry,
Clinical Biochemistry, School of Nursing, Torbat Jam
University of Medical Sciences, Torbat Jam, Iran
3
4
School of Chemistry, College of Science, University
of Tehran, 14155-6455 Tehran, Iran
Razi Vaccine and Serum Research Institute, Agricultural
Research, Education and Extension Organization, Karaj, Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
benzodiazepines have been used as anticoagulant [2],
anti-infammatory [3], antiepileptic [4, 5], antibacterial
[6], antidepressant [7], and analgesic agents [8]. Diferent
methods have been reported for the synthesis of benzodi-
azepines and their derivatives. For instance, 1,5-benzodi-
azepine derivatives can be synthesized by the condensa-
tion reactions of o-phenylenediamine with α,β-unsaturated
carbonyl compounds [9], -haloketones [10], and various
aldehydes [11–17]. Furthermore, the synthesis of 1,5-ben-
zodiazepines has been reported in the presence of diferent
catalysts, such as polyphosphoric acid [18], BF3.Et2O [19],
NaBH4 [20], CF3COOH/dehydroacetic acid (DHA) [21],
ceric ammonium nitrate (CAN) [22], [H − NMP][HSO4]
as a Bronsted acidic ionic liquid [23], CeCl3.7H2O/NaI
supported on silica gel [24], ZnCl2 [25], SiO2/ZnCl2 [26],
Fe3O4 nanoparticles [27], SiO2–H2SO4 under microwave
irradiation [28], ZnS [29], acetic acid under microwave
irradiation [30], and MgO/POCl3 under solvent-free con-
ditions [31].
dissolved in deionized water (100 mL for 0.1 mol of Fe3+)
and stirred well at 60 °C to aford a clear solution. The citric
acid, in an appropriate molar ratio to the used metal nitrates,
was then added to the clear solution and stirred vigorously.
Then, NH4OH was added dropwise to adjust the pH to 7,
and then a cationic surfactant (surfactant/strontium= 0.4)
was added to the solution. Finally, the viscous brown gel
produced after the evaporation of the solvent was calcined
at 900 °C for 1 h.
General procedure for the synthesis of 4‑substi‑
tuted‑1,5‑benzodiazepines (4a–j)
At frst, the SrFe12O19 (0.02 g) was dried in a round-bot-
tomed fask containing a magnetic stirrer at 100 °C. The
mixture of the 4,4-dimethyl cyclohexane-1,3-dione (1 mmol,
0.140 g), o-phenylenediamine derivatives (1 mmol), and
SrFe12O19 (0.02 g) were heated for 20 s under solvent-
free conditions at 140 °C. Then, the aromatic aldehydes
(1 mmol) were added to the mixture of reaction stirred at
140 °C for 2 min. The reaction completion was monitored
by the thin layer chromatography (TLC). After completion
of the reaction, the mixture was dissolved in hot EtOH, and
then, the SrFe12O19 magnetic nanoparticles were easily sepa-
rated from the solution by an external magnet. After a sim-
ple fltration, the solution was cooled to aford the product.
The residue was purifed by recrystallization from ethanol.
The catalyst was subsequently washed with hot EtOH, dried
under vacuum and reused for several times without signif-
cant loss of activity. The spectral data of new compounds
are given below:
In this work, in the continuation of our researches
[32, 33], we developed an efcient and rapid method for
the synthesis of 1,5-benzodiazepinesby the reaction of
o-phenylenediamine, 4,4-dimethyl cyclohexane-1,3-dione,
and various aldehydes in the presence of the synthesized
SrFe12O19 magnetic nanocatalyst under green solvent-free
conditions.
Experimental
Materials and methods
All the chemicals were obtained from Merck Company
and used without further purifcation. The melting points
were measured by the capillary tube method with an Elec-
trothermal 9200 apparatus. Infrared (IR) spectra were
recorded on a Fourier-transform (FT)-IR Bruker Tensor 27
instrument. 1H NMR (250 MHz) and 13C NMR (62.9 MHz)
spectra were run on a Bruker DPX using tetramethylsilane
(TMS) as the internal standard in CDCl3 and DMSO. Mass
spectrometry (MS) analysis was performed on a model
5973 mass selective detector (Agilent).The X-ray powder
difraction (XRD) data of the prepared SrFe12O19 nanopar-
ticles were collected by a Philips X’pert MPD difractom-
eter using the Cu Kα radiation source (λ = 0.15478 nm).
The scanning electron microscopy (SEM) image was taken
with SEM (MV2300).
3,3,7‑Trimethyl‑2,3,4,5,10,11‑hexahydro‑11‑[phenyl]‑1H‑di
benzo[b,e] [1, 4] diazepin‑1‑one (4b)
FT-IR (KBr) υm1ax: 3440, 3300, 3057, 2962, 2869, 1580,
and 1452 cm−1; H NMR (250 MHz, DMSO-d6) δH: 1.01
(s, 3H, CH3), 1.05 (s, 3H, CH3), 1.99 (s, 3H, CH3), 2.09-
2.56 (m, 4H, 2CH2), 3.44 and 4.36 (dt, 2J=5, 1H, CH), 5.70
(d, J = 5.25, 1H, Ar–H), 6.08 (d, J = 5.5, 1H, Ar–H), 6.32
(s, 1H, N–H), 6.37 (s, 1H, Ar–H), 6.81 (d, J= 7.75, 1H,
Ar–H), 6.98–7.10 (m, 5H, Ar–H), 8.70 (s, 1H, N–H) ppm;
13C NMR (62.5 MHz, DMSO-d6) δC: 20.61, 27.74, 29.04,
32.18, 44.53, 49.90, 56.15, 110.28, 120.40, 120.58, 121.05,
126.20, 127.69, 128.12, 128.93, 131.82, 138.74, 145.27,
155.07, 192.22 ppm; MS (m/z, %): 332 ([M+·], 32), 276
(12), 255 (74), 248 (21), 234 (12), 209 (12), 132 (18), 105
(29), 91 (62), 77 (100).
Synthesis of SrFe12O19 nanoparticles
The SrFe12O19 magnetic nanoparticles were synthe-
sized according to previous reports [33–38]. Briefy, the
Fe(NO3)3.9H2O and Sr(NO3)3 powders (Fe/Sr = 10) were
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O
R
Ar
H
Ar
O
H
N
3a-h
O
H2N
+
SrFe12O19 MNPs
R
R
HN
NH2
Solvent free, 140 °C
20 seconds
N
H
140 °C
2 min
O
H2N
2a, b
1
O
4a-k
5
MNPs: Magnetic Nanoparticles
Scheme 1 Synthesis of 1,5-Benzodiazepines 4a-j using SrFe12O19 MNPs
3,3,7‑Trimethyl‑2,3,4,5,10,11‑hexahydro‑11‑[(4‑chloro)
phenyl]‑1H‑dibenzo[b,e] [1, 4] diazepin‑1‑one (4g)
0.3750 Å. The number of docking independent runs was set
to 50 with the step sizes of 0.2 Å and 5°. Among the fnal
docked conformations of each compound, the conformation
with the lowest Gibbs free energy was selected for further
study. Also, the hydrogen bonds and hyrophobic interactions
between diferent studied compounds and the GABA recep-
tor were evaluated and represented schematically by Lig-
Plot+software v 1.4. The docked compounds were ranked
based on the lowest binding energy, number, and length of
hydrogen bonds. Some bioactivity properties, such as log P
and ligand efciency were also calculated.
FT-IR (KBr) υmax: 3311, 3232, 3088, 2956, 2870, 1577, and
1
1514 cm−1; H NMR (250 MHz, CDCl3) δH: 1.05 (s, 3H,
CH3), 1.14 (s, 3H, CH3), 2.11 (s, 3H, CH3), 2.17–2.64 (m,
4H, 2CH2), 4.29 (s, 1H, CH), 5.86 (s, 1H, N–H), 6.23 (s,
1H, NH), 6.29 (s, 1H, Ar–H), 6.53–6.59 (2d, J= 7.5, 2H,
Ar–H), 7.01 (d, J=8, 1H, Ar–H), 7.08 (d, J=8, 1H, Ar–H)
ppm; 13C NMR (62.5 MHz, CDCl3) δC: 20.48, 27.68, 28.83,
32.32, 46.59, 49.69, 57.38, 111.04, 120.32, 121.67, 121.93,
122.16, 124.89, 128.14, 128.26, 128.51, 132.11, 133.83,
136.57, 142.61, 152.71, 193.63 ppm; MS (m/z, %): 366
([M+·], 38), 255 (100), 157 (15), 112 (35), 105 (21), 75 (29).
Results and discussion
Application of SrFe12O19 nanoparticles
in the synthesis of 1,5‑benzodiazepines
Molecular docking method
The structures of all compounds were designed by the Mar-
vinsketch software (version 6.2.2). Then, the structures were
optimized with the molecular mechanic method (MM+force
feld) by the Hyperchem software. Also, the 3-D structure
of gamma-aminobutyric acid (GABA) receptor (PDB ID:
4cof) was retrieved from the protein data bank (www.pdb.
org). The water molecules and other ligands were removed
from the GABA receptor before docking. CastP server
(http://sts.bioengr.uic.edu/castp/) and FTsite server (http://
ftsite.bu.edu/cite) were used for the validation of the recep-
tor pocket [39] and determination of the ligand binding site
[40], respectively. The required charge and hydrogens were
added to the docking system. The docking simulation was
performed using the Lamarckian Genetic Algorithm (LGA)
method by the Autodouck Tools 4.2 to investigate the block-
ing efects of 4a-j compounds on the gamma-aminobutyric
acid (GABA) receptor. The X, Y, and Z centers of the grid
box were set to 6.142, −4.343, and 147.942, respectively.
Furthermore, the number of points in each dimension was
adjusted to X: 86, Y: 98, and Z: 50 with the spacing of
The role of the SrFe12O19 magnetic nanoparticles, as nano-
catalyts, for the synthesis of 4-substituted-1,5-benzodiaz-
epines 4a-j was investigated by the three-component dom-
ino condensation of 4,4-dimethyl cyclohexane-1,3-dione 1,
o-phenylendiamine derivatives 2a-b, and aromatic aldehydes
3a-h under solvent-free conditions at 140 °C (Scheme 1).
At frst, the reaction conditions were optimized. Table 1
reports the reaction times and yields under various
Table 1 The optimization of reaction condition for the synthesis of
1,5-Benzodiazepine 4f
Entry
Catalyst
Solvent
Condition
Time
Yield (%)
1
2
3
4
5
6
SrFe12O19
SrFe12O19
SrFe12O19
–
SrFe12O19
SrFe12O19
–
–
–
–
r.t.
N.R.
1 h
140 s
6 h
10 h
6 h
–
120 °C
140 °C
140 °C
Refux
Refux
80
90
–
trace
65
H2O
EtOH
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Journal of the Iranian Chemical Society
Table 2 Synthesis of
1,5-Benzodiazepine products
4a-j in the presence of
SrFe12O19 MNPs
Entry No.
R
H
Aldehydes
Products
Yield (%) m.p. (°C) m.p. [Ref.]
1
2
3
4
4a
4b
4c
4d
85
89
94
92
247–249
251–252 [41]
O
H
H
O
O
H
N
O
N
H
CH3
252*
New
O
H
N
O
N
H
H
120–121
194–196
115–117 [42]
195–197 [41]
H
H
O2N
H
O2N
N
O
N
H
H
O2N
H
N
O
O
O
O2N
O
N
H
5
6
7
4e
4f
H
94
90
96
275–276
245–247
240–242
280–282 [15]
251–253 [41]
New
H
NO2
H
N
NO2
N
H
H
O
O
H
Cl
H
N
Cl
N
H
4g
CH3
H
Cl
H
N
O
Cl
N
H
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Journal of the Iranian Chemical Society
Table 2 (continued)
Entry No.
R
H
Aldehydes
Products
Yield (%) m.p. (°C) m.p. [Ref.]
8
4h
75
255
256–258 [23]
O
H
Cl
Cl
Cl
Cl
H
N
O
N
H
9
4i
4j
H
H
O
H
78
87
230
220
225 [42]
OH
H
N
O
OH
N
H
10
217–218 [42]
O
H
MeO
H
MeO
N
O
N
H
4,4-Dimethyl cyclohexane-1,3-dione (1 mmol, 0.140 g), o-phenylenediamine derivatives (1 mmol), and
SrFe12O19 (0.02 g) was heated for 20 s under solvent-free conditions at 140 °C. Then, the aromatic alde-
hydes (1 mmol) were added to the mixture of reaction stirred at 140 °C for 2 min
SrFe12O19
R
R
SrFe12O19
H2N
H2N
O
O
O
SrFe12O19
R
HN
N
NH2
3
NH2
Ar
H
2
O
O
H2O
O
H2O
O
1
SrFe12O19
SrFe12O19
SrFe12O19
6
5
R
Ar
H
H
N
Ar
H
N
O
SrFe12O19
O
Ar
H
R
H
R
N
N
N
N
H
SrFe12O19
O
7
8
4
Scheme 2 Proposed mechanism for the synthesis of 1,5-Benzodiazepines
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Journal of the Iranian Chemical Society
Fig. 1 2D representation of hydrogen bonds and hydrophobic inter-
actions between the synthesized compounds and GABA receptor.
The docking was performed by the AutoDock Tools, and the results
were analyzed by the LigPlot+ software. The green dashed lines
denote the hydrogen bonds in Å. The compounds 4c and 4d, shown
here, have higher binding afnities among all the studied compounds.
Lysine274, Valine53, Valine50, and Aspargine54 residues are the
main amino acids contributing in the interactions
conditions. Accordingly, the best result was obtained after
140 s under solvent-free conditions. In the absence of the
catalyst under solvent-free conditions, the yield of the
desired product was trace even after 6 h (Table 1, entry 4).
These optimized reaction conditions were extended to a
range of o-phenylendiamines, 4,4-dimethyl cyclohexane-
1,3-dione, and aromatic aldehydes in the presence of the
SrFe12O19 MNPs under solvent-free conditions at 140 °C.
The new products were characterized by their melting
1
points and the usual spectroscopic techniques, i.e., IR, H
NMR, 13C NMR, and MS spectroscopies. The melting points
of the synthesized products were compared with those avail-
able in the literature (Table 2). The scope of reaction was
tested by the use of various benzaldehydes bearing either
electron releasing or electron withdrawing substituents. The
yields of products 4a–4g were high showing the positive
role of electron withdrawing substituents. While electron
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Journal of the Iranian Chemical Society
Fig. 2 Schematic diagram of the docking procedure in this study. At
frst, the compounds were designed by Marvinsketch and then opti-
mized by Hyperchem. Then, the ligands and protein were prepared
using AutoDock Tools, and the system was fnally docked after set-
ting the grid box. A 3-D view of the interactions between 4c and the
GABA receptor is shown using the CLC drug discovery
releasing groups of OH and OMe led to the signifcant drop
in the yield of 4i-j. The drop in the yield of 4h may be as a
result of steric hindrance of 2-Cl group.
intermediate 6. Condensation of the enamine 6 and aldehyde
3 is accomplished to produce the imine 7, which afords the
desired fnal 1,5-benzodiazepines 4 after the intramolecular
Mannich reaction and isomerization.
A plausible mechanism for the studied reaction is shown
in Scheme 2. The SrFe12O19 MNPs plays a signifcant role
in the acceleration of the reaction. At frst, in the presence
of SrFe12O19, the intermediate 5, which is produced from the
reaction of 4,4-dimethyl cyclohexane-1,3-dione 1 and o-phe-
nylendiamines 2, was isomerized to the more stable enamine
Molecular docking analysis
Gamma-aminobutyric acid type A (GABAA) recep-
tors, which mediate neuronal inhibition, are parts of the
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Journal of the Iranian Chemical Society
Table 3 Calculated binding energy, electrostatic energy, ligand ef-
ciency and log P for the compounds docked
neurotransmitter ligand-gated ion channels. The efects of
GABA on the GABAA receptors are known to be modu-
lated by a range of therapeutically necessary drugs, such as
anesthetics, barbiturates, and benzodiazepines (BZs). Before
docking the synthesized benzodiazepine compounds, we
need to identify the binding sites of BZs, and therefore, the
clonazepam and lorazepam drugs were frst docked with the
GABA receptor. Accordingly, in the binding site of BZs,
Lys274 in the γ subunit and Val53, Val50, Asn54, Glu52,
and Thr271 in the α subunit were found to have the major
role. These sites are important in the molecular docking
studies and de novo drug design [43].
Component Binding
Electro-
energy
Ligand efciency Log P
energy (Kcal/ static
mol)
Clonazepam −8.01
Lorazepam −7.43
−1.23
−0.08
−0.08
−0.09
−1.34
−0.26
−0.97
−0.04
−0.14
−0.03
−0.27
−0.09
−0.35
−0.36
−0.33
−0.32
−0.34
−0.34
−0.24
−0.26
−0.25
−0.27
−0.26
−0.25
2.79
3.17
4.50
4.97
3.51
3.51
4.45
4.18
5.49
4.78
4.22
3.41
4a
4b
4c
4d
4e
4f
4g
4h
4i
−8.01
−8.08
−9.2
−9.08
−6.61
−6.6
−6.58
−7.1
−6.58
−6.46
After fnding the binding sites of BZs, each compound
was docked with the GABA receptor. Figure 1 shows the
docking mode of the compounds with the GABA receptor.
The best docking score (the lowest ΔG) was selected among
thirty docked compounds. The obtained results revealed that
the docked compounds can competitively occupy the binding
pocket of the BZs. Some polar residues in the binding site
of the BZs, including Asp48, Val50, Ser51, Glu52, Val53,
Gln185, and Lys274, interact with the studied compounds
in the form of hydrogen bonds or electrostatic interactions
(Fig. 1). The docking binding energy of -9.2 kcal/mol was
selected among ten docked compounds. Figure 1 shows the
interaction diagram for the compounds 4c and 4d with the
α and γ subunits of the GABA receptor. The compounds
were embedded into the binding site of BZs in the GABA
receptor. The seventeen residues surrounding the BZs bind-
ing site, including the Asp48, Met49, Val50, Ser51, Glu52,
Val53, Asn54, Leu183, Pro184, Gln185, Phe186, Thr220,
Gln270, Thr271, Leu272, Pro273, and Lys274 signifcantly
contribute in the stabilization of the 4c-GABA receptor com-
plex. Lys274 and val53, the crucial residues in the binding
pocket of the BZs, are partly responsible for the binding of
the BZs to the GABA receptor (Fig. 2). The compounds 4c
and 4d showed higher binding afnity to the GABA receptor,
and therefore, they have more inhibitive efect than the other
studied compounds.
4j
Fig. 3 XRD pattern of SrFe12O19 nanoparticles
Also, the compounds 4c and 4d establish 3 and 2 hydro-
gen bonds, respectively. Moreover, the average length the
hydrogen bonds length in 4c is shorter, and therefore, 4c is
more strongly bound to the receptor. The estimated values
of binding energy, electrostatic energy, and ligand efciency
for the compounds−receptor complex are listed in Table 3.
Suggestion using drugs
The BZs that can cross the blood brain barrier (BBB) are
efective. The evaluation of the brain–blood crossing in vitro
is difcult. Therefore, we used an alternative method based
on log P (fat-soluble factor). The values of log P (lipophilic-
ity), indicating the biological activity of small molecules,
were obtained using the Marvin software [43]. A compound
Fig. 4 SEM image of SrFe12O19 nanoparticles
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Journal of the Iranian Chemical Society
Fig. 5 FT-IR spectrum of the
SrFe12O19 nanoparticles, inset:
FT-IR of the same compounds
obtained by Jean et al. [45]
can cross the BBB when its log P is at least 2.0 [44]. The
values of log P for all selected compounds are between 3.26
and 5.49 (Table 3). Accordingly, all of the synthesized com-
pounds have log P values higher than 2, which is necessary
for their sufcient entry into the brain. Also, the obtained
log P values of the studied compounds are higher than those
of clonazepam and lorazepam.
successful formation of SrFe12O19 nanoparticles. According
to the SEM image, the SrFe12O19 particles are spherical with
the average size of about 70 nm (Fig. 4).
FT-IR of SrFe12O19 MNPs (Fig. 5) shows a broad band
around 3421 cm−1 related to the stretching vibration of
the adsorbed H2O molecules; the band corresponding to
the bending vibrations of H2O is seen at 1646 cm−1. The
spectrum displays two weak bands at 840 and 1077 cm−1
corresponding to the vibrations of nitrate groups (remain-
ing from the initial reactant). The large bands at 1456 and
859 cm−1 could be assigned to the carboxylate vibration
(–COO−) from the used organic acids. The sharp bands at
441, 551, 601 cm−1 are related to the SrFe12O19. All these
observations were in agreement with the consequences
obtained by Jean et al. [45].
Characterization of the SrFe12O19 nanoparticles
The X-ray difraction pattern of the prepared SrFe12O19
MNPs with a magnetoplumbite structure is displayed
in Fig. 3. The XRD pattern showed twelve characteristic
peaks including 2θ=30.55°, 32.53°, 34.39°, 35.47°, 37.33°,
40.63°, 42.67°, 55.51°, 57.01°, 63.37°, 67.87°, and 72.85°
which can be indexed to the (110), (107), (114), (201),
(203), (205), (206), (217), (304), (220), (204), and (317)
lattice planes, respectively. The results defnitely confrm the
We investigated the recovery and reusability of the
SrFe12O19 nanocatalyst for the production of the com-
pound 4f as a typical example. As shown in Fig. 6, the
catalyst was recycled four times without signifcant loss of
activity. The yields of the frst four successive runs were
90, 87, 85, and 82%, respectively.
100
80
60
40
20
0
Conclusion
The SrFe12O19 magnetic nanoparticles [46–49] can be
used as green solid acid nanocatalysts in our facile and
efcient developed approach for the synthesis of 4-substi-
tuted-1,5-benzodiazepines under solvent-free conditions.
Several advantages of this approach include its operational
simplicity, excellent product yields, non-chromatographic
purifcation, short reaction time, simple and easy work-
up procedure, and environmentally benign conditions.
1
2
3
4
Cycle
Fig. 6 Reusability of SrFe12O19 MNPs for the synthesis of compound
4f
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Journal of the Iranian Chemical Society
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The results showed that the SrFe12O19 nanoparticles are
efective, recoverable, and reusable catalysts. They are
easily separated from the reaction mixture by the use of
an external magnet. The interaction parameters between
the obtained products and the GABA receptor were evalu-
ated by LigPlot+ software v.1.4. The electrostatic energy,
ligand efciency, log P, and total binding energy of the
compounds with the receptor were also calculated. The
log P values of the synthesized compounds, which were
greater than 2, were higher than those of the clonazepam
and lorazepam.
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