Syntheses of novel 1,5-benzodiazepine derivatives: Crystal structures, spectroscopic characterizations, Hirshfeld surface analyses, molecular docking studies, DFT calculations, corrosion inhibition anticipation, and antibacterial activities

Article abstract of DOI:10.1002/jhet.4167

A series of newly pyrazolo-1,5-benzodiazepine derivatives (5-7) was performed and characterized by using ¹H, ¹³C-NMR spectroscopic measurements. The molecular and crystal structures of two compounds 2 and 7 have also been further exa

Full text of DOI:10.1002/jhet.4167

Syntheses of novel 1,5-Benzodiazepine derivatives: crystal structures,
spectroscopic characterizations, Hirshfeld surface analyses, molecular
docking studies, DFT calculations, corrosion inhibition anticipation and
antibacterial activities
Lhoussaine El Ghayatia, Yusuf Sertb, Nada Kheira Sebbara,c*, Youssef Ramlid, Noureddine
e
Hamou Ahabchanea, Ahmed Talbaoui , Joel T. Maguef , Brahim El Ibrahimig, Mohamed
Labd Tahac, El Mokhtar Essassia, Nabil Al-Zaqrih*, Ali Alsalmeh.
aLaboratory of Heterocyclic Organic Chemistry, Medicines Science Research Center,
Pharmacochemistry Competence Center, Mohammed V University in Rabat, Faculté des Sciences,
Av. Ibn Battouta, BP 1014 Rabat, Morocco. bBozok University Department of Physics
Yozgat/Turkey; cLaboratory of Chemistry and Environment, Applied Bioorganic Chemistry Team,
Faculty of Sciences, Ibn Zohr University, Agadir, Morocco; dLaboratory of Medicinal Chemistry,
Drug Sciences Research Center, Faculty of Medicine and Pharmacy, Mohammed V
e
University, Rabat, Morocco; Laboratoire de Biologie des Pathologies Humaines, Faculté des
f
Sciences, Université Mohammed V, Rabat, Morocco; Department of Chemistry, Tulane
g
University, New Orleans, LA 70118, USA; Applied Chemistry-Physic Team, Faculty of
h
Sciences, University of Ibn Zohr, Agadir, Morocco. Department of chemistry, College of
Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
______________
Corresponding authors: hDepartment of chemistry, College of Science, King Saud University,
P.O. Box 2455, Riyadh 11451, Saudi Arabia; E-mail: nalzaqri@ksu.edu.sa (N. Al-Zaqri).
cLaboratory of Chemistry and Environment, Applied Bioorganic Chemistry Team, Faculty of
Sciences, Ibn Zohr University, Agadir, Morocco; E-mail: snounousebbar@gmail.com
(N.K.SEBBAR).
Abstract
A series of newly pyrazolo-1,5-benzodiazepine derivatives (5-7) was performed and
1
characterized by using H, 13C-NMR spectroscopic measurements. The molecular and
crystal structures of two compounds 2 and 7 have also been further examined by single-
crystal X-ray crystallography showing that the alkyl groups are beard by sulfur atom and to
pyrazolic nitrogen atom in position 2 and not in position 1 of the tricyclic compounds as
described in the literature. In addition, through Hirshfeld surface analysis, molecular
docking studies and DFT calculations, the closest contact between the active atoms of the
compound can be determined. Also, the Monte Carlo simulations outcomes show that
compounds 2 and 7 can be considered as a good acidic corrosion inhibitor for the aluminum
metal, while emphasizing that the compound 7 provides enhanced prevention. Finally,
compounds 1 to 7 were evaluated for their antibacterial activity against Gram-positive and
Gram-negative microbial strains such as Escherichia coli, Pseudomonas aeruginosa,
Staphylococcus aureus and Streptococcus. The results obtained demonstrated the
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antibacterial activity of compounds 1 to 7 tested using the minimal inhibitory concentration
(MIC).
Keywords: 1,5-benzodiazepines, Hirshfeld surface, Crystal, Molecular docking, DFT,
Monte Carlo simulation, Antibacterial activity.
I | INTRODUCTION
The field of heterocyclic chemistry has become increasingly important in recent
years. Indeed, the heterocyclic structures, whether of synthetic or natural origin, appear as a
particularly interesting support in very varied areas (pharmacy, medicine, industry .....) [1-4]
.
It is noted that two-thirds of the organic compounds, known in the literature, are
[8-
heterocycles: containing at least one heteroatom (most often nitrogen, oxygen or sulfur)
11]. In particular, 1,5-benzodiazepines are well-known for their various therapeutic
properties including anticonvulsant, anti-inflammatory, analgesic, hypnotic, sedative and
hypnotic activities [12-17]. They are also used to relieve pain of skeletal muscle joints and the
spasticity resulting from cerebral palsy and paraplegia, athetosis and stiff-man syndrome.
Recently they have been reported to show antileukamic, antiplatelet, antilucer, endothelia
antagonist and vasopressin antagonist activities [18]. In addition, benzodiazepines are a
useful precursor for the synthesis of other fused ring compounds such as triazolo-,
oxadiazolo, oxazino-, furano or pyrazolo-benzodiazepines [19-23]. Benzodiazepines (BZD)
are classified as drugs known for their remarkable activity on the central nervous system
[25]
(CNS) [24]. The area of biological interest of 1,5-benzodiazepines
is extended to various
diseases such as cancer [26], viral infection (non-nucleoside reverse transcriptase inhibitors
of HIV-1 [27-29] and cardiovascular disorders [27-30]. Indeed, the nucleus 1,5-benzodiazepine is
a preferred carrier existing in active compounds belonging to a variety of biological targets
such as peptide hormones (Cholecystokinins CCKA and CCKB) [31-33], enzymes
interleukins ICE [34-36] and potassium inhibitors (Ik) [30] (Scheme 1).
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R1
O
O
O
O
N
H
HO
O
N
N
O
O
H
NH
N
N
N
R2
O
H
NH
R3
Cholecystokinin A (CCKA)
Cholecystokinin B (CCKB)
ICE Inhibitor
O
Cl
O
O
N
N
NH
Cl
Potassium inhibitors Ik
Scheme 1. Examples of bioactive molecules derived from 1,5-benzodiazepine.
In continuation of our previous works [23, 37-39], we are interested in the preparation of
condensed nitrogen heterocyclic compounds containing 1,5-benzodiazepine nucleus (5-7).
Their structures were clarified on the basis of spectral data and confirmed by single-crystal
X-ray diffraction in the case of compounds 2 and 7. They are also characterized using DFT
to compute and predict the corresponding spectral data and Z matrix coordinates at the
B3LYP / 6-31G (d, p) level and at the theoretical level. The molecular docking studies from
the Protein Data Bank (4GQS) on an inhibitor were carried out using Auto-Dock Vina
program. Moreover, aluminum, copper and iron metals, as well as their alloys, are widely
used in various industrial applications due to their attractive physicochemical properties.
Nonetheless, the contact of these metallic materials with aggressive environments (i.e. acid
media) throughout their utilization involves their degradation, which leads to noticeable
economic and safety loss [40]. As a solution to overcome this problematic, the use of
corrosion inhibitors, such as organic-based compounds, is required [41]. Recently, the Monte
Carlo simulations have been used to investigate the adsorption process of several organic
inhibitors onto different metallic surfaces [42]. Conferring to the obtained computational
data, the adsorption energy (or binding energy) was effectively correlated with the observed
inhibition effectiveness. From which, the higher protection ability of an organic inhibitor
has been associated with its great adsorption energy on the metal surface [43-44]. In this
context, we further aim in this work to expect the tendency of the newly synthesized
compounds to prevent the corrosion of aluminum, copper and iron in acidic medium using
this theoretical approach. Finally, compounds (1-7) were evaluated for their antibacterial
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activity against Gram-positive and Gram-negative bacteria such as Escherichia coli,
Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus.
2 | RESULTS AND DISCUSSION
2.1. Chemical synthesis of 1,5-benzodiazepines 5-7
Initially, we prepared 1-ethyl-4-phenyl-1,5-benzodiazpine-2-thione 2 by sulfurization
[45]
of 1-ethyl-4-phenyl-1,5-benzodiazpin-2-one 1
with phosphorus pentasulfide (P2S5)
added in small portions to the freshly distilled pyridine. The reaction mixture was heated to
100°C for 4 hours (Step a). Thereafter, 3-[N-2-(aminophenyl)-N-ethylamino]-5-
phenylpyrazole 3 was obtained by condensation of hydrazine hydrate with compound 2
[23]
(Step b) (Scheme 2). It is worthy to note that in a previous work
concerning the action
of 3-[N-2-(aminophenyl)-N-ethylamino]-5-phenylpyrazole 3 with carbon disulfide in
refluxing pyridine, we isolated in all cases a single product whose structure could
correspond to pyrazolo-1,3,5-benzotriazepine-4-thione 4A or to pyrazolo 1,5-
benzodiazepine-4-thione 4B (Step c) (Scheme 2). To differenciate between the two
structures A and B, we have used a chemical method consisting of the alkylation of the
compound obtained under solid-liquid phase transfer catalysis conditions by various
alkylating agents (methyl iodide, ethyl and allyl bromide). In all cases we isolated a single
dialkylated compound, allowing to reject the structure 4A which would lead, under the
same reaction conditions, to a monoalkylated compound coming from the alkylation of the
sulfur atom of the thioamide group of the seven membered rings. As an extension of this
work and in order to reexamine the structures of compounds obtained, we proceeded to the
alkylation of compound 4B by other alkylating agents: such as propargyl bromide, benzyl
chloride and ethyl bromoacetate in DMF in the presence of K2CO3 as base, and tetra n-butyl
ammonium bromide (TBAB) as catalyst. In all cases we have isolated the dialkylated
pyrazolobenzodiazepine 5-7 in good yields (Step d); (Scheme 2).
To confirm the structure of compounds 5-7 a crystallography study of compound 7
has been undertaken showing that the two ethoxycarbonyl methyl groups are beared by the
sulfur atom and the pyrazolic nitrogen atom in position 2 and not in position 1 of the
tricyclic compound 7 as proposed by the authors [23]
.
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Scheme 2. Synthesis of 1,5-benzodiazépine-2-thione derivatives: 2-7.
A plausible mechanism has been proposed for the formation of compound 3 (Scheme 3): the
initial step corresponds to the attack of the amino group of hydrazine on the carbon atom of
the thiocarbonyl group of the seven membered ring leading to the intermediate [A] which
undergoes to an intramolecular cyclization involving the hydrazine amino group and the
electrophilic carbon atom of the in position 4 of the bicyclic compound to afford the
instable tricyclic compound [B]. The latter, after the cleavage of C4-N5 bond leads to the
pyrazolic compound [C] which after the loss of a hydrogen sulfide molecule gives the
compound 3.
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Scheme 3. Plausible mechanism for synthesis of compound 3
Also, a plausible mechanism proposed for the formation of compound 4B is depicted in
scheme 4: the amino group of compound 3 attacks the carbon atom of carbon disulfide to
lead after a loss of a hydrogen sulfide molecule to the isothiocyanate intermediate [D].
which undergoes an intramolecular cyclization corresponding to the attack of the
nucleophilic pyrazolic carbon atom on the isothiocyanate carbon atom leading to the
tricyclic compound [D]. which aromatizes to compound [E] that may exist under the
tautomeric form 4B.
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Scheme 4. Plausible mechanism for synthesis of compound 4B
2.2. Crystal structures of 1,5-benzodiazepine derivatives: 2 and 7.
The title compounds 1,5-benzodiazepine derivatives (2 and 7) was selected and X-ray
intensity data were collected at 100 K on a Bruker D8 VENTURE PHOTON 100 CMOS
diffractometer equipped with an X-ray generator operating at 50 kV and 10 mA, using
CuKα radiation. A complete data set was processed using SAINT. The 3D structure (Figure
1) was solved by direct methods (SHELXT) and refined by full matrix, least-squares
methods on F2 using SHELXL. The crystallographic analysis of the 1,5-benzodiazepine
derivatives (2 and 7) obtained by cyclic condensation, N-3 deprotection and alkylation
reactions confirmed that the structure of the compound is shown in Figure 1 and Table 1.
Interestingly, these compounds crystallize in orthorhombic (2) and monoclinic (7) crystals,
and this system has space groups of P212121 (2) and P121/n1 (7). The crystallographic data
have been assigned to the CCDC deposit number (see Table 1).
Figure 1: ORTEP d plots, where the ellipsoids are drawn at the 50% probability level of the
compounds (2 and 7).
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Table 1. Experimental Details
Compound 2
Crystal data
Compound 7
Chemical formula
CCDC Deposition number
Mr
C17H16N2S
1523021
280.38
C26H28N4O4S
1958927
492.58
Orthorhombic, P212121
Monoclinic, P 121/n 1
Crystal system, space group
Temperature (K)
296
120(2)
12.1229(12),
8.8222(8),
8.4001 (8), 9.6239 (9),
18.0037 (18)
a, b, c (Å)
23.626(2)
β (°)
V (Å3)
Z
-
1455.5 (2)
4
101.407 (2)
2476.9(4)
4
Radiation type
µ (mm−1)
Crystal size (mm)
Mo Kα
0.21
0.32× 0.14 × 0.05
Bruker SMART APEX
CCD
Mo-Kα
0.171
0.207 x 0.218 x 0.314
Bruker Smart APEX CCD
Diffractometer
No. of measured, independent and
observed [I> 2σ(I)] reflections
Rint
R[F2> 2σ(F2)], wR(F2), S
No. of reflections
13778, 3544, 2226
46470, 6622, 5595
0.050
0.045, 0.117, 1.02
3544
0.033
0.038, 0.110, 1.07
6622
No. of parameters
183
417
Δρmax, Δρmin (e Å−3)
0.30, -0.14
0.48, −0.21
2
.3. Theoretical details and Hirshfeld details
The basic idea that DFT is based on is that the energy of the molecule can be
determined using electron density instead of wave function. The superiority of DFT
methods is that electron correlations are included in the calculations and the obtained
results are in better agreement with the experimental results. It also requires less calculation
and DFT is a variational method. From here in this work, the three-dimensional geometries
of the compound 2 and 7 were drawn in the GaussView interface package program [46] and
calculated in the gas phase in the GAUSSIAN 09 package program [47]. The theoretical
calculations were performed using the Density Functional Theory (DFT)/Becke-3-
LeeYang-Parr (B3LYP) [48-50]. which is a quantum mechanical method. In the Hirshfeld
surface analysis section aimed at studying molecular interactions and possible hydrogen
[51]
bonds, calculations were performed using the Crystal Explorer 3.1 program
.
Subsequently, after optimization in chloroformic solution, the highest occupied molecular
orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of compounds 2
and 7 were analyzed. Then, use the functional atomic orbital method B3LYP and 6-31G (d,
1
p) basis, GIAO-Gauge-Inclusive to calculate the theoretical H and 13C NMR chemical
displacements of compounds 2 and 7, and compare them with the experimental NMR
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spectra in a chloroform solvent. In this manuscript, the ligands of compounds 2 and 7 and
the PDB: 4GQS code were generated using the Auto Dock Vina software [52]
.
2
.3.1. Molecular Geometric Structure
In this section, use the B3LYP function and the 6-31G (d, p) base level to calculate
the optimal structures (bond length and angle) of compounds 2 and 7 in the crystallographic
information file (cif). The optimized structure is shown in Figure 2 [46-50]. Additionally, the
obtained some selected experimental and theoretical values were listed in Table 2. As seen
from the Table 2, there is some inconsistencies between experimental and theoretical
results, this is due to phase differences. Because the obtained experimental results are taken
in solid phase, while theoretical results are taken in gas phase (ideal situation). To our best
knowledges according to literature, no computational and experimental analyses on
compound 2 and 7 were reported or published.
Now, let's look at some results (bond lenghts and angles) for both compound 2 and 7,
respectively. In this study for compound 2, N1-C7, N1-C6, N3-C9 and N3-C1 bond lenghts
were computed at 1.289, 1.391, 1.363 and 1.432 Å and observed at 1.274, 1.409, 1.353 and
1.434 Å in x-ray, respectively. The same group looking at Compound 7; N1-C7, N1-C6,
N2-C9 and N2-C1 bond lenghts were calculated at 1.282, 1.405, 1.396 and 1.430 Å with
B3LYP function and 6-31G(d,p) basis set. Also, these distances in experimental x-ray study
were observed as 1.2827, 1.4206, 1.3930 and 1.4319 Å, respectively. In the literature, 7-
chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide [51], N1-C2, N1-C7, N4-
C3 and N4-C5 (depending on their numbering format) are calculated as 1, 269 / 1.293,
1.391 / 1.390, 1.464 / 1.487 and 1.284 / 1.333Å using HF / B3LYP and base 6-31G (d, p)
respectively. According to the reports, based on experiments, these binding times are 1.260,
1.260, 1.500 and 1.300 Â [51]. In our study of compound 2, with B3LYP function and base
pairs 6-31G (d, p), the calculated C9-S1 (thione) bond length is 1.672 Å, while that
observed in B2LYP is 1.667 Å [51] X-ray data. On the other hand, for compound 7, the
calculated values of the SI-C7 and SI-C19 bond lengths (sulfanyl groups) are 1.791 and
1.817 Â, respectively, and are reported as 1.7729 and 1.7948 Â, respectively as
experimental. For
2
-
[[(2-methoxy) sulfanyl] -4-(2-methylpropyl)-6-oxo-1,6-
[53]
dihydropyrimidine-5-carbonitrile
S1-C10 (depending on its numbering format), the
bond length calculated with the function B3LYP / M06-2X and base 6-31G (d, p) is 1.837 /
1.820 Å, which is reported as 1.800 Å based on experiments.
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Next, let's look at some of the binding angles of the results for compounds 2 and 7,
respectively. In compound 2, the bond angles C9-N3-C1, C7-N1-C6, N1-C7-C8, N3-C9-
C8, N3-C9-S1 and C8-C9-S1 are calculated as 123.5, 121.5, 120.4, 114.5, 124.8 and 120, 6
° Å have the function B3LYP, and the base 6-31G (d, p) is fixed, and these angles are
reported as 122.8, 120.0, 120.8, 115.5, 124.2 and 120.2 ° respectively by experiments. In
compound 7, the bond angles C7-S1-C19, C7-N1-C6, C9-N2-C1, N1-C7-C8 and N1-C7-S1
are calculated as 99.8, 125.5, fixed B3LYP function and 6-31G ( d, p) base angles of 115.7,
126.5 and 117.8°, which were reported as 101.14, 123.53, 114.67, 126, 62 and 119.42°,
respectively in the experiments. For the molecule 7-chloro-2-methylamino-5-phenyl-3H-
1,4-benzodiazepine-4-oxide molecule [51], C2-N1-C7, N1-C2-C3, N1-C7-C6, C3-N4-C5,
N4-C5-C6 and C5-C6-C7 bond angles (depending on their numbering format) were
calculated at 120.2/119.9, 122.2/122.2, 125.2/125.2, 120.0/118.7, 120.0/119.7 and
123.3/124.2° respectively with HF/B3LYP functionals and base 6-31G(d,p). These bond
angles were reported experimentally as 115.0, 115.1, 120.0, 106.8183, 120.0 and 120.0°,
respectively [51]. In addition, comparison of the selected theoretical results with the B3LYP
function and the 6-31G base set (d, p) shows excellent agreement, and further results of
optimized molecular structure can be studied using the following method Table 2.
Table 2. Selection of optimized structure parameters of the compounds 2 and 7.
Bond angles (°)
Optimized bond
angles
Bond lenghts (Å)
X-Ray
DFT/B3LYP/ 6-
31 G(d,p)
Optimized
X-Ray
DFT/B3LYP/ 6-31
G(d,p)
bond lenghts
Compound 2
C9-N2-C16
C9-N2-C1
C7-N1-C6
C1-N2-C16
C2-C1-C6
C2-C1-N2
C6-C1-N2
C5-C6-N1
C1-C6-N1
N1-C7-C10
N1-C7-C8
N3-C9-C8
N3-C9-S1
C8-C9-S1
119.3(2)
119.1
123.5
121.5
117.4
118.7
118.2
123.0
115.7
125.9
118.9
120.4
114.5
124.8
120.6
118.8
121.9
119.3
S1-C9
N1-C7
N1-C6
N2-C9
N2-C1
N2-C16
C1-C2
C1-C6
C2-C3
C2-H2
C3-C4
C3-H3
C4-C5
C4-H4
C5-C6
C5-H5
C7-C10
1.657(3)
1.274(3)
1.409(4)
1.353(4)
1.434(4)
1.476(4)
1.391(4)
1.405(4)
1.367(4)
0.9300
1.383(5)
0.930
1.368(5)
0.9300
1.386(4)
0.9300
1.493(4)
1.672
1.289
1.391
1.363
1.432
1.486
1.407
1.423
1.388
1.083
1.399
1.085
1.385
1.086
1.411
1.085
1.481
122.8(2)
120.0(2)
117.9(2)
118.3(3)
118.4(3)
123.3(2)
116.4(3)
125.0(2)
118.7(2)
120.8(2)
115.5(2)
124.2(2)
120.2(2)
119.1(3)
121.7(3)
119.2(3)
C11-C10-C15
C11-C10-C7
C15-C10-C7
Compound 7
C7-S1-C19
C20-O2-C21
C24-O4-C25
C7-N1-C6
C9-N2-C1
C9-N2-C17
C1-N2-C17
101.14(5)
116.77(9)
117.05(9)
123.53(9)
114.67(8)
116.52(8)
119.48(8)
99.8
S1-C7
S1-C19
O1-C20
O2-C20
O2-C21
O3-C24
O4-C24
1.7729(11)
1.7948(11)
1.1994(14)
1.3416(14)
1.4574(14)
1.2026(13)
1.3356(13)
1.791
1.817
1.209
1.352
1.448
1.210
1.345
116.2
116.7
125.5
115.7
116.8
119.8
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C9-N3-N4
C10-N4-N3
C10-N4-C23
N3-N4-C23
C2-C1-C6
C2-C1-N2
C6-C1-N2
C5-C6-N1
C1-C6-N1
N1-C7-C8
N1-C7-S1
103.67(8)
113.16(8)
128.66(9)
117.88(8)
119.46(10)
120.25(9)
120.29(9)
115.03(9)
126.46(9)
126.62(9)
119.42(8)
104.5
113.1
129.6
117.2
118.7
120.7
120.6
115.1
126.1
126.5
117.8
O4-C25
N1-C7
N1-C6
N2-C9
N2-C1
N2-C17
N3-C9
N3-N4
N4-C10
N4-C23
C8-C9
1.4668(14)
1.2827(14)
1.4206(14)
1.3930(13)
1.4319(13)
1.4700(13)
1.3282(13)
1.3756(11)
1.3521(13)
1.4439(13)
1.4188(14)
1.453
1.282
1.405
1.396
1.430
1.469
1.326
1.367
1.364
1.443
1.425
Figure 2. The optimized and ORTEP structures of compound 2 and compound 7.
2
.3.2. Hirshfeld surface calculations
The Crystal Explorer 3.1 [53-57] program was used for the Hirshfeld surface analysis
of compounds 2 and 7, and all the results obtained are presented in Figure 3-4. Here, cif*
files of the structures were used to obtain the graphs of the structures. As shown in figures
2 and 4, there are three colors on the surface: red, blue and white. The dark red dots
indicate strong hydrogen bonding points, the white dots indicate contacts close to the van
der Waals separation, and the last blue dots indicate longer contacts [53-57]. The dnorm values
were found as from -0.1142 to 1.3782 for compound 2 and from -0.2665 to 1.6826 for
Compound 7. Now, if we analyse for compounds 2 and 7 one by one; as seen from Figure 3
(a) the interaction distances of both S-H bonds were determined as 2.721Å and the
contribution of inter-contacts to the Hirshfeld surfaces were obtained as H-H (55.2%), C-
H/H-C (24.6%), S-H/H-S (11.6%) and N-H/H-N (4.7%) as seen from the (Figure 3 (b-e)),
respectively.
On the other hand, as seen from Figure 4(a) the interaction distances of O-H and N-H
bonds were determined as 2.254Å and 2.953Å, respectively. In addition, the contribution of
internal contacts to the Hirshfeld surface is also obtained as H-H (53.6%), C-H/H-C
(18.7%), O-H/H-O (16.5%), N-H/H-N (6.2%) and S-H/H-S (3.8%) as seen from the
(Figure 4(b-f)), respectively.
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Figure 3. The 3D Hirshfeld surface (a) and 2D fingerprint histograms (b-e) of compound 2.
Figure 4. The 3D Hirshfeld surface (a) and 2D fingerprint histograms (b-f) of compound 7.
2
.3.3. HOMO-LUMO Analyses
The formation of the transition state of chemical reactivity according to the Frontier
Molecular Orbital Theory (FMO) is due to the interaction between the frontier orbitals
(HOMO and LUMO) of the reactive regions and this analysis is very important for
theoretical organic chemistry. In this part, firstly compound 2 and 7 were optimized in
chloroform solvent, then by using the obtained chk* file HOMO and LUMO distributions
of the compound 2 and 7 were calculated with functional B3LYP and 6-31G(d,p) basis set.
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The results for compound 2 and 7 were listed in Table 3 and also the distributions were
shown in Figure 5. In this figure, positive phase is represented with the red color and the
negative phase is with the green color. The LUMO is largely focused almost over the whole
molecular moiety except C16-C17 parts whereas the region of HOMO spreads
approximately over the benzodiazepine group (with S part) and partially over the C16, C17
and C1 (positive phase) atoms for compound 2. When it comes to Compound 7, The
LUMO is largely focused almost over the whole molecular moiety except C24-C26, C19-
C20-O2-C21-C22 parts whereas the region of HOMO spreads approximately all over the
benzodiazepine group and S1 atom except with C11 benzene ring and O4-C25-C26, C19-
O1-C20-O2-C21-C22 parts. In literature, the energy differences of HOMO and LUMO (ΔE
gap) provides a measure for the stability of the compound, so the lower value of ΔE is
related to the higher stability [58]. Additionally, if the HOMO-LUMO energy differences of
a molecule are small, the electron distribution can be easily manipulated and the
polarization is large, and when the energy differences are large, the electron distribution
differs less and the polarization is low. As seen from the Table 3, the HOMO-LUMO
energy gap (|EHOMO- ELUMO|) was calculated as 4.091 eV and 4.063 eV for compound 2 and
7, respectively in the chloroform solvent. These results support the above-mentioned
literature related to stability. Additionally, the other related descriptor was calculated and
listed as in Table 3.
Table 3. HOMO and LUMO energy values and other related parameters of compound 2 and 7.
Parameters (eV)
Compound 2
-1.771
Compound 7
-1.238
ELUMO (eV)
EHOMO (eV)
-5.862
-5.301
4.091
5.862
1.771
4.063
5.301
1.238
Energy bandgap |EHOMO- ELUMO
Ionization potential (I = -EHOMO
Electron affinity (A = -ELUMO
|
)
)
2.045
0.244
2.031
0.246
Chemical hardness (h = (I-A)/2)
Chemical softness (z = 1/2h)
3.817
3.269
Electronegativity (χ = (I+A)/2)
-3.817
3.561
-1164.873834
-3.269
2.631
-1925.259890
Chemical potential (μ = -(I+A)/2)
Electrophilicity index (w = μ2/2h)
Sum of Electronic and zero point Energies (a.u)
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Figure 5. HOMO and LUMO plots of compound 2 and 7 with B3LYP/6-31G(d,p).
2
.3.4. NMR Analyses
1
13
In this part, the experimental H and C NMR spectra of compound 2 and 7 were
recorded in chloroform solution (Figure 2). To reinforce the experimental results, calculate
1
the theoretical chemical displacements of H NMR and 13C NMR using the B3LYP
function and 6-31G(d, p) bases. The IEFPCM model and the GIAO method are used after
optimization of the same solvent [59-60]. The experimental and calculated NMR values
were given in Table 4 and 5. The theoretical results were obtained by
using
equation, here
is the isotropic chemical shift,
is the isotropic
absolute shielding of the compound 2 and 7 and
is the isotropic absolute shielding of
tetramethylsilane. From Table 4 and 5, we can conclude that there is very good consistency
between the calculated and experimental chemical shifts of compound 2 and 7.
13
1
Table 4. The experimental and computed C and H-NMR isotropic chemical shifts (with respect
to TMS, all values in ppm) of compound 2.
Atoms
Compound 2-13C-NMR
Compound 2-1H-NMR
Atoms
H2
δexp.
δcal.
δexp.
δcal.
C1
128.87
128.78
7.25- 8.5
8.00
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C2
C3
110.23
113.62
114.80
117.07
132.16
150.57
41.15
H3
H4
7.67
7.77
7.76
3.10
4.77
8.76
7.94
7.93
7.89
9.02
3.87
5.06
1.27
2.82
1.67
110,22-128,15
C4
H5
C5
H8A
H8B
H11
H12
H13
H14
H15
H16A
H16B
H17A
H17B
H17C
3.15
4.17
C6
139.84
144.26
35.99
C7
7.25- 8.5
C8
C9
192.93
185.55
125.00
117.73
116.64
119.54
116.42
116.83
47.67
C10
C11
C12
C13
C14
C15
C16
C17
4.12
1.15
110,22-128,15
44.26
14.7
6.87
13
1
Table 5. The experimental and computed C and H-NMR isotropic chemical shifts (with respect
to TMS, all values in ppm) of compound 7.
Atoms
Compound 7-13C-NMR
δexp. δcal.
142.17
Compound 7-1H-NMR
δexp. δcal.
Atoms
H2
C1
C2
130.04
108.60
113.75
111.44
117.53
131.68
154.57
100.58
151.14
134.97
118.93
119.64
116.41
118.06
116.60
118.07
35.91
7.21
7.41
7.36
7.28
7.62
7.82
7.90
7.87
8.15
3.90
4.00
1.70
1.31
1.11
3.11
3.82
5.08
4.00
1.36
1.68
1.11
4.66
4.35
4.18
5.35
1.45
1.80
1.27
119.32
119.65
123.72
125.95
142.42
158.46
109.12
160.85
143.56
145.30
128.37
128.55
128.63
129.93
130.36
50.51
H3
7.02- 7.14
7.37- 7.49
C3
H4
C4
H5
C5
H12
C6
H13
C7
H14
C8
H15
C9
H16
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
C20
C21
C22
C23
C24
C25
C26
H17A
H17B
H18A
H18B
H18C
H19A
H19B
H21A
H21B
H22A
H22B
H22C
H23A
H23B
H25A
H25B
H26A
H26B
H26C
3.75
1.35
4.15
4.17
13.01
5.99
32.73
32.04
1.30
169,42
61.77
157.21
54.48
14.08
8.13
4.54
4.20
41.99
44.42
167,60
61.26
157.43
55.31
14.18
7.91
1.25
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2
.3.5. Molecular Docking Studies
The goal of this part is to investigate the molecular docking between compound 2 and
7 ligands and CYP2C19 protein: 4GQS (PDB code) [61]. The CYP2C19 which is a vital
member of cytochrome P-450 enzyme superfamily and has a very important role in drug
[6 ]
metabolism 2 . Before docking, it is necessary to delete all-natural ligands attached to
receptor molecule to clear the active site for more efficient calculations. First, the PDB and
PDBQT forms of the ligand (compounds 2 and 7 optimized with B3LYP / 6-31G (d, p))
And the protein receptor is prepared by Discover Studio Visualizer 4.0 software (DSV 4.0)
[63]. Then active sites of 4GQS protein were determined as GLY437, VAL436, CYS435,
ARG433, SER429, PHE428, PRO427, HIS368, LEU366, SER365, ILE362, ARG335,
VAL331, THR305, THR302, THR301, GLU300, GLY298, ALA297, ASP293, PHE226,
ASN218, ILE215, GLN214, VAL208, ILE205, ARG124, TRP120, PHE114, ILE112,
ARG97 and ILE42 residues and the grid boxes were determined according to the these
active residues: 70x78x80 Å3, spacing=0.375 and x, y, z centers: -70.672, 19.218 and -
42.74. Therefore, between compound 2+4GQS and compound 7+4GQS molecular docking
interactions were given at Table 6 and the obtained 2D and 3D forms were depicted in
Figure 6 and 7, respectively. From the Table 6 and Figure 6 and 7, it can be said that the
best docking result occurs between compound 7 and 4GQS with -7.9 kcal/mol binding
energy, 1.61904 μM inhibition constant and four conventional hydrogen bonding. Here, the
inhibition constants (Ki) for each conformer were computed from Ki = exp(ΔG/RT)
equation, where ΔG, R and T are respectively the docking energy, the gas constant
(1.9872036 × 10-3 kcal / mol) and the ambient temperature (298.15 K). As a result, from in
silico based molecular docking scores support that compound 2 and 7 ligands are potent
4GQS protein inhibitors. The obtained all docking results and bonding types could be seen
clearly from the Figure 6, 7 and 8, respectively.
Table 6. Binding affinity and RMSD results for 4GQS inhibitors of compounds 2 and 7 in different
positions.
Compound 2-4GQS
Compound 7-4GQS
Mode
Affinity
rmsdl.b.
rmsdu.b.
Inhibition
Constants
(μM)
Affinity
rmsdl.b.
rmsdu.b.
Inhibition
Constants
(μM)
(kcal/mol)
(kcal/mol)
1
2
3
4
-7.6
-7.0
-6.7
-6.7
0.000
17.164
17.593
31.303
0.000
21.001
20.503
32.310
2.68633
7.39542
12.2706
12.2706
-7.9
-7.6
-6.2
-6.1
0.000
2.213
2.481
2.647
0.000
3.295
6.092
5.753
1.61904
2.68633
28.5343
33.7806
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5
6
-6.6
-6.4
-6.4
-6.2
-6.1
-6.1
20.566
2.895
23.812
6.679
14.5266
20.3594
20.3594
28.5343
33.7806
33.7806
-5.8
-5.8
-5.8
-5.6
-5.6
-5.5
3.756
24.549
24.548
24.861
25.010
3.827
6.598
8.591
8.782
7.683
6.840
7.646
56.0492
56.0492
56.0492
78.5543
78.5543
92.9974
7
2.523
3.436
8
27.771
20.891
14.167
29.654
22.988
15.645
9
10
Figure 6. The molecular docking results of compound 2 with 4GQS protein, 2D forms (a) and 3D
forms (b).
Figure 7. The molecular docking results of compound 7 with 4GQS protein, 2D forms (a) and 3D
forms (b).
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Figure 8. The three-dimensional structure of 4GQS protein with the title molecules 2 and 7.
2
.4. Inhibiting tendency against metallic corrosion
As the inhibition of corrosion using organic compounds is largely attributed to their
adsorption on the metal surface [64], it is important to examine the affinity of the newly
synthesized derivatives to interact with the surface of selected metals (i.e. Fe, Cu and Al).
For this, the Monte Carlo simulations were performed employing universal as the force
field by considering the periodic boundary conditions [65, 67]. It is well known that in acidic
solutions the surface of pure metals is almost clean without the presence of oxide form.
Accordingly, the simulations were carried out on Fe(110), Cu(111) and Al(111) surfaces [68,
69]. Five layers with similar surficial density (i.e. number of atoms per layer) of these
surfaces with 60 Å as a vacuum region were used to build the suitable box of simulations.
Concerning the electrostatic and Van der Waals energetic components, they were
calculated using Ewald and atom-based summation approaches, respectively. As the acidic
environment is considered in this prediction study, the protonated form of these compounds
(noted as C2-H and C7-H) was also treated. On the other hand, the current simulations were
extended to study also the affinity of the water molecule and H3O+ ion to be adsorbed onto
selected metallic substrates, which are the principal constituents of acidic solutions. In this
work, the binding energy (EBinding) of different compounds is calculated according to the
following expression:
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(1)
Where
,
and
represent the energy of the whole system, metal surface,
is the adsorption energy. All listed calculations in this
adsorbed compound, while
section were performed employing Materials Studio 6.0 software.
To investigate the probable interfacial interactions of developed compounds in their
neutral and protonated forms with the iron, copper and aluminum surfaces, the Monte Carlo
simulations were conducted. The calculated binding energies for different
compound/surface systems are depicted in Figure 9. It is evident from calculated values
(Ebinding = –Eads) that studied derivatives could be adsorbed spontaneously onto all selected
metallic surfaces [70]. Furthermore, for neutral and protonated forms, the binding energy
was found to increase as follows: compound 7 > compound 2. This indicates the great
tendency of compound 7 to interact with studied metal surfaces rather than compound 2.
Such a trend can be attributed to the presence of more favorable sites of adsorption in
[
]
71
compound 7 (i.e. heteroatoms and π-electrons) as compared to compound 2
.
[
]
72
Considering the binding energy/inhibition efficiency linear relationship
, for all
considered metals, the expected inhibition effectiveness toward corrosion of these
compounds can be ranked as compound 7 > compound 2. Besides, we can note that the
calculated Ebinding depends on the chemical nature of the metal surface, which is ranked as
Al(111) >> Fe(110) > Cu(111) for the same compound. These finding outlines that the
anticipated inhibition effectiveness of a given compound will be reduced in the same
ranking. In other words, the developed derivatives can doubtless act as good inhibitors
against aluminum corrosion as compared to other studied metal in this work.
To get a credible vision on the ability of these compounds to protect metal toward
corrosion, it is important to consider further the adsorption affinity of the constituents of
aggressive media i.e. acidic solution. In this regard, the interfacial interactions of a water
molecule and H3O+ ion with metal surfaces should be taken in our case. The calculated
Ebinding of water molecule and H3O+ ion on the studied surfaces are graphically presented in
Figure 9. According to the illustrated data, H2O and H3O+ species can adsorb spontaneously
on the chosen metal surfaces. By comparing their affinity to interact with the metal surface
and corresponding ones for investigating organic compounds; it is clear that H2O shows a
lower affinity meaning the capacity of the synthesized compounds to replace pre-adsorbed
water molecules onto all considered metal surfaces. Nevertheless, H3O+ specie was
exhibited a great tendency to interact with Fe(110) and Cu(111) surfaces in comparison
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with the synthesized compounds, which outlines the competitive effect at the metal/solution
interface leading to lower inhibition property of these compounds for iron and copper metal
in acid media. The opposite behavior is observed in the case of Al(111) from which the
developed derivatives have a significant priority to adsorb onto the aluminum surface.
Hence, these derivatives can show the enhanced capacity to control the aluminum corrosion
in acid solution as compared to iron and copper metals.
Figure 9. Binding energy of the newly synthesized compounds 2 and 7, as well as a water molecule
and H3O+ ion, onto Al(111) surface.
Further to the energetic aspect (i.e. Ebinding), it is also needed to study the adsorption
process of these compounds from a geometrical side. As good inhibition effectiveness is
expected for the aluminum, we are limited in Figure 10 to present a more stable adsorption
configuration of these derivatives in their neutral (C2 and C7) and protonated (C2-H and
C7-H) forms on the Al(111) surfaces. It can be seen in the last figure that the investigated
organic compounds in both protonation forms are closely placed on the Al(111) surface,
which reveals their adsorption. In this configuration, we can note the parallel adsorption
geometry of the benzodiazepine moiety for both derivatives. Whereas, the extra-
substituents are either parallel or directed away from the Al(111) surface as can be noted
for C7 and C7-H molecules, respectively. In this regard, the parallel orientation can offer
better coverage of the aluminum surface that increases by rising molecular volume of the
derivative (i.e. compound 7 > compound 2). These findings underline the capacity of these
compounds to effectively protect aluminum toward corrosion in the following order:
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compound 7 > compound 2, which confirms further the energetic analysis of the adsorption
process.
Figure 10. Side and top (above-left) views of the more stable adsorption configuration of the newly
synthesized derivatives in their neutral (C2 and C7) and protonated (C2-H and C7-H) forms onto
the Al(111) surfaces.
2.5
.
Antibacterial activity
In order to compare and analyze the antibacterial properties provided by the
compounds (2-7) and commercially available antibiotics such as chloramphenicol (Chlor)
and ampicillin (Amp), we tested the following strains of Staphylococcus aureus (ATCC-
25923) , Escherichia coli (ATTC-25922), Pseudomonas aeruginosa (ATCC-27853) and
Streptococcus (ATCC-29212), the applicability of compounds (1-7) as antibacterial agents
was evaluated by the disc diffusion method [73,76 ]. Figure 11 summarizes the inhibition
diameter (mm) values of compounds (1-7) and the commercially available antibiotics Chlor
and Amp. The disc diffusion test is used to determine the MIC of synthesized derivatives of
[1,5]benzodiazepines (1-7). The results of the antibacterial activity of the tested compound
2 obtained by sulfurization of 1-éthyl 4-phényl -1,5-benzodiazépin-2-one 1 with
phosphorus pentasulfide (P2S5) resulted in anti-bacterial activity is increase of MIC =
15μg/mL for Escherichia coli and Streptococcus fasciens, 7,5 for Staphylococcus aureus
and MIC = 3,75μg/mL for Pseudomonas aeruginosa. Moreover, in order to increase the
inhibitory activity of pyrazolo [1,5] benzodiazépine-4-thione 3 has been via reaction
hydrazine by compound 2. the (5)-N-[methyl(ethyl)-2-aminophenylamino-5(3)-
phenylpyrazole 3 showed a similar better activity against the two bacterial strains as that
tested by compound 3, with a MIC of 3,75 μg/mL for Pseudomonas aeruginosa,
Staphylococcus aureus, MIC = 7,5 μg/mL for Escherichia coli, and 30μg/mL for
Streptococcus fasciens. However, compound 3 with carbon disulfide in the presence of
pyridine, demonstrated a decrease activity with an MIC of 30 μg/mL for Escherichia coli,
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Pseudomonas aeruginosa, and Streptococcus fasciens, and 7,5 μg/mL for Staphylococcus
aureus. Indeed, among the 3 alkylated products 5, 6 and 7, the compound 7 which has
showed a better activity, with a MIC of 3,75 μg / mL for Escherichia coli and 7,5 μg / mL
for Staphylococcus aureus and 15 μg / mL for Pseudomonas aeruginosa, and Streptococcus
fasciens. In particular, derivatives functionalized by ester groups and benzene rings have
the strongest antibacterial activity (92% of pathogenic bacteria are sensitive to these
compounds). Studies such as antifungal, anti-inflammatory, anti-cancer and anti-parasitic
tests must also be conducted, as the literature shows that these subjects have many
interesting results. Other bacteria should also be tested to extend this research.
The results are presented in the form of antibiograms below:
Figure 11. The figure below summarizes the antibacterial activity of the synthesized compounds
(1-7) against the bacteria tested (E. coli, Pseudomonas aeruginosa, Staphylococcus aureus and
Streptococcus). Chlorine, chloramphenicol (30 µg / mL); Ampere, ampicillin (10 µg / mL); DMSO,
dimethylsulfoxide (1%).
Table 7: Antibacterial activity of the compounds (1-7) represented as Minimum Inhibitory
Concentration [MIC (µg/mL)]
MIC (µg/mL)
E. coli
30
15
P. aeruginosa
S. aueus
30
S. fasciens
3,75
1
2
7,5
3,75
7,5
15
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3
4
5
6
7,5
30
7,5
30
3,75
30
30
3,75
7,5
30
30
30
3,75
30
30
30
7
3,75
6.25
15
6.25
7,5
12.5
15
3.75
Chlor
3 | EXPERIMENTAL SECTION
3.1. General
The spectroscopic characterizations of the synthesized compounds (2-7) were achieved by
recording NMR spectra: 1H-NMR (300 MHz) and 13C-NMR (75 MHz), respectively, which
were measured on a Bruker Avance DPX 300 instrument. Thin-layer chromatography
(TLC) and column chromatography were carried out on silica plates (Merck 60 F254) and
silica gel (Merck 60, 230-400 mesh) respectively. Melting points of compounds 2-7 were
determined in open capillaries. The chemical shifts (δ) were expressed in ppm and the
coupling constants (J) in Hertz (Hz), downfield from TMS [tetramethylsilane, Si(CH3)4]
which has been assigned a chemical shift of zero, TMS as an internal reference.
3.2. Procedure of Synthesis compound 2
To a solution of 1-ethyl-4-phenyl-1,5-benzodiazepin-2-one 1 (0.80 g, 3.04 mmol) in
20 ml of pyridine was added phosphorus pentasulfide (0.84 g, 3.65 mmol). The mixture
was refluxed for 4 h. After cooling, the solvent was evaporated under reduced pressure. The
residue formed was washed with hot water [77]. The compound obtained was crystallized
from ethanol to afford crystals of the title compound.
Compound 2: Yield (%)= 80; mp = 345K; 1HNMR (300 MHz, CDCl3): 1.15 (t, J=7,14Hz,
3H); 3.15 (d, J =12Hz, 1H); 4.2 (q, J =7.14Hz 2H); 4.7 (d, J =12Hz, 1H); 7.25-8.5 (m, 9H);
13CNMR (75 MHz, CDCl3): 14.17 (CH3); 35.99 (CH2); 44.26 (NCH2); 110.22-
128.15(CHar); 128.87(Car); 139.84(Car); 141.18 (Car); 144.26 (C=N); 192.93 (C=S).
3.3. Procedure of Synthesis compound 3
Dissolve 0.01 mole of 1-ethyl-4-phenyl-1,5-benzodiazepine-2-thione 2 in 40 ml of
ethanol and add one equivalent (or excess) of hydrazine hydrate. The mixture was stirred at
room temperature for 48 hours. After cooling, the solvent was concentrated under reduced
pressure, and the residue obtained was chromatographed on a silica gel column using a
((90/10) hexane / ethyl acetate eluent).
1
Compound 3: Yield (%) = 35; mp = 423K; H NMR (300 MHz, CDCl3): 1.23 (t, J = 7.0
Hz, 3H); 3.53 (q, J = 7 Hz, 2H); 5.62 (s, 1H); 5.90 (m, 2H); 7.12-7.54 (m, 9H). 13C NMR
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(75 MHz, CDCl3): 13.60 (CH3); 41.80 (CH2); 98.48 (CH); 124.74-129.62 (CHar); 108.84,
125.43, 126.31, 149.87(Car); 150.51 (C=N).
3.4. Synthesis procedure of compound 4:
To a solution of 0.01 mol of 3- [N-2- (aminophenyl) N-ethylamino] -5-
phenylpyrazole 3 solubilized in a minimum of pyridine, were added 20 ml of carbon
disulfide. The mixture reaction was left under magnetic stirring at room temperature
overnight. The yellow precipitate formed was filtered and recrystallized from ethanol.
1
Compound 4: Yield (%) = 85; mp = 553K; H NMR (300 MHz, DMSO-d6): 1.25 (t, J =
6.9 Hz, 3H); 3.75 (q, J = 6.9 Hz, 2H); 7.13–7.71 (m, 9H ); 11.24 (s, 1H, NH); 12.97 (s, 1H,
NH). 13CNMR (75 MHz, DMSO-d6): 13.60 (CH3); 40.09 (CH2); 119.76(C3), 123.92-
136.57(CHar); 136.57-150.02(Car), 192.78 (C=S) (see figures S1-S2 (Supporting
Information: spectrum 1H and 13H NMR for Compound 4B).
3.5. General procedure of synthesis compounds 5-7:
To a solution of 0.01 mol of 10-ethyl-3-phenylpyrazolo[4,3-c][1,5]benzodiazepine-
4-thione 4 in 60 ml of dimethylformamide were added 0.02 mol of alkylating agent :
(propargyl bromide, benzyl chloride or ethyl bromoacetate) and 0.02 mol of K2CO3 and
0.001 mol of tetra-n-butylammonium bromide (TBAB). The mixture was stirred at room
temperature for 24 hours. After filtration of potassium carbonate and evaporation of
dimethylformamide in reduced pressure, the residue obtained was chromatographed on a
silica column (eluent: ethyl acetate / hexane 30:70).
Compound 5: Yield (%) = 75; mp = 404 K; 1H NMR (300 MHz, DMSO-d6): 1.22 (t, 3H,
J = 7Hz, CH3); 3.04 (t, 1H, J = 2.7Hz, HCCH2S); 3.37 (t, 1H, J = 2.7Hz, HCCH2N); 3.68
(q, 2H, J = 7Hz, CH2); 3.79 ( d, 2H, J = 2.7Hz, SCH2CC); 4.64 (d, 2H, J = 2.7Hz,
NCH2CC); 7.02-7.55 (m, 9Har). 13C NMR (75 MHz, DMSO-d6): 12.88 (CH3); 17.51
(CH2); 33.15 (CH2); 41.23 (CH2); 73.11 (CH); 76.02 (CH); 78.18 (Cq); 79.94 (Cq); 119.23-
130.07 (CHar); 142.09-159.99 (Car) (see figures S3-S4 (Supporting Information: spectrum
1H and 13H NMR for Compound 5).
1
Compound 6: Yield (%) = 60; mp = 408K; H NMR (300 MHz, DMSO-d6): 1.20 (t, J =
7.2 Hz, 3H, CH3); 3.63 (q, 2H, J = 7.2 Hz , CH2); 4.19 (s, 2H, SCH2); 5.03 (s, 2H, NCH2);
13
6.94-7.47 (m, 19CHar), C NMR (75 MHz, DMSO-d6): 12.94 (CH3); 33.28 (CH2); 41.23
(CH2); 51.79 (CH2); 119.76-137.92 (CHar); 144.72-159.84 (Car, C3’, C5’) (see figures S5-
S6 (Supporting Information: spectrum 1H and 13H NMR for Compound 6).
Compound 7: Yield (%) = 60; mp= 419K; 1H NMR (300 MHz, CDCl3): 1.25 (t, 3H, CH3);
1.30 (t, 3H, CH3); 1.35 (t, 3H, CH3); 3.75 (q, 2H, CH2); 4.17 (q, 2H, CH2); 4.20 (q, 2H,
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13
CH2); 4.15 (s, 2H, SCH2); 4.54 (s, 2H, NCH2); 7.02-7.50 (m, 9Har). C NMR (75 MHz,
CDCl3): 13.01 (CH3); 14.08 (CH3); 14.18 (CH3); 32.73 (CH2); 41.99 (CH2); 50.51 (CH2);
61.26 (CH2); 61.77 (CH2); 119.32 -130.36 (CHar); 142.09-160.85 (Car, C3 ', C5'); 167,60
1
(C=O); 169,42(C=0) (see figures S7-S8 (Supporting Information: spectrum H and 13H NMR
for Compound 7).
4| CONCLUSIONS
The studies carried out in the framework of this work show that the 1,5-
benzodiazepine fraction constitutes an interesting scaffolding, present in several drugs and
natural products. In addition, we report the synthesis of new 1,5-benzodiazepine derivatives
(2-7). Their structure has been elucidated using X-ray crystallography and spectroscopy
techniques. By specifically showing that the alkyl group is connected to the sulfur atom and
the pyrazole nitrogen atom in position 2 instead of position 1 of the tricyclic compound as
described in the literature, we have confirmed the structure of pyrazolodiazepine 5-7. The
theoretical method used allows to reproduce the X-ray geometrical parameters, spectral
1
13
data and chemical displacements of H and C NMR. Hirshfeld surface analysis was used
to confirm the presence of intermolecular interactions in compounds 2-7. The use of
quantum chemistry DFT and in silico based molecular docking studies can reproduce the
experimental spectral data well. The Monte Carlo simulation’s outcomes reveal the ability
of these derivatives to act as good corrosion inhibitors for aluminum in acid media as
compared to iron and copper metals, in which the anticipated inhibition prevention order is
compound 7 > compound 2. The 1,5-benzodiazepine derivatives 2-7 exhibited antibacterial
activity and could act as potent antibacterial agents.
Conflicts of interest
There are no conflicts to declare.
Acknowledgment
Researchers Supporting Project number (RSP-2020/78), King Saud University, Riyadh,
Saudi Arabia, Authors would like to thank Prof. Dr. Fatih Ucun for his helpful contribution
and Gaussian Calculations and JTM thanks Tulane University for support of the Tulane
Crystallography Laboratory.
Abbreviations
Chlor-Chloramphenicol;
Amp-Ampicillin;
DMSO-dimethylsulfoxyde
This article is protected by copyright. All rights reserved.

MIC-Minimum Inhibitor Concentration
BHI-Brain heart infusion
HOMO-highest occupied molecular orbital
LUMO-lowest unoccupied molecular orbital
DSV 4.0-Discover Studio Visualizer 4.0
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