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

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 Ghayati^a, Yusuf Sert^b, Nada Kheira Sebbar^a,c*, Youssef Ramli^d, Noureddine

e

Hamou Ahabchane^a, Ahmed Talbaoui , Joel T. Mague^f, Brahim El Ibrahimi^g, Mohamed

Labd Taha^c, El Mokhtar Essassi^a, Nabil Al-Zaqri^h*, Ali Alsalme^h.

^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

This article has been accepted for publication and undergone full peer review but has

not been through the copyediting, typesetting, pagination and proofreading process

which may lead to differences between this version and the Version of Record. Please

cite this article as doi: 10.1002/jhet.4167

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).

R₁

O

N

H

HO

O

N

O

H

NH

N

R₂

O

H

NH

R₃

Cholecystokinin A (CCKA)

Cholecystokinin B (CCKB)

ICE Inhibitor

O

Cl

O

N

NH

Cl

Potassium inhibitors I_k

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

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 K₂CO₃as 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]

.

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-N₅bond leads to the

pyrazolic compound [C] which after the loss of a hydrogen sulfide molecule gives the

compound 3.

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.

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).

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 K_α

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

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.

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

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 d_normvalues

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.

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.

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 (|E_HOMO- E_LUMO|) 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

E_LUMO(eV)

E_HOMO(eV)

-5.862

-5.301

4.091

5.862

1.771

4.063

5.301

1.238

Energy bandgap |E_HOMO- E_LUMO

Ionization potential (I = -E_HOMO

Electron affinity (A = -E_LUMO

|

)

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)

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

δ_exp.

δ_cal.

δ_exp.

δ_cal.

C1

128.87

128.78

7.25- 8.5

8.00

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

δ_exp.δ_cal.

142.17

Compound 7-¹H-NMR

δ_exp.δ_cal.

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

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 K_i= exp(ΔG/RT)

equation, where ΔG, R and T are respectively the docking energy, the gas constant

(1.9872036 × 10^-3kcal / 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)

1

2

3

4

-7.6

-7.0

-6.7

0.000

17.164

17.593

31.303

0.000

21.001

20.503

32.310

2.68633

7.39542

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

5

6

-6.6

-6.4

-6.2

-6.1

20.566

2.895

23.812

6.679

14.5266

20.3594

28.5343

33.7806

-5.8

-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

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).

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 (E_Binding) of different compounds is calculated according to the

following expression:

(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

(E_binding= –E_ads) 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 E_bindingdepends 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

E_bindingof 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

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. E_binding), 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:

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,

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

3

4

5

6

7,5

30

7,5

30

3,75

30

3,75

7,5

30

3,75

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

(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 K₂CO₃and

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, 19CH_ar), 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,

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

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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Article Doi

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

DOI: 10.1002/jhet.4167

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Article abstract of DOI:10.1002/jhet.4167

Full text of DOI:10.1002/jhet.4167

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