Synthesis, X-ray, spectroscopic characterization, Hirshfeld surface analysis, DFT calculation and molecular docking investigations of a novel 7-phenyl-2,3,4,5-tetrahydro-1H-1,4- diazepin-5-one derivative

Article abstract of DOI:10.1016/j.molstruc.2021.130146

The tetrahydrodiazepine ring in the title molecule, C₁₁H₁₂N₂O, adopts a twisted envelope conformation. In the crystal, inversion dimers are formed by N[sbnd]H?O hydrogen bonds which are connected into corrugated layers by

Full text of DOI:10.1016/j.molstruc.2021.130146

Journal of Molecular Structure 1234 (2021) 130146
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis, X-ray, spectroscopic characterization, Hirshfeld surface
analysis, DFT calculation and molecular docking investigations of a
novel 7-phenyl-2,3,4,5-tetrahydro-1H-1,4- diazepin-5-one derivative
Wedad Al Garadia,#, Youness El Bakri
a,b,#,∗
f
, Chin-Hung Lai
c,d,∗
a
, El Hassane Anouare,
a
Lhoussaine El Ghayati , Joel T. Mague , El Mokhtar Essassi
a
Laboratoire de Chimie Organique Hétérocyclique, Centre de Recherche des Sciences des Médicaments, Pôle de Compétences Pharmacochimie, URAC 21,
Faculté des Sciences, Université Mohammed V Rabat, Avenue Ibn Battouta, BP 1014, Rabat, Morocco
b
Department of Theoretical and Applied Chemistry, South Ural State University, Lenin prospect 76, Chelyabinsk, 454080, Russian Federation
c
Department of Medical Applied Chemistry, Chung Shan Medical University, Taichung 40241, Taiwan
d
Department of Medical Education, Chung Shan Medical University Hospital, 402 Taichung, Taiwan
e
Department of Chemistry, College of Sciences and Humanities in Al-Kharj, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
f
Department of Chemistry, Tulane University, New Orleans, LA 70118, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The tetrahydrodiazepine ring in the title molecule, C11 H12 N O, adopts a twisted envelope conformation.
2
Received 25 January 2021
Revised 13 February 2021
Accepted 17 February 2021
Available online 24 February 2021
In the crystal, inversion dimers are formed by N–HꢀO hydrogen bonds which are connected into corru-
gated layers by N–HꢀO hydrogen bonds and C–Hꢀπ(ring) interactions. However, the Hirshfeld surface
analysis indicated that the most important intermolecular interaction for the title compound is the HꢀH
contact. Moreover, the DFT-B3LYP study showed that the title compound should have a slightly differ-
ent geometry in the gas phase with respect to that in the solid phase. The antitumor activity of the
novel tetrahydrodiazepine derivative is investigated by investigating its binding affinity into the active
site of Checkpoint Kinase Chk1/SB218078. Docking outputs reveal moderate Checkpoint Kinase inhibition
by tetrahydrodiazepine derivative.
Keywords:
Crystal structure
Tetrahydrodiazepine
Hirshfeld surface analysis
DFT calculations
Molecular docking
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
turn secondary structures [10–12] and exhibits anticonvulsant ac-
tivity [13], antibacterial activity against multidrug-resistant My-
The development of general approaches to rare heterocyclic
scaffolds and studies on their structure and reactivity are impor-
tant in synthetic, theoretical, and medicinal chemistry. The explo-
ration of novel structures in drug discovery has gained increasing
interest and relevance [1]. Among the small molecules employed in
this field, molecular scaffolds that mimic peptide secondary struc-
tures are particularly useful for the identification and develop-
ment of therapeutic agents [1,2]. For example, 1,4-benzodiazepine
is an important scaffold or fragment that has been studied ex-
tensively and frequently appears in biologically active molecules
and drugs [3]. In particular, a large number of 1,4-benzodiazepines
act as anxiolytic, antidepressant, anticonvulsant, and antihypnotic
agents [4–7] and some of them exhibit antitumor activity [8,9].
The seven-membered 1,4-diazepin-2-one ring mimics β- and γ -
cobacterium tubercolosis strains [14], antitumor properties [15],
and lymphocyte function-associated antigen-1 (LFA-1) antagonists
[16,17]. For these reasons, the development of new strategies for
the synthesis of 1,4-diazepin-2-ones is ever evolving. The most re-
ported synthetic approaches to 1,4-benzodiazepine skeletons in-
clude reaction of 2-aminobenzoic acids and their derivatives or
2-aminobenzophenones with α-amino acids [18,19], cycloconden-
sation of 2-halobenzoic acid derivatives or 2-halobenzophenones
with diamines [20], and the Pictet-Spengler reaction of N,N’-
dimethyl-N-phenyl-1,2-ethanediamine with aldehydes [21,22]. The
diazepinone ring is reported in the literature to be prepared from
linear precursors by intramolecular reductive amination [12,23–
25], lactam formation [26–28], and transamidation [29]. Also, the
preparation of 1,4-diazepin-2-ones involves iminophosphorane in-
termediates by means of an intramolecular aza-Wittig reaction or
hydrolysis of the iminophosphoranes to the corresponding amino
derivatives followed by intramolecular cyclocondensation [30]. The
limit of these procedures is that they involve some preparative dif-
ficulties and require several steps [31–37].
∗
Corresponding authors.
E-mail addresses: yns.elbakri@gmail.com (Y.E. Bakri), chlai125@csmu.edu.tw (C.-
H. Lai).
#
Both of these authors contributed equally to this paper
https://doi.org/10.1016/j.molstruc.2021.130146
0
022-2860/© 2021 Elsevier B.V. All rights reserved.

W.A. Garadi, Y.E. Bakri, C.-H. Lai et al.
Journal of Molecular Structure 1234 (2021) 130146
Scheme 1. Schematic representation of the synthesis of the title compound.
2. Experimental and calculated methods
2
.1. Synthesis
A solution of (0.1 mol) of ethyl benzoylacetate and 10 mL of
xylene was added, dropwise, over 40 min. to a refluxing solution
of 0.1 mol ethylene diamine and 100 mL of xylene. During this
time an oily layer separated. On cooling, the oil solidified to a hard
mass. The xylene layer was decanted and discarded. The solid was
suspended in about 100 ml of chloroform and the mixture was fil-
tered. The solid was recrystallized from ethanol to afford the title
compound as colorless crystals (Scheme 1).
Thin-layer chromatography and column chromatography were
carried out, respectively, on silica plates (Merck 60 F254) and silica
gel (Merck 60, 230–400 mesh). The NMR spectra were performed
on a Bruker Avance DPX300 instrument. The chemical shifts (δ) are
expressed in ppm. Mass spectra were performed on a Perkin-Elmer
SCIEX API unit 300. The samples are ionized by the electrospray
technique (ESI). Elemental analysis was performed on a Euro EA -
CHNSO Elemental Analyzer.
Colorless crystal, Yield: 67%; m.p: 214–216 °C. 1H NMR
(
600 MHz, DMSO–d ) δ ppm: 3.41 (m, 4H, CH ), 4.52 (m, 1H, CH),
6 2
7
4
.45–7.50 (m, 5H, CHar). 13C NMR (151 MHz, DMSO–d ) δ ppm:
6
2.41, 47.60, 91.50, 126.95, 128.38, 129.26, 139.45, 152.03, 170.02.
+
HRMS (ESI) Calculated for C11 H12N O: [M + H ] = 188.09, Found:
2
+
[
M + H ] = 188.23. Elemental analysis Calculated: C, 70.19%; H,
6
.43%; N, 14.88%; O, 8.50% Found: C, 69.96%; H, 6.76%; N, 15.05%;
O, 8.23%.
Fig. 1. The title molecule with labeling scheme and 50% probability ellipsoids.
2
.2. X-ray structure determination
exchange utilizing the B3 functional, together with the LYP correla-
tion functional [43–45] in conjunction with the basis set def2-SVP
A colorless block-like specimen of C11 H12N O, approximate di-
2
3
mensions 0.26 × 0.20 × 0.18 mm , was used for the X-ray crys-
tallographic analysis. The X-ray intensity data were measured on a
Bruker D8 VENTURE PHOTON 100 CMOS system equipped with an
[
46]. After obtaining the converged geometry, the harmonic vibra-
tional frequencies were calculated at the same theoretical level to
confirm the number of imaginary frequency is zero for the sta-
tionary point. Both the geometry optimization and harmonic vi-
brational frequency analysis of the title compound were done by
the Gaussian 16 program [47]. A more detailed analysis about the
electronic property of the title compound was performed by using
the NBO 3.1 implemented in the Gaussian 16 program [48].
˚
INCOATEC IμS micro–focus source (Cu-Kα, λ = 1.54178 A) and a
mirror monochromator.
A hemisphere of data was processed using SAINT [38]. The
structure (Fig. 1) was solved by direct methods and refined by
full-matrix least squares method on F2 using SHELXT and SHELXL
[
39,40]. All the hydrogen atoms were revealed in the first differ-
ence Fourier map and were included as riding contributions with
isotropic displacement parameters.
2.4. Hirshfeld surface analysis
At the end of the refinement, the final difference Fourier map
showed no peaks of chemical significance and the final value of
R1 was 0.0336. The geometrical calculations were carried out us-
ing the program PLATON [41]. The molecular and packing diagrams
were generated using DIAMOND [42]. The details of the crystal
data and structure refinement are given in Table 1.
Both the definition of a molecule in a condensed phase and
the recognition of distinct entities in molecular liquids and crys-
tals are fundamental concepts in chemistry. Based on Hirshfeld’s
partitioning scheme, Spackman et al. [49] proposed a method to
divide the electron distribution in a crystalline phase into molecu-
lar fragments [50,51]. Their proposed method partitioned the crys-
tal into regions where the electron distribution of a sum of spheri-
cal atoms for the molecule dominates over the corresponding sum
of the crystal. Because it derived from Hirshfeld’s stockholder par-
titioning, the molecular surface is named as the Hirshfeld surface.
In this study, the Hirshfeld surface analysis of the title compound
was performed utilizing the Crystal Explorer program [52].
2
.3. DFT details
The structure in the gas phase of the title compound was opti-
mized by means of density functional theory. The DFT calculation
was performed by the hybrid B3LYP method, which is based on
the idea of Becke and consider a mixture of the exact (HF) and DFT
2

W.A. Garadi, Y.E. Bakri, C.-H. Lai et al.
Journal of Molecular Structure 1234 (2021) 130146
Table 1
Crystal data and structure refinement details.
Parameter
Value
CCDC deposit No
Chemical formula
Formula weight
Temperature
1,974,554
C11H12N2O
188.23 g/mol
150(2) K
Wavelength
1.54178 A˚
3
Crystal size
0.181 × 0.197 × 0.260 mm
colorless block
Crystal habit
Crystal system
Space group
Monoclinic
C 1 2/c 1
Unit cell dimensions
a = 13.6868(6) A˚
α = 90°
b = 13.8189(6) A˚
c = 12.1418(5) A˚
2005.29(15) A˚
β = 119.166(1)°
γ = 90°
3
Volume
Z
8
Density (calculated)
Absorption coefficient
F(000)
1.247 g/cm3
−
1
0.657 mm
800
Data collection and structure refinement
Diffractometer
Bruker D8 VENTURE PHOTON 100 CMOS
Radiation source
INCOATEC IμS micro-focus source (Cu-Kα (λ = 1.54178 A˚ ))
Theta range for data collection
Index ranges
4.89 to 72.23°
−16 ≤ h ≤ 16, -15 ≤ k ≤ 17, -14 ≤ l ≤ 14
7515
Reflections collected
Independent reflections
Coverage of independent reflections
Absorption correction
Max. and min. transmission
Refinement method
Refinement program
Function minimized
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices
1942 [R(int) = 0.0290]
98.1%
multi-scan
0.8900 and 0.8480
Full-matrix least-squares on F2
SHELXL-2018/1 [39,40]
ꢀw(Fo2 - Fc2)2
1942 / 0 / 176
1.060
1807 data; I > 2σ(I)
all data
R1 = 0.0336, wR2 = 0.0823
R1 = 0.0355, wR2 = 0.0838
w = 1/[σ2(Fo2)+(0.0344P) + 1.2724P]
2
Weighting scheme
2
2
where P=(Fo +2Fc )/3
Extinction coefficient
0.0041(3)
Largest diff. peak and hole
R.M.S. deviation from mean
0.217 and −0.177 eA˚
−
3
0.038 eA˚
−
3
Table 2
Hydrogen-bond geometry ( A˚ , °).
2
.5. Molecular docking study
The antitumor activity of tetrahydrodiazepine derivative is in-
D–H···A
D–H
HꢀA
DꢀA
D–HꢀA
vestigated using molecular docking study. The Checkpoint Kinase
Chk1/SB218078 is chosen a target enzyme (pdb code 1NVS). The
intermolecular interactions between the docked compound and the
active residues of the target enzyme have been determined using
Autodock package [53]. The starting geometries of Checkpoint Ki-
nase Chk1/SB218078 and its original docked ligand were download
from the RCSB data bank web site (PDB code 1NVS) [54]. Wa-
ter molecules were removed; polar hydrogen atoms and Kollman
charge were added to the extracted receptor using the automated
tool in AutoDock Tools 4.2. The active site is identified based on co-
crystallized receptor-ligand complex structure of Checkpoint Kinase
Chk1/SB218078 [54]. The re-docking of the original ligand acetohy-
droxamic acid into the active site is well reproduced with a RMSD
N2–H2AꢀO1i
0.947(16)
0.905(16)
0.996(13)
1.019(14)
1.913(16)
1.924(16)
2.755(14)
2.970(15)
2.8591(12)
2.7937(12)
3.6160(13)
3.7285(15)
177.0(13)
160.4(14)
145.0(12)
131.9(10)
N1–H2ꢀO1ii
C5–H5AꢀCg1iii
C5–H5BꢀCg1iv
Symmetry codes: (i) −x + 1/2, −y + 1/2, −z + 1; (ii) x, −y + 1, z − 1/2; (iii)
−x + 1/2, y − 1/2, −z + 1/2; (iv) −x + 1, −y + 1, −z + 1.
and ϕ(3)
=
140.85(19)° [55]. The total puckering amplitude
˚
is 0.6757(13) A. The C6ꢀC11 benzene ring is inclined to the
mean plane defined by N1/C1ꢀC4 (deviation from mean plane:
˚
˚
−
0.0220(5) A (C1); 0.0300(8) A (C2); r.m.s. deviation 0.0213) by
˚
value less than 0.94 A. The docking calculations have been carried
4
3.55(4)° while the inclination to the mean plane of the full
out using an Intel (R) Core (TM) i5–3770 CPU @ 3.40 GHz worksta-
tion.
diazepine ring is 41.46(6)°. The bond distances and the interbond
angles are as expected (Table S3 in the supporting information).
For example, the N1—C4 and N2—C5 distances (1.4438(14) and
˚
3
. Results and discussion
1.4487(13) A) are significantly longer than the N1—C3 and N2—C1
˚
2
distances (1.3473(14) and 1.3426(13) A) due to the sp hybridiza-
tion of the latter carbon atoms. In the crystal, N2—H2AꢀO1
hydrogen bonds (Table 2) form inversion dimers which are linked
into corrugated sheets parallel to the bc plane by N1–H1ꢀO1
hydrogen bonds and C5—H5AꢀCg1 and C5—H5BꢀCg1 interactions
(Table 2 and Figs. 2 and 3).
3
.1. Structure description
The tetrahydrodiazepine ring adopts
a
twisted enve-
lope conformation with Cremer-Pople puckering parameters
˚
˚
Q(2) = 0.5025(12) A, Q(3) = 0.3729(12) A, ϕ(2) = 52.83(14)°
3

W.A. Garadi, Y.E. Bakri, C.-H. Lai et al.
Journal of Molecular Structure 1234 (2021) 130146
Fig. 2. Packing viewed along the c-axis direction with N–HꢀO hydrogen bonds shown by blue dashed lines. The C–Hꢀπ(ring) interactions are shown by green dashed lines.
Fig. 3. Packing viewed along the b-axis direction with intermolecular interactions depicted as in Fig. 2.
4

W.A. Garadi, Y.E. Bakri, C.-H. Lai et al.
Journal of Molecular Structure 1234 (2021) 130146
Fig. 4. The B3LYP-optimized geometry of the title compound (bond lengths in A˚ , bond angles in°).
Table 3
The B3LYP-optimized, and the X-ray structural parameters
for the title compound (The atomic designations can be
seen in Fig. 1; bond lengths in A˚ , bond and dihedral angles
in°).
B3LYP
X-ray
C3-C6
1.497
1.408
1.397
1.398
1.376
1.448
1.530
1.444
1.381
1.477
1.369
1.226
118.4
127.8
−40.05
−47.60
1.4962(14)
1.3960(15)
1.3908(17)
1.383(2)
C6-C7
C7-C8
C8-C9
C3-N1
1.3473(14)
1.4438(14)
1.5193(15)
1.4487(13)
1.3426(13)
1.4547(15)
1.3715(14)
1.2633(12)
118.79(10)
127.67(10)
−41.72(14)
−45.60(15)
N1-C4
C4-C5
C5-N2
N2-C1
C1-C2
C2-C3
C1-O1
ࢬC7-C6-C11
ࢬN1-C3-C2
ࢬN1-C3-C6-C7
ࢬC3-N1-C4-C5
3
.2. The comparison between the gas-phase geometry and the
solid-phase one
The B3LYP-optimized geometry of the title compound is de-
picted in Fig. 4 and the bond distance and interbond angles ob-
tained from this optimization are compared to the experimental
(
X-ray) values for the title compound in Table 3. It is evident from
Table 3 that the B3LYP-optimized geometry shows little deviation
from the experimental geometry. To quantify the difference be-
tween the calculated and experimental geometries, the structure
comparer contained in the ChemCraft program was used to obtain
their root-mean-square deviations (RMSD) [56]. A weighted RMSD
of 0.1089 was obtained to indicate that the optimization gave an
RMSD of 0.1496, 0.0480, 00,830, and 0.0301 for H atoms, C atoms,
N atoms, and O atoms, respectively.
Fig. 5. The dnorm Hirshfeld surface of the title compound (red: negative, white:
zero, blue: positive; scale: −0.6042 to 1.9277 a.u.).
5

W.A. Garadi, Y.E. Bakri, C.-H. Lai et al.
Journal of Molecular Structure 1234 (2021) 130146
Fig. 6. The 2D fingerprint plot of the title compound (a) full, (b) resolved by the H•••O contacts, (c) resolved by the HꢀN contacts, (d) resolved by the HꢀH contacts.
3
.3. The Hirshfeld analysis of the title compound
standard 0.6–2.6 a.u. view with the de and d distance scales dis-
i
played on the graph axes and including the reciprocal contacts, we
found the most important interaction involving hydrogen in the ti-
tle compound was the HꢀH contact. The contribution of the HꢀO,
HꢀN, and HꢀH contacts are 14.8%, 1.6%, and 57.8%, respectively.
The standard resolution molecular Hirshfeld surface (dnorm) of
the title compound is depicted in Fig. 5. The surface is shown as
transparent so the molecular moiety can be visualized in a simi-
lar orientation for all the structures around which they were cal-
culated. The 3D dnorm surface can be used to identify very close
intermolecular interactions being negative (positive) when inter-
molecular contacts are shorter (longer) than the sum of the van
der Waals radii. The dnorm value is mapped onto the Hirshfeld sur-
face with the red regions representing closer contacts with a neg-
ative dnorm value while the blue regions represent longer contacts
with a positive dnorm value. The white regions represent contacts
equal to the sum of the van der Waals radii and have a dnorm value
of zero. As depicted in Fig. 5, the important interactions in the ti-
tle compound may be HꢀO and HꢀN hydrogen bonds. In order to
understand the relative importance of HꢀO hydrogen bonds over
HꢀN hydrogen bonds, we calculated the 2D fingerprint plots for
the title compound.
3
.4. Frontier molecular orbitals analysis
The important aspect of the frontier molecular orbital theory is
the focus on the highest occupied and lowest unoccupied molecu-
lar orbitals (HOMO and LUMO). Instead of thinking about the total
electron density in a nucleophile, the localization of the HOMO or-
bital should be considered because electrons from this orbital have
the most chance to participate in the nucleophilic attack, while
a site where the lowest unoccupied orbital is localized is a good
electrophilic site. The frontier orbital of the title compound was
further investigated in this study and its HOMO and LUMO were
depicted in Fig. 7. As depicted in Fig. 7, the electron density of its
HOMO was mostly distributed in the diazepanone moiety, while
that of its LUMO was mostly distributed over the phenyl ring.
Furthermore, the quantum chemistry descriptors (chemical
hardness η, softness S, electronegativity χ and electrophilicity ω)
The 2D fingerprint plots (Fig. 6) highlight particular atom pair
contacts and enable the separation of contributions from differ-
ent interaction types that overlap in the full fingerprint. Using the
6

W.A. Garadi, Y.E. Bakri, C.-H. Lai et al.
Journal of Molecular Structure 1234 (2021) 130146
Fig. 7. Optimized structure, quantum parameters and frontier molecular orbitals of title compound.
derived from the conceptual Density Functional Theory of the ti-
tled compound were also listed in Fig. 7. The conceptual DFT
3.5. Molecular electrostatic potential (MEP)
(
CDFT) is a branch of DFT and aims to provide an accurate explana-
MEPs are fundamentally measures of the interaction strength
of the nearby charges, nuclei and electrons at a particular posi-
tion and thus enabling us to visualize the charge distribution and
charge-related characteristics of molecules. In order to make data
of the electrostatic potential easy to interpret, a visual represen-
tation with a chromatogram is used. Generally, red represents the
lowest electrostatic potential value and may be attacked by elec-
trophiles. On the contrary, blue represents the highest electrostatic
potential and may be attacked by nucleophiles. The full density
matrix is used to generate the total density of the title compound
and the resulting MEP is mapped on its surface (Fig. 8). As de-
picted in Fig. 8, the oxygen atom of the C=O group in the title
compound is responsible for the nucleophilic attack due to the fact
that it has the largest electronegativity among all kinds of atoms
in the title compound. Moreover, MEP also shows the two N–H
groups in the title compound could act as the hydrogen bonding
donors.
tion of some frequently mentioned concepts such as electronega-
tivity and softness. Therefore, CDFT can make some empirical prin-
ciples, for example, the electronegativity equalization principle, the
hard and soft acid-base principle, the maximum hardness princi-
ple to have a wider range of applications. In advance accordance
to Koopmans’ theory, the vertical ionization potential (I), and elec-
tron affinity (EA) of a molecule is:
I = −EHOMO
(
1)
EA = −ELU MO
Then, the global chemical reactivity parameters such as the chem-
ical hardness (η), softness (S), electronegativity (χ), and elec-
trophilicity (ω) can be represented as
Chemical hardness is an important feature of chemical species
and can be defined as the resistance of atoms, ions or molecules
to deform or polarize their electron clouds. The harder a molecule,
the greater its ability to prevent its electron cloud from twisting
or polarizing. Softness is closely related to reactivity. The softer
a molecule, the greater its chemical reactivity. In a molecule, the
electronegativity of an atom or a functional group is its ability to
attract the bonding electrons to itself. The greater the electroneg-
ativity of an atom or functional group, the stronger its ability to
attract bonding electrons. Electrophilicity can be regarded as the
size of the reactivity of an electron-deficient system with a nu-
cleophile. The greater the electrophilicity of an electron-deficient
molecule, the greater its reactivity with a nucleophile [57]. Based
on the analysis the frontier orbital, the phenyl ring should be the
electrophilic site in the titled compound.
3.6. The results of the NBO analysis
Although some evidences showed that the Mulliken charge
displacement around molecular site is useful tool to find out
the cause of inducement of drug potential [58], however, Finkel-
mann et al. compared several partial atomic charge schemes and
showed that the NPA charges is a good choice for molecular mod-
eling and design [59]. Therefore, the results of the natural pop-
ulation analysis about the title compound was summarized in
Fig. 9. As depicted in Fig. 9, the N1 atom (See the atomic des-
ignation in Fig. 1) bears the most negative charge and should be
7

W.A. Garadi, Y.E. Bakri, C.-H. Lai et al.
Journal of Molecular Structure 1234 (2021) 130146
Fig. 8. Molecular Electrostatic Potential (MEP) map of the investigated molecule (the isodensity value = 0.004 a.u.).
Fig. 9. The results of the natural population analysis.
the most susceptible to the electrophilic attack among the atoms
3.7. Molecular docking analysis
in the title compound. As a hydrogen bond forms, there should
be an orbital interaction between the nonbonding orbital of the
The ability of the novel tetrahydrodiazepine derivative to in-
hibit Checkpoint Kinase Chk1/SB218078 is estimated by predicting
the binding energy of the stable complex compound- Checkpoint
Kinase, number of conventional intermolecular hydrogen bonding
established between the synthesized compound and active site
residues of Checkpoint Kinase Chk1/SB218078. Indeed, the formed
complex displayed a negative binding energy of −4.67 kcal/mol,
which is a signpost that the inhibition of Checkpoint Kinase
Chk1/SB218078 is thermodynamically favorable. Docking results re-
veal that the binding interactions are mainly of π-type (Fig. 10).
Indeed, three π-alkyl interactions are formed between the aro-
hydrogen-bonded acceptor (n ) and the antibonding orbital of the
A
∗
H-Donor bond (σH-D ). Therefore, the bond strength or bond or-
der of σH-D should be weakened (decreased) due to such or-
bital interaction. If the stronger the n ꢀσ
∗
∗
orbital interaction,
A
H-D
the stronger the hydrogen bond D–HꢀA. The result of the NBO
analysis shows that there should be three strong hydrogen bonds
in the title compound which its E(2)(n ꢀσ
∗
) > 0.5 kcal/mol.
H-D
A
They are C4-HꢀN1, C4-H’ꢀN1, and C5-HꢀN2 (See the atomic des-
ignations in Fig. 1). The related NBO results are summarized as
Table 4 shows.
8

W.A. Garadi, Y.E. Bakri, C.-H. Lai et al.
Journal of Molecular Structure 1234 (2021) 130146
Table 4
The results of the NBO analysis.
E(2) (in kcal/mol)
The occupancy of σH-D
∗
The bond order of σH-Db
The type of nA
The electron configuration of nA
The type of orbital interaction
LP1 of N1a
LP1 of N1a
LP1 of N2a
s(3.15%)p(96.84%)d(0.01%)
s(3.15%)p(96.84%)d(0.01%)
s(1.24%)p(98.75%)d(0.01%)
LP(N1)-σ (C4-H)
∗
∗
∗
8.46
1.25
8.47
0.02904
0.01142
0.02851
0.9068
0.9200
0.7485
LP(N1)-σ (C4-H’)
LP(N2)-σ (C5-H)
Please see the atomic designations in Fig. 1.
b. The listed values were the atom-atom overlap-weighted NAO bond order.
Fig. 10. 3D (left) and 2D (left) intermolecular interactions of name of compound and active amino acids of Checkpoint Kinase Chk1/SB218078.
matic ring of tetrahydrodiazepine derivative and Leu-A137, Ala-
A36, and Cys-A87; and π-σ interaction between sigma bonds of
the aromatic ring and Leu-A15 (Fig. 10). Further, a carbon hydro-
gen bond is formed between the methine of Gly16 and the keto
group of the seven-member ring of tetrahydrodiazepine derivative
Lhoussaine El Ghayati: Visualization, Invistigation and data cu-
ration.
Joel T. Mague: Performed the X-ray experiments and analyzed
and interpreted the data.
El Mokhtar Essassi: Conceptualization and supervision.
˚
of a distance 3.05 A (Fig. 10).
Declaration of Competing Interest
There are no conflicts to declare.
Acknowledgements
Conclusion
In this study, an efficient and atom-economic method to syn-
thesize the diazepinone derivatives. The synthesized compound,
C11 H12N O was further investigated by X-ray crystallograpical, DFT-
2
B3LYP, and Hirshfeld surface analysis studies. In the crystal, the ti-
tle compound form inversion dimers by N–HꢀO hydrogen bonds
which are connected into corrugated layers by N–HꢀO hydrogen
bonds and C–Hꢀπ(ring) interactions. However, the Hirshfeld sur-
face analysis indicated that the most important intermolecular in-
teraction for the title compound is the HꢀH contact. Moreover, the
DFT-B3LYP study showed that the title compound should have a
slightly different geometry in the gas phase with respect to that
in the solid phase. The molecular docking study expected mod-
erate affinity of tetrahydrodiazepine to bind to Checkpoint Kinase
Chk1/SB218078 active site, and that binding interactions are mainly
of π-type.
The support of NSF-MRI Grant # 1228232 for the purchase of
the diffractometer and Tulane University for support of the Tu-
lane Crystallography Laboratory are gratefully acknowledged. We
also thank the National Center for High-performance Computing
(Taiwan) for providing computing time. The authors also gratefully
acknowledge Mohammed V University (Morocco) for the financial
assistance and facilitation to facilitate this study. Special thanks are
also due to Reviewers and Editors for their very helpful suggestions
and comments.
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