Synthesis, Crystal structure, Hirshfeld surface Analysis and computational approach of new 2-methylbenzimidazo[1,2-a]pyrimidin-4(1H)-one

Article abstract of DOI:10.1016/j.molstruc.2021.130497

The present article describes the synthesis of the new compound 2-methylbenzimidazo[1,2-a]pyrimidin-4(1H)-one. The electronic and spatial structure of this molecule was studied theoretically and experimentally. The title molecule, C₁₁H₉N₃O, is slightly twisted and bowed based on the recent crystallographic study, while the DFT-B3LYP study shows that the title compound is fully planar in the gas phase. This discrepancy between the experimentally determined geometry and the B3LYP optimized one may be due to the crystal packing. In the crystal, a layer structure is formed by N—H???N and C—H???O hydrogen bonds together with π-stacking and C—H???π(ring) interactions. However, the Hirshfled surface analysis showed that the most important intermolecular interaction for the title compound is the H???H contact. Based on the wide biological interest, molecular docking and molecular dynamics studies were performed for the above titled compound with the poly(ADP-ribose)polymerase (PARP) enzyme target and the result shows that there is a good binding affinity and stability in PARP complex system.

Full text of DOI:10.1016/j.molstruc.2021.130497

Journal of Molecular Structure 1239 (2021) 130497
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis, Crystal structure, Hirshfeld surface Analysis and
computational approach of new
2-methylbenzimidazo[1,2-a]pyrimidin-4(1H)-one
Youness El Bakria,b,∗, Chin-Hung Laic,d,∗, Subramani Karthikeyane, Lei Guof, Sajjad Ahmadg,
Ali Ben-Yahyaa, Joel T. Magueh, El Mokhtar Essassia
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 G.S. Gill Research Institute, Guru Nanak College (Autonomous), Chennai, 600 042, India
f School of Material and Chemical Engineering, Tongren University, Tongren, 554300, China
g Department of Health and Biological Sciences, Abasyn University, Peshawar, 25000, Pakistan
h 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 present article describes the synthesis of the new compound 2-methylbenzimidazo[1,2-a]pyrimidin-
4(1H)-one. The electronic and spatial structure of this molecule was studied theoretically and experimen-
tally. The title molecule, C11 H9N3O, is slightly twisted and bowed based on the recent crystallographic
study, while the DFT-B3LYP study shows that the title compound is fully planar in the gas phase. This
discrepancy between the experimentally determined geometry and the B3LYP optimized one may be due
to the crystal packing. In the crystal, a layer structure is formed by N—H•••N and C—H•••O hydrogen
bonds together with π-stacking and C—H•••π(ring) interactions. However, the Hirshfled surface analysis
showed that the most important intermolecular interaction for the title compound is the H•••H contact.
Based on the wide biological interest, molecular docking and molecular dynamics studies were performed
for the above titled compound with the poly(ADP-ribose)polymerase (PARP) enzyme target and the result
shows that there is a good binding affinity and stability in PARP complex system.
Received 26 March 2021
Revised 13 April 2021
Accepted 15 April 2021
Available online 21 April 2021
KEYWORDS:
2-aminobenzimidazole
Crystal structure
Hirshfeld surface Analysis
DFT calculations
Molecular docking
Molecular dynamics simulation
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
inhibitors, anti-metabolic agents, antitubercular agents, antineo-
plastic agents, benzodiazepine receptor agonists, calcium channel
Condensed benzimidazoles represent a suitable platform for the
construction of planar molecules applying the strategy of diver-
sity oriented synthesis. Benzimidazo[1,2-a]pyrimidin-4-one is an
example of a class of fused tricyclic systems having three ni-
trogen atoms in the rings. Nitrogen-containing heterocyclic com-
pounds are essential core structures in several natural products
and biologically active pharmaceuticals and agrochemicals [1-4].
For example, Benzimidazo[1,2-a]pyrimidine derivatives are widely
found in nature and have gained much attentions due to their
broad biological activities [5-6], such as anticancer agents, anti-
blockers, kinesin inhibitor, and Parkinson’s drug candidates [7–
10]. Some of the biologically active benzimidazo[1,2-a]pyrimidine
derivatives are shown in Fig. 1 [11]. Therefore, the design concept
of benzimidazo[1,2-a]pyrimidin-4-one combines the broad spec-
trum and wide range of biological activities of both benzimidazole
and pyrimidine moieties and is an area of current interest.
There were several approaches to develop the benzimidazo[1,2-
a]pyrimidinones: the intramolecular substitution reaction of halide
with amines [12], the reaction of 2-amino benzimidazole with
propionic esters and α,β-unsaturated esters [13], the one-pot,
three-component condensation reactions of β-dicarbonyl com-
pounds, aldehyde and 2-amino benzimidazole in the presence
of catalyst [14-15], the reactions of 2-aminobenzimidazole with
several electrophiles, including nitrile, α,β-unsaturated carbonyl
compounds, cyanoacetate, acetylene-dicarboxylate [16] and the
inflammation agents, antimalarial agents, DNA-topoisomerase
I
∗
Corresponding authors.
E-mail addresses: yns.elbakri@gmail.com (Y. El Bakri), chlai125@csmu.edu.tw (C.-
H. Lai).
https://doi.org/10.1016/j.molstruc.2021.130497
0022-2860/© 2021 Elsevier B.V. All rights reserved.

Y. El Bakri, C.-H. Lai, S. Karthikeyan et al.
Journal of Molecular Structure 1239 (2021) 130497
Table 1
Crystal data and structure refinement details.
Chemical formula
C11 H9N3O
Mr
199.21
Crystal system, space group
Temperature (K)
Monoclinic, P21/n
150
˚
a, b, c (A)
10.4216 (4), 5.3394 (2), 16.0791 (5)
β (°)
95.372 (2)
890.79 (6)
4
3
˚
V (A )
Z
Radiation type
Cu K
0.82
α
μ (mm−1
)
Crystal size (mm3)
0.28 × 0.11 × 0.03
Data collection
Diffractometer
Bruker D8 VENTURE PHOTON 100 CMOS
Absorption correction
Multi-scan SADABS [34]
Tmin, Tmax
0.89, 0.97
No. of measured, independent and observed [I > 2σ(I)] reflections
6551, 1778, 1476
Rint
0.035
−1
˚
(sinθ/λ)max (A
)
0.625
R[F2 > 2σ(F2)], wR(F2), S
0.037, 0.095, 1.08
No. of reflections
1778
No. of parameters
H-atom treatment
173
All H-atom parameters refined
−3
˚
ꢀρmax, ꢀρmin (e A
)
0.20, −0.16
X-ray crystallography, DFT-B3LYP computation and Hirshfeld sur-
face analysis.
2. Materials and Methods
2.1. General Methods
The NMR spectra were measured on a BrukerAvance DPX300
instrument. The chemical shifts (δ) are expressed in ppm down
field from TMS as an internal reference. Mass spectra were per-
formed on a Perkin-Elmer SCIEX API unit 300. The samples are
ionized by the ion spray technique (IS). Elemental analysis was
performed on a Euro EA - CHNSO Elemental Analyzer. TLC and
column chromatography were carried out, respectively, on silica
plates (Merck 60 F254) and silica gel (Merck 60, 230-400 mesh).
The title compound: Colorless solid, Yield: 87%. mp: 191-193°C.
1H NMR 300 MHz, (CDCl3), δ: 12.09 (s, 1H, NH), 7.32-7.35 (t,
2H, CH-Ar), 7.15-7.17 (d, 2H, CH-Ar), 5.34 (s, 1H, CH), 2.16 (s,
3H, CH3). 13C NMR75 MHz, (CDCl3) δ: 198.3, 169.82, 153.6, 134.1,
130.1, 125, 123.3, 97.3, 25.5. HRMS (IE) Calculated for C11 H9N3O:
[M+H+]=199.07, Found 199.21. Elemental analysis Calculated: C,
66.32%; H, 4.55%; N, 21.09%; O, 8.03%, Found: C, 66.45%; H, 4.38%;
N, 20.94%; O, 8.23%.
Fig. 1. Examples of biologically active benzimidazo[1,2-a]pyrimidine derivatives.
reaction of 2-aminobenzimidazole with Baylis-Hillman adducts
and their derivatives [17]. In this paper, we describe the synthesis
of 2-methylbenzimidazo[1,2-a]pyrimidin-4(1H)-one obtained by
condensation reaction of 2-amino-1H-benzimidazole and ethyl
acetoacetate.
Moreover, due to the wide biological interest of the title com-
pound, we found a target enzyme of the title compound, poly(ADP-
ribose)polymerase (PARP), using SWISS target prediction server
[18]. PARP establishes a super group of proteins containing PARP
catalytic domains associated with the repair of DNA, the guide-
line of cellular energy pools, and the interpretation of inflamma-
tory genes. PARP-1 is an atomic catalyst which catalyzes DNA re-
pair through cleavage of NAD+ to nicotinamide and ADP-ribose to
form long, extended ADP-ribose polymers on target proteins. PARP-
1 inhibition leads to sustained DNA damage and ultimately apop-
tosis when used in combination with DNA damaging agents such
as temozolomide (TMZ), thus providing for chemopotentiation in
vitro and in vivo. PARP-1 inhibitors have likewise appeared to func-
tion as single specialists through a type of manufactured lethality
by abusing a DNA repair blemish found in tumors communicating
inadequate BRCA1/2-qualities. Thus, hindrance of PARP-1 which is
over-communicated in tumors is required to frustrate intracellular
DNA repair and improve the antitumor impacts of disease treat-
ments [19-22]. In this regard, we have performed molecular dock-
ing and molecular dynamics studies with the title compound in
PARP systems to identify in silico binding suitability.
2.2. X-ray crystallography
A colorless plate-like specimen of C11 H9N3O with approximate
dimensions 0.28 × 0.11 × 0.03 mm3 was selected and X-ray in-
tensity data were collected at 150 K on a Bruker D8 VENTURE
PHOTON 100 CMOS diffractometer equipped with an X-ray gen-
erator operating at 50 kV and 1.0 mA, using CuK radiation of
α
˚
wavelength 1.54178 A. A hemisphere of data was processed us-
ing SAINT [29]. The structure (Fig. 2) was solved by direct methods
and refined by full-matrix, least squares methods on F2 using the
SHELXT and SHELXL-97 programs [30-31]. All the non-hydrogen
atoms were revealed in the first difference Fourier map and were
refined with anisotropic displacement parameters. A second dif-
ference map showed all the hydrogen atoms which were then in-
cluded in the refinement with isotropic displacement parameters.
At the end of the refinement, the final difference Fourier map
showed no peaks of chemical significance and the final residual
is 0.0215. The geometrical calculations were carried out using the
Due to our interests about the design and synthesis of hetero-
cyclic systems with potent pharmacological properties [23-28], we
try to in-advance develop potential inhibitors for PARP-1 based on
the benzimidazo[1,2-a]pyrimidin-4(1H)-one skeleton. Therefore, we
further perform the characterization of the title compound by the
2

Y. El Bakri, C.-H. Lai, S. Karthikeyan et al.
Journal of Molecular Structure 1239 (2021) 130497
Fig. 2. The title molecule with labeling scheme and 50% probability ellipsoids
˚
(the bond length of O1-C7 is 1.2281(18) A and the bond angle of C10-N1-C6 is
106.09(11)°, please see the more detailed results of the X-ray crystallographical
study in Table 2S-6S of the supporting information).
program PLATON [32]. The molecular and packing diagrams were
generated using DIAMOND [33]. The details of the crystal data and
structure refinement are given in Table 1.
•••
•••
O
Fig. 3. Packing viewed along the a-axis direction with N—H
N and C—H
2.3. Hirshfeld surface calculations
hydrogen bonds shown, respectively, by blue and black dashed lines. The π-stacking
and C—H•••π(ring) interactions are shown, respectively, by orange and green
dashed lines..
Based on Hirshfeld’s partitioning scheme, Spackman et al.
[35] proposed a method to divide a molecule’s electron distribu-
tion in the crystal phase into some fragments [36-37]. The method
they proposed divides the crystal into multiple regions, in which
the electron distribution of the sum of the spherical atoms of the
molecules dominates over the sum of the corresponding crystals.
Because it is derived from Hirshfeld’s shareholder distribution, the
molecular surface is called the Hirshfeld surface. In this study, us-
ing the Crystal Explorer program, the title compound was sub-
jected to Hirshfeld surface analysis [38].
at the same theoretical level to confirm that the imaginary num-
ber of the saddle point is zero. Subsequently, the NBO analysis was
performed to investigate the electronic properties of the title com-
pound [43]. All the calculations were performed by the Gaussian
16 program [44].
2.5. Molecular docking & dynamics
2.4. DFT calculations
The chemical structure for the title compound was drawn us-
ing ChemDraw Pro 12 and the structure energetically minimized
using a conjugate gradient algorithm with the Optimized Poten-
tial for Liquid Simulations (OPLS 2005) routine contained in the
Schrödinger 2018-2 software (Biologics Suite 2018−3; Schrödinger)
[45]. The protein (PDB ID: 4L6S) was found based on the Swiss
target prediction server and the structure was prepared for dock-
ing analysis using the protein preparation wizard panel. The active
site residues were picked up from the co-crystal binding site of
the PARP complex. Once both small and macromolecule were pre-
pared they were submitted for docking analysis using an induced
fit docking panel and 20 different binding poses were generated for
the PARP–title compound adduct. The best binding pose was taken
As aforementioned, we tried to know the relationship between
the intrinsic electron properties of the molecule and its biological
activity. So our calculation was only performed in the gas phase.
The gas phase structure of the title compound was optimized with
the aid of density functional theory. The DFT calculation is per-
formed by the hybrid B3LYP method, which is based on the idea
of Becke and considers the mixing of the exact (HF) and DFT ex-
changes, using the B3 functional and LYP correlated functional [39-
41]. In this study, the basis set def2-SVP is used in the B3LYP cal-
culation [42]. After obtaining the convergent geometry, the har-
monic vibrational frequencies of the title compound are calculated
Fig. 4. The dnorm Hirshfeld surface of the title compound (red: negative, white: zero, blue: positive; scale: -0.6530 to 1.3260 a.u.).
3

Y. El Bakri, C.-H. Lai, S. Karthikeyan et al.
Journal of Molecular Structure 1239 (2021) 130497
•••
•••
•••
O contacts, (d) resolved by the H H contacts.
Fig. 5. The 2D fingerprint plot of the title compound (a) full, (b) resolved by the H
N contacts, (c) resolved by the H
based on the binding energy and number of interacting residues
with PARP and further subjected to a molecular dynamics simu-
ergy of the system. A series of 2 ps steps was integrated to record
the simulation. A six stage NPT ensemble default relaxation process
was carried out before performing the molecular dynamics simu-
lation. In the first stage, a solute-restrained Brownian dynamics of
the ensemble was carried out while keeping the energy constant
using the NVT condition. In the second stage, the Berendsen ther-
mostat was used and the NVT (canonical) ensemble was allowed to
relax with respect to temperature with velocity resembling of ev-
ery 1 ps applied to non-hydrogen solute sample. Subsequently, the
NVT ensemble was changed to an NPT ensemble with a Berendsen
barostat and the system was kept at 1 atm pressure followed by
lation analysis. The PARP complex system was built using a peri-
3
˚
odic boundary condition with a 10 A cubic box from the centre
of mass of the PARP complex. A TIP3P water solvation system was
used in a buffer system with charged ions placed isotropically to
neutralise the Ewald charge summation of the solvated PARP com-
plex entity. The system was minimized with maximum iterations
of 5000 steps with a gradient convergence threshold of 1.0 kcal
˚
mol−1 −1. Once the system was minimized, the system was sub-
A
jected to Newtonian dynamics of the model system to evaluate en-
4

Y. El Bakri, C.-H. Lai, S. Karthikeyan et al.
Journal of Molecular Structure 1239 (2021) 130497
Scheme 1. Synthesis of the title compound.
Table 2
˚
Hydrogen-bond geometry (A, °).
•••
•••
•••
•••
D—H A
D—H
A
D—H
H
A
D
A
i
•••
Cg3
N2—H2A
N3
1.00 (2)
1.85 (2)
2.8541 (18)
3.7159 (16)
3.378 (2)
174.5 (18)
137.0 (13)
144.2 (14)
ii
•••
C5—H5
0.949 (18)
1.023 (19)
2.966 (17)
2.494 (19)
iii
•••
C11—H11B
O1
3.2. Description of the crystal structure
The compound was characterized by X-ray as depicted in Fig. 2.
The molecule is slightly twisted end-to-end as well as showing
a slight bowing. This is indicated by the dihedral angles between
the C1•••C6, the C1/C6/N1/C10/N3 and the N1/C7/C8/C9/N2/C10
planes of 1.76(9) and 3.13(9)°, respectively. The bond distances and
the bond angles are as expected for the formulation. In the crys-
tal, inversion dimers are formed by N2—H2A•••N3 hydrogen bonds
(Table 2) and these are formed into oblique stacks along the b-axis
direction by slipped π-stacking interactions between inversion-
related C1/C6/N1/C10/N3 rings (centroid•••centroid = 3.6529(8)
Fig. 6. The MEP of the title compound (the color range is -6.919e-2 ~ 6.919e-2 a.u).
system equilibration of 1 ns. Then the ensemble was subjected to
a 50 ns molecular dynamics run [46].
3. Results and Discussion
3.1. Synthesis
˚
A). The stacks are connected into layers parallel to (101) by C11—
In a flask containing 2g of 2-amino-1H-benzimidazole (0.015
mol) and 1.89 mL of ethyl acetoacetate (0.015 mol) in 10 mL of
N,N-dimethylformamide was heated under reflux during 1h. After
cooling, the precipitate formed was filtered off under vacuum and
the mixture was washed with ethanol. The residue obtained was
recrystallized from ethanol to afford the title compound as color-
less crystals (see Scheme 1).
H11B•••O1 hydrogen bonds (Table 2) and the layers are associated
via complementary C5—H5•••Cg3 interactions (Table 2 and Fig. 3).
Symmetry codes: (i) −x+1, −y, −z+1; (ii) −x+1/2, y+1/2,
−z+1/2; (iii) −x+3/2, y−1/2, −z+1/2.
The result of the B3LYP geometric optimization for the title
compound are compared with that of the crystallographic study.
For ease of comparison, Table 1S summarizes the selected geo-
Fig. 7. The (a) and (b) best binding pose and ligplot of titled compound complex with PARP.
5

Y. El Bakri, C.-H. Lai, S. Karthikeyan et al.
Journal of Molecular Structure 1239 (2021) 130497
Fig. 8. (a) RMSD plot (b) RMSF plot for above the titled compound complex with PARP.
metric parameters of the gas and solid phase structures. These
parameters indicate that the optimized geometry of B3LYP devi-
ates slightly from the experimental values. To quantify the differ-
ence between the calculated and experimental geometry, the built-
in structure comparator in the ChemCraft program is used to ob-
tain its root-mean-square deviation (RMSD, Chemcraft- a graphical
software for visualizing quantum chemical calculations. Chemcraft-
prog.com). The weighted RMSD obtained is 1.053, indicating that
the recent theoretical levels give H atom, C atom, N atom and O
atom to have RMSD 1.680, 0.2952, 0.2311 and 0.2945, respectively.
The discrepancy between the B3LYP-optimized geometry and the
X-ray measured one may be due to the crystal packing [47].
in Fig. 4. The surface appears to be transparent, so the molecu-
lar moieties can be visualized in a similar direction to all struc-
tures that are calculated around it. The 3D dnorm surface can be
used to recognize very close intermolecular interactions. When the
intermolecular contact is shorter (longer) than the van der Waals
radius, the value of dnorm is negative (positive). The dnorm value
is mapped to the Hirshfeld surface through red, white or blue. The
red area represents a closer contact with a negative standard value,
and the blue area represents a longer contact with a positive stan-
dard value. In addition, the contacts represented by the white area
are equal to the Van der Waals interval, and the dnorm is zero. As
shown in Fig. 4, the important interactions in the title compound
may be H•••O and H•••N hydrogen bonds. To understand the rela-
tive importance of H•••O hydrogen bonds relative to H•••N hydro-
gen bonds, we examined the 2D fingerprint of the title compound.
The 2D fingerprint map highlights specific atom pair contacts
and separates contributions from the different interaction types
that overlap in the full fingerprint. Using the standard 0.6-2.6 view,
displaying the de and di distance scales on the graph axis, and in-
3.3. The Hirshfeld analysis of the title compound
Defining molecules in the condensed phase and recognizing dif-
ferent entities in molecular liquids and crystals are both the ba-
sic concepts of chemistry. The molecular Hirshfeld surface with
the standard resolution (dnorm) of the title compound is shown
6

Y. El Bakri, C.-H. Lai, S. Karthikeyan et al.
Journal of Molecular Structure 1239 (2021) 130497
Table 3
The NBO results of the title compound.
The interaction
energy (in
kcal/mol)b
The type of orbital
interaction
The occupancy
The bond order
∗
c
The type of nA
LP1 of O1a
The electron configuration of nA
of σH-D
of σH-D
s(56.33%)p(43.66%)d(0.02%)
LP1(O1)-σ∗(N2-H)a
LP1(O1)-σ∗(C5-H)a
LP1(O1)-σ∗(C8-H)a
LP2(O1)-σ∗(C8-H)a
LP2(O1)-σ∗(C5-H)a
LP1(N2)-σ∗(C11-H)a
LP1(N2)-σ∗(C11-H’)a
LP1(N3)-σ∗(N2-H)a
LP1(N3)-σ∗(C2-H)a
LP1(N3)-σ∗(C3-H)a
LP1(N3)-σ∗(C4-H)a
LP1(N3)-σ∗(C5-H)a
LP1(N3)-σ∗(C8-H)a
0.01
0.24
0.21
0.01
0.35
0.08
0.08
0.33
0.17
0.01
0.01
0.01
0.01
0.01660
0.01497
0.01008
0.01008
0.01497
0.00870
0.00870
0.01660
0.01456
0.01358
0.01343
0.01497
0.01008
0.6796
0.7664
0.7618
0.7618
0.7664
0.7436
0.7436
0.6796
0.7650
0.7665
0.7667
0.7664
0.7618
LP2 of O1a
LP1 of N2a
LP1 of N3a
s(0.00%)p(99.91%)d(0.08%)
s(0.00%)p(100.00%)d(0.00%)
s(30.03%)p(69.89%)d(0.08%)
a
Please see the atomic designations in Fig. 2.
b
c
The interaction energy was calculated basing on the second-order perturbation theory.
The listed values were the atom-atom overlap-weighted NAO bond order.
cluding reciprocal contacts, we found that the most important in-
teraction involving hydrogen in the title compound is H•••H con-
tact (Fig. 5). The contributions of H•••O, H•••N and H•••H con-
tacts were 11.4%, 10.6% and 38.8%, respectively (Fig. 5).
tical material. As long as its hyperpolarizability (β) is bigger than
urea, it has the potential to become a nonlinear optical material.
On the same theoretical level, the hyperpolarizability of urea was
calculated to be 66.7918 a.u.. In contrast, β of the title compound
was calculated to be 499.5831 a.u., about 7.5 times that of urea.
Therefore, we think that the nonlinear optical properties of the ti-
tle compound are worth further exploration.
3.4. Molecular electrostatic potential (MEP)
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 value and may be attacked by nucleophiles. The full den-
sity matrix is used to generate the total density of the title com-
pound and the resulting MEP is mapped on its surface (Fig. 6). As
depicted in Fig. 6, both the nitrogen and oxygen atoms in the title
compound are responsible for nucleophilic attack due to the fact
that they have larger electronegativities with respect to the carbon
and hydrogen atoms.
3.7. Molecular docking analysis
Molecular docking studies are useful to understand the bind-
ing mechanism between macromolecule and small molecule [49].
Fig 7 shows the best binding pose of the title compound complex
with Poly(ADP-ribose)polymerase (PARP). The best binding poses
were taken based on the glide energy (-41.69 kcal/mol) and dock-
ing score (-9.42 kcal/mol), and number of interacting residues.
Fig. 7(b) shows that there are three hydrogen bond contacts be-
tween the title compound and PARP complex system. Two residues
are hydrophobic in nature (TYR896 contact with O atom, Les880
contacts with O atom) and the positively charged ARG878 residue
form a H-bond contact through the NH atom of the title com-
pound. The docking results shows that the title compound has a
good binding affinity towards the PARP complex system.
3.5. The result of the NBO analysis
3.8. Molecular dynamics analysis
The relative strength of the H•••O hydrogen bond with respect
to that of the H•••N hydrogen bond could be investigated by the
second-order perturbation theory. As a hydrogen bond forms, there
should be an orbital interaction between the nonbonding orbital of
the hydrogen-bonded acceptor (nA) and the antibonding orbital of
the H-Donor bond (σH-D∗). Therefore, the bond strength or bond
Following the docking studies, the best binding pose of PARP
with the title compound complex was further subjected to molec-
ular dynamics simulation. The molecular dynamics results provide
information on the binding stability [49] of the title compound in
the PARP complex system during 50 ns simulation time.
∗
order of σH-D should be weakened (decreased) due to such orbital
In general, a Root Mean Square Deviation (RMSD) plot is used
to understand the average changes of backbone atoms in initial to
final protein complex frame and monitoring these RMSD plots will
give more structural insight on the protein complex conformation
and system equilibration during the simulation time. In Fig. 8a,
RMSD plot shows that the PARP-title compound complex system
interaction. The orbital interaction strength basing on the second-
order perturb∗ation theory, the occupancy of σH-D∗, and the bond
order of σH-D were summarized in Table 3.
3.6. The nonlinear optical property of the title compound
˚
converged and stabilized at below 3A which is generally known
Due to their applications in modern optical technologies such as
laser frequency doubling, optical data storage, telecommunications,
and laser protective device, the nonlinear optical (NLO) materi-
als have gotten significant attentions [48]. In this study, not only
the medical use of the title compound was examined but the title
compound can be as a nonlinear optical material was also consid-
ered. It’s easy to see if a compound is suitable as a nonlinear op-
as small or globular conformation. The Root Mean Square Fluc-
tuation (RMSF) plot indicates N and C terminal fluctuation of the
protein during the simulation time and Fig. 8(b) indicates that C
α
and B factors are good and no more deviations occurs at during
50 ns simulation. The green color vertical bar indicates that the ti-
tle compound contacts with the PARP complex system during the
simulation.
7

Y. El Bakri, C.-H. Lai, S. Karthikeyan et al.
Journal of Molecular Structure 1239 (2021) 130497
Fig. 9. (a) interaction fraction plot (b) time line representation of interacting residues in PARP-titled compound complex system. (c) schematic of detailed titled compound
atom interactions with the PARP protein residues.
In addition to this PARP-titled compound interaction contacts
were also monitored thought the 50 ns simulation time and repre-
sented in Fig 9. From the above results shows that ARG 878, TYR
896 and ALA 880 residues have 99%, 89%, 70% H-bond contacts re-
spectively, also in total 6 residual contacts found during the 50 ns
simulation time period.
Author Contributions
Youness El Bakri: Synthesized and characterized the title
molecule, Wrote the paper; Final approval of the version submit-
ted.
Chin-Hung Lai and Subramani Karthikeyan: Performed
quatum-chemical calculations, analyzed and interpreted the data.
Lei Guo, Ali Ben-Yahya: Analyzed and interpreted the data, con-
tributed reagents, materials, analysis tools or data.
Joel T. Mague: Performed the X-ray experiments, analyzed and
interpreted the data.
Fig. 9(c) clearly shows the final molecular dynamics output of
PARP-title compound complex system interaction plot and from
that we also found a pi-pi stacking contact with TYR 889 at 41%.
The overall molecular dynamics results suggest that the title com-
pound was very stable in the PARP complex system during the 50
ns simulation time.
El Mokhtar Essassi: Conceptualization and supervision.
All authors have read and agreed to the published version of
the manuscript.
4. Conclusion
Declaration of Competing Interest
To sum up, we report the synthesis of a new benzimidazo[1,2-
a]pyrimidine derivative. The molecular structure was characterized
by NMR (1H and 13C) and HR-MS methods and confirmed by the X-
ray crystallography and DFT-B3LYP study. A difference is found be-
tween the X-ray determined structure and the DFT optimized one
and ascribed to the crystal packing. The Hirshfeld surface analy-
sis showed that the most important intermolecular interaction for
the title compound is the H••••••H contact. Docking studies re-
veal that the title compound has a good binding affinity towards
PARP complex system with good interacting residues. The molecu-
lar dynamics results also suggest that the title compound has good
binding stability in PARP complex system during a 50 ns simula-
tion time and these derivatives show promise for future optimiza-
tion and biological studies.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
Acknowledgment
The authors also gratefully acknowledge Mohammed V Univer-
sity (Morocco) for the financial assistance and facilitation to facil-
itate this study. The support of NSF-MRI Grant #1228232 for the
purchase of the diffractometer and Tulane University for support of
the Tulane Crystallography Laboratory are gratefully acknowledged.
We also thank the National Center for High-performance Comput-
ing (Taiwan) for providing computing time. Special thanks are also
8

Y. El Bakri, C.-H. Lai, S. Karthikeyan et al.
Journal of Molecular Structure 1239 (2021) 130497
due to Reviewers and Editors for their very helpful suggestions and
comments.
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