Novel antioxidant quinoxaline derivative: Synthesis, crystal structure, theoretical studies, antidiabetic activity and molecular docking study

Article abstract of DOI:10.1016/j.molstruc.2021.130484

New quinoxaline derivative, N-(4-methyl-2-nitrophenyl)-2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetamide (NPOQA) has been synthesized and characterized by IR, ¹H &¹³C NMR, ESI-MS and single crystal X-ray diffraction analysis using exper

Full text of DOI:10.1016/j.molstruc.2021.130484

Journal of Molecular Structure 1239 (2021) 130484
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Novel antioxidant quinoxaline derivative: Synthesis, crystal structure,
theoretical studies, antidiabetic activity and molecular docking study
Mohcine Missiouia, Salma Mortadab, Walid Guerraba, Goncagül Serdarog˘luc, Savas¸ Kayad,
Joel T. Maguee, El Mokhtar Essassif, My El Abbes Faouzib, Youssef Ramlia,∗
a Laboratory of Medicinal Chemistry, Drug Sciences Research Center, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat Morocco
b Laboratories of Pharmacology and Toxicology, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
c Sivas Cumhuriyet University, Math. and Sci. Edu., 58140, Sivas, Turkey
d Sivas Cumhuriyet University, Health Services Vocational School, Department of Pharmacy, 58140, Sivas, Turkey
e Department of Chemistry, Tulane University, New Orleans, LA 70118, United States
f Laboratoire de Chimie Organique Hétéerocyclique, Faculté des Sciences, Université Mohammed V in Rabat, Rabat Morocco
a r t i c l e i n f o
a b s t r a c t
Article history:
New quinoxaline derivative, N-(4-methyl-2-nitrophenyl)-2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetamide
(NPOQA) has been synthesized and characterized by IR, 1H &13 C NMR, ESI-MS and single crystal X-
ray diffraction analysis using experimental and theoretical methods. The thermodynamic quantities and
quantum chemical parameters were predicted by using B3LYP/6–311G∗∗ level to investigate the physical
and electronic properties of the compound. Frontier Molecular Orbital “FMO” and Natural Bond Orbital
“NBO” analyses of the compound were performed to enligten the possible rectivity trend and intramolec-
ular interactions contibuted to the decreasing of the stabilization. In addition, the newly synthesized com-
pound was evaluated for its in vitro antidiabetic activity against α-glucosidase and α-amylase enzymes
and for antioxidant activity by utilizing several tests as DPPH (1, 1-diphenyl-2-picryl hydrazyl), ABTS (2,
Received 24 February 2021
Revised 15 April 2021
Accepted 16 April 2021
Available online 21 April 2021
Keywords:
Quinoxaline
Crystal
Theoretical studies
Antioxidant
Antidiabetic
Docking
ꢀ
2 -azino-bis(3-ethyl benzthiazoline-6-sulfonicacid), reducing power test (FRAP) and Hydrogen Peroxide
Activity H2O2. Finally, Molecular docking studies were performed to investigate the binding mode be-
tween the quinoxaline derivative NPOQA and α-glucosidase and α-amylase. Docking calculations showed
an important binding affinity as compared to standard drug acarbose, -6.5 and -6.9 kcal/mol successively
for α-glucosidase and α-amylase, which are in agreement with the results of in vitro studies.
© 2021 Published by Elsevier B.V.
1. Introduction
agent [13,14]. In 2019, according to the International Diabetes Fed-
eration (IDF) an estimated 4.2 million deaths were assigned to high
The study of nitrogen heterocycles compounds consists in one
of the main branches of organic chemistry due to their role in
all kinds of biological processes [1]. The presence of nitrogen-
based heterocyclic nuclei has proven to be key for developing ther-
motropic liquid crystals, notably as a rigid core, and important
scaffold for this application is quinoxaline [2–5]. Thus, quinoxaline
and its derivatives have been extensively studied play an interest-
ing role as basic skeleton for the synthesis of many other phar-
macologically and biologically active agents [6,7]. Notably, these
N-heterocycles have been reported to exhibit antidiabetic [7] and
antioxidant activities [8,9]. Similarly, a wide variety of molecules
including N-aryl acetamides have been reported in last few years
to act as potential antidiabetic agent [10–12] and as antioxidant
blood-glucose levels; It affects 463 million people worldwide and
this number is projected to rise to 700 million by 2045, around
25% of the World’s population in both developed and developing
countries [15]. Therefore, the therapeutic use of antioxidants in the
treatment and prevention of diabetic complications has been con-
sidered [16]. Many studies have searched for effective and safe in-
hibitors of α-amylase and α-glucosidase [17–22], from medicinal
plants or from chemical synthetic products [23–26], to treat Type
2 diabetes mellitus (T2DM). The purpose of the current work is to
synthesize novel quinoxaline-N-aryl acetamide hybrid system and
evaluate it as antidiabetic and antioxidant agent, so, in continu-
ation of our recent work focused on the synthesis and biological
evaluation of novel heterocyclic compounds [27–31], herein, our
results are presented.
∗
Corresponding author.
E-mail address: y.ramli@um5s.net.ma (Y. Ramli).
https://doi.org/10.1016/j.molstruc.2021.130484
0022-2860/© 2021 Published by Elsevier B.V.

M. Missioui, S. Mortada, W. Guerrab et al.
Journal of Molecular Structure 1239 (2021) 130484
Table 1
Crystal data and structure refinement details.
Value
Parameter
18H16N4O4
Chemical formula
Mr
C
352.35
Crystal system
Space group
Temperature (K)
θ min, θ max
Triclinic
P -1
150
4.4, 72.5°
˚
a, b, c (A)
4.560 (2), 13.286 (7), 14.199 (7)
α, β, γ (°)
104.895 (6), 93.352 (7), 91.677 (7)
3
˚
V (A )
829.0 (8)
Z
2
Radiation type
Mo Ka
μ (mm−1
)
0.10
Fig. 1. ORTEP view of the molecular structure of NPOQA with labeling scheme
and 50% probability ellipsoids. The intramolecular hydrogen bond is depicted by
a dashed line.
Crystal size (mm)
Diffractometer
0.31 × 0.22 × 0.07
Bruker Smart APEX CCD
Multi-scan
Absorption correction
TWINABS (Sheldrick, 2009) [36]
0.97, 0.99
Tmin, Tmax
2. Experimental section
No. of measured, independent and
observed [I > 2σ(I)] reflections
Rint
12,368, 12,368, 9222
0.023
2.1. Synthesis and crystallization of N-(4-methyl-2-nitrophenyl)−2-
(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetamide
(NPOQA)
−1
˚
(sin θ/λ)max (A
)
0.690
R [F2 > 2σ(F2)], wR(F2), S
0.045, 0.129, 1.10
No. of reflections
12,368
No. of parameters
286
H-atom treatment
H-atom parameters constrained
All commercial chemicals were purchased from Sigma-Aldrich
and used as received. Follow up of the reaction and checking
the purity of the compound were made by TLC on silica gel-
precoated aluminum sheets (Fluorescent indicator 254 nm, Fluka,
Germany) and the spots were detected by exposure to UV lamp at
λ 254/366 nm for few seconds. The melting point was obtained
on a Büchi Melting Point SMP-20 apparatus and is uncorrected.
The 1H NMR and 13C NMR spectra were recorded on a Bruker
Avance 300 NMR Spectrometer in DMSO–d6. The chemical shifts
δ are reported in parts per million (ppm); the IR spectrum was
obtained using the Bruker-VERTEX 70 device and the associated
software OPUS, in ATR (attenuated total reflectance) mode. Mass
spectra were recorded on an API 3200 LC/MS/MS mass spectrome-
ter using electrospray ionization (ESI) in positive polarity.
−3
˚
ρmax
,
ρmin (e A
)
0.29, −0.28
2.3. Computational and theoretical study
All DFT/B3LYP level [37,38] computations of the compound
NPOQA were performed at 6–311G∗∗ basis set [39,40], in both the
gas and water media. In water environment simulation, PCM “Po-
larized Continuum Model” [41-43] was used. The frequency calcu-
lations were performed for both the structure verification of the
compound and to get the thermochemical and physicochemical
quantities. After affirming of the structure, the possible reactivity
tendency was calculated by using the FMO “Frontier Molecular Or-
bital” energies. In this context, Koopmans’ Theorem [44] has de-
fined the “the ionization energy (I) and electron affinity (A)” via
using the HOMO and LUMO energies as follows
(2 g, 12.4 mmol) of 3-methylquinoxalin-2(1H)-one, was dis-
solved in dimethylformamid (DMF) then added (3.4 g, 14,8 mmol)
of 2–chloro-N-(4-methyl-2-nitrophenyl)acetamide, for the removal
of the proton we used potassium bicarbonate as a base (2.5 g,
18.6 mmol), for the phase transfer catalysis conditions a tip of a
spatula of the BTBA was used, then stirred for 2 h under reflux at
80 °C. After the consumption of the starting reagents, a 500 ml of
water was added to the reaction mixture, the main product pre-
cipitated, then filtered and dried and recrystallized from ethanol.
I= -EHOMO
A= -ELUMO
Then, the (I) and (A) values have been used for calculating the
global reactivity identifiers, referring on the CDFT (Conceptual Den-
sity Functional Theory) [45–48] as follows.
I + A
χ = −
2
2.2. Single crystal X-ray structure determination
I − A
η =
A
single
Pale
red
crystal
with
dimension
2
0.31 × 0.22 × 0.07 mm3 of the compound was selected and
X-ray intensity data were collected at 150 K on a Bruker Smart
APEX CCD diffractometer equipped with an X-ray generator op-
erating at 50 kV and 40 mA, using Mo-Kα radiation of wave
μ2
ω =
2η
˚
length 0.71073 A. The complete sphere of data was processed
I + A
Nmax
=
(
using SAINT [32]. The structure (Fig. 1) was solved by direct
methods and refined by full-matrix least squares method on F2
using SHELXT and SHELXL programs [33,34]. The molecular and
packing diagrams were generated using DIAMOND [35]. Crystal
and refinement details are presented in Table 1.
2 I − A
)
Here, these values define as follows χ “electronic chemical
potential”, η “global hardness”, ω “electrophilicty”, and
“maximum charge transfer capability”.
In addition, two useful parameters hae been introduced as ω−
“the electrodonating power” and ω+ “the electroaccepting power”
terms [49], and they have been calculated by the following formu-
lae.
Nmax
CCDC 2,053,356 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data centre, 12, Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336,033).
ω+ ≈ (I + 3A)2/ 16 I − A
(
(
))
2

M. Missioui, S. Mortada, W. Guerrab et al.
Journal of Molecular Structure 1239 (2021) 130484
2.4.2. α-amylase inhibition assay
ω− ≈ (3I + A)2/ 16 I − A
Furthermore, the back donation contribution to the chemical
behavior is also important in the molecular systems, and Gomez
and coworkers [50] have introduced Eback-donation “back-donation
energy” as follows.
The α-amylase assay was performed by reacting various con-
centrations of the compound NPOQA with α-amylase and starch
solution by following the DNSA method with minor modification
[58]. The target compounds were dissolved in DMSO and all the
evaluated samples were dissolved in tampon phosphqate with var-
ious concentrations.
(
(
))
η
εback−donation = −
4
The sample solution (10μL) was mixed with 240μL (sodium
phosphate buffer 0.02 M pH6.9) containing α-amylase (240 U/mL),
and incubated at 37 °C for 20 min. After pre-incubation, 250 μL
of 1% starch solution (1%, sodium phosphate buffer 0.02, pH 6.9)
were added to each tube and incubated for 15 min. Add 1 ml of
dinitrosalicylic acid to stop the reaction, then incubate the solution
in a water bath at 90 °C for 10 min. The mixture was diluted with
1 mL deionized water and the absorbance (Abs) was measured at
540 nm.
The NBO "Natural Bond Orbital" study introduced by Weinhold
et al. [51–54] was performed to estimate the intramolecular inter-
actions. Based on the NBO, the lowering of the stabilization energy
has been defined as below, with qi “bonding orbital occupancy”, εi
and εj “bonding and antibonding orbital energies” (diagonal ele-
ments) and the off-diagonal NBO Fock matrix element.
2
Fij
(
)
2
( )
E
=
Eij = qi
(
The percentage inhibitions were tested at different concentra-
tions, and the IC50 values were determined. The control sample
was prepared without α-amylase and acarbose was used as a stan-
dard drug (positive control).
ε j − εi
)
G09W [55] and GausView 6.0.16 [56] packages were used to
perform all quantum chemical computations and pictorial repre-
sentations of the related results, respectively.
2.5. Docking methodology
2.4. Antidiabetic study
The molecular docking study was performed to investi-
gate the binding mode between the compound NPOQA and
α-glucosidase and α-amylase. The preparation of the pro-
teins/ligands, generation of receptor grid, and docking were per-
formed on AutoDock 1.5.6 as described [59]. The 3D struc-
ture of the compound N-(4-methyl-2-nitrophenyl)−2-(3-methyl-2-
oxoquinoxalin-1(2H)-yl)acetamide was obtained using CIF file after
crystallization and DRX study. The 3D structure of acarbose was
prepared and optimized using molecular builder module imple-
mented in ChemDraw. Gasteiger partial charges were added, non-
polar hydrogen atoms were merged and rotatable bonds were de-
fined. The crystal structure of α-amylase (PDB Id: 4GQR; resolu-
ρ-Nitrophenyl-α-d-glucopyranoside
(pNPG),
α-glucosidase
from Saccharomyces cerevisiae, α-amylase from Bacillus licheni-
formis, buffer Solution, DMSO (Dimethylsulfoxide): organic polar
solvent for solubilizing products, Sodium Carbonate: solution to
stop the reaction, acarbose. All other reagents and standards were
of analytical reagent (AR) grade.
In this investigation the synthesized compound was evalu-
ated for the antidiabetic action via two in-vitro assays namely,
α-amylase and α-glucosidase inhibition method and results were
compared with acarbose standard reference in both α-glucosidase
and α-amylase methods.
˚
˚
tion 1.2 A) [60] and α-glucosidase (PDB Id: 5NN5; resolution 2.0 A)
[61] were downloaded from the PDB database (http://www.rcsb.
org/pdb). AutoDock tool (ADT) was employed to prepare proteins
by adding missing hydrogen atoms, assigning Kollman united atom
2.4.1. α-glucosidase inhibition assay
The α-glucosidase inhibitory activity of the compound NPOQA
was performed by using ρ-nitrophenyl-α-d-glucopyranoside
(ρNPG)) as a substrate according to the method described by Kee
et al. [57] With minor modifications. The α-glucosidase method
is based on the inhibition of the enzyme.α-glucosidase, which
hydrolyses pNPG (4-Nitrophenyl-α-d-glucopyranoside) to α-d-
glucopyranose and P-nitrophenol of yellow color. The target
compound was dissolved in DMSO and all the evaluated sam-
ples were dissolved in tampon phosphqate at a series of different
concentrations such as 500, 250, 125, 62, 5 and 31,25 μM. The
desired concentrations of enzyme were prepared in PBS (pH 6.8,
50 mM). A mixture of 150 μl of the sample and 100 μl of PBS
(pH = 6.7) containing the α-glucosidase enzyme solution (0.1 U /
ml) was incubated at 37 °C for 10 min, after incubation, 200 μl of
pNPG (1 mM) was added to the mixture . The mixtures were in-
cubated at 37 °C for 30 min. Then 1 ml Na2CO3 (0.1 M) was added
to stop the reaction and the absorbance (Abs) was measured at
405 nm. The result of the antidiabetic activity of our synthesis
product was expressed in percentage of inhibition of enzymes
studied according to the following formula:
˚
˚
type charges. Grid maps of 40 - 48 −70 A and 72- 60 −70 A
˚
dimensions with 0.375 A spacing were prepared using AutoGrid.
Other AutoDock parameters were set at their default values. Molec-
ular docking employed the Lamarck Genetic Algorithm (LGA) and
the Solis and Wets search methods. And for comparison, molecu-
lar docking of reference inhibitor (acarbose) was carried out with
α-amylase and α-glucosidase.
2.6. Antioxidant activity
ꢀ
DPPH (2,2-diphenyl-1-picrylhydrazyl), ABTS (2,2 -Azinobis-(3-
Ethylbenzthiazolin-6-Sulfonic Acid), (H2O2) hydrogen peroxide and
ascorbic acid were purchased from Sigma–Aldrich. All other
reagents and standards were of analytical reagent (AR) grade.
2.6.1. Radical scavenging activity dpph
The DPPH radical activity assay was performed following
[62] with minor modification. The method using the stable free
radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) is based upon the re-
duction of DPPH free radical. Different concentrations of the pre-
pared compound (500, 250, 125, 62.5, 31.25 μM) were tested. The
DPPH solution was prepared by dissolving 3,9 mg of DPPH in
50 mL of the methanol. Then, 50μL of each concentration was
added to 1,2 ml of methanol and 250μL of the prepared DPPH so-
lution (0.02 mM). The reaction mixture incubated in the dark for
30 min. The control was prepared by adding 1,25 mL of methanol
to 250 μL of DPPH. Ascorbic acid was used as the standard. The
ꢀ
ꢁ
Abs Control − AbsCompound
Inhibition %
=
∗ 100
( )
AbsControl
Where AbsControl refers to the absorbance of control (enzyme
and buffer), AbsCompound refers to the absorbance of sample (en-
zyme and inhibitor).
Acarbose was used as a positive control to compare the ob-
tained results. The same reaction mixture without α-glucosidase
was used as negative control where no improvement in absorbance
was observed.
3

M. Missioui, S. Mortada, W. Guerrab et al.
Journal of Molecular Structure 1239 (2021) 130484
Scheme 1. Synthesis procedure for preparation of (NPOQA).
absorbances of solutions were spectrophotometrically examined at
517 nm. The radical activity is expressed as inhibition ratio of ini-
tial concentration of DPPH radical and is calculated according to
3. Results and discussions
The synthesis of the compound (NPOQA) is depicted in
Scheme1. The starting material, 3-methylquinoxalin-2(1H)- one
was prepared through treatment of o-phenylenediamine with
sodium pyruvate in acetic acid [66]. This compound was
the formula:
∗
DPPH(%) = [(AbsDPPH – AbsSample)/AbsDPPH
]
100
Where AbsDPPH is the absorbance of DPPH radical and Abssample
is the absorbance in the presence of sample. The activity result in
this assay was expressed as IC50, which represents the concentra-
tion of the sample required to inhibit 50% of the free radical activ-
ity.
proven to be
a good synthons for different highly biologi-
cally active compounds. The lactam function of quinoxalinone is
very reactive and so it condensed with 2–chloro-N-(4-methyl-2-
nitrophenyl)acetamide. Structure of NPOQA was elucidated on the
basis of spectral data.
Yield 80%, mp= 266.7 – 268.5 °C, FT-IR (ATR, υ, cm-1): 3251
2.6.2. Radical scavenging activity abts
The ABTS assay was performed as previously described by
Tuberoso et al. [63] ABTS+ radical were generated by oxidation
of ABTS with potassium persulfate. The blue-green ABTS was pro-
duced through the reaction between 2 mM ABTS and 70 mM
potassium persulfate in water. The mixture was left to stand in
the dark for 12–16 h before use. The ABTS+ solution as diluted
with methanol to an absorbance of 0.700 0.005 at 734 nm. Then
2 mL of diluted ABTS solution were mixed with 100 μL of sam-
ples and absorbance was measured after 1 min incubation at room
temperature. A standard curve was obtained by using Ascorbic acid
as standard solution. The results were expressed as μM Ascorbic
acid equivalent.
–
–
O amide), 833 υ(C Harom), 1601
υ(N H amide), 1651 υ(C
=
υ(C Carom), 1408 υ(C H CH3qin), 1470 υ(NO2); 1H NMR (DMSO–
d6) δ ppm: 2.37 (3H, s, CH3,quin); 2.49 (3H, s, CH3,arom); 5.17
(2H, s, CH2); 10.64 (1H, s, NH); 7.35–7.92 (m, J = 7.5 Hz, 7HAr);
=
–
13C NMR (DMSO–d6) δ ppm: 44.91 (CH2 NQuin); 19.99 (CH3,arom);
–
–
=
21.11 (CH3,Quin); 142.35 (C NO2); 165.45 (C Oacetamid); 154.29
(C = N,Quin); 157.57 (C = O quin). Its mass spectrum showed a
molecular ion peak (MH+, m/z = 353,12) which conforms to its
molecular formula C18 H16 N4O4. SM (ESI+), IR and NMR spectra are
given in the Supplementary Material Tables S1-S3.
The melting point was highly increased, compared to the pre-
cursor [66], yet our compound shown a moderate melting point if
it was compared by the compounds of the same family [67–69]
On the basis of 1H NMR spectrum which exhibited three sig-
nals at δ 2.49, 5.17 and 10.64 ppm referring to methyl group, CH2
bound to the quinoxaline nitrogen and NH of acetamide group
respectively, and revealed the absence of signal at δ 10.66 ppm
corresponding hydrogen of the lactam which confirms the re-
action between 3-methylquinoxalin-2(1H)-one and 2–chloro-N-
(4-methyl-2-nitrophenyl) acetamide [69]. Its 13C NMR spectrum
showed signals at δ 19.99, 21.11, 44.91, 142.35,154.29, 157.57 and
165.45 referring to CH3 of the phenyl ring, methyl group, CH2
bound to quinoxaline nitrogen group, carbon liked to nitro group,
C = N of quinoxaline group, C = O of quinoxaline group and Carbon
of acetamide group respectively. IR spectrum of NPOQA showed
band at 3251cm−1 for NH group and 1470 cm−1 due to NO2 group,
in addition the spectrum displayed absorption band at 1651 cm−1
characteristics for the carbonyle group. The elemental analyses and
spectral data were in agreement with its structure.
2.6.3. Ferric reducing power assay (FRAP)
The ferric ion (Fe3+) reducing power assay was performed as
previously described by Amarowicz et al. [64] with minor modifi-
cations. Briefly, 1 mL of the samples were mixed with 2.5 mL of
0.2 M sodium phosphate buffer (pH 6.6) and 2.5 mL of 1% potas-
sium ferricyanide. The mixtures were incubated in a boiling wa-
ter bath at 50 °C for 2 min. Then, 2.5 mL of 10% trichloroacetic
acid was added and centrifuged at 3000 rpm for 10 min. Finally,
2.5 mL of the supernatant were mixed with 2.5 mL distilled water
and 0.5 mL FeCl3 solution (0.1%, w/v). The absorbance was mea-
sured at 700 nm and the results were expressed as ascorbic acid
equivalent.
2.6.4. Hydrogen peroxide activity H2O2
The hydrogen-donating activity, measured utilizing hydrogen
peroxide radicals as the hydrogen acceptor was performed as pre-
viously described by Muruhan et al. [65] with minor modifications.
Briefly a solution of hydrogen peroxide (40 mM) was prepared in
phosphate buffer (pH 7.4). Different concentrations of the prepared
compound (62.5, 31.25, 15.62, 7.81 and 3.9 μM) were added to a
hydrogen peroxide solution (0.6 mL, 40 mM). The absorbance of
hydrogen peroxide at 230 nm was determined after 10 min against
a blank solution containing phosphate buffer without hydrogen
peroxide (or ascorbic acid as the control). The hydrogen peroxide
percentage activity was then calculated using the following equa-
tion:
3.1. X-ray crystallography
The quinoxaline moiety is slightly non-planar as seen by the
dihedral angle of 1.4 (1)° between the mean planes of the con-
stituent rings. The dihedral angle between the mean planes of the
C1/C6/N1/C7/C8/N2 and the C12···C17 rings is 78.51(5)° while the
nitro group is twisted from co-planarity with the latter ring by
16.5(1)°. The intramolecular N3—H3A···O3 hydrogen bond (Table 2
and Fig. 2) partially aids in determining the conformation of that
portion of the molecule. The bond lengths and interbond angles
are normal for the given formulation. In the crystal, thick chains
of molecules extending along the a-axis direction are formed by
N3—H3A···O2, C16—H16···O2 and C18—H18···O1 hydrogen bonds
Ab
ꢀ
H2O2% = Ab −
× 100
ꢀ
Ab
Where Ab’ is the absorbance of the control reaction and Ab is
the absorbance in the presence of the samples.
4

M. Missioui, S. Mortada, W. Guerrab et al.
Journal of Molecular Structure 1239 (2021) 130484
Table 2
Table 3
˚
Hydrogen-bond geometry (A, °).
The calculated physiochemical quantities of the compound at
B3LYP/6–311G∗∗ level.
Cg2 is the centroid of the C1···C6 benzene ring.
D—H···A
D—H
H···A
D···A
D—H···A
Gas
Water
N3—H3A···O2i
0.91
0.91
0.99
0.95
0.98
2.15
2.03
2.90
2.56
2.53
2.840(2)
2.647(2)
3.809(3)
3.288(3)
3.391(3)
132
124
153
134
146
DM (debye)
α (au)
3.901
5.291
N3—H3A···O3
253.048
341.275
C10—H10B···Cg2i
C16—H16···O2ii
C18—H18B···O1iii
E (au)
−1215.394590
−1215.371074
−1215.450046
215.818
−1215.411957
−1215.388460
−1215.467289
215.593
H (au)
G (au)
Symmetry codes: (i) x − 1, y, z; (ii) −x + 2, −y + 1, −z; (iii) −x + 1, −y + 1,
−z.
Ethermal (kcal/mol)
Cv (cal/molK)
S (cal/molK)
85.677
85.729
166.210
165.910
341.275 au in the water phase, due to the existence of the nitro (-
NO2) and carbonyl groups. Besides, the changing of the free energy
of the compound implied that the compound had higher stability
in the water (−1215.450046 au) phase than the gas (−1215.467289
au). The
E and
H quantities of the compound were com-
puted as −1215.394590 au and −1215.371074 au in the gas and as
−1215.411957 au and −1215.388460 au in the water. Ethermal (in
kcal/mol), Cv (in cal/molK), and S (in cal/molK) values were calcu-
lated as 215.818, 85.677, and 166.210 in the gas, whereas they were
predicted as 215.593, 85.729, and 165.910, respectively.
3.2.2. Natural bond orbital study
NBO analysis provides highly descriptive information about the
reactivity behavior of organic [70–72] and inorganic systems [73–
75] by predicting possible intermolecular interactions. Table 4
summarized the interactions that had the higher energy contri-
butions to the lowering of the stabilization energy. Accordingly,
the charge flow to aromatic ring from each of the lone pairs
of the nitrogen atoms were determined as the highest contribu-
tions to E(2), which were LP (1) N25 (EDi = 1.59816e) → ꢀ∗
C1-C6 (EDj = 0.44453e) and LP (1) N32 (EDi = 1.64156e) → ꢀ∗
Fig. 2. Detail of the intermolecular interactions in a portion of one chain. N—H···O
and C—H···O hydrogen bonds are depicted, respectively, by blue and black dashed
lines while C—H···π(ring) and CO···π-ring interactions are shown, respectively, by
green and purple dashed lines. (For interpretation of the references to colour in
this figure legend, the reader is referred to the web version of this article.)
C12-C13 (EDj
=
0.46356e) with the energies of 38.35 and
43.35 kcal/mol, respectively. Besides, the ꢀ C12-C13 → ꢀ∗ N36-
O38 (EDj = 0.61901e) interaction was determined by the energy
of 30.95 kcal/mol, remarkable. Also, the charge flow to each of an-
tibonding orbitals ꢀ∗ C14-C15 (EDj = 0.29765e) and ꢀ∗ C16-C17
(EDj = 0.27819e) from filled orbital ꢀ C12-C13 had a striking en-
ergy of 20.07 and 14.00 kcal/mol, respectively. The E(2) values for
the charge movement to each of ꢀ∗ C2-C3, ꢀ∗ C4-C5, and ꢀ∗
C7-N24 unfilled orbitals from ꢀ C1-C6 filled orbital were calcu-
lated as 17.03, 18.97, 12.61 kcal/mol, respectively. The E(2) values
for the other resonance interactions occurred in the nitro substi-
tuted aromatic rings were calculated as 19.00, 20.85, 23.93, and
17.67 kcal/mol for the interactions of ꢀ C14-C15 → ꢀ∗ C12-C13,
ꢀ C14-C15 → ꢀ∗ C16-C17, ꢀ C16-C17 → ꢀ∗ C12-C13, and ꢀ C16-
C17 → ꢀ∗ C12-C13, respectively. Also, the E(2) values for ꢀ C7-
N24→ ꢀ∗ C1-C6 and ꢀ C7-N24→ ꢀ∗ C8-O42 interactions were
predicted as 14.77 and 13.34 kcal/mol, respectively.
Fig. 3. The optimized structures of the compound NPOQA at B3LYP/6–311G∗∗ level.
together with C10—H10B···Cg2 interactions (Table 2 and Fig. 2)
and assisted by π-stacking interactions between the N4O4 por-
tion of the nitro group and the C12···C17 ring at x − 1, y, z
3.2.3. Global reactivity study
Global reactivity identifiers obtained from the (I) and (A) val-
ues have been widely applied to a lot of scientific disciplines to
evaluate the chemical behavior of the organic [76–79] and/or in-
organic [80–82] molecular systems. In this study, the calculated
reactivity parameters were given in Table 5. Accordingly, HOMO
energy of the compound decreased whereas the LUMO energy in-
creased, in the water simulation media. Thus, the energy gap of
the compound was enlarged in the water phase in comparison to
the gas phase. The EHOMO and ELUMO energies of the compound
were calculated as −6.391 and −2.995 eV in gas and as −6.508 and
−2.975 eV in the water, respectively. It can be said that the com-
pound is more reactive in the water phase because of the larger
E value, that is, the E values of the compound are calculated
˚
˚
(N4···ring centroid = 3.462(2) A, O4···ring centroid = 3.330 (2) A,
N4O4···centroid = 85.85 (10)°).
3.2. Theoretical studies
3.2.1. Quantum chemical studies
The optimized and verified structure of the compound by the
absence of the negative value in frequencies was presented in
Fig. 3, and the physical quantities were summarized in Table 3.
The dipole moment and polarizability behavior of the compound
were affected by the solvent media, namely, they were estimated
in 3.901 D and 253.048 au in the gas phase and in 5.291 D and
5

M. Missioui, S. Mortada, W. Guerrab et al.
Journal of Molecular Structure 1239 (2021) 130484
Table 4
NBO analysis results of the compound at B3LYP/6–311G∗∗ level.
Donor(i)
Gas
EDi/e
Acceptor (j)
EDj/e
E(2)/ kcalmol−1
E(j)-E(i)/ a.u
F(i.j)/ a.u
ꢀ C1-C6
1.57496
1.70495
1.68763
1.84750
1.63515
1.66361
1.67441
1.59816
1.64156
ꢀ∗ C2-C3ꢀ∗ C4-C5ꢀ∗ C7-N24
ꢀ∗ C1-C6ꢀ∗ C4-C5
ꢀ∗ C1-C6ꢀ∗ C2-C3
ꢀ∗ C1-C6ꢀ∗ C8-O42
ꢀ∗ C14-C15ꢀ∗ C16-C17ꢀ∗ N36-O38
ꢀ∗ C12-C13ꢀ∗ C16-C17
ꢀ∗ C12-C13ꢀ∗ C14-C15
ꢀ∗ C1-C6
0.329290.298680.18842
0.444530.29868
0.444530.32929
0.444530.33158
0.297650.278190.61901
0.463560.27819
0.463560.29765
0.44453
17.0318.9712.61
21.2316.62
18.2022.49
14.7713.34
20.0714.0030.95
19.0020.85
23.9317.67
38.35
0.290.300.29
0.280.30
0.270.28
0.340.33
0.310.310.15
0.260.29
0.260.29
0.29
0.0640.0690.057
0.0720.063
0.0650.071
0.0690.062
0.0720.0600.064
0.0650.070
0.0730.065
0.095
ꢀ C2-C3
ꢀ C4-C5
ꢀ C7-N24
ꢀ C12-C13
ꢀ C14-C15
ꢀ C16-C17
LP (1) N25
LP (1) N32
ꢀ∗ C12-C13
0.46356
43.35
0.27
0.099
Fig. 4. HOMO& LUMO (isoval:0.02), and MEP (isoval:0.0004) pilots of the compound at B3LYP/6–311G∗∗ level in the gas phase.
Table 5
indicated that the electron-rich region (orange color) in moderate
The quantum chemical parameters of the
size covered the oxygen atoms, whereas the electron-poor region
(blue color) of the compound coated the around of hydrogen atom
of the secondary amin group. The remaining parts of the com-
pound seem neutral for both the electrophilic and nucleophilic at-
tack because of the green color, but there were sprinkle the slight
positive potential (light blue) on the electron density surface of the
compound NPOQA.
compound NPOQA at B3LYP/6–311G∗∗ level.
Gas
Water
H (-I) (eV)
L (-A) (eV)
E (L-H) (eV)
μ (eV)
−6.391
−2.995
3.397
−6.508
−2.975
3.533
−4.693
1.698
−4.741
1.766
η (eV)
ω (eV)
6.485
6.364
Nmax (eV)
εback-donat. (eV)
ω+ (au)
2.763
2.684
3.3. Enzyme inhibitory activities
−0.425
0.160
−0.442
0.155
In an array to explore the in vitro antidiabetic activity, quinox-
aline derivative was screened for the α-amylase and α-glucosidase
inhibitory properties. Effects were compared with the commer-
cially available inhibitor, acarbose (Ac). Inhibitory activities of the
compound were evaluated at different concentrations and results
were given in Fig. 5A,B. Acarbose and NPOQA showed a dose de-
pendent inhibitory effect on enzymes.
ω− (au)
0.332
0.329
as 3.397 eV in gas and 3.533 eV in the water, respectively. Besides,
the compound is harder in the water (1.766 eV) than the gas phase
(1.698 eV). From Table 5, (ω) and Nmax indexes (in eV) were cal-
culated higher in the gas (ω=6.485 and Nmax= 2.763) than the
gas water (ω=6.364 and Nmax= 2.684). Also, the (ω+) and (ω−)
indexes implied that the compound more likely prefer the elec-
trodonating tendency than the electroaccepting behavior, in both
phases. The (ω+) and (ω−) values of the compound were estimated
as 0.160 and 0.332 in the gas and as 0.155 and 0.329 in the water
media.
The results showed that the compound NPOQA had
remarkable inhibitory effect on α-glucosidase activity (IC50
83.78 0.888 μM). NPOQA has a dose-dependent inhibitory ef-
a
fect on α-glucosidase and it showed a statistically highly signifi-
cant as P < 0.001, which is comparable to others N-aryl acetamides
hybrid system [10,11], similar result was found for α-amylase.
NPOQA showed a considerable activity (IC50 199.7
0.952 μM).
Therefore, it considered as an active compound for this application
(Table 6).
The HOMO, LUMO and MEP profiles of the compound were
illustrated in Fig. 4 to give a clear picture for the nucleophilic
(HOMO) and electrophilic (LUMO) attack sites. Except for the
methyl groups and for oxygen atoms of the nitro group, HOMO
density of the compound spread out overall molecular surface. On
the other hand, LUMO density did lay out completely on the 3-
methyl-2-oxoquinoxalin ring of the compound. Besides, MEP plots
3.4. Antioxidant activity
In vitro antioxidant activity of NPOQA complexe was evalu-
ated by using radical methods, DPPH, ABTS, FRAP, The antioxi-
6

M. Missioui, S. Mortada, W. Guerrab et al.
Journal of Molecular Structure 1239 (2021) 130484
Fig. 5. A)α-amylase inhibitory activities of NPOQA; B) α-glucosidase inhibitory activities of NPOQA.
Fig. 6. Molecular docking of acarbose with α–amylase and α-glucosidase. (A) Binding of acarbose with glucosidase, (B) amino acid residues and various interactions involved
in acarbose-glucosidase complex, (C) binding of acarbose with -amylase (D) amino acid residues and various interactions involved in acarbose-amylase complex.
Table 6
dant property of the tested samples was evaluated at different
IC50 of the NPOQA enzyme inhibitory activity:.
concentrations and Ascorbic Acid was used as a standard for the
comparison of the activity. The obtained result of DPPH assay
showed a good antioxidant activity, with IC50 value (104, 1 4,
(IC50 μmol/ml)
Compound
NPOQA
α-glucosidase
α-amylase
83.78
72.58
0.888∗∗∗∗
199.7
115.6
0.952∗∗∗∗
65 μM), while IC50 value of ascorbic acid (78, 11 0, 68 μM). The
NPOQA have developed an important antioxidant activity in the
ABTS test, and better than other similar heterocyclic compounds
[13]. With a correlation to the antioxidant activity shown in the
DPPH test (Table 7), it showed the average antioxidant ability
Acarbose
0.682
0.574
Values represent mean
standard deviation (n = 3).
Values with the same superscript on the same row are sig-
nificantly similar (P (<0,0001)).
7

M. Missioui, S. Mortada, W. Guerrab et al.
Journal of Molecular Structure 1239 (2021) 130484
Fig. 7. Molecular docking of NPOQA with α-glucosidase. (A) Binding of NPOQA with α-glucosidase, (B) (2D) amino acid residues and various interactions involved in NPOQA-
glucosidase complex, (C) (3D) amino acid residues and various interactions involved in NPOQA-glucosidase complex, (D)binding of NPOQA with glucosidase hydrophobic
pocket.
Table 7
same family [8]. The synthesized compound NPOQA demonstrated
Antioxidant activities (DPPH, ABTS, FRAP and H2O2) of NPOQA. Data are expressed
a strong activity, with IC50 value (5,06 0,48 μM), while IC50 value
of ascorbic acid (7,45 1,11 μM).
as mean
SD (n = 3).
DPPH
ABTS
FRAP
H2O2
(IC50 μM)
(μM AAE)
(μM AAE)
(IC50 μM)
3.5. Molecular docking
NPOQA
104,1
4,65
330,30
3,44
298,54 6,59
5,06 0,48
7,45 1,11
Ascorbic Acid
78,11 0,68
̵
̵
Molecular docking study was performed to analyze the bind-
ing modes of the studied compound against α-glucosidase and
α-amylase enzyme. The results showed that both acarbose and
NPOQA were able to bind to the active site of α-glucosidase, the
calculated binding energy was found to be −6.5 and −6.9 kcal/mol
successively for acarbose and NPOQA (Table 8). Several hydro-
gen bonded interactions were observed between various hydroxyl
groups of acarbose and amino acids Ser3, Pro312, Arg252, Gly403,
(330,30
3,44 μM AA). Moreover, in the FRAP method, the high-
est reducing power was interestingly observed also in the NPOQA
(298,54 6,59 μM AAE). The FRAP value indicates that the com-
pound has a ferric reducing antioxidant power and it has a rel-
atively high antioxidant activity compared to compounds of the
Table 8
.The calculated binding energy for acarbose and NPOQA.
Acarbose glucosidase
Glucosidase
Amylase
Affinity kcal/mol
Risidus
Affinity kcal/mol
Risidus
acarbose
−6.5
−6.9
ASN470, THR567, SER566, LEU538,
ASN570, TYR191, GLY335, ARG190,
ARG189, ASP243, HIS562
−6.6
THR6,GLN8, SER3,PRO4,
ARG252,ASP402,GLY403,ARG421,
PRP332, PHE335, THR336, THR11,
ARG398, GLY334, ASN5, ARG92
ASP402,ARG398, SER289, TYR333,
ARG421, PRO332
NPOQA
Leu538, asp243, ASN570, TYR191,
SER566, THR56
−7.6
8

M. Missioui, S. Mortada, W. Guerrab et al.
Journal of Molecular Structure 1239 (2021) 130484
Fig. 8. Molecular docking of NPOQA with Amylase. (A) Binding of NPOQA with amylase, (B) (2D) amino acid residues and various interactions involved in NPOQA-amylase
complex, (C) (3D) amino acid residues and various interactions involved in acarbose-amylase complex, (D)binding of NPOQA with amylase hydrophobic pocket.
Arg421, Thr 11, Arg398, Gly334, Asn5 and Arg5 of α-glucosidase
enzyme (Fig. 6). Exploration of molecular interaction of NPOQA
shows several hydrogen’s bonds (Asn570, Tyr191, Ser566, Thr567),
Pi-anion interactions with Asp243, and a Pi-alkyl interaction be-
tween the methyl and Leu538. The studied compound NPOQA was
well accommodated in the binding pocket of α-glucosidase as
shown in Fig. 7. Results showed that compound NPOQA has an
important binding affinity as compared to standard drug acarbose.
Which are in agreement with the results of in vitro studies.
terized by different spectroscopic techniques. The structure was
resolved by the XRD analysis and this illustrates that the quinox-
aline unit is not quite planar. FMO analyses revealed that the
electrodonating potency (0.332au) of the compound was greater
than the electroaccepting capability (0.160au) in both phases. In
addition, the HOMO density of the compound expanded on the
whole molecular surface more than the LUMO, and the 3-methyl-
2-oxoquinoxalin ring was liable for the electrophilic attacks. NBO
analyses showed that the n→ П∗ and П→ П∗ interactions were
greatly responsible for the decreasing of the stabilization energy.
The compound NPOQA was evaluated for its in vitro antidiabetic
and antioxidant activities ; It showed an excellent antidiabetic and
antioxidant activities. In addition to this, molecular docking studies
were carried to investigate the binding mode between NPOQA and
the two enzymes, α-glucosidase and α-amylase. Thus, this study
explores, theoretical prediction, antidiabetic, antioxidant activi-
ties and docking studies of quinoxaline-N-aryl acetamide hybrid
system for development of potential multifunctional medicinal
candidates.
We have also performed molecular docking of NPOQA and acar-
bose with α–amylase. The calculated binding affinity was pre-
dicted to be −6.6 and −7.6 Kcal/mol successively for acarbose and
NPOQA (Table 8). Compound NPOQA was lockted at the hydropho-
bic pocket of the enzyme (Fig. 8). Surrounded by the residues ASP-
402, ARG-398, SER-289, TYR-333, ARG-421, PRO-332 forming a sta-
ble hydrophobic binding. Detailed analysis showed that the methyl
group in position 3 of the NPOQA formed π-alkyl interactions with
the residues Arg-398 in addition to an π-anion and π-alkyl be-
tween phenyl group and residues Asp-402 and Pro-332. All these
interactions helped NPOQA to anchor in the binding site of the α-
amylase and explain the higher binding affinity compared to acar-
bose. The magnitude of the binding affinity and the different inter-
actions indicates that the studied compounds NPOQA and acarbose
interacted strongly with α -amylase, confirming the in vitro data.
Author contributions
Mohcine Missioui: Performed experiments, Wrote a draft the
paper. (Chemical section).
Salma Mortada: Performed experiments, Wrote a draft the pa-
per. (Biological section).
4. Conclusion
Walid Guerrab: Performed the molecular docking study
Goncagül Serdarog˘lu: Performed the X-ray crystallographic
analysis, wrote the paper.
In this research, new quinoxaline derivative, N-(4-methyl-
2-nitrophenyl)−2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetamide
(NPOQA) has been synthesized, with significant yield and charac-
Savas¸ Kaya: Performed the computational chemistry analysis.
9

M. Missioui, S. Mortada, W. Guerrab et al.
Journal of Molecular Structure 1239 (2021) 130484
Joel T. Mague: Collected and processed the X-ray data
El Mokhtar Essassi: Conceptualization, methodology.
M. E. Abbes Faouzi: Supervision (Biological section).
Youssef Ramli: Conceptualization, methodology, supervision,
Wrote the paper.
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Authors are grateful to Mohammed V University and to Sci-
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All quantum chemical calculations were performed at High Per-
formance and Grid Computing Center (TR-Grid e-Infrastructure).
The support of NSF-MRI Grant #1228232 for the purchase of the
diffractometer and Tulane University for support of the Tulane
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found, in the online version, at doi:10.1016/j.molstruc.2021.130484.
activity and inhibition of α-glucosidase,
J Mol Struct 1234 (2021) 130177,
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