M. Missioui, M.A. Said, G. Demirtas¸ et al.
Journal of Molecular Structure 1247 (2022) 131420
Table 2
2.4. Docking in silico studies
˚
Hydrogen-bond geometry (A, °).
Docking calculations of the NMPOQA and drugs were accom-
plished using the Autodock Vina wizard in PyRx 0.8 [52] (available
visualization engine and valuable software for molecular docking
[53]. Both the occupancies of the disordered title ligand crystal
0.503(2) NMPOQAa /0.497(2) NMPOQAb binding modes of the NM-
POQA (a and b) under the same conditions have been explored
for comparison. Settings in the program include: Grid box cen-
ter_x = 12.117, center_y = -11.3843, center_z = 4.6603, size_x = 25,
size_y = 25 and size_z = 25 for the NMPOQA against Remdesivir
drug. Whereas the grid box for the NMPOQA against the Donepizl
drug is: center_x = 5.0229, center_y = 65.044, center_z = 55.8104,
size_x = 25, size_y = 25 andsize_z = 25. The exhaustiveness
for all is 8. The energy minimization of the ligand and protein
was performed using the default settings in the Autodock Vina-
PyRx. The CIF files of the NMPOQA (CCDC= 2061622), Donepizl
(CCDC= 1525480) and Remdesivir (CCDC= 1438375) were con-
verted to PDB file type using Biovia Discovery Studio 4.5 [54] and
were introduced as input to Autodock vina in PyRx. The proteases
(PDB code 1EVE and 6M03) were saved in PDB format after dele-
tion of the water molecules and ligands. Schematic diagrams of
protein-ligand interactions were generated using the LIGPLOT pro-
gram [55].The PyMOL molecular viewer was used to present the
Cg2 is the centroid of the C1… C6 benzene ring.
D—H…
A
D—H
H…
A
D…
A
D—H…
A
N3—H3A…O2i
C10—H10A… Cg2i
0.91
0.99
1.90
2.78
2.801 (3)
3.571 (4)
170
137
Symmetry code: (i) x+1, y, z.
(DMSO-d6) δ ppm: 2.49 (3H, s, CH3,quin); 3.73 (3H, s, CH3 methoxy);
5.11 (2H, s, CH2); 10.32 (1H, s, NH); 6.75–7.82 (m, J=7.3 Hz, 8HAr);
13C NMR (DMSO-d6) δppm: 55.14 (CH2); 45.30 (CH3 methoxy); 21.09
(CH3 quin); 164.26 (C-O); 165.53 (C=Oacetamid); HRMS (ESI-MS)
(m/z) calculated for C18 H17 N3O3 323,13 found 324.12936
Based on of 1H NMR spectrum of NMPOQA which exhib-
ited four signals at δ 2.49, 3.73, 5.11 and 10.64 ppm referring
to a methyl group, CH3 of the methoxy group, CH2 bound to
the quinoxaline nitrogen and NH of acetamide group respectively.
Besides, we revealed the absence of a signal at δ 12.29 ppm
corresponding hydrogen of the lactam which confirms the re-
action between 3-methylquinoxalin-2(1H)-one and 2-chloro-N-(4-
methoxyphenyl)acetamide. Regarding the 13C NMR spectrum, there
are signals at 21.09 ppm, 45.30 ppm, 55.14 ppm, 164.26 ppm and
165.63 ppm referring to the carbon of, the CH3 group linked to
the quinoxaline entity, the CH3 of the methoxy group, the CH2
entity, the carbon linked to the oxygen of methoxy group and
finally the carbon of acetamide group respectively. The presence
of the characteristic signals of the precursors simultaneously con-
firms the structure of our compound. Concerning the FT-IR spec-
trum, it shows mainly characteristic peaks at 3251 υ, 1651 υ and
1215 υ referring respectively to the C=O bond of the amide en-
tity, the NH bond of acetamide group, and finely the C-O bond of
methoxy entity. Its mass spectrum showed a molecular ion peak
(MH+, m/z = 324,129) which conforms to its molecular formula
C18 H17 N3O3. SM (ESI+), IR and NMR spectra are given in the Sup-
plementary Material Tables S1–S3.
3. Results and discussion
3.1. Synthesis
The synthesis of the compound (NMPOQA) is depicted in
Scheme 1. The starting material, 3-methylquinoxalin-2(1H)- one
was prepared through treatment of o-phenylenediamine with ethyl
pyruvate in acetic acid [42]. This compound was proven to be a
good synthon for different highly biologically active compounds.
The lactam function of quinoxalinone is very reactive and so it
is condensed with 2-chloro-N-(4-methoxyphenyl)acetamide (CN-
MPA). The structure of NMPOQA was elucidated the based on spec-
tral data.
3.2. Single crystal X-ray structure determination
The conformation of the molecule can be described as a "spat-
ula" with the dihydroquinoxaline unit as the blade and the long
side chain as the handle (Fig. 1). The dihydroquinoxaline por-
tion is not quite planar as indicated by the 2.58(17)° dihedral
angle between its constituent planes. The C10/C11/O2/N3 unit of
the side chain is nearly perpendicular to the mean plane of the
dihydroquinoxaline moiety as indicated by the C8—N2—C10—C11
torsion angle of -96.95 (30)°. In the side chain, the C12···C17
benzene ring is rotationally disordered over two sites 52.3 (2)°
apart in a 0.503 (2)/0.497(2) ratio with the slightly larger compo-
nent making an 86.0 (1)° dihedral angle with the mean plane of
the C1/C6/N1/C7/C8/N2 ring. In the crystal, N3—H3A···O1 hydro-
gen bonds abetted by C10—H10A···Cg2 interactions (Table 2) form
chains of molecules extending along the a-axis direction (Fig. S4,
Supplementary Materials). The chains pack across inversion cen-
ters with normal van der Waals contacts (are also shown in Sup-
plementary Materials Figs. S5 and S6).
3.1.1. 3-Methyl-1H-quinoxalin-2-one (MQO)
Yield 91%, mp=219.3-220.5°C, FT-IR (ATR, υ, cm-1) 1568 υ
(C=N), 1663 υ (C=O), 2710, 2843, 2898, 2963, 3007 υ(C-H, aro-
matic), 3430 υ (N-H). 1H NMR (DMSO-d6) δ ppm: 2.40 (3H,
s, CH3), 7.27 (2H, m, Harom), 7.28 (1H, d,
J
=
8.86 Hz, H
arom), 12.29 (1H, s, N-H). 13C NMR (DMSO-d6) δppm: 20.51
(CH3), 115.22, 123.04, 127.86, 129.31 (C-HArom), 131.65 (Carom-N),
131.91 (Carom-N), 159.22 (C=O); HRMS (ESI-MS) (m/z) calculated
for C9H8N2O 160.06, found 160.17
3.1.2. 2-Chloro-N-(4-methoxyphenyl)acetamide (CNMPA)
Yield 80%, color: beige, mp=125.6-127.3°C, Rf, FT-IR (ATR, v,
cm-1) 3292 v (N-H amide), 1029 v (N-C amide), 1660 v (C=O
amide), 3073 v(C-Harom), 827 v(C-Cl), 2959 v(C-H,CH2), 1H NMR
(DMSO-d6) ppm: 3.74 (3H, s, CH3); 4.24 (2H, s, CH2), 6.93-7.5 (4H,
m, J =1.3Hz, Harom), 10.23 (1H, s, NH), 13C NMR (DMSO-d6) δ
ppm: 43.48 (CH2), 55.23 (CH3), 131.53 (Carom-N), 155.51 (Carom -O),
113.92–120.92 (CArom); 164.13 (C=O); HRMS (ESI-MS) (m/z) calcu-
lated for C9H10ClNO 183,64, found 184.0105
3.3. Computational study
3.3.1. Geometric optimization of the compound
3.1.3. N-(4-methoxyphenyl)-2-(3-methyl-2-oxoquinoxalin-1
(2H)-yl)acetamide (NMPOQA)
In this study, the theoretical structure of the compound NM-
POQA was calculated using DFT/B3LYP, 6-311++G(d,p) method. Be-
cause of having a disorder, calculations were only figured out
for the situation that the benzene group is almost perpendicu-
lar to 3-methylquinoxalin-2(1H)-one group. For initial values, this
Yield 85%, color : beige, mp= 166.5–168.3°C, FT-IR (ATR, υ,
cm-1): 3251 υ(N-Hamide); 1651 υ(C=Oamide); 752 υ(C-Harom); 1539
υ(C=Carom); 1470 υ(C-H CH3);); 1215 υ(C-Omethoxy); 1H NMR
4