FT-IR, NMR and UV-visible spectral investigations, theoretical

calculations, topological analysis, chemical stablity and molecular docking

study on novel bioactive compound: the 5-(5-nitro furan-2-ylmethylen), 3-
N-(2-methoxy phenyl),2-N’-(2-methoxyphenyl) imino thiazolidin-4-one

Rachida Rahmania,b,*, Fouzia Perveenc, Nadia Benhalimaa,d, Ahmed Djafria,e, Nawel

Khelloula,f, Abdelkader Chouaiha, Ayada Djafrig, Mohammed Benali Kanounh, Souraya
Goumri-Saidi

a Laboratory of Technology and Solid Properties (LTPS), Abdelhamid Ibn Badis University - Mostaganem,
27000 Mostaganem, Algeria
b Department of Process Engineering, Faculty of Sciences and Technology, Ahmed Zabana - University of

Relizane, 48000 Relizane, Algeria

c Research Centre for Modeling and Simulation, National University of Science and Technology, Islamabad,

Pakistan.
d Physics Department, Faculty of Sciences, Dr. Tahar Moulay University of Saida - POBox 138, 20002 Saida,

Algeria
e Centre de Recherche Scientifique et Technique en Analyses Physico-chimiques (CRAPC), BP 384-Bou-Ismail-

RP 42004, Tipaza-Algeria
f Faculty of Sciences and Technology, Mustapha Stambouli University of Mascara B.P.763, 29000, Mascara,

Algeria.
g Laboratoire de Synthèse Organique Appliquée (LSOA), Département de Chimie, Faculté des Sciences,

Université d'Oran 1 - Ahmed Ben Bella, 31000 Oran, Algeria.

hDepartment of Physics, College of Science, King Faisal University, P.O. Box 400, Al-Ahsa, 31982, Saudi

Arabia.
i,*College of Science, Department of Physics, Alfaisal University, P.O. Box 5092, Riyadh 11533, Saudi Arabia.

Abstract
In this work a thiazole derivative, 5-(5-nitro furan-2-ylmethylen), 3-N-(2-methoxy
phenyl),2-N'-(2-methoxyphenyl) imino thiazolidin-4-one (abbreviated by NF2MT), was
characterized through Fourier transform infrared, UV-Vis, 1H and 13C nuclear magnetic
resonance (NMR) spectroscopy. Besides, a complete and detailed vibrational assignment have
been achieved by means of DFT calculations using the B3LYP theory and the 6 311G(d,p)
basis set. Based on the electron density distribution, reduced density gradient and atoms-in
molecules analyses have been performed to describe and identify the intra and intermolecular
interactions within the molecule. Non-covalent interactivities between non-bonded atoms
were also characterized. Additionally, the frontier molecular orbitals and global chemical
reactivity descriptors of NF2MT were further investigated using DFT, revealing the most
important electronic properties of the compound. The TD-DFT method at CAM-B3LYP/6-
311G(d,p) level with the chloroform solvent and polarized continuum model was applied to
obtain optical behavior as well as the electronic transitions for the molecule. On the other
hand, molecular properties such as atomic charges (Mulliken and NBO) and molecular

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electrostatic potential were calculated to locate the most reactive sites in the molecule that
promote hydrogen bond formation. Molecular docking studies were also carried out to predict
and display binding sites of NF2MT with its target protein. The biological activity was tested
with Acetylcholinesterase and Butyrylcholinesterase.

Keywords: RDG/AIM, molecular docking, thiazolidinones, furan, spectroscopy.

*Corresponding author: sosaid@alfaisal.edu

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1. Introduction
The research of new organic compounds presenting a good biological activity is one of
the serious challenges in organic design. Among these organic compounds, those containing
five-membered heterocycles with two heteroatoms, especially thiazolidinones, have been
investigated for aplenty applications such as biological [1], photovoltaic [2,3] and
optoelectronic [4,5]. Otherwise, thiazolidinone motif is the core structure of several organic
compounds possessing a large spectrum of bioactivities [6,7]. Furthermore, it has been shown
that the thiazole moiety is a fascinating building block in medicinal chemistry for synthesizing
and designing various bioactive molecules [8-10]. Molecular systems with one or more
thiazole moieties are very valuable compounds and many research papers have been reported
their biological activity using molecular docking [11,12]. On the other hand, molecular
docking studies revealed that due to the existence of heteroatoms such as nitrogen, oxygen
and sulfur in the structure represent valuable binding sites for hydrogen interactions [13-15].
Nowadays, numerous research papers were dedicated to X-ray diffraction study and quantum
chemical calculations of thiazole derivatives [16-21].
In the present work, we are going to report a detailed spectroscopic study as well as
molecular docking of 5-(5-nitro furan-2-ylmethylen), 3-N-(2-methoxy phenyl),2-N’-(2-
methoxyphenyl) imino thiazolidin-4-one. Synthesis, molecular structure and Hirshfeld surface
analysis of this compound were reported previously [22]. The nuclear magnetic resonance
spectroscopy (NMR) and infrared spectroscopy are analytical techniques which have enabled
chemists to investigate large and complex biomolecules and predicting their corresponding
vibrational properties. These spectroscopic methods are combined as well as computational
approaches to wholly describe a molecular structure. On the other hand, the Density
functional theory calculations are used to compute molecular properties which are difficult to
obtain experimentally. Intra- and intermolecular interactions along with the non-bonded
interactions are explored using the RDG isosurface and AIM analysis based on the electron
density and its derivatives. These properties are calculated in the bond and ring critical points.
The chemical stability of the title compound is demonstrated by the calculation of the global
reactivity descriptors, namely, hardness, softness, chemical potential, and electrophilicity
index. These parameters can be obtained from the HOMO-LUMO analysis. The experimental
and theoretical UV-visible vibrational analyses are performed to obtain the most important
electronic transitions in the heading compound. In addition, molecular properties such as
Mulliken and NBO charge analysis and molecular electrostatic potential (MEP) are

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calculated. Molecular docking investigation of the studied molecule is also performed to
determine its biological activity.
2. Experimental and Computational Details
Synthesis, solid-state structure and spectral data (IR, 1H NMR, 13C NMR) of the title
compound are reported in our previous work [22]. IR spectra were recorded in KBr pellet on a
JASCO FT/IR 4210 Fourier Transform Infrared Spectrometer. The 1H NMR and 13C NMR
were recorded on Brüker Ac DPX-200(300MHz) spectrometer in chloroform as solvent using
tetramethylsilane as internal reference standard.
Density functional theory (DFT) has proved to be extremely useful in studies of the
molecular and electronic structures of organic and inorganic compounds [23]. Calculations on
5-(5-nitro furan-2-ylmethylen), 3-N-(2-methoxy phenyl),2-N'-(2-methoxyphenyl) imino
thiazolidin-4-one (NF2MT) are carried out using the quantum calculation GAUSSIAN 09
program and Gauss-View molecular visualization software [24,25]. The parent structure for
the calculations is achieved from the X-ray coordinates and this structure is optimized at the
DFT method with the B3LYP functional [26-27] and the 6-311g basis set with diffuse (s) and
(p) functions. This calculation is followed by vibrational analysis to ensure that the obtained
structure represents a true local minimum. The theoretical vibrational spectrum is interpreted
by the means of Potential Energy Distribution using Vibrational Energy Distribution Analysis
program [28]. The nuclear magnetic resonance chemical shift calculations are performed
employing the Gauge-Independent Atomic Orbital method. Time dependent density
functional theory method was used to calculate the excited states and the electronic transitions
with the CAM-B3LYP functional [29]. The obtained spectrum is visualized by the GaussSum
program [30]. The solvent effect is included in both NMR and UV-visible calculations using
chloroform solvent with the Polarized Continuum Model (CPCM) [31]. Furthermore, related
molecular parameters such as Mulliken and NBO charges, molecular electrostatic potential,
energy of HOMO, energy of LUMO, band gap energy, ionization potential, electron affinity,
electronegativity, chemical potential, hardness, softness, electrophilicity index and dipole
moment are determined for the title compound by using the same level of theory.
Additionally, the nature of non-covalent interactions present in the title compound was
examined in detail by AIM using Multiwfn software [32] and the isosurfaces are visualized
using VMD software package [33].

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3. Results and discussion
3.1. Structural analysis and molecular structure
The molecular structure and the numbering atom scheme of NF2MT are shown in
Figure 1. The optimized geometrical parameters (bond lengths, bond angles and dihedral
angles) for NF2MT calculated using DFT/B3LYP method with 6-311G(d,p) basis set have
been reported previously along with experimental parameters [22]. As can be seen in Figure
1, the structure of NF2MT consists of a central thiazole group surrounded by two
methoxyphenyl moieties and a nitrofuran group. In addition to the geometry established by
single crystal X-ray diffraction, the structure of NF2MT is confirmed by spectroscopic
methods and is used to perform other theoretical calculations.

Fig. 1. Optimized geometry with atomic numbering scheme of NF2MT at B3LYP/6-311G(d,p) level.

3.2. Vibrational Study : 1H and 13C NMR Spectral Analysis

The infrared spectroscopy has always been an effective tool to identify the
functional groups of organic molecules. The title compound was characterized by FTIR and
theoretical vibrational frequencies were predicted using B3LYP functional with 6-311G (d,p)
basis set. The NF2MT molecule has 141 normal modes of vibrations and the potential energy
distribution (PED) was calculated for each normal mode. The systematic errors of theoretical
wavenumbers have been identified and reduced by using a scaling factor 0.967 for B3LYP/6-
311G (d,p) level of theory [34]. Theoretical and experimental FT-IR spectra are indicated in
Fig. 2 and the major band assignments with their contributions are given in Table 1.
Nitro Group Vibrations
5

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In the present study, the N–O stretching vibration, with a PED of 83%, is calculated at 1550
cm−1 with B3LYP/6-311G (d,p) level of theory and found at 1541 cm−1 in the FT-IR
spectrum. The observed NO2 in-plane bending vibration is assigned at 809 cm–1 in the FT-IR
spectrum. This vibration is computed at 805 and 799 cm–1 for the scissoring modes.
Furthermore, the out-of-plane vibration is calculated at 720 cm–1.
The N–C stretching vibration between nitro group and furan ring is predicted at 1336 and
1326 cm−1 with the same level of theory and it is observed at 1351 cm−1 in FT-IR spectrum.
The δCNO rocking vibration between nitro and furan groups is calculated at 524 cm−1.
Furan and methyne moieties Vibrations
Vibrational analysis of furan ring is made on the basis of C−H, C−C, C=C and C−O
vibrations. The symmetric and asymmetric CH stretching vibrations of the furan ring appear
at 3153 and 3121 cm-1 in FT-IR and estimated at 3171 and 3146 cm-1, respectively. The
methyne bridge connected to both furan and thiazolidinone moieties exhibits pure CH
stretching vibration at 3073 cm-1 with a contribution of 100%. The C=C double bond
stretching vibrations of both furan and methyne moieties are observed at 1608 and 1515 cm−1
in the FT-IR spectrum. These vibrations are calculated at 1600, 1527 and 1455 cm−1. The
C−O and C−C stretching vibrations are predicted at 1367, 1242 and 1202 cm-1 and obtained
experimentally at 1375 cm-1. The in-plane and out of plane vibrations for these two moieties
are evaluated in the range 1002-953 cm-1 (FT-IR: 972 and 961 cm-1) and 887-782 cm-1 (FT-IR:
882 and 789 cm-1), respectively.
Imino-thiazolidinone Group Vibrations
The imino-thiazolidinone group contains C=O, C=N, C−S, C−C and C−N bonds. The C=O
and C=N stretching vibrations are observed at 1733 and 1649 cm1 in FT-IR and calculated at
1729 and 1667 cm1 with the PED involvements of 76 and 72%. Literature review revealed
that the C-S stretching vibration with a moderate intensity occurring in the region 700-600
cm−1 [35]. The C S stretching vibration is found at 688 cm−1 in the FT-IR spectrum. This
band is quantified at 700 and 483 cm−1 with PED contributions of 16% and 21 %. The C−N
and C−C stretching vibrations are predicted at 1143, 1134 and 1023 cm1, respectively. The
in-plane and out of plane vibrations for this ring are estimated at 858 cm-1 (FT-IR: 862 cm-1)
and 728, 724 cm-1, respectively.
Phenyl ring Vibrations
The predicted IR bands, using B3LYP/6-311G(d,p) level of theory, in the ranges 3104–3088
and 3081–3065 cm–1 are assigned to the symmetric and asymmetric CH stretching vibrations,

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respectively. The concomitant experimental band is observed at 3046 cm-1 in the FT-IR
spectrum. The CC stretching vibrations are estimated in the spectrum 1590-1564 cm-1 (FT-IR:
1558 cm-1) and 1296-1287 cm-1 (FT-IR: 1303-1281 cm-1). The in-plane C–H bending
vibrations are computed in the range 1269–1035 cm–1 and the corresponding experimental
values are found in the region 1267–1043 cm–1 in FT-IR. The out-of-plane C–H bending
vibrations are predicted in the region 949–513 cm–1 and observed in the region 933–518 cm–1
in FT-IR. These results are in agreement with previous data and literature values [36,37].
Methoxy Group Vibrations
The calculated asymmetric CH stretching vibrations of the methoxy groups occur in the
region 3037–2962 cm–1, whereas the symmetric vibrations give peaks at 2909 and 2904 cm–1.
In FT-IR, These vibrations appear at 2945 and 2842 cm–1, respectively. The C–O stretching
vibrations of the two methoxy groups are calculated at 1021 and 1018 cm−1 with a PED of 73
and 50%. This vibration gives rise to a band at 1022 cm–1 in the FT-IR spectrum. The
scissoring and rocking vibrations of CH3 groups are observed at 1467, 1438 and 1419 cm–1
and predicted between 1474 and 1421 cm–1. Besides, the out of plane vibrations are estimated
at 1132 and 1131 cm–1. The computed values are very similar to the experimental values.
Table 1
Experimental and calculated wavenumbers obtained at B3LYP functional with 6311g(d,p)
basis set.

Exp. B3LYP/6-311G (d,p) Vibrational Assignments with PED

Mode
FT-IR Unscaled Scaled Int (≥(10)%)
141 3153 3279 3171 4.63 νCH (94)
140 3121 3254 3146 1.11 νCH (94)
139 3210 3104 7.50 νCH(R1)s (88)
138 3206 3100 9.33 νCH(R2)s (87)
137 3200 3094 12.13 νCH(R1)s (90)
136 3194 3088 19.85 νCH(R2)s (84)
135 3186 3081 14.94 νCH(R1)as (97)
134 3182 3077 13.89 νCH(R2)as (88)
133 3178 3073 3.14 νC5H5 (100)
132 3172 3067 3.66 νCH(R1)as (93)
131 3046 3170 3065 0.58 νCH(R2)as (89)
130 3141 3037 16.22 ν(CH3)R1as (92)
129 3132 3029 18.23 ν(CH3)R2as (88)
128 3071 2969 31.84 ν(CH3)R1as (98)
127 2945 3063 2962 32.46 ν(CH3)R2as (95)
126 3009 2909 57.83 ν(CH3)R1s (91)
125 2842 3003 2904 52.43 ν(CH3)R2s (89)
124 1733 1788 1729 112.98 νO4=C7 (76) + νN3=C8 (10)
123 1649 1724 1667 857.21 νN3=C8 (72) + νO4=C7 (10)
122 1608 1655 1600 149.62 νC5=C6 (71) + δHCC (10)
121 1644 1590 37.42 νCC(R1) (59) + δHCC (14)
120 1632 1578 45.97 νCC(R2) (56) + δHCC (11)
119 1558 1629 1575 9.07 νCC(R1) (49) + δCCC (23)
118 1617 1564 2.71 νCC(R2) (54) + δCCC (10)

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117 1541 1603 1550 103.79 νNO2as(83)
116 1515 1579 1527 73.84 νC=C (74) + δHCC (10)
115 1490 1536 1486 111.07 νCC (41) + δHCC (10)
114 1467 1525 1474 62.59 δHCC (33) + δCCC (18)
113 1506 1456 78.57 δCH3 (47) + HCOC (16)
112 1504 1455 216.34 νCC (60)
111 1503 1454 20.59 δCH3 (54) + HCOC (12)
110 1494 1445 19.55 νCC (17) + δCH3 (50)
109 1493 1444 6.30 δCH3 (53) + HCOC (12)
108 1491 1442 8.99 δCH3 (59) + HCOC (22)
107 1438 1488 1439 3.11 νCC (18) + δHCC (58)
106 1472 1423 23.62 δHCC (75)
105 1419 1469 1421 7.57 νCC (12) + δHCC (49) + δHCH (10)
104 1375 1414 1367 1.05 νCO (54) + δHCC (22)
103 1351 1381 1336 154.81 νNC (55)
102 1372 1326 839.24 νNC (49)
101 1303 1340 1296 58.94 νCC (71)
100 1281 1331 1287 17.30 νCC (56)
99 1316 1272 88.05 δHCC (38)
98 1267 1312 1269 19.65 δHCC (21)
97 1307 1264 62.61 νOC (11) + δHCC (29)
96 1250 1293 1250 109.55 νOC (13) + δHCC (27)
95 1285 1242 125.04 νCC(24)+ νOC (22)+ δHCC (14)
94 1235 1279 1237 97.64 νCC (22) + νOC (27) + δHCC (12)
93 1261 1219 112.80 νOC (23)+ δHCC (13)
92 1243 1202 60.70 νCC (33) + νOC (11) + δCCO (16)
91 1188 1211 1171 79.38 HCOC (31)
90 1207 1167 9.81 δHCH (10) + HCOC (53)
89 1156 1202 1162 24.23 δHCC (24) + HCOC (25)
88 1187 1148 12.00 δHCC (79)
87 1184 1145 9.90 δHCC (61)
86 1182 1143 91.95 νNC (15) + δHCC (11)
85 1173 1134 85.06 νNC (27)
84 1171 1132 2.78 HCOC (64) + δHCH (11)
83 1170 1131 1.06 HCOC (67) + δHCH (17)
82 1109 1135 1097 48.98 δHCC (31) + νCC (28)
81 1134 1096 59.37 νCC (42) + δHCC (26)
80 1054 1071 1036 24.77 νCC (43) + δHCC (12)
79 1043 1070 1035 40.63 νCC (49) + δHCC (11)
78 1058 1023 39.00 νCC (16) + νOC (16)
77 1022 1055 1021 34.75 νCO (73)
76 1052 1018 30.52 νCO (50)
75 972 1036 1002 31.39 δHCC (53) + δCOC (20)
74 961 994 961 1.57 δCOC (54) + δHCC (13)
73 986 953 8.21 δCOC (45) + δHCC (35)
72 981 949 0.05 HCCC (67) + CCCC (23)
71 933 971 939 0.07 HCCC (71) + CCCC (14)
70 920 946 915 1.20 HCCC (67) + CCCC (11)
69 906 936 905 5.48 HCCC (81) + CCCC (10)
68 882 917 887 3.56 HCCC (71)
67 906 876 14.26 HCCC (68)
66 862 887 858 8.01 δOCC (11) + δNCN (10)
65 847 872 843 73.86 δCCC (22)
64 861 832 4.68 HCCC (54)
63 818 854 826 6.53 HCCC (77)
62 809 833 805 29.30 δONO (61)
61 826 799 16.06 δONO (35)
60 782 816 789 37.83 HCCC (75) + HCCC (11)
59 761 796 769 8.55 δCCC (26) + νOC (14)

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58 746 774 748 15.46 δCCC (18) + νOC (13)
57 761 736 55.30 HCCC (63) + γOCCC (12)
56 733 760 734 52.58 HCCC (78)
55 753 728 4.60 γOCNC (18)
54 748 724 2.99 γOCNC (46)
53 745 720 24.91 γOCON (76)
52 740 716 0.57 CCCC (51)
51 724 700 9.19 νSC (16) + δOCC (10)
50 668 695 672 1.34 γCCOC (61)
49 682 660 26.56 δCCC (36)
48 632 640 619 8.86 δCNC (21)
47 599 614 594 3.23 γCCCN (21) + δCCC (20) + CNCC (16)
46 613 593 39.53 δCCC (25)
45 602 582 5.59 γCCCN (12)
44 596 576 0.98 CCOC (70) + COCC (10)
43 561 575 556 5.99 CCCC (33) + δCOC (19)
42 551 570 551 23.23 δCOC (25)
41 559 541 18.66 CCCC (11) + δCCC (10)
40 556 538 6.25 CCCC (15)
39 542 524 0.36 δCNO (67)
38 518 531 513 0.38 CCCC (11)
37 493 518 501 3.76 δCOC (13)
36 500 483 26.29 νSC (21) + δCCN (13)
35 468 481 465 3.94 CCCC (22) + γOCCC (13) + δOCC (11)
34 472 456 0.89 γCCOC (52)
33 446 457 442 1.57 CCCC (41)
32 419 436 422 2.51 νNC (44) + δCCO (28)
31 387 375 0.01 δCOC (14)
30 347 335 3.37 δNCC (11)
29 344 333 1.61 CCCC (22)
28 337 325 2.56 δNCO (15) + δCNC (10)
27 314 304 1.11 γCCOC (37) + γNCOC(10)
26 301 291 1.34 CCCC (10)
25 296 287 0.24 CCCC (20) + HCOC (16)
24 275 266 5.01 δCOC (11)
23 251 243 1.68 δCOC (58)
22 242 234 1.20 δCOC (37) + HCOC(13)
21 239 231 1.64 HCOC (46) + HCOC (15)
20 227 219 2.46 HCOC (40)
19 192 186 0.11 δNCO (28)
18 184 178 0.83 CCCC (25) + δCCC (11)
17 184 178 0.10 γNCOC (54) + CCNO (11)
16 157 152 0.97 CCCC (41)
15 134 130 1.77 CCCC (27)
14 127 123 0.18 CCNO (26) + COCC (19) + γCCOC (15)
13 104 100 1.74 CCCC (14) + γCCCN (11)
12 92 89 3.94 COCC (48)
11 88 85 4.60 COCC (56) + COCC (10)
10 80 77 0.16 CCCC (31) + CCNO (23)
9 69 67 0.99 CCNO (38) + δCCO (10)
8 64 62 1.74 γNCCC (20) + δCCO (15)
7 50 49 0.72 CCNO (25) + COCC (16)
6 43 42 0.53 γNCCC (18) + δCNC (17) + δCCO (15)
5 28 27 1.88 CCNO (26) + γCCCN (14) + COCC (10)
4 27 26 1.21 δCNC (39) + δCCC (30)
3 21 20 0.16 CCNC (62)
2 15 15 0.69 CNCC (44) + CCCC (24)
1 12 11 0.46 CNCC (74)

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: Stretching, δ: Bending, : Torsion, γ: Out-of-plane,

Fig. 2. The experimental FT-IR and theoretical IR spectra of NF2MT.

The characterization of the compound was further enhanced by the use of 1H and 13C NMR
spectroscopy. The 1H and 13C NMR spectra of the title compound recorded using TMS as an
internal standard and chloroform (CDCl3) as solvent. (1H, 13C) NMR chemical shift values
(with respect to TMS [38]) were calculated with B3LYP/6-311G(d,p) level using Gauge
Independent Atomic Orbital (GIAO) approach [39,40], and compared with experimental
values. The results are collected in Table 2 together with the experimental values.
The 1H NMR spectrum showed two singlets broad signals at 3.80 and 3.89 ppm with six
protons integral due to the CH3 protons of methoxy moieties. The corresponding theoretical
values of the mentioned peaks are estimated from 3.51 to 4.01 ppm. In the 1H-NMR spectrum,
the aromatic proton signals appear as a multiplet in the region 6.57–6.75 ppm whereas the
calculated values are determined in the region 6.56–7.63 ppm. The methine proton H5
appears as a singlet at 7.41 ppm and predicted at 7.30 ppm.
The 13C-NMR spectra of the title compound show signal at 55.81 and 55.95 ppm due
to the C22 and C21 atoms of methoxy groups. These signals were measured at 55.80 ppm and
56.41 ppm, respectively. The carbon C5 of the methine bridge is observed at 113.50 ppm and
quantified at 115.86 ppm. Note that the chemical shift of the carbon C1 is deblinded 156.16
ppm experimentally and 162.26 ppm theatrically, because of direct relation of this carbon to
the nitro electro-attractor group. The peak of the carbonyl carbon atom C7 is appeared at

10

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 174.57 ppm and calculated at 169.66 ppm theoretically. As can be seen from Table 2, the
theoretical 1H and 13C chemical shift results for the title compound are in good agreement
with the experimental findings. The small shifts can be explained as a consequence of the
change in the molecular environment.

Table 2
The experimental and calculated (B3LYP/6-311G(d, p)) 1H and 13C NMR data (ppm) for
NF2MT.
1H-NMR 13C-NMR

Atoms Experimental Theoretical Atoms Experimental Theoretical

H2 7.367 7.278 C1 156.163 162.263
H3 6.754 6.636 C2 114.192 118.860
H5 7.411 7.303 C3 116.044 120.087
H11 6.897 6.805 C4 154.937 160.837
H12 7.558 7.565 C5 113.505 115.868
H13 7.143 7.159 C6 150.045 143.396
H14 7.489 7.386 C7 174.575 169.665
H17 6.871 6.777 C8 152.205 156.210
H18 7.194 7.201 C9 128.348 132.663
H19 7.083 7.003 C10 165.160 164.082
H20 6.960 6.891 C11 112.169 113.761
H21a 3.802 3.513 C12 129.810 136.371
H21b 3.802 3.724 C13 121.171 124.905
H21c 3.892 4.076 C14 131.166 137.281
H22a 3.802 3.685 C15 136.798 143.148
H22b 3.892 3.747 C16 150.533 155.978
H22c 3.892 4.056 C17 112.527 113.824
C18 126.274 130.545
C19 121.771 125.825
C20 123.037 129.200
C21 55.957 56.414
C22 55.816 55.801

3.3. Topological features: RDG analysis and AIM analysis

In a molecular system intra-and inter non-bonded interactions can be explored using the
reduced density gradient (RDG) analysis based on the electron density and its derivatives
[41,42]. These interactions and their graphical visualization are obtained as follows:
1 |∇𝜌(𝑟)|
𝑅𝐷𝐺(𝑟) = 1/3
2(3𝜋𝑟2) 𝜌(𝑟)4/3
where 𝜌(𝑟) and ∇𝜌(𝑟) are the electron density and the gradient of 𝜌(𝑟) at the point r,
respectively. The graphical representation of 𝜌(𝑟) versus sign(λ2)ρ provides useful
information regarding the strength and nature of the interactions, where sign(λ2)ρ is the
second eigenvalue of the electron density. To explain the nature of interactions the value and
sign of sign(λ2)ρ are used. The attractive, repulsive and Van der Waals interactions

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correspond to sign(λ2)ρ < 0, sign(λ2)ρ > 0 and sign(λ2)ρ  0, respectively. The 2D scatter
plot and the 3D RDG isosurface densities of the title compound are shown in Fig. 3. As can
be seen in this figure, the red region indicates strong repulsive interactions mainly observed in
centers of thiazole, furan and aromatic rings. Whereas, the green region is recognized as
intermediate interactions or Van der Waals weak attractive interactions due to H⋅⋅⋅H
interaction. Furthermore, the strong steric effect is marked by the red color. RDG analysis
confirms the previous results obtained by the HS analysis to identify interacting regions in the
molecular packing of the title compound [22]. As previously reported on this molecule, the
Hirshfeld surface and RDG analyses are in good agreement. Therefore, the interacting regions
in the molecular packing are highlighted by the RDG analysis.

Fig. 3. 2D scatter and isosurface density plots illustrating the non-bonded interactions for NF2MT

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 Topological properties such as electron density ρ(r) and its Laplacian ∇2ρ(r),
eigenvalues (1, 2 and 3)of the Hessian matrix 1/3 ratio and bond ellipticity (ɛ) are very
important parameters due to their ability to describe various intra- and intermolecular
interactions in a molecular system [43, 44]. These parameters are used to quantify and
understand the nature of the interactions. Therefore, to investigate the topological properties
of the title compound additional calculations using Bader’s theory of atoms in molecules
(AIM) [45] were performed in the gas phase at the same level of theory as geometry
optimization. These properties are calculated in the bond critical points (BCPs) and ring
critical points (RCPs) by using Multiwfn software. The AIM analysis results of the BCPs and
RCPs for the title compound in gas phase at the B3LYP/6-31G(d,p) level of theory are
summarized in Table 3. Figure 4(a) displays the molecular graphics of the title compound in
gas phase showing the geometry of all BCPs and RCPs and exhibiting two BCPs
(C1O3···S1 and C22O6···S1), four RCPs (RCP1, RCP2, RCP3 and RCP4) and the new
RCPN1 and RCPN2, and Figure 4(b) displays the 3D interbasin solid surfaces of all critical
points of the molecule. The BCPs are identified in red color and the RCPs in yellow. The
graphical description of QTAIM analysis of the title compound confirms the existence of
BCPs between S1 and O6 atoms, and between S1 and O3 atoms as shown in Figure 4(a).
These two weak non-covalent interactions are characterized by the distances 3.2399 and
2.9655 Å. The nature of the weak interaction between non-bonded atoms is confirmed by the
above RDG analysis. As previously defined by Koch and Popelier criteria [46], charge density
values for the two BCPs are in the range of 0.002–0.040 a.u. On the other hand, the most
important value for ρ(r) is noted for RCP4 (0.0531 a.u.). The four RCP1, RCP2, RCP3 and
RCP4 have eigenvalues of the Hessian matrix with positive signs, as can be seen in Table 3. If
1/3  1 and 2(r)  0 the interaction is ionic and closed-shell nature of the interaction. The
positive value of the 2(r) also means a charge depletion at the BCPs [47]. The ellipticity ()
at BCP is defined as a sensitive index to monitor the  character of bonds and is related to 1
and 2. Lower values of  confirm that there is electron delocalization in aromatic ring. As
depicted in Table 3, the two BCPs have lower positive values of  (0.6402 and 0.0812 a.u.)
indicating the structure stability.

Table 3
Analysis of the Bond Critical Points (BCPs) and Ring critical point (RCPs) for the title
compound in gas phase by using B3LYP/6-31G(d,p) calculations.
Parameters# (r) 2(r) 1 2 3 1/3  Distance (Å)

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RCP1 0.0207 0.1566 0.0900 0.0153 0.0819 1.0989 1.1866
RCP2 0.0205 0.1553 0.0149 0.0805 0.0897 0.1661 1.1859
RCP3 0.0325 0.2125 0.1332 0.1075 0.0282 4.7234 1.2619
RCP4 0.0531 0.3621 0.2062 0.2137 0.0579 3.5613 1.2805
RCPN1 0.0081 0.0335 0.0036 0.0345 0.0046 0.7826 2.2804
RCPN2 0.0101 0.0500 0.0456 0.0110 0.0066 6.9091 1.5964
BCP1 0.0084 0.0307 0.0033 0.0396 0.0055 0.6000 0.6402 3.2399
BCP2 0.0113 0.0419 0.0568 0.0071 0.0077 7.3766 0.0812 2.9655

# Parameters are in a.u.

(a)

(b)

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 Fig. 4. Molecular graphic of the title compound in gas phase showing the geometry of bond critical points
(BCPs) and ring critical points (RCPs) at the B3LYP/6-31G(d,p) level of theory: (a) BCPs (3,1) and RCPs
(3,+1) details, and (b) 3D interbasin solid surfaces.

3.4. Chemical stability and electronic transitions

3.4.1. Frontier molecular orbitals and global chemical reactivity descriptors
The highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital
(LUMO) represent the ability to donate and accept an electron, respectively. These orbitals
known as Frontier molecular orbitals (FMOs) are particularly important to predict the
chemical stability and the reactivity of organic compounds [48,49]. The HOMO, LUMO,
band gap and dipole moment of the title molecule are listed in Table 4. The distribution of
HOMO and LUMO orbitals for the ground state and the density of state spectrum (DOS) are
shown in Figure 5(a) and 5(b), respectively. The green and the red lines in the DOS designate
the occupied and unoccupied molecular orbitals, respectively. The DOS analysis indicates that
the energy band gap is about 2.771 eV obtained with B3LYP/6-311G(d,p) level of theory.
This low value reveals that the title molecule is a soft molecule, more polarizable and is
generally related with a high chemical reactivity [50]. The distribution of FMOs shows that
the HOMO is concentrated over the methoxy phenyl ring and the imino fragment whereas the
LUMO is concentrated over the nitrofuran, methylene and the imino thiazolidinone moieties.
It is well known that chemical reactivity and strength of structure relationship can be
highlighted by calculating the global chemical reactivity descriptors (GCRD) parameters.
These parameters (ionization potential, electron affinity, electronegativity, chemical potential,
hardness, softness and electrophilicity index ) can be obtained using general equations
reported in the literature [51-53]. The GCRD computed values for the title molecule are listed
in Table 4. From Table 4, the electrophilic behavior of the molecule is confirmed by the
global electrophilicity index () which has a greater value of 7.1025 eV. On the other hand,
the chemical stability of the title molecule is explained by the chemical potential (P) value
which is 4.4365 eV. The chemical hardness () low value of 1.3856 eV can indicate that the
charge transfer is occurring within the molecule.
The hyper-hardness () descriptor was introduced previously to describe the structure-
property relationship of organic molecules and to investigate their theoretical reactivity or
stability [54]. The following equation was used to calculate the hyper-hardness (Γ):
 = ELUMO  2EHOMO + EHOMO1

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As reported in Table 4, in addition to the chemical potential value, the stability of the title
molecule is also confirmed by the positive value of Γ (+2.2909 eV).

Table 4
Calculated energy values of NF2MT by B3LYP/6-311G(d,p) level of theory.
Parameters Calculated energies
E (a.u.) 1862.6
EHOMO (eV) 5.8221
ELUMO (eV) 3.0509
EHOMO1 (eV) 6.3024
ΔEHOMOLUMO (gap) (eV) 2.7712
Dipole Moment () (Debye) 3.9463
Ionization potential (I) 5.8221
Electron affinity (A) 3.0509
Electronegativity () 4.4365
Chemical potential (P) 4.4365
Chemical hardness () 1.3856
Chemical softness (s) 0.3608
Electrophilicity index () 7.1025
Hyper-hardness (Γ) 2.2909

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 Fig. 5. HOMO-LUMO plot(a) and total density of states (TDOS) diagram (b) for NF2MT

3.4.2. Absorption Spectra

Time-dependent density functional theory currently remains the most mature tool to interpret
and predict the optical spectra of organic, inorganic, and biological molecules [55,56]. The
experimental UV-Visible spectrum of NF2MT was measured in chloroform. The electronic
transitions of NF2MT were investigated by the TD-DFT method employing CAM-B3LYP
functional and 6-311G(d,p) basis set. The chloroform solvent effect was considered using the
Polarized Continuum Model (CPCM). The collected results (vertical excitation energies,
transition wavelength, oscillator strength (f) and contributions) are given in Table 5. The
resultant UV-visible absorption spectrum and the experimental one are illustrated in Figure 6.
As indicated in Fig. 6(a), there are two peaks at 278.61 and 396.33 nm. The proportionate
calculated absorption peaks (Fig. 6(b)) are found at  = 269.72 nm, f = 0.4239 and  =
383.01 nm, f = 0.6376. These two peaks correspond to n and  transitions,
respectively. The experimental and simulated UV-Vis peaks are in good agreement
with each other. From Table 5, we can see that the highest value of transition wavelength
(=383.01 nm) is described by the HOMO1  LUMO and HOMOLUMO transitions
with contributions of 74% and 21%, respectively. Furthermore, the transition found at 269.72
nm containsHOMO1  LUMO+1 (59%) and HOMO  LUMO+1 (15%) transitions.

Table 5
Absorption spectrum data obtained by TD-DFT method with B3LYP/6-311g(d,p) basis set
(contribution≥10%)
Electronic transitions abs (nm) Eex (ev) F MO Contributions
S0S1 383.01 3.2371 0.6376 HOMO1  LUMO (74%)
HOMO  LUMO (21%)

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S0S2 339.90 3.6476 0.0581 HOMO  LUMO (66%)
HOMO1  LUMO (20%)
S0S3 308.71 4.0162 0.0000 HOMO9  LUMO (71%)
HOMO9  LUMO+1 (25%)
S0S4 288.68 4.2949 0.0061 HOMO2  LUMO (79%)
S0S5 275.43 4.5015 0.0008 HOMO14  LUMO (69%)
HOMO14  LUMO+1 (24%)
S0S6 274.59 4.5152 0.0627 HOMO3  LUMO (38%)
HOMO7  LUMO (17%)
S0S7 269.72 4.5967 0.4239 HOMO1  LUMO+1 (59%)
HOMO  LUMO+1 (15%)
S0S8 262.79 4.7180 0.0232 HOMO3  LUMO (39%)
HOMO7  LUMO (23%)
HOMO7  LUMO+1 (10%)
S0S9 259.34 4.7808 0.0213 HOMO  LUMO+2 (23%)
HOMO  LUMO+1 (17%)
HOMO  LUMO+3 (14%)
HOMO1  LUMO+1 (13%)
S0S10 252.42 4.9119 0.1362 HOMO6  LUMO (57%)
HOMO4  LUMO (15%)

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 Fig. 6. Experimental (a) and simulated (b) UV-Vis spectra of NF2MT.

3.5. Molecular Properties : Mulliken and NBO Charges and Molecular

Electrostatic Potential
Atomic charge calculations play an important role in the description of the electron
distribution in molecular systems [57,58]. The calculated Mulliken and NBO charge values
using the B3LYP/6-311G(d,p) level of theory are listed in Table 6. The results of Table 6
reveals that the two analyses predict the same tendencies and the NBO charges are slightly
longer than Mulliken charges. All hydrogen atoms have net positive charges. Thus, all carbon
atoms connected to these electropositive atoms exhibit negative charges. The other carbon
atoms have positive charges due to the electronegativity of the oxygen and nitrogen atoms
attached. The oxygen (O4) and carbon (C14) atoms of the carbonyl group have the highest
negative and positive charge values, respectively.

Table 6
Mulliken and NBO atomic charges of NF2MT using B3LYP/6-311g(d,p) level of theory.
B3LYP /6-31G (d,p) B3LYP /6-31G (d,p) B3LYP /6-31G (d,p)
Atoms Atoms Atoms
Mulliken NBO Mulliken NBO Mulliken NBO
S1 0.289 0.353 C8 0.260 0.381 H5 0.141 0.247
O1 -0.283 -0.393 C9 0.086 0.110 H11 0.108 0.211
O2 -0.262 -0.370 C10 0.240 0.347 H12 0.097 0.203
O3 -0.254 -0.443 C11 -0.126 -0.286 H13 0.096 0.206
O4 -0.327 -0.575 C12 -0.076 -0.167 H14 0.092 0.214
O5 -0.346 -0.519 C13 -0.105 -0.222 H17 0.106 0.209
O6 -0.356 -0.531 C14 -0.002 -0.163 H18 0.092 0.201
N1 0.146 0.477 C15 -0.028 0.095 H19 0.091 0.203

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N2 -0.486 -0.485 C16 0.208 0.307 H20 0.090 0.210
N3 -0.317 -0.485 C17 -0.124 -0.283 H21a 0.131 0.187
C1 0.360 0.392 C18 -0.088 -0.190 H21b 0.112 0.164
C2 -0.091 -0.232 C19 -0.099 -0.218 H21c 0.118 0.169
C3 -0.109 -0.255 C20 -0.035 -0.194 H22a 0.128 0.184
C4 0.183 0.318 C21 -0.132 -0.194 H22b 0.109 0.162
C5 -0.039 -0.245 C22 -0.134 -0.195 H22c 0.121 0.170
C6 -0.374 -0.227 H2 0.137 0.245
C7 0.533 0.683 H3 0.119 0.230

The molecular electrostatic potential (MEP) is a very useful descriptor for identifying the
electrophilic and nucleophilic sites of organic molecules. The MEP is used to investigate the
chemical reactivity and to understand the process of biological recognition [59-61]. The
negative (red and yellow) regions of MEP were related to electrophilic reactivity and the
positive (blue) regions to nucleophilic reactivity. The importance of this later lies in the fact
that it simultaneously displays molecular size, shape and positive, negative and neutral
electrostatic regions in terms of color grading and is very helpful in the research of molecular
structure with its physicochemical property relationship [62-64]. To identify reactive regions
for electrophilic and nucleophilic attack for the title molecule, MEP at the B3LYP/6-31(d,p)
optimized geometry was calculated and the corresponding map is shown in Figure 7. As seen
in Figure 7, evidently the most negative potentials are located on the oxygen atoms of the
nitrophenyl and thiazolidinone moieties with a minimum value of -135.5 KJ/mol. However,
the maximum positive potentials are distributed on the hydrogen atoms around phenyl cycles
with a maximum value of 135.5 KJ/mol.

Fig. 7. The MEP map calculated with B3LYP\6-311G(d,p) level of theory.

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3.6. Molecular Docking Methodology
Chemical Computing Inc., MOE: 2017 software has been employed to import, optimize
and dock the molecular structure of NF2MT compound. Molecular structures of NF2MT were
imported and optimized using MM force field and entered structures in MOE database. The
optimized X-ray crystallographic structure of Acetylcholinesterase (PDB ID: 2X8B), with
XRD resolution of 2.95 Å and Butyrylcholinesterase (PDB ID :1XLW) with XRD resolution
of 2.1 Å was obtained from protein data bank [65,66] and imported into MOE visualize for
docking simulation. All water molecules were removed macromolecular system. Before
docking simulations, 2X8B and 1XLW were protonated 3D with minimum energy state using
the MOPAC 7.0 and amber force field. After pre-preparation of 2X8B and 1XLW as well as
NF2MT, X-ray structure of 2X8B and 1XLW were allowed to dock with the optimized
NF2MT molecule under default parameters with RMS gradient of 0.01 kcal/mol. A number of
docked conformations and docking poses were recorded based on lowest free energy values.
The docked conformation having minimum energy and maximum stability was selected as a
final docking pose [67].
3.7. DNA-Binding Studies by Molecular Docking
Molecular docking is exploited as a theoretical method to comprehend noncovalent
interactions between small molecules and enzymes. Molecular docking technique is most
suitable and reliable methods for structure-based drug designing [68,69]. It is frequently
valuable for the selection of compound that can significantly bind with macromolecules i.e
DNA and enzymes to further utilize computationally screened compound for experimental
studies [70].
The possible interactions of NF2MT with acetylcholinesterase (PDB ID :2X8B), and
Butyrylcholinesterase (PDB ID :1XLW) were investigated using molecular docking
methodology. The lowest energy docked conformations of the NF2MT has been depicted in
Figure 8 in the form of pose view images. Blue blurred portions present at the right side of
Figure 8 indicated the direct exposure of compounds with the residues of acetylcholinesterase
and Butyrylcholinesterase, whereas presence of dotted lines in the shape of curves revealed
solvent contact with the compound-1. The investigations of docked structures specified that
NF2MT interacted with both enzymes through arene-arene, hydrophobic and Van der Waal’s
interactions with NF2MT Figure 8 (left). acetylcholinesterase interacted with compound-1 via
developing arene interaction of its aromatic ring of Trp (385) residue with five membered
furan ring of compounds. On the other hand, Butyrylcholinesterase demonstrated only Van
der Waal’s interactions with NF2MT but it fitted well into binding pocket of

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Butyrylcholinesterase containing a number of residues at close proximity being Ser(235),
Glu(238), Val(233), Tyr(396), Ala(232), Thr(234), Ser(287), Phe(357), Thr(287), Gly(360),
Val(361). Highest binding constant (Kb) was found to be for Butrylcholinesterae which
possesses perfect binding pocket for NF2MT molecules (Table 7).For the comprehension of
macroscopic interaction, the electronic, as well as steric descriptors, which have been
calculated on the basis of molecular docking data, are listed in Table 8.
It is well established that EHOMO and ELUMO give an extent of electron donating and
accepting nature of a species. Compounds having more significant value of EHOMO, have a
greater tendency to donate electrons and those compounds which have a low value of ELUMO,
have grander tendency to accept electrons. Hence in case of Actyl Cholinesterase NF2MT has
greater EHOMO and lesser ELUMO revealing that when NF2MT acts electron donor, its binding
strength is decreased whereas while interaction with Butyrylcholinesterase NF2MT is acting
as electron acceptor withdrawing electrons from electron rich enzyme residues leading to the
higher binding affinity of NF2MT with Butyrylcholinesterase residues (Table 8). Calculated
steric descriptor included like molar refractivity (MR), heat of formation (Hf) and hydrophobic
surface volume (Vsurf). MR, which is a measure of the polarizability of the molecule and is
directly related with the binding strength, was higher for Butyrylcholinesterase illustrating the
greater binding strength of Butyrylcholinesterase with NF2MT compound, Table 8, [71]. The
lesser positive value of heat of formation (Hf) for Butyrylcholinesterase further ratified the
comparably stable and stronger complex formation of Butyrylcholinesterase with NF2MT,
Table 9. It was also observed that the value of hydrophobic surface volume (Vsurf) is
comparatively greater for Butyrylcholinesterase than Actyl Cholinesterase due to the greater
contact of the hydrophobic surface of the compound NF2MT with Butyrylcholinesterase.
Greater hydrophobic connection is ascribed to the greater overlapping of compound NF2MT
with more enzyme residues.

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Fig. 8. Pose view analysis of molecular docked complexes of (a) Acetylcholinesterase, (c) Butyrylcholinesterase
with NF2MT and their ligplots (b and d) calculated at PM3 semi-empirical level.

Table 7
Binding constants and free energy values for the ds.DNA complexes calculated from
molecular docking data.
Molecular docking
Complex code
“Kb”/ M-1 (-∆G) KJmol-1
Acet –NF2MT 2.42 × 106 -36.42
Buty–NF2MT 3.96 × 106 -37.65

Table 8
Data set of electronic descriptors calculated from molecular docking data.
Complexes EHOMO ELUMO Eele Evander EIP ETotal
(kcal/mol) (kcal/mol) (kcal/mol) (kcal/mol) (kcal/mol) (kcal/mol)
Acet-NF2MT -8.8967 -1.7942 -693708.0 12.6166945 8.8967 -122140.09
Buty-NF2MT -9.1195 -1.8492 -1179573 12.9227018 9.1195 -122142.41

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Table 9
Data set of steric descriptors calculated from molecular docking data.
Complexes Hf (kcal/mol) MR Slog P Vsurf Dipole
Acet-NF2MT -7.3667 12.1500 5.0136 442.1647 4.3368
Buty-NF2MT -9.6900 297.2120 5.0136 632.542 7.5059

4. Conclusions
We reported thiazole derivative, 5-(5-nitro furan-2-ylmethylen), 3-N-(2-methoxy
phenyl),2-N'-(2-methoxyphenyl) imino thiazolidin-4-one (abbreviated by NF2MT), was
characterized through Fourier transform infrared, UV-Vis, 1H and 13C nuclear magnetic
resonance (NMR) spectroscopy. Theoretical and experimental FT-IR spectra were analyzed in
light of major band assignments with their contributions to the vibrational spectrum. We
performed a toplogical analysis of the molecular system intra-and inter non-bonded
interactions by investigating the reduced density gradient (RDG) found in good agreement
with Hirshfeld surface. We completed this analysis with Bader’s theory of atoms in molecules
(AIM) that were performed in the gas phase. The nature of the weak interaction between non-
bonded atoms was confirmed by the RDG analysis. Furthermore, the charge density
investigation has revealed delocalization in aromatic ring and structure stability. The
calculation of Frontier molecular orbitals and the orbitals (HOMO, LUMO) have suggested
that the investigated molecule is soft, polarizable and exhibit a high chemical reactivity. The
calculation of electrophilicity index was estimated to 7.1025 eV. Molecular docking was
employed as a theoretical method to comprehend noncovalent interactions between small
molecules and enzymes, mainly with acetylcholinesterase, and Butyrylcholinesterase were
investigated to find the lowest energy docked conformations.

Acknowledgments
The authors gratefully acknowledge the financial support via PRFU project from The
Algerian Ministry of Higher Education and Scientific Research, the Directorate General of
Scientific Research and Technological Development (DGRSDT), and Abdelhamid Ibn Badis
University of Mostaganem. S. Goumri-Said thank the office of research at Alfaisal University
in Saudi Arabia for funding this research work through internal project number C20431.

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