Spectroscopic and reactive properties of a newly synthesized quinazoline derivative: Combined experimental, DFT, molecular dynamics and docking study

Article abstract of DOI:10.1016/j.molstruc.2017.01.032

The molecular geometry, the normal mode wavenumbers and corresponding vibrational assignments, natural bond orbital analysis and the HOMO-LUMO analysis of 3-(4-oxo-phenethyl-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)propanamide were performed by B3LYP level of theory using the 6-311++G(d,p)(5D,7F) basis set. The experimentally obtained wavenumbers are in agreement with the theoretically predicted wavenumbrs. From the MEP plot it is evident that the negative charge covers carbonyl group, mono substituted phenyl ring, O₅₉ atom and the positive region is over the nitrogen atoms and hydrogen atoms. NLO behavior of the title molecule was investigated by the determination of the first and second order hyperpolarizabilities. The molecular orbitals and molecular electrostatic potential map are also reported. The NMR spectra and Fukui indices are also analyzed. Molecule sites important from the aspect of reactivity have been determined by calculations of average local ionization energy (ALIE), Fukui functions and bond dissociation energies (BDE). BDE for hydrogen abstraction served us to investigate the possibility for autoxidation mechanism of the investigated molecule. Molecular dynamics (MD) simulations were used in order to investigate which atoms of the title molecule have the most pronounced interactions with water molecules. Molecular docking studies reveal that the inhibitor forms a stable complex with HNE as is evident from the binding affinity ?10.9 kcal/mol and the results suggest that the compound exhibit inhibitory activity against HNE.

Full text of DOI:10.1016/j.molstruc.2017.01.032

Accepted Manuscript
Spectroscopic and reactive properties of a newly synthesized quinazoline
derivative: Combined experimental, DFT, molecular dynamics and docking study
Adel S. El-Azab, Shyma Mary Y, Sheena Mary Y, C.Yohannan Panicker, Alaa A.-
M. Abdel-Aziz, Menshawy A. Mohamed, Stevan Armaković, Sanja J. Armaković, Christian Van
Alsenoy
PII:
S0022-2860(17)30032-7
10.1016/j.molstruc.2017.01.032
MOLSTR 23337
DOI:
Reference:
To appear in:
Journal of Molecular Structure
Received Date:
Accepted Date:
10 September 2016
08 January 2017
Please cite this article as: Adel S. El-Azab, Shyma Mary Y, Sheena Mary Y, C.Yohannan Panicker,
Alaa A.-M. Abdel-Aziz, Menshawy A. Mohamed, Stevan Armaković, Sanja J. Armaković, Christian
Van Alsenoy, Spectroscopic and reactive properties of a newly synthesized quinazoline derivative:
Combined experimental, DFT, molecular dynamics and docking study, Journal of Molecular
Structure (2017), doi: 10.1016/j.molstruc.2017.01.032
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Highlights




IR, Raman, NMR spectra and NBO analysis were reported.
Most reactive sites are predicted by using MEP plot
BDEs are calculated to investigate autoxidation and degradation properties
The compound might exhibit inhibitory activity against HNE

ACCEPTED MANUSCRIPT
Spectroscopic and reactive properties of a newly synthesized quinazoline derivative:
Combined experimental, DFT, molecular dynamics and docking study
a,b
c
c
c,d
Adel S.El-Azab , Shyma Mary Y , Sheena Mary Y *, C.Yohannan Panicker , Alaa A.-
a,e
b,f
g
h
M. Abdel-Aziz , Menshawy A. Mohamed , Stevan Armaković , Sanja J. Armaković ,
Christian Van Alsenoyi
aDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University,
Riyadh 11451, Saudi Arabia
bDepartment of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo
1
1884, Egypt
cDepartment of Physics, Fatima Mata National College, Kollam, Kerala, India.
dDepartment of Physics, TKM College of Arts and Science, Kollam, Kerala, India.
eDepartment of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura,
Mansoura, Egypt
fDepartment of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin
Abdulaziz University, AlKharj, Saudi Arabia
gUniversity of Novi Sad, Faculty of Sciences, Department of Physics,
Trg D. Obradovića 4, 21000 Novi Sad, Serbia
hUniversity of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry
and Environmental Protection, Trg D. Obradovića 3, 21000 Novi Sad, Serbia
iDepartment of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020
Antwerp, Belgium
*
author for correspondence: email: sypanicker@rediffmail.com
Abstract
The molecular geometry, the normal mode wavenumbers and corresponding vibrational
assignments, natural bond orbital analysis and the HOMO-LUMO analysis of 3-(4-oxo-
phenethyl-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)propanamide were
performed by B3LYP level of theory using the 6-311++G(d,p)(5D,7F) basis set. The
experimentally obtained wavenumbers are in agreement with the theoretically predicted
wavenumbrs. From the MEP plot it is evident that the negative charge covers carbonyl
group, mono substituted phenyl ring, O59 atom and the positive region is over the
1

ACCEPTED MANUSCRIPT
nitrogen atoms and hydrogen atoms. NLO behaviour of the title molecule was
investigated by the determination of the first and second order hyperpolarizabilities. The
molecular orbitals and molecular electrostatic potential map are also reported. The NMR
spectra and Fukui indices are also analyzed. Molecule sites important from the aspect of
reactivity have been determined by calculations of average local ionization energy
(ALIE), Fukui functions and bond dissociation energies (BDE). BDE for hydrogen
abstraction served us to investigate the possibility for autoxidation mechanism of the
investigated molecule. Molecular dynamics (MD) simulations were used in order to
investigate which atoms of the title molecule have the most pronounced interactions with
water molecules. Molecular docking studies reveal that the inhibitor forms a stable
complex with HNE as is evident from the binding affinity -10.9 kcal/mol and the results
suggest that the compound exhibit inhibitory activity against HNE.
Keywords: DFT; IR and Raman; BDE; RDF; Quinazoline; Molecular docking.
1
.
Introduction
Quinazolines repesent the most interesting group of heterocycles that contain
pyrimidine nucleus in their structure, which exhibit various biological activities including
containment of inflammatory disorders such as osteoarthritis [1], inflammatory bowel
syndrome [2] and neuro-degenerative impairments [3], invoking interest in synthesis of
their analogs. Al-Suwaidan et al. [4] reported the synthesis and biological evaluation of
2
-substituted-3-((4-oxo-3-phenethyl-3,4-dihydroquinazolin-2-yl)thio)-N-(3,4,5-tri
methoxyphenyl)propanamide as anticancer agents. Quinazolinones are associated with a
wide range of biological and pharmacological activies such as analgesic [5], anti-
inflammatory [6], antifungal [7, 8], antiviral [9] and antihistaminic activities [10, 11].
Olgen et al. [12] reported the antimicrobial and antiviral screening of novel indole
carboxamide and propanamide derivatives. Naqvi et al. [13] reported the design,
synthesis and molecular docking of substituted 3-hyrazinyl-3-oxo-propanamides as anti-
tubercular agents. In the present work, IR and Raman spectra of the title ocmpound are
reported both experimentally and theoretically. The natural bonding orbital analysis,
molecular electrostatic potential, first and second hyperpolarizability studies are also
reported. Due to the different potential biological activity of the title compound,
molecular docking of the title compound is also reported.
2

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Emerging organic pollutants such as pharmaceutical care products represent great
threat for the environment. Great attention is paid to the synthesis of new biologically
active molecules which serve as the active components in new drugs. Their frequent
usage has led to the fact that representatives of this class of compounds have been
detected in all types of water all over the world [14]. These molecules are synthesized to
be very stable, because of which conventional water purification methods are not
effective [15,16], while in the same time advanced oxidation processes are seen as an
alternative [14,15, 17,18]. Systematic investigation of reactive properties of newly
synthesized biologically active molecules is prerequisite for the development of water
purification methods. In this regard forced degradation studies very useful, but in the
same time they are long and expensive procedures. DFT calculations and MD simulations
present effective and inexpensive tools for optimization and rationalization of reactivity
studies related to biologically active molecules [19-22].
2
.
Experimental details
A mixture of 2-mercapto-3-phenethylquinazolin-4(3H)-one (2 mmol, 564 mg)
and 3-chloro-N-(3,4,5-trimethoxyphenyl)propanamide(2.1 mmol, 575 mg) in 15 ml
acetone containing anhydrous potassium carbonate (3 mmol, 415 mg) was stirred at room
temperature for 12 h. The reaction mixture was filtered, the solvent was removed under
reduced pressure and the solid obtained was dried and recrystallized from ethanol. Mp:
0
+
2
16-218 C, yield 93%, MS: M =519. The FT-IR spectrum (Fig.1) was recorded using
KBr pellets on a DR/Jasco FT-IR 6300 spectrometer. The FT-Raman spectrum (Fig.2)
was obtained on a Bruker RFS 100/s, Germany. For excitation of the spectrum the
emission of Nd:YAG laser was used, excitation wavelength was 1064 nm, maximal
power was 150 mW and measurement was carried out on solid sample. Nuclear
1
13
magnetic resonance ( H and C NMR) spectra were recorded on Bruker 500 MHz
spectrometer using CDCl as solvernt; the chemical shifts are expressed in δ ppm using
3
TMS as internal standard.
3
.
Computational details
Calculations of the title compound were carried out using Gaussian 09 software
[23] by using B3LYP/6-311++G(d,p)(5D,7F) basis set [24, 25] and the theoretically
predicted wavenumbers are multiplied by a scaling factor of 0.9613 [26]. The optimized
3

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geometrical parameters (Fig.3) are given in Table 1. The assignments of the wave
numbers are done by GAUSSVIEW program [27] and the potential energy distribution
(PED) is calculated with the help of GAR2PED software package [28]. Jaguar 9.0
program [29], as implemented in Schrödinger Materials Science Suite 2015-4, was used
for the DFT calculations of average local ionization energy (ALIE) surfaces, Fukui
functions and bond dissociation energies (BDE), while Desmond program [30-33] was
used for MD simulations and calculations of radial distribution functions (RDFs). In
cases of DFT calculations B3LYP exchange-correlation functional [34] was used with 6-
3
11++G(d,p), 6-31+G(d,p) and 6-311G(d,p) basis sets, respectively, for calculations of
ALIE, Fukui functions and BDEs. For MD simulations OPLS 2005 force field [35] was
employed with simulation time of 10 ns and withisothermal–isobaric (NPT) ensemble
class. Modeling of system was performed by placing one title compound molecule in the
cubic box with ~3000 water molecule. The value of cut off radius was set to 12 Å, while
temperature and pressure were set to 300 K and 1.0325 bar, respectively. Simple point
charge (SPC) model [36] was used for the description of solvent. Noncovalent
interactions were determined with the help of method by Johnson [37, 38], which is also
implemented in Jaguar 9.0 program.
4
.
Results and discussion
In the following discussion, the mono, poly, ortho-substituted phenyl rings are designated
as PhI, PhII and PhIII respectively and the quinazoline ring as PhIV.
4
.1.
Geometrical parameters
In the phenyl rings of the title compound, the C-C bond lengths lie in the range
1
.3937-1.3997Å for PhI, 1.3928-1.4046Å for PhII and 1.3833-1.4090Å for PhII, which
are in agreement with the reported values [39]. The bond lengths of C -N (1.3822Å),
5
3
C -N (1.3857Å), C -N (1.4155Å), C -N (1.4252Å) and C -N (1.3780Å) are
3
3
4
15
4
40
39
37
39
shorter than the normal C-N bond length (1.48Å) and this shows the effect of resonance
in this region of the molecule [40]. The shortening of the bond length of C -O
2
1
5
(
1.2205Å) and C -O (1.2197Å) shows a double bond character. The C-O bond lengths
37 38
of the title compound are C -O =1.3707Å, C -O = 1.4361Å, C -O = 1.3737Å, C -
4
6
54
55
54
47
49
50
O = 1.4392Å, C -O = 1.3713Å and C -O = 1.4378Å and all the C-O bond lengths
4
9
45
59
60
59
4

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are greater than the average distance of 1.362Å [41] which is due to hydrogen bonding in
the molecule [42].
In the title compound, the C-S bond lengths are 1.7846 and 1.8383Å while the
reported values are in the range 1.7675-1.8641Å [43] and 1.7710-1.8110Å [44]. At C22
position, the bond angles are C -C -C = 118.6˚, C -C -C = 120.7˚ and C -C -C
3
1
22
23
31
22
19
23
22
19
=
120.7˚ and the reduction in the angle C -C -C is due to presence of adjacent
31 22 23
methylene groups. At N position, the bond angles C -N -C is increased by 1.0˚, C -
4
33
4
15
33
N -C is increased by 2.6˚ and C -N -C is decreased by 3.6˚ from 120˚ and this is due
4
16
15
4
16
to the interaction between O and the methylene at C position. At C position, the bond
2
16
15
angles, N -C -C is decreased by 5.4˚ and C -C -O is increased by 5.0˚ from 120˚ and
4
15
14
14
15
2
this variation is due to the interaction between O and the adjacent methylene groups.
2
Similarly at C position, the bond angles C -C -C = 118.9˚, N -C -C = 119.1˚ and C -
5
6
5
14
3
5
6
14
C -N = 122.0˚ and this asymmetry in angles is due to the interaction between the
5
3
quinazoline ring and PhIII ring. Similarly at C position, the bond angles N -C -N =
3
3
3
33
4
1
24.9˚ and N -C -S = 115.6˚ and this asymmetry in angles is due to the interaction
4 33 1
between the quinazoline ring and adjacent moieties. Similarly at N position, the bond
3
9
angles C -N -C = 130.1˚, C -N -H = 117.1˚ and C -N -H = 112.6˚ and this
4
0
39
37
40
39
48
37
39
48
asymmetry in angles is due to the interaction between the NH group and the oxygen atom
O . The quinazoline moeity is planar with respect to the phenyl ring PhIII, as is evident
3
8
from the torsion angles C -C -N -C = -179.6˚, C -C -C -C = -179.9˚, C -C -C -N
4
6
5
3
33
6
5
14
15
12
14
15
=
179.1˚ and C -C -C -N = 179.9˚ and the CH groups at C and C are tilted from
12 14 5 3 2 19 16
the phenyl ring PhI, as is evident from the torsion angles, C -C -C -C = -178.5˚, C -
2
9
31
22
19
31
C -C -C = 89.7˚, C -C -C -C = 178.5˚ and C -C -C -C = -88.7˚. The
2
2
19
16
25
23
22
19
23
22
19
16
propanamide group is tilted from the phenyl ring PhII according to the torsion angles,
C -C -C -N = -178.7˚, C -C -N -C = -60.4˚, C -C -C -N = 177.7˚ and C -
4
6
42
40
39
42
40
39
37
45
41
40
39
41
C -N -C = 121.6˚.
4
0
39
37
4
.2.
IR and Raman spectra
The calculated (scaled) wave numbers, observed IR, Raman bands and
assignments are given in table 2.
For the title compound, the CH stretching modes of the phenyl rings are assigned
-1
-1
-1
in the range 3065-3033 cm for PhI, 3078-3070 cm for PhII and 3077-3045 cm for
5

ACCEPTED MANUSCRIPT
-1
PhIII rings theoretically [45]. Experimentally bands are observed at 3065, 3031 cm in
-1
IR and 3060, 3034 cm in Raman spectrum. The phenyl ring stretching modes of the title
-1
-1
compound are assigned at 1558, 1468, 1288 cm (IR), 1467 cm (Raman), in the range
-
1
-1
1
1
580-1290 cm (DFT) for PhI with PEDs in the range 53-76%, 1572, 1368 cm (IR),
-1
-1
573, 1543, 1460, 1363, 1250 cm (Raman), in the range 1571-1247 cm (DFT) for PhII
-1
-1
with PEDs in the range 40-84% and 1543 cm (Raman), in the range 1582-1306 cm
DFT) for PhIII with PEDs in the range 47-81%. In the present case the PED analysis
(
-1
-1
-1
gives ring breathing modes at 1009 cm for PhI, 1017 cm for PhII and 1083 cm for
PhIII, as expected [45, 46]. For these ring breathing modes, IR intensities are less than 10
-1
except for the mode 1017 cm which has an IR intensity of 75.11. Similarly the Raman
-1
-1
activity for the mode 1083 cm is very low, while the other modes, 1009 and 1017 cm
have a Raman activity around 18. The PEDs of all these modes are in between 40 and
2%. Raj et al. [44] reported the ring breathing mode of a poly-substituted benzene ring
5
-1
-1
-1
at 1025 cm in IR, 1027 cm in Raman and 1032 cm theoretically. For ortho substituted
-1
-1
phenyl ring the ring breathing mode is reported at 1041 cm [47] and at 1086, 1011 cm
-1
(
theoretically) [48] and at 1020 cm (theoretically) [49]. For the title compound, the in-
-1
-1
plane CH deformation modes are assigned at 1136 cm (IR), 1135, 1059 cm (Raman)
-1
-1
-1
for PhI, 1182 cm (IR), 1181, 1152 cm (Raman) for PhII and 1204, 1005 cm (Raman)
-1
for PhIII. The DFT calculations give these modes in the ranges 1311-1062 cm for PhI,
-1
-1
1
180-1152 cm for PhII and 1265-1007 cm for PhIII, as expected [45]. For the mono
substituted ring PhI, the IR intensities and Raman activities are less than 10, except for
-1
the mode at 1176 cm , the Raman activity is high with a value of 46.25. The PEDs of
these modes lie in the range 42 to 77%. For the rings PhII and PhIII, the IR intensities are
-1
high with PEDs around 50%. The out-of-plane C-H modes are assigned at 824 cm (IR),
-1
-1
9
62, 892, 824 cm (Raman), 962, 949, 894, 827, 826 cm (DFT) for PhI with low IR
-1
intensities and Raman activities, 856, 857 cm (DFT) for PhII with IR intensities around
-
1
-1
2
9
0 and low Raman activities and 944, 850, 750 cm (IR), 943, 850, 748 cm (Raman),
-1
64, 946, 853, 751 cm (DFT) for PhIII with low IR intensities and Raman activities
-1
except for the mode at 751 cm . The PEDs of all the out-of-plane CH deformation modes
are high.
6

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-1
The N-H vibrations give rise to bands in the regions, 3500-3300 cm (stretching),
-1
1
500-1300, 700-600 cm (bending) [45, 50, 51] and for the title compound the DFT
-1
calculations give these modes at 3439 with a PED of 100%, 1442 and at 613 cm with
-1
PED around 50%.Mary et al. [52] reported a band at 3343 cm in the IR spectrum, 3340
-1
-1
cm in Raman spectrum and 3433 cm theoretically as N-H stretching mode. For the title
-1
compound, the C-N stretching modes are assigned at 1322, 1214, 1204 cm in Raman
-1
and in the range 1324-965 cm theoretically which are in agreement with literature [45,
-1
-1
5
0, 53, 54]. The C=N stretching mode is observed at 1515 cm in IR and 1519 cm
theoretically with high IR intensity and PED of 43% as expected [27]. For the title
-1
-1
compound C-S stretching modes are observed at 632 cm in the IR spectrum, 633 cm in
-1
the Ramam spectrum and at 668, 635 cm theoretically as expected [45].
The C=O stretching mode [45, 50, 53] is expected in the region 1750-1650 cm-1
-1
and in the present case this modes appear at 1675, 1662 cm in the IR spectrum, and at
-1
1
680, 1660 cm in the Raman spectrum. The DFT calculations give these modes at 1673
-1
and 1663 cm and the IR intensities of these modes are very high and the PED
contribution is 73%. For the title compound, the C=O deformation bands are observed at
-1
-1
-1
7
73, 500 cm (IR), 772, 682, 502, 471 cm (Raman) and at 771, 684, 495, 470 cm
-1
theoretically which are expected in the regions 625 ± 70 and 540 ± 80 cm , respectively
-1
[
45]. The C-O-C stretching modes are expected in the range 1200-850 cm [45, 55]. The
-1
skeletal C-O deformation can be found in the region 320 ± 50 cm [45]. As expected,
-1
the C-O-C vibrations are assigned at 1196, 1054, 1017, 977, 953, 910 cm theoretically
for the title compound with PEDs ranging from 42 to 78%, which are in agreement with
-1
the literature [53]. Experimentally bands are observed at 1020, 911 cm in the IR
-1
spectrum and at 1049, 1020, 911 cm in the Raman spectrum.
The stretching vibrations of the CH group and deformation modes of CH group
2
2
(scissoring, wagging, twisting and rocking modes) appears in the regions 3000 ± 20,
-1
2
900 ± 25, 1450 ± 30, 1330 ± 35, 1245 ± 45, 780 ± 55 cm respectively [45, 50, 53]. The
-1
CH stretching modes are observed at 2996, 2972, 2932 cm (IR), 3023, 2963, 2948,
2
-1
-1
2
930 cm (Raman) and in the range 3025-2929 cm theoretically. The deformation
-1
modes of CH are assigned at 1417, 1348, 1238 cm in the IR spectrum, 1330, 1322,
2
-1
1
273, 1214, 1102 cm in the Raman spectrum and in the ranges 1444-1420 (scissoring),
7

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-1
1
417-1324 (wagging), 1301-1216 (twisting), 1161-928 (rocking) cm theoretically as
expected [45, 50, 53]. For the title compound, the CH stretching modes are assigned at
3
3
008, 2979, 2902 cm-1 in the Raman spectrum and in the range 3015-2900 cm-1
-1
theoretically and these modes are expected in the region 2900-3050 cm [45]. The
deformation modes of the methyl group of the title compound are assinged as 1460, 1437,
-
1
1
1
4
408, 1395 cm in the Raman spectrum and in the ranges 1456-1399 (scissoring) and
-
1
170-1121 cm (rocking) theoretically as expected [45].
.3. NMR spectra
1
13
The H and C NMR isotropic shielding are calculated with the GIAO method
1
[
56,57]. The experimental NMR values are: H NMR (DMSO-d ): δ 10.39 (s, 1H), 8.18-
6
7
3
1
1
.30 (m, 9H), 7.03 (s, 2H), 4.72 (d, 2H, J= 6.0 Hz), 4.26 (d, 2H, J= 6.5 Hz), 3.73 (s, 6H),
1
3
.62 (s, 3H), 3.04 (t, 2H, J= 6.5Hz), 1.64 (d, 3H, J = 6.0 Hz). C NMR (DMSO-d ) δ:
6
7.5, 33.4, 45.5, 46.2, 55.6, 60.0, 96.8, 118.8, 125.7, 125.9, 126.4, 126.6, 128.5, 133.5,
34.5, 134.9, 137.5, 146.7, 152.6, 155.5, 160.3, 169.1.
The TMS shielding: σcalc (TMS) calculated previously at the same theoretical
level and numerical values of chemical shift δcalc = σ (TMS) - σ
together with
calc
calc
calculated values of σ (TMS), are given in Table 3. The protons of the phenyl rings
calc
resonate in the range 7.9837-7.7091 for PhI, 7.0741-6.9133 for PhII and 8.707-7.5011
ppm for PhIII theoretically. The chemical shifts of the hydrogen atoms outside the rings
have the following values theoretically: CH group between PhI and PhIV are in the
2
range 4.9345-3.4158, CH group near to the sulfur atom S are 7.5054, 7.3882, CH
2
2
1
group near to the carbonyl group is 3.7117, 2.8111 and for the amide hydrogen the shift
is 6.2513 ppm. The hydrogen atoms of the CH groups resonate theoretically in the range
3
4
.8518-3.6869, 4.4506-4.1358, 5.0915-3.9398 ppm for the CH groups at C , C and
3 60 50
C55 positions. The range of 13C NMR chemical shifts of aromatic carbon atoms are
1
3
normally greater than 100 ppm [58, 59] and in the present work C NMR chemical shifts
of entire phenyl carbon atoms are greater than 100 ppm as expected in literature. The
predicted shifts lie in the range 137.5733-126.5891 for PhI, 156.7075-117.6511 PhII and
1
46.9364-121.7319 for PhIII rings. For the methoxy carbon atoms C , C and C the
45 46 47
chemical shifts are high due to the presence of the oxygen atoms. The chemical shifts of
carbon atoms in the CH groups are 55.2783 (C ), 42.2848 (C ), 41.1976 (C ), 38.0028
2
19
16
34
8

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(
C ) ppm and in the CH groups are 65.0711 (C ), 65.5945 (C ), 65.1381 ppm (C ).
6
4
3
60
50
55
The carbonyl group C posses a high chemical shift theoretically (164.4661 ppm) due to
3
7
the presence of the oxygen atom. For the quinazoline ring carbon atoms the shifts are
61.9221 (C ) and 158.3237 (C ) and the high shift is due to the presence of
1
3
3
15
neighboring substituent. The experimental NMR spectra are given in Figs. 4 and 5.
4
.4.
Frontier Molecular Orbital analysis
The ionization energy (I) and electron affinity (A) can be expressed through
HOMO and LUMO orbital energies as I = -EHOMO = 7.342 and A = -ELUMO = 5.004 eV
and the HOMO-LUMO gap = 2.338 eV. A large energy gap is associated with a hard
molecule and small gap with a soft molecule [60].The electro-negativity (χ) [61],
chemical hardness (η) and electronic potential were computed using the orbital energy of
the HOMO and the orbital energy of the LUMO at the DFT level. The ionization
potential (μ) of the molecule is calculated using Koopman’s theorem [62, 63] and is given
by μ = -(I+A)/2 and η = (I-A)/2 and electronegativity χ = (I+A)/2. Parr et al. [64] have
proposed electrophilicity index as a measure of energy lowering due to maximal electron
2
flow between donor acceptor and ω = μ /2η. The quantum chemical descriptors are μ = -
6
.173, η = 1.169, χ = 6.173 and ω = 16.30 eV. The HOMO and LUMO plots are given in
Fig.6.
.5.
4
Molecular Electrostatic Potential (MEP)
To predict reactive sites for electrophilic and nucleophilic attack for the title
compound, the MEP at the B3LYP optimized geometry was calculated (Fig.7). The
different values of the electrostatic potential at the surface are represented by different
colours. Potential increases in the order red < orange < yellow < green < blue. The
negative (red, orange and yellow) regions of the MEP are related to electrophilic
reactivity. From the MEP plot it is evident that the negative charge covers carbonyl
group, mono substituted phenyl ring, O59 atom and the positive region is over the
nitrogen atoms and hydrogen atoms. The electrostatic potential value is largely
responsible for the interaction of a substrate to its receptor binding sites since they
recognize each other [65, 66].
4
.6
ALIE surface, Fukui functions and indices, non-covalent interactions
9

ACCEPTED MANUSCRIPT
Sjoberg et al. [67, 68] have introduced ALIE as quantum molecular descriptor for
the investigation of reactivity of aromatic compounds. This descriptor turned out to be
very useful tool when it comes to the assessment of local reactivity properties of some
molecule and is defined as a sum of orbital energies weighted by the orbital densities:

i

r

i
I

r



,
(1)




r

i


where i

r
r
represents the electronic density of the i-th molecular orbital at the point ,

i represents the orbital energy and


r

is the total electronic density function. The
values of ALIE are mapped to the electron density surface and show the molecule areas
where it is the most easily to remove the electrons, i.e. the molecule parts where the
electrons are least tightly bound. These areas are the ones where molecule is prone to
electrophilic attacks. Representative ALIE surface of the title molecule is presented in
Fig. 8.
ALIE surface presented in Fig.8 determine the near vicinity of sulfur atom S1 to
have the lowest ALIE values, designated by the red color. In this case the lowest ALIE
value is around 186 kcal/mol and the mentioned location of S1 is the most vulnerable to
the electrophilic attacks. Molecule locations characterized by the highest ALIE values,
designated by the blue color, are the methyl groups and hydrogen atom H48. In the case
of mentioned molecule the highest ALIE values are having values of around 346
kcal/mol.
Using the method of Johnson et al. [37, 38] it is possible to perform the analysis
of charge density between atoms that are not covalently bonded and to locate
intramolecular noncovalent interactions. These noncovalent interactions could be
responsible for some specific structural and reactive properties. Intramolecular
noncovalent interactions of title molecule have been determined and visualized with
corresponding strengths (in terms of electron density) in Fig. 9.
It can be seen in Fig. 9 that concerning the title compound molecule there are total of
six intra-molecular non-covalent interactions. The strongest non-covalent interaction is
the one between sulfur atom S1 and hydrogen atom H17, for which the strength has been
3
calculated to be –0.017 electron/bohr . On the other side the weakest non-covalent
10

ACCEPTED MANUSCRIPT
interaction was calculated to be in the case of interaction between carbon atom C6 and
3
hydrogen atom H42, with the corresponding strength of just 0.001 electron/bohr . It is
also interesting to mention the two non-covalent interactions involving oxygen atom O49
and the two adjacent methyl groups, with corresponding strengths of –0.011 and –0.012
electron/bohr3.
Beside MEP and ALIE surfaces it is also useful to employ the concept of Fukui
functions in order to gain further insight into the local reactivity properties of the title
molecule. Fukui functions show the changes of electron density after the addition or
+
–
removal of charge. There are two Fukui functions, f and f functions, and in Jaguar
program they are calculated in the finite difference approximation according to the
following equations:
N 
N



r

 


r



f 
,
,
(2)
(3)
N 
N



r

 


r



f 
where N represents the number of electrons in reference state of the molecule, while

is
fraction of electron which default value is set to be 0.01 [69].
Once the Fukui function values have been obtained with Jaguar program it is
possible to visualize them as iso-surfaces or to map them to the electron density surface.
In this work, for the purpose of visualization, values of Fukui functions have been
mapped to the electron density surface, Fig. 10. Positive color (purple in Fig. 10a)
denotes areas at molecular surface where electron density increases with the addition of
+
charge in the case of f function, while negative color (red in Fig. 10b) denotes areas at
molecular surface where electron density decreases with the removal of charge in case of
f– function. Results presented in Fig. 10a indicate that with the addition of charge electron
density significantly increases in the near vicinity of six member ring with two nitrogen
atoms and its adjacent benzene rings, indicating that this part of molecule acts as an
electrophile in the case of charge addition. The location of red color in case of Fig. 10b
indicates that benzene ring with three attached oxygen atoms with methyl groups presents
area where electron density decreases after the removal of charge, i.e. the molecule
location that acts as nucleophile with the removal of charge.
11

ACCEPTED MANUSCRIPT
The Fukui indices are also a local reactivity descriptor that gives the preferred
regions where a chemical species will change its density when the number of electrons is
modified and it indicates the propensity of the electronic density to deform at a given
position upon accepting or donating electrons [70-72]. Also, it is possible to define the
th
corresponding condensed or atomic Fukui indices on the j atom site as,
¯
f = q (N) - q (N-1)
(4)
(5)
(6)
j
j
j
+
f = q (N+1) - q (N)
j
j
j
0
f = ½[q (N+1) - q (N-1)]
j
j
j
¯
+
For an electrophilic f (r), nucleophilic or free radical attack f (r), on the reference
j
j
molecule, respectively. In these equations, q is the atomic charge (evaluated from
j
th
Mulliken population analysis, electrostatic derived charge, etc.) at the j atomic site is the
neutral (N), anionic (N + 1) or cationic (N - 1) chemical species. Morell et al., [73] have
recently proposed a dual descriptor (∆f(r)), which is defined as the difference between the
nucleophilic and electrophilic Fukui function and is given by,
+
¯
∆
f(r) = [f (r) - f (r)]
(7)
For nucleophilic attack, ∆f(r) > 0 and for an electrophilic attack ∆f(r) < 0. Under this
situation, dual descriptors ∆f(r) provide a clear difference between nucleophilic and
electrophilic attack at a particular site with their sign. From the values reported in Table
4
, according to the condition for dual descriptor, nucleophilic site for in our title
compound is S , C and N (positive value i.e. ∆f(r) > 0). Similarly the electrophilic
1
6
3
attack site is C , C , C and C37 (negative value i.e. ∆f(r) < 0). The behavior of
5
15
33
molecules as electrophiles/nucleophiles during reaction depends on the local behavior of
molecules.
4
.7.
Nonlinear optical studies
The calculated first hyperpolarizability of the title compound is 5.465 × 10-30 esu,
which is 42.04 times that of standard NLO material urea (0.13 × 10-30 esu) [74]. The
reported values of hyperpolarizability of similar derivatives are 5.05×10-30 esu and 6.00 ×
1
0-30 esu [48, 49]. The average second hyperpolarizability is <γ> = (γxxxx + γyyyy + γzzzz
+
2
γxxyy + 2γxxzz + 2γyyzz)/5. The theoretical second order hyperpolarizability was calculated
using the Gaussian09 software and is equal to -53.027 × 10-37 esu [75]. We conclude that
the title compound is an attractive object for future studies of nonlinear optical properties.
12

ACCEPTED MANUSCRIPT
4
.8.
Natural Bonding orbital analysis
The natural bond orbitals (NBO) calculations were performed using NBO 3.1
program [76] and the possible interactions are given in tables 5 and 6.
The intra-molecular hyper-conjugative interactions in the molecular system are:
N -C from S of n (S )→*(N -C ), N -C from O of n (O )→*(N -C ), N -C
3
33
1
2
1
3
33
4
15
2
2
2
4
15
4
33
from N of n (N )→*(N -C ), N -C from N of n (N )→*(N -C ), C -N from
3
1
3
4
33
3
33
4
1
4
3
33
37
39
O of n (O )→*(C -N ), C -O from N of n (N )→*(C -O ), C -C from
3
8
1
38
37
39
37
38
39
1
39
37
38
47
46
O49 of n (N )→ *(C -C ), C -C from O54 of n (O )→*(C -C ) and C -C
1
49
47
46
47
46
1
54
47
46
41
45
from O of n (O )→*(C -C ) having electron densities, 0.37197, 0.09782, 0.06033,
5
9
2
59
41
45
0
3
.37197, 0.08000, 0.26078, 0.04620, 0.40309, 0.37757e and stabilization energies, 24.95,
0.34, 16.18, 56.09, 26.53, 59.79, 7.77, 10.14 and 9.12 KJ/mol.
The natural hybrid orbitals with high energies, considerbale p-character, low
occupation numbers are: n (S ), n (O ), n (O ), n (O ), n (O ), n (O ) with energies, -
2
1
2
2
2
38
2
49
2
54
2
59
0
9
1
.24978, -0.24517, -0.23949, -0.34379, -0.36606, -0.37165a.u and p-characters, 100,
9.99, 99.99, 94.16, 89.71, 88.97% and low occupation numbers, 1.82884, 1.85356,
.86700, 1.92712, 1.90599, 1.90982 and the orbitals with lower energies, high occupation
numbers are, n (S ), n (O ), n (O ), n (O ), n (O ), n (O ) with energies, -0.63412, -
1
1
1
2
1
38
1
49
1
54
1
54
0
4
1
.67228, -0.66684, -0.53312, -0.49570, -0.49287 a.u with p-characters, 31.99, 58.17,
1.88, 63.33, 68.32, 68.85% and high occupation numbers, 1.98015, 1.97619, 1.97557,
.94413, 1.95217, and 1.95138.
Thus, a very close to pure p-type lone pair orbital participates in the electron
donation to the n (S )→*(N -C ), n (N )→*(O -C ), n (O )→*(N C ),
1
1
6
36
1
2
5
54
2
3
7- 18
n (O )→*(N -C ), n (O )→*(N -C ), n (N )→*(N C ) and n (N )→*(N C )
2
4
2
36
2
5
2
54
1
6
7- 36
1
7
6- 36
interactions in the compound.
4
.9
Reactive and degradation properties based on autoxidation and hydrolysis
Since forced degradation studies could be complicated and tedious procedures,
DFT calculations can be readily employed for the initial assessment of degradation
properties of important molecules [77-80]. Concretely, calculations of BDEs for
hydrogen abstraction can be of particular interest for the initial assessment of
autoxidation mechanism. If the BDE for hydrogen abstraction at some particular
molecule location has the value within certain interval than it can be concluded that
13

ACCEPTED MANUSCRIPT
autoxidation mechanism is possible. In this regard it is important to mention that
allperoxy radicals have similar BDE values (87-92 kcal/mol) for which it can be
approximated that are independent of the chemical surrounding [81, 82]. Study of Wright
et al. [83] states that molecules are the most sensitive towards the autoxidation
mechanism for the BDE values in the range between 75 and 85 kcal/mol. Similarly,
according to Gryn'ova et al. [84] thermodynamic favorability of C-H bond dissociation is
strongly favored for BDE values below 85 kcal/mol, disfavored for BDE values higher
than 90 kcal/mol and questionable for the BDE values in the range between 85 and 90
kcal/mol [19].
In this work BDE values of hydrogen abstraction have been calculated in order to
determine whether the investigated molecule is prone to autoxidation process or not.
Besides, BDE values for the rest of the single acyclic bonds have also been calculated in
order to determine the weakest bonds and thus to locate the possible molecule’s location
suitable for the start of degradation. All BDEs have been presented in the Fig. 11.
BDE values for hydrogen abstraction presented in Fig. 11 clearly indicate that the
title compound molecule is not suitable for the autoxidation mechanism since all BDE
values for hydrogen abstraction are significantly higher than 90 kcal/mol. This result also
indicates that the investigated molecule is stable in the open air and in the presence of
oxygen. On the other side the lowest BDE values for the rest of the single acyclic bonds
have been calculated in the case of bonds denoted with numbers 26 and 27, indicating
that degradation process could start by the detaching of methyl groups. Beside bonds 26
and 27 it is also important to mention that BDE for the bond 15 is also low and can be
considered as significant. Namely, this bond is connecting two large parts of molecule
and in the same time involves sulfur atom S1, which is important reactive center
according to the results obtained by ALIE surfaces. Concretely, ALIE value is the lowest
for precisely S1 atom.
Due to the frequent usage, biologically active molecules accumulate in water
resources. In certain cases hydrolysis mechanism is very significant for the degradation
of these molecules. Although it is hard to predict whether some molecule can be
influenced by the hydrolysis in the extent which is suitable for degradation, it is possible
to use the MD simulations and to determine which atoms of the investigated molecules
14

ACCEPTED MANUSCRIPT
have significant interactions with water molecules by calculations of RDFs. RDF, g(r),
determines the probability of finding a particle in the distance r from another particle
[85]. RDFs of atoms with pronounced interactions with water molecules have been
presented in Fig. 12. According to the calculated RDFs presented in Fig. 12 there are four
carbon atoms and four non-carbon atoms with significant interactions with water
molecules. Four carbon atoms have practically the same peak distance located at
somewhat more than 3.5 Å, while maximal g(r) values are around 1.4, except in the case
of carbon atom C37 for which the maximal g(r) value is somewhat less than 1.2.
Among the non-carbon atoms, oxygen atoms O2 and O38 are very similar in
terms of peak distance. Namely, maximal g(r) values in cases of these tow atoms are
located at distance of around 2.6 Å, while there is significant difference in their maximal
g(r) values (around 0.8 for O2 and around 1.0 for O38). Interesting situation can be seen
for oxygen atom O49, for which RDF there are three distinct solvation spheres. The
influence of hydrolysis could be of certain significance because mentioned oxygen atom
O49 is connected to methyl group which is characterized by very low BDE value. By all
means the most significant interaction with water molecules occurs in the case of
hydrogen atom H48, which maximal g(r) value is located at around 1.7 Å.
4
.10 Molecular docking studies
Human neutrophil elastase (HNE) has been implicated as a major contributor to
tissue destruction in various disease states, including emphysema. HNE is capable of
digesting the underlying elastin structure of the alveolar walls of the lung [86]. To
evaluate the inhibiting activity of the title compound on HNE we have carried out
molecular docking study. The 3D crystal structure of HNE was obtained from Protein
Data Bank (PDB ID: 1HNE) [87] and the molecular docking simulations were performed
on AutoDock-Vina software [88] as reported previously [89]. The ligand binds at the
catalytic site of substrate (Fig. 13) by weak non-covalent interactions most prominent of
which are H-bonding and π-π stacking interactions. Arg147 and Gly193 form hydrogen
bonds with the carbonyl groups. A strong hydrogen bond is formed between NH group
and Phe41 amino acid. Phe192, Phe41 and Leu143 hold the aromatic rings by pi-pi
stacking interactions (Fig. 14). The inhibitor forms a stable complex with HNE as is
evident from the binding affinity -10.9 kcal/mol (ΔG in kcal/mol) values (table 7). The
15

ACCEPTED MANUSCRIPT
preliminary results suggest that the compound exhibit inhibitory activity against HNE.
However biological tests need to be done so as to validate the computational predictions.
5
.
Conclusion
The spectroscopic properties of 3-((4-oxo-3-phenethyl-3,4-dihydroquinazolin-2-yl)thio)-
N-(3,4,5-trimethoxyphenyl) propanamide were investigated by FT-IR and FT-Raman
techniques. The geometry of the molecule was fully optimized, vibrational spectra were
calculated and fundamental vibrations were assigned on the basis of potential energy
distribution of the vibrational modes using GAR2PED program. Themolecular orbital
calculations such as natural bond orbitals, HOMO-LUMO energy gap and mappedp
moolecular electrostatic potential surfaces were also performed. The delocalization of
electron density of various constituents of the molecule has been discussed with the aid of
NBO analysis. The calculated first hyperpolarizability of the title compound is 42.04
times that of standard NLO material urea and the title compound and its derivative are
good objects for further studies of nonlinear optics. ALIE descriptor recognized sulfur
atom S1 as significant reactive center prone to electrophilic attacks. According to the
analysis of non-covalent interactions the title compound molecule is characterized by
total of six such interactions, among which the strongest one is between sulfur atom S1
and hydrogen atom H17. Further analysis of local reactivity properties by Fukui functions
indicated two specific parts of the title compound molecule which could possible act as
electrophile (six member ring with two nitrogen atoms and adjacent benzene ring) and
nucleophile (near vicinity of benzene rings to which three oxygen atoms are attached).
Calculated BDE values for hydrogen abstraction indicate that the investigated molecule is
not prone to autoxidation mechanism and that it is very stable in the open air. RDFs as
obtained after MD simulations indicate that the most significant interactions with water
molecules occurred in the case of hydrogen atom H48. Concerning the RDFs it is also
meaningful to notice that oxygen atom O49, involved in the bonds with the low BDE
values, also has significant interactions with water molecules which indicates that
hydrolysis mechanism could be of importance in the case of the title compound molecule.
Molecular docking study shows that the ligand binds at the catalytic site of substrate by
weak non-covalent interactions most prominent of which are H-bonding and pi-pi
stacking interactions; Arg147 and Gly193 form hydrogen bonds with the carbonyl
16

ACCEPTED MANUSCRIPT
groups; A strong hydrogen bond is formed between NH group and Phe41 amino acid;
Phe192, Phe41 and Leu143 hold the aromatic rings by pi-pi stacking interactions. The
theoretically obtained geometrical parameters are in agreement with that of similar
derivatives.
Acknowledgments
The authors extend their appreciation to the Deanship of Scientific Research at King
Saud University for funding the work through the research group project No. RG-1435-
0
46. The authors would like to thank the University of Antwerp for access to the
University’s CalcUA supercomputer cluster. Part of this work has been performed thanks
to the support received from Schrödinger Inc.
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Figure captions
Fig.1 FT-IR spectrum of 3-(4-oxo-phenethyl-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-
trimethoxyphenyl) propanamide
Fig.2 FT-Raman spectrum of 3-(4-oxo-phenethyl-3,4-dihydroquinazolin-2-ylthio)-N-
(
3,4,5-trimethoxyphenyl) propanamide
Fig.3 Optimized geometry of 3-(4-oxo-phenethyl-3,4-dihydroquinazolin-2-ylthio)-N-
3,4,5-trimethoxyphenyl) propanamide
(
1
Fig.4 H NMR spectrum of the title compound
1
3
Fig.5 C NMR spectrum of the title compound
26

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Fig.6 HOMO-LUMO plots of 3-(4-oxo-phenethyl-3,4-dihydroquinazolin-2-ylthio)-N-
(3,4,5-trimethoxyphenyl) propanamide
Fig.7 MEP plot of 3-(4-oxo-phenethyl-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-
trimethoxyphenyl) propanamide
Fig.8 ALIE surface of the title molecule
Fig.9 Visualization of intra-molecular non-covalent interactions with their
corresponding strengths [electron/bohr3]
+
–
Fig.10 Fukui functions a) f and b) f of the title molecule
Fig.11 BDEs of all single acyclic bonds of the title molecule
Fig.12 Significant RDFs for the interactions with water molecules: a) carbon atoms and
b) non-carbon atoms
Fig.13 The ligand and the co-crystallized inhibitor embedded into the catalytic site of
HNE
Fig. 14 The docked confirmation of ligand binds at the catalytic site of HNE. H-bond, pi-
pi stacking interactions are represented by green and violet dotted lines,
respectively
27