Quantum chemical, experimental, theoretical spectral (FT-IR and NMR) studies and molecular docking investigation of 4,8,9,10-tetraaryl-1,3-diazaadamantan-6-ones

Article abstract of DOI:10.1007/s11164-019-03838-9

Abstract: The compounds 4,8,9,10-tetraaryl-1,3-diazaadamantan-6-ones (a–e) were synthesized and characterized by FT-IR, ¹H and ¹³C NMR spectra, and the spectral data have been theoretically analyzed by the DFT method. The electronic properties including a highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO) and related parameters were calculated with B3LYP/6-311 G (d, p) basis set. The observed HOMO and LUMO mappings describe the different charge transfer possibilities within the molecule. Besides, the reactive properties of the molecules have been addressed based on the frontier molecular orbital analysis. The Molecular Electrostatic Potential and Fukui function analysis reveal the sites for electrophilic attack and nucleophilic reactions in the molecule. The intramolecular contacts have been interpreted using Natural Bond Orbital analysis and the thermodynamic properties also presented. The molecular docking study has been executed to study the binding interactions of the synthesized compounds with H1N1 swine virus-M2 proton channel and COX-2 protein. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-019-03838-9

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-019-03838-9
Quantum chemical, experimental,
theoretical spectral (FT‑IR and NMR) studies
and molecular docking investigation
of 4,8,9,10‑tetraaryl‑1,3‑diazaadamantan‑6‑ones
G. Vengatesh1 · M. Sundaravadivelu1
Received: 2 March 2019 / Accepted: 16 April 2019
© Springer Nature B.V. 2019
Abstract
The compounds 4,8,9,10-tetraaryl-1,3-diazaadamantan-6-ones (a–e) were synthe-
1
sized and characterized by FT-IR, H and 13C NMR spectra, and the spectral data
have been theoretically analyzed by the DFT method. The electronic properties
including a highest occupied molecular orbital (HOMO), lowest unoccupied molec-
ular orbital (LUMO) and related parameters were calculated with B3LYP/6-311 G
(d, p) basis set. The observed HOMO and LUMO mappings describe the diferent
charge transfer possibilities within the molecule. Besides, the reactive properties of
the molecules have been addressed based on the frontier molecular orbital analysis.
The Molecular Electrostatic Potential and Fukui function analysis reveal the sites for
electrophilic attack and nucleophilic reactions in the molecule. The intramolecular
contacts have been interpreted using Natural Bond Orbital analysis and the thermo-
dynamic properties also presented. The molecular docking study has been executed
to study the binding interactions of the synthesized compounds with H1N1 swine
virus-M2 proton channel and COX-2 protein.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-019-03838-9) contains supplementary material, which is available to authorized users.
*
M. Sundaravadivelu
msundargri@gmail.com
1
Department of Chemistry, The Gandhigram Rural Institute-Deemed to be University,
Gandhigram, Tamilnadu 624 302, India
Vol.:(0123456789)
1 3

G. Vengatesh, M. Sundaravadivelu
Graphical abstract
Keywords 1,3 diazaadamantanone · Fukui function · MEP · NBO · NMR ·
Molecular docking
Introduction
The biological activities of adamantane core containing compounds were early recog-
nized after the discovery of amantadine and its derivatives as efective therapies against
infuenza viruses [1–4]. Since they have intensive biological properties, several drugs
containing adamantane core have been discovered, which are now available in the
market, Fig. 1. Furthermore, several adamantane derivatives were proved to possess
potent biological activities against human immunodefciency viruses (HIV) [5, 6], anti-
infammatory [7–9], central nervous activities [10–12], anti-diabetic [13, 14] and anti-
microbial [15–19]. The 1,3 diazaadamantanone core containing derivatives are of great
importance as conformationally rigid analogs of medicinally active compounds. This
derivative has great antimicrobial activities [20]. In view of vast varieties of biologi-
cal activities of adamantane derivatives, we synthesized fve tetraaryl substituted 1,3
diazaadamantanone derivatives, namely 4,8,9,10-tetraaryl-1,3-diazaadamantan-6-ones.
1 3

Quantum chemical, experimental, theoretical spectral (FT‑IR…
H2N
O
NH2
N
N
H
O
OH
N
Amantadine
Rimantadine
Vildagliptin
H
N
NH2
N
O
O
Memantine
Tromantadine
O
O
OH
N
OH
NH2
O
N
Adapalene
Saxagliption
Fig. 1 Available adamantane core containing drugs
The literature review revealed that synthesis and conformational studies of the
4,8,9,10-tetraaryl-1,3-diazaadamantan-6-one were carried out using NMR and XRD
[21, 22].
In the literature, to the best of our insight, there is no DFT and docking study done
for the title compound. The biological activities of the compounds are based on the
electronic properties of the molecule (HOMO, LUMO, dipole movement, total energy,
etc.). In this investigation, the electronic properties of fve tetraaryl substituted 1,3 dia-
zaadamantanones have been studied using density functional theory, a B3LYP method
with 6-311 G (d, p) basis set. The frontier molecular orbitals such as HOMO and
LUMO determine the way the molecule interacts with other species which enables us
to characterize the chemical reactivity of the molecule. The stability of the molecule
arising from hyper-conjugative interaction and charge delocalization has been analyzed
using Natural Bonding Orbital (NBO) analysis and Molecular Electrostatic Potential
(MEP) analysis. The current investigation also deals with molecular docking study
of the fve 4,8,9,10-tetraaryl-1,3-diazaadamantan-6-one in H1N1 swine viruses and
COX-2 protein.
1 3

G. Vengatesh, M. Sundaravadivelu
Experimental details
The synthesis and crystal structure of the studied 4,8,9,10-tetraaryl-1,3-diazaada-
mantan-6-ones (a–e; Fig. 2) have been reported earlier [21, 22]. In this investiga-
tion, fve 4,8,9,10-tetraaryl-1,3-diazaadamantan-6-ones (a–e) are synthesised and
compounds are confrmed by spectral techniques. The FT-IR spectra had been
recorded using a JASCO FT/IR-4700 spectrometer in the region 4000–400 cm−1 as
1
a KBr pellet. The H and 13C NMR spectra were recorded in a Bruker AVANCER
III HD 400 MHz instrument at 300 K. The compound was dissolved in CDCl3 and
chemical shifts are reported in ppm relative to tetramethyl silane (TMS). The 1H and
13C NMR spectra had been recorded at a base frequency of 400 MHz and 100 MHz,
respectively. Synthesis procedure for the compounds (a–e) and their FT-IR and
NMR spectra are shown in the supporting information.
General procedure for the synthesis of compounds (a–e)
Compounds 1−5 were synthesised by the methods reported in literature [21, 22].
The compound 1–5 (1 mmol) was dissolved in chloroform and 2 mmol of paraform-
aldehyde was added. The mixture was refuxed and monitored by TLC. After the
complete disappearance of the starting material, there was evaporation of the solvent
(a)
(b)
(d)
(c)
(e)
Fig. 2 Structure of the synthesized compound a–e
1 3

Quantum chemical, experimental, theoretical spectral (FT‑IR…
in the resulting mixture, and it was washed with cold water to obtain colorless solid
as a resulting product (Scheme 1).
4,8,9,10-tetraphenyl-1,3-diazaadamantan-6-one (a); Colorless power, mp 210 °C;
IR (KBr, cm−1): 3086, 3054, 3027. 2982, 2951, 2878, 1705, 1601; 1H-NMR (CDCl3/
TMS, 400.22 MHz) 3.98 (2H, s), 4.44 (2H, s), 4.76 (2H, s), 4.85 (2H, s), 6.77 (6H,
m), 7.02 (4H, d), 7.30 (2H, t), 7.40 (4H, t), 7.61 (4H, d). 13C-NMR (CDCl3/TMS,
100.63 MHz) 50.17, 64.26, 68.55, 69.42, 126.36, 126.96, 127.31, 127.51, 128.10,
129.10, 138.00, 139.66, 213.70.
4,8,9,10-tetrakis(4-methoxyphenyl)-1,3-diazaadamantan-6-one
(b);
Colorless
power, mp 188 °C; IR (KBr, cm−1): 3066, 3034, 2992, 2953, 2903, 2866, 2833,
1
1695, 1608; H-NMR (CDCl3/TMS, 400.22 MHz) 3.63 (6H, s), 3.82 (6H, s), 3.87
(2H, s), 4.36 (2H, s), 4.67 (2H, s), 4.81 (2H, s), 6.36 (4H, d), 6.92 (8H, m), 7.50
(4H, d). 13C-NMR (CDCl3/TMS, 100.63 MHz) 50.48, 55.19, 55.31, 63.57, 67.89,
68.97, 112.87, 114.35, 128.10, 129.18, 130.03, 132.39, 157.70, 158.81, 214.15.
4,8,9,10-tetrakis(4-chlorophenyl)-1,3-diazaadamantan-6-one (c); Colorless power,
1
mp 198 °C; IR (KBr, cm−1): 3083, 3048, 2947, 2892, 2875, 1705, 1593; H-NMR
(CDCl3/TMS, 400.22 MHz) 3.85 (2H, s), 4.34 (2H, s), 4.69 (2H, s), 4.73 (2H,
s), 6.84 (4H, s), 6.90 (4H, s), 7.41 (4H, s), 7.50 (4H, s). 13C-NMR (CDCl3/TMS,
100.63 MHz) 49.76, 63.56, 68.15, 68.58, 127.57, 128.26, 129.42, 132.82, 133.67,
135.94, 137.63, 212.25.
4,8,9,10-tetra-p-tolyl-1,3-diazaadamantan-6-one (d); Colorless power, mp 211 °C;
IR (KBr, cm−1): 3051, 3022, 2958, 2916, 2882, 2860, 1701, 1514; 1H-NMR
(CDCl3/TMS, 400.22 MHz) 2.08 (6H, s), 2.36 (6H, s), 3.90 (2H, s), 4.38 (2H, s),
4.68 (2H, s), 4.81 (2H, s), 6.59 (4H, d), 6.85 (4H, d), 7.19 (4H, d), 7.47 (4H, d).
Compounds
Ph
Yield %
88
a
b
c
C6H5
p-OCH3 C6H4
p-Cl C6H4
p-CH3 C6H4
p-F C6H4
80
89
d
e
82
90
Scheme 1 Synthesis of compound a–e
1 3

G. Vengatesh, M. Sundaravadivelu
13C-NMR (CDCl3/TMS, 100.63 MHz) 20.78, 21.11, 50.42, 63.93, 68.25, 69.35,
126.90,127.84, 128.04, 129.72, 135.13, 135.68, 136.98, 137.08, 214.20.
4,8,9,10-tetrakis(4-fuorophenyl)-1,3-diazaadamantan-6-one (e); Colorless power,
mp 236 °C; IR (KBr, cm−1): 3062, 3045, 2947, 2885, 1705, 1601; 1H-NMR (CDCl3/
TMS, 400.22 MHz) 3.87 (2H, s), 4.36 (2H, s), 4.70 (2H, s), 4.78 (2H, s), 6.54 (4H,
s), 6.97 (4H, s), 7.12 (4H, s), 7.55 (4H, s). 13C-NMR (CDCl3/TMS, 100.63 MHz)
50.00, 63.47, 68.02, 68.62, 114.11, 114.32, 115.98, 116.20, 128.52, 128.60, 129.66,
129.74, 133.23, 133.26, 135.24, 135.27, 160.04, 160.90, 162.49, 163.36, 212.73.
Computational details
The theoretical calculations of the studied compounds are carried out with the
Gaussian 09 W software package using the Becke’s three-parameter hybrid
exchange function with the LeeYang-Parr (LYP) correlation function (B3LYP)
method. The molecular structure of 4,8,9,10-tetraaryl-1,3-diazaadamantan-
6-ones in the ground state was optimized using Density Functional Theory
(DFT). The optimized structure and other electronic properties had been pur-
sued by the Gauss View 5.0 program. The electronic properties such as High-
est Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular
Orbital (LUMO), HOMO–LUMO energy gap (ΔE), ionization potential (I), elec-
tron afnity (A), electronegativity (χ), global hardness (η) and global softness
(σ) were computed using the EHOMO and ELUMO energies at the B3LYP/6‒311 G
(d, p) level of theory. The Molecular Electrostatic Potential (MEP) map also was
viewed using the Gauss View 5.0 program. The Natural Bond Orbital (NBO)
was calculated on the studied compounds at the B3LYP level utilizing the basis
set 6-311 G (d, p).
Assessment of the binding afnities of H1N1 swine virus M2 proton channel
and cyclooxygenase-2 (COX-2) protein in the synthesized compounds was done
with molecular docking simulation. The docking simulation was achieved using
the Auto dock 4.2.6 software program to predict the protein–ligand interactions.
Initially, the structure of 1,3 diazaadamantanones was optimized with minimiz-
ing its energy at B3LYP/6-311 G (d, p) level of theory. The 3D X-ray crystal
structure of the H1N1–M2 proton channel and COX-2 were acquired from the
protein data bank (http://www.rcsb.org; PDB ID: 2RLF, 4COX) [23, 24]. The
downloaded protein structures were cleaned by removing water and co-crystal-
lised ligands. The active site of the enzyme was defned to include active sites of
the residues within the grid size of 100 Å × 100 Å × 70 Å and 60 Å × 60 Å × 60 Å
in H1N1–M2 proton channel and COX-2 protein, respectively. The most popu-
lar Lamarckian Genetic Algorithm (LGA) was employed for docking [25]. As
required in the LGA, polar hydrogen atoms and Kolhman charges were added to
the structure of proteins by using the Auto Dock Tools (ADT). The binding site
of the ligand–protein was viewed by the molecular graphics software of PYMOL
and UCSF Chimera.
1 3

Quantum chemical, experimental, theoretical spectral (FT‑IR…
Result and discussion
FT‑IR spectral study
The calculated wavenumber and observed FT-IR frequency of the compound a-e
are given in Table 1. In the following discussion, the compound a is taken as a rep-
resentative compound. The asymmetric and symmetric CH stretching frequency of
the aromatic phenyl rings appeared at 3086–3026 cm−1, the calculated frequency
appeared at 3212–3133 cm−1. Aliphatic asymmetric and symmetric CH stretching
frequency of the diazaadamantan-6-one appeared in the range of 2982–2878 cm−1,
and the theoretically calculated frequency appeared at 3132–3033 cm−1. Strong
adsorption bands in the vicinity of the 1705 cm−1 in the experimental FT-IR spec-
trum of the representative compound are assigned to the C=O stretching with cal-
culated scaled wavenumber 1710 cm−1. The aromatic asymmetric and symmetric
C=C stretching frequency appeared at 1601 cm−1, the theoretically calculated fre-
quency appeared at 1545 cm−1. Correlation between the experimental and calculated
wavenumbers are obtained by plotting a correlation graph of compounds a–e and are
given in supporting information. The result shows a good linear correlation with the
calculated wavenumbers. The correlation equation and linear correlation coefcients
(R2) are given in Table S1.
NMR spectral study
1
The experimental H NMR spectrum for compound a–e in CDCl3 solvent is given
in supporting information. The optimized molecular structures of compound a–e
1
were used to stimulate H NMR spectrum at DFT/B3LYP 6311G (d, p) level using
1
the gauge-independent atomic orbital (GIAO) method and computed H and 13C
NMR spectra are shown in supporting information in Table S2, S3 [26, 27]. The
predicted proton chemical shifts are in good agreement with the experimental data.
The compound a is taken as a representative compound for experimental 1H and 13
C
NMR spectral discussion. The one pair of benzylic protons H-4 and 10 appeared
in the range of δ 4.85 ppm, another pair of benzylic protons H-8 and 9 appeared at
δ 4.76 ppm. The H-4 and 10 protons that appeared in the upfeld region are due to
parallel orientation of C-8 and 9 phenyl groups (ring current efect). The bridgehead
(H-5 & 7) and piperidine nitrogen bridging protons (H-2) appeared at δ 3.98 and
4.44 ppm, respectively. The aromatic protons appeared at δ 6.77–7.63 ppm.
The correlation graph of compounds is given in supporting information. The cor-
relation graph is drawn between the experimental and calculated chemical shifts val-
ues of the compounds a–e. The relations between the experimental and calculated
chemical shifts values equations are given in Table 2. In all the fve compounds,
the 13C NMR calculations gave better linear correlation coefcients (R2) than for
1H NMR chemical shift. A small deviation between the experimental and computed
chemical shifts of these compounds are noted, and this may be due to the orientation
and stereochemistry of the aryl groups.
1 3

G. Vengatesh, M. Sundaravadivelu
1 3

Quantum chemical, experimental, theoretical spectral (FT‑IR…
Table 2 Relations between the
Compounds
Analysis
R2
Correlation equations
experimental and calculated
chemical shifts of compounds
a–e
a
1H NMR
13C NMR
1H NMR
13C NMR
1H NMR
13C NMR
1H NMR
13C NMR
1H NMR
13C NMR
0.9596
0.9863
0.9754
0.9793
0.9746
0.9954
0.9877
0.9968
0.9835
0.6561
δcal =1.0869 δexp−0.6069
δcal =1.0234 δexp +12.9751
δcal =1.1253 δexp−0.9446
δcal =0.9838 δexp +12.5073
δcal =1.1163 δexp−0.8815
δcal =1.0107 δexp +12.9282
δcal =1.1240 δexp−0.7669
δcal =1.0141 δexp +12.3283
δcal =1.1524 δexp−0.9654
δcal =0.9570 δexp +15.9153
b
c
d
e
Thermodynamic study
Table 3, indicates thermodynamic parameters of compounds a-e. Mentioned param-
eters for each molecule are calculated by using B3LYP/6-311G (d, p) basis set. The
frequency calculations are to determine the zero-point energies, Gibbs-free ener-
gies, enthalpy, entropy, as well as the heat capacity for a molecular system. A higher
value of Gibbs-free energies implies more stable molecules. The stability order of
the studied compound is b>d>a>e>c, indicating that compounds with elec-
tron donating groups are more stable compared to compounds with electron with-
drawing groups. The values of enthalpy, entropy zero-point vibrational energy and
heat capacity can be obtained at any temperature and are useful in estimating the
direction of chemical reactions. The results of the free energy, entropy, enthalpy,
and zero-point vibrational energy can be used for synthesis of new molecules which
include tetraaryl 1,3-diazaadamantan derivatives.
Frontier molecular orbital analysis
The optimized geometry of the compounds a–e is illustrated in Fig. 3. Both the
highest occupied molecular orbital (HOMO) and lowest unoccupied molecular
Table 3 Theoretically computed thermodynamic parameters of the title compound employing B3LYP/6-
311G (d, p) basis set
Compounds
a
b
c
d
e
Enthalpy (hartrees)
Gibbs free energy (hartrees)
0.5528
0.4684
0.6924
0.6017
415.59
0.5185
0.4376
309.23
0.6706
0.5800
403.00
0.5226
0.4457
312.64
Zero-point vibrational energy (k cal 329.90
mol−1
Heat capacity (cal mol−1 K−1
Entropy (cal mol−1 K−1
)
)
108.38
177.52
124.71
190.82
107.00
170.29
115.81
190.61
103.93
161.73
)
1 3

G. Vengatesh, M. Sundaravadivelu
Fig. 3 Optimized geometry (B3LYB/6-311 G (d, p) (5D, 7F)) of synthesized compounds a–e
orbital (LUMO) and their properties are very useful for a chemical reaction. The
HOMO, HOMO-1, LUMO and LUMO+1 plots of the studied molecules are shown
in Fig. 4. In the title compounds (a–e), HOMO is located over any one of the axi-
ally oriented aryl rings and LUMO is located over the carbonyl group. In the case
of compound c, LUMO is located in one of the equatorially orientated aryl rings.
The higher value of HOMO indicates the ability of the molecule to donate elec-
trons to an appropriate acceptor molecule and a lower value of LUMO indicates the
ability of the molecule to accept electrons for an appropriate donor molecule. From
Table 4, it is evident that the HOMO for the title compound increased in the order
b (p-OCH3), d (p-CH3), a (H), e (p-F), c (p-Cl). This result reveals that the electron
donating group increases the nucleophilicity of the molecule. In the case of LUMO,
the order decreases c, e, a, d and b. This result reveals that the electron withdraw-
ing group increases the electrophilicity of the molecule. The energy of HOMO is
directly related to the ionization potential (I) and LUMO energy is directly related to
the electron afnity (A) of the molecule [28]. The global chemical reactivity descrip-
tors such as hardness, softness, chemical potential, electronegativity, and electrophi-
licity are calculated using the HOMO and LUMO values. These parameters are cal-
culated using the following equations [29–32], and the corresponding values for the
compounds (a–e) are presented in Table 4.
I = −EHOMO
(1)
A = −ELUMO
(2)
1 3

Quantum chemical, experimental, theoretical spectral (FT‑IR…
Fig. 4 The HOMO, HOMO-1, LUMO and LUMO+1 orbital of compound a–e. (a) represent compound
a, (b) represent compound b, (c) represent compound c, (d) represent compound d and (e) represent
compound e
(I + A)
Chemical potential(ꢀ) = −
(3)
2
(I + A)
Electronegativity(ꢀ) =
(4)
2
(I − A)
Global hardness(ꢀ) =
(5)
2
1 3

G. Vengatesh, M. Sundaravadivelu
Fig. 4 (continued)
Table 4 HOMO and LUMO energies and the global parameters of synthesized compounds (a–e)
Compound HOMO (eV) LUMO (eV) ΔE (eV) Total energy µ (eV) χ (eV) η (eV) S (eV)
a
b
c
d
e
−6.0679
−5.5699
−6.5471
−5.9424
−6.3920
−0.9532
−0.7714
−1.4601
−0.8190
−1.2852
5.1146
4.7984
5.0869
5.1234
5.1068
−1421
−1879
−3259
−1578
−1818
−3.5105 3.5105 2.5573 0.1955
−3.1706 3.1706 2.3992 0.2084
−4.0036 4.0036 2.5435 0.1965
−3.3807 3.3807 2.5617 0.1951
−3.8386 3.8386 2.5534 0.1958
1
Softness(S) =
(6)
2ꢀ
In the title compound (a–e), HOMO is located over any one of the axially ori-
ented aryl rings and LUMO is located over the carbonyl group. In the case of com-
pound c, LUMO is located in one of the equatorially orientated aryl rings. The ΔE
for the title compounds is around 5.1 eV. The ΔE is higher which confrms that the
molecule has a stable structure and also indicates that minimum charge transfer
interaction occurs within the molecule [33]. The higher ionization potential dem-
onstrates that, the higher energy is required to remove an electron from the HOMO.
The lower value of electron afnity indicates that the molecule easily undergoes an
electrophilic reaction. From Table 4, the compound d has the highest energy gap
value which means the low chemical reactivity (high kinetic stability), while the
compound b has the lowest value which means the highest chemical reactivity [34,
35]. Electronegativity represents the electron attracting capability of the molecule.
The higher the electronegativity, the stronger is the attracting power to accept an
electron from a donor molecule. From Table 4, it is observed that electronegativity
1 3

Quantum chemical, experimental, theoretical spectral (FT‑IR…
of the studied molecules follows the order c>e>a>d>b. This result indicates
that electron withdrawing group (c and e) containing compound easily accepts an
electron from the acceptor molecule. Chemical potential is related to reactivity and
stability of the molecule. The negative chemical potential value shows that the com-
pound is stable. The chemical potential value increases by the substitution of an
electron donating group. The highest value of chemical potential, −3.1706 eV was
obtained for the p-OCH3 substituted molecule. The order of the chemical potential in
the studied compounds are b>d>a>e>c. The unsubstituted molecule has higher
total energy compared to the substituted molecule. The order of the total energy in
the studied compounds is a>d>e>b>c. Higher hardness and lower softness val-
ues confrm that the molecule is less polarizable and higher molecular hardness is
associated with the molecule [36, 37].
Molecular electrostatic potential
Molecular electrostatic potential (MEP) are three-dimensional diagrams which can
be used to visualize the net electrostatic efect produced at that point by total charge
density distribution (electron+proton) of the molecule. MEP surface correlates with
chemical reactivity (electrophilic, nucleophilic), dipole moments, and the electron-
egativity of the molecule [38–40]. The MEP is a useful technique for studying the
electrostatic interaction with its adjacent groups and surroundings. It is additionally
used to predict the reactivity of the molecule towards the biological systems and
hydrogen bonding interaction [41]. The diferent values of the electrostatic poten-
tial at the MEP surface are represented by diferent colors; red and yellow repre-
sent regions of more and slightly electron rich electrostatic potential, respectively.
The green and blue color represent the region most positive and of zero electrostatic
potential, respectively.
As it can be seen from Fig. 5, the red region is mainly localized on a carbonyl
group of the ring, showing a most favorable site for the electrophilic attack, the yel-
low regions are localized on the phenyl groups. In Fig. 5b, for the MEP surface for
the methoxy-substituted phenyl ring, the red region is localized on carbonyl and
methoxy groups of the compound, with yellow color spread over the phenyl groups.
As observed in Fig. 5c and e, the red region is mainly localized on a carbonyl group,
the slightly electron rich yellow region localized on fuorine and chlorine atoms,
whereas more positive and zero electrostatic potential are localized over the phe-
nyl groups which are most reactive sites for a nucleophilic attack. These results are
expected because MEP correlates with electron density and electronegativity of the
molecule.
The natural bond orbital (NBO) analysis
The natural bond orbital (NBO) analysis provides an efcient method to understand
the various second-order interactions between the flled orbitals of one subsystem
and vacant orbitals of another subsystem, which supplement the analysis of both
the intra and intermolecular interactions. Computationally calculated localized
1 3

G. Vengatesh, M. Sundaravadivelu
Fig. 5 Molecular electrostatic potential surface of synthesized compounds a–e
molecular orbitals are used to study the distribution of electron density in atoms, in
bonds and in between the atoms. The stabilization energy (E(2)) for various conjuga-
tive interactions can be obtained from the second order perturbation theory [42]. In
NBO analysis the larger the E(2) value, the more intensive is the interaction between
electron donors and electron acceptors and the greater the extent of conjugation of
the whole system. The intensive interactions are given in the supporting information
Table S4–S8. The interaction result is a loss of occupancy from the localized NBO
of the idealized Lewis structure into an empty non-Lewis orbital [43, 44]. For each
donor, NBO (i) and acceptor NBO (j), the stabilization energy (E(2)) associated with
electron delocalization i to j is estimated by Eq. (7) [45]
F(i, j)2
E(2) = ΔEij = qi
,
(7)
ꢀi − ꢀj
where qi is the donor orbital occupancy, εi and εj are diagonal elements, and F(i,j) is
the of-diagonal NBO Fock matrix element.
In the compounds (a–e), NBO analysis shows that strong intermolecular hypercon-
jugative interaction occurs in π and a lone pair of electrons. The larger the stabilization
energy E(2) of the compound, the greater is the stability of the molecule. In the studied
compounds, the E(2) value are greater for the delocalization of the electrons between the
bond present in the substituted phenyl rings and lone pair electron containing atoms.
The lone pair electrons in nitrogen and oxygen atoms are delocalized to nearby anti-
bonding orbitals with high stabilization energy around 19–20 kJ mol−1. A strong intra-
molecular hyper-conjugative interaction is present within the substituted phenyl rings
1 3

Quantum chemical, experimental, theoretical spectral (FT‑IR…
with the stabilization energy around 19–22 kJ mol−1. In the studied compounds, two
pairs of phenyl rings are present, one pair oriented in the axial position and another
pair oriented in the equatorial position. In fuoride, chloride, methoxy substituted com-
pounds, four phenyl rings exhibit two sets of stabilization energy and electron density.
This is due to the presence of one pair of phenyl rings in axial positions and another
pair of phenyl rings in equatorial positions.
Local reactivity descriptors
The Fukui function gives information about the tendency of a molecule to lose or
gain an electron thus predicting which atom in the molecule would be more prone to
a nucleophilic or electrophilic attack. It is one of the most broadly used among local
reactivity determinants. The Fukui functions such as nucleophilic attack, electrophilic
attack, and radical attack have been calculated [46]. The individual atomic charges cal-
culated by Mulliken population analysis (MPA) and B3LYP/6-31G(d,p) level of theory
have been used to calculate the Fukui function. Fukui functions are calculated using the
following Eqs. (8)–(11),
For electrophilic attack fj− = qj(N) − qj(N − 1),
(8)
For nucleophilic attack fj+ = qj(N + 1) − qj(N),
(9)
For free radical attack fj0 = [qj(N + 1) − qj(N − 1)],
(10)
here, qj is the atomic charge at the jth atomic site, and (N), (N+1) and (N−1) are
the total electrons present in the neutral, anion and cation state of the studied mole-
cule, respectively [47]. Morell et al. [48] proposed a dual descriptor (Δf(r)), which is
defned as the diference between the nucleophilic and electrophilic Fukui function
and is given by the Eq. (11),
[
]
Δf(r) = f+(r) − f−(r) .
(11)
If Δf(r)>0, then the site is favored for a nucleophilic attack, whereas if Δf(r)<0,
then the site may be favored for an electrophilic attack. The calculated Fukui function
values are reported in Table S9–S13. The title compounds are susceptible to more elec-
trophilic attack than the nucleophilic attack. The results of the Fukui function analysis
are in good agreement with the MEP results. The isosurface density of the Fukui func-
tion for electrophilic attack (f−) and nucleophilic attack (f+) is also shown in Fig. 6.
Molecular docking analysis
Molecular docking analysis of 2RLF
The interaction between the ligand and the targeted proteins is presented in Fig. 7.
The binding energy, inhibition constant (ki) and reference root mean square
1 3

G. Vengatesh, M. Sundaravadivelu
Fig. 6 The nucleophilic Fukui functions (f+) and electrophilic Fukui functions (f−) and isosurface density
of the studied compounds in the gas phase (isosurface value=0.03; isosurface density=0.0004)
deviation (RMSD) are listed in Table 5. The docking results revealed that the syn-
thesized 1, 3-diazaadamantanone derivatives (a–e) in the binding pocket of 2RLF
displayed two types of interactions (π–π and π-sigma interactions). The residues
PHE54, PHE55, LYS49, and ILE51 are in close contact with the ligands. Inhibition
constant (ki) provides information about the ligand binding afnity to the protein
[49]. The result reveals that ligand a interacts with 2RLF protein and exhibits the
lower inhibition constant (883.62 nM) and lower binding energy (−8.26 kcal/mol)
compared with other ligands (b, c, d, and e).
It can be seen from Table 5, that the binding interaction of tetraaryl-1,3-dia-
zaadantan-6-one with the H1N1-M2 channel swine virus are much stronger than
those with the simple adamantane (amantadine, rimantadine, and memantine). This
suggests that the H1N1-M2 channel has lower binding afnities to the simple ada-
mantane, and it may be due to the studied compounds (a–e) containing π–π and
π-sigma interactions.
Molecular docking analysis of 4COX
The interaction between the ligand and the targeted proteins is presented in Fig. 8,
and essential parameters are shown in Table 6. Among the ligands (a–e) studied,
ligand c exhibited the highest docking score (binding energy—11.13 kcal/mol) and
inhibition constant (6.98 nM) in the active site of 4COX. Moreover, the ligands
1 3

Quantum chemical, experimental, theoretical spectral (FT‑IR…
Fig. 7 Molecular docking studies of synthesized compounds (a–e) against H1N1 swine virus
Table 5 Molecular docking parameters of compound (a–e) against H1N1 swine virus (2RLF)
Compound
Free energy of
binding (kcal/
mol)
Inhibition constant, Ki Reference RMS Closed content
a
b
−8.26
−8.22
883.62 nM
937.39 nM
12.87
11.48
PHE55, PHE54, ILE51
PHE47, ILE51, LYS49,
PHE54
c
−7.43
3.59 µM
12.9
PHE54, PHE47, PHE55,
ILE51
d
e
−7.43
−7.58
3.56 µM
2.76 µM
11.3
14.44
PHE54, PHE55, ILE51
PHE54, PHE55, ILE51,
LYS49
Amantadinea −4.96
Rimantadinea −5.22
Memantineaa −5.52
231.93 µM
150.15 µM
90.48 µM
17.32
16.67
16.16
PHE, LYS, SER
PHE, LYS, ILE
PHE, LYS, SER
aReference compound (simple adamantane)
studied did not demonstrate any hydrogen bond interaction with the active sites of
the protein, and it showed the least binding energies, because of π-sigma interac-
tions. This docking post analysis revealed that the compound c is oriented with the
non-covalent interactions surrounded by the side chains of LEU145 and LEU224 in
1 3

G. Vengatesh, M. Sundaravadivelu
Fig. 8 Molecular docking studies of synthesized compounds (a–e) against COX–2 protein
the target protein. The interaction of the ligands (a–e) with studied protein residue
are shown in Table 6.
These results in Table 6 reveal that the 4COX protein interaction with tetraaryl-
1,3-diazaadantan-6-one (a–e) exhibits the higher binding energy compared with the
simple adamantane (amantadine, rimantadine, and memantine). This may be due to
studied compounds (a–e) exhibiting π–π and π-sigma interactions but in the case of
amantadine, rimantadine and memantine this type of interaction is not possible.
Conclusion
In the present investigation, we have synthesized 4,8,9,10-tetraaryl-1,3-diaza-
adamantan-6-ones (a–e) and characterized by FT-IR, 1H and 13C NMR spec-
tra and experimental spectra compared with theoretical spectra. The computed
HOMO–LUMO energies with negative values and small orbital energy gap show
that the molecule is stable and the molecule readily undergoes electrophilic reac-
tion. The MEP reveals that the phenyl groups and the carbonyl group are the most
reactive sites for nucleophilic attack and electrophilic attack, respectively. The NBO
investigation demonstrates that a strong interaction exists within the phenyl groups
and the lone pair electron of oxygen and nitrogen with the anti-bonding orbitals of
carbon atoms. The docking results revealed that the compounds (a–e) in the bind-
ing pocket of 2RLF displayed mainly π interaction with PHE residues. Similarly,
the compounds (a–e) in the binding pocket of 4COX displayed mainly π interaction
1 3

Quantum chemical, experimental, theoretical spectral (FT‑IR…
1 3

G. Vengatesh, M. Sundaravadivelu
with LEU residue. The synthesized compounds have higher binding energy com-
pared to simple adamantanes. This preliminary result revealed that the compounds
(a–e) might exhibit anti-H1N1 swine virus and anti-COX-2 activity, which will be
of use for developing new drugs. However, biological tests should be done to vali-
date the computational predictions.
Acknowledgements The authors thank the UGC, New Delhi for Major Research Project (Grant No.
42-358/2013 (SR)) & UGC-Special Assistance Program (SAP). The authors gratefully acknowledge the
DST- FIST NMR facility of Department of Chemistry, Gandhigram Rural Institute-Deemed to be Univer-
sity for recording NMR spectra.
Compliance with ethical standards
Confict of interest The authors declare that they have no confict of interest in the manuscript.
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