Spectroscopic investigations and molecular docking study of 3-(1H-imidazol-1-yl)-1-phenylpropan-1-one, a potential precursor to bioactive agents

Article abstract of DOI:10.1016/j.molstruc.2015.12.075

The optimized molecular structure, vibrational wavenumbers, corresponding vibrational assignments of 3-(1H-imidazol-1-yl)-1-phenylpropan-1-one have been investigated theoretically and experimentally. The calculated geometrical parameters of the title comp

Full text of DOI:10.1016/j.molstruc.2015.12.075

Journal of Molecular Structure 1109 (2016) 131e138
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Spectroscopic investigations and molecular docking study of 3-(1H-
imidazol-1-yl)-1-phenylpropan-1-one, a potential precursor to
bioactive agents
Monirah A. Al-Alshaikh , Sheena Mary Y , C.Yohannan Panicker , Mohamed I. Attia c d,
a
b
b
,
*
,
c
e
Ali A. El-Emam , C.Van Alsenoy
Department of Chemistry, College of Sciences, King Saud University, Riyadh 11451, Saudi Arabia
Department of Physics, Fatima Mata National College, Kollam, Kerala, India
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Giza
2622, Egypt
a
b
c
d
1
e
Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, Antwerp B-2020, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 October 2015
Received in revised form
The optimized molecular structure, vibrational wavenumbers, corresponding vibrational assignments of
3-(1H-imidazol-1-yl)-1-phenylpropan-1-one have been investigated theoretically and experimentally.
The calculated geometrical parameters of the title compound are in agreement with the reported XRD
data. The HOMO and LUMO analysis is used to determine the charge transfer within the molecule. The
stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been
analyzed using NBO analysis. Molecular electrostatic potential was performed by the DFT method and
from the MEP plot, it is evident that the negative charge covers the carbonyl group and the nitrogen atom
27 December 2015
Accepted 28 December 2015
Available online 30 December 2015
Keywords:
DFT
3
N of the imidazole ring and the positive region is over the remaining portions of the molecule. The first
and second hyperpolarizabilities are calculated and the first hyperpolarizability of the title compound is
16.99 times that of standard NLO material urea and the title compound and its derivatives are good
object for further studies in nonlinear optics. The docked ligand title compound forms a stable complex
with plasmodium falciparum and gives a binding affinity value of ꢀ5.5 kcal/mol and the preliminary
results suggest that the compound might exhibit antimalarial activity against plasmodium falciparum.
Imidazole
Hyperpolarizability
Molecular docking
NBO
©
2015 Elsevier B.V. All rights reserved.
1
. Introduction
having azole moiety constitute the mainstay for treatment of fungal
infections owing to their safety profile and good therapeutic index
[4]. Azoles are nitrogen-containing five membered heterocyclic
compounds with electron-rich property. Thereby, they can easily
bind with the enzymes and receptors in organisms through weak
interactions such as coordination bonds, hydrogen bonds, ion-
dipole, p-p stacking as well as van der Waals force etc., leading to
diverse biological activities. The antifungal activity of azoles is
attributed to the co-ordination binding of the heterocyclic nitrogen
An increased incidence of both community-acquired and
nosocomial invasive fungal infections has been witnessed over the
past few decades. Nosocomial invasive and systemic fungal in-
fections are considered one of the major causes of morbidity and
mortality, particularly in patients with weakened or compromised
immune systems such as patients with cancer or AIDS and in organ
transplant cases [1,2]. In addition, Candida species represent the
main agent for nosocomial fungal infections worldwide with
Candida albicans being the cause for the majority of invasive can-
didiases with about 30e40% of mortality [3]. Antifungal agents
atom to the heme iron atom in the binding site of 14a-demethylase
enzyme causing depletion of ergosterol. The ability of azoles to
interact with the heme of many host cytochrome P450 enzymes,
particularly mammalian CYP3A4, is the reason for the appearance
of systemic azole toxicity [5,6]. Imidazole is a 1,3-diaza five
membered heterocyclic azole. A plethora of imidazole-bearing
antifungals have been used to treat fungal diseases due to their
*
Corresponding author.
E-mail address: cyphyp@rediffmail.com (C.Yohannan Panicker).
http://dx.doi.org/10.1016/j.molstruc.2015.12.075
022-2860/© 2015 Elsevier B.V. All rights reserved.
0

132
M.A. Al-Alshaikh et al. / Journal of Molecular Structure 1109 (2016) 131e138
low toxicity and broad antimicrobial spectrum including yeasts and
fungal strains. Accordingly, researchers were encouraged to
develop new antifungal agents incorporating imidazole moiety [7].
N-Alkylated imidazole moiety is a common feature in many anti-
fungal agents used in clinics, namely clotrimazole, miconazole,
econazole and ketoconazole [8]. Therefore, much more attention
has been paid in the investigations of such kind of antifungal im-
idazoles. The clinically available antifungal agents suffer from the
development of drug resistance, undesirable side effects and high
risk of toxicity [9]. This necessitates continuous efforts to develop
new potent antifungal agents with fewer side effects in order to
address these therapeutic issues. The title compound is an azole-
containing compound bearing N-alkylated imidazole moiety and
is the building block of a number of anti-Candida agents [10e12].
Spectroscopic studies of certain imidazole derivatives are
already reported [13e15]. The present work describes the natural
bond orbital analysis, molecular frontier orbital analysis, nonlinear
optical properties and molecular potential surface study of the title
compound. The experimentally observed infrared and Raman
bands have been assigned with the help of the calculated vibra-
tional frequencies and potential energy distribution analysis. In
addition, a molecular docking study of the title compound is also
reported due to the diverse biological activities of the imidazole
derivatives [16e18].
Fig. 2. FT-Raman spectrum of 3-(1H-imidazol-1-yl)-1-phenylpropan-1-one.
3. Computational details
All calculations have been performed with the Gaussian09
2
. Experimental details
software [20] using the density functional theoretical method [21].
The theoretical calculations were performed with the hybrid B3LYP
functional, i.e. a combination of the Becke's three parameter ex-
change functional [22] and Lee-Yang-Parr correlation functional
[23,24]. The DFT calculations were reported to provide excellent
vibrational frequencies of organic compounds if the calculated
frequencies are scaled to compensate for the approximate treat-
ment of electron correlation, for basis set deficiencies and for the
anharmonicity [25]. The optimized structure parameters (Fig. 3)
and frequencies were calculated using the DFT/B3LYP method at
6 e 311 þþ G(d) (5D, 7F) basis set level. The absence of imaginary
frequencies confirmed that the stationary points correspond to
minima on the potential energy surface. The vibrational assign-
ments of the title compound are done with the help of Guassview
program [26] and GAR2PED software [27]. The optimized
geometrical parameters with the XRD data are given in Table 1.
A pure sample of the title compound was prepared via the re-
action of 3-(dimethylamino)-1-phenylpropan-1-one hydrochloride
with imidazole in water following the previously reported proce-
dure of Attia et al. [19].
The FT-IR spectrum (Fig. 1) was recorded using KBr pellets on a
DR/Jasco FT-IR 6300 spectrometer with a spectral resolution of
ꢀ
1
2
cm . The FT-Raman spectrum (Fig. 2) was obtained on a Bruker
RFS 100/s, Germany, and for excitation of the spectrum, the emis-
sion of Nd:YAG laser was used, excitation wavelength was 1064 nm,
maximal power was 150 mW and measurement was carried out on
solid sample.
Fig. 1. FT-IR spectrum of 3-(1H-imidazol-1-yl)-1-phenylpropan-1-one.
Fig. 3. Optimized geometry of 3-(1H-imidazol-1-yl)-1-phenylpropan-1-one.

M.A. Al-Alshaikh et al. / Journal of Molecular Structure 1109 (2016) 131e138
133
ꢀ
1
Table 1
The CH
stretching modes are observed at 2965, 2921 cm in the
2
Optimized geometrical parameters of the title compound.
ꢀ1
IR spectrum, 2999, 2965, 2944, 2918 cm in the Raman spectrum
and theoretically in the range 3008e2919 cm . The deformation
ꢀ
1
Bond lengths (DFT/XRD) (Å)
O1eC15
N2eC22
N3eC22
C4eH5
C4eC14
C6eC8
C8eC10
C10eC12
C12eC14
C15eC16
C16eH18
C19eH20
C22eH23
C24eC26
1.2179/1.2152
1.3672/1.3445
1.3141/1.3098
1.0841/0.9300
1.4018/1.3909
1.3938/1.3832
1.3963/1.3762
1.3892/1.3812
1.4026/1.3937
1.5242/1.5052
1.0958/0.9700
1.0908/0.9700
1.0812/0.9300
1.3718/1.3493
N2eC19
N2eC26
N3eC24
C4eC6
C6eH7
C8eH9
C10eH11
C12eH13
C14eC15
C16eH17
C16eC19
C19eH21
C24eH25
C26eH27
1.4587/1.4576
1.3812/1.3612
1.3747/1.3622
1.3927/1.3842
1.0850/0.9300
1.0854/0.9300
1.0851/0.9300
1.0838/0.9300
1.4976/1.4960
1.0957/0.9700
1.5312/1.5142
1.0903/0.9700
1.0801/0.9300
1.0790/0.9300
modes of the CH
groups are assigned at 1444, 1415, 1366, 1294,
in the IR spectrum, 1444, 1415, 1370, 1351,
2
ꢀ1
1
269, 1252 cm
ꢀ1
1270 cm in the Raman spectrum and at 1441, 1418 (scissoring),
1
362, 1355 (wagging), 1296, 1267 (twisting), 1254, 1132 (rocking)
ꢀ1
cm theoretically as expected [29e31].
For phenyl rings, the CeH stretching modes are expected above
ꢀ1
3
000 cm [29]. In the title compound, the phenyl CH streching
ꢀ
1
modes are theoretically assigned in the range 3079e3042 cm
.
ꢀ
1
Experimentally, these bands are observed at 3060 cm in the IR
ꢀ
1
and at 3068 cm in Raman spectrum. The phenyl ring stretching
ꢀ1
ꢀ1
modes are assigned at 1575 cm (IR), 1580 cm (Raman) and in
the range 1579e1308 cm (DFT). The sixth phenyl ring stretching
ꢀ1
Bond angles (DFT/XRD) ꢀ( )
mode, the ring breathing vibration appears as a weak band near
C19eN2eC22
C22eN2eC26
H5eC4eC6
C6eC4eC14
C4eC6eC8
126.8/127.0
C19eN2eC26
C22eN3eC24
H5eC4eC14
C4eC6eH7
H7eC6eC8
126.9/126.9
105.2/104.1
120.6/119.8
119.9/119.9
120.1/119.9
120.0/119.8
120.0/119.9
119.9/119.9
120.5/120.7
119.1/118.6
118.3/118.9
120.2/120.8
109.2/109.0
112.4/113.0
110.1/109.0
112.1/111.4
108.1/109.3
110.4/109.3
112.4/112.9
125.7/123.6
110.5/110.9
105.8/106.1
132.3/126.9
ꢀ1
106.2/106.0
119.0/119.8
120.4/120.5
120.0/120.2
120.0/120.1
120.0/120.1
120.0/120.2
121.0/119.7
118.5/119.7
122.7/122.5
121.0/120.6
118.7/118.6
109.4/109.0
105.6/107.8
109.8/109.0
109.0/109.3
110.7/109.3
106.4/108.0
121.9/123.6
121.4/124.6
128.1/124.6
121.9/126.9
1000 cm in mono-, 1-3-di- and 1,3,5-tri substituted benzenes
[29,32]. In the present case, the PED analysis gives ring breathing
ꢀ1
mode at 1009 cm for the phenyl ring [29]. The CeH deformation
modes of the phenyl ring, in-plane and out-of-plane modes are
C6eC8eH9
H9eC8eC10
C6eC8eC10
ꢀ
1
C8eC10eH11
H11eC10eC12
C10eC12eC14
C4eC14eC12
C12eC14eC15
O1eC15eC16
C15eC16eH17
C15eC16eC19
H17eC16eC19
N2eC19eC16
N2eC19eH21
C16eC19eH21
N2eC22eN3
N3eC22eH23
N3eC24eC26
N2eC26eC24
C24eC26eH27
expected above and below 1000 cm , respectively [29]. The in-
plane CH deformation bands of the phenyl ring are observed at
C8eC10eC12
C10eC12eH13
H13eC12eC14
C4eC14eC15
O1eC15eC14
C14eC15eC16
C15eC16eH18
H17eC16eH18
H18eC16eC19
N2eC19eH20
C16eC19eH20
H20eC19eH21
N2eC22eH23
N3eC24eH25
H25eC24eC26
N2eC26eH27
ꢀ1
ꢀ1
1
063, 1013 cm in the IR spectrum, 1285, 1161, 1139, 1066 cm in
the Raman spectrum and theoretically in the range
ꢀ1
1
283e1010 cm . The CH out-of-plane deformation modes are
ꢀ
1
ꢀ1
assigned at 907, 825 cm in the IR spectrum, 905, 827 cm in the
ꢀ1
Raman spectrum and theoretically in the range 969e727 cm . The
ring substituent deformation modes are also identified and
assigned (Table 2) and most of the modes are not pure but contains
significant contributions from other modes.
For the title compound, the imidazole ring stretching modes are
ꢀ1
ꢀ1
observed at 1329, 1092, 997 cm in the IR spectrum, 1328 cm in
the Raman spectrum and theoretically at 1479, 1472, 1331, 1097,
ꢀ1
9
98 cm . This is in agreement with the work of Almajan et al. [33].
ꢀ1
Torsion angles (DFT/XRD) ꢀ( )
C14eC4C6C8
Sandhyarani et al. reported the CeN stretching mode at 1319 cm
0.0/0.3
C4eC6eC8eC10
0.0/-1.3
0.0/0.8
[34]. Benzon et al. reported the imidazole ring, CeN stretching
C6eC8eC10eC12
C6eC4eC14eC12
C10eC12eC14eC4
C4eC14eC15eO1
C4eC14eC15eC16
O1eC15eC16eC19
C22eN2eC19eC16
C15eC16eC19eN2
C26eN2eC22eN3
C22eN3eC24eC26
C22eN2eC26eC24
ꢀ0.0/0.8
ꢀ0.0/1.2
ꢀ0.0/-1.7
ꢀ179.5/-175.7
0.6/5.2
C8eC10eC12eC14
C6eC4eC14eC15
C10eC12eC14eC15
C12eC14eC15eO1
C12eC14eC15eC16
C14eC15eC16eC19
C26eN2eC19eC16
C24eN3eC22eN2
C19eN2eC22eN3
N3eC24eC26eN2
C19eN2eC26eC24
ꢀ1
ꢀ1
modes at 1247, 1129, 938 cm theoretically, 1248, 1135, 926 cm
in the Raman spectrum and 924 cm in the IR spectrum [13]. The
CeN stretching modes are reported at 1268, 1220, 1151 cm the-
oreticaly for benzimidazolium salts by Malek et al. [35]. The C]N
179.9/178.0
ꢀ180.0/-177.5
0.5/5.1
ꢀ179.5/-173.9
ꢀ179.9/177.3
78.2/89.2
ꢀ
1
ꢀ
1
0.1/-1.7
ꢀ1
stretching modes were reported in the range 1535e1666 cm [36],
ꢀ97.4/-87.0
179.5/179.6
0.3/0.2
0.0/-0.1
ꢀ0.3/-0.2
ꢀ1
ꢀ1
1
592 cm experimentally and theoretically at 1584 cm [37]. For
ꢀ0.2/-0.1
an imidazole derivative, the C]N stretching mode is theoeretically
176.6/177.0
0.2/0.1
ꢀ1
ꢀ1
assigned at 1464 cm , 1462 cm
in the IR spectrum and at
in the Raman spectrum [13]. The C19eN mode is
observed at 1212 cm in the IR spectrum, 1209 cm in the Raman
ꢀ
1
ꢀ176.6/-177.1
1464 cm
2
ꢀ1
ꢀ1
ꢀ1
spectrum and theoretically at 1214 cm for the title compound.
4
. Results and discussion
4.2. Nonlinear optical properties (NLO)
4.1. IR and raman spectra
Hyperpolarizabilities are very sensitive to the employed basis
The calculated (scaled) wave numbers, observed IR, Raman
set and level of theoretical approach [38e40] because the electron
correlation can change the value of hyperpolarizability. Urea is one
of the prototypical molecules used in the study of the nonlinear
properties of molecular systems. Therefore, it has been frequently
used as a threshold value for comparative purposes. The calcula-
tions of the total molecular dipole moment, linear polarizability
and first order hyperpolarizability from the Gaussian output have
been previously explained in detailed [41] and DFT has been
extensively used an effective method to investigate the organic NLO
material [42]. The polar properties of the title compound were
calculated by the density functional theory using the B3LYP method
with 6 e 311 þþ G(d) (5D, 7F) basis set using the Gaussian09
bands and assignments are given in Table 2 and in the following
discussion, the phenyl ring is designated as PhI and imidazole ring
ꢀ
1
as PhII. The bands observed at 1675 cm
in the IR spectrum,
ꢀ
1
ꢀ1
1
672 cm in the Raman spectrum and at 1671 cm (DFT) are
assigned as the stretching modes of the carbonyl (C]O) group.
According to literature, the stretching mode of the C]O group is
ꢀ1
expected in the range 1850e1550 cm [28]. The in-plane and out-
of-plane bending modes of the C]O group are reported in the
ꢀ1
ranges 725 ± 95 and 595 ± 120 cm [29]. For the title compound,
the C]O deformation bands are theoretically assigned at 616,
ꢀ
1
5
60 cm (DFT).
The stretching and deformation modes of the CH
in the regions 3020e2875, 1480-725 cm , respectively [29e31].
2
groups appear
program prackage. The calculated first hyperpolarizability of the
ꢀ
1
ꢀ30
title compound is 2.209 ꢁ 10
e.s.u, which is 16.99 times that of

134
M.A. Al-Alshaikh et al. / Journal of Molecular Structure 1109 (2016) 131e138
Table 2
Calculated (scaled) wavenumbers, observed IR, Raman bands and assignments of the title compound.
B3LYP/6 e 311 þþ G(d) (5D,7F)
IR
Raman
Assignmentsa
-
y
(cm 1
ꢀ
)
IR
I
R
A
y(cm
ꢀ1
)
y(cm
ꢀ1
)
3
3
3
3
3
3
3
3
3
2
2
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
9
9
9
9
9
9
8
8
8
8
7
7
7
6
6
6
6
6
6
6
5
4
4
3
3
3
2
2
1
1
9
6
5
134
110
108
079
071
062
052
042
008
966
947
919
671
579
560
479
472
469
441
426
418
362
355
331
308
296
283
267
254
214
178
159
142
132
097
067
054
034
010
009
98
79
69
50
48
05
83
24
17
04
81
70
27
94
89
74
47
16
11
07
60
70
12
96
79
25
74
16
53
38
2
1
0
3.71
3.34
5.33
7.20
12.13
25.38
8.37
0.23
8.79
14.17
3.44
12.08
193.14
28.50
12.56
34.42
32.62
9.48
11.99
25.30
4.60
53.40
43.31
1.30
9.75
48.76
9.63
19.87
12.49
26.11
126.24
53.86
3.36
1.36
18.87
3.41
28.16
7.34
7.56
9.93
8.14
5.49
0.23
57.24
0.60
1.26
9.69
0.43
2.59
0.49
107.96
94.90
42.83
135.56
169.13
76.37
123.15
46.53
27.14
76.41
33.54
84.19
75.13
123.96
10.86
3.71
10.74
3.68
5.76
5.44
8.62
8.02
5.53
45.05
3.98
2.48
0.64
9.66
12.13
5.69
39.58
8.23
6.61
2.09
5.96
1.52
11.07
13.79
6.68
23.06
3.32
41.86
0.04
2.35
0.02
0.09
1.46
0.04
1.52
14.82
0.34
0.62
0.28
1.50
1.58
0.01
0.09
3.11
0.37
5.69
0.06
1.46
0.12
0.01
1.74
0.49
1.50
1.89
2.66
0.58
0.11
0.41
3.02
3131
3111
e
3133
3112
e
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
d
d
d
d
d
d
y
d
d
y
d
d
d
y
d
d
d
y
y
d
y
d
y
y
d
CHII(98)
CHII(99)
CHII(98)
CHI(96)
CHI(94)
CHI(93)
CHI(96)
CHI(94)
e
e
e
3068
e
3060
e
e
e
e
e
2999
2965
2944
2918
1672
1580
e
CH
CH
CH
CH
2
2
2
2
(97)
(98)
(96)
(99)
2965
e
2921
1675
1575
e
C ¼ O(80)
PhI(57),
PhI(65),
d
d
y
d
y
CHI(18)
CHI(19)
CCII(25),
CHII(23),
PhI(55)
e
e
CNII(32),
CCII(24),
CHI(15),
d
y
CHII(29)
2
CNII(17), dCH (14)
e
e
e
e
1444
e
1444
e
CH
2
(76)
CHI(21),
y
PhI(69)
1415
1366
e
1415
1370
1351
1328
e
CH
CH
CH
2
2
2
(86)
(53),
(53),
y
CNII(23)
yCNII(20)
y
yPhI(63)
1329
e
CNII(59),
CHI(15),
CCII(13),
dCHII(10)
1294
e
e
CH
PhI(15),
CH (41),
2
(47),
y
PhI(27)
CH (17),
CNII(13),
CH (23),
CNII(11),
CH (18), CHI(17)
1285
1270
e
d
y
2
dCHI(48)
1269
1252
1212
1175
e
2
d
y
y
CHII(18)
CN(12),
CN(47)
CHII(31),
CHII(35),
d
y
2
yCNII(14)
1209
1180
1161
1139
e
CC(33),
CHI(69)
d
2
d
e
CHI(77),
CH (65),
CNII(64), d
y
PhI(17)
CNII(22)
CHII(27)
CHI(55)
CCII(28)
CH (19)
CNII(11),
PhII(10),
CH (36),
PhI(19)
e
2
y
1092
1063
e
e
1066
e
PhI(23), d
CHII(60), y
1036
1013
e
1034
e
CC(55),
d
2
CHI(46),
PhI(35),
y
d
d
CH
2
(14)
(15)
1005
e
dCH
2
997
979
e
CNII(44),
PhI(66),
CHI(81),
CC(45),
d
y
t
2
d
PhII(15)
977
e
g
y
g
g
PhI(14)
¼ O(11),
e
e
d
C
y
PhI(10)
e
e
CHI(89)
CHI(82)
907
e
905
e
dPhII(82)
g
g
825
e
827
e
CHI(97)
CHII(81),
t
PhII(13)
CC(39),
C ¼ O(13),
PhII(18)
e
803
e
d
d
CH
CH
2
2
(25),
(46),
y
g
dPhII(10)
1.66
e
t
PhI(10)
32.76
48.08
1.98
34.08
38.80
17.53
37.10
3.47
1.14
6.70
4.53
0.59
0.01
0.52
1.08
5.53
6.68
0.11
0.87
0.58
e
e
g
CHII(79),
t
e
e
t
d
PhI(30),
PhI(29),
g
d
CHI(40),
PhII(14),
d
CH
2
(16)
e
705
e
yCC(30)
691
671
e
gCHII(96)
670
642
617
e
t
t
PhI(62),
PhII(95)
gCHI(30)
620
e
d
t
d
g
C
¼ O(41),
d
PhI(14), PhII(20)
t
PhII(66),
PhI(72)
d
PhI(11), gCN(10)
e
e
562
474
411
e
565
e
C ¼ O(38),
g
CC(11),
CH2(21)
CC(19),
tPhI(17)
d
t
t
d
d
d
d
CC(52),
PhI(60),
PhI(83)
CH
CN(71)
CC(46),
d
416
395
e
g
g
C ¼ O(10)
¼ O(17), PhI(24)
CH (20)
e
2
(24),
d
C
d
e
e
e
e
d
2
e
e
CH
2
(33),
d
CC(34)
e
157
e
g
g
CC(31),
CN(41),
t
PhI(31),
t
CH
CH
C ¼ O(18)
(40), CN(12)
CC(10)
2
(15),
gC ¼ O(10)
e
dCC(38),
d
t
2
(12)
e
e
tCN(27),
t
CH
2
(38),
6.35
2.23
e
e
t
g
C ¼ O(30),
t
CH
2
t
e
e
CN(35),
dCH
2
(40),
d

M.A. Al-Alshaikh et al. / Journal of Molecular Structure 1109 (2016) 131e138
135
Table 2 (continued )
B3LYP/6 e 311 þþ G(d) (5D,7F)
IR
Raman
Assignmentsa
-
y
(cm 1
ꢀ
)
IR
I
R
A
y
(cm
ꢀ1
)
y(cm
ꢀ1
)
3
2
0
8
0.41
1.80
4.20
7.14
e
e
t
t
C ¼ O(46),
t
CH
(37)
2
(40)
-
-
CN(50), CH
t
2
a
y-stretching; d-in-plane deformation; g-out-of-plane deformation; t-torsion; PhI-Phenyl ring; PhII-imidazole ring; potential energy distribution (%) is given in brackets in
the assignment column.
ꢀ
30
standard NLO material urea (0.13 ꢁ 10
second hyperpolarizability
e.s.u) [43]. The average
is
n
s
2
(O
*(N
1
)/
s
*(C15eC16),
n
1
(N
2
)/
p
*(N
3
eC22
)
and
1 3
n (N )/
<
g>
¼
2
eC22) with stabilization energies 21.23, 47.50 and 9.31 kJ/mol
(g
xxxx
þ
g
yyyy
þ
gzzzz þ 2gxxyy þ 2
g
xxzz þ 2
gyyzz)/5. The theoretical
and electron densities 0.05940e, 0.38144e, and 0.04196e. The NBO
analysis also describes the bonding in terms of the natural hybrid
second order hyperpolarizability was calculated using the
ꢀ
37
Gaussian09 software and is equal to ꢀ11.614 ꢁ 10
e.s.u [44].
orbital n
with considerable p-character (100%) and low occupation number
(1.88831) and the other n (O ) occupy a lower energy orbital
ꢀ0.69024 a.u.) with p-character (43.37%) and high occupation
number (1.97778). Thus, a very close to pure p-type lone pair orbital
participates in the electron donation to the n (O )/ *(C15eC16),
(N )/ *(N eC22) and n (N )/ *(N eC22) interactions in the
2
(O
1
), which occupy a higher energy orbital (ꢀ0.26945 a.u.)
Accordingly, we conclude that the title compound is an attractive
object for future studies of nonlinear optical properties.
1
1
(
4
.3. Natural bond orbital analysis (NBO)
2
1
s
n
1
2
p
3
1
3
s
2
The natural bond orbitals (NBO) calculations were performed
compound. The results are tabulated in Table 4.
using the NBO 3.1 program [45] as implemented in the Gaussian09
package at the DFT/B3LYP level in order to understand various
second-order interactions between the filled orbitals of one sub-
system and vacant orbitals of another subsystem, which is a mea-
sure of the intermolecular delocalization or hyper conjugation. In
NBO analysis, large stabilization energy E(2) value shows the
intensive interaction between electron-donors and electron-
acceptors, and greater the extent of conjugation of the whole sys-
tem, the possible intensive interaction are given in Table 3. The
second-order perturbation theory analysis of Fock-matrix in NBO
basis shows strong intra-molecular hyper-conjugative interactions
4.4. Frontier molecular orbital analysis
The HOMO (highest occupied molecular orbital) and LUMO
(lowest unoccupied molecular orbital) energy gap of the title
compound has been calculated at the B3LYP/6 e 311 þþ G(d)
(5D,7F) level. These orbitals determine the way the molecule in-
teracts with other species. Fig. 4 shows the distributions and energy
levels of HOMO and LUMO orbitals computed at the B3LYP level for
the title compound. The HOMO is mainly localized on the imidazole
are formed by orbital overlap between n(O), n(N) and
s
*(CeN),
ring, CH
the CH
2
and carbonyl groups. The LUMO is mainly delocalized in
2
group, carbonyl group and the phenyl ring. This shows a
p
*(CeN), *(CeO), *(CeO), bond orbitals which result in intra-
s
p
molecular charge transfer causing stabilization of the system. The
important intra-molecular hyper-conjugative interactions are
charge transfer from the imidazole ring to the phenyl ring through
the methylene and carbonyl groups. The value of the energy
Table 3
Second-order perturbation theory analysis of Fock matrix in NBO basis corresponding to the intra-molecular bonds of the title compound.
Donor(i)
Type
ED/e
Acceptor(j)
Type
ED/e
E(2)a
E(j)-E(i)b
F(ij)c
N2eC22
s
1.98634
e
N2eC19
N2eC26
s
s
*
*
0.02693
0.02244
1.76
2.04
1.14
1.26
0.040
0.045
e
N3eC22
C14eC15
p
s
e
1.86756
1.98023
e
C24eC26
C4eC6
C4eC14
p
*
0.01866
0.01523
0.02284
21.54
1.99
2.13
0.33
1.24
1.23
0.078
0.044
0.046
s
s
*
*
e
e
e
e
e
e
e
e
e
C10eC12
C12eC14
C16eC19
s*
s*
s*
0.01446
0.02166
0.01883
2.25
1.84
1.29
1.25
1.23
1.03
0.047
0.042
0.033
e
C15eC16
s
e
1.98354
e
N2eC19
C12eC14
s
s
*
*
0.02693
0.02166
2.42
2.12
0.99
1.21
0.044
0.045
e
C16eC19
C24eC26
s
s
p
1.98194
1.98579
1.86234
C14eC15
N2eC19
N3eC22
s
s
p
*
*
*
0.06484
0.02693
0.38144
2.44
5.14
14.95
1.05
1.04
0.28
0.046
0.065
0.061
e
LPO1
s
e
1.97778
e
C14eC15
C15eC16
s
s
*
*
0.06484
0.05940
1.86
1.50
1.12
1.07
0.041
0.036
e
e
p
s
1.88831
C14eC15
C15eC16
s
*
*
0.06484
0.05940
19.61
21.23
0.70
0.65
0.106
0.106
e
s
e
LPN2
1.55450
e
N3eC22
C16eC19
p
s*
*
0.38144
0.01883
47.50
6.41
0.28
0.62
0.104
0.063
e
e
C24eC26
p*
0.30939
31.60
0.29
0.089
e
LPN3
-
s
1.92739
-
N2eC22
C24eC26
s
s
*
*
0.04196
0.01866
9.31
5.61
0.82
0.95
0.078
0.066
a
E(2) means energy of hyper-conjugative interactions (stabilization energy in kJ/mol).
Energy difference (a.u) between donor and acceptor i and j NBO orbitals.
F(i,j) is the Fock matrix elements (a.u) between i and j NBO orbitals.
b
c

136
M.A. Al-Alshaikh et al. / Journal of Molecular Structure 1109 (2016) 131e138
Table 4
chemical potential
m
¼
ꢀ7.051 eV and the global
NBO results showing the formation of Lewis and non-Lewis orbitals.
2
electrophiliciy ¼
m
/2
h
¼ 15.430 eV. It could be concluded that the
Bond(A-B) ED/ea
EDA% EDB% NBO
s%
p%
66.62
chemical potential of the title compound is negative and it indicates
that the compound is stable.
2
.00
s
N2-C22
1.98634 64.49 35.51 0.8031(sp )Nþ 33.38
2.32
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
0.79862
e
e
0.5959(sp )C
30.12
69.88
e
1.86756 56.87 43.13 0.741(sp1 )Nþ
.00
0.00 100.0
0.00 100.0
4.5. Molecular electrostatic potential (MEP)
p
N3-C22
1
.00
0.28527
e
e
0.6567(sp )C
e
2
.25
s
C14-C15
1.98023 52.11 47.89 0.7219(sp )Cþ
30.80
35.64
69.20
64.36
Molecular electrostatic potential at a point in the space around a
molecule gives an indication of the net electrostatic effect produced
at that point by the total charge distribution of the molecule and
correlates with dipole moments, electronegativity, partial charges
and chemical reactivity of the molecules [47]. It provides a visual
method to understand the relative polarity of the molecule. The
different values of the electrostatic potential at the MEP surface are
represented by different colours: red, blue and green represent the
regions of most negative, most positive and zero electrostatic po-
tential, respectively. The negative electrostatic potential corre-
sponds to an attraction of the proton by the aggregate electron
density in the molecule (shades of red), while the positive elec-
trostatic potential corresponds to the repulsion of the proton by the
atomic nuclei (shade of blue). The negative (red and yellow) regions
of the MEP were related to the electrophilic reactivity and the
positive (blue) regions to the nucleophilic reactivity. From the MEP
plot (Fig. 5), it is evident that the negative charge covers the
1
.80
0.66455
e
e
0.6920(sp )C
e
1
.90
s
C15-C16
1.98354 48.02 51.98 0.6930(sp )Cþ
34.49
26.23
65.51
73.77
2
.81
0.64285
e
e
0.7210(sp )C
e
2
.63
s
C16-C19
1.98194 50.65 49.35 0.7117(sp )Cþ
27.51
28.18
72.49
71.82
2
.55
0.62329
e
e
0.7025(sp )C
e
1
.73
s
C24-C26
1.98579 48.64 51.36 0.6974(sp )Cþ
36.56
38.02
63.44
61.98
1
.63
0.69421
e
e
0.7167(sp )C
e
1
.00
p
C24-C26
1.86234 48.30 51.70 0.6950(sp )Cþ
0.00 100.0
0.00 100.0
1
.00
0.25205
e
e
e
e
0.7190(sp )C
sp0.76
e
n1O1
1.97778
0.69024
56.63
43.37
e
n2O1
1.88831
0.26945
e
e
e
e
sp1.00
0.00 100.00
e
n1N2
1.55450
0.24958
sp99.99
0.09
99.01
66.74
e
n1N3
-
1.92739
e
e
sp2.00
-
33.26
-
ꢀ0.34085
-
-
-
a
ED/e in a.u.
carbonyl group and the nitrogen atom N
3
of the imidazole ring and
the positive region is over the remaining portions of the molecule.
4.6. Molecular docking
In addition to the well-documented antifungal activity of
imidazole derivatives, several imidazole and fused imidazole
structures are associated with a wide range of biological activities
including antiviral [48], anticancer [49,50], antitrypanosomal [51],
antimalarial [52e54], antihistaminic [55] and anticoagulant [56]
activities. Thus, it was of interest to study the molecular docking
of the title molecule as an inhibitor of plasmodium falciparum, the
causative agent of malaria. High resolution crystal structure of
plasmodium falciparum was downloaded from the protein data
bank website (PDB ID: 3PBL) and all molecular docking calculations
were performed on AutoDock-Vina software [57]. The 3D crystal
structure of plasmodium falciparum was obtained from the Protein
Data Bank and the protein was prepared for docking by removing
the co-crystallized ligands, water and co-factors and the Auto Dock
Tools (ADT) graphical user interface was used to calculate the
Kollman charges and polar hydrogens. The ligand was prepared for
docking by minimizing its energy at the B3LYP/6 e 311 þþ G(d)
(5D,7F) level of theory and the partial charges were calculated by
Geistenger method. The active site of the enzyme was defined to
Fig. 4. HOMO-LUMO plots of 3-(1H-imidazol-1-yl)-1-phenylpropan-1-one.
separation between the HOMO and LUMO is 3.222 eV. The lowering
of the HOMO-LUMO band gap is essentially a consequence of the
large stabilization of the LUMO due to the strong electron-acceptor
ability of the electron-acceptor group. Using HOMO and LUMO
orbital energies, the ionization energy and electron affinity can be
expressed as: I ¼ -EHOMO, A ¼ -ELUMO [46]. The hardness
chemical potential are given the following relations
¼ (I-A)/2
and
h and
m
h
m
¼ - (I þ A)/2, where I and A are the first ionization potential
and electron affinity of the chemical species [46]. For the title
compound, the EHOMO ¼ ꢀ8.662 eV, ELUMO ¼ ꢀ5.440 eV, Energy
gap ¼ HOMO-LUMO ¼ 3.222 eV, Ionization potential I ¼ 8.662 eV,
Electron affinity A ¼ 5.440 eV, global hardness
h
¼ 1.611 eV,
Fig. 5. MEP plot of 3-(1H-imidazol-1-yl)-1-phenylpropan-1-one.

M.A. Al-Alshaikh et al. / Journal of Molecular Structure 1109 (2016) 131e138
137
include the residues of the active site within the grid size of
0 Å ꢁ 40 Å ꢁ 40 Å and the most popular algorithm, Lamarckian
4
Genetic Algorithm (LGA) available in Autodock was employed for
docking and the docking protocol was tested by extracting co-
crystallized inhibitor from the protein and then docking the
same. The docking protocol predicted the same conformation as
was present in the crystal structure with RMSD value well within
the reliable range of 2 Å [58]. Amongst the docked conformations,
one which binds well at the active site was analyzed for detailed
interactions in Discover Studio Visualizer 4.0 software. The ligand
binds at the active site of the substrate (Figs. 6 and 7) by weak non-
covalent interactions. The amino acids Phe202, Tyr167 shows
p-p
interaction with the phenyl ring and Asn165, Gln203 forms
Hebond interaction with the C]O group and imidazole ring,
respectively. The docked ligand title compound forms a stable
complex with plasmodium falciparum and gives a binding affinity
(
D
G in kcal/mol) value of ꢀ5.5 (Table 5). These preliminary results
suggest that the compound might exhibit antimalarial activity
against plasmodium falciparum (Fig. 8).
Fig. 7. The docked protocol reproduced the co-crystallized conformation with H-bond
(green), p-anion (brown), alkyl (pink) and H-bond receptor surface.(For interpretation
of the references to colour in this figure legend, the reader is referred to the web
version of this article.)
4.7. Geometrical parameters
Table 5
In the title compound, the carbonecarbon bond lengths (DFT/
The binding affinity values of different poses of the title compound predicted by
AutodockVina.
XRD) in the phenyl ring lie in the range 1.3927e1.4026/
.3762e1.3937 Å and these values are somewhere in between the
normal values for a single (1.54 Å) and a double (1.33 Å) bond [59].
The C22eN
bond length (DFT/XRD) ¼ 1.3141/1.3098 Å shows
typical double bond characteristics. However, the C24eN
¼ 1.3747/
.3622, C26eN
1
Mode
Affinity (kcal/mol)
Distance from best mode (Å)
e
RMSD l.b.
RMSD u.b.
e
3
1
2
3
4
5
6
7
8
9
ꢀ5.5
ꢀ5.2
ꢀ5.1
ꢀ5.1
ꢀ5.0
ꢀ5.0
ꢀ5.0
ꢀ5.0
ꢀ5.0
0.000
2.584
26.737
3.207
2.719
1.520
22.820
3.923
2.749
0.000
3.287
28.337
4.036
3.638
2.180
26.244
5.431
4.733
3
1
2
¼ 1.3812/1.3612, C22eN ¼ 1.3672/1.3445 bond
2
lengths (DFT/XRD) are shorter than the normal CeN single bond
length of about 1.48 Å, while the reported corresponding values are
1
.407, 1.395, 1.3874 Å [60] and 1.4176, 1.4001, 1.391 Å [13]. At N
position, the bond angles (DFT/XRD) are C26eN
eC22 ¼ 106.2/106.0,
26eN eC19 ¼ 126.8/127.0 and this
eC19 ¼ 126.9/126.9 and C22eN
asymmetry in angles reveal the steric repulsion between the
imidazole ring and adjacent CH groups. The imidazole ring is tilted
from the adjacent methylene groups, as is evident from the torsion
2
2
ꢂ
C
2
2
2
angles,
C
24eC26eN
2
eC19
¼
ꢀ176.6,
C
26eN
2
eC19eC16
¼
78.2,
ꢂ
N
3
eC22eN
2
eC19 ¼ 176.6 and C22eN
2
eC19eC16 ¼ ꢀ97.4 .
Fig. 8. Pictorial representation of the ligand embedded in the active site of human
dopamine D3 receptor.
5. Conclusions
The vibrational spectroscopic studies of 3-(1H-imidazol-1-yl)-1-
phenylpropan-1-one were reported theoretically and experimen-
tally. Potential energy distribution of normal modes of vibrations
Fig. 6. Schematic presentation of the interaction of dopamine D3 receptor and ligand.

138
M.A. Al-Alshaikh et al. / Journal of Molecular Structure 1109 (2016) 131e138
was done with the help of GAR2PED software. The HOMO is mainly
localized on the imidazole ring, CH and carbonyl groups and the
LUMO is mainly delocalized in the CH group, carbonyl group and
Fox, Gaussian, Inc., Wallingford CT, 2010.
[
[
[
21] W. Kohn, L.J. Sham, Phys. Rev. A140 (1965) 1133e1138.
22] A.D. Becke, J. Chem, Phys. 98 (1993) 5648e5652.
23] B.K. Paul, N. Guchhait, Comput. Theor. Chem. 1012 (2013) 20e26.
2
2
the phenyl ring and the lowering of the HOMO-LUMO energy gap
supports for the bioactivity of the molecule. MEP predicts the most
reactive part in the molecule and from the MEP plot, it is evident
that the negative charge covers the carbonyl group and the nitro-
[24] C. Lee, W. Yang, R.G. Parr, Phys. Rev. B37 (1988) 785e789.
[
[
[
25] N.C. Handy, P.E. Masley, R.D. Amos, J.S. Andrews, C.W. Murray, G. Laming,
Chem. Phys. Lett. 197 (1992) 506e515.
26] R. Dennington, T. Keith, J. Millam, GaussView, Version 5, Semichem Inc.,
Shawnee Mission, KS, 2009.
27] J.M.L. Martin, C.V. Alsenoy, GAR2PED, a Program to Obtain a Potential Energy
Distribution from a Gaussian Archive Record, University of Antwerp, Belgium,
3
gen atom N of the imidazole ring and the positive region is over
the remaining portions of the molecule. The first and second
hyperpolarizability values are also reported and the title compound
is a good object for further studies in nonlinear optics. From the
molecular docking study, the ligand binds at the active site of the
substrate by weak non-covalent interactions and the amino acids
2007.
[28] G. Socrates, Infrared Characteristic Group Frequencies, John Wiley and Sons,
New York, 1981.
[29] N.P.G. Roeges, A Guide to the Complete Interpretation of Infrared Spectra of
Organic Structures, John Wiley and Sons Inc., New York, 1994.
[30] N.B. Colthup, L.H. Daly, S.E. Wiberly, Introduction to Infrared and Raman
Spectroscopy, Academic Press, New York, 1990.
Phe202, Tyr167 shows
p-p interaction with the phenyl ring and
[
31] R.M. Silverstein, F.X. Webster, Spectrometric Identification of Organic Com-
Asn165, Gln203 forms Hebond interaction with the C]O group
and imidazole ring, respectively.
th
pounds, 6 , John Wiley Asia, 2003.
[32] G. Varsanyi, Assignments of Vibrational Spectra of Seven Hundred Benzene
Derivatives, Wiley, New York, 1974.
[
[
[
[
[
33] G.L. Almajan, S.F. Barbuceanu, L. Farcasanau, C. Draghici, Rev. Chim. Buchar. 62
2011) 386e390.
34] N. Sandhyarani, G. Skanth, S. Berchmanns, V. Yegnaraman, T. Pradeep,
J. Colloid Interface Sci. 209 (1999) 154e161.
Acknowledgements
(
The authors would like to extend their sincere appreciation to
the Deanship of Scientific Research at King Saud University for
funding this work through the Research Group Project No. PRG-
35] K. Malek, A. Puc, G. Schroeder, V.I. Rybachenko, L.M. Proniewich, Chem. Phys.
327 (2006) 439e451.
36] S. Genç, N. Dege, A. Çetin, A. Cansiz, M. Sekerci, M. Dinçer, Acta Cryst. E60
(2004) o1580.
37] H. Tanak, Y. K o€ ysal, Y. Ünver, M. Yavuz, S¸ . I s¸ ik, K. Sanck, Mol. Phys. 108 (2010)
1436-23.
1
27e139.
References
[
[
38] A.E. Reed, L.A. Curtiss, F. Weinhold, Chem. Soc. 102 (1988) 899e926.
39] J.P. Foster, F. Weinhold, J. Am. Chem. Soc. 102 (1980) 7211e7218.
[1] S.K. Fridkin, W.R. Jarvis, Clin. Microbiol. Rev. 9 (1996) 499e511.
[2] J.R. Wingard, H. Leather, Biol. Blood Marrow Transpl. 10 (2004) 73e90.
[3] M.A. Pfaller, D.J. Diekema, Crit. Rev. Microbiol. 36 (2010) 1e53.
[4] W. Wang, C. Sheng, X. Che, H. Ji, Z. Miao, J. Yao, W. Zhang, Arch. Pharm. Chem.
Life Sci. 342 (2009) 732e739.
[40] H. Sekino, R.J. Bartlett, J. Chem. Phys. 84 (1986) 2726e2733.
[41] J. Henriksson, T. Saue, P. Norman, J. Chem. Phys. 128 (2008) 105e112.
[42] J.P. Hermann, D. Ricard, J. Ducuing, Appl. Phys. Lett. 23 (1973) 178e180.
[43] C. Adant, M. Dupuis, J.L. Bredas, Int. J. Quantum. Chem. 56 (2004) 497e507.
[44] C. H a€ tting, O. Christiansen, P. Jørgensen, Chem. Phys. Lett. 282 (1998)
[
[
5] J.T. Slama, J.L. Hancock, T. Rho, L. Sambucetti, K.A. Bachmann, Biochem.
Pharmacol. 55 (1998) 1881e1892.
6] H. Ji, W. Zhang, M. Zhang, M. Kudo, Y. Aoyama, Y. Yoshida, C. Sheng, Y. Song,
S. Yang, Y. Zhou, J. Med. Chem. 46 (2003) 474e485.
139e149.
[45] E.D. Glendening, A.E. Reed, J.E. Carpenter, F. Weinhold, NBO Version 3.1,
Gaussian Inc., Pittsburgh, PA, 2003.
[46] R.J. Parr, R.G. Pearson, J. Am. Chem. Soc. 105 (1983) 7512e7516.
[47] S. Sebastian, N. Sundaraganesan, Spectrochim. Acta A 75 (2010) 941e952.
[48] C.A. Dvorak, R. Apodaca, A.J. Barbier, C.W. Berridge, S.J. Wilson, J.D. Boggs,
W. Xiao, T.W. Lovenberg, N.I. Carruthers, J. Med. Chem. 48 (2005) 2229e2238.
[49] J. Chen, S. Ahn, J. Wang, Y. Lu, J.T. Dalton, D.D. Miller, W. Li, J. Med. Chem. 55
(2012) 7285e7289.
[
[
7] B. Narasimhan, D. Sharma, P. Kumar, Med. Chem. Res. 20 (2011) 1119e1140.
8] D.J. Sheehan, C.A. Hitchcock, C.M. Sibley, Clin. Microbiol. Rev. 12 (1999)
40e79.
[9] M.A. Hossain, M.A. Ghannoum, Exp. Opin. Invest. Drugs 9 (2000) 1797e1813.
[
[
[
[
[
[
10] M.N. Aboul-Enein, A.A. El-Azzouny, M.I. Attia, O.A. Saleh, A.L. Kansoh, Arch.
Pharm. Chem. Life Sci. 344 (2011) 794e801.
11] M.I. Attia, A.A. Radwan, A.S. Zakaria, M.S. Almutairi, S.W. Ghoneim, Chem.
Cent. J. 7 (2013) 168.
[50] R. Wang, C. Chen, X. Zhang, C. Zhang, Q. Zhong, G. Chen, Q. Zhang, S. Zheng,
G. Wang, Q.-H. Chen, J. Med. Chem. 58 (2015) 4713e4726.
[51] G. Andriani, E. Amata, J. Beatty, Z. Clements, B.J. Coffey, G. Courtemanche,
W. Devine, J. Erath, C.E. Juda, Z. Wawrzak, J.T. Wood, G.I. Lepesheva,
A. Rodriguez, M.P. Pollastri, J. Med. Chem. 56 (2013) 2556e2567.
[52] L. Zhang, R. Sathunuru, D. Caridha, B. Pybus, M.T. O'Neil, M.P. Kozar, A.J. Lin,
J. Med. Chem. 54 (2011) 6634e6646.
12] M.I. Attia, A.S. Zakaria, M.S. Almutairi, S.W. Ghoneim, Molecules 18 (2013)
12208e12221.
13] K.B. Benzon, H.T. Varghese, C.Y. Panicker, K. Pradhan, B.K. Tiwary, A.K. Nanda,
C. Van Alsenoy, Spectrochim. Acta A 151 (2015) 965e979.
14] N. Sundaraganesan, S. Ilakiamani, P. Subramani, B.D. Joshua, Spectrochim. Acta
A 67 (2007) 628e635.
15] K.B. Benzon, H.T. Varghese, C.Y. Panicker, K. Pradhan, B.K. Tiwary, A.K. Nanda,
C. Van Alsenoy, Spectrochim. Acta A 146 (2015) 307e322.
16] S.A. Laufer, W. Zimmermann, K.J. Ruff, J. Med. Chem. 47 (2004) 6311e6325.
17] O. Uçucu, N.G. Karaburun, I. I s¸ kdag, Farmaco 56 (2001) 285e290.
18] C.A. Hamilton, Pharmacol. Ther. 54 (1992) 231e248.
19] M.I. Attia, H.A. Ghabbour, A.A. El-Azzouny, O.A. Al-Deeb, M.S. Almutairi, H.-
K. Fun, J. Chem. 2013 (2013) 1e5. Article ID 515309.
20] Gaussian 09, Revision B.01, M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scu-
seria, M.A. Robb, J.R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G.A.
Petersson, H. Nakatsuji, M. Caricato, X. Li, H.P. Hratchian, A.F. Izmaylov, J.
Bloino, G. Zheng, J.L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J.
Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J.A.
Montgomery, Jr., J.E. Peralta, F. Ogliaro, M. Bearpark, J.J. Heyd, E. Brothers, K.N.
Kudin, V.N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A.
Rendell, J.C. Burant, S.S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J.M. Millam, M.
Klene, J.E. Knox, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E.
Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, R.L.
Martin, K. Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador, J.J. Dannenberg,
S. Dapprich, A.D. Daniels, O. Farkas, J.B. Foresman, J.V. Ortiz, J. Cioslowski, D.J.
[53] A.M. Sanz, F. G oꢁ mez-Contreras, P. Navarro, M. S ꢁa nchez-Moreno, S. Boutaleb-
Charki, J. Campuzano, M. Pardo, A. Osuna, C. Cano, M.J.R. Yunta, L. Campayo,
J. Med. Chem. 51 (2009) 1962e1966.
[54] G.N. Vazquez, M.D.M.R. Vilchis, L.Y. Mulia, V. Melendez, L. Gerena,
A.H. Campos, R. Castillo, F.H. Lui, Eur. J. Med. Chem. 41 (2006) 135e141.
[55] M. Govoni, R.A. Bakker, I. van de Wetering, M.J. Smit, W.M.B.P. Menge,
H. Timmerman, S. Elz, W. Schunack, R. Leurs, J. Med. Chem. 46 (2003)
5812e5824.
[56] J.J. Hangeland, T.J. Friends, K.A. Rossi, J.M. Smallheer, C. Wang, Z. Sun,
J.R. Corte, T. Fang, P.C. Wong, A.R. Rendina, F.A. Barbera, J.M. Bozarth,
J.M. Luettgen, C.A. Watson, G. Zhang, A. Wei, V. Ramamurthy, P.E. Morin,
G.S. Bisacchi, S. Subramaniam, P. Arunachalam, A. Mathur, D.A. Seiffert,
R.R. Wexler, M.L. Quan, J. Med. Chem. 57 (2014) 9915e9932.
[57] O. Trott, A.J. Olson, J. Comput. Chem. 31 (2010) 455e461.
[58] B. Kramer, M. Rarey, T. Lengauer, Proteins Struct. Funct. Genet. 37 (1999)
228e241.
[
[
[
[
€
ꢁ
ꢂ
[
[59] P. Sykes, A Guide Book to Mechanism in Organic Chemistry, sixth ed., Pearson
Education, India, New Delhi, 2004.
[60] Y.S. Mary, P.J. Jojo, C.Y. Panicker, C. Van Alsenoy, S. Ataei, I. Yildiz, Spectrochim.
Acta A 122 (2014) 499e511.