Vibrational spectroscopic investigations and molecular docking studies of biologically active 2-[4-(4-phenylbutanamido)phenyl]-5-ethylsulphonyl-benzoxazole

Article abstract of DOI:10.1016/j.molstruc.2017.07.023

The optimized molecular structure, vibrational wavenumbers, corresponding vibrational assignments of 2-[4-(4-phenylbutanamido)phenyl]-5-ethylsulphonyl-benzoxazole have been investigated experimentally and theoretically using Gaussian09 software. The waven

Full text of DOI:10.1016/j.molstruc.2017.07.023

Accepted Manuscript
Vibrational spectroscopic investigations and molecular docking studies of biologically
active 2-[4-(4-phenylbutanamido)phenyl]-5-ethylsulphonyl-benzoxazole
K. Jalaja, Monirah A. Al-Alshaikh, Y. Sheena Mary, C. Yohannan Panicker, Ali A. El-
Emam, Ozlem Temiz-Arpaci, C. Van Alsenoy
PII:
S0022-2860(17)30954-7
10.1016/j.molstruc.2017.07.023
MOLSTR 24050
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 27 January 2016
Revised Date: 1 June 2017
Accepted Date: 11 July 2017
Please cite this article as: K. Jalaja, M.A. Al-Alshaikh, Y.S. Mary, C.Y. Panicker, A.A. El-Emam, O.
Temiz-Arpaci, C.V. Alsenoy, Vibrational spectroscopic investigations and molecular docking studies of
biologically active 2-[4-(4-phenylbutanamido)phenyl]-5-ethylsulphonyl-benzoxazole, Journal of Molecular
Structure (2017), doi: 10.1016/j.molstruc.2017.07.023.
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Graphical abstract
Title of the paper: Synthesis, Vibrational Spectroscopic investigations, molecular
docking, antibacterial and antimicrobial studies of 2-[4-(4-phenylbutanamido)phenyl]-5-
ethylsulphonyl-benzoxazole

ACCEPTED MANUSCRIPT
Vibrational Spectroscopic investigations and molecular docking studies of biologically active
2-[4-(4-phenylbutanamido)phenyl]-5-ethylsulphonyl-benzoxazole
Jalaja Ka,b, Monirah A.Al-Alshaikhc, Sheena Mary Yd, C.Yohannan Panickerd*, Ali A.El-
Emame, Ozlem Temiz-Arpacif, C.Van Alsenoyg
aDepartment of Physics, IES College of Engineering, Chittilappilly, Thrissur, Kerala, India
bR and D, Bharathiar University, Coimbatore, Tamilnadu, India
cDepartment of Chemistry, College of Science, King Saud University, Riyadh 11451, Saudi
Arabia
dDepartment of Physics, Fatima Mata National College, Kollam, Kerala, India
eDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University,
Riyadh 11451, Saudi Arabia
fDepartment of Pharmaceutical Chemistry, Ankara University, TR-06100 Tandogan, Ankara,
Turkey
gDepartment of Chemistry, Universityof Antwerp, Groenenborgerlaan 171, B-2020, Antwerp,
Belgium
*author for correspondence:email: cyphyp@rediffmail.com
Abstract
The optimized molecular structure, vibrational wavenumbers, corresponding vibrational
assignments of 2-[4-(4-phenylbutanamido)phenyl]-5-ethylsulphonyl-benzoxazole have been
investigated experimentally and theoretically using Gaussian09 software. The wavenumbers
were assigned by potential energy distribution and the frontier molecular orbital 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. The MEP analysis shows that the negative electrostatic potential regions are
mainly localized over the oxygen’s of the carbonyl and sulfonyl groups and nitrogen atom of
the benzoxazole ring and are possible sites for electrophilic attack and the positive regions are
localized over the NH group as possible sites for nucleophilic attack. From the molecular
docking study, the ligand binds at the active sites of the protein by weak non-covalent
interactions most prominent of which are H-bonding, cation-π and sigma-π interactions.
Keywords: DFT; benzoxazole; ethylsulphonyl; Molecular docking.
1.
Introduction
Benzoxazoles are an important class of organic compounds, revealing a wealth of
interesting applications and as such, have attracted much interest in the research community
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and naturally occurring benzoxazoles [1] continue to offer tempting lead structures for
medicinal chemists to design novel drug candidates, aiming to expand upon the considerable
therapeutic uses [2, 3]. Metal derivatives of benzoxazole and benzothiazole have attracted
much attention due to their optical and luminescent properties [4]. Derivatives of
benzoxazole mainly exhibit antimicrobial [5, 6] and antiviral [7, 8] activities. The
benzoxazole derivatives have been also under investigation because of their potential
applicability using a light emitting element in light emitting devices and an electronic device
[9, 10]. Carboxyamidotriazole is a non-cytotoxic anti-tumor drug and it inhibits tumor cell
proliferation and induces cell apoptosis in vitro and has been undergoing clinical trials for
treating a variety of cancers [11, 12]. Zeyrek et al. [13] reported the experimental and
theoretical characterization of 2-(4-bromobenzyl)-5-ethylsulphonyl-1,3-benzoxazole. In the
present study, both experimental and molecular modeling are combined for studying the
optimized molecular structural parameters, vibrational spectra, total dipole moment, first and
second order hyperpolarizabilities and HOMO-LUMO energies for the title compound using
DFT/M05/ 6-311+G(d,p) (5D, 7F). In the present work, inhibitory of tyrosinase active 2-[4-
(4-phenylbutanamido)phenyl]-5-ethylsulphonyl-benzoxazole (compound 3) is re-synthesized
[14] and molecular docking studies is reported.
2.
Experimental details
2.1
Materials and Methods
The chemicals and solvents were purchased from Sigma-Aldrich Co. (Taufkirchen,
Munich Germany) and Fisher Scientific (Pittsburgh, PA, USA) and were used without
purification. Silica gel HF254 chromatoplates (0.3 mm) were used for TLC and the mobile
phase
was
chloroform/methanol
(10:0.5)
for
compound
3
(2-[4-(4-
phenylbutanamido)phenyl]-5-ethylsulphonyl-benzoxazole). Melting point was recorded on a
Stuart Scientific SMP 1 (Bibby Scientific Limited, Staffordshire, UK) instrument and
uncorrected. NMR spectra were recorded on a Varian Mercury 400 MHz NMR spectrometer
(Palo Alto, CA, USA) in CDCl3 or dimethylsulfoxide (DMSO-d6); tetramethylsilane (TMS)
was used as an internal standard. The mass spectra were recorded on a Waters ZQ Micromass
LC-MS spectrometer (Milford, MA, USA) using the ESI (+) method. Elemental analyse was
performed on an LECO 932 CHNS (St. Joseph, MI, USA) instrument and was within ±0.4%
of theoretical value.
2.2
General for the preparation of compound 3
5-Ethylsulphonyl-2-(p-amino-phenyl)benzoxazole (1) was synthesized by heating
0.01 mol 4-ethylsulphonyl-2-aminophenol. HCl with 0.01 mol p-amino-benzoic acid in 24 g
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polyphosphoric acid was stirred 3h. At the end of the reaction period, the resiude was poured
into ice-water, stirred and was neutralized with excess of 10% NaOH solution extracted with
benzene. The benzene solution was dried over anhydrous sodium sulphate and evaporated
under diminished pressure. The residue was boiled with 200 mg charcoal in ethanol and
filtered and a crude product was obtained and recrystallized from ethanol-water mixture and
compound 1 was dried in vacuo. Benzene butanoic acid (0.5 mmol) and thionyl chloride (1.5
ml) were refluxed in benzene (5 ml) at 80°C for 3 h. excess thionyl chloride was removed in
vacuo. The benzenebutanoyl chloride (2) were dissolved in ether (10 ml) and this solution
added during 1 h to a stirred, ice-cold mixture of 5-ethylsulphonyl-2-[p-amino-
phenyl]benzoxazole (1), (0.5 mmol), sodium bicarbonate (0.5 mmol), diethyl ether (10 ml)
and water (10 ml). The mixture was kept stirred overnight at room temperature and filtered.
The precipitate was washed with water, 2 N HCl and water, respectively and finally with
ether to give 3 (scheme 1, supporting material) [14]. The product was recrystallized from
ethanol-water as needles which are dried in vacuo. The chemical, physical and spectral data
of the compound 3 is reported below:
Compound 3: 2-[4-(4-phenylbutanamido)phenyl]-5-ethylsulphonyl-benzoxazole
1
C25H24N2O4S, yield: 41.72%, Mp: 250-251°C. H-NMR (400 MHz, d-DMSO, (δ ppm) J =
Hz): 10.327 (s, 1H), 8.263-8.259 (d, 1H, J4,6=1.6 Hz), 8.193-8.171 (d, 2H, J2’,3’=J6’,5’=8.8
Hz), 8.051-8.029 (d, 1H, J7,6=8.8 Hz), 7.936-7.910 (dd, 1H, J6,4=1,6 Hz, J6,7=8.6 Hz), 7.882-
7.861 (d, 2H, J3’,2’=J5’,6’=8.8 Hz), 3.413-3.350 (m, 2H), 7.323-7.195 (m, 5H), 2.668-2.630 (t,
2H), 2.419-2.382 (t, 2H), 1.946-1.909 (m, 2H), 1.128 (t, 3H) MS (70 eV) m/z: 449.8 (M++H)
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 RFS100/S FT-
Raman spectrometer (Nd:YAG laser, 1064 nm excitation).
2.3
Tyrosinase, AChE and BChE inhibitory activity
Inhibition of tyrosinase (EC 1.14.1.8.1, 30U, mushroom tyrosinase, Sigma) was
determined using the modified dopachrome method with L-DOPA as substrate [15]. Assays
were conducted in a 96-well microplate and an ELISA microplate reader (VersaMax
Molecular Device, USA) was used to measure absorbance at 475 nm. Forty microliters of
compounds dissolved in DMSO with 80 µl of phosphate buffer (pH 6.8), 40 µl of L-DOPA
were put each in well. Each sample was accompanied by a blank that had all the components
except for L-DOPA. Results were compared with a control consisting of 50% DMSO in place
of sample. The percentage tyrosinase inhibition was calculated as follows:
% Inhibiton = (Absorbancecontrol-Absorbancesample)/Absorbancecontrolx100
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AChE and BChE inhibitory activities were measured by slightly modifying the
spectrophotometric method developed by Elmann et al. [16]. Electric eel AChE (Type-VI-S,
EC3.1.1.7, Sigma) and horse serum BChE (EC 3.1.1.8, Sigma) were used while
acetythiocholine iodide and butyrylthiocholine chloride (Sigma, St. Louis, MO, USA) were
employed as substrates of the reaction. 5,5’-Dithio-bis(2-nitrobenzoic)acid (DTNB, Sigma,
St. Louis, MO, USA) was used for the measurement of the anticholinesterase activity. All
reagent and conditions were same as described in [17]. Briefly in this method, 140 µl of
sodium phosphate buffer (pH8.0), 20 µl of test solution and 20 µlAChE/BChE solution were
added by multichannel automatic pipette (Gilson pipetman, France) in a 96 well microplate
and incubated for 15 min at 25˚C. The reaction was initiated with the addition of 10 µl
acetythiocholine iodide/ butyrylthiocholine chloride. Hydrolysis of acetythiocholine iodide/
butyrylthiocholine chloride was monitored by the formation of the yellow 5-thio-2-nitro-
benzoate anion as a result of reaction of DTNB with thiocholines, catalyzed by enzymes at
412 nm utilizing a 96-well microplate reader (VersaMax molecular Devices, USA). The
measurements and calculations were evaluated by using Softmax PRO 4.3.2.IS software.
Percentage of inhibition of AChE/BChE was determined by comparison of rates of reaction
of samples relative to blank sample (ethanol in phosphate buffer pH 8.0) using the Formula
(E-S)/E × 100, where E is the activity of enzyme without test sample and S is the activity of
enzyme with test sample. The experiments were done in triplicate. Galanthamine used as
reference was purchased from Sigma (St. Louis, MO, USA) (Table 1).
3.
Computational details
Calculations of the title compound were carried out with Gaussian09 software program [18]
using M05/ 6-311+G(d,p) (5D, 7F) basis set to predict the molecular structure and vibrational
wavenumbers. Minnesota Functionals are developed by Truhlar’s group is based on
approximated exchange-correlation energy functionals in density functional theory. These
functionals are meta-GGA approximations, include terms that depend on the kinetic energy
density, and are based on flexible functional forms. M05 belongs to the first family of
Minnesota functionals are published in 2005 and it includes dispersion effects which are not
included in the case of widely used B3LYP functional. Zhao and Truhlar [19] have also
demonstrated better performance of M05 over B3LYP for main group thermochemistry.
Additionally, study by Zhao et al. [20] further confirms the performance of M05 family of
functional when it comes to the general purpose applications in thermochemistry, kinetics,
and noncovalent interactions involving nonmetals and suggests this functional to be used. We
also decided to use it since it is also recommended to be used for studies involving both
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metallic and nonmetallic elements. It is expected that upon using this functional a better
description of the geometric structure and calculated properties will be obtained [21]. Density
functional theory has been proven to be extremely useful in treating the electronic structure of
organic molecules. The basis set 6-311+G(d,p) (5D, 7F), which is an effective level with
reasonable cost to study fairly large organic molecules, was utilized. As the DFT hybrid
functional tends to overestimate the wavenumbers of the fundamental modes, a scaling factor
of 0.9613 has been uniformly applied to the calculated wavenumbers [22]. The assignments
of the calculated wavenumbers are aided by the animation option of GAUSSVIEW program
[23] and potential energy distribution by GAR2PED software package [24]. The theoretically
optimized geometrical parameters (Fig. 3) are given in Table 2.
4.
Results and discussion
4.1
IR and Raman spectra
The calculated (scaled) wavenumbers, observed IR, Raman bands and assignments
are given in Table 3. The NH stretching vibration [25] appears strongly and broadly in the
region 3490 ± 60 cm-1. For the title compound, the NH stretching band is observed in the IR
spectrum at 3375 cm-1 and the theoretical value is 3524 cm-1. The downshift of about 149 cm-
1
in the IR spectrum is due to the strong intra-molecular hydrogen bonding [26]. The hyper-
conjugative interactions, C21-O23 from N22 of n1(N22)→π*(C21-O23) and C21-N22 from O23 of
n2(O23)→σ*(C21-N22) support the above argument. The CNH vibration in which N and H
atoms move in opposite directions of carbon atom in the amide moiety appears at 1468 (IR),
1465 cm-1 (DFT) and the CNH vibration in which N and H atoms move in the same direction
of carbon atom in the amide group appear at 1281 cm-1 (DFT) [27, 28]. The NH rock in plane
is assigned at 1218 cm-1 theoretically [26]. The out of plane wagging of NH [25] is active
with a broad band in the region 790 ± 70 cm-1 and band at 834 cm-1 (DFT) is assigned as this
mode. Panicker et al. [29] reported NH deformation bands at 1538, 1220 cm-1 in IR spectrum
and at 1538, 1223 cm-1 theoretically. The NH deformation modes are reported at 1523, 1260,
1210, 875 cm-1 experimentally, 1518, 1256, 1221, 865 cm-1 theoretically by Sheeja et al. [26].
The CN stretching vibration [25] coupled with δNH is active in the region 1275±55 cm-1. In
the present case the CN stretching band is observed at 1240 cm-1 in the IR spectrum and at
1237, 1229 cm-1 theoretically. Bhagyasree et al. [30] reported CN stretching modes at 1247
and 1236 cm-1 for a similar derivative. The C=N stretching mode is expected in the range
1670-1500 cm-1 [31, 32] and in the present case this mode is assigned at 1617 cm-1 in the IR
spectrum, 1616 cm-1 in the Raman spectrum and at 1614 cm-1 theoretically.
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The carbonyl stretching C=O vibration [25, 28, 31] is expected in the region 1750-
1680 cm-1 and in the present case this mode appears at 1751 cm-1 in IR spectrum, 1750 cm-1
in Raman spectrum. The DFT calculations give this mode at 1751 cm-1. The in-plane and out-
of-plane C=O deformations are expected in the regions 625 ± 70 and 540 ± 80 cm-1,
respectively [25]. The C=O deformation bands are observed at 561 cm-1 in the IR spectrum,
560 cm-1 in the Raman spectrum and at 651, 563 cm-1 theoretically. For the title compound,
the COC stretching modes are observed at 1044 cm-1 in the IR spectrum, 1182 cm-1 in the
Raman spectrum and at 1182, 1045 cm-1 theoretically as expected [30, 31].
The asymmetric and symmetric stretching vibrations of SO2 are reported in the range
1330 ± 60 and 1180 ± 45 cm-1 respectively [25]. For the title compound, the DFT calculations
give these modes at 1313 and 1125 cm-1. These SO2 stretching modes are observed at 1130
cm-1 in the IR spectrum and at 1314, 1128 cm-1 in the Raman spectrum. The SO2 deformation
bands are expected in the regions 535 ± 40, 485 ± 50, 405 ± 65, 320 ± 40 cm-1 [25]. In the
present case, these bands are observed at 511 cm-1 in the Raman spectrum and the DFT
calculations give SO2 modes at 513, 425, 379 and 327 cm-1 and most of the bands are not
pure but contains significant contributions from other modes also. Rodriguez et al. [33]
reported the SO2 bands in the range 1242-1394, 590-632 and 460-470 cm-1. The C-S
stretching modes are assigned at 701 cm-1 in IR, 699 cm-1 in Raman and at 704, 660 cm-1
theoretically as expected [25].
The stretching vibrations of the CH2 group (the asymmetric and symmetric stretch)
appears in the regions 3000 ± 20 and 2900 ± 25 cm-1 respectively [25, 28]. The CH2
stretching modes are observed at 2970, 2932 cm-1 in the IR spectrum, 3030, 3010, 2980,
2934, 2920 cm-1 in the Raman spectrum and in the range 3032-2929 cm-1 theoretically. The
deformation modes of CH2 are observed at 1378, 1298, 1203 cm-1 in the IR spectrum, 1347,
1272, 1244, 1205 cm-1 in the Raman spectrum and in the range 1434-1100 cm-1 theoretically
as expected [25]. The asymmetric stretching vibrations of CH3 are expected in the range
2950-3050 cm-1 and symmetric CH3 vibrations in the range of 2900-2950 cm-1 [25, 28]. The
stretching modes of the methyl group are calculated (DFT) to be 3050, 3027 and 2954 cm-1.
The bands observed at 3025 cm-1 in the IR spectrum and at 3030 cm-1 in the Raman spectrum
was assigned as stretching modes of the methyl group. The deformation modes of the methyl
group are assigned at 1430-952 cm-1 theoretically and only one band is observed in the IR
spectrum at 1343 cm-1. The methyl torsions [25] often assigned in the region 185 ± 65 cm-1.
In the following discussion, the mono-, para- and tri-substituted phenyl rings and the
benzoxazole ring are designated as PhI, PhII, PhIII and PhIV, respectively. The phenyl CH
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stretching modes are observed at 3082, 3064 (IR), 3093, 3056 (Raman) for PhI, 3105 (IR) for
PhII and 3167 (IR), 3125 (Raman) for PhIII rings as expected [25]. The DFT calculations
give these modes in the range 3091-3054 cm-1 for PhI, 3115-3071 cm-1 for PhII and 3157-
3121 cm-1 for PhIII rings. The phenyl ring possesses six ring stretching modes and these
modes are observed at 1458 (IR), 1458 (Raman) for PhI, 1490 (Raman) for PhII and 1593,
1555 (IR), 1554, 1427 cm-1 (Raman) for PhIII rings. These phenyl ring modes are expected in
the range 1000-1600 cm-1 [25, 27] and the DFT calculations give these modes in the range,
1602-1310 cm-1 for PhI, 1603-1320 cm-1 for PhII and 1591-1349 cm-1 for PhIII rings. The
ring breathing mode of the phenyl ring appears as a weak band near 1000 cm-1 in mono
substituted benzenes and in the present case the DFT calculations give 1010 cm-1 as the ring
breathing mode for PhI. The ring breathing mode of the para substituted benzene compounds
with entirely different substituents has been reported in the range 700-830 cm-1 and in the
present case the band at 733 cm-1 (DFT) is assigned as the ring breathing mode of PhII [25].
In asymmetric tri-substituted benzene, when all the three substituents are light, the ring
breathing mode falls in the range 500-600 cm-1; when all the three substituents are heavy, it
appears above 1100 cm-1 and in the case of mixed substituents, it falls in the range 600-750
cm-1 [27]. For the tri-substituted phenyl ring PhIII, the ring breathing mode is assigned at
1095 cm-1 theoretically. Madhavan et al. [34] reported the ring breathing mode for a
compound having two tri-substituted benzene rings at 1110 and 1083 cm-1. The in-plane and
out-of-plane CH deformations of the phenyl rings are expected above 1000 cm-1 and below
1000 cm-1 [25]. In the present case, the in-plane CH deformation modes are observed at 1121,
1063 (IR), 1292, 1118, 1070 (Raman) for PhI, 1262, 1164 (IR), 1162, 982 (Raman) for PhII
and at 1182 cm-1 (Raman) for PhIII rings. The out-of-plane CH deformations are assigned at
878 (IR), 820 (Raman) for PhI, 958, 923, 842, 788 cm-1 (IR), 958, 840, 789 (Raman) for PhII
and at 920, 870 cm-1 (Raman) for PhIII. Most of the modes are not pure, but contains
significant contributions from other modes also.
4.2
Geometrical parameters
The aromatic rings of the title compound are somewhat irregular and the spread of C-
C bond distance is 1.3900-1.3961 in PhI, 1.3814-1.4012 in PhII and 1.3827-1.4022Å for
PhIII, which are similar to the spread reported by Bhagyasree et al. [35]. For the title
compound, the CN bond lengths are, C35-N46 = 1.2943, C37-N46 = 1.3807, C24-N22 = 1.3992
and C21-N22 = 1.3829Å. In the present case, the C=O bond length is 1.2104, C-O bond
lengths are 1.3719, 1.3545 and S=O bond lengths are 1.4549 and 1.4550Å. The C-O and C-N
bond lengths are different because of the difference in electro-negativity between O, N and S
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atoms and also assume a double bond character in C35-N46. For the title compound, the C-S
bond lengths are 1.8085 and 1.7923Å. Mary et al. [36] reported the C-S and S=O bond
lengths as 1.8021, 1.8260Å and 1.4739, 1.4731Å for a similar derivative. The bond angles at
C35 position, C31-C35-O45 (117.2˚), C31-C35-N46 (127.9˚) and O45-C35-N46 (115.0˚) indicates
the π bond character of the bonds. Bond angles C39-C37-N46 (131.3˚) and C38-C36-O45 (128.4˚)
are higher than 120˚ indicates the presence of hyper-conjugative interaction. At C6 position,
the bond angle C1-C6-C5 is 118.2˚ and this reduction in angle from 120˚ reveals the
interaction between the mono-substituted phenyl ring and the adjacent methylene groups. At
C24 position, the bond angles, C25-C24-N22 is increased by 3.4˚ and C26-C24-N22 is reduced by
2.6˚ from 120˚, which reveals the steric interaction between ring II and the NH group.
Similarly at C21 position, the bond angles are N22-C21-O23 = 123.6, O23-C21-C18 = 122.6 and
N22-C21-C18 = 113.8˚ and this asymmetry between the angles reveals the interaction between
C=O group with the neighboring units. The changes in CCO and CCN angles are due to the
difference in electronegativity between O, N and S atoms. The ethylsulphonyl moiety is tilted
from the ring PhIII as is evident from the torsion angles C37-C39-C42-S47 = 178.8, C39-C42-S47-
C50 = -95.0, C38-C40-C42-S47 = -178.8 and C40-C42-S47-C50 = 84.6˚.
4.3
Frontier Molecular orbitals
Knowledge of the highest occupied molecular orbital (HOMO) and lowest
unoccupied molecular orbital (LUMO) and their properties such as their energy is very useful
to gauge the chemical reactivity of the molecule. The HOMO and LUMO energies are very
useful for physicists and chemists and are very important terms in quantum chemistry [37].
The pictorial representation of the HOMO and the LUMO is shown in Fig.4. The HOMO
lies at -8.30 eV and whereas the LUMO is located at -5.114 eV and is delocalized over the
entire molecule with the exception, of the ethyl group of the ester function. This shows that
an eventual charge transfer occurs within the molecule, and that the frontier orbital energy
gap is 3.186 eV. The lower the energy gap the more easily are the electrons excited from the
ground to the excited state. The energy gap explains the eventual charge transfer interaction
within the molecule and is useful in determining molecular electrical transport properties.
Both the HOMO and LUMO orbital are the main orbitals that decide on the chemical stability
of the molecule. By using the HOMO and LUMO energy values, the global chemical
reactivity descriptors such as hardness, chemical potential, electro-negativity and
electrophilicity index as well as local reactivity can be defined [38]. Pauling introduced the
concept of electro-negativity as the power of an atom in a molecule to attract electrons to it.
Hardness (η), chemical potential (ꢀ) and electro-negativity (χ) are defined using Koopman’s
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theorem as η = (I-A)/2 = 1.593 eV, ꢀ= -(I+A)/2 = -6.707 eV and χ = (I+A)/2 = 6.707 eV,
where A and I are the ionization potential and electron affinity of the molecule. I= -EHOMO
=
8.30 eV and A = -ELUMO = 5.114 eV. One can also relate the stability of the molecule to
hardness, which means that the molecule with a lower energy gap shows higher reactivity.
Parr et al. [39] have defined a descriptor to quantify the global electrophilic power of the
molecule as the electrophilicity index, ω = ꢀ2/2η = 14.192 eV. The usefulness of this new
reactivity quantity has been demonstrated recently in understanding the toxicity of various
pollutants in terms of their reactivity and site selectivity [40].
4.4
Nonlinear Optical studies
Nonlinear optics deals with the interaction of applied electromagnetic fields in various
materials to generate new electromagnetic fields, altered in wavenumber, phase, or other
physical properties [41]. Quantum chemical calculations have been shown to be useful in the
description of the relationship between the electronic structure of systems and its NLO
response [42]. The first order hyperpolarizability of the title compound is calculated (using
M05/ 6-311+G(d,p) (5D, 7F) basis set) and is found to be 14.7×10-30 esu. The calculated
hyperpolarizability of the title compound is 113.08 times that of the standard NLO material
urea (0.13×10-30esu) [43]. The theoretical second order hyperpolarizability was calculated
using the Gaussian09 software and is equal to -97.5×10-37 esu. We conclude that the title
compound and its derivatives are an attractive object for future studies of nonlinear optical
properties.
4.5
Molecular Electrostatic Potential
Molecular electrostatic potential (MEP) at a point in space around a molecule gives
information about the net electrostatic effect produced at that point by the total charge
distribution over the molecule [44]. Moreover, the MEP surface helps to predict the reactivity
of a wide variety of chemical systems in both electrophilic and nucleophilic reactions, the
study of biological recognition processes and hydrogen bonding interactions [45]. The
different values of the electrostatic potential at the surface are represented by different colors;
red represents regions of most electro negative electrostatic potential, blue represents regions
of most positive electrostatic potential and green represents regions of zero potential. The
electrostatic potential increases in the order red < orange < yellow < green < blue [44]. To
predict reactive sites for electrophilic and nucleophilic attack in the investigated molecule,
the MEP surface is plotted for the title compound at DFT level [46]. Fig.5 shows the
electrostatic potential contour map of the title compound. The negative electrostatic potential
corresponds to an attraction of a proton by the aggregate electron density in the molecule
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(shades of red and yellow) and the positive electrostatic potential corresponds to the repulsion
of a proton by the nuclei (shades of blue). As can be seen from the Fig. 5, the negative
electrostatic potential regions are mainly localized over the oxygen’s of the carbonyl and
sulfonyl groups and nitrogen atom of the benzoxazole ring and are possible sites for
electrophilic attack. The positive regions are localized over the NH group as possible sites for
nucleophilic attack.
4.6
Natural Bond Orbital Analysis
The natural bond orbital (NBO) calculations were performed using NBO 3.1 program
[47] as implemented in the Gaussian09 package at the M05/ 6-311+G(d,p) (5D, 7F) and in
NBO analysis large stabilization energy E(2) value shows the intensive interaction between
electron donors and electron- acceptors and the possible intensive interaction are given in
Table 4. The various important hyper-conjugative interactions are: C21-O23 from N22 of
n1(N22)→π*(C21-O23), C21-N22 from O23 of n2(O23)→σ*(C21-N22), C35-N46 from O45 of
n2(O45)→π*(C35-N46), S47-O49 from O48 of n3(O48)→π*(S47-O49), S47-O48 from O49 of
n3(O49)→π*(S47-O48) with electron densities, 0.25556, 0.08093, 0.31126, 0.14398, 0.14511 e
and stabilization energies, 54.56, 28.40, 34.74, 23.21, 23.38 kJ/mol. The NBO analysis also
describes the bonding in terms of the natural hybrid orbital lone pair atoms and the orbitals
with higher energy and considerable p-character (100%) are: n2(O23), n2(O45), n3(O48), n3(O49)
with higher energy orbitals, -0.25593, -0.35152, -0.27384, -0.27331 a.u and low occupation
numbers, 1.85982, 1.72496, 1.78711, 1.78655. The orbitals with lower energy and high
occupation numbers are: n1(O23), n1(O45), n1(O48), n1(O49) with lower energy orbitals, -
0.67797, -0.59820, -0.76111, -0.76120 a.u and p-characters, 42.81, 63.36, 26.67, 26.58% and
high occupation numbers, 1.97414, 1.96833, 1.98228, 1.98218. Thus, a very close to pure p-
type lone pair orbital participates in the electron donation to the π*(C-C) orbitals for
n2(O45)→π*(C-C) and n2(O23)→π*(C-C) interactions respectively in the compound. The
results are tabulated in Table 5.
4.7
Biological activity and Molecular Docking
In this work we have used several freely available online tools in order to calculate
important descriptors valuable for the assessment of potential biological activity. Firstly,
using ALGOPS 2.1 program [48], we have calculated values of well known parameters, logP
and logS, frequently used for the assessment of important pharmaceutical properties. LogP
denotes octanol/water partition coefficient and this parameter is usually employed for the
assessment of lipophilicity of molecules. If logP takes value of ≤2 then such molecule is a
candidate for the transdermal delivery [49], while according to Yano et al. [50] the optimal
10

ACCEPTED MANUSCRIPT
value of logP for nonsteroidal anti-inflammatory drugs is ~ 2.5. The calculated logP value for
the title molecule is rather high (4.4) for transdermal use, but it is relatively close to the logP
values of commercially known drug such as indomethacin (3.8) [51]. Another important
parameter for the drug delivery is aqueous solubility (logs), which is also readily available for
calculation with ALGOPS 2.1 program. Calculated value of logS in the case of title molecule
is -4.83. Although more than 80% of drug molecules have logs values higher than -4.0, there
are also many molecules with logs between -4.0 and -6.0 [52], emphasizing relatively good
aqueous solubility of the title molecule. Another online tool that can be used for prediction of
activities based on structure is PASS (Prediction of Activity Spectra) [53]. PASS analysis
(table 6) of the 2-(p-(4-phenylbutanecarboxyamido)phenyl)-5-(ethylsulfonyl)benzoxazole
predicts amongst other activities, anti-diabetic activity with Pa (Probability to be active)
value of 0.430. Diabetes mellitus is characterized by chronic elevated blood glucose levels.
Glycogen Phosphorylase (GP), a key enzyme in the regulation of glycogen metabolism,
exists in two inter-convertible forms: the dephosphorylated form, GPb, and the
phosphorylated form, Gpa. Glycogen phosphorylase a (GPa) has been exploited as a specific
target of inhibitors that might prevent glycogenolysis under high glucose conditions in type II
diabetes [54, 55]. To evaluate the inhibitory nature of the compound against Glycogen
Phosphorylase a (Gpa) enzyme, molecular docking studies were carried out. The 3D crystal
structure of GPa was obtained from Protein Data Bank (PDB ID: 2GPA) [56]. 2GPA has a
good resolution (2 Å) and attached co-crystallized inhibitors were used to identify the active
site. Molecular docking is an efficient tool to get an insight into ligand-receptor interactions.
All molecular docking calculations were performed on AutoDock-Vina software [57]. The
AutoDock Tools (ADT) graphical user interface was used to calculate Kollmann charges for
the protein and to add polar hydrogen. Water molecules and co-crystallized ligands were
removed. The ligand was prepared for docking by minimizing its energy at M05/ 6-
311+G(d,p) (5D, 7F) level of theory. Partial charges were calculated by Geistenger method.
Torsion and rotatable bonds were defined. The active site of the enzyme was defined to
include residues of the active site within the grid size of 40 Å × 40 Å × 40 Å. Lamarckian
Genetic Algorithm (LGA) available in Auto Dock Vina was employed for docking. The
docking protocol was tested by removing co-crystallized inhibitor from the protein and then
docking it at the same site. To evaluate the quality of docking results, the common way is to
calculate the Root Mean Square Deviation (RMSD) between the docked pose and the known
crystal structure confirmation. RMSD values up to 2 Å are considered reliable for the
docking protocol [58]. The docking protocol we employed predicted a similar confirmation
11

ACCEPTED MANUSCRIPT
with RMSD value well within the allowed range of 2Å (Fig.6). Amongst the docked
confirmations of the title compound, the confirmation which was close to the confirmation of
co-crystallized ligand scored well was visualized for ligand-protein interactions in Discover
Studio Visualizer 4.0 and pymol software. The ligand binds at the active sites of the protein
by weak non-covalent interactions most prominent of which are H-bonding, cation-π and
sigma-π interactions. Amino acids viz. Asn284, Phe285, Lys574, Thr676, Gly677 and
Arg292 form H-bonds with the ligand (Figs.7 and 8). The residues Gly135 and Leu136 hold
the phenyl rings of the compound by alkyl-π interactions. Glu672 is involved in a cation-π
interaction with the ligand. Binding free energy (ꢁG in kcal/mol) of -10.7 as predicted by
Autodock Vina (Table 7) suggests good binding affinity. The inhibitor forms a stable
complex with GPa as is evident from the ligand-receptor interactions.
5
Conclusion
The molecular structural parameters and vibrational wavenumbers have been obtained using
density functional theory. Detailed vibrational assignments of the observed IR and Raman
bands have been proposed on the basis of potential energy distribution analysis and most of
the modes have wavenumbers in the expected range. The molecular electrostatic potential has
been mapped for predicting sites and relative reactivity towards electrophilic and nucleophilic
attack. The first and second order hyperpolarizabilities are calculated the first order
hyperpolarizability is 113.08 times that of the standard NLO material urea and hence the title
compound and its derivatives are good objects for future studies of nonlinear optics. In
summary, the title compound, 2-[4-(4-phenylbutanamido)phenyl]-5-ethylsulphonyl-
benzoxazole was re-synthesized and subjected to pharmacological evaluation. The results
showed that it possessed a weak to moderate tyrosinase inhibitory activity and was
unsuccessful in inhibition assays against AChE and BChE.
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-1436-23. The authors are thankful to University of Antwerp for access to the
University’s CalcUA Supercomputer Cluster.
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Figure captions
Fig.1 FT-IR spectrum of 2-[4-(4-phenylbutanamido)phenyl]-5-ethylsulphonyl-benzoxazole
Fig.2 FT-Raman spectrum of 2-[4-(4-phenylbutanamido)phenyl]-5-ethylsulphonyl-
benzoxazole
Fig.3 Optimized geometry of 2-[4-(4-phenylbutanamido)phenyl]-5-ethylsulphonyl-
benzoxazole
Fig.4 HOMO-LUMO plots of 2-[4-(4-phenylbutanamido)phenyl]-5-ethylsulphonyl-
benzoxazole
Fig.5 MEP plot of 2-[4-(4-phenylbutanamido)phenyl]-5-ethylsulphonyl-benzoxazole
Fig.6 Ligand-Protein interactions, H-bonds, cation-π and sigma-π interactions are represented
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Fig.8 The ligand and the co-crystallized inhibitor embedded into the catalytic site of GPa
18

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Table 1: Tyrosinase, acetylcholinesterase (AChE) and butrylycholinesterase (BChE) inhibitory activity of the synthesized compound 3 [19]
Inhibitory activity
against tyrosinase
(percentage ±SEMa) (percentage ±SEM) (2000
Inhibitory activity against
AChE and BChE
Compound No
R
X
(2000 µg/ml
µg/ml)
3
−H
−(CH2)3−
54.29±2.45
NA
Alpha-Kojic acid
(reference for tyrosinase
inhibition)
-
Galanthamine (reference
for AChE, BChE
inhibition)
-
1

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Table 2
Optimized geometrical parameters of the title compound
Bond lengths (Å)
C1-C2
1.3900
1.3905
1.0849
1.3960
1.0961
1.0926
1.0979
1.3829
1.0064
1.3838
1.0863
1.3981
1.3719
1.3827
1.3807
1.3894
1.0835
1.4550
1.0934
1.0925
C1-C6
1.3961
1.0852
1.3903
1.0869
1.0960
1.0956
1.0955
1.2104
1.4006
1.0790
1.3976
1.0832
1.2943
1.3545
1.3889
1.0829
1.7923
1.8085
1.5130
1.0910
C1-H7
1.0868
1.3903
1.0853
1.5045
1.5286
1.5215
1.5179
1.3992
1.4012
1.3814
1.0836
1.4528
1.3972
1.3917
1.0828
1.4022
1.4549
1.0918
1.0922
C2-C3
C2-H8
C3-C4
C3-H9
C4-C5
C4-H10
C6-C12
C5-C6
C5-H11
C12-H14
C15-H17
C18-H20
C21-O23
C24-C25
C25-H28
C27-C31
C29-H33
C35-N46
C36-O45
C38-C40
C39-H43
C42-S47
S47-C50
C50-C53
C53-H56
C12-H13
C15-H16
C18-H19
C21-N22
N22-H34
C25-C27
C26-H30
C29-C31
C35-O45
C36-C38
C37-N46
C39-C42
C40-H44
S47-O49
C50-H52
C53-H55
C12-C15
C15-C18
C18-C21
N22-C24
C24-C26
C26-C29
C27-H32
C31-C35
C36-C37
C37-C39
C38-H41
C40-C42
S47-O48
C50-H51
C53-H54
Bond angles (˚)
C2-C1-C6
C1-C2-C3
C2-C3-C4
C3-C4-C5
C4-C5-C6
C1-C6-C5
C6-C12-H13
121.0
120.1
119.5
120.1
121.0
118.2
109.5
C2-C1-H7
119.5
119.8
120.3
C6-C1-H7
119.4
120.1
120.3
C1-C2-H8
C2-C3-H9
C3-C2-H8
C4-C3-H9
C3-C4-H10 120.1
C4-C5-H11 119.5
C1-C6-C12 120.9
C6-C12-H14 109.3
C5-C4-H10 119.8
C6-C5-H11 119.5
C5-C6-C12 120.9
C6-C12-C15 112.8
1

ACCEPTED MANUSCRIPT
H13-C12-H14
C12-C15-H16
H16-C15-H17
C15-C18-H19
H19-C18-H20
C18-C21-N22
C21-N22-C24
N22-C24-C25
C24-C25-C27
C24-C26-C29
C25-C27-C31
C26-C29-C31
C27-C31-C29
C31-C35-O45
C37-C36-C38
C36-C37-C39
C36-C38-C40
C37-C39-C42
C38-C40-C42
C39-C42-C40
C35-O45-C36
C42-S47-O49
O48-S47-C50
S47-C50-H52
H51-C50-C53
C50-C53-H55
H54-C53-H56
Dihedral angles (˚)
C6-C1-C2-C3
C2-C1-C6-C5
H7-C1-C6-C12
106.4
110.1
106.1
109.7
106.3
113.8
129.5
123.4
119.6
120.8
121.4
120.2
118.8
117.2
124.2
119.8
115.8
116.5
120.7
123.0
104.4
107.9
107.9
102.2
113.3
109.5
108.6
H13-C12-C15 109.1
C12-C15-H17 109.4
H16-C15-C18 108.9
C15-C18-H20 110.5
H19-C18-C21 106.2
C18-C21-O23 122.6
C21-N22-H34 115.6
N22-C24-C26 117.4
C24-C25-H28 119.6
C24-C26-H30 119.8
C25-C27-H32 119.7
C26-C29-H33 119.7
C27-C31-C35 119.5
C31-C35-N46 127.9
C37-C36-O45 107.4
C36-C37-N46 108.9
C36-C38-H41 122.2
C37-C39-H43 122.0
C38-C40-H44 120.2
C39-C42-S47 118.7
C35-N46-C37 104.4
C42-S47-C50 104.5
O49-S47-C50 106.7
S47-C50-C53 114.6
H52-C50-C53 112.2
C50-C53-H56 110.9
H55-C53-H56 108.2
H14-C12-C15 109.5
C12-C15-C18 112.6
H17-C15-C18 109.5
C15-C18-C21 112.7
H20-C18-C21 111.0
N22-C21-O23 123.6
C24-N22-H34 114.8
C25-C24-C26 119.2
C27-C25-H28 120.8
C29-C26-H30 119.4
C31-C27-H32 118.9
C31-C29-H33 120.1
C29-C31-C35 121.7
O45-C35-N46 115.0
C38-C36-O45 128.4
C39-C37-N46 131.3
C40-C38-H41 122.0
C42-C39-H43 121.5
C42-C40-H44 119.1
C40-C42-S47 118.3
C42-S47-O48 107.9
O48-S47-O49 120.8
S47-C50-H51 105.7
H51-C50-H52 108.0
C50-C53-H54 111.8
H54-C53-H55 107.7
-0.0 H7-C1-C2-C3
-0.0 C2-C1-C6-C12
-2.0 C1-C2-C3-C4
-179.9 H7-C1-C2-H8
178.2 H7-C1-C6-C5
0.1 C1-C2-C3-H9
-0.0
179.8
179.8
2

ACCEPTED MANUSCRIPT
H8-C2-C3-C4
-179.7 H8-C2-C3-H9
179.7 H9-C3-C4-C5
-0.0 C3-C4-C5-H11
-0.1 C4-C5-C6-C1
-179.6 H11-C5-C6-C12
150.2 C1-C6-C12-C15
-31.6 C5-C6-C12-C15
-57.4 C6-C12-C15-C18
0.0
C2-C3-C4-C5
-0.1
C2-C3-C4-H10
C3-C4-C5-C6
-179.8 H9-C3-C4-H10
179.6 H10-C4-C5-C6
-0.1
-179.8
-178.2
34.0
H10-C4-C5-H11
H11-C5-C6-C1
C1-C6-C12-H14
C5-C6-C12-H14
C6-C12-C15-H17
0.1
2.1
C4-C5-C6-C12
C1-C6-C12-H13
-87.7 C5-C6-C12-H13
90.5 C6-C12-C15-H16
-147.8
58.8
-179.4 H13-C12-C15-H16 -63.1
H13-C12-C15-H17 -179.3 H13-C12-C15-C18 58.7 H14-C12-C15-H16 -179.1
H14-C12-C15-H17 64.7 H14-C12-C15-C18 -57.4 C12-C15-C18-H19 -56.6
C12-C15-C18-H20 60.3 C12-C15-C18-C21 -174.8 H16-C15-C18-H19 65.9
H16-C15-C18-H20 -177.2 H16-C15-C18-C21 -52.3 H17-C15-C18-H19 -178.6
H17-C15-C18-H20 -61.7 H17-C15-C18-C21 63.2 C15-C18-C21-N22 -146.0
C15-C18-C21-O23 35.4 H19-C18-C21-N22 93.8 H19-C18-C21-O23 -84.8
H20-C18-C21-N22 -21.4 H20-C18-C21-O23 160.0 C18-C21-N22-C24 -177.4
C18-C21-N22-H34 1.6
O23-C21-N22-C24 1.2
O23-C21-N22-H34 -180.0
C21-N22-C24-C25 -2.2 C21-N22-C24-C26 178.1 H34-N22-C24-C25 178.7
H34-N22-C24-C26 -0.9 N22-C24-C25-C27 -179.4 N22-C24-C25-H28 0.5
C26-C24-C25-C27 0.3
C26-C24-C25-H28 -179.8 N22-C24-C26-C29 179.5
N22-C24-C26-H30 -0.5 C25-C24-C26-C29 -0.2 C25-C24-C26-H30 179.8
C24-C25-C27-C31 -0.1 C24-C25-C27-H32 179.8 H28-C25-C27-C31 180.0
H28-C25-C27-H32 -0.1 C24-C26-C29-C31 -0.1 C24-C26-C29-H33 -180.0
H30-C26-C29-C31 179.9 H30-C26-C29-H33 0.0
C25-C27-C31-C29 -0.1
C25-C27-C31-C35 179.6 H32-C27-C31-C29 179.9 H32-C27-C31-C35 -0.3
C26-C29-C31-C27 0.2
H33-C29-C31-C35 0.4
C26-C29-C31-C35 -179.5 H33-C29-C31-C27 -179.9
C27-C31-C35-O45 179.3 C27-C31-C35-N46 -1.1
C29-C31-C35-O45 -1.0 C29-C31-C35-N46 178.7 C31-C35-O45-C36 179.6
N46-C35-O45-C36 -0.1 C31-C35-N46-C37 -179.6 O45-C35-N46-C37 0.1
C38-C36-C37-C39 0.4
O45-C36-C37-N46 0.1
C38-C36-C37-N46 -179.4 O45-C36-C37-C39 179.9
C37-C36-C38-C40 -0.5 C37-C36-C38-H41 178.7
O45-C36-C38-C40 -179.8 O45-C36-C38-H41 -0.6 C37-C36-O45-C35 -0.0
3

ACCEPTED MANUSCRIPT
C38-C36-O45-C35 179.4 C36-C37-C39-C42 0.2
N46-C37-C39-C42 180.0 N46-C37-C39-H43 1.2
C36-C37-C39-H43 -178.5
C36-C37-N46-C35 -0.1
C39-C37-N46-C35 -179.9 C36-C38-C40-C42 -0.1 C36-C38-C40-H44 178.2
H41-C38-C40-C42 -179.3 H41-C38-C40-H44 -1.0 C37-C39-C42-C40 -0.8
C37-C39-C42-S47 178.8 H43-C39-C42-C40 178.0 H43-C39-C42-S47 -2.4
C38-C40-C42-C39 0.8
H44-C40-C42-S47 2.9
C38-C40-C42-S47 -178.8 H44-C40-C42-C39 -177.5
C39-C42-S47-O48 19.6 C39-C42-S47-O49 151.7
C39-C42-S47-C50 -95.0 C40-C42-S47-O48 -160.8 C40-C42-S47-O49 -28.7
C40-C42-S47-C50 84.6 C42-S47-C50-H51 -58.5 C42-S47-C50-H52 -171.4
C42-S47-C50-C53 67.0 O48-S47-C50-H51 -173.2 O48-S47-C50-H52 73.9
O48-S47-C50-C53 -47.7 O49-S47-C50-H51 55.7 O49-S47-C50-H52 -57.2
O49-S47-C50-C53 -178.8 S47-C50-C53-H54 -64.7 S47-C50-C53-H55 176.0
S47-C50-C53-H56 56.6 H51-C50-C53-H54 56.7 H51-C50-C53-H55 -62.6
H51-C50-C53-H56 178.0 H52-C50-C53-H54 179.3 H52-C50-C53-H55 60.1
H52-C50-C53-H56 -59.3
4

ACCEPTED MANUSCRIPT
Table 3
Calculated (scaled) wavenumbers, observed IR, Raman bands and assignments of the title
compound
M05/6-311+G(d,p) (5D, 7F)
υ(cm-1)
IRI
-
RA
-
IR
υ(cm-1)
Raman
υ(cm-1)
Assignmentsa
-
-
3524
3157
3122
3121
3115
3111
3108
3091
3083
3071
3065
3057
3054
3050
3032
3027
3014
2976
2975
2972
2954
2951
2931
2929
1751
23.87 259.02
3.41 67.97
5.26 190.38
1.28 23.09
5.13 63.32
0.84 35.63
1.30 43.13
20.27 331.72
48.91 61.42
28.21 105.84
22.98 89.13
9.15 84.26
7.43 30.47
15.60 11.89
8.59 117.22
15.56 88.19
25.89 6.02
3375
-
υNH(100)
υCHIII(97)
υCHIII(99)
υCHIII(93)
υCHII(96)
υCHII(97)
υCHII(99)
υCHI(96)
3167
-
-
3125
-
-
-
-
-
-
3105
-
-
3093
3082
-
υCHI(95)
-
-
υCHII(95)
υCHI(96)
3064
-
-
-
υCHI(94)
-
3056
-
υCHI(100)
υCH3(69), υCH2(29)
υCH3(33), υCH2(66)
υCH3(73), υCH2(26)
υCH2(86)
-
-
3030
3030
3010
2980
-
3025
-
4.43 209.80
8.04 27.68
20.74 65.54
18.17 187.19
29.51 22.97
40.36 321.09
2.12 30.61
216.57 254.83
-
υCH2(98)
-
υCH2(88)
2970
-
υCH2(96)
-
-
υCH3(100)
υCH2(94)
-
-
2932
-
2934
2920
1750
υCH2(98)
υCH2(100)
υC=O(78)
1751
1

ACCEPTED MANUSCRIPT
1614
213.17 3996.78
1617
1616
υC=N(45),
υPhIII(10), υPhII(20)
υPhII(51), υPhIII(10)
υPhI(60), υPhIII(15)
υPhIII(61), υPhI(13)
υPhI(72), υPhII(11)
υPhII(53), υPhIII(14)
υC=N(24), υPhII(16),
υPhIII(41)
1603
1602
1591
1576
1570
1552
66.47 1986.46
25.57 86.00
13.71 450.15
0.82 9.30
-
-
-
-
1593
-
-
-
32.08 183.99
129.58 2959.63
-
-
1555
1554
1487
1465
1042.44 943.16
19.95 62.38
-
1490
-
δNH(14), υCN(17),
δCHII(10), υPhII(44)
δNH(40), δCHII(28),
υPhII(20)
1468
1461
1434
1430
18.53 2.06
12.12 1.85
3.71 135.96
1458
1458
δCHI(22), υPhI(48)
δCH2(89)
-
-
-
-
δCH3(47), υPhIII(16),
δCHIII(12)
1429
1423
1418
13.40 203.61
7.17 19.89
3.08 18.28
-
-
-
1427
δCH3(39), υPhIII(45)
δCH3(94)
-
-
δCH2(25), δCHI(12),
υPhI(47)
1417
1411
2.39 18.77
38.19 613.06
-
-
δCH2(52), δCHI(10),
υPhI(13)
1408
1408
υPhIII(43), υCN(18),
δCHIII(15)
1397
1386
1380
1349
1347
1342
25.35 12.64
245.12 310.73
9.01 8.69
-
-
δCH2(87)
-
-
υPhII(48), δCHII(28)
δCH2(90)
1378
-
64.83 18.40
44.23 59.29
14.42 13.16
-
-
δCH3(20), υPhIII(41)
δCH2(54), υCC(25)
δCH3(50), υPhIII(44)
-
1347
-
1343
2

ACCEPTED MANUSCRIPT
1320
1313
1310
1308
1288
1281
173.51 524.07
177.23 25.15
8.64 14.84
11.85 35.04
0.21 0.66
17.06 4.29
-
-
υPhII(56), δCH2(14)
υSO2(75)
-
1314
-
-
υPhI(74)
1298
-
δCH2(52), δCHI(22)
δCHI(79), δCH2(13)
δNH(41), υCC(12),
υPhII(16), υCO(13)
δCH2(64)
-
-
1292
-
1270
1267
1246
1237
1233
1229
1218
1214
1206
1183
1182
1158
1147
1140
1125
1121
1100
4.27 12.10
43.18 36.83
24.27 35.88
37.52 635.56
233.71 726.87
37.52 287.18
14.06 187.99
59.30 56.86
18.70 4.25
-
1272
1262
-
δCHII(69)
-
1244
δCH2(70), υSO2(12)
υCN(44), δCH2(25)
δCH2(56), υCN(21)
υCN(48), δCH2(29)
δCHIII(45), δNH(39)
δCH2(62), δCH3(15)
δCH2(66), δCH3(19)
υCC(28), δCH2(19)
υCO(41), δCHIII(45)
δCHII(75)
1240
-
-
-
-
-
-
-
-
-
1203
1205
4.07 48.58
11.28 63.32
67.31 499.34
0.60 3.96
1180
-
-
1182
1162
-
1164
-
δCHI(81), υPhI(11)
υCN(29), δCH2(24)
υSO2(81)
215.20 53.14
280.27 40.95
1.20 4.62
-
-
1130
1121
-
1128
1118
-
δCHI(81), υPhI(12)
δCH2(56),
68.30 35.15
δCHIII(17),
υPhIII(12)
1095
8.40 22.01
-
-
δCHIII(51),
υPhIII(44)
1094
1060
1046
16.14 59.01
7.43 2.82
4.01 2.25
-
-
υPhII(18), δCHII(53)
υPhI(24), δCHI(49)
υCC(45), δCH3(25)
1063
-
1070
-
3

ACCEPTED MANUSCRIPT
1045
1041
29.15 6.78
1044
-
-
-
υCC(27), υCO(40)
υCC(49), υPhIII(13),
δCHIII(10)
10.40 23.58
1028
92.07 2.08
-
1031
υPhIII(44),
δCHIII(22), υCO(12)
υCC(63), δCH2(13)
δCH3(46), δCH2(48)
δCHI(39), υPhI(56)
δCH2(65), δCHII(10),
υPhI(11)
1022
1012
1010
1005
31.09 33.87
9.67 3.97
4.39 21.03
12.55 0.79
-
-
-
-
-
-
1007
1002
980
966
958
953
952
12.77 3.86
0.53 38.55
0.35 0.41
0.01 0.05
2.23 2.64
-
982
δCHII(50), υPhI(16)
δPhI(16), γCHI(76)
γCHII(96)
-
-
958
958
-
-
-
-
γCHI(80), τPhI(12)
δCH3(44), υCC(28),
δCH2(15)
941
10.96 2.45
-
-
υCC(33), δNH(14),
υCN(22)
937
921
919
907
0.01 0.04
0.43 0.43
0.02 0.94
7.57 183.58
-
-
γCHI(92)
923
-
γCHII(87)
-
-
920
904
γCHIII(79), τPhII(13)
δPhIV(47), υCO(23),
υPhIII(10)
895
881
876
5.40 99.85
1.09 1.06
7.84 1.70
-
892
-
δPhIII(47), γCHI(23)
γCHI(80), τPhI(12)
γCHIII(79),
878
-
870
τPhIII(10)
836
834
819
815
19.14 1.33
9.30 1.00
1.59 0.91
7.49 3.91
842
-
840
-
γCHII(62)
γNH(44), γCHII(18)
γCHI(77)
-
820
-
813
δCH2(26), γCHI(26)
4

ACCEPTED MANUSCRIPT
807
796
793
791
8.40 4.39
1.46 26.01
2.44 3.96
37.41 0.62
-
805
-
υCC(20), δCH2(22),
δPhI(18), δPhII(15)
υCC(19), γCHIII(20),
δPhI(22), δPhII(25)
γCHII(27),
-
-
-
γCHIII(43)
788
789
γCHII(48),
γCHIII(30)
749
741
82.91 3.71
18.14 8.63
-
-
δCH2(53), δCH3(22)
τPhI(25), γCHI(14),
γCC(11), δC=O(11)
τPhIII(49), τPhIV(27)
υPhII(45), γCC(20),
τPhIV(15), τPhIII(11)
τPhI(32), γCHI(19),
δCH2(20)
742
742
736
733
0.85 1.94
21.53 5.63
-
-
-
-
723
5.36 4.78
-
725
709
704
3.95 9.91
-
712
699
δCH2(77)
93.47 10.35
701
υCS(47), δSO2(12),
δPhIV(12)
689
6.14 1.84
-
-
τPhII(51), τPhIV(14),
γCN(10)
680
660
46.65 0.40
-
-
668
-
τPhI(54), γCHI(36)
δPhIV(21), υCS(38),
δPhIII(15)
41.55 16.77
651
0.66 10.29
-
-
δPhII(29), γC=O(20),
δPhIV(24)
616
605
598
596
1.61 8.73
0.04 4.32
3.65 5.52
14.00 0.86
-
618
-
δPhII(77)
606
-
δPhI(87)
600
-
γCS(23), τPhIII(42)
γC=O(25), δPhI(20),
δPhIII(24)
596
5