Synthesis and spectroscopic study of three new oxadiazole derivatives with detailed computational evaluation of their reactivity and pharmaceutical potential

Article abstract of DOI:10.1016/j.molstruc.2018.07.026

Local reactivity properties and potential for application in new pharmaceutical compounds have been addressed for the three newly synthetized oxadiazole derivatives (2-(5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl)pyrazine (ORTHONITRO), 2-(5-(3-nitrophenyl)-1,3,4-oxadiazol-2-yl)pyrazine (METANITRO) and 2-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)pyrazine (PARANITRO), by application of computational molecular modeling. Within the framework of density functional theory (DFT) this study encompassed calculations of molecular electrostatic potential (MEP), average local ionization energies (ALIE) and bond dissociation energies for hydrogen abstraction (H-BDE). MD simulations have been used in order to assess the influence of water and to identify the atoms of these molecules with preference towards the interaction with water molecules. Molecular docking procedure has been applied in order to check the binding activity of these derivatives against the Glucan endo-1.6-beta-glucosidase inhibitor, Acrocylindropepsin inhibitor and Chymosin inhibitor proteins. The pharmaceutical potential of these derivatives has been assessed by the calculations of the well-established drug likeness parameters. A strong out-of-plane CH mode of the phenyl rings are observed at 769 cm^?1 for ORTHONITRO, 768 cm^?1 for METANITRO and at 848 cm^?1 for PARANITRO in the IR spectrum as expected for substituted benzenes. The VCD signals, corresponding to C[dbnd]N and NO₂ modes of the title compounds are good markers for assigning of absolute configuration. In the title compounds, in ORTHONITRO, the oxadiazole ring is tilted from the phenyl and pyrazine ring while for METANITRO and PARANITRO, there is a planar orientation. The first hyperpolariazabilities of ORTHONITRO, METANITRO and PARANITRO are respectively, 34.83, 54.50 and 174.05 times that of urea. For all the compounds, HOMO is delocalized over the pyrazine and oxadiazole rings, while LUMO is delocalized over whole molecule, except pyrazine ring of ORTHONITRO, over phenyl ring and NO₂ group of METANITRO and in the entire molecule of PARANITRO. The title compounds are docked with the proteins, Glucan endo-1.6-beta-glucosidase inhibitor, Acrocylindropepsin inhibitor and Chymosin inhibitor and METANITRO exhibits more inhibitory activity against the receptors than the other ligands. The results obtained from anti-TB activity are more promising as the compounds were found to be more potent than reference standard, ORTHONITRO (MIC = 1.6 μg/ml), METANITRO (MIC = 0.8 μg/ml), PARANITRO (MIC = 1.6 μg/ml), streptomycin (MIC = 6.2 μg/ml) and pyrazinamide (MIC = 3.1 μg/ml).

Full text of DOI:10.1016/j.molstruc.2018.07.026

Accepted Manuscript
Synthesis and spectroscopic study of three new oxadiazole derivatives with detailed
computational evaluation of their reactivity and pharmaceutical potential
Y. Sheena Mary, Pankaj B. Miniyar, Y. Shyma Mary, K.S. Resmi, C. Yohannan
Panicker, Stevan Armaković, Sanja J. Armaković, Renjith Thomas, B. Sureshkumar
PII:
S0022-2860(18)30845-7
10.1016/j.molstruc.2018.07.026
MOLSTR 25431
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 9 May 2018
Revised Date: 6 July 2018
Accepted Date: 7 July 2018
Please cite this article as: Y.S. Mary, P.B. Miniyar, Y.S. Mary, K.S. Resmi, C.Y. Panicker, S. Armaković,
S.J. Armaković, R. Thomas, B. Sureshkumar, Synthesis and spectroscopic study of three new
oxadiazole derivatives with detailed computational evaluation of their reactivity and pharmaceutical
potential, Journal of Molecular Structure (2018), doi: 10.1016/j.molstruc.2018.07.026.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Synthesis and spectroscopic study of three new oxadiazole derivatives with detailed
computational evaluation of their reactivity and pharmaceutical potential
a*
b
a
a
Y.Sheena Mary , Pankaj B.Miniyar , Y.Shyma Mary , K.S.Resmi , C.Yohannan
a
c
d
e
f
Panicker , StevanArmaković , Sanja J. Armaković , Renjith Thomas , B.Sureshkumar
a
Department of Physics, Fatima Mata National College, Kollam, Kerala, India
b
Department of Pharmaceutical Chemistry, Sinhgad Institute of Pharmacy, Narhe, Pune,
University of Pune, Ganeshkhind, India
c
University of Novi Sad, Faculty of Sciences, Department of Physics, Trg D. Obradovića
4
, 21000 Novi Sad, Serbia
d
University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry
and Environmental Protection, Trg D. Obradovića 3, 21000 Novi Sad, Serbia
e
Department of Chemistry, St. Berchmans College (Autonomous), Changanacherry,
Kerala, India
f
Department of Chemistry, S.N. College, Kollam, Kerala, India
*
author for correspondence: email: sypanicker@rediffmail.com
Abstract
Local reactivity properties and potential for application in new pharmaceutical
compounds have been addressed for the three newly synthetized oxadiazole derivatives
(
2-(5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl)pyrazine
nitrophenyl)-1,3,4-oxadiazol-2-yl)pyrazine (METANITRO) and 2-(5-(4-nitrophenyl)-
,3,4-oxadiazol-2-yl)pyrazine (PARANITRO), by application of computational
(ORTHONITRO),
2-(5-(3-
1
molecular modeling. Within the framework of density functional theory (DFT) this study
encompassed calculations of molecular electrostatic potential (MEP), average local
ionization energies (ALIE) and bond dissociation energies for hydrogen abstraction (H-
BDE). MD simulations have been used in order to assess the influence of water and to
identify the atoms of these molecules with preference towards the interaction with water
1

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molecules. Molecular docking procedure has been applied in order to check the binding
activity of these derivatives against the Glucan endo-1.6-beta-glucosidase inhibitor,
Acrocylindropepsin inhibitor and Chymosin inhibitor proteins. The pharmaceutical
potential of these derivatives has been assessed by the calculations of the well-established
drug likeness parameters. A strong out-of-plane CH mode of the phenyl rings are
-1
-1
-1
observed at 769 cm for ORTHONITRO, 768 cm for METANITRO and at 848 cm for
PARANITRO in the IR spectrum as expected for substituted benzenes. The VCD signals,
corresponding to C=N and NO modes of the title compounds are good markers for
2
assigning of absolute configuration. In the title compounds, in ORTHONITRO, the
oxadiazole ring is tilted from the phenyl and pyrazine ring while for METANITRO and
PARANITRO, there is a planar orientation. The first hyperpolariazabilities of
ORTHONITRO, METANITRO and PARANITRO are respectively, 34.83, 54.50 and
1
74.05 times that of urea. For all the compounds, HOMO is delocalized over the pyrazine
and oxadiazole rings, while LUMO is delocalized over whole molecule, except pyrazine
ring of ORTHONITRO, over phenyl ring and NO group of METANITRO and in the
2
entire molecule of PARANITRO. The title compounds are docked with the proteins,
Glucan endo-1.6-beta-glucosidase inhibitor, Acrocylindropepsin inhibitor and Chymosin
inhibitor and METANITRO exhibits more inhibitory activity against the receptors than
the other ligands. The results obtained from anti-TB activity are more promising as the
compounds were found to be more potent than reference standard, ORTHONITRO (MIC
=
1.6 µg/ml), METANITRO (MIC = 0.8 µg/ml), PARANITRO (MIC =1.6 µg/ml),
streptomycin (MIC =6.2 µg/ml) and pyrazinamide (MIC =3.1 µg/ml).
Keywords: DFT, ALIE; RDF; BDE; Pyrazine; Molecular docking.
1
.
Introduction
The pyrazine nucleus is found in drug pyrazinamide which is used as first line
agent in the treatment of tuberculosis. But it has developed resistance by the M.Tb. so
there is urgent need to develop new derivatives of pyrazinamide having greater potency
[1]. In the present study, an attempt has been made to cyclise various substituted pyrazin-
2
-carbohydrazides into 1,3,4-oxadiazole derivatives to explore the possibilities against
M.Tb. Hence the various condensed oxadiazole and pyrazine derivatives have been
1
synthesized whose characterization has been made by Infrared and H Nuclear magnetic
2

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Resonance and Mass spectroscopy studies and their anti-tubercular activity have been
screened against MTb H RV. A combination of density functional theory (DFT)
3
7
calculations, molecular dynamics (MD) simulations, drug likeness parameters and
molecular docking procedures has been applied in order to address the fundamental
reactive properties of the newly synthetized oxadiazole derivatives. The aforementioned
computational tools are known to be highly efficient when it comes to the detailed
understanding of newly synthetized organic molecules [2-6]. Since these newly
synthetized oxadiazole derivatives have the potential to be applied as pharmaceutical
compounds, locating their reactive sites is of high importance for understanding their
degradation properties as well [7-13].
2
2
.
Experimental
.1. Materials and Instrumentation
The starting material, pyrazinamide was extracted from the tablet PZA CIBA 750
mg, as per the procedure given in the Indian Pharmacopeia (IP). It was characterized by
melting point and IR. The chemicals and organic solvents used for synthesis were of
laboratory grade (LR) grade. The progress of the reaction and purity of the compounds
was confirmed by Merck pre-coated Thin Layer Chromatography (TLC) plates and spots
were rendered visible by exposing to UV light and iodine fumes. Melting points were
determined in open capillaries using melting point apparatus (VEEGO VMP-D) and
reported as uncorrected. FT-IR spectra (Fig.S1-supporting material) were recorded on
-1 1
JASCO FTIR 4100 series in the range of 4000-400 cm . HNMR spectra were recorded
on Varian-NMR-Mercury 300 using DMSO as a solvent and their chemical shifts are
recorded in δ (parts per million) units with respect to tetramethylsilane (TMS) as an
internal standard. Mass spectra were recorded using time of flight detector.
2
.2. Organic synthesis
Pyrazinoic acid 2 [14] was prepared from pyrazinamide by alkaline hydrolysis.
The core intermediate pyrazinoic acid hydrazide 4 was prepared from pyrazinoic acid 2
by esterification followed by hydrazinolysis. The hydrazones 5 (a,b,d) were prepared by
condensation of hydrazide 4 with different substituted aromatic aldehyde in ethanol. The
final compounds 6 (ORTHONITRO, METANITRO and PARANITRO) was prepared
3

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according to procedure described in literature. The structure of the final compounds was
1
fully characterized on the basis of melting points, IR, HNMR, mass spectra.
Synthesis of pyrazinoic acid 2 [14]: Yield 50%; m. p. 224-226°C.
Synthesis of pyrazinoic acid hydrazide 4 [14]:Yield 60%; m. p. 175-177°C.
General procedure for synthesis of pyrazine-2-carbohydrazide 5 [15]
A mixture of pyrazinoic acid hydrazide 4 (1mmol), substituted aromatic aldehyde
(1mmol) in ethanol (5mL) was heated under reflux with stirring for 30 min. Water (5mL)
was added and the precipitated product was filtered and re-crystallized from ethanol.
General procedure for synthesis of 2,5-disubstituted-1,3,4-oxadiazole 6 [15]
Pyrazine-2-carbohydrazide 5a,b,d (0.75mmol) and ceric ammonium nitrate (CAN)
(1mmol) were ground in a mortar and pestle at room temperature without any solvent for
2
0 min. Dichloromethane (5mL) was added followed by addition of water (5mL). The
organic phase was separated and dried over MgSO . The mixture was concentrated and
4
the solid residue was re-crystallized from dichloromethane (Fig.S2 - scheme-supporting
material). ORTHONITRO: 2-(5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl)pyrazine (6h):
Yield 72%; m. p. 135-137°C. METANITRO: 2-(5-(3-nitrophenyl)-1,3,4-oxadiazol-2-
1
yl)pyrazine (6i): Yield 42%; m. p. 156-158°C; HNMR (300 MHz, DMSO) (δ ppm):
8
.767-8.96 (m, 3H, pyrazine), 7.750-7.802 (m, 4H, aromatic). PARANITRO: 2-(5-(4-
1
nitrophenyl)-1,3,4-oxadiazol-2-yl)pyrazine (6j): Yield 53%; m. p. 180-182°C; HNMR
(
300 MHz, DMSO) (δ ppm): 8.767-8.820 (m, 3H, pyrazine), 7.985-8.103 (m, 4H,
aromatic).
.3. Anti-tubercular activity [16]
00µl of sterile de-ionized water was added to all outer perimeter wells of sterile 96
wells plate to minimized evaporation of medium in the test wells during incubation. The
6 wells plate received 100µl of the Middlebrook 7H9 broth and serial dilution of
2
2
9
compounds were made directly on plate. The final synthesized derivative concentrations
tested were 100 to 0.8 µg/ml. Plates were covered and sealed with para film and
incubated at 37°C for five days. After this time, 25µl of freshly prepared 1:1 mixture of
Alamar Blue reagent and 10% tween 80 was added to the plate and incubated for 24 hrs.
A blue color in the well was interpreted as no bacterial growth, and pink color was scored
4

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as growth. The Minimum Inhibitory Concentration (MIC) was defined as lowest drug
concentration which prevented the color change from blue to pink.
3
.
Computational details
In this work we have first applied Schrödinger Materials Science Suite 2018-
1
(SMSS) for computational studies of the three new oxadiazole derivatives. SMSS
software package contains MacroModel [17] program for calculations based on classical
potentials, Jaguar [18-20] program for DFT calculations and Desmond [21-24] program
for MD simulations. Initially, conformers of ORTHONITRO, METANITRO and
PARANITRO oxadiazole derivatives have been obtained thanks to the employment of
MacroModel program in conjunction with OPLS3 [21, 25-27] force field. This was
followed by geometrical optimizations of all conformers employing B3LYP exchange-
correlation functional [28] and 6-31G(d,p) basis set with Jaguar program. For further
detailed calculations based on DFT approach, the lowest energy conformers have been
chosen. True ground states had been confirmed via vibrational analysis. In all cases
vibrational analysis resulted only in positive wavenumbers. To obtain MEP, ALIE and
Fukui indices values with Jaguar program, a single point energy calculations at
B3LYP/6-311++G(d,p) level of theory have been performed. H-BDE and BDE values
have been obtained also thanks to the DFT calculations with Jaguar program using
B3LYP functional, but with 6-311G(d,p) basis set. Geometrical optimizations at
B3LYP/6-31G(d,p) level of theory produce reliable geometries for small organic
molecules, such as the ones investigated in this study. In the same time, much larger
basis set 6-311++G(d,p) is computationally affordable for single point calculations in
order to obtain information about MEP, ALIE and Fukui indices. Calculations of BDE
and H-BDE values is time consuming due to the certain number of fragments, therefore
in these cases we have used large basis set but without diffuse functions, since only the
fragments in ground state geometries have been considered. MD simulations were based
on the OPLS3 force field, including simulation time of 10 ns, temperature of 300 K,
pressure of 1.0325 bar and cut-off radius of 12Å. System for MD simulations was
modeled by placing of one oxadiazole derivative molecule to the simulation box with
~3000 water molecules. The system was considered as isothermal–isobaric (NPT)
ensemble. Simple point charge (SPC) model [24] was used for the description of
5

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solvent. Preparation of input files, visualization of results and calculations of drug
likeness parameters have been performed with Maestro graphical user interface (GUI) of
SMSS [29]. Wavenumber calculations, analysis of frontier molecular orbitals, NBO
analysis and calculations of hyperpolarizabilites have been performed with Gaussian09
[30] software package and GaussView5 [31] program. Wavenumbers and IR spectra
have been obtained by re-optimization of geometries (Fig.1) obtained by Jaguar program
at the same level of theory used for optimization by Jaguar program. Theoretically
obtained wavenumbers were scaled by a scaling factor of 0.9613 [32], while the
vibrational assignments have been done with GAR2PED program [33].
4
4
.
Results and discussion
.1. Results of anti-tubercular activity
The final compounds were tested for in vitro anti-tuberculosis activity against
MTbH R by Microplate Alamar Blue Assay (MABA) method. Pyrazinamide and
3
7
V
Streptomycin were used as standard in this test. Primary anti-tuberculosis activity
screening results of these compounds can be seen in Table 1. From the MIC
determination, MTb H37Rv was found to be sensitive to compounds ORTHONITRO,
METANITRO and PARANITRO. The results obtained from anti-TB activity are more
promising as the compounds were found to be more potent than reference standard,
streptomycin (MIC = 6.2µg/ml) and pyrazinamide (MIC = 3.1µg/ml).
4
.2. Local reactivity descriptor: MEP and ALIE surfaces, Fukui indices
In order to identify the most reactive molecular areas towards the electrophilic
attacks, in this work we have used a combination of MEP and ALIE descriptors. While
MEP descriptor indicates the molecule sites with abundance or excess of electrons and
can be used for identification of molecular sites prone to both electrophilic and
nucleophilic attacks, ALIE descriptor is better descriptor for the identification of
molecule sites prone to electrophilic attacks. Namely, ALIE indicates the energy
required to remove an electron from the certain site of molecule. In general, MEP and
ALIE are widely used for identification of representative reactive molecular sites [7, 34-
4
2]. In this work we have visualized MEP and ALIE by mapping their values to the
electron density surface, Fig.2. While MEP surfaces identify all oxygen and nitrogen
atoms of investigated oxadiazole derivatives as potentially sensitive towards the
6

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electrophilic attacks, ALIE surfaces identify only nitrogen atoms in this context.
Unfortunately, MEP surfaces of molecules investigated in this work cannot be used to
identify the most reactive oxadiazole derivative, since minimal and maximal MEP
values of these molecules are very similar. However, there are relatively significant
differences in minimal ALIE values. This allows identification of the ORTHONITRO
derivative as the most sensitive towards the electrophilic attacks, since minimal ALIE
values have been calculated precisely for this derivative. Fukui indices have been also
used in order to identify the most reactive molecular sites of ORTHONITRO,
HOMO
METANITRO and PARANITRO oxadiazole derivatives. Namely, the fNN
and
LUMO
fNN
Fukui indices have been calculated, whose high positive values indicate
preference to donate/receive electrons, respectively. The calculations of Fukui indices
have been done with Jaguar program, according to the references [43, 44]. They are
particularly useful when there is a possibility to compare their values between similar
molecules, which is the case in the present work. Fukui indices have been summarized
in Fig.3. In cases of all three oxadiazole derivatives the highest nucleophilic character
HOMO
has been indicated for oxadiazole unit, as the highest fNN
values have been calculated
for nitrogen and oxygen atoms of this five-membered ring. On the other side the highest
LUMO
electrophilic character has been indicated for the NO
2
group, as the highest fNN
LUMO
values have been calculated for atoms of this group. The highest fNN
values have
been calculated in case when NH
.3. Sensitivity towards autoxidation and influence of water
Thanks to the fact that correlation has been established between H-BDE and
2
group takes meta position.
4
sensitivity towards the autoxidation mechanism [2, 45], DFT calculations can be used in
order to predict the sensitivity of new organic molecules towards the one of the most
important reaction mechanisms [46]. Sensitivity of new organic molecule towards the
autoxidation mechanism can be suspected in cases when H-BDE values are calculated to
be somewhere in the interval between 70 and 85kcal/mol [47, 48]. Sensitivity towards
this mechanism is also reflected by H-BDE values between 85 and 90kcal/mol, but they
should be taken with caution [48]. H-BDE values lower than 70kcal/mol are not
indicating sensitivity towards autoxidation due to the reasons explained elsewhere [2,
7

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4
5, 47]. H-BDE and BDE values for the remaining single acyclic bonds
ORTHONITRO, METANITRO and PARANITRO oxadiazole derivatives are provided
in Fig.4. In cases of all the three oxadiazole derivatives very high H-BDE values have
been calculated, indicating that title molecules are not sensitive towards the autoxidation
mechanism. This also indicates that presence of air do not affect their stability
significantly. BDE calculated for the remaining single acyclic bonds indicate that NH
2
group could detach first during the degradation of these derivatives, since the lowest
BDE have been calculated for bond connecting NH group to benzene ring. The lowest
2
2
BDE has been calculated in case of ortho position of NH group, indicating that bond
connecting NH group to benzene ring in case of the ORTHONITRO derivative could
2
be the most vulnerable of all three investigated derivatives. The presence of organic
pharmaceutical waste in various water resources induces the necessity to evaluate the
stability of newly synthetized organic molecules in water. This can be conveniently
performed thanks to the MD simulations and calculations of radial distribution functions
(RDF), which enables identification of molecule’s atoms with preference to interact with
water molecules. The results regarding representative RDFs are presented in Fig.5.
RDFs presented in Fig.5 indicate that all three investigated oxadiazole derivatives have
week interactions with water molecules, and therefore high stability in water of these
molecules is expected. In all cases two carbon atoms belonging to pyrazine unit and
nitrogen atom belonging to NO group had the most important RDFs, however their
2
highest g(r) values are located at high distances, indicating weak interactions with water
molecules. RDFs also indicate that degradation of these derivatives in water under
natural conditions is hard to be expected.
4
.4. Geometrical parameters
The geometrical parameters of the title compounds are given in table S1
(
supporting material). For the title compounds, the Caromatic-Nnitro bond lengths are
.4696Å (ORTHONITRO), 1.4685 Å (METANITRO) and 1.4665Å (PARANITRO) and
the N-O bond lengths are 1.2636Å, 1.2617Å (ORTHONITRO), 1.2632Å, 1.2639Å
METANITRO) and 1.2643Å, 1.2641Å (PARANITRO) and the reported values are
1
(
1
1
.4781Å (DFT), 1.4753Å (XRD) for C-N and 1.2250Å, 1.2245Å (DFT), 1.2232Å,
.2262Å (XRD) for N-O [49]. The C-N-O and O-N-O bond angles in the title compounds
8

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are in the range 117.5-118.0° (DFT) and 124.0-124.4°. The reported values of CNO
angles are in the range 117.6° (DFT), 118.1-118.4° (XRDF) [49]. The C=N and C-O
bond distances in the oxadiazole rings of the title compounds are, 1.3150Å, 3159Å and
1
.3951Å, 1.3928Å for ORTHONITRO, 1.3171Å, 1.3159Å and 1.3971Å, 1.3961Å for
METANITRO and 1.3178Å, 1.3167Å and 1.3980Å, 1.3941Å for PARANITRO which
are in agreement with reported values: 1.2951Å, 1.2947Å (DFT), 1.2933Å, 1.2923Å
(
XRD) (C=N) and 1.3704Å, 1.3640Å (DFT) and 1.3863Å, 1.3652Å (XRD) (C-O)
49].The reported values of N-N bond length of oxadiazole ring are 1.3833Å (DFT)
[
1
1
.3922Å (XRD) [50] while in the present case, the values are 1.4266Å (ORTHONITRO),
.4236Å (METANITRO) and 1.4219Å (PARANITRO). The C-N and C-C bond lengths
in the pyrazine ring of the title compounds are: 1.3479Å, 1.3534Å, 1.3472Å, 1.3534Å
and 1.4065Å, 1.3985Å for ORTHONITRO, 1.3479Å, 1.3539Å, 1.3470Å, 1.3535Å and
1
1
.4066Å, 1.3986Å for METANITRO and 1.3480Å, 1.3541Å, 1.3470Å, 1.3539Å and
.4067Å, 1.3986Å for PARANITRO respectively, which are less than the normal C-N
bond length (1.49Å) and CC bond length (1.54Å) and in agreement with literature [51].
The bond angles around C3 position in all the title compound are C4-C3-N2, C4-C3-C7,
C7-C3-N2 are 121.6°, 120.1° and 118.3° respectively. This asymmetry is attributed to the
interaction of pyrazine and oxadiazole rings [51]. In the title compound ORTHONITRO,
the oxadiazole ring is tilted from the phenyl and pyrazine ring as is evident from the
torsion angles, C13-C12-C9-N10 = 144.6°, C13-C12-C-O8 = -41.3°, C17-C12-C9-O8 =
1
36.5°, C17-C12-C9-N10 = -37.6° and N2-C3-C7-N11 = 175.9°, N2-C3-C7-O8 = -4.3°,
C4-C3-C7-N11 = -4.0°, C4-C3-C7-O8 = 175.9° while for METANITRO and
PARANITRO, these angles are 0.0° and 180.0°, which shows a planar orientation.
4
.5. IR and VCD spectra
The observed IR bands with assignments and theoretically obtained scaled
wavenumbers are given in Table S2 (supporting information) and the phenyl, pyrazine
and oxadiazole rings are designated as Ph, Pz and Ring in the following discussion.
-1
-1
The NO stretching modes are assigned at 1537, 1385 cm (IR), 1539, 1388 cm
2
-1
-1
(
DFT) for ORTHONITRO, 1523, 1379 cm (IR), 1532, 1388 cm (DFT) for
-1
-1
METANITRO and at 1535 cm (IR), 1531, 1387 cm (DFT) for PARANITRO [52, 53]
-1
-1
-
and the reported values are at 1562 and 1369 cm (DFT), 1365 cm (IR) and at 1369 cm
9

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1
(
Raman) [54]. The NO
2
deformation modes are expected in the following regions: 910-
-1
-1
6
90 cm and 610-470 cm [52] and for the title compounds, the NO deformation modes
2
-1
-1
are assigned at 804, 677, 548 cm in IR, 805, 679, 544 cm (DFT) for ORTHONITRO,
-1
-1
-1
8
31, 542 cm in IR, 829, 657, 544 cm (DFT) for METANITRO and at 805, 501 cm in
-1
IR, 803, 665, 531 cm (DFT) for PARANITRO and the reported values are at 776, 551
-1
-1
cm (IR) and at 772, 671, 548 cm (DFT) [54]. The C-N stretching vibrations are
-1
-1
-1
assigned at 1247 cm (IR), 1242 cm (DFT) for ORTHONITRO, 1248 cm (IR), 1243
-1
-1
-1
cm (DFT) for METANITRO and at 1240 cm IR), 1237 cm (DFT) for PARANITRO
as expected [52].
-1
The C=N stretching modes are assigned at 1456, 1429 cm for ORTHONITRO,
-1
-1
1
439, 1429 cm for METANITRO and at 1429, 1428 cm for PARANITRO
theoretically which are in agreement with literature [52]. DFT computation gives the
-1
-1
oxadiazole ring N-N stretching at 939 cm for ORTHONITRO, 944 cm for
-1
METANITRO and at 956 cm for PARANITRO [49, 55]. For the title compound, the C-
-1
-1
O stretching modes are assigned at 1073, 923 cm for ORTHONITRO, 1073, 925 cm
-1
for METANITRO and at 1081, 936 cm for PARANITRO theoretically [49].
The pyrazine CH stretching modes of the title compound are assigned 3120, 3113,
-
1
-1
3
3
095 cm for ORTHONITRO, 3120, 3114, 3096 cm for METANITRO and at 3120,
-1
114, 3096 cm for PARANITRO theoretically [51] and the experimentally observed
-1
-1
values are at 3099 cm for ORTHONITRO and at 3124, 3039 cm for METANITRO
-
1
and at 3126, 3070 cm for PARANITRO in the IR spectrum. The pyrazine ring
stretching modes of the title compounds are assigned at 1550, 1475, 1200, 1105, 1004
-1
-1
-1
cm for ORTHONITRO, 1545 cm for METANITRO and 1520, 1158, 1041, 1000 cm
for PARANITRO in the IR spectrum and the PED analysis gives these modes in the
-1
-1
ranges, 1549-1002 cm for ORTHONITRO, 1548-1009 cm for METANITRO and
-1
1
547-1002 cm for PARANITRO [51, 56] which are in agreement with the reported
-
1
-1
values at 1525, 1120 cm (IR) and at 1551, 1524, 1182, 1117, 1009 cm (DFT) [56]. The
-1
-1
pyrazine ring breathing modes were assigned at 985 cm for ORTHONITRO, 984 cm
-1
for METANITRO and 985 cm for PARANITRO theoretically [56]. For the title
compounds, the pyrazine ring CH bending modes were assigned in the ranges 1322-1155
-1
-1
-1
cm (in-plane), 976-860 cm (out-of-plane) for ORTHONITRO, 1300-1155 cm (in-
10

ACCEPTED MANUSCRIPT
-1
-1
plane), 976-860 cm (out-of-plane) for METANITRO and at 1318-1095 cm (in-plane),
-1
9
76-921 cm (out-of-plane) for PARANITRO, theoretically. The experimentally
-1
-1
observed values are in the ranges 1323-858 cm for ORTHONITRO, 1297-870 cm for
-1
METANITRO and at 1277 cm for PARANITRO in the IR spectrum which are in
agreement with the literature [51, 56].
The phenyl ring C-C stretching modes are assigned in the ranges 1615, 1572,
-1
-1
-1
1
509 cm (IR), 1604-1325 cm (DFT) for ORTHONITRO, 1619, 1581, 1473, 1420 cm
-1
-1
(
IR), 1609-1322 cm (DFT) for METANITRO and 1580, 1464, 1399, 1340 cm (IR),
-1
1
602-1338 cm (DFT) for PARANITRO as expected [52]. The 1,2-disubstituted phenyl
-1
ring breathing mode of ORTHONITRO is assigned at 1048 cm in the IR spectrum and
-1
at 1045 cm theoretically [57], the 1,3-disubstituted benzene ring of METANITRO, the
-1
ring breathing mode is assigned at 995 cm (DFT) and for 1,4-disubstituted phenyl ring
-1
of METANITRO, the ring breathing mode is assigned at 1013 cm theoretically as
expected [52,57]. The in-plane CH deformation modes of the phenyl rings are assigned
-1
-1
at 1048 cm (IR), in the range 1287-1045 cm (DFT) for ORTHONITRO, 1185, 1085
-1
-1
-1
cm (IR), 1272-1037 cm (DFT) for METANITRO and at 1182, 1116 cm (IR), 1307-
-1
1
000 cm (DFT) for PARANITRO as expected [52]. The out-of-plane phenyl CH
-1
bending modes are assigned theoretically in the ranges, 976-770 cm for
-1
-1
ORTHONITRO, 964-770 cm for METANITRO and 1005-854 cm for PARANITRO
[52]. According to Roeges [52], a strong γCH mode absorption band is observed at
-1
-1
-1
7
55±35 cm for 1,2-, near 765 cm for 1,3- and at 840± 50 cm for 1,4-disubstituted
-1
-1
phenyl rings and in the present case, this mode is observed at 769 cm (IR), 770 cm
-1
-1
(
DFT) for ORTHONITRO, 768 cm (IR), 765 cm (DFT) for METANITRO and at 848
-1
-1
cm (IR), 854 cm (DFT) for PARANITRO [52, 58, 59]. Also for 1,3-substituted
-1
benzenes, an out of plane ring deformation in the neighborhood of 685 cm is observed
-1
and this band is observed at 675 cm in the IR spectrum and finds support from
-1
computational results at 682 cm for the phenyl ring of METANITRO [52, 58].
Vibrational circular dichroism (VCD) gives differences in right and left circularly
polarized light passing through the molecules [60]. The ring stretching modes of the
rings, C-H and C=N, NO stretching modes generate VCD signals and these are efficient
2
markers of configuration identification. The VCD bands (Fig.S3-supporting material) at
11

ACCEPTED MANUSCRIPT
-1
-1
-1
1
096 cm for ORTHONITRO, 1547, 1403, 1343 cm for METANITRO and 987 cm
for PARANITRO, which are the ring stretching modes, are good markers of
configuration, showing left polarization while the ring stretching modes, 1605, 1414,
-
1
-1
1
1
330 cm (ORTHONITRO), 1497, 1462, 1103, 983 cm (METANITRO) and 1605,
-1
400, 1342 cm (PARANITRO) show right polarization. The CH modes showing left
-1
and right polarization are, 3111, 1264, 977 cm (ORTHONITRO), 3145, 1248, 1032,
-1
-1
9
49, 854, 818 cm (METANITRO), 3130, 3094, 1302, 1224, 860 cm (PARANITRO)
-1
-1
and 3127, 900 cm (ORTHONITRO), 3120, 1007 cm (METANITRO), 3113, 1318,
-1
-1
9
59, 923, 876 cm (PARANITRO), respectively. The VCD signals at 1455 cm (C=N
-1
-1
-1
modes), 1390 cm (NO ), 1246 cm (C-N) for ORTHONITRO, 1431 cm (C=N), 1390
2
-1
-1
-1
-1
cm (NO2), 1234 cm (CN) for METANITRO and 1527 cm (NO
2
), 1426 cm (C=N),
35 cm (CO) for PARANITRO are good markers for assigning of absolute
configuration.
-
1
9
4
.6. Nonlinear optical properties
In the presence of an applied electric field, the energy of molecular system is a
function of the electric field and polarizability and hyperpolarizability values will
illustrate the response of the system and determines the NLO properties [61]. The
computed values of dipole moment, polarizability and first order hyperpolarizability
-23
-30
values are: 4.637 Debye, 2.527 × 10
esu, 4.528 × 10 esu for ORTHONITRO, 1.440
-23
-30
Debye, 2.609× 10
esu, 7.085 × 10 esu for METANITRO and 4.925 Debye, 2.741 ×
-23
-30
1
0
esu, 22.627 10
esu for PARANITRO. The energy gaps for 3.885, 4.03, 3.898
eV for ORTHONITRO, METANITRO and PARANITRO respectively which are lower
than that of urea (6.706eV) [62] and the first hyperpolariazabilities of ORTHONITRO,
METANITRO and PARANITRO are respectively, 34.83, 54.50 and 174.05 times that of
urea [62]. The reported first order hyperpolarizability of oxadiazole derivative is 2.414×
-30
1
0
esu [50].
4
.7. Frontier molecular orbital analysis
The HOMO-LUMO plots of the title compounds are presented in Fig.6 and for all
compounds HOMO and LUMO are delocalized over the entire molecule and participate
in energy transfer in the systems. The energy of HOMO and LUMO are directly related
to ionization potential and electron affinity. From the HOMO and LUMO energies, the
12

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ionization potential I=-EHOMO and electron affinity A=-ELUMO [63]. The ionization
potential, electron affinity and HOMO-LUMO energy gap are respectively, 8.555, 5.127,
3
5
.428 eV for ORTHONITRO, 8.498, 5.244, 3.254 eV for METANITRO and 8.438,
.374, 3.064 eV for PARANITRO. Classification of a molecule as hard and soft is
possible on the basis of chemical hardness. Large HOMO-LUMO gap indicates that the
title molecules are hard. The chemical descriptors are given by hardness η= (I-A)/2;
2
chemical potential µ = -(I+A)/2 and electrophilicity index ω = µ /2η [64].The values of
chemical descriptors vary in the order: η: ORTHONITRO (1.714 eV)> METANITRO
(1.627 eV)> PARANITRO (1.532 eV); µ are nearly same for all derivatives;
ORTHONITRO (-6.841 eV), METANITRO (-6.871 eV), PARANITRO (-6.906 eV)
and ω varies as; ORTHONITRO (13.652 eV) < METANITRO (14.508 eV) <
PARANITRO (15.566eV). Positional changes of nitro group affects η and ω values. The
inverse values of the hardness is designated at softness of the molecule which is the
property of molecule that measures degree of chemical reactivity and this is a useful
parameter giving the toxicity of various pollutants in terms of their reactivity and site
selectivity [65]. Molar refractivity (MR) is a term used in quantitative structure property
relationship, given as, MR= 1.333παN, where α is the polarizability and N is the
Avogadro number [66]. For the title compounds, MR values are also same for all
derivatives, ORTHONITRO (63.562), METANITRO (65.624), PARANITRO (68.944)
and this is responsible for the binding nature of the molecular assembly and can be used
for the cure of different diseases [67].
4
.8. Natural Bond Orbital analysis
Using the NBO 3.1 program [68] as implemented in the Gaussian09 package the
natural bond orbitals (NBO) calculations were performed for the title compounds and the
important results are presented in tables S3 and S4 (supporting material). The strong
intra-molecular hyper-conjugative interactions due to nitrogen atoms are:
n (N )→σ*(C -C ), n (N )→σ*(C -C ), n (N )→σ*(O -C ) and n (N )→σ*(C -O )
1
2
3
4
1
5
3
4
1
10
8
9
1
11
7
8
with energies, 9.17, 9.06, 10.84, and 10.89 kcal/mol. for ORTHONITRO; n (N )→σ*(
1
2
C
3
-C
4
),
n
1
(N
5
)→σ*(
C
3
-C
4
),
n
1
(N10)→σ*(
O
8
-C
9
),
n
1
(N11)→σ*(C
7
-O
8
)
and
n (O )→π*(C -N ) with energies, 9.15, 9.08, 11.04, 11.05 and 33.11 kcal/mol. for
2
8
9
10
1 2 3 4 1 5 3 4 1 8 9
METANITRO; n (N )→σ*(C -C ), n (N )→σ*(C -C ), n (N10)→σ*( O -C ) and
13

ACCEPTED MANUSCRIPT
n
1
(N11)→σ*(C
PARANITRO.
The strong intra-molecular hyper-conjugative interactions due to oxygen atoms
(O
)→π*(C
σ*(N -O ) having energies, 32.75, 18.36, 153.52 and 18.83 kcal/mol. for
7
-O
8
) with energies, 9.13, 9.08, 11.05 and
11.02 kcal/mol. for
are: n
2
8
9 2 3 2
-N10), n
(O19)→σ*(N18-O20), n (O19)→π*( N18-O20) and n (O20)→
1
8
19
2 2 3
ORTHONITRO; n (O19)→σ*(N18-O20), n (O20)→σ*(N18-O19) and n (O20)→ π*( N18-
O ) with energies, 18.60, 18.50 and 176.23 kcal/mol. for METANITRO; n (O )→π*(C -
1
9
2
8
7
N ) n (O )→σ*(N -O ), n (O )→π*( N -O ) and n (O )→ σ*( N -O ) with
1
1
2
19
18
20
3
19
18
20
2
20
18
19
energy values, 32.80, 18.52, 176.43 and 18.55 kcal/mol. for PARANITRO.
.9. Drug likeness parameters
Frequently used drug likeness parameters have been addressed in order to evaluate
4
the potential of the newly synthetized oxadiazole derivatives for pharmaceutical
calculations. Study of drug likeness parameters in this study encompassed calculations of
AlogP, number of hydrogen bond donors and acceptors (HBD and HBA, respectively),
number of rotatable bonds, polar surface area (PSA) and molar refractivity. All of these
parameters have been calculated with Maestro program, and the results are summarized in
Table 2. According to the Lipinski’s rule of five [69, 70], AlogP values below 5 are
considered to be adequate in terms of hydrophobicity/lipophilicity of drug candidates.
However, the AlogP values of oxadiazole derivatives are equal to 1.08, which are the
values that satisfy even the conditions defined by Congreeve et al. [71], according to
which the lead drug candidates should have the AlogP values lower than 3. Other drug
likeness parameters are also having representative values. In general HBD and HBA
should have values of 5 and 10, respectively, while for the presently investigated
derivatives these parameters take values of 0 and 5, respectively. PSA for these derivatives
2
have been calculated to be 107.84 Å , which is lower than the upper border level of 140
2
Å . Finally, the value of molecular refractivity has been calculated to be 68.85, which is in
the desired range between 40 and 130 for drug candidates, as reported by Ghose et al.
[72].
4
.10. Molecular docking
Molecular docking was employed to recognize the active site of the receptor, and
acquire the best geometry of ligand-receptor complex. PASS (Prediction of Activity
14

ACCEPTED MANUSCRIPT
Spectra) [73,74] is an online tool which predicts different types of activities and the
PASS analysis of the compounds, ORTHONITRO, METANITRO and PARANITRO,
predicts activities given in the Table 3. We selected the activities Glucan endo-1.6-beta-
glucosidase inhibitor, Acrocylindropepsin inhibitor and Chymosin inhibitor with
probability to be active value above 70%. High resolution crystal structure of the
corresponding inhibitors beta-D-glucanglucohydrolase (1LQ2), botulinum neurotoxin
type A (3QW5) and chymosin inhibitor (1CZI), were downloaded from the protein data
bank website. The docked ligands form stable complexes with the receptors as shown in
Fig.7. The amino acid interactions of the corresponding receptors beta-D-
glucanglucohydrolase, botulinum neurotoxin type A and chymosin inhibitor with the
ligands are detailed in Fig.S4 (supporting information). The binding free energy values of
ORTHONITRO, METANITRO and PARANITRO with the receptors predicted by
AutodockVina is depicted in Table 4. The binding affinity of ORTHONITRO,
METANITRO, PARANITRO with the receptors beta-D-glucanglucohydrolase,
botulinum neurotoxin type A and chymosin inhibitor are, -6.3, -6.6, -6.4; -7.7, -8.0, -7.6;
-7.7, -7.8, -7.6 kcal/mol., respectively. Botulinum neurotoxin type A (BoNT/A) is the
potent disease agent in botulism, a potential biological weapon and an effective
therapeutic drug for involuntary muscle disorders. The neurotoxin, botulinum toxin
type A, has been used successfully, in some patients, as an analgesic for myofascial
pain syndromes, migraine, and other headache types. The toxin inhibits the release of
the neurotransmitter, acetylcholine, at the neuromuscular junction thereby inhibiting
striated muscle contractions. In the majority of pain syndromes where botulinum toxin
type A is effective, inhibiting muscle spasms is an important component of its activity
[
75, 76]. A novel analgesic pyrazine derivative, crotonine, was isolated from the leaves
of Croton tiglium L. and series of pyrazinederivatives show analgesic activities [77-
9]. All molecular docking calculations were performed on AutoDock 4.2 [80,81] and
7
Auto Dock-Vina-1.1.2 software [82,83] and as reported in literature [54, 84]. These
results suggest that the compound METANITRO exhibits more inhibitory activity against
the receptors than the other ligands. Botulinum neurotoxin type A with METANITRO
form stable complex with binding free energy -8.0kcal/mol and METANITRO can be
15

ACCEPTED MANUSCRIPT
developed as a new analgesic drug. However biological tests need to be done to validate
the computational predictions.
Conclusions
MEP surfaces indicate sensitivity of all nitrogen and oxygen atoms, while ALIE
surfaces indicate that only nitrogen atoms are sensitive towards the electrophilic attacks.
2
Fukui indices indicate that oxadiazole unit has the nucleophilic nature, while NO group
possesses the electrophilic nature. H-BDE values indicate stability towards the
autoxidation mechanism, while BDE values for the remaining single acyclic bonds
2
indicate that NO group is bonded most weakly in the ortho position (ORTHONITRO
derivative). MD simulations and RDFs indicate high stability of these derivatives in
water. Theoretical calculations of the wavenumbers together with FT-IR spectral analysis
of three oxadiazole derivatives were reported and the vibrational wavenumbers are
assigned with the aid of potential energy distribution. Chemical stability and
hyperconjugative interactions in the molecular systems are discussed with the aid of
frontier molecular orbital and natural bond orbital analysis. Drug likeness parameters,
especially the AlogP values, emphasize the pharmaceutical potential of the studied
oxadiazole. The title compounds are docked with the proteins of Glucan endo-1.6-beta-
glucosidase inhibitor, Acrocylindropepsin inhibitor and Chymosin inhibitor and
Botulinum neurotoxin type A with METANITRO form stable complex with binding free
energy -8.0 kcal/mol and METANITRO can be developed as a new analgesic drug since
METANITRO exhibit more inhibitory activity against the receptors than the other
ligands. From the anti-tubercular activity, it was found that meta nitro substitution helps
to enhance the anti-TB activity as compared with ortho and para nitro substitution. The
results obtained from anti-TB activity are more promising as the compounds were found
to be more potent than reference standard, streptomycin and pyrazinamide.
Acknowledgment
Part of this work has been performed thanks to the support received from Schrödinger
Inc. Part of this study was conducted within the project funded by the Ministry of
Education, Science and Technological Development of Serbia, grant number III41017.
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Figure captions
Fig.1 Optimized geometries of (a) ORTHONITRO (b) METANITRO (c) PARANITRO
Fig.2 MEP and ALIE surfaces: (a) ORTHONITRO (b) METANITRO (c)PARANITRO
25

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Fig.3 Fukui indices of investigated oxadiazole derivatives (a) ORTHONITRO (b)
METANITRO (c) PARANITRO
Fig.4 H-BDE (red color) and BDE (blue color) values for (a) ORTHONITRO (b)
METANITRO (c) PARANITRO oxadiazole derivatives
Fig.5 Representative RDFs in cases of oxadiazole derivatives (a) ORTHONITRO (b)
METANITRO (c) PARANITRO
Fig.6 HOMO-LUMO plots of (a) ORTHONITRO (b) METANITRO (c) PARANITRO
Fig.7. (A) The ligands (a) ORTHONITRO (b) METANITRO (c) PARANITRO
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(
a) ORTHONITRO (b) METANITRO (c) PARANITRO embedded in the
catalytic site ofbotulinum neurotoxin type A (C) The ligands (a) ORTHONITRO
b) METANITRO (c) PARANITRO embedded in the catalytic site of chymosin
inhibitor
(
26

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Table 1
Determination of MIC against MTb H RV of the title compounds
3
7
Compound code
ORTHONITRO
METANITRO
PARANITRO
Pyrazinamide
Streptomycin
MIC (µg/ml)
1.6
0.8
1.6
3.1
6.2
1

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Table 2
Frequently considered drug likeness parameters calculated for investigated oxadiazole
derivatives
Descriptor
ORTHONITRO, METANITRO, PARANITRO
Hydrogen Bond Donor (HBD)
Hydrogen Bond Acceptor (HBA)
0
5
1
AlogP
1.08
107.84
68.85
27
2
Polar surface area (PSA)[Å ]
Molar refractivity
Number atoms
Number of rotatable bonds
3