Exploring the detailed spectroscopic characteristics, chemical and biological activity of two cyanopyrazine-2-carboxamide derivatives using experimental and theoretical tools

Article abstract of DOI:10.1016/j.saa.2019.117414

This article represents the spectroscopic and computational studies of two new pyrazine compounds. In order to establish the structure and functional nature of the compounds, we have employed Fourier transformed infrared (FT-IR) and Raman spectra, nuclear

Full text of DOI:10.1016/j.saa.2019.117414

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Exploring the detailed spectroscopic characteristics, chemical and
biological activity of two cyanopyrazine-2-carboxamide
derivatives using experimental and theoretical tools
Shargina Beegum, Y. Sheena Mary, Y. Shyma Mary, Renjith
Thomas, Stevan Armaković, Sanja J. Armaković, Jan Zitko,
Martin Dolezal, C. Van Alsenoy
PII:
S1386-1425(19)30804-2
https://doi.org/10.1016/j.saa.2019.117414
SAA 117414
DOI:
Reference:
Spectrochimica Acta Part A: Molecular and Biomolecular
Spectroscopy
To appear in:
Received date: 24 June 2019
Revised date:
13 July 2019
21 July 2019
Accepted
date:
Please cite this article as: S. Beegum, Y.S. Mary, Y.S. Mary, et al., Exploring the detailed
spectroscopic characteristics, chemical and biological activity of two
cyanopyrazine-2-carboxamide derivatives using experimental and theoretical tools,
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy(2019),
https://doi.org/10.1016/j.saa.2019.117414
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Exploring the detailed spectroscopic characteristics, chemical and biological activity of two
cyanopyrazine-2-carboxamide derivatives using experimental and theoretical tools
Shargina Beeguma, Y.Sheena Marya, Y.Shyma Marya, Renjith Thomasb*, Stevan Armakovićc,
Sanja J. Armakovićd, Jan Zitkoe, Martin Dolezale, C. Van Alsenoyf
a Department of Physics, Fatima Mata National College, Kollam, Kerala, India
b Department of Chemistry, St Berchmans College (Autonomous), Changanassery, Kerala, India
686101
cUniversity of Novi Sad, Faculty of Sciences, Department of Physics, Trg D. Obradovića 4,
21000 Novi Sad, Serbia
dUniversity of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and
Environmental Protection, Trg D. Obradovića 3, 21000 Novi Sad, Serbia
eFaculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203,
Hradec Kralove, 500 05, Czech Republic
fDepartment of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020, Antwerp,
Belgium
*author for correspondence: renjith@sbcollege.ac.in
Abstract
This article represents the spectroscopic and computational studies of two new pyrazine
compounds. Inorder to establish the structure and functional nature of the compounds, we have
employed fourier transformed infrared (FT-IR) and Raman spectra, nuclear magnetic resonance
(NMR) spectra, and ultraviolet (UV) absorptions and have compared them with the simulated
computational spectra and found that they are in the agreeable range. Simulated
hyperpolarisability values are used to obtain the nonlinear optic (NLO) activity of the compound,
to be used in organic electronic materials. The charge transfer and related properties was
investigated by the simulation of electronic spectrum with time dependent density functional
theory (TD-DFT). Natural transition orbitals (NTO) provides information about which region of
the molecules are more involved in the electronic transitions and the charge transfer properties
for the lowest energy excitation have been analyzed on the basis of electron density variation.
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Molecular dynamics simulations provides information about the behavior of the molecule in
solutions. frontier orbital analysis and study of various reactivity rdescriptors like ALIE and
fukui provided deep knowledge on the reactivity side. Molecular docking has been also
performed to investigate the interaction between title molecules and exhibits inhibitory activity
against Pseudomonas aeruginosaEnoyl-Acyl carrier protein reductase (Fabl).
Keywords: DFT; ALIE; RDF; Carboxamide; Docking; BDE.
1.
Introduction
Pyrazine is an important heterocyclic aromatic compound of biological and industrial
significance that occur in nature and may be synthesized in numerous ways. Its derivatives are
well known and important and contain two nitrogen atoms in its aromatic ring and can carry
substituent at one or more of the four ring carbon atoms. Nitrogen containing hetrerocyclci
compounds find high applications in drug industry as well as agriculture in the form of insect
repllents[1]. Some bacteria can use pyrazine derivatives as a source of subsistence energy [2].
Substituted pyrazines are present in many of the food forms like meat, poultry products, protein
containing vegetables etc [3]. Tetramethylpyrazine, called as ligustrazine is present in some
Chinese natural herbs, which could act as antioxidants to scavenge dangerous free radicals [4].
Tuberculosis, a deadly infectious disease now is taking many drug resistant forms, and is making
the treatment and management very difficult. Hence new antibacterial agents are required to
combat the drug resistant TB infections [5]. Pyrazinamide is an important anti TB agent used as
a first line agent for tuberculosis therapy [6] and even it can be fatal to semidormant
mycobacteria [7]. Aminopyrazine have been reported to be inhibitor of MK-2 which plays a
critical role in regulating TNFα, a cytokine that is over produced in several inflammatory
diseases like rheumatoid arthritis [8] and some of its derivatives are used for the treatment of
glaucoma [9]. Theyshows various types of pharmacological activities like antibacterial,
antifungal, antiviral, anti-oxidant and anti-cancer activities [10,11] and also pyrazinamides and
pyrazine sulphonamides have been used on various topics as oral anti-diabetics, nutrition
supplement, insecticides and fungicides [1]. Pyrazines are also anthropogenic, especially
dihydropyrazines and are vital for almost all forms of life due to its ability to intercalate DNA by
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affecting the process of apotosis [12]. Pyrazines are well established to act as exo-bidentate
ligands [13] and besides their medicinal uses, pyrazines have found technical applications in
several organic electronics applications [14]. Pyrazines have been intensively investigated as
effective corrosion inhibitors in different acid medium [15-17].
The present study performs a detailed analysis of experimental and simulated spectra of
the
two
cyanopyrazine-2-carboxamide
derivatives,
and
5-cyano-3-((4-
5-cyano-3-((4-
methoxybenzyl)amino)pyrazine-2-carboxamide
(CMOBAPC)
methylbenzyl)amino)pyrazine-2-carboxamide (CMBAPC). FT-IR, FT-Raman, frontier
molecular orbital analysis, natural bond orbital analysis, non-linear optical properties and
molecular electrostatic potential study are reported. The biological activities of the compounds
are predicted by molecular docking study. In this study we consider title molecules as possibly
suitable for application in pharmaceutical industry. In case they are found in pharmaceutical
formulations they could produce certain damage to the environment [18-23], once they are
dumped into some type of water. Therefore in this study we were also motivated to assess their
degradation properties based on DFT calculations and MD simulations. Modern techniques for
the removal of pharmaceutical waste are based on oxidation, which induces degradation [24].
Autoxidation tendency of a molecule is in correlation with bond dissociation energies for
abstraction of hydrogen atoms (H-BDE) [25-28]. DFT calculations are widely used in
environmental studies [29] and the concept of H-BDE allows employment of DFT calculations
for inexpensive assessment of degradation properties as well. Stability in water is also very
important for the removal of pharmaceutical waste and for which MD analysis are of great
importance, as they enable one to explicitly include solvent molecules and to identify which
atoms have significant interactions with solvent. In the same time we have performed detailed
TD-DFT calculations in order to see information into the charge transfer properties of the lowest
energy excitation.
2.
Experimental details- Spectral analysis
The title compounds (see Fig.1) can be easily synthesized by homolytic amidation of
commercially available 6-chloropyrazine-2-carbonitrile (1) to resulting 3-chloro-5-
cyanopyrazine-2-carboxamide (2), which subsequently undergoes nucleophilic substitution of
chlorine by corresponding benzylamine (Scheme 1). The amino dehalogenation reaction utilizes
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potassium carbonate as a base and proceeds at RT to completion in approximately 1 hour
1
(checked by TLC). The identity of compounds was assessed by H and 13C NMR spectra and
melting point determination. The results were fully consistent with the declared structures.
NMR spectra of the compounds were obtained using Varian VNMR S500 at 500 MHz for P-
NMR and 125 MHz for 13C-NMR using DMSO-d6 and the chemical shift is measured using
TMS as the refrence. The FT-IR spectra (Fig.S1-supporting information) and FT-Raman spectra
(Fig.S2- supporting information) were analysed using a DR/Jasco FT-IR 6300 and Bruker RFS
100/s spectrometer. Element analysis were done with on EA-1110 CHN analyser. UV-VIS
spectra were measured in methanolic solution, where the concentrations of title compounds were
approximately 1.10-4 mol/L. Methanol (CHROMASOLV®, for HPLC, ≥ 99.9%, Sigma-Aldrich,
Germany) was used as a solvent and a blank sample. The spectra were recorded on UV-2600
UV-VIS spectrophotometer in the range 200–600 nm, the path length of the cuvette was 10 mm.
3. Computational details
Computational simulations related to this paper was performed by a variety of softwares.
The molecules were optimised using Gaussian09 program [30] employing the generic B3LYP
functional along with CC-pVDZ (5D, 7F) basis set to reach an optimised geometry. Frequency
calculations were also performed to make sure that there are no imaginary frequencies to confirm
the minimal structure. The IR spectra generated was used to analyse the fundamental modes; but
they have been overestimated by the DFT hybrid B3LYP functional, hence a scaling factor of
0.9613 had to be used in order to make it in accordance with the experimental data [31]. The
wave number assignments were performed using Gaussview [32] and GAR2PED software
packages [33]. Simulated structure of the compounds CMBAPC and CMOBAPC are provided
in Fig. 1 and geometric parameters are provided in the Table S1 (supporting information).
Some features of the Schrödinger Materials Science Suite 2017-4 [34] like Jaguar [35-37]
and Desmond [38-41] were used to do some specilaised DFT studies and molecular dynamics
simulations. In Jaguar also, B3LYP functional[42] along with 6-311++G(d,p), 6-31+G(d,p) and
6-311G(d,p) basis sets were used for Average Local Ionisation Energy (ALIE), Fukui functions
and Bond Dissociation Energies (BDE), respectively. CAM-B3LYP [43] functional was used to
do time dependent density functional theory calculations (TD-DFT) along with 6-31+G(d,p)
basis sets to simulate the electronic spectra [44]. For MD simulations OPLS 3 force field [38,
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45-47] was used, with cut off radius to 12 Å, simulation time 10 ns, temperature to 300 K and
pressure to 1.0325 bar. For solvent atmosphere, simple point charge (SPC) [48] approach was
used and the molecules are placed in a cage of about 3000 water molecules. Electron density
analysis employing the method developed by Johnson et al was used to study the intra-molecular
noncovalent interactions [49, 50]. Maestro GUI [51] was used for the preparation of input files
when Schrödinger Materials Science Suite 2017-1 was used. Multiwfn [52-55] program for the
analysis of wave function was used for the investigation of charge transfer due to the excitation.
Electron density variation was visualized with the aid of VMD program [56-62], while Tachyon
[63] was used for rendering of figures.
4.
Results and discussion
4.1
Geometrical Parameters
In the present case the pyrazine bond lengths C1-C2, C2-N3, N3-C4, C4-C5, C5-N6, N6-C1
are 1.4026, 1.337, 1.3305, 1.4424, 1.3512, 1.336 Å for CMBAPC and 1.4026, 1.3371, 1.3304,
1.443, 1.3516, 1.3358 Å for CMOBAPC respectively. For a similar derivative the reported
values are 1.4060, 1.3580, 1.3260, 1.4370, 1.3600 and 1.354 Å [64]. The CN bond length in the
pyrazine rings of CMBAPC and CMOBAPC are much lesser than normal C-N single bond
which is 1.49 Å [65]. The two C-C bond lengths of pyrazine are also smaller than that of
normal C-C single bond of 1.54 Å [66]. The C=O bond lengths for CMBAPC is 1.2364 Å and
for CMOBAPC is 1.2362 Å whereas the reported values are 1.2253 Å, 1.2203 Å and 1.2123 Å
[67]. The bond lengths C5-N10 and C11-N10 are 1.3475 and 1.457 Å for CMBAPC and it is
1.3469 and 1.4598 Å for CMOBAPC. The C28-N30 bond length for CMBAPC and C24-N26 bond
length for CMOBAPC are 1.3518 Å and 1.352 Å respectively which is shorter than the normal
CN single bond length 1.49 Å and hence these bonds can be confirmed to have some double
bond or conjugate bond character [68]. The variation in the C=O and CN bond lengths are
congruous with the inference that the hydrogen bond decreases its double bond characteristics
[69]. For CMBAPC and CMOBAPC the bond angles at C1 position, C2-C1-C8, C2-C1-N6, N6-C1-
C8 are 119.4, 123.4, 117.2° respectively. This indicates the interaction between the pyrazine ring
and C≡N. The C8≡N9 bond length in CMBAPC and CMOBAPC is 1.163 Å. At C4position, for
CMBAPC the bond angles C5-C4-C28, N3-C4-C5, N3-C4-C28 and for CMOBAPC the bond angles
C5-C4-C24, N3-C4-C5, N3-C4-C24 are 121.6, 121.2, 117.2° respectively which shows the
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interaction between the pyrazine ring and C=ONH2. At C5 position the bond angles for
CMBAPC and CMOBAPC, C4-C5-N6, C4-C5-N10, N6-C5-N10 are 119.7, 121.6, 118.6° and 119.7,
121.6, 118.7° respectively. The interaction between pyrazine and NH bond is the main reason for
the asymmetry. At N10 position, for CMBAPC, the angles C5-N10-H33, C11-N10-H33, C5-N10-C11
are 114.5, 120.9, 124.3° and for CMOBAPC the angles C5-N10-H34, C11-N10-H34, C5-N10-C11 are
114.6, 120.7, 124.5° respectively and the asymmetry of the angles at this position indicates the
interaction of NH with neighboring units [70, 71]. At C12 position, the bond angles C11-C12-C13,
C11-C12-C14, C13-C12-C14 for CMBAPC and CMOBAPC are 120.5, 121.4, 118.2° and 120.9,
121.1, 118.0° respectively and this asymmetry shows the interaction between phenyl ring and
CH2 group. At C19 position, the bond angles for CMBAPC, C15-C19-C24, C17-C19-C24, C15-C19-
C17 are 121.6, 120.7, 117.7° and for CMOBAPC, the bond angles C15-C19-O29, C17-C19-O29, C15-
C19-C17 are 115.7, 125.0, 119.4° respectively which shows the interaction of the phenyl ring with
the CH3 group for CMBAPC and -OCH3 group of CMOBAPC. The C-C bond lengths in the
phenyl ring lies in the range 1.3939-1.4053 Å for CMBAPC and in the range 1.3887-1.4075 Å
for CMOBAPC. The reported values of C-C bond length for benzene is 1.3993 Å [72] and for
benzaldehyde is 1.3973 Å [73].
4.2
IR and Raman spectra
The experimental IT and Raman spectral data, was compared with the scaled simulated
spectra and are represented in Table 1. The potential energy distribution and assignments of the
vibrational modes are also included in the table. The phenyl and pyrazine rings are represented
by the letters Ph and Pz respectively. υC=O modes are assigned at 1682 cm-1 theoretically, 1688
cm-1 (IR), 1681 cm-1(Raman) for CMBAPC and at 1682 cm-1 theoretically, 1686cm-1 (IR), 1684
cm-1(Raman) for CMOBAPC as expected. The C=O stretching has a PED of 60% for both
CMBAPC and CMOBAPC with IR Intensity 419.40, 410.17 and Raman activity 37.67, 38.90
respectively. The NH2 stretching give rise to bands at 3450-3150 cm-1 and its deformations,
rocking, twisting and wagging modes are expected in the range 1640-1580 cm-1, 1170-1080 cm-1,
820-730 cm-1 and 730-610 cm-1 respectively [74-77]. The NH2 stretching modes are assigned at
3447 cm-1 (IR), 3578, 3423 cm-1 (Raman), 3572, 3425 cm-1 (DFT) for CMBAPC and at 3389 cm-
1
(IR), 3436 cm-1 (Raman), 3573, 3425 cm-1 (DFT) for CMOBAPC. For the modes at 3572 and
3425 cm-1 the IR intensities are 87.73 and 63.06 and Raman activities are 84.99 and 163.74 for
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CMBAPC with a PED of 99%. For CMOBAPC the modes at 3573 and 3425 cm-1 have IR
intensities 87.07 and 62.16 and Raman activities 85.08 and 163.38 and PED of 99%.
The NH2 deformation are seen at 1501,1050, 605, 603 cm-1 (DFT), 1506, 601 cm-1 (IR),
1506, 601 cm-1 (Raman) for CMBAPC with PEDs of 61%, 50%, 58%, 44% respectively and at
1501, 1050, 605, 602 cm-1(DFT), 1505, 1055, 601 cm-1 (IR), 1504, 1057, 603 cm-1 (Raman) for
CMOBAPC with 61%, 54%, 59% and 47% PEDs respectively. The IR and Raman of these
modes for CMBAPC are 236.50, 0.26, 3.20, 4.58 and 17.10, 29.27, 3.71 and 4.46 and for
CMOBAPC they are 235.36, 0.37, 5.32, 7.31 and 17.75, 29.20, 4.17, and 4.63 respectively. NH
stretching, in-plane and out-of-plane bending modes are assigned at 3293, 1305, 693 cm-1
(DFT), 3259, 1303, 693 cm-1 (IR), 3293, 1308, 693 cm-1 (Raman) for CMBAPC and for
CMOBAPC these modes are at 3296, 1571, 690 cm-1 (DFT), 3297, 1574, 692 cm-1 (IR), 3294,
1570, 693 cm-1 (Raman) respectively which is in good agreement with the expected values. The
N-H stretching mode has a PED of 99% with IR intensities 187.24 (CMBAPC), 186.93
(CMOBAPC) and Raman activities 132.77 (CMBAPC), 129.67 (CMOBAPC). The PED of the
N-H deformation modes are 49% and 43% for CMBAPC and 43% and 39% for CMOBAPC.
Deformation mode at 1305 cm-1, the IR and Raman are respectively 24.29 and 25.89 and for the
mode at 693 cm-1, the IR intensity and Raman activity are 41.29 and 1.12 for CMBAPC. For the
deformation mode at 1571cm-1 for CMOBAPC the IR intensity and Raman activity are
respectively 524.17 and 13.59 and for the mode at 690 cm-1, the IR intensity and Raman activity
are 53.45 and 0.79. The CN stretching modes are observed at 1045 cm-1 (IR), 1097, 1039 cm-1
(Raman), 1098, 1034, 1050 cm-1 (DFT) for CMBAPC with IR intensities 2.07, 4.18, 0.26,
Raman activities 28.77, 2.35, 29.27 and PED 41%, 45% and 39% respectively and at 1055,
1096, 1027 cm-1 (IR), 1057, 1031 cm-1 (Raman), 1050, 1094, 1029cm-1 for CMOBAPC with IR
intensities 0.37, 4.11, 26.45, Raman activities 29.20, 33.21, 3.89 and PED 38%, 44%, and 37%
respectively and the expected range for these modes are 1100-1300 cm-1[74-77].
The CH2 stretching and deformation modes are assigned at 2865, 1332, 1184 cm-1 (IR),
2887, 1333, 1283, 1194 cm-1 (Raman), 2963, 2893, 1421, 1331, 1283, 1199 cm-1 (DFT) for
CMBAPC and at 2970,1284 cm-1 (IR), 2970, 2893, 1338, 1284 cm-1 (Raman), 2972, 2895, 1423,
1334, 1286, 1195 cm-1 (DFT) for CMOBAPC where the expected range is 2900-3100 cm-1 for
CH2 stretching and 800-1500 cm-1for deformations [74]. For CMBAPC the stretching mode at
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2963 cm-1 has a PED of 99% with IR intensity of 6.01 and Raman activity of 86.45 and the mode
at 2893 cm-1 has a PED of 100% with IR of 38.66 and Raman of 165.32. For the deformation
modes at 1421, 1331,1283 and 1199 cm-1 the IR intensity are 25.63, 56.17, 19.32 and 30.92 and
Raman activities are 11.21, 16.63, 23.18 and 33.34 and the PEDs are 90, 68, 42 and 63%. For
CMOBAPC the stretching modes at 2972, 2895 cm-1 have 100% PED with IR intensities 5.03,
41.13 and Raman activities 80.46 and 165.77. The deformation modes of CMOBAPC have IR
intensities of 10.40, 116.61, 28.39, 63.24 and Raman activities of 11.82, 27.09, 39.47, 22.38 with
PEDs 85, 64, 69 and 62%. The CH3 stretching and deformation modes for CMBAPC are
assigned at 1402, 1019 cm-1 (IR), 2994, 2968, 2905, 1412, 1381, 1012 cm-1 (Raman), 2995,
2966, 2910, 1414, 1399,1381, 1342, 1010 cm-1 (DFT) with a PED of 100% for the modes at
2995, 2966 cm-1 and also the IR intensities are 15.00, 15.73 and Raman activities are 72.42 and
113.79 whereas for the mode at 2910 cm-1 has a PED of 60% with 34.86 IR intensity and 278.30
Raman activity. And for CMOBAPC these modes are assigned at 3020, 2944, 1408, 1117 cm-1
(IR), 3020, 2940, 2880 cm-1 (Raman), 3017, 2948, 2885, 1421, 1405, 1403, 1149, 1114cm-1
(DFT). The PED for the modes at 3017 cm-1 is 91% with IR intensity 23.03 and Raman activity
158.71. For the modes at 2948 and 2885 cm-1 the PED is 100% with IR intensities 39.51 and
63.28 and Raman activities of 70.81 and 163.05. All these modes are in accordance with the
expected range 2860-3000 cm-1 (stretching) and the 1365-1485 cm-1 (deformations) [74].
The C≡N stretching mode indicates absorption at 2200-2280 cm-1 [74, 78]. In the present
case the C≡N stretching vibration is assigned at 2238 cm-1 (IR), 2262 cm-1 (Raman), 2257 cm-1
(DFT) with low IR 2.19 and a high Raman 536.23 for CMBAPC and at 2245 cm-1 (IR), 2247
cm-1 (Raman), 2257 cm-1 (DFT) with low IR 2.39 and a high Raman 541.06 for CMOBAPC with
a PED of 89% for both the compounds.
C-C stretching are found theoretically at 1188, 1183 cm-1 for CMBAPC with IR
intensities 6.80, 9.40 and Raman activities 16.94, 19.85 and PEDs of 44% and 40%. For
CMOBAPC, C-C stretching band is observed at 1184 cm-1 theoretically. These bands are not
observed in the IR and Raman. The PED for this band is 41% with IR intensity 9.86 and Raman
activity 30.34.
CH stretching modes of the pyrazine ring are usually in the range of 3000-3100 cm-1
[65] and for these molecules, they are assigned at 3076 cm-1 (DFT), 3088 cm-1 (IR), 3080 cm-1
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(Raman) with low IR intensity of 3.50 and Raman activity of 148.33 for CMBAPC and at 3076
cm-1 with low IR intensity of 3.59 and Raman activity of 150.20 for CMOBAPC theoretically
and 99% PED for both the title compounds. The pyrazine ring stretching modes are at 1530,
1424, 1234 cm-1 in the IR, 1533, 1435, 1230 cm-1 in the Raman, 1523-1228 cm-1 theoretically
for CMBAPC and at 1527, 1434, 1260, cm-1 in the IR spectrum, 1525, 1437, 1260cm-1 in the
Raman spectrum, 1522-1228 cm-1 with theoretically for CMOBAPC. For CMBAPC and
CMOBAPC the PEDs are in the range 58-50%. The modes at 1523 and 1228 cm-1 for CMBAPC
have IR intensities 118.40 and 28.24 and have Raman activities 210.73 and 9.07. For
CMOBAPC the modes at 1522 and 1228 cm-1 have IR intensities of 112.89 and 27.78 and
Raman activities of 211.96 and 8.73. The ring breathing modes of CMBAPC and CMOBAPC
are assigned at 1097 cm-1 (Raman), 1098 cm-1 (DFT) and 1096 cm-1 (IR), 1094 cm-1 (DFT)
respectively. The mode is having a very low IR intensity of 2.07, Raman activity of 28.77 and a
PED of 48% for CMBAPC and for CMOBAPC the IR intensity is low (4.11) with Raman
activity 33.21 and PED 46%. The CH deformation modes of the pyrazine ring are assigned at
1424 cm-1 (IR), 1435 cm-1 (Raman), 1434 cm-1 (DFT) with IR intensity 11.97, Raman activity
15.29 and the PED is 44%, 844 cm-1 (Raman), 848 cm-1 (DFT) with IR intensity 9.40, Raman
activity 0.28 and the PED is 82% for CMBAPC and 1434 cm-1 (IR), 1437 cm-1 (Raman), 1434
cm-1 (DFT) with IR intensity 10.92, Raman activity 16.74 and the PED is 44% 847 cm-1 (DFT)
with IR intensity 9.22, Raman activity 0.29 and the PED is 82% for CMOBAPC.
The phenyl CH stretching modes for CMBAPC and CMOBAPC are assigned at 3051,
3021 cm-1 (IR), 3057, 3037 cm-1 (Raman), 3064, 3057, 3042, 3040 cm-1 computationally with
PEDs 96% for the first two vibrations and 94% for the other two. The IR intensities are 7.61,
26.39, 9.71, 17.45 and the Raman activities are 171.49, 139.12, 103.12, 39.88 for these modes
and 3095 cm-1 (IR), 3091, 3057 cm-1 (Raman), 3092 (PED 96%), 3079 (PED 99%), 3055 (PED
100%), 3047 cm-1 (PED 96%) theoretically, with IR intensities 10.17, 5.34, 11.0, 13.51 and
Raman activities 128.40, 139.32, 63.68, 73.11 respectively. The phenyl ring stretching modes
are assigned at 1612, 1480, 1381, 1283 cm-1 in the Raman spectrum, 1605-1283 cm-1
theoretically for CMBAPC with a PED of 66% and 44% and 1610 cm-1 in the IR spectrum,
1609, 1390, 1316 cm-1 in the Raman spectrum, 1606-1315 cm-1 theoretically for CMOBAPC and
the PED values are 60% and 55%. The IR and Raman for these modes are 0.62, 19.32 and 97.60
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and 23.18 for CMBAPC and 33.25, 39.57 and 103.38, 16.43 for CMOBAPC. The ring breathing
mode is assigned for mono and 1,3-substituted benzenes, [74, 79] around 1000 cm-1. Ring
breathing mode of mono and 1, 3-substituted benzenes is reported at 1009 cm-1 [80] and 972,
974 cm-1 [81]. The Ph ring breathing mode is at 830 cm-1 (Raman), 826 cm-1 (DFT) for
CMBAPC and the PED is 68% with IR intensity 4.50 and Raman activity 34.92 and at 832 cm-1
(Raman), 831 cm-1 (DFT) for CMOBAPC with PED 42%, IR intensity 19.05 and Raman activity
28.89.
4.3
NMR spectra
1
The H and 13C NMR chemical shifts (δ) are simulated using the B3LYP functional with
GIAO formalism using the cc-pVDZ basis sets. The simulated values are and are compared with
the experimental chemical shifts provided in the table S2 of supplementary files [82]. For
CMBAPC, the protons of the Ph and Pz rings resonate in the ranges, 7.4374 to 8.5528 ppm and
8.7571 ppm (simulation). The corresponding experimental shift are observed at 7.17-7.31 ppm
and 8.33 ppm. In the case of CMOBAPC the corresponding values are, 6.8566-7.8029ppm,
8.749 ppm (simulation), 6.85-7.33 ppm and 8.27 ppm (expt). δ) of the hydrogen atoms of the
CH2 group are 4.0202, 7.8101 ppm (simulation) and 4.60ppm (expt) for CMBAPC. CMOBAPC
δ are 4.3403, 5.1302 ppm (simulation) and 4.51 ppm (expt). δ of the protons of the CH3 group
are 2.1086, 2.866, 2.714 ppm (simulation) and 2.32 ppm (expt) for CMBAPC and for
CMOBAPC the corresponding values are 4.134, 4.3683, 4.1193 ppm (simulation) and 3.72 ppm
(expt). The δ of the hydrogen atoms associated with nitrogen atoms are 5.7579 (H31),
8.3372(H32), 5.7975(H33) ppm (simulation) and 8.05, 8.46, 9.44 ppm (expt) for CMBAPC and
for CMOBAPC the values are 7.9689 (H27), 5.6206(H28), 8.4902(H34), 8.34, 7.98, 9.34 ppm.
High values are shown because of the presence of electronegative nitrogen atoms. In the present
13
case, C NMR chemical shifts of the phenyl ring lie in the range 126.7819-138.5741 ppm for
CMBAPC and in the range 108.7584-160.4545 ppm for CMOBAPC which are greater than 100
ppm as expected in literature. For the pyrazine ring the predicted δ for CMBAPC is in the range
125.4737-149.7834 ppm and for CMOBAPC the range is 126.2343-149.9856 ppm. For other
carbon atoms the predicted δ are 119.0965 ppm (C8), 52.254 ppm (C11), 24.531 ppm (C24),
168.5289 ppm (C28) for CMBAPC and for CMOBAPC the corresponding values are 119.4674
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(C8), 50.2523 (C11), 170.0456 (C24), 56.2693 (C30) ppm. For both the title compounds CMBAPC
and CMOBAPC the predicted δ agrees with the obtained results.
4.4
Nonlinear optical properties
Compounds with non linear optical properties are very important in the design of high
end electronic materials used for display and communication. The ability of a compound to show
this property can be obtained from the hyperpolarisability data of the simulated Raman spectra of
the compounds. The simulated polarizability values of CMBAPC and CMOBAPC are
6.6472×10-23 and 7.3960×10-23 esu. The first order hyperpolarizabilities are 5.9414×10-30 and
5.9675×10-30 esu for CMBAPC and CMOBAPC. It is in agreement with the reported analogues
[65, 83]. The most interesting feature is that the values are 15.93 and 16.01 times with the
property of urea, which is a standard NLO material [84]. The theoretically predicted second
order hyperpolarizabilites are -17.889×10-37 esu for CMBAPC and -20.027×10-37 esu for
CMOBAPC which are comparable with that of similar derivative [70]. Hence both compounds
can be developed as possible materials with a potential to shows non linear optical activities.
4.5
Frontier Molecular Orbital analysis
Frontier molecular orbitals like HOMO and LUMO are very important in governing the
reactivity preferences of any compound. For the compounds under the study, the pictures of the
HOMO and LUMO are provided in the Fig.S3 of the supporting information. In CMBAPC, the
HOMO is dfound to be spread over the entire molecule, except Ph ring and CH3 group while in
CMOBAPC, HOMO is over the entire molecule except Ph ring and OCH3 group. The LUMO is
delocalized over the pyrazine ring, C≡N, C=O and NH2 group for CMBAPC and CMOBAPC.
The energy values of the FMO's can be used to get some interesting reactivity indices of the
compounds. Ionization energy (I) and electron affinity (E) can be written as: I= -EHOMO, A = -
ELUMO [85]. Other parameters like hardness η, electronegativity χ and chemical potential μ can
be written as : η = (I-A)/2, χ = (I+A)/2 and μ = - (I+A)/2[85]. The energy gap for CMBAPC and
CMOBAPC are EHOMO = -8.6213 eV, ELUMO = -6.1192 eV, energy gap = 2.5021 eV. The I, A, η,
μ, χ and global electrophilicity (ω = μ2/2η) for CMBAPC and CMOBAPC are 8.6213 eV, 6.1192
eV, 1.2511 eV, -7.3703 eV, 7.3703 eV, 21.710 eV respectively.
4.6
Molecular Electrostatic Potential (MESP) analysis for reactivity
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MESP is an important took to predict the overall reactivity of a molecule towards
reagents like nucleophilies and electrophiles. It identifies the charge regions of the molecules and
provides the nature of such sites. This analysis is very much important for the prediction of
biological activity of the molecules. The colour codes helps to interpret the results in an easy
manner. Red regions are more electronegative regions, which attracts electrophiles, and blue
regions are more electropositive, which attracts more nucleophiles [86]. The general colour order
is as follows - red< orange <yellow< green< blue [87]. In the MESP plot (Fig.S4- supporting
information) for CMBAPC, red regions are over the C=O, C≡N and the Ph and for CMOBAPC,
it is over the C=O, C≡N, Ph and OCH3 group. Thus, there are both electrophilic and nucleophilic
regions in the molecules, suggesting high degree of reactivity and interaction towards polar
media.
4.7
interactions
These functions also predicts the reactivity of the atoms/groups towards charged reagents.
Average Local Ionisation Energy (ALIE), Fukui functions and noncovalent
ALIWE is used to predict the molecule sites which will be more prone to the attack of
electrophilic reagents. If the ALIE values are small, electrons are more loosely bound, hence can
be removed easily [88-91]. The ALIE diagram for the compounds CMBAPC and CMOBAPC
molecules are provided in Fig.2 which indicate the lie values are almost same for both
molecules. In cases of both molecules minimal ALIE values are located in the near vicinity of
aromatic ring and nitrogen N6, suggesting these region as possibly sensitive towards
electrophilic attacks. These results are in accordance with our previously reported results
regarding other pyrazine based molecules [92, 93]. In the present study the lowest ALIE values
are somewhat near ~200 kcal/mol, while maximal ALIE ~370 kcal/mol. Study of density of
electrons between atoms of title pyrazine molecules revealed formation of three and two intra
molecular noncovalent interactions in the cases of CMBAPC and CMOBAPC, respectively.
These noncovalent interactions are visualized and denoted in Fig.2, while strengths of these
noncovalent interactions are provided in Table S3. The results in Table S3 suggests that the
strongest noncovalent interaction formed in the case of CMOBAPC molecule, denoted with
number 2 and with corresponding strength of –0.033 electron/bohr3. Corresponding noncovalent
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interaction in the case of CMBAPC has somewhat lower strength, –0.025 electron/bohr3. The
strength of noncovalent interaction marked with number 1 is somewhat higher in the case of
CMBAPC comparing to CMOBAPC molecule. The third noncovalent interaction in the case of
CMBAPC has weak strength of–0.007 electron/bohr3.
In order to further search possibly important reactive sites we will refer to the results of
Fukui functions [94]. In the cases of CMBAPC and CMOBAPC molecules, Fukui functions are
presented in Fig.S5 (supporting information). In Fig.S5a, related to f+ function, there are several
locations within the CMBAPC and CMOBAPC molecules characterized by the positive (purple)
color, which indicates increase of electron density as a consequence of charge addition. In the
case of CMBAPC the most intensive purple color is located in the near C2, while in the case of
CMOBAPC the most intensive purple color is located in the near C24, designating these atoms
as electrophilic after the addition of charge. On the other side in Fig.S5b, related to Fukui f–
function, for both molecules the most intensive red color, which determines positions where
electron density decreases after the removal of charge, is located in the near oxygen atoms (O30
for CMBAPC and O25 for CMOBAPC) and cyano groups, designating these locations as
nucleophilic after the removal of charge.
4.8
Natural Bonding Orbital (NBO) analysis
NBO 3.1 version [95] implemented in the Gaussian 09 software package was used to
generate output files required for the NBO studies. This study can lead light into the various type
of hyperconjugative interactions possible in the molecules. In the case of CMBAPC, the hyper-
conjugative interactions are: C1-N6 from C2 of n1(C2)→π*(C1-N6), C4-C5 from N3 of
n1(N3)→σ*(C4-C5), C4-C5 from N6 of n1(N6)→σ*(C4-C5), C1-C8 from N9 of n1(N9)→σ*(C1-C8),
C28-N30 from O29 of n2(O29)→σ*(C28-N30) and C28-O29 from N30 of n1(N30)→ σ *(C28-O29) with
electron densities 0.45495, 0.04617, 0.04617, 0.03917, 0.05542 and 0.35616e and stabilization
energies 103.12, 10.43, 9.42, 12.46, 21.39 and 71.53 kcal/mol. The stabilisation energy is highest
for n1(C2)→π*(C1-N6), and the value is more that 100 kcal/mol, which stabilises the molecule to
a larger extend. Natural hybrid orbital n2(O29), occupy a higher energy orbital -0.26476 a.u with
high degree of p-character (98.82%) and low occupation number (ON) 1.87291 and the other
n1(O29) occupy a lower energy orbital -0.69218a.u with p-character 38.53% and high
ON1.97172.
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In the case of CMOBAPC, the strong hyper-conjugative interactions observed are: C1-
N6 from C2 of n1(C2)→ σ *(C1-N6), C4-N5 from N3 of n1(N3)→σ*(C4-N5), C4-N5 from N6 of
n1(N6)→σ*(C4-C5), C1-C8 from N9 of n1(N9)→σ*(C1-C8), C24-N26 from O25 of n2(O25)→σ*(C24-
N26), C24-O25 from N26 of n1(N26)→ σ *(C24-O25), C17-C19 from O29 of n1(O29)→σ*(C17-C19) and
C17-C19 from O29 of n2(O29)→π*(C17-C19) with electron densities, 0.45475, 0.04618, 0.04618,
0.03918, 0.05543, 0.35615, 0.02726 and 0.38501e and stabilization energies, 103.05, 10.43, 9.42,
12.45, 21.39, 71.49, 6.85 and 28.21 kcal/mol. Here also, the highest stabilisisation value is more
than 100 kcal/mol indicating very high stability for the molecule. The NHO with higher energies,
and low ON are n2(O25) and n2(O29) with energies, -0.26418, -0.30098a.u and p-characters,
98.83, 100% and ON, 1.87296 and 1.84950, but the orbitals with lower energies and high ON are,
n1(O25) and n1(O29) with energies, -0.69170, -0.55367a.u and p-characters, 38.53, 58.76% and
ON, 1.97172 and 1.96749. Thus, a very close to pure p-type lone pair orbital participates in the
electron donation to the
*(C1-N6) orbital for n1(C2)→ *(C1-N6), σ*(C4-C5) orbital for
n1(N3)→σ*(C4-C5), n1(N6)→ σ*(C4-C5), σ*(C1-C8) orbital for n1(N9)→σ*(C1-C8), σ*(C24-
N26)orbital for n2(O25) →σ*(C24-N26), *(C24-O25) orbital for n1(N26)→ *(C24-O25), σ*(C17-C19)
orbital for n1(O29)→ σ*(C17-C19),and *(C17-C19) orbital for n2(O29)→ *(C17-C19) interaction
in the compound. The results provided in the Tables S4 and S5 (supporting information). The
entire data shows that both molecules are highly stabilised by hyperconjugative interactions. This
is having enormous effect on other phyisco-chemical and biological activity of the molecule.
4.9
Autoxidation and hydrolysis studies
Oxidative degradation of organic pollutants, especially pharmaceutical ones, is
considered to be one of the most important tools for their efficient removal from water resources.
DFT calculations are particularly useful for the investigation of sensitivity towards oxidation
[96-99]. Concerning the autoxidation mechanism, sensitivity of organic molecules towards this
mechanism is related to the H-BDEs [24, 100, 101]. Interval of H-BDEs in range of 70 to 85
kcal/mol [102, 103] reflects high sensitivity towards autoxidation mechanism, while interval of
H-BDEs between 85 to 90 kcal/mol reflects sensitivity towards autoxidation mechanism to low
extent [103]. H-BDE values lower than 70 kcal/mol don’t reflect at all sensitivity towards
autoxidation mechanism [25, 102, 104]. Information about H-BDE values for CMBAPC and
CMOBAPC molecules are provided in Fig.S6 (supporting information) and Table S6 (supporting
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information). Calculated H-BDE values indicate that both CMBAPC and CMOBAPC molecules
possess two hydrogen atoms (denoted with bond number 3 in Fig.S6) for which BDE value lies
in the interval between 70 and 85 kcal/mol. Namely, BDE values for hydrogen atoms connected
to carbon atom C12 for CMBAPC (C11 for CMOBAPC) are equal to ~84/82 kcal/mol,
respectively. These H-BDE values indicate significant sensitivity towards autoxidation
mechanism thanks to which pyrazine molecules investigated in this study might be prone to
efficient degradation via oxidation. In this work we have also performed MD simulations in
order to obtain an insight into the stability of title molecules in water. This was of particular
importance since pharmacological molecules eventually end up in some type of water. After MD
simulations we have calculated RDFs in order to see which atoms of molecules show any
interactions with water molecules. RDFs of CMBAPC and CMOBAPC are provided in Fig.S7
(supporting information). According to the RDF results provided in Fig.S7 it can be concluded
that both pyrazine derivatives investigated in this work have two H atoms with RDFs showing
significant interactions with solvent water. Both of those hydrogen atoms belong to NH2 group.
However, although maximal g(r) values for these two atoms are located at distance lower than 2
Å, their maximal g(r) values are not so high, indicating that their interactions with water
molecules after all are not so significant. Comparing CMBAPC and CMOBAPC it can be seen
that CMOBAPC has somewhat stronger interactions with solvent, according to the interaction
energy with solvent (Eint) provided in Fig.S7, due to the presence of one more oxygen atom
(O29) which has relatively significant RDF profile characterized with two solvation spheres.
4.10 TD-DFT study on pyrazine derivatives molecule
In this study we have performed TD-DFT calculations to acquire UV spectra of the
pyrazine derivatives and to analyze, thanks to the concept of natural transition orbitals (NTO)
[105], which part of molecule’s are the most important for the UV absorption. TD-DFT
calculations also served us to investigate the charge transfer properties of pyrazine derivatives. In
Fig.S8 (supporting information) we provide computationally obtained UV spectra of pyrazine
derivatives investigated in this work. Both pyrazine derivatives investigated in this work have
two specific absorption peaks at ~230 and ~370 nm, indicating that structural difference between
them doesn’t introduce significant changes when it comes to the light absorption properties. In
Fig.S9 (supporting information) we are providing frontier molecular orbitals, and “particle” and
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“hole” NTOs of the first excitation. In the case of CMBAPC (Fig.S9a) it can be seen that the first
excitation “hole” and “particle” NTOs practically match the HOMO and LUMO orbitals,
meaning that the first (and the lowest energy) excitation is mainly due to the HOMO to LUMO
transition. However, this is not the case with CMOBAPC pyrazine derivative for which HOMO
and the first excitation “hole” NTO do not fully match, while LUMO and the first excitation
“particle” NTO match. After further inspection it was found that the first excitation “hole” NTO
actually matches HOMO-1 orbital, indicating the importance of transition from HOMO-1 to
LUMO orbital in the case of CMOBAPC pyrazine derivative. To analyze charge transfer within
molecule using Multiwfn program [52-55] we have performed an analysis of the charge for the
first excitation based on the electron density difference, according to the method described in
[106]. Method provided in [106] is defined for charge transfer in one dimension, however in the
implementation in Multiwfn program the method is generalized in three dimensions.
As introduced in [106] a quantity called charge transfer length (CT length) can be used
for quantification of charge transfer. This quantity has been defined as a distance between bary
centers of C+ and C– functions. Definition of C+ and C– functions relies on the electron density
variation between the excited and the ground state and other important information on these
functions can be seen in [106]. Before visualization of bary centers of positive and negative parts
of C+ and C– functions we are providing electron density variation due to the first excitation,
Fig.S10 (supporting information). Green and blue colored area actually indicate where comes to
the increase and decrease, respectively, in electron density as a consequence of excitation.
According to the results presented in Fig.S10, as a consequence of the first excitation electron
density changes mainly at ring containing nitrogen atoms and nitrogen atoms N9 and N10 (for
both pyrazine derivatives). Electron density variation clearly emphasizes the importance of the
aforementioned molecule part when it comes to the first excitation and is in accordance with the
results obtained with NTOs. Namely, “particle” and “hole” NTOs of the first excitation
(Figs.S9b and S9d) also emphasize the importance of the same part of molecule as electron
density variation in Fig.S10 (supporting information). Further, we will refer to the barycenters of
positive and negative parts of C+ and C–functions, which are visualized in Fig.S11 (supporting
information). C functions and their barycenters for title pyrazine derivatives indicate that CT
length is ~1.57 Å for both molecules, initially suggesting that the excitation is of local type (LE),
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meaning that holes and electrons share the same spatial range to high extent. However, since CT
length is not significantly low to straightforwardly indicate LE type of excitation, we have also
calculated the so called Δr coefficient, according to the paper [107], whose value also helps in
identification of excitation type. It is suggested in the paper [107] that LE modes are
characterized by Δr value lower than 2.0 Å. In the cases of pyrazine derivatives CMBAPC and
CMOBAPC the following values for Δr index have been obtained: 1.36 Å and 0.66 Å, which
clearly indicate a LE mode of excitation. Δr index has also been calculated by the Multiwfn
program.
4.11 Drug likeness
Drug likeness of newly synthetized title molecules has been assessed by calculation of
well- known parameters which indicate the potential of some organic molecules to be considered
as drug candidates. Lipinski’s rule of five [108, 109] recognizes the values of some parameters to
be considered active in humans. Moderately lipophilic character is desired, combined with HBD
and HBA values lower than 5 and 10, respectively. In the same time mass should be lower than
500 u. Table S7 (supporting information) indicates that pyrazine derivatives CMBAPC and
CMOBAPC fulfill all of these prerequisites. Ghose et al. [110] proposed that suitable drug
candidate should possesses molar refractivity . Number of rotatable bonds turned out also to be
important parameter and Veber et al. [111] stated that for good oral bioavailability number of
rotatable bonds should be lower than 10. This is also fulfilled by CMBAPC and CMOBAPC. It
is also very important to emphasize that AlogP takes value lower than 3, which is very important
for the “rule of three” defined by Congreeve et al. [112], for the lead compounds in drug
discovery.
4.12
Molecular docking studies
Literature sources indicate that the pyrazine derivatives are extensively used in the anti-
tubercular treatment [113], [114]. By the docking studies we want to make lucid whether the
title compounds can act as ENR inhibitors. High resolution crystal structure of Pseudomonas
aeruginosa Enoyl-Acyl carrier protein reductase (Fabl) was downloaded from the RSCD protein
data bank website with PDBID: 4NQZ [115]. Docking was done using Auto Dock Vina [116]
and as reported in literature [117]. The candidate drug binds at the active site (Fig.3 and
Fig.S12- supporting information) with the aid of weak non-covalent interactions. For the title
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compounds CMBAPC, amino acid TYR149 shows hydrophobic π-π stacked interaction with the
phenyl ring, hydrophobic π-alkyl interaction with the phenyl ring and with carbon in the phenyl
ring. For CMOBAPC amino acid ILE20, ALA21 and SER93 forms H-bond with N of C≡N in
the pyrazine ring, SER148 forms hydrogen bond with hydrogen of NH group, LYS166 shows
carbon-hydrogen bond with oxygen of C=O in the pyrazine ring, ILE20 and LEU147 shows
hydrophobic pi-alkyl interaction with the pyrazine ring and ALA192 shows hydrophobic pi-alkyl
interaction with phenyl ring. The docked ligands form a stable complex with Enoyl-Acyl carrier
protein reductase (Fabl) and got binding affinity values of -6.7 kcal/mol for CMBAPC and -6.5
kcal/mol for CMOBAPC (Table 2).These results suggest that the title compounds might exhibit
inhibitory activity against Pseudomonas aeruginosaEnoyl-Acyl carrier protein reductase (Fabl).
5.
Conclusion
The vibrational spectroscopic analysis of two cyanopyrazine-2-carboxamide derivatives,
CMBAPC and CMOBAPC are carried out experimentally and theoretically and are found in
close agreeement. Using natural bond orbital analysis, stability of the title compounds arising
from hyper conjugative interactions and charge delocalization have been analyzed. Compounds
shows excellent NLO properties over the standard material urea. Molecular docking studies
proves that the compounds exhibit inhibitory activity against Pseudomonas aeruginosaEnoyl-
Acyl carrier protein reductase (Fabl). ALIE surface shows that the benzene ring and nitrogen
atoms N6 could be sensitive towards electrophilic attacks. Fukui functions showed the
electrophilic character after the charge addition in the cases of carbon atoms C2 (CMBAPC) and
C24 (CMOBAPC). H-BDE values showed that both of the pyrazine derivatives are sensitive
towards autoxidation mechanism, thanks to the fact that two hydrogen atoms per each molecule
have H-BDE values of ~83 kcal/mol. RDFs indicated that each pyrazine derivative have two
hydrogen molecules with maximal g(r) values located at distances lower than 2 Å, however
maximal g(r) values in these cases are relatively low, so it is not expected that these two
molecules have significant interactions with water. TD-DFT calculations in combinations with
NTOs and charge transfer analysis by Multiwfn program indicated the most important molecule
sites for the lowest energy excitation. Electron density variation and the concepts of C+/–
functions and Δr parameter, indicated that the first excitation is of LE type.
Acknowledgment
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Part of this work has been performed thanks to the support received from Schrödinger Inc. Part
of this study was conducted within the project supported by the Ministry of Education, Science
and Technological Development of Serbia, grant numbers III41017.
References
[1]
[2]
[3]
[4]
[5]
Y.S. Higasio, T. Shoji, Heterocyclic compounds such as pyrroles, pyridines, pyrollidins,
piperdines, indoles, imidazol and pyrazins, Appl. Cataly. A: General 221 (2001) 197-207.
R. Müller, S. Rappert, Pyrazines: occurrence, formation and biodegradation, Appl.
Microbiol. Biotechnol. 85 (2010) 1315-1320.
J.A. Maga, C.E. Sizer, Pyrazines in foods, A review, J. Agric. Food Chem. 22(1) (1973)
22-30.
M. Asif, Piperazine and Pyrazine containing molecules and their diverse pharmacological
activities, Int. J. Adv. Sci. Res., 1 (2015) 5-11.
H. Tamioka, Current Status of Some Antituberculosis Drugs and the Development
of new Antituberculous Agents with Special Reference to their In Vitro and In Vivo
Antimicrobial Activities, Curr. Pharm. Design 12 (2006) 4047-4070.
V.B. Mathew, S.D. Arikkatt, T.J. Sindhu, M. Chandran, A.R. Bhat, K. Krishnakumar, A
review of Biological potential of pyrazine and related heterocyclic compounds, World J.
Pharm. Pharm. Sci. 3 (2014) 1124-1132.
[6]
[7]
[8]
D. A. Mitchison, Pyrazine – on the antituberculosis drug frontline, Natur. Med. 2 (1996)
635-636.
S. Lin, S. Malkani, M. Lombardo, L. Yang, S.G. Mills, K. Chapman, J. Thompson,
W.X. Zhang, R. Wang, R.M. Cubbon, E.A. O’neill, J.J. Hale, Design, synthesis, and
biological evaluation of aminopyrazine derivatives as inhibitors of mitogen-activated
protein kinase-activated protein kinase 2 (MK-2), Bioorg. Med. Chem. Lett. 25 (2015)
5402-5408.
[9]
H.H. Chen, A. Namil, B. Severns, J. Ward, C. Kelly, C. Drace, M.A. McLaughlin, S.
Yacoub, B. Li, R. Patil, N. Sharif, M.R. Hellberg, A. Rusinko, I.H. Pang, K.D. Combrink,
In vivo optimization of 2,3-diaminopyrazine Rho Kinase inhibitors for the treatment of
glaucoma, Bioorg. Med. Chem. Lett. 24 (2014) 1875–1879.
19

Journal Pre-proof
[10] T.I. El-Emary, Synthesis and Biological Activity of Some New Pyrazolo[3,4-
b]Pyrazines, J. Chin. Chem. Soc. 53 (2006) 391-401.
[11] M. Hamada, V. Roy, T.R. McBrayer, T. Whitaker, C. Urbina-Blanco, S.P. Nolan, J.
Balzarini, R. Snoeck, G. Andrei, R.F. Schinazi, L.A. Agrofoglio, Synthesis and broad
spectrum antiviral evaluation of bis(POM) prodrugs of novel acyclic nucleosides, Eur. J.
Med.Chem.67 (2013) 398-408.
[12] M. Dolezal, J. Zitko, Pyrazine derivatives: a patent review (June 2012 – Present), Expert
Opinion on Therapeutic patents, 25 (2015) 33 – 47.
[13] L. Carlucci, G. Liani, D. M. Proserpie, A. Sironi, 1-, 2-, and 3-Dimensional Polymeric
Frames in the Coordination Chemistry of AgBF4 with Pyrazine. The First Example of
Three Interpenetrating 3-Dimensional Triconnected Nets, J. Am. Chem. Soc. 117 (1995)
4562-4569.
[14] S. Achelle, C. Baudequin, N. Ple, Luminescent materials incorporating pyrazine or
quinoxaline moieties, Dyes and Pigments, 98 (2013) 575-600.
[15] S. Deng, X. Li, H. Fu, Two pyrazine derivatives as inhibitors of the cold rolled steel
corrosion in hydrochloric acid solution, Corros. Sci. 53 (2011) 822-828.
[16] X. Li, S. Deng, H. Fu, Three pyrazine derivatives as corrosion inhibitors for steel in 1.0
M H2SO4 solution, Corros. Sci. 53 (2011) 3241-3247.
[17] M. Bouklah, A.Attayibat, S. Kertit, A. Ramdani, B. Hammouti, A pyrazine derivative as
corrosion inhibitor for steel in sulphuric acid solution Appl. Surf. Sci.242
(2005) 399-406.
[18] S. Armaković, S. J. Armaković, J. P. Šetrajčić, I. J. Šetrajčić, Active components of
frequently used β-blockers from the aspect of computational study, J. Mol. Model. 18(9)
(2012) 4491-4501.
[19] S. J. Armaković, S. Armaković, N. L. Finčur, F. Šibul, D. Vione, J. P. Šetrajčić, B.
Abramović, Influence of electron acceptors on the kinetics of metoprolol photocatalytic
degradation in TiO2 suspension. A combined experimental and theoretical study, RSC
Adv. 5(67) (2015) 54589-54604.
[20] M. Blessy, R. D. Patel, P. N. Prajapati, Y. Agrawal, Development of forced degradation
and stability indicating studies of drugs-A review, J. Pharm. Anal. 4(3) (2014) 159-165.
20

Journal Pre-proof
[21] B. Abramović, S. Kler, D. Šojić, M. Laušević, T. Radović, D. Vione, Photocatalytic
degradation of metoprolol tartrate in suspensions of two TiO2-based photocatalysts with
different surface area. Identification of intermediates and proposal of degradation
pathways, J. Hazard. Mater. 198 (2011) 123-132.
[22] D.D. Četojević-Simin, S.J. Armaković, D.V. Šojić, B.F. Abramović, Toxicity assessment
of metoprolol and its photodegradation mixtures obtained by using different type of TiO
2 catalysts in the mammalian cell lines, Sci. Total Environ. 463 (2013) 968-974.
[23] J. A. War, K. Jalaja, Y.S. Mary, C.Y. Panicker, S. Armaković, S.J. Armaković, S.K.
Srivastava, C. Van Alsenoy, Spectroscopic characterization of 1-[3-(1H-imidazol-1-yl)
propyl]-3-phenylthiourea and assessment of reactive and optoelectronic properties
employing DFT calculations and molecular dynamics simulations, J. Mol. Struct. 1129
(2017) 72-85.
[24] S.W. Hovorka, C. Schöneich, Oxidative degradation of pharmaceuticals: theory,
mechanisms and inhibition, J. Pharm. Sci. 90(3) (2001) 253-269.
[25] P. Lienard, J. Gavartin, G. Boccardi, M. Meunier, Predicting drug substances
autoxidation, Pharm. Res. 32(1) (2015) 300-310.
[26] G.L. de Souza, L.M. de Oliveira, R.G. Vicari, A. Brown, A DFT investigation on the
structural and antioxidant properties of new isolated interglycosidic O-(1→ 3) linkage
flavonols, J. Mol. Model. 22(4) (2016) 1-9.
[27] Z. Sroka, B. Żbikowska, J. Hładyszowski, The antiradical activity of some selected
flavones and flavonols. Experimental and quantum mechanical study, J. Mol. Model.
21(12) (2015) 1-11.
[28] H. Djeradi, A. Rahmouni, A. Cheriti, Antioxidant activity of flavonoids: a QSAR
modeling using Fukui indices descriptors, J. Mol. Model. 20(10) (2014) 1-9.
[29] S. Armaković, S.J. Armaković, S. Pelemiš, D. Mirjanić, Influence of sumanene
modifications with boron and nitrogen atoms to its hydrogen adsorption properties, Phys.
Chem. Chem. Phys. 18(4) (2016). 2859-2870.
[30] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, G.
Scalmani, V. Barone, B. Mennucci, G.A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H.
P. Hratchian, A.F. Izmaylov, J. Bloino, G. Zheng, J.L. Sonnenberg, M. Hada, M. Ehara,
21

Journal Pre-proof
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H.
Nakai, T. Vreven, J.A. Montgomery, Jr., J.E. Peralta, F. Ogliaro, M. Bearpark, J.J. Heyd,
E. Brothers, K.N. Kudin, V.N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K.
Raghavachari, A. Rendell, J.C. Burant, S.S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J.M.
Millam, M. Klene, J.E. Knox, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.
Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W.
Ochterski, R.L. Martin, K. Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador,
J.J.Dannenberg, S. Dapprich, A.D. Daniels, O. Farkas, J.B. Foresman, J.V. Ortiz,
J.Cioslowski, D.J. Fox, Gaussian 09, Revision B.01, Gaussian, Inc., Wallingford CT,
2010.
[31] J.B. Foresman, in: E. Frisch (Ed.), Exploring Chemistry with Electronic Structure
Methods: A Guide to Using Gaussian, Gaussian Inc., Pittsburg, PA, 1996.
[32] R. Dennington, T. Keith, J. Millam, Semichem Inc., Shawnee Mission KS, GaussView,
Version 5, 2009.
[33] J.M.L. Martin, C. Van Alsenoy, GAR2PED, A Program to Obtain a Potential Energy
Distribution from a Gaussian Archive Record, University of Antwerp, Belgium, 2007.
[34] Materials Science Suite 2017-4, Schrödinger, LLC, New York, NY. 2017.
[35] A.D. Bochevarov, E. Harder, T.F. Hughes, J.R. Greenwood, D.A. Braden, D.M. Philipp,
D. Rinaldo, M.D. Halls, J. Zhang, R.A. Friesner, Jaguar: A high‐performance quantum
chemistry software program with strengths in life and materials sciences, Int. J. Quantum
Chem. 113(18) (2013) 2110-2142.
[36] Schrödinger Release 2017-4: MS Jaguar, Schrödinger, LLC, New York, NY. 2017.
[37] L.D. Jacobson, A.D. Bochevarov, M.A. Watson, T.F. Hughes, D. Rinaldo, S. Ehrlich,
T.B. Steinbrecher, S. Vaitheeswaran, D.M. Philipp, M.D. Halls, Automated Transition
State Search and Its Application to Diverse Types of Organic Reactions, J. Chem. Theor.
Comput. 13(11) (2017) 5780-5797.
[38] D. Shivakumar, J. Williams, Y. Wu, W. Damm, J. Shelley, W. Sherman, Prediction of
absolute solvation free energies using molecular dynamics free energy perturbation and
the OPLS force field, J. Chem. Theor. Comput. 6(5) (2010) 1509-1519.
22

Journal Pre-proof
[39] Z. Guo, U. Mohanty, J. Noehre, T.K. Sawyer, W. Sherman, G. Krilov, Probing the
α‐Helical Structural Stability of Stapled p53 Peptides: Molecular Dynamics Simulations
and Analysis, Chem. Biol. Drug Design, 75(4) (2010) 348-359.
[40] K.J. Bowers, E. Chow, H. Xu, R. O. Dror, M.P. Eastwood, B.A. Gregersen, J.L. Klepeis,
I. Kolossvary, M.A. Moraes, F.D. Sacerdoti. Scalable algorithms for molecular dynamics
simulations on commodity clusters. in SC 2006 Conference, Proceedings of the
ACM/IEEE. 2006. IEEE.
[41] V.B. Bregović, N. Basarić, K. Mlinarić-Majerski, Anion binding with urea and thiourea
derivatives, Coord. Chem. Rev. 295 (2015) 80-124.
[42] A.D. Becke, Density‐functional thermochemistry. III. The role of exact exchange, J.
Chem. Phys. 98(7) (1993). 5648-5652.
[43] T. Yanai, D.P. Tew, N.C. Handy, A new hybrid exchange–correlation functional using
the Coulomb-attenuating method (CAM-B3LYP), Chem. Phys. Lett. 393(1) (2004) 51-
57.
[44] Y. Cao, T. Hughes, D. Giesen, M.D. Halls, A. Goldberg, T.R. Vadicherla, M. Sastry, B.
Patel, W. Sherman, A.L. Weisman, Highly efficient implementation of pseudospectral
time‐dependent density‐functional theory for the calculation of excitation energies of
large molecules, J. Comput. Chem. 37(16) (2016) 1425-1441.
[45] E. Harder, W. Damm, J. Maple, C. Wu, M. Reboul, J.Y. Xiang, L. Wang, D. Lupyan,
M.K. Dahlgren, J.L. Knight, OPLS3: a force field providing broad coverage of drug-like
small molecules and proteins, J. Chem. Theor. Comput. 12(1) (2015) 281-296.
[46] W.L. Jorgensen, D.S. Maxwell, J. Tirado-Rives, Development and testing of the OPLS
all-atom force field on conformational energetics and properties of organic liquids, J.
Am. Chem. Soc. 118(45) (1996) 11225-11236.
[47] W.L. Jorgensen, J. Tirado-Rives, The OPLS [optimized potentials for liquid simulations]
potential functions for proteins, energy minimizations for crystals of cyclic peptides and
crambin, J. Am. Chem. Soc.110(6) (1988) 1657-1666.
[48] H.J. Berendsen, J.P. Postma, W.F. van Gunsteren, J. Hermans, Interaction models for
water in relation to protein hydration, in Intermolecular forces. 1981, Springer. p. 331-
342.
23

Journal Pre-proof
[49] A. Otero-de-la-Roza, E.R. Johnson, J. Contreras-García, Revealing non-covalent
interactions in solids: NCI plots revisited, Phys. Chem. Chem. Phys. 14(35) (2012)
12165-12172.
[50] E.R. Johnson, S. Keinan, P. Mori-Sanchez, J. Contreras-Garcia, A.J. Cohen, W. Yang,
Revealing noncovalent interactions, J. Am. Chem. Soc. 132(18) (2010) 6498-6506.
[51] Schrödinger Release 2017-4: Maestro, Schrödinger, LLC, New York, NY. 2017.
[52] T. Lu, F. Chen, Multiwfn: a multifunctional wavefunction analyzer, J. Comput. Chem.
33(5) (2012) 580-592.
[53] T. Lu, F. Chen, Quantitative analysis of molecular surface based on improved Marching
Tetrahedra algorithm, J. Mol. Graphics Model. 38 (2012) 314-323.
[54] L. Tian, C. Feiwu, Calculation of molecular orbital composition, Acta Chim. Sinica. 69
(2011) 2393-2406.
[55] M. Xiao, T. Lu, Generalized Charge Decomposition Analysis (GCDA) Method, J. Adv.
Phys. Chem. 4 (2015) 111-124.
[56] W. Humphrey, A. Dalke, K. Schulten, VMD: visual molecular dynamics, J. Mol.
Graphics, 14(1) (1996) 33-38.
[57] J.E. Stone, J. Gullingsrud, K. Schulten. A system for interactive molecular dynamics
simulation. in Proceedings of the 2001 symposium on Interactive 3D graphics. 2001.
ACM.
[58] J. Eargle, D. Wright, Z. Luthey-Schulten, Multiple Alignment of protein structures and
sequences for VMD, Bioinformatics, 22(4) (2006) 504-506.
[59] D. Frishman, P. Argos, Knowledge‐based protein secondary structure assignment,
Proteins: Struct. Funct. Bioinformatics, 23(4) (1995) 566-579.
[60] A. Varshney, J. F.P. Brooks, W. V. Wright, Linearly Scalable Computation of Smooth
Molecular Surfaces, in IEEE Computer Graphics and Applications, 1994.
[61] M.F. Sanner, A.J. Olson, J.-C. Spehner. Fast and robust computation of molecular
surfaces. in Proceedings of the eleventh annual symposium on Computational geometry.
1995. ACM.
24

Journal Pre-proof
[62] R. Sharma, M. Zeller, V.I. Pavlovic, T.S. Huang, Z. Lo, S. Chu, Y. Zhao, J.C. Phillips, K.
Schulten, Speech/gesture interface to a visual-computing environment. IEEE Computer
Graphics and Applications, 2000. 20(2): p. 29-37.
[63] J.E. Stone, An efficient library for parallel ray tracing and animation. 1998, Masters
Theses, http://scholarsmine.mst.edu/masters_theses/1747.
[64] Y.S. Mary, A. A. Saadi, K. Haruna, R. Thomas, Roxy M S, S. Popoola, V. Santhosh.
Conformational profile, vibrational assignments, NLO properties and molecular docking
of biologically active herbicide1,1-dimethyl-3-phenylure. Heliyon, 5, 6 (2019) , e01987
DOI: https://doi.org/10.1016/j.heliyon.2019.e01987
[65] J. Lukose, C.Y. Panicker, P.S. Nayak, B. Narayana, B.K. Sarojini, C. Van Alsenoy,
A.A. Al-Saadi, Synthesis, structural and vibrational investigation on 2-phenyl-N-
(pyrazin-2-yl)acetamide combining XRD diffraction, FT-IR and NMR spectroscopies
with DFT calculations, Spectrochim. Acta. 135 (2015) 608-616.
[66] W. He, G. Zhou, J. Li, A. Tian, Molecular design of analogues of 2, 6-diamino-3, 5-
dinitropyrazine-1-oxide, J. Mol. Struct. Theochem. 668 (2004) 201-208.
[67] H. Takeuchi, M. Sato, T. Tsuji, H. Takashima, T. Egawa, S. Konaka, J. Mol. Struct. 485-
486 (1999) 175-181.
[68] S.M. Bakalova, A.G. Santos, I. Timcheva, J. Kaneti, I.L. Filipova, G.M. Dobrikov, V.D.
Dimitrov, Electronic absorption and emission spectra and computational studies of some
2-aryl, 2-styryl, and 2-(4’-aryl)butadienyl quinazolin-4-ones, J. Mol. Struct. Theochem.
710 (2004) 229-234.
[69] E.D. Stevens, Low-temperature experimental electron density distribution of formamide,
Acta. Cryst. 34B (1978) 544-551.
[70] S.H.R. Sebastian, M.A. Al-Alshaikh, A.A. El-Emam, C.Y. Panicker, J. Zitko, M.
Dolezal, C. Van Alsenoy, Spectroscopic, quantum chemical studies, Fukui functions, in
vitro antiviral activity and molecular docking of 5-chloro-N-(3-nitrophenyl) pyrazine-2-
carboxamide, J. Mol. Struct. 1119 (2016) 188-199.
[71] M. Barthes, G. De Nunzio, M.Ribet, Polarons or proton transfer in chains of peptide
groups ?, Synth. Met. 76 (1996) 337-340.
25

Journal Pre-proof
[72] K. Tamagawa, T. Iijima, M. Kimura, Molecular structure of benzene, J. mol. Struct.30
(1976) 243-253.
[73] K.B. Borizenko, C. W. Bock, I. Hargittai, Molecular Geometry of Benzaldehyde and
Salicylaldehyde: A Gas-Phase Electron Diffraction and ab Initio Molecular Orbital
Investigation, J. Phys. Chem. 100 (1996) 7426-7434.
[74] N.P.G. Roeges, A Guide to the Complete Interpretation of Infrared Spectra of Organic
Structures, John Wiley and Sons Inc., New York, 1994.
[75] R.M. Silverstein, G.C. Bassler, T.C. Morril, Spectrometric Identification of Organic
Compounds, fifth ed., John Wiley and Sons Inc., Singapore, 1991.
[76] N.B. Colthup, L.H. Daly, S.E. Wiberly, Introduction of Infrared and Raman
Spectroscopy, Academic Press, New York, 1975.
[77] L.J. Bellamy, The Infrared Spectrum of Complex Molecules, third ed., Chapman and
Hall, London, 1975.
[78] J. Coates, Encyclopedia of Analytical Chemistry, in: R.A. Meyers (Ed.), Interpretation of
Infrared Spectrum, A Practical Approach, John Wily and Sons Ltd., Chichester, 2000.
[79] G. Varsanyi, Assignments of Vibrational Spectra of Seven Hundred Benzene
Derivatives,Wiley, NewYork,1974.
[80] A.S. El-Azab, K. Jalaja, A.A.M. Abdel-Aziz, A.M. Al-Obaid, Y.S. Mary, C.Y. Panicker,
C.VanAlsenoy, Spectroscopic analysis (FT-IR, FT-Raman and NMR) and molecular
docking study of ethy 2-(4-oxo-3-phenethly-3,4-dihydroquinazolin-2-ylthio)-acatate,
J. Mol. Struct. 1119 (2016)451-461.
[81] Y.S. Mary, K. Raju, C.Y. Panicker, A.A. Al-Saadi, T. Thiemann, Molecular
conformational analysis, vibrational spectra, NBO analysis and first hyperpolarizability
of (2E)-3-(3-chlorophenyl)prop-2-enoic anhydride based on density functional theory
calculations, Spectrochim. Acta 131 (2014) 471-483.
[82] K. Wolinski, J.F. Hinton, P. Pulay, Efficient implementation of the gauge independent
atomic orbital method for NMR chemical shift calculations, J. Am. Chem. Soc. 112
(1990) 8251-8260.
[83] Y.S Mary, C,Y Panicker, R. Thomas, B. Narayana, S. Samshuddin, B.K. Sarojini, S.
Armaković, S. J. Armaković, G. G.Pillai, Theoretical studies on the structure and various
26

Journal Pre-proof
hysico-chemical and biological properties of a terphenyl derivative with immense anti-
protozoan activity. Polycyclic Aromatic Compounds (2019).
https://doi.org/10.1080/10406638.2019.1624974
[84] C. Adant, M. Dupuis, J.L. Bredas, Ab initio study of the nonlinear optical properties of
urea, electron correlation and dispersion effects, Int. J. Quantum Chem. 56 (2004) 497-
507.
[85] R.G. Parr, R.G. Pearson, Absolute hardness, companion parameter to absolute
electronegativity, J. Am. Chem. Soc. 105 (1983) 7512-7516.
[86] A.M. Koster, M. Leboeuf, D.R. Salahub, Molecular Electrostatic Potentials from Density
Functional Theory, Theor. Comput. Chem. 3 (1996) 105-142.
[87] D. Majumdar, S. Das, R.Thomas, Z. Ullah, S. S. Sreejith, D. Das, K. Bankura, D. Mishra,
Syntheses, X-ray crystal structures of two new Zn(II)-dicyanamide complexes derived
from H2vanen-type compartmental ligands: Investigation of thermal,photoluminescence,
in vitro cytotoxic effect and DFT-TDDFT studies. Inorganica Chimica Acta 492 (2019):
221-234 https://doi.org/10.1016/j.ica.2019.04.041
[88] J.S. Murray, J.M. Seminario, P. Politzer, P. Sjoberg, Average local ionization energies
computed on the surfaces of some strained molecules, Int. J. Quantum Chem. 38(S24)
(1990) 645-653.
[89] P. Politzer, F. Abu‐Awwad, J.S. Murray, Comparison of density functional and Hartree–
Fock average local ionization energies on molecular surfaces, Int. J. Quantum Chem.
69(4) (1998) 607-613.
[90] F.A. Bulat, A. Toro-Labbé, T. Brinck, J.S. Murray, P. Politzer, Quantitative analysis of
molecular surfaces: areas, volumes, electrostatic potentials and average local ionization
energies, J. Mol. Model. 16(11) (2010) 1679-1691.
[91] P. Politzer, J.S. Murray, F.A. Bulat, Average local ionization energy: a review, J. Mol.
Model. 16(11) (2010) 1731-1742.
[92] S. Beegum, Y.S. Mary, H.T. Varghese, C.Y. Panicker, S. Armaković, S.J. Armaković, J.
Zitko, M. Dolezal, C. Van Alsenoy, Vibrational spectroscopic analysis of cyanopyrazine-
2-carboxamide derivatives and investigation of their reactive properties by DFT
calculations and molecular dynamics simulations, J. Mol. Struct. 1131 (2017) 1-15.
27

Journal Pre-proof
[93] P.K. Ranjith, E.S. Al-Abdullah, F.A.M. Al-Omary, A.A. El-Emam, P.L. Anto, Y.S.
Mary, S. Armaković, S.J. Armaković, J. Zitko, M. Dolezal, C. Van Alsenoy, FT-IR and
FT-Raman characterization and investigation of reactive properties of N-(3-iodo-4-
methylphenyl)pyrazine-2-carboxamide by molecular dynamics simulations and DFT
calculations. J. Mol. Struct. 1136 (2017) 14-24.
[94] A. Michalak, F. De Proft, P. Geerlings, R. Nalewajski, Fukui functions from the relaxed
Kohn-Sham orbitals, J. Phys. Chem.A, 103(6) (1999) 762-771.
[95] E. D. Glendening, A.E. Reed, J.E. Carpenter, F. Weinhold, NBO Version 3.1, TCI,
University of Wisconsin, Madison, 1998
[96] X. Ren, Y. Sun, X. Fu, L. Zhu, Z. Cui, DFT comparison of the OH-initiated degradation
mechanisms for five chlorophenoxy herbicides, J. Mol. Model. 19(6) (2013) 2249-2263.
[97] L.-l. Ai, J.-y. Liu, Mechanism of OH-initiated atmospheric oxidation of E/Z-CF3CF=
CFCF3: a quantum mechanical study, J. Mol. Model. 20(4) (2014) 1-10.
[98] W. Sang-aroon, V. Amornkitbamrung, V. Ruangpornvisuti, A density functional theory
study on peptide bond cleavage at aspartic residues: direct vs cyclic intermediate
hydrolysis, J. Mol. Model. 19(12) (2013) 5501-5513.
[99] J. Kieffer, É. Brémond, P. Lienard, G. Boccardi, In silico assessment of drug substances
chemical stability, J. Mol. Struct. THEOCHEM, 954(1) (2010) 75-79.
[100] K.A. Connors, G.L. Amidon, V.J. Stella, Chemical stability of pharmaceuticals: a
handbook for pharmacists, 1986: John Wiley & Sons.
[101] D. Johnson, L. Gu, Autoxidation and antioxidants, Encycl. Pharm. Technol. 1 (1988)
415-449.
[102] J.S. Wright, H. Shadnia, L.L. Chepelev, Stability of carbon‐centered radicals: Effect of
functional groups on the energetics of addition of molecular oxygen, J. Comput. Chem.
30(7) (2009) 1016-1026.
[103] G. Gryn'ova, J.L. Hodgson, M.L. Coote, Revising the mechanism of polymer
autooxidation, Org.Biomol. Chem. 9(2) (2011) 480-490.
[104] T. Andersson, A. Broo, E. Evertsson, Prediction of Drug Candidates' Sensitivity Toward
Autoxidation: Computational Estimation of C-H Dissociation Energies of
Carbon‐Centered Radicals, J. Pharm. Sci. 103(7) (2014) 1949-1955.
28