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

Article abstract of DOI:10.1016/j.molstruc.2017.01.079

The FT-IR and FT-Raman spectra of N-(3-iodo-4-methylphenyl)pyrazine-2-carboxamide were recorded and the experimentally observed wavenumbers are compared with the theoretically obtained wavenumbers. The redshift of the N[sbnd]H stretching mode in the IR spectrum from the computed value indicated the weakening of the N[sbnd]H bond. The ring breathing modes of the phenyl ring and pyrazine ring are assigned at 819 and 952?cm^?1 theoretically. Using natural bond orbital analysis, the stability of the molecule arising from hyperconjugative interaction and charge delocalization has been analyzed. The most reactive sites in the molecule were identified by molecular electrostatic potential map. The calculations of the average local ionization energy (ALIE) were used for visualization and determination of molecule sites possibly prone to electrophilic attacks. Further information on possible reactive centers of title molecule has been obtained by calculations of Fukui functions. Vulnerability of title molecule towards autoxidation mechanism was investigated by calculations of bond dissociation energies (BDE), while vulnerability towards hydrolysis was investigated by calculations of radial distribution functions (RDF) as obtained after molecular dynamics (MD) simulations. Molecular docking studies suggest that the compound might exhibit inhibitory activity against mGluRs.

Full text of DOI:10.1016/j.molstruc.2017.01.079

Accepted Manuscript
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
P.K. Ranjith, Ebtehal S. Al-Abdullah, Fatmah A.M. Al-Omary, Ali A. El-Emam, P.L.
Anto, Mary Y. Sheena, Stevan Armaković, Sanja J. Armaković, Jan Zitko, Martin
Dolezal, C. Van Alsenoy
PII:
S0022-2860(17)30122-9
10.1016/j.molstruc.2017.01.079
MOLSTR 23384
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 28 November 2016
Revised Date: 26 January 2017
Accepted Date: 27 January 2017
Please cite this article as: P.K. Ranjith, E.S. Al-Abdullah, F.A.M. Al-Omary, A.A. El-Emam, P.L. Anto,
M.Y. Sheena, 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, Journal of Molecular Structure
(2017), doi: 10.1016/j.molstruc.2017.01.079.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
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
Ranjith P.Ka, Ebtehal S. Al-Abdullahb, Fatmah A. M. Al-Omaryb, Ali A. El-Emamb, Anto
P.La, Sheena Mary Yc*, Stevan Armakovićd, Sanja J. Armakoviće, Jan Zitkof, Martin Dolezalf,
C. Van Alsenoyg
aDepartment of Physics, Christ College (Autonomous), Irinjalakuda, Thrissur, University of
Calicut, Kerala, India
b Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University,
Riyadh 11451, Saudi Arabia
cDepartment of Physics, Fatima Mata National College, Kollam, India
dUniversity of Novi Sad, Faculty of Sciences, Department of Physics,
Trg D. Obradovića 4, 21000 Novi Sad, Serbia
eUniversity of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and
Environmental Protection, Trg D. Obradovića 3, 21000 Novi Sad, Serbia
fFaculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203,
Hradec Kralove, 500 05, Czech Republic
gDepartment of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020,
Antwerp, Belgium
author for correspondence:email:sypanicker@rediffmail.com
ABSTRACT
The FT-IR and FT-Raman spectra of N-(3-iodo-4-methylphenyl)pyrazine-2-carboxamide
were recorded and the experimentally observed wavenumbers are compared with the
theoretically obtained wavenumbers. The redshift of the N-H stretching mode in the IR
spectrum from the computed value indicated the weakening of the N-H bond. The ring
breathing modes of the phenyl ring and pyrazine ring are assigned at 819 and 952 cm-1
theoretically. Using natural bond orbital analysis, the stability of the molecule arising from
hyperconjugative interaction and charge delocalization has been analyzed. The most reactive
sites in the molecule were identified by molecular electrostatic potential map. The
calculations of the average local ionization energy (ALIE) were used for visualization and
determination of molecule sites possibly prone to electrophilic attacks. Further information on
possible reactive centers of title molecule has been obtained by calculations of Fukui
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functions. Vulnerability of title molecule towards autoxidation mechanism was investigated
by calculations of bond dissociation energies (BDE), while vulnerability towards hydrolysis
was investigated by calculations of radial distribution functions (RDF) as obtained after
molecular dynamics (MD) simulations. Molecular docking studies suggest that the compound
might exhibit inhibitory activity against mGluRs.
Keywords: Pyrazine; Carboxamide; ALIE; BDE; RDF; Molecular docking
1.
Introduction
Considerable attention has been devoted to pyrazine derivatives which have long been
known for their diverse chemotherapeutic properties. Pyrazinamide was early recognized as a
first line drug for the treatment of tuberculosis [1,2]. As a result of evolution of resistant
strains of Mycobacterium tuberculosis [2], several pyrazine derivatives were prepared and
proved to exhibit marked activity against multidrug resistant tuberculosis strains [3-8]. In
addition, pyrazine nucleus was reported to constitute the essential pharmacophore in several
pyrazine-based antiviral [9, 10], anticancer [11-13], antimicrobial [14], antimalarial [15]
trypanosomicidal [16] and insecticidal [17] agents. Moreover, pyrazine derivatives were
reported as organic light-emitting diodes (OLEDs) [18,19] and corrosion inhibitors [20-22].
The title compound N-(3-iodo-4-methylphenyl)pyrazine-2-carboxamide (1) was found to be
the most active antimycobacterial in vitro against M. tuberculosis H37Rv (minimum
inhibitory concentration (MIC) < 2.0 µg/mL) [23]. The structure-antimycobacterial activity
relationship studies of N-phenylpyrazine-2-carboxamides showed the positive influence of
halogen substitution in position 3 and methyl group in position 4 of the phenyl ring for the
antimycobacterial activity [23-25]. Biologically active organic molecules are stable structures
that are accumulating in the environment due to the frequent use an improper dumping. Their
stability prevents degradation under natural conditions, while at the same time it was shown
that they are toxic to aquatic organisms [26,27]. Forced degradation via advanced oxidation
processes is seen as substitute to conventional purification methods [26,27, 28-32]. However,
experiments and procedures based on forced degradation are complex and time consuming, so
it is necessary to find ways how to perform their optimization and rationalization. This can be
done by DFT calculations and MD simulations [33-36], since molecular modeling techniques
can be used for prediction of reactive properties of investigated molecules. Results obtained
by inexpensive computational experiments can further be used for understanding how forced
degradation procedures can be improved. In the present work, the vibrational spectroscopic
studies of N-(3-iodo-4-methylphenyl)pyrazine-2-carboxamide (IMPPC) are reported
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experimentally and theoretically. The molecular docking studies are also reported due to the
different potential biological activities of the title compound.
2.
Experimental details
The title compound (1, Scheme 1) was prepared following the previously described
procedure [23] via the reaction of pyrazine-2-carboxylic acid (A) (5 mmol) with thionyl
chloride (7.5 mmol) in dry toluene to yield the corresponding acyl chloride (B), which was
subsequently reacted with 3-iodo-4-methylaniline (5 mmol) in dry acetone with pyridine (5
mmol). The reaction was stirred at room temperature for1 hour, then poured into cold water.
The crude product was collected, adsorbed on silica and purified by flash-chromatography
(silica, gradient elution ethyl-acetate in hexane 0-30%). The yield of chromatographically
pure product was 84% of theoretical yield related to acid (A). Elementary composition
(CHON) of 1 was in the range of ±0.4% of calculated values and the melting point was
consistent with literature (141-142°C) measured, 142-143°C from literature [23]. The FT-IR
spectrum (Fig. 1) was recorded using KBr pellets on a DR/JASCO FT-IR 6300 spectrometer.
The FT-Raman spectrum (Fig. 2) was obtained on a Bruker RFS 100/s, Germany. For
excitation of the spectrum, the emission of Nd:YAG laser was used with an excitation
wavelength of 1064 nm, a maximal power 150 mW; measurement of solid sample.
3.
Computational details
Calculations of the title compound were carried with using the Gaussian09 program
[37] using the B3LYP/ccpVDZ basis set to predict the molecular structure and wavenumbers
in the gaseous phase and a scaling factor of 0.9613 had to be used for obtaining a
considerably better agreement with the experimental data [38]. The structural parameters
corresponding to the optimized geometry of the title compound (Fig. 3) are given in Table 1.
The assignments of the calculated wavenumbers are done using GAR2PED [39] and
Gaussview software [40]. In this work, the DFT calculations have also been performed by
Jaguar 9.0 program [41], while the molecular modeling (MD) simulations have been
performed by Desmond program [42-44]. Both of these programs have been used as
implemented in Schrödinger Materials Science Suite 2015-4. DFT calculations with Jaguar
program have been done with B3LYP exchange-correlation functional [45], with 6-
311++G(d,p), 6-31+G(d,p) and 6-311G(d,p) basis sets for the calculations of ALIE, Fukui
functions and BDEs, respectively. In the case of MD simulations the OPLS 2005 force field
[46] has been employed, with simulation time set to 10 ns within isothermal-isobaric (NPT)
ensemble class. The MD simulations system was modeled by placing one IMPPC molecule
into the cubic box with ~3000 water molecules. Other parameters include temperature of 300
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K, pressure of 1.0325 bar and cut off radius of 12 Å. Simple point charge (SPC) model [47]
was used for the description of solvent. Noncovalent interactions in Jaguar program have been
investigated by the method developed by Johnson et al. [48, 49]. When Schrödinger Materials
Science Suite 2015-4 was used, Maestro GUI [50] was used for the preparation of input files
and analysis of results.
4.
Results and discussion
In the following discussion, phenyl and pyrazine rings are designated as Ph and Pz
respectively.
4.1
Geometrical parameters
The C-N and C-C bond lengths in the pyrazine ring of the title compound are 1.3366,
1.3392, 1.3424 and 1.3338 Ǻ and 1.4013, 1.4037 Ǻ, respectively, which are shorter than the
normal C-N bond length (1.49 Ǻ) and the C-C bond length (1.54 Ǻ). The reported C-N and C-
C bond lengths (B3LYP/SDD) of the pyrazine ring are 1.4104, 1.3577, 1.3577, 1.3608 Ǻ and
1.4121, 1.3517 Ǻ [51]. The bond lengths C10-N12 and C13-N12 (the carboxamide linker) are
1.3808 Ǻ and 1.4111 Ǻ which are also shorter than the normal C-N single bond and these
bonds have some character of a double or conjugated bond [52]. The C-C bond lengths in the
phenyl ring are in the range 1.3942-1.4071 Ǻ. At N12 position, the angles C10-N12-H22
=
116.3°, C10-N12-C13 = 128.3° and C13-N12-H22 = 115.1°, this asymmetry of angles is due to the
weakening of the N-H bond. At C18 position, the angles C15-C18-I27, C20-C18-I27, C15-C18-C20
are 117.1, 120.9 and 122.0°, respectively. This asymmetry is due to the iodine substitution in
the phenyl ring. The bond angles C4-C5-N6, C4-C5-C10, C10-C5-N6 are 121.3, 122.7 and 115.9°,
respectively. This asymmetry is attributed to the interaction of pyrazine ring and carboxamide
group. The bond angles C18-C20-C23, C16-C20-C23, C18-C20-C16 at C20 are 123.6, 120.5, 116.0°
and the asymmetry is due to the interaction of the neighboring groups.
4.2
IR and Raman spectra
The calculated scaled wavenumbers, observed IR, Raman bands and assignments are
given in Table 2. According to literature, the NH vibrations are expected in the regions,
3390±60 cm-1 (stretching), 1500-1200 and 790±70 cm-1 (bending modes) [53-56]. For the title
compound, these modes were assigned at 3365 cm-1 (IR), 3370 cm-1 (Raman), 3464 (DFT)
(stretching), 1486, 1225 602 cm-1 (IR), 600 cm-1 (Raman), 1485, 1223, 601 cm-1 (DFT). For
the title compound, the N-H stretching mode has an IR intensity of 17.68 and Raman activity
of 125.00 with a PED of 100%. The PED of N-H deformation modes of the title compound
are in between 41 and 52%. For the deformation mode at 601 cm-1, the IR intensity is low
while the other two modes have high IR intensity for the title compound. In the present case,
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the N-H stretching mode is red shifted by 99 cm-1 in the IR spectrum from the computed
value, which indicates the weakening of the N-H bond [57]. The C-N stretching modes are
expected in the range 1275±55 cm-1 [53] and the bands at 1211 cm-1 in the Raman spectrum
and at 1214, 1105 cm-1 (DFT) with moderate IR intensities and PEDs around 40% are
assigned as the C-N stretching modes of the title compound. The reported C-N stretching
modes are at 1265, 1239 cm-1 in the IR spectrum and at 1261, 1248 cm-1 (DFT) [58]. For the
title compound, the carbonyl stretching vibration is observed at 1695 cm-1 in the IR spectrum
and at 1696 cm-1 in the Raman spectrum which is expected in the region 1715-1600 cm-1 [53]
while the computed value is 1708 cm-1 with an IR intensity of 225.95 and Raman activity
176.10 and the PED is 64%.
The CH3 modes are expected in the regions, 3050-2900 cm-1 (stretching), 1485-1350,
1100-900 cm-1 (deformation modes) according to literature [53] and for the title compound,
these modes are assigned at 2975, 2920 cm-1 (IR), 3005, 2970, 2918 cm-1 (Raman), 3001,
2973, 2915 cm-1 (DFT) (stretching), 1437, 1402, 1368, 1030 cm-1 (IR), 1403, 1370, 1028 cm-1
(Raman), 1436, 1404, 1364, 1032, 990 cm-1 (DFT) (bending). Analysis of vibrational spectra
of substituted benzenes shows that the stretching vibrations of C-I corresponds to a band
around 340 cm-1 experimentally [59,60]. The carbon-iodine stretching band of the title
compound is assigned at 333 cm-1 theoretically. Zainuri et al. reported the CI stretching mode
at 317 cm-1 [61].
For the title compound, the phenyl CH stretching bands are observed at 3134, 3029
cm-1 in the IR spectrum and 3120, 3036 cm-1 in the Raman spectrum, while the computed
values are in the range 3136-3032 cm-1 which are in agreement with the literature [53,62]. The
phenyl ring stretching modes of the title compound are observed at 1590, 1458, 1342, 1290
cm-1 in the IR spectrum, at 1583, 1460, 1285 cm-1 in the Raman spectrum and at 1586, 1553,
1453, 1346 and 1287 cm-1 theoretically (DFT) [53]. The tri-substituted phenyl ring breathing
mode of the title compound is assigned at 819 cm-1 (IR), 822 cm-1 (Raman) and 819 cm-1
(DFT) with PED 58% which is in agreement with the literature [63]. The in-plane and out-of-
plane C-H deformations of the phenyl ring are expected above and below 1000 cm-1
respectively [53] and these modes of the title compound were assigned at 1270, 1203, 1147
cm-1 (IR), 1263, 1149 cm-1 (Raman), 1265, 1201, 1149 cm-1 (DFT) (in-plane CH bending
modes) and 877 cm-1 (IR), 967, 878, 834 cm-1 (DFT) (out-of-plane bending modes). The IR
bands in the region of 2676-1800 cm-1 and the large broadening seen in the IR spectrum
support the intra-molecular hydrogen bonding [64].
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The pyrazine C-H stretching modes of the title compound were observed 3070 cm-1 in
IR spectrum and at 3064 cm-1 in Raman spectrum while the computed values are 3062, 3055,
3052 cm-1 theoretically which are expected in the range 3100-3000 cm-1 [65]. In the present
case, the pyrazine ring stretching modes were observed at 1525,1120 cm-1 in the IR spectrum
and at 1526,1175 cm-1 in the Raman spectrum while the PED analysis gives these modes at
1551, 1524, 1182, 1117, 1009 cm-1 which are in agreement with literature [66,67]. In the
present case, the pyrazine ring stretching modes have IR intensities in the range 2.82 to 38.52
and Raman activities 0.45 to 149.28 and the PEDs are around 60%. For the title compound,
the ring breathing mode of the pyrazine ring was assigned at 954 cm-1 in the Raman spectrum
and 952 cm-1 in (DFT) with low IR intensity and Raman activity, while the reported value is
at 1015 cm-1 (DFT) [66]. For the title compound, the in-plane and out-of-plane CH bending
modes of the pyrazine ring were assigned at1395, 1352, 1246 cm-1 and 959, 928, 855, 838 cm-
1
theoretically. The experimentally observed values are 932, 860 cm-1 in the IR spectrum and
1240 cm-1 and 861 cm-1 in the Raman spectrum which are in agreement with the literature
[66].
4.3
Natural bond orbital analysis
The natural bond orbitals (NBO) calculations were performed using the NBO 3.1
program [68] to find the various interactions in the molecular system and the important
interactions are with stabilization energies, 10.82, 10.77, 22.62, 50.62 kJ/mol in
n1(N3)→σ*(C4-C5), n1(N6)→σ*(C4-C5), n2(O11)→σ*(C10-N12), n1(N12)→π*(C10-O11). The
important hybrid orbital of the molecular system are: n2(O11) and n2(I27) with higher energies,
-706.653, -712.219 kJ/mol. and with low occupation numbers, 1.87640 and 1.97761 and the
p-character is nearly 100%. The orbital n1(O11) and n1(I27) have lower energies, -1830.052
and -1617.151 kJ/mol with p-characters, 35.59 and 89.51% and high occupations numbers,
1.97534 and 1.99302. The various interactions are presented in Tables S1 and S2 (supporting
materials).
4.4
Nonlinear optical properties
The calculated first hyperpolarizability of the title compound is 13×10-30 esu which is
100 times that of standard NLO material urea (0.13×10-30 esu) [69]. For a pyrazine derivative
the first hyperpolarizabilty is reported at 9.77×10-30 esu [51]. We conclude that the title
compound is an attractive object for future studies of nonlinear optical properties.
4.5
Frontier molecular orbitals
In order to understand global stability and reactive properties of the title compound we
have investigated frontier molecular orbitals. Namely, the highest occupied molecular orbital
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(HOMO) and lowest unoccupied molecular orbital (LUMO) are the main molecular orbitals
that take part in reactions with other molecular structures. Distribution of HOMO and LUMO
provides important insight into the reactive properties of organic molecules, Figure 4.
Visualization presented in Fig. 4 indicates the importance of iodine atom, as HOMO is
practically completely localized in the near vicinity of this atom. This result designates iodine
atom to act as electron donor during the interactions with other molecules. On the other side
LUMO orbital is mainly delocalized over the nitrogen containing six member ring,
designating this part of the molecule to be electron acceptor during the interactions with other
molecules. LUMO is also delocalized over the other six member ring, including nitrogen atom
that connects two rings. Using information on the energies of HOMO and LUMO, useful and
frequently used quantum-molecular descriptors such as the ionization energy and electron
affinity can be calculated according to the following simple relations: I = -EHOMO, A = -
ELUMO, η = (-EHOMO + ELUMO)/2 and ꢀ = (EHOMO + ELUMO)/2 [70]. Parr et al. [71] proposed the
global electrophilicity power of a ligand as ω = ꢀ2/2η. For the title compound, energy
difference between HOMO and LUMO, HOMO-LUMO gap, is equal to 3.29eV, which is
relatively high value indicating significant stability of this potentially pharmaceutical
molecule. Ionization potential, I, and electron affinity, A, are calculated to be 8.57eV and 6.55
eV, respectively. The values of HOMO-LUMO gap and global hardness (η = 1.64eV) are
almost the same as in the case of other pyrazine derivative that we have previously
investigated [72]. Although the stability parameters of these derivatives are practically the
same, there are significant differences in the values of chemical potential and global
electrophilicity. Namely, the value of chemical potential of the presently investigated pyrazine
derivative is -4.35 eV, which is higher than the value of -6.85 in the case of pyrazine
derivative investigated in our previous paper [72]. Also, the calculated electrophilicity of the
title molecule is 2.56eV, which is significantly lower than the value of electrophilicity of
derivative in the work of Joseph et al. 2013, with the value of 14.31eV, meaning that the title
molecule is much more stable.
4.6
Molecular electrostatic potential map
To predict the reactive sites of electrophilic and nucleophilic attacks for the
investigated molecule, the molecular electrostatic potential (MEP) at the B3LYP/ccpVDZ
optimized geometry was calculated [73-76]. The negative (red and yellow) regions of MEP
were related to electrophilic reactivity and the positive (blue) regions to nucleophilic
reactivity (Fig. 5). From the MEP, it is evident that the negative charge covers the carbonyl
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group and the positive region is over the NH group. The high electronegativity of the carbonyl
group makes it the most reactive part of the molecule.
4.7
ALIE surfaces, Fukui functions and noncovalent interactions
The local reactivity properties of organic molecules can be investigated by
calculations of average local ionization energy (ALIE) values, as introduced by Sjoberg et al.
[77,78]. ALIE is defined as sum of orbital energies weighted by the orbital densities
according to the following equation:
r
ρi
(
ρ
r
)
εi
)
I
(
r =
)
r
.
(1)
∑
(
r
i
r
r
ρ
(
r
)
εi
, denotes
where
denotes electronic density of the i-th molecular orbital at the point
r
i
r
ρ
(
r
)
orbital energy, while
denotes total electronic density function. In case of this quantum-
molecular descriptor important molecule sites from the aspect of electrophilic attacks can be
visualized by mapping of its values to the electron density surface. In this way the areas with
the lowest ALIE values indicate molecule sites where electrons are least tightly bound and
therefore sites that are the most vulnerable to electrophilic attacks, Fig. 6. Analysis of the
IMPPC’s ALIE surface indicates three interesting molecule sites, possibly prone to
electrophilic attacks. According to Fig. 6, these molecule sites are located in the near vicinity
of the iodine atom I27 and the nitrogen atoms N3 and N6. These molecule sites are
characterized by the lowest ALIE values of around 185 kcal/mol. On the other side, molecule
sites characterized by the highest ALIE values, where electrons are most tightly bonded, are
near vicinities of hydrogen atoms H7, H8 and H22, characterized by values of around 377
kcal/mol. According to the distribution of red color in Fig. 6, iodine atom I27 is certainly the
most vulnerable atom towards electrophilic attacks.
Thanks to the analysis of electron density within IMPPC molecule intramolecular
noncovalent interactions have been detected and visualized, Fig. 7. In the case of the title
molecule, there are two intramolecular noncovalent interactions formed between the oxygen
atom O11 and the hydrogen atom H17 and between the carbon atom C18 and the iodine atom
I27. Noncovalent interaction between oxygen and hydrogen atoms is much stronger than
noncovalent interaction between carbon and iodine atom.
Other interesting molecule sites from the aspect of local reactivity have been detected
by calculations of the Fukui functions, presented in Fig. 8. This important quantum-molecular
descriptor shows how electron density changes with the addition or removal of charge. These
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functions in Jaguar program are calculated with the help of finite difference approach,
according to the following equations:
δ
(
ρ N +
(
r
)
−
ρ N
(
r
)
)
f + =
f − =
,
,
(2)
(3)
δ
δ
(
ρ N −
(
r
)
δ
−
ρ N
(
r
)
)
where
N stands for the number of electrons in reference state of the molecule, while stands
δ
for the fraction of electron which default value is set to be 0.01 [79]. In this work, the Fukui
functions have been visualized by mapping of their values to the electron density surface.
Positive color in the case of Fukui
the amount of electron density increased as charge has been added. On the other side, negative
color in the case of Fukui
– function, Fig. 8b, is red color and shows molecule sites where the
f
+, Fig. 8a, is purple color and shows molecule sites where
f
amount of electron density decreased as charge was removed. Results presented in Fig. 8a
indicate that the carbon atom C2 and the nitrogen atom N6 are molecule sites where electron
density increases with the addition of charge, therefore designating these atoms as
electrophilic. On the other side, results presented in Fig. 8b indicate that red color is localized
also in the near vicinity of heterocyclic ring, this time in the near vicinity of carbon atoms C4
and C5, designating these parts of molecule as nucleophilic.
4.8
Reactive and degradation properties based on autoxidation and hydrolysis
In order to predict the degradation properties based on autoxidation and hydrolysis
mechanisms in this work, we have also calculated the bond dissociation energies (BDEs) and
the radial distribution functions (RDFs). Calculations of BDE for hydrogen abstraction allow
possibility to predict molecule sites where autoxidation process could start. These results also
indicate to what extent the molecule is sensitive to open air and presence of oxygen, which is
of particular significance in pharmaceutical industry. In this regard, the BDE also contributes
to the forced degradation studies, since they can be used for determination or confirmation of
degradation path of a specific organic pharmaceutical molecule [80-83]. If the BDE for
hydrogen abstraction ranges from 70 to 85 kcal/mol, then the molecule of interest is the most
vulnerable to autoxidation mechanism, according to the study of Wright et al. [84]. Gryn'ova
et al. [85] reported practically the same values, but also leaving “space” for the BDE values
ranging between 85 and 90 kcal/mol, regarding to these values as possibly important for the
autoxidation mechanism. BDE values for hydrogen abstraction lower than 70 kcal/mol, are
not suitable for the autoxidation mechanism since the formed radicals are resistant to the O2
insertion [84, 86, 87]. The BDE values of the title molecule are shown in Fig. 9. The red
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colored values correspond to the BDE values for hydrogen abstraction, while blue colored
values correspond to the BDE values for the rest of the single acyclic bonds. High stability of
the title molecule is confirmed by the results provided in Fig. 9. Since there are no BDE
values for hydrogen abstraction lower than 90 kcal/mol, it can be stated that the title molecule
is stable in open air and in the presence of oxygen. Concerning the BDE values for the rest of
the single acyclic bonds, the lowest BDE value were calculated for the carbon-iodine bond
between, indicating that degradation mechanism could start by detaching of the mentioned
iodine atom.
In order to determine to what extent hydrolysis mechanism could be important for the
degradation of title molecule, we also calculated the RDF after MD simulations. In Fig. 10,
the RDFs of atoms with the most pronounced interactions with water molecules have been
presented. The RDF, g(r), indicated the probability of finding a particle in the distance r from
another particle [88]. The results provided in Fig. 10 indicate that only four atoms of the title
molecule have relatively significant interactions with water molecules. These atoms are
carbon atoms C1, C10, C23 and iodine atom I27. All of these atoms have very similar g(
profiles. The peak distance in all cases is located between 3.5 and 3.8 Å. According to the
maximal g( ) values the most important RDF is certainly for iodine atom I27. However,
r)
r
relatively high peak distances and absence of the hydrogen atoms with significant RDF
profiles indicate that the title molecule is highly stable in water surrounding, which is
significant from the pharmaceutical point of view.
4.9
Molecular docking
The metabotropic glutamate receptors (mGluRs) are family C G-protein-coupled
receptors which participate in the modulation of synaptic transmission and neuronal
excitability throughout the central nervous system. Large progress has been made in
determining the mechanisms by which mGluRs are activated and the ligands that can
modulate receptor activity. The widespread expression of mGluRs makes these receptors
particularly attractive drug targets, and recent studies continue to validate the therapeutic
utility of mGluR ligands in neurological and psychiatric disorders such as Alzheimer’s
disease, Parkinson’s disease, anxiety, depression, and schizophrenia [89]. The molecular
docking simulations were performed on AutoDock-Vina software [90] and the 3D crystal
structure of metabotropic glutamate receptor 5 (mGluR5) was obtained from Protein Data
Bank (PDB ID: 3LMK) [91]. The docking of the title compound with metabotropic glutamate
receptor was done as previously reported [92]. The ligand (1) binds at the catalytic site of
substrate by weak non-covalent interactions most prominent of which are H-bonding and
10

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alkyl-π interactions (Figs. 11 and 12). Backbone oxygen of Asp309 forms H-bond of 2.31 Ǻ
to ligand’s carboxamide hydrogen. Arg310, Tyr64, Val392 amino acids hold the benzene
aromatic ring of 1 by alkyl-π interactions. The ligand (1) forms a stable complex with mGluR
as is evident from the binding affinity (ꢁG in kcal/mol) value -6.6 (Table 3). Shana et al. [92]
reported that the ligand binds at the active sites of the protein by weak non-covalent
interactions most prominent of which are H-bonding, alkyl-π and sigma-π interactions and
predicted a binding free energy of -9.8 kcal/mol and the inhibitor forms a stable complex with
FAK. These preliminary results suggest that the compound might exhibit inhibitory activity
against mGluRs.
5.
Conclusions
The experimental, structural and vibrational wavenumber assignments of the title
compound were successfully analyzed. The theoretically predicted geometrical parameters are
in agreement with that of similar derivatives. The HOMO is delocalized over the iodine atom,
methyl group and the phenyl ring while the LUMO is all over the molecule except iodine and
methyl group. The MEP analysis showed that the negative charge covers the carbonyl group
and the positive region is over the NH group. Thanks to the DFT calculations of ALIE values,
iodine atom I27 has been determined as the most important concerning the electrophilic
attacks. The Fukui functions recognized heterocyclic ring as important reactive center as well.
The BDE values for hydrogen abstraction indicated that the title molecule is highly stable in
open air and in the presence of oxygen. At the same time, the BDE for the rest of single
acyclic bonds indicated that the degradation could start by detachment of iodine atom. High
stability of the title molecule was also confirmed by RDFs, since there are only four atoms
with significant interactions with water molecules and since there are not hydrogen atoms
with significant profiles of RDFs. The title compound forms a stable complex with mGluR as
is evident from the binding affinity value.
Acknowledgements
The authors would like to extend their sincere appreciation to the Deanship of
Scientific Research at King Saud University for funding this work through the Research
Group Project No. RG-1435-062. Part of this work has been performed thanks to the support
received from Schrodinger Inc.
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94-104.
Figure captions
Scheme 1: Synthesis of the title compound.
Fig. 1: FT-IR spectrum of N-(3-iodo-4-methylphenyl)pyrazine-2-carboxamide
Fig. 2: FT-Raman spectrum of
Fig. 3: Optimized geometry of
N
-(3-iodo-4-methylphenyl)pyrazine-2-carboxamide
-(3-iodo-4-methylphenyl)pyrazine-2-carboxamide
N
Fig. 4: HOMO, LUMO plots of
Fig. 5: MEP plot of -(3-iodo-4-methylphenyl)pyrazine-2-carboxamide
Fig. 6: ALIE surface of -(3-iodo-4-methylphenyl)pyrazine-2-carboxamide
N-(3-iodo-4-methylphenyl)pyrazine-2-carboxamide
N
N
Fig. 7: Intramolecular noncovalent interactions and their strengths (in electron/bohr3) of
N-(3-
iodo-4-methylphenyl)pyrazine-2-carboxamide
+ and b) – of the
Fig. 8: Fukui functions a) f f N-(3-iodo-4-methylphenyl)pyrazine-2-
carboxamide
Fig. 9: BDEs of all single acyclic bonds of N-(3-iodo-4-methylphenyl)pyrazine-2-
carboxamide
Fig. 10: RDFs of
N-(3-iodo-4-methylphenyl)pyrazine-2-carboxamide's atoms with significant
interactions with water molecules
20

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Fig. 11: The detailed interactions of ligand with the amino acids of mGluRs and H-bond
surface shown
Fig. 12: The docked ligand embedded in the catalytic site of mGluRs
21

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Table 1
Geometrical parameters of the title compound
Bond lengths (Ǻ)
C1-C2
1.4013
1.3366
1.4037
1.5170
1.4111
1.4048
1.3949
1.0929
1.5065
1.0994
C1-N6
1.3338
1.0947
1.0951
1.2181
1.0133
1.3942
1.0918
1.4071
1.1025
C1-H7
1.0948
1.3392
1.3424
1.3808
1.4033
1.0863
1.4048
2.1208
1.1024
C2-N3
C2-H8
N3-C4
C4-C5
C4-H9
C5-N6
C5-C10
N12-C13
C13-C15
C15-C18
C16-H21
C20-C23
C23-H26
C10-O11
N12-H22
C14-C16
C15-H19
C18-C20
C23-H24
C10-N12
C13-C14
C14-H17
C16-C20
C18-I27
C23-H25
Bond angles (°)
C2-C1-N6
C1-C2-N3
C2-N3-C4
C5-C4-H9
N6-C5-C10
C5-C10-N12
122.3
C2-C1-H7
C1-C2-H8
N3-C4-C5
C4-C5-N6
C1-N6-C5
120.8
120.9
122.5
121.3
116.2
N6-C1-H7
N3-C2-H8
N3-C4-H9
C4-C5-C10
C5-C10-O11
116.9
117.1
116.3
122.7
121.5
122.0
115.7
121.2
115.9
113.6
O11-C10-N12 124.9
C13-N12-H22 115.1
C14-C13-C15 119.1
C16-C14-H17 121.2
C18-C15-H19 119.9
C20-C16-H21 118.2
C10-N12-C13 128.3
N12-C13-C14 123.7
C13-C14-C16 119.0
C13-C15-C18 120.4
C14-C16-C20 123.5
C15-C18-C20 122.0
C16-C20-C18 116.0
C20-C23-H24 111.5
H24-C23-H25 106.8
C10-N12-H22 116.3
N12-C13-C15 117.2
C13-C14-H17 119.7
C13-C15-H19 119.8
C14-C16-H21 118.3
C15-C18-I27
117.1
C20-C18-I27
120.9
C16-C20-C23 120.5
C20-C23-H25 111.6
H24-C23-H26 108.1
Dihedral angles (°)
N6-C1-C2-C3
C18-C20-C23 123.6
C20-C23-H26 110.6
H25-C23-H26 108.1
-0.5
C2-C1-C6-C5
-0.6 C1-C2-N3-C4
0.8
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C2-N3-C4-C5
-0.1
N3-C4-C5-N6
-1.1 N3-C4-C5-C10
-177.5
-38.4
178.0
178.2
179.7
-0.1
C4-C5-N6-C1
1.4
C4-C5-C10-O11
N6-C5-C10-N12
C10-N12-C13-C14
C15-C13-C14-C16
C13-C14-C16-C20
C14-C16-C20-C18
C15-C18-C20-C23
140.8 C4-C5-C10-N12
145.0 C5-C10-N12-C13
-2.2 C10-N12-C13-C15
N6-C5-C10-O11
O11-C10-N12-C13
N12-C13-C14-C16
C14-C13-C15-C28
C13-C15-C18-I27
C15-C18-C20-C16
I27-C18-C20-C23
-35.8
-1.1
-179.6
0.0
0.0
-0.1
0.0
N12-C13-C15-C18
C13-C15-C18-C20
C14-C16-C20-C23
-180.0
0.0
-180.0
179.9
-180.0 I27-C18-C20-C16
-0.1
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Table 2
Calculated scaled wavenumbers, observed IR, Raman bands and vibrational assignments with
potential energy distribution (PED) of the title compound
B3LYP/ccpVDZ
IR
Raman
υ(cm-1)
3370
3120
3064
-
Assignments(PED)a
υ(cm-1)IRI
RA
υ(cm-1)
3365
3134
3070
-
-
3464 17.68 125.00
3136 8.83 58.93
3062 4.80 59.39
3055 15.61 128.58
3052 33.75 381.75
3034 2.60 113.83
3032 24.59 52.78
3001 15.52 77.74
2973 8.91 89.13
2915 20.99 266.62
1708 225.95 176.10
1586 92.44 516.36
1553 58.25 17.16
1551 38.52 84.50
1524 2.82 149.28
1485 520.52 422.51
1453 24.20 3.28
1436 13.88 13.46
1404 30.31 8.59
1395 8.06 14.86
1364 19.05 5.39
1352 82.00 97.49
1346 4.94 12.93
1287 100.73 167.38
1265 1.14 4.25
υNH(100)
υCHPh(98)
υCHPz(98)
υCHPz(96)
-
-
υCHPz(95)
-
3036
-
υCHPh(98)
3029
-
υCHPh(98)
3005
2970
2918
1696
1583
-
υCH3(99)
2975
2920
1695
1590
-
υCH3(100)
υCH3(100)
υC=O(64), δNH(19)
υPh(65),δCHPh(23)
υPh(52),δNH(21)
υPz(60),δCHPz(13)
υPz(67), δCHPz(22)
δNH(47), υPh(10), δCHPh(10)
υPh(48), δCH3(17), δCHPh(27)
δCH3(97)
-
-
1525
1486
1458
1437
1402
-
1526
-
1460
-
1403
-
δCH3(51), δCHPh(10), υPh(17)
δCHPz(57), υPz(20)
δCH3(91)
1368
-
1370
-
δCHPz(62), υPz(17)
υPh(49), δCHPh(22)
υPh(60), υCN(14)
δCHPh(53), υPh(13)
1342
1290
1270
-
1285
1263
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1246 17.51 38.60
1223 25.81 96.34
1214 20.37 230.08
1201 18.97 4.33
1182 10.47 18.15
1149 7.36 26.47
1117 2.98 14.03
1105 109.96 1.45
1032 5.83 26.22
1009 2.98 0.45
-
1240
-
δCHPz(41), υPz(23)
1225
-
δNH(41), υCC(22), υPh(12)
υCN(38), υPh(19), δCHPh(11)
δCHPh(43), υCC(12), υPh(13)
υPz(90)
1211
-
1203
-
1175
1149
-
1147
1120
-
δCHPh(58), υPh(15)
υPz(59), δCHPz(23)
υCN(41), υPz(22)
-
1030
-
1028
-
δCH3(64), δCHPh(20)
υPz(60)
998
990
967
959
952
928
878
855
838
834
819
761
754
714
702
683
646
601
560
543
529
37.61 19.09
26.25 38.60
28.10 1.77
0.16 0.69
1.72 0.61
1.40 2.13
18.56 6.25
24.08 20.71
8.26 4.12
16.45 1.55
7.14 2.73
5.75 7.02
4.25 22.15
2.77 6.95
7.69 0.83
3.28 1.09
14.58 4.44
0.52 4.21
1.13 1.52
17.33 21.90
47.48 2.10
997
-
-
δPh(49), υPh(16)
-
δCH3(46), γCHPh(18), υPh(11)
γCHPh(67), δCH3(21)
γCHPz(89)
-
-
-
-
-
954
-
υPz(63), δPz(18)
932
877
860
-
γCHPz(81)
-
γCHPh(64),τPh(25)
γCHPz(58), τPz(11)
γCHPz(49), δC=O(14), τPz(18)
γCHPh(85)
861
-
-
-
819
766
752
712
698
-
822
766
-
υPh(58), δPh(13), γCHPz(12)
τPz(55), γCHPz(28)
δPz(27), υCC(16), δPh(26)
γC=O(33), δPz(27)
720
705
685
647
600
558
540
525
δPz(32), τPh(16), γC=O(17)
τPh(60), γCC(25)
648
602
562
-
δPh(71), υCI(10)
γNH(52), τC=O(21)
δPz(76)
γCN(28), τPh(28), γCI(14), γCC(14)
δPh(16), δC=O(21), γCC(11),
530
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τPz(13)
476
429
422
399
365
336
333
272
209
199
176
153
148
130
118
64
6.80 2.78
1.15 0.28
10.66 1.50
10.45 0.57
3.32 0.77
3.90 2.80
0.31 1.60
2.06 2.80
0.94 5.61
0.57 2.26
4.07 3.43
1.70 1.74
0.76 0.66
0.55 1.84
0.91 3.56
2.85 4.07
0.54 3.99
475
-
δPh(39), τPz(31)
428
-
τPh(63), γCI(23)
419
420
τPz(36), δCC(19), δCN(18)
τPz(53), δCC(18)
398
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
γCC(25), τPz(16), τPh(26)
τPh(29), γCC(25), δC=O(11)
δCN(19), υCI(36), δCC(15)
δCC(30), δPh(28), τCH3(25)
τPz(35), τPh(32)
340
-
-
215
197
177
155
-
υCI(18), δCI(23), δPh(20)
τNH(26), δCI(19), τCH3(28)
τCC(48), γCI(12)
τCC(50), γCI(13), τPh(14)
δCI(27), δCN(12), τPh(11), τPz(14)
τPh(37), τPz(27), τCH3(39)
τCC(45), τNH(31)
-
-
62
-
50
δC=O(30), γCC(14), δNH(12),
δCN(10)
34
23
0.79 1.05
0.57 4.44
-
-
-
-
τC=O(46), τCC(11), τPh(15)
τNH(47), τCC(39)
aυ-stretching; δ-in-plane deformation; γ-out-of-plane deformation; τ-torsion; Ph-phenyl ring; Pz-
pyrazine ring. IR intensity, IRI and Raman activity, RA are expressed in KM/Mole and Ǻ4/AMU.
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Table 3
The binding affinity values of different poses of the title compound predicted by
AutoDockVina
Mode Affinity (kcal/mol)
Distance from best mode (Ǻ)
RMSD l.b.
0.000
RMSD u.b.
0.000
1
2
3
4
5
6
7
8
9
-6.6
-6.2
-6.2
-6.0
-5.6
-5.5
-5.4
-5.4
-5.4
21.414
1.487
24.151
2.080
21.754
18.358
26.367
21.945
22.683
3.071
24.426
20.149
27.361
24.695
25.091
6.994
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