Synthesis and evaluation of molecular structure from torsional scans, study of molecular characteristics using spectroscopic and DFT methods of some thiosemicarbazones, and investigation of their anticancer activity

Article abstract of DOI:10.1007/s11696-021-01595-x

Synthesis of 2-((2-aminopyridin-3-yl) methylene) hydrazinecarbothioamide (APHT) was attempted. Elemental analysis and NMR spectra were used to ascertain its formation. Torsional potential energy scans for all five of its rotating bonds were made to get ap

Full text of DOI:10.1007/s11696-021-01595-x

Chemical Papers
https://doi.org/10.1007/s11696-021-01595-x
ORIGINAL PAPER
Synthesis and evaluation of molecular structure from torsional scans,
study of molecular characteristics using spectroscopic and DFT
methods of some thiosemicarbazones, and investigation of their
anticancer activity
K. Srishailam1,2,5 · K. Ramaiah3,4 · K. Laxma Reddy4 · B. Venkatram Reddy5 · G. Ramana Rao5
Received: 14 November 2020 / Accepted: 8 March 2021
© Institute of Chemistry, Slovak Academy of Sciences 2021
Abstract
Synthesis of 2-((2-aminopyridin-3-yl) methylene) hydrazinecarbothioamide (APHT) was attempted. Elemental analysis and
NMR spectra were used to ascertain its formation. Torsional potential energy scans for all fve of its rotating bonds were made
to get approximate dihedral angles. UV–Vis spectra were measured for APHT and 2-((2-aminopyridin-3-yl) methylene)-
N-methylhydrazinecarbothioamide (APMHT). Their anticancer activity was determined experimentally, for human carcinoma
cell lines pertaining to liver, colorectal, and lung. For both APHT and APMHT, frontier molecular orbital parameters, NLO
behaviour, and NBO characteristics were determined using DFT/B3LYP/6-311++G(d,p) level of theory. TD-DFT was used
to compute absorption maxima (λmax) of electronic transitions for both molecules in DMSO-d6 solvent. Frontier molecular
orbitals were used to understand origin of UV–Vis spectra and chemical reactivity of the two molecules. Good agreement
was found between measured and computed structure parameters. This is also true of experimental and theoretical UV–Vis
spectra. The computations demonstrated that both the molecules were good for NLO applications, which was substantiated
by NBO analysis. Existence of bifurcated intramolecular hydrogen bond was predicted for both APHT and APMHT.
Keywords Hydrazinecarbothioamides · Torsional potentials · Barrier heights · Vibrational spectra · DFT · Anticancer
activity
Introduction
2005), anticonvulsant (Jatav et al. 2008), antifungal (Tiwari
et al. 2007), anti-infammatory (Giri et al. 2009), antibacte-
rial (Yousef et al. 2013), antituberculosis (Mohamed et al.
2004), antiviral (Padmapriya et al. 2016), analgesic (Van
Zyl 2001) and HIV-TB coinfection efects (Banerjee et al.
2011). A brief account of some of these biological activities
is worth reporting. For instance, a study of formyl thiosemi-
carbazones having diferent heterocyclic systems confrmed
that their anticancer activity arose from the side chain adja-
cent to the heterocyclic nitrogen atom and conjugated NNS
tridentate ligand system of thiosemicarbazone (Blanz et al.
1970). It was found that the antifungal activity exhibited
by metal complexes of thiosemicarbazones was decided by
the substituent group at N(1) and N(4) positions of the thio-
semicarbazone (West et al. 1993). This prompted intense
research activity involving 2-formylpyridine, 2-benzopyri-
dine and 2-acetylpyridine N(4)-substituted thiosemicarba-
zones (West et al. 1994, 1995; Liberta and West 1992). The
utility of the thiosemicarbazones as antimicrobial inhibitors
Heterocyclic thiosemicarbazones are known for their thera-
peutic value (Blanz et al. 1970) and biological activity (El-
Sharief and Moussa 2009), such as antitumour (Cao et al.
* B. Venkatram Reddy
bvreddy67@yahoo.com
1
Department of Physics, SR University, Warangal,
TS 506371, India
2
Department of Physics, S R Engineering College, Warangal,
TS 506371, India
3
Chemistry Division, H&S Department, Malla Reddy
Engineering College for Women (Autonomous Institution),
Hyderabad 500100, India
4
Department of Chemistry, National Institute of Technology,
Warangal, TS 506004, India
5
Department of Physics, Kakatiya University, Warangal,
TS 506009, India
Vol.:(0123456789)
1 3

Chemical Papers
was also investigated (Akbar Ali et al. 1971). The efcacy
of thiosemicarbazones as antiviral agent was frst demon-
strated using p-aminobenzaldehyde-3-thiosemicarbazone
and some of its derivatives against vaccinia virus in mice
(Barber et al. 1992). Thiosemicarbazones were also found
to inhibit a host of viral infections such as adenovirus, rhi-
novirus, herpes virus, poliovirus, and RNA tumour virus
(El-Bindary et al. 1999). It is also known that the therapeutic
value of heterocyclic thiosemicarbazones is due to their abil-
ity to inhibit ribonucleotide reductase (a key enzyme in the
synthesis of DNA precursors, in mammalian cells) (Blanz
et al. 1970). Hence, we reported results of investigations
for, 2-((2-amino-pyridin-3-yl) methylene)-N-ethylhydrazi-
necarbothioamide (APTA) (Ramaiah et al. 2019). Now, we
thought it worthwhile to extend some of these investiga-
tions to two related heterocyclic thiosemicarbazones, namely
2-((2-aminopyridin-3-yl) methylene) hydrazinecarbothio-
amide (APHT) and 2-((2-aminopyridin-3-yl) methylene)-
N-methylhydrazinecarbothioamide (APMHT). The purpose
is to (1) synthesize APHT; (2) make elemental analysis and
refux for one hour. The precipitate, yellow in colour, was
separated by fltration, washed with cold ethanol, and dried
under vacuum. The compound was purifed by recrystalliza-
tion. The yield was 90%. It melted at 184 °C as determined
with STURT SMP 30 melting-point apparatus and was
uncorrected. In order to ascertain the formation of required
compound, elemental analysis was made and NMR spectra,
both 1H and 13C, were recorded. For performing the elemen-
tal analysis, CARLO-ERBA model EA 1108 analytical unit
(Triad, NJ, USA) was used. 1H and 13C NMR spectra were
measured at room temperature on BRUKER AVANCE 400
MHz (13C resonates at 100 MHz) NMR instrument, using
deuterated dimethylsulfoxide (DMSO-d6) as solvent and
tetra methylsilane (TMS) as internal standard.
Electronic spectral measurements
Both APHT and APMHT are solids at room temperature.
UV–Vis spectra of these compounds were obtained in the
range 200–400 nm, in a solution of DMSO-d6, with 1 cm
quartz cell using Perkin-Elmer UV–Vis LAMBDA-25 dou-
ble-beam spectrophotometer, at room temperature.
1
record H and 13C NMR spectra, for APHT; (3) measure
UV–Vis spectra, for APHT and APMHT; (4) measure anti-
cancer activity, for APHT and APMHT; and (5) make DFT
analysis, for both molecules, in order to
In vitro cytotoxicity studies
(a) make torsional potential energy scans to get prelimi-
nary values of dihedral angles around rotating bonds
for APHT,
Hep G2 (hepatocellular liver carcinoma cell line), COLO
205 (colorectal carcinoma cell line), and NCI-H460 (lung
carcinoma cell line) provided by National Centre for Cell
Sciences (NCCS), Pune, India, were used to evaluate in vitro
anticancer activity of the compounds APHT and APMHT,
against the above human cancer cell lines. This was achieved
by following the usual procedure of comparing with the cor-
responding activity of the standard drug cisplatin (CP). A
quantitative colorimetric method for the determination of
cell viability was employed. This method consists of measur-
ing the cell viability in the presence of APHT (or APMHT)
by MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetra-
zolium bromide)-microcultured tetrazolium assay method
(Shekan et al. 1990; Monks et al. 1991). Metabolic activity
of viable cells is the assessed parameter, which gets refected
in the reduction of pale yellow tetrazolium salt (MTT) to
a dark blue formazan that is not soluble in water. This
ofers direct quantifcation, after solubilization with DMSO
because the absorbance of formazan is related to the number
of viable cells. Ninety-six well plates were used to plate Hep
G2, COLO 205, and NCI-H460 at a density 1 × 104 cells/
well. The cells were allowed to grow overnight in the full
medium, before switching to low-serum media. DMSO of
1% was utilized as a control. After 48 h of treatment with
various concentrations of APHT (or APMHT), the cells were
incubated with MTT (2.5 mg mL−1) in the CO2 chamber
for 2 h. Then, the medium was removed. Formazan crystals
were dissolved by adding 100 mL of DMSO to each well.
(b) make geometry optimization,
(c) simulate UV–Vis spectra to compare them with cor-
responding experimental spectra, and
(d) fnd nonlinear optical (NLO) properties, frontier molec-
ular orbital(FMO) parameters and natural bond orbital
(NBO) characteristics.
This article contains results obtained therefrom.
Experimental details
Materials and solvents used in this work were purchased
from Sigma-Aldrich and Spectrochem as high-purity chemi-
cals and were used as received.
Synthesis of APHT
The synthesis of 2-((2-aminopyridin-3-yl) methylene) hydra-
zinecarbothioamide (APHT) is shown schematically in Fig.
FS1 (see supplementary information). Equimolar ethanolic
solutions of thiosemicarbazide (0.0911 g) and 2-aminoni-
cotinaldehyde (0.122 g) were mixed together. Glacial acetic
acid was used as a catalyst by adding 2 ml of it to the reac-
tion mixture. The entire mixture was heated at 70 °C under
1 3

Chemical Papers
The optical density at 570 nm, which has direct correlation
with cell quantity, was read for each plate after thorough
mixing. Following usual practice, the results are represented
as percentage viability. All the measurements were repeated
thrice for the purpose of accuracy.
N16–C18, C18–N20) in order to obtain dihedral angles cor-
responding to C2–C13, N15–N16, N16–C18, and C18–N20
bonds (see Table S1 of supplementary information), which
can be employed as starting values for further computations.
Note that the computations were made at 1083 (i.e. 3×361)
data points for the three pairs of bonds, as each pair of bond
contains 19×19=361 such points. The values of dihedral
angles obtained, as above, were used in rigorous geometry
optimization, by allowing all structural parameters to relax,
simultaneously. This procedure gave a nonplanar structure
of C1 symmetry for APHT. Absence of imaginary or nega-
tive frequencies substantiated the reliability of the results for
optimized structure.
Computational considerations
Required calculations were made using the Gaussian 09/DFT
program package (Frisch et al. 2010). Becke’s three param-
eter hybrid exchange functional B3 (Becke 1993) in conjunc-
tion with Lee–Yang–Parr (LYP) correlation functional (Lee
et al. 1988) using enlarged basis set 6-311++G(d,p).
In order to get chemically meaningful results, DFT geom-
etry optimization should be initiated with the experimental
structure data if available, or a structure, obtained by using
theoretical methods, that is as close to the fnal structure as
possible. For APHT, experimental information is not avail-
able. There are fve bonds (C–NH2 pyridyl, C–CN, N–N,
N–CS, C–NH2 aliphatic) in APHT, around which rotation
is permitted. Their values are not known with certainty. If
calculations are initiated, using assumed values for the dihe-
dral angles associated with these fve bonds, and then the
possibility of getting unrealistic results, such as generation
of negative frequencies, may not be avoided. We addressed
this problem, for biphenyl carboxaldehyde (BPA), by pair-
ing bonds that can rotate and evaluating torsional potential
energy at various values of dihedral angles about the paired
bonds (Srishailam et al. 2019). But, each BPA molecule con-
tained only one pair of rotating bonds. APHT has multiple
such pairs. Hence, we want to examine the method used
for BPA in order to check whether it works, for APHT as
well. Therefore, torsional potential energy, as a function of
angle of rotation, around C–CN bond (i.e. C2–C13 bond; see
Fig. 4 for numbering of atoms), was estimated, between 0°
and 180° at intervals of 10° corresponding to each value of
angle of rotation around C–NH2 (pyridyl) bond (i.e. C1–N10
bond) in increments of 10°, between 0° and 180°, for APHT,
without disturbing all other structure parameters imported
from Gauss View (Dennington et al. 2009). This provides
19 data sets, each consisting of 19 data points (i.e. a total of
19 × 19 = 361 data points). In each data set, one can iden-
tify the minimum energy conformer and the corresponding
angle of rotation around the C2–C13 bond (note that there
are 19 minimum energy points, see Table S1 of supplemen-
tary information). Then, a graph was drawn showing rela-
tive energy (which is the energy of rotamer with respect to
the energy of rotamer of the lowest energy) versus angle of
rotation around the C1–N10 bond. This gave us the dihe-
dral angle around C1–N10 bond, corresponding to the stable
rotamer. The above procedure was repeated for the pair of
bonds C–CN, N–N (i.e. C2–C13, N15–N16), N–N, N–CS
(i.e. N15–N16, N16–C18), and N–CS, C–NH2 aliphatic (i.e.
From the above discussion, it should be clear that the
torsional potential energy was evaluated at 1444 difer-
ent data points (361 data points for each of the four bond
pairs). It may appear that these is a collection of discrete
and disconnected data points. This is not true because the
data relationship under discussion propagates from C–NH2
pyridyl to C–NH2 aliphatic with the help of common bonds
C–CN, N–N, and N–CS, which are common to the bond
pairs (C–NH2 pyridyl, C–CN; C–CN, N–N), (C–CN, N–N;
N–N, N–CS) and (N–N, N–CS; N–CS, C–NH2 aliphatic),
respectively. Hence, the data corresponding to 1444 data
points are related, interconnected, and correlated just like
the elements of a matrix. Hence, an analysis of these data
points is expected to yield reliable, convincing, and scientif-
cally acceptable results, for the dihedral angles, to be used
as preliminary values, as in the case of APHT presented in
the preceding paragraph.
In the case of APMHT, geometry optimization pro-
cess was initiated using its X-ray structure imported from
Ramaiah et al. (2018) and CDCC fle number 1576355. This
also yielded nonplanar structure of C1 symmetry.
To simulate electronic absorption spectra of APHT and
APMHT, time-dependent density functional theory (TD-
DFT) was used employing B3LYP/6-311++G(d, p) basis
set. Solvent efects were accounted for, by the Polarisable
Continuum Model (PCM) through the integral equation
formalism (IEF-PCM) variant (Scalmani and Frisch 2010)
integrated into Gaussian 09 program package. Computed
values of absorption maxima were compared with their cor-
responding observed values in UV–Vis spectra.
To understand NLO behaviour of APHT and APMHT,
computation of the total molecular dipole moment (μt) and
its components, total molecular polarizability (αt) and its
components, anisotropy of polarizability (∆α), and frst-
order static hyperpolarizability (βt) was attempted accord-
ing to Buckingham’s defnition (Buckingham 1967) using
density functional theory based on fnite feld approach.
Using frontier molecular orbital energies, comprising
of highest occupied molecular orbital (HOMO) and low-
est unoccupied molecular orbital (LUMO), we obtained
1 3

Chemical Papers
values for molecular electronic properties, of APHT
and APMHT, such as ionization potential (I), electron
affinity (A), global hardness (η), chemical potential (µ),
and global electrophilicity power (ω), using well-known
expressions for them (Gece 2008; Fukui 1982; Koopmans
1933; Parr et al. 1999).
Results and discussion
Elemental analysis and NMR signals
In order to ascertain that the synthesized product is the
required compound C7H9N5S (APHT; M=195.2 g mol−1),
the product compound was subjected to elemental analysis.
This yielded 43.01%C; 35.92%N; 4.62%H; and 16.35%S.
Using these values, it is easy to derive the empirical for-
mula of the compound C7H9N5S, with formula weight
195.2 g mol−1 (Ramaiah et al. 2019). This is the same as
the molecular weight M of the required compound. There-
fore, molecular formula of synthesized product is C7H9N5S
(APHT). It is to be noted that a limitation of elemental
analysis is that it cannot tell anything about actual structure
of the molecule. Since, the isomers may exist with same
molecular formula and diferent structural arrangements.
It is known that NMR signals depend on chemical envi-
ronment of atoms in a given molecule. Hence, it is essential
to examine NMR spectra of APHT to gain further insight
Natural bond orbital (NBO) computations were accom-
plished, by means of NBO 3.1 program (Reed et al. 1988)
as implemented in the Gaussian 09W program package
at the DFT/B3LYP/6-311++G(d,p) level, in order to
understand various second-order interactions between
the filled orbitals of one subsystem and vacant orbitals
of another subsystem, with the aim of quantifying delo-
calization (or hyper conjugation). To this end, second-
order perturbation analysis of Fock matrix in NBO basis
of each of the molecules APHT and APMHT was made
to evaluate donor–acceptor interactions. The interactions
reflect themselves as a loss of occupancy from the local-
ized NBO of the idealized Lewis structure into an empty
non-Lewis orbital. The stabilization energy associated
with the hyperconjugation is evaluated using the equa-
tion given by Reed et al. (1988) and Chocholoušová et al.
(2004).
1
into its structure. The H NMR and 13C NMR spectra of
APHT are shown in Figs. 1 and 2, respectively. As expected,
there are nine proton signals corresponding to nine hydrogen
atoms in Fig. 1 and seven chemical shifts corresponding to
seven carbon atoms in Fig. 2. They are assigned below.
Fig. 1 Experimental 1H NMR
Spectrum of APHT
1 3

Chemical Papers
Fig.2 Experimental 13C NMR
Spectrum of APHT
1H NMR (400 MHz, DMSO-d6): δ ppm11.25 (s, 1H,
NHCS), 8.06 (s,1H, aromatic-H), 8.01 (s, 1H, HC=N),
7.54 (d, J=7.6 Hz, 1H, pyridyl-H), 6.67 (t, J=5.6 Hz, 1H,
pyridyl-H), 7.05 (s, 2H, NH2 pyridyl), 8.20(s, 2H, terminal
NH2). It is to be noted that the chemical shifts at 2.56 ppm
and 3.43 ppm, in 1H NMR of APHT, correspond to residual
hydrogen atoms present in DMSO-d6 (Gottlieb et al. 1997),
due to incomplete deuteration.
(H14, H17) in APHT, which is immensely enhanced in
APMHT due to repulsion between H21 atom and the
adjacent bulky methyl group, favouring a nonplanar
structure, in order to minimize the steric hinderance.
The most stable rotamer of the molecule is decided by
the balance between these two opposing efects. The rela-
tive contribution of the efects dictates the angle of rotation
around the bonds exhibiting internal rotation. This sensitive
balance is signifcantly afected by two factors. These are (1)
the extent of correlation energy that is accommodated by the
theoretical method, and (2) the size of the basis set used for
the computations (Tsuzuki et al. 1999; Sancho-García and
Pérez-Jiménez 2002, 2003).
13C NMR (100 MHz, DMSO-d6): δ ppm 177.48(C=S),
156.64(C = N), 149.92, 146.22, 141.04, 112.37, 110.62
(pyridyl carbons).
Equilibrium molecular geometry and bifurcated
intramolecular hydrogen bonding
The information required for obtaining starting values of
dihedral angles, one around each of the fve bonds C1–N10,
C2–C13, N15–N16, N16–C18, and C18–N20, in the case of
APHT, is presented in Table S1 (see supplementary infor-
mation). A graphical representation of this information
appears in Fig. 3. From Table S1 (see supplementary infor-
mation) and Fig. 3, it can be inferred that the set of fve dihe-
dral angles associated with C1–N10, C2–C13, N15–N16,
N16–C18, and C18–N20 bonds were (0°, 180°), 160°, 180°,
180°, and (0°, 180°), respectively. It is not surprising that the
minimum energy is obtained for two diferent values of dihe-
dral angles, 0° and 180°, around C1–N10 bond, for pyridyl
NH2 moiety as the corresponding conformers are identical
Equilibrium molecular geometry of APHT and APMHT is
a result of two opposing efects, as stated below:
1. conjugation between the π–electron charge of the ring
and lone pairs on the fve nitrogen atoms (N6, N10, N15,
N16, N20; see Fig. 4) favouring a coplanar conforma-
tion. This tendency for coplanarity is further assisted by
the bifurcated intramolecular hydrogen bond between
N15 and (H12, H21) atoms, and
2. the steric repulsion between the amino pyridyl ring
and the side chain, which mainly arises from repulsion
between two pairs of orthohydrogens (H7, H14) and
1 3

Chemical Papers
Fig. 3 Relative torsional potential energy of minimum energy conformers as a function of rotation angle around C1–N10, C2–C13, N15–N16,
N16–C18, and C18–N20 using DFT/B3LYP/6-311++G(d,p) formalism to get initial values of dihedral angles for APHT
1 3

Chemical Papers
Fig. 4 Optimized molecular
structure of a APHT (EAPHT
=
−2479.237 × 103 kJ mol−1), b
APMHT (EAPMHT =−2582.463
× 103 kJ mol−1), showing num-
bering of atoms and bifurcated
intramolecular hydrogen bond
due to indistinguishability of amino hydrogen atoms (note
that on 180° rotation around C1–N10 bond H12 takes the
place of H11 and vice versa). This is also true for terminal
NH2 group, which is a part of the aliphatic side chain. Note
that both amino groups have C2v local symmetry. Hence, out
of the four possible sets of values (0°, 0°), (0°, 180°), (180°,
0°), and (180°, 180°), for dihedral angles around C1–N10
and C18–N20, any one set can be used as initial values. All
of them will give identical results. We preferred (0°, 180°)
set as starting values for dihedral angles around C1–N10 and
C18–N20 bonds, respectively, for geometry optimizations.
Thus, we are left with 0°, 160°, 180°, 180° and 180° as
initial values for the twist angles around C1–N10, C2–C13,
N15–N16, N16–C18 and C18–N20 bonds, respectively,
for further computations. Geometry optimization refned
them to − 12.42°, 176.24°, 174.02°, 177.18° and − 173.17°
(positive or negative sign signifes direction of rotation,
anticlockwise or clockwise, which has no bearing on the
magnitude of dihedral angles). They agree well with the
corresponding experimental values reported for APTA from
X-ray analysis (Ramaiah et al. 2019) (see Table S2).
In order to generate optimized molecular geometry for
APHT and APMHT, we solved self-consistent feld equa-
tions iteratively. The resulting structures are shown in Fig. 4.
Optimized structure data comprising of bond lengths, bond
angles, and dihedral angles, for APHT and APMHT, are col-
lected in Table S2, whereas they are put together in Table 1,
for geometry of bifurcated intramolecular hydrogen bond in
them. They are compared with corresponding X-ray experi-
mental values for APMHT and APTA in the same tables
(data for bifurcated intramolecular hydrogen bond were read
from corresponding experimental fgure). It can be inferred
from Table S2 that the calculated structure parameters of
APMHT agree fairly well with their corresponding X-ray
1 3

Chemical Papers
Table 1 Bifurcated
Molecule
APHT
X–D···A
X–Da
D···Aa
X······Aa
∠X–D···Aa
intramolecular hydrogen bond
geometry (bond length in Å,
bond angle in degrees) for
APHT and APMHT
N10–H12···N15
N20–H21···N15
N10–H12···N15
N20–H21···N15
N10–H12···N15
N20–H21···N15
1.008
1.008
1.008 (0.860)
1.009 (0.860)
1.008 (0.886)
1.010 (0.864)
2.09
2.33
2.09 (2.16)
2.26 (2.29)
2.09 (2.16)
2.25 (2.29)
2.85
2.69
2.81 (2.79)
2.69 (2.67)
2.81 (2.81)
2.69 (2.67)
127.03
99.36
127.30 (130.42)
104.36 (106.55)
127.20 (130.00)
105.00 (106.78)
APMHTb
APTAc
aValue in braces corresponds to experiment
bExperimental value from reference Ramaiah et al. (2018)
cFrom reference Ramaiah et al. (2019)
results (Ramaiah et al. 2018), whereas for APHT, the struc-
ture data are in good agreement with X-ray results for both
APMHT and APTA (Ramaiah et al. 2019). For example for
APMHT, according to the computations presented here, the
average values of intra-ring C–N bond, intra-ring C–C bond,
pyridyl C–NH2 bond, C2–C13 bond and aliphatic C–NH2
bond distances are 1.336 Å, 1.403 Å, 1.361 Å, 1.449 Å, and
1.345 Å, respectively. These values agree well with corre-
sponding values 1.337 Å, 1.391 Å, 1.360 Å, 1.455 Å, and
1.322 Å generated from X-ray studies, respectively. Mak-
ing similar comparison for bond angles that are expected
to be afected by the presence of ring nitrogen atom, it can
be found that the angles ∠ C4–C5–N6, ∠ C5–N6–C1 and
∠ N6–C1–C2, with computed values 123.87°, 118.83°,
and 122.31° agree exceptionally well with the correspond-
ing X-ray results 124.0°, 118.7°, and 121.8°, for APMHT,
respectively.
by the value of its frst-order hyperpolarizability. Hence,
density functional theory has been used extensively to exam-
ine organic NLO materials (Sun et al. 2009a, b; Ahmed et al.
2009, 2010; Abraham et al. 2009; Sagdinc and Esme 2010).
The NLO parameters evaluated are presented in Table S3
(see supplementary information). The NLO behaviour of a
given material is normally evaluated by comparing its total
molecular dipole moment (µt) and mean frst-order hyper-
polarizability (βt) with corresponding values of urea, which
are 1.3732 Debye and 372.8×10–33 cm5/esu, respectively.
For APHT, the values of μt and βt are: 1.5306 Debye and
1787.9282×10–33 cm5/e.s.u, respectively, whereas the cor-
responding values are 1.8115 Debye and 1782.3167×10–33
cm5/e.s.u for APMHT. Thus, µt and βt for APHT are 1.11
and 4.79 times that of corresponding values for urea. Cor-
responding fgures for APMHT are 1.32 and 4.78. Hence,
APHT and APMHT are strong candidates for NLO applica-
tions. NLO activity of a molecular system is measured by
the value of its hyperpolarizability. It arises from intramo-
lecular charge transfer that can be ascribed to electron cloud
association through π-conjugated structure of electrons (Ari-
vazhagan and Jeyavijayan 2011). The components of hyper-
polarizability are useful to understand charge delocalization
in the molecule. The maximum charge delocalization occurs
along βxxx in the molecules under investigation.
On the basis of computation, we identifed the existence
of bifurcated intramolecular hydrogen bond, wherein H12
and H21 atoms are involved in hydrogen bonding with N15
atom (N10–H12···N15 and N20–H21···N15), in both APHT
and APMHT. Detailed geometry of this bonding is presented
in Table 1 and compared with corresponding X-ray experi-
mental parameters for APMHT (Ramaiah et al. 2018) and
APTA (Ramaiah et al. 2019). It is clear from this table that
there is good agreement between the theoretical and cor-
responding experimental parameters.
Frontier molecular orbitals (FMO)
Nonlinear optical (NLO) properties
UV–Vis spectrum
When electromagnetic radiation passes through a NLO
material, it interacts with it. As a consequence, it under-
goes changes in its propagation properties, namely phase,
frequency, amplitude or other propagation characteristics
associated with the incident radiation resulting in new felds
(Sun et al. 2009a, b). If these changes are signifcant, then
the NLO material can be employed for optical logic, optical
switching, optical memory and frequency shifting (Andraud
et al. 1994; Geskin et al. 2003; Nakano et al. 2002; Sajan
et al. 2006). NLO behaviour of a given material is dictated
Experimental UV–Vis absorption bands occurring due to
electronic transitions are shown in Figure FS6, for APHT
and APMHT. These data are compared with their corre-
sponding simulated counterparts evaluated by TD-DFT/
B3LYP/6-311++G(d,p) formalism in Table 2, for both the
molecules.
Frontier molecular orbitals are of considerable help in
proper understanding of these transitions. They play key
role in quantum chemistry, as they determine the molecular
reactivity of conjugated systems (Choi and Kertez 1997) and
1 3

Chemical Papers
Table 2 Electronic absorption parameters for APHT and APMHT as
bands at λmax = 355 and 299 nm, with associated oscilla-
tor strengths f=0.7084 and 0.0764, respectively. These are
also in good agreement, with corresponding experimental
electronic transitions near λmax =356 and 300 nm. TD-DFT
calculations prove that the above experimental bands arise
mainly due to H→L and H-2→L transitions, respectively
(H and L denote HOMO and LUMO, respectively). On ana-
lysing the molecular orbital coefcients, we can attribute
H → L and H-2 → L electronic transitions to n → π* and
π→π* excitations, respectively.
evaluated by TD-DFT/B3LYP/6-311++G(d,p) formalism
Absorption maximum λmax(nm)
Oscillator strength
Calculated
Experimental
APHT
359
301
355
299
356
301
356
300
0.7027
0.1068
0.7084
0.0764
APMHT
capability of a molecule to absorb electromagnetic radiation.
HOMO plays the role of an electron donor, whereas LUMO
acts as the electron acceptor (Fukui 1982; Koopmans 1933).
Important HOMO–LUMO and their vicinal molecular orbit-
als involved in diferent electronic transitions are shown in
Fig. 5 and Fig. FS4, for APHT and APMHT, respectively.
According to TD-DFT/B3LYP/6-311++G(d,p) calculations
APHT should have two electronic transitions at λmax =359
and 301 nm, with corresponding oscillator strengths
f = 0.7027 and 0.1068. These are in excellent agreement,
with corresponding observed electronic transitions near
λmax =356 and 301 nm, for APHT (see Table 2). Similarly,
for APMHT, the theory predicts two electronic absorptions
Chemical reactivity
The frontier molecular orbital parameters computed using
DFT/B3LYP/6-311++G(d,p) procedure are composed in
Table 3, for the two molecules under investigation. Energy
gap is defned as the diference between the HOMO and
LUMO orbital energies. Using the data in Table 3, this
quantity is estimated at 2.0267 and 2.0627 eV, in APHT
and APMHT, respectively. These are comparatively low
values, characteristic of conjugated molecules. This entails
high chemical reactivity as it is energetically favourable to
accumulate electrons in high-lying LUMO by exciting elec-
trons from low-lying HOMO. Moreover, a molecule with
Fig. 5 Frontier molecular orbit-
als of APHT
1 3

Chemical Papers
Table 3 Frontier molecular orbital parameters of APHT and APMHT
whereas the corresponding values for π*-antibonds are in
the range from 0.3354 to 0.4522. As a consequence of this
intense charge delocalization, the molecule generates total
stabilization energy of 124.96 kcal mol−1 from the pyri-
dyl ring alone. The interactions π (C1–N6)→π* (C4–C5);
π (C2–C3) → π* (C1–N6, C13–N15); π (C4–C5) → π*
(C2–C3); LP (1) N10→π* (C1–N6); and LP (1) N16→π*
(C13–N15) possess large stabilization energy in the range
26.30 to 48.15 kcal mol−1, according to the NBO analysis.
As a result of π-electron cloud movement from donor to
acceptor (i.e. ICT), the molecule gets more polarized. From
this, we can infer that the NLO properties of APHT originate
from ICT. This observation supports the conclusion arrived
at, in section on NLO properties, regarding the usefulness
of the molecule for nonlinear optical applications. Similar
conclusion can be made for APMHT by examining the data
reported in Table S5 (see supplementary information).
by DFT/B3LYP/6-311++G(d,p) method
Frontier molecular orbital parameter
Value (eV)
APHT
APMHT
HOMO energy
LUMO energy
Frontier molecular orbital energy gap
Ionization energy (I)
− 7.5334
− 5.5067
2.0267
− 7.5547
− 5.4920
2.0626
7.5334
7.5547
Electron afnity (A)
5.5067
5.4920
1.0313
− 6.5233
20.6309
0.4848
Global chemical hardness (η)
Chemical potential (µ)
Global Electrophilicity Index (ω)
Global chemical softness(s)
1.01335
− 6.5200
20.9755
0.4934
a small frontier orbital gap is easily polarizable and usu-
ally shows high chemical reactivity and low kinetic stability
(Sinha et al. 2011; Lewis et al. 1994; Kosar and Albayrak
2011). Further, since the chemical potential (µ) for the mol-
ecules being studied is negative (see Table 3), they are stable
(Nakano et al. 2002).
In vitro cytotoxicity studies
A comparison was made of the data corresponding to
in vitro percentage cell viability for human carcinoma cell
lines Hep G2 (liver), COLO 205 (colorectal) and NCI-H460
(lung), at diferent concentrations of APHT, APMHT and
the standard drug cisplatin (CP) in Table 4. These data were
utilized to obtain survival curves for the said carcinoma cell
lines by drawing percentage cell viability vs concentration
(μM) graphs, depicted in Fig. 6. These were drawn using
GraphPad prism 9.01 version (see GraphPad prism user
guide, GraphPad prism Inc, www.graphpad.com).
Natural bond orbital (NBO) analysis
The results of NBO analysis, for APHT and APMHT, are
reported in Tables S4 and S5 (see supplementary informa-
tion), respectively. They contain only major contributors to
the stabilization energy. In NBO method, all orbitals are
chosen mathematically so as to incorporate highest possi-
ble percentage of the electron density (ED). Consequently,
they are a convenient means of providing a clear ‘natural
Lewis structure elucidation of the wave function (Ψ)’. In
addition, it is a tool to examine charge transfer (or conjuga-
tive interaction) at molecular level, apart from being useful
to prove the existence of intra- and intermolecular bonding
and interaction among bonds precisely. For instance, sig-
nifcant value of stabilization energy E(2) indicates strong
interaction between the electron donors and electron accep-
tors resulting in greater extent of conjugation of the entire
structure. The delocalization of electron density between
occupied Lewis-type (bonding or lone pair) NBO orbitals
and empty non-Lewis (anti bonding or Rydberg) NBO orbit-
als implies stabilization of donor–acceptor interaction. Intra-
molecular hyperconjugative interactions arise due to overlap
between the bonding π-orbitals and antibonding π*-orbitals.
This leads to intramolecular charge transfer (ICT) stabilizing
the system. Such interactions are noticed as an enhance-
ment in the electron density in pyridyl C2–C3, C4–C5 and
C1–N6 antibonding orbitals. They cause weakening of the
corresponding bonds. The electron density for APHT at the
conjugated π-bonds of the pyridyl ring is between 1.6326
and 1.6835 (see Table S7 of supplementary information),
It is common to use the response parameter IC50, which
is the concentration of the compound (or drug) at which the
cell viability gets inhibited by 50%, to evaluate the efective-
ness of a new compound (or drug) against carcinoma cell
lines. These values, for APHT, APMHT and CP, were deter-
mined by making a linear regression analysis for percent-
age absorbance and corresponding concentration (μM) for
a given sample (or drug), using GraphPad prism 9.01 ver-
sion. The software fts the data to a straight line y=mx+c,
where ‘m’ is the slope and ‘c’ is the intercept made by it on
the y-axis. Values of ‘m’ and ‘c’ depend on the compound.
Using these values, along with y=50, in the above equation,
IC50 value corresponding to a given compound and chosen
carcinogenic cell line was obtained. These values for Hep
G-2, COLO 205 and NCI-H460 are listed in Table 5.
From this table, it is evident that the ratio of IC50 of
APHT to that of CP is 1.9, 2.6, and 2.0, for Hep G-2, COLO
205, and NCI-H460, respectively. Similar quantity for
APMHT is 5.4, 3.3 and 9.0. This implies that, even though
APHT and APMHT exhibit anticancer activity, their con-
centration for 50% inhibition is 1.9–2.6 times higher than
that of CP for APHT, whereas the same quantity is 3.3–9.0
times higher than CP for APMHT. Hence, it can be inferred
1 3

Chemical Papers
Table 4 Comparison of in vitro
% cell viability for human
carcinoma cell lines Hep G2
(liver), COLO 205 (colorectal),
and NCI-H460 (lung) at various
concentrations of APHT,
APMHT, and CP
Concentra- % of cell viability for
tion (μM)
Hep G2
COLO 205
NCI-H460
APHT APMHT CP
APHT APMHT CP
APHT APMHT CP
100
50
25
12.5
6.125
3.125
8.44
20.22
33.77
53.85
61.44
77.41
26.06
52.25
67.37
78.35
84.11
90.09
5.82 16.59
20.99
48.88
54.46
69.65
79.43
89.28
7.68
9.52
19.47 20.15
30.17 30.54
47.75 42.34
59.69 54.44
9.44
32.52
45.99
53.85
64.44
78.02
7.84
16.47
27.73
39.67
47.77
69.15
14.95 35.15
27.76 51.46
40.39 63.65
55.86 73.75
75.91 84.73
71.5
63.66
College for Women (Autonomous Institution), Hyderabad, India, for
support and encouragement during this research work.
that anticancer activity of both APHT and APMHT is not
as good as the standard drug CP, for carcinoma cell lines
considered here. However, it is important to note that APHT
is better than APMHT as an anticancer agent.
Authors’ contributions K. Srishailam—Computations and data anal-
ysis; K. Ramaiah—Investigation of biological activity; K. Laxma
Reddy—Conceptualization, Resources; B. Venkatram Reddy—Formal
analysis, Writing–Original Draft; G. Ramana Rao—Writing–Review
& Editing.
Conclusions
Funding No funding is received from any organization for this
submission.
Structural studies yielded C1 point group symmetry for
both molecules investigated. Theoretical structure param-
eters agree well with their experimental counterparts for
APMHT, whereas theoretical values for APHT exhibit good
agreement with X-ray values for both APMHT and APTA.
Geometry of bifurcated intramolecular hydrogen bonding
between (H12, N15) and (N15, H21) atoms, in APHT and
APMHT, as evaluated here using DFT exhibits good agree-
ment with available experimental data. Further, measured
electronic spectra agree well with their simulated spectra.
It was found that APHT and APMHT were good candidates
for NLO applications. It was shown, using NBO analysis,
that intramolecular charge transfer (ICT) was responsible
for NLO properties in these molecules. Investigation of anti-
cancer activity of APHT and APMHT revealed that they
do exhibit such activity against human carcinoma cell lines
Hep G2, COLO 250 and NCI-H460. But they are less efec-
tive, when compared to standard drug CP in this respect.
However, APHT is a better anticancer agent in comparison
with APMHT.
Declarations
Conflict of interest No potential confict of interest was reported by
the authors.
Ethical approval All the co-authors have approved for submission.
Consent to participate All the co-authors have given consent to par-
ticipate in the submission.
Consent to publish All the co-authors have given consent to publish
this manuscript.
References
Abraham JP et al (2009) Efcient p-electron conjugated push–pull
nonlinear optical chromophore 1-(4-methoxyphenyl)-3-(3,4-
dimethoxyphenyl)-2-propen-1-one: a vibrational spectral study.
J Mol Sruct 917:27–36. https://doi.org/10.1016/j.molstruc.2008.
06.031
Ahmed AB et al (2009) Crystal structure, vibrational spectra and theo-
retical studies of l-histidinium dihydrogen phosphate-phosphoric
acid. J Mol Struct 920:1–7. https://doi.org/10.1016/j.molstruc.
2008.09.029
Supplementary Information The online version contains supplemen-
tary material available at https://doi.org/10.1007/s11696-021-01595-x.
Acknowledgements The authors sincerely acknowledge fnancial sup-
port, under SAP-DRS-II, extended by the University Grants Commis-
sion, New Delhi, India, through their Lr.No.F.530/24/DRS-II, 2015
(SAP). They are thankful to Sophisticated Analytical Instrumenta-
tion Facility (SAIF), IIT Madras, Chennai, India (Raman), and NIT-
Warangal, (NMR, IR, and UV–Vis) for spectral measurements. The
frst author (KSS) is grateful to the management of SR University,
Warangal, India, for permitting him to undertake the reported inves-
tigations. Second author (KR) thanks the Malla Reddy Engineering
Ahmed AB et al (2010) Crystal studies, vibrational spectra and non-
linear optical properties of l-histidine chloride monohydrate.
Spectrochim Acta A 75:293–298. https://doi.org/10.1016/j.saa.
2009.10.026
Akbar Ali M et al (1971) Metal Metal chelates of dithiocarbazic acid
and its derivatives. II. Complexes of the Schif bases formed by
condensation of S-methyldithiocarbazate with acetone and pyr-
idine-2-aldehyde. Inorganica Chim Acta 5:493–498. https://doi.
org/10.1016/S0020-1693(00)95973-5
1 3

Chemical Papers
Andraud C et al (1994) Theoretical and experimental investigations
of the nonlinear optical properties of vanillin, polyenovanillin,
and bisvanillin derivatives. J Am Chem Soc 116:2094–2102
Arivazhagan M, Jeyavijayan S (2011) Vibrational spectroscopic,
frst-order hyperpolarizability and HOMO, LUMO studies of
1, 2-dichloro-4-nitrobenzene based on Hartree–Fock and DFT
calculations. Spectrochim Acta A 79:376–383. https://doi.org/
10.1016/j.saa.2011.03.036
Hep G-2
100
90
80
70
60
50
40
30
20
10
0
APHT
APMHT
CP
Banerjee D et al (2011) Novel isatinyl thiosemicarbazones deriva-
tives as potential molecule to combat HIV-TB co-infection. Eur
J Med Chem 46:106–121. https://doi.org/10.1016/j.ejmech.
2010.10.020
Barber DE et al (1992) Silane alcoholysis by a nickel(II) complex in a
N, O, S ligand environment. Inorg Chem 31:4709–4711
Becke AD (1993) Density-functional thermo chemistry. III. The role
of exact exchange. J Chem Phys 98:5648–5652. https://doi.org/
10.1063/1.464913
0
10 20 30 40 50 60 70 80 90 100
Concentration (µM)
COLO 205
Blanz EJ Jr et al (1970) Carcinostatic activity of thiosemicarbazones
of formyl heteroaromatic compounds. VII. 2-Formylpyridine
derivatives bearing additional ring substituents. J Med Chem
13:1124–1130
100
APHT
90
80
70
60
50
40
30
20
10
0
APMHT
Buckingham AD (1967) Permanent and induced molecular moments
and long-range inter molecular forces. Adv Chem Phys 12:107–
142. https://doi.org/10.1002/9780470143582.ch2
CP
Cao S-L et al (2005) Synthesis and in vitro antitumor activity of 4(3H)-
quinazolinone derivatives with dithiocarbamate side chains.
Bioorganic Med Chem Lett 15:1915–1917. https://doi.org/10.
1016/j.bmcl.2005.01.083
Chocholoušová J et al (2004) First local minimum of the formic acid
dimer exhibits simultaneously red-shifted O-H⋯O and improper
blue-shifted C–H⋯O hydrogen bonds. Phys Chem Chem Phys
6:37–41. https://doi.org/10.1039/B314148A
0
10 20 30 40 50 60 70 80 90 100
Concentration (µM)
Choi CH, Kertez M (1997) Conformational information from vibra-
tional spectra of styrene, trans-Stilbene, and cis-Stilbene. J Phys
Chem A 101:3823–3831. https://doi.org/10.1021/jp970620v
Dennington R et al (2009) Gauss View, Version 5.0. Semichem Inc.
Shawnee Mission
NCI-H460
100
90
80
70
60
50
40
30
20
10
0
APHT
APMHT
CP
El-Bindary AA et al (1999) Thermodynamics of substituted pyra-
zolone. V: potentiometric and conductometric studies of com-
plexes of some transition metals with 4-(4-acetophenyl)hydra-
zono-3-methyl-2- pyrazolin-5-one. Can J Chem 77:1305–1309
El-Sharief AMSh, Moussa Z (2009) Synthesis, characterization and
derivatization of some novel types of mono and bis-imidazolidi-
neiminothiones and imidazolidineiminodithiones with antitumor,
antiviral, antibacterial and antifungal activities-part I. Eur J Med
Chem 44:4315–4334. https://doi.org/10.1016/j.ejmech.2009.07.
019
0
10 20 30 40 50 60 70 80 90 100
Concentration (µM)
Frisch MJ et al (2010) Gaussian 09, Revision B.01 Gaussian, Inc.
Wallingford
Fukui K (1982) Role of frontier orbitals in chemical reactions. Science
218:747–754
Fig. 6 In vitro percentage cell viability in APHT and APMHT com-
pared with that of CP at various concentrations for human carcinoma
cell lines Hep G2, COLO 205, and NCI-H460 (survival curves)
Gece G (2008) The use of quantum chemical methods in corrosion
inhibitor studies. Corros Sci 50:2981–2992. https://doi.org/10.
1016/j.corsci.2008.08.043
Geskin VM et al (2003) Origin of high second- and third-order non-
linear optical response in ammonio/borato diphenylpolyene zwit-
terions: the remarkable role of polarized aromatic groups. J Am
Chem Soc 125:15651–15658. https://doi.org/10.1021/ja035862p
Giri RS et al (2009) Design, synthesis and characterization of novel
2-(2,4-disubstituted-thiazole-5-yl)-3-aryl-3H-quinazoline-4-one
derivatives as inhibitors of NF-kB and AP-1 mediated transcrip-
tion activation and as potential anti-infammatory agents. Eur J
Med Chem 44:2184–2189. https://doi.org/10.1016/j.ejmech.2008.
10.031
Table 5 IC50 Values (μM) for APHT, APMHT, and CP
Compound
IC50 value (μM)
Hep G-2
COLO 205
NCI-H460
APHT
APMHT
Cisplatin
21.04 0.15
58.50 0.04
10.77 0.18
39.32 1.10
49.29 0.09
14.81 0.14
6.43 0.11
28.58 0.09
3.16 0.15
Gottlieb HE et al (1997) NMR Chemical shifts of common laboratory
solvents as trace impurities. J Org Chem 62:7512–7515
Hep G-2 hepatocellular liver carcinoma cell line, COLO 205 colorec-
tal adenocarcinoma cell line, NCI-H460 lung cancer cell line
1 3

Chemical Papers
Jatav V et al (2008) CNS depressant and anticonvulsant activities
of some novel 3-[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl
quinazoline-4(3H)-ones. Eur J Med Chem 43:1945–1954. https://
doi.org/10.1016/j.ejmech.2007.12.003
Sancho-García JC, Pérez-Jiménez AJ (2003) Nitrobenzene rotational
energy barrier: A survey of several ab initio methods. J Chem
Phys 119:5121–5127
Scalmani G, Frisch MJ (2010) Continuous surface charge polarizable
continuum models of solvation. I. General formalism. J Chem
Phys 132:114110. https://doi.org/10.1063/1.3359469
Koopmans TA (1933) Ordering of wave functions and eigen energies
of the individual electrons of an atom. Physica 1:104–113
Kosar D, Albayrak C (2011) Spectroscopic investigations and quantum
chemical computational study of (E)-4-methoxy-2-[(p-tolylimino)
methyl]phenol. Spectrochim Acta A 78:160–167. https://doi.org/
10.1016/j.saa.2010.09.016
Shekan P et al (1990) New colorimetric cytotoxicity assay for antican-
cer-drug screening. J Natl Cancer Inst 82:1107–1112. https://doi.
org/10.1093/jnci/82.13.1107
Sinha L et al (2011) Raman, FT-IR spectroscopic analysis and frst-
order hyperpolarisability of 3-benzoyl-5-chlorouracil by frst prin-
ciples. J Mol Simul 37:153–163. https://doi.org/10.1080/08927
022.2010.533273
Lee C et al (1988) Development of the Colic–Salvetti correlationen-
ergy formula into a functional of the electron density. Phys Rev B
37:785–789. https://doi.org/10.1103/PhysRevB.37.785
Lewis DFV et al (1994) Interaction of a series of nitriles with the
alcohol-inducible isoform of P450: computer analysis of struc-
ture-activity relationships. Xenobiotica 24:401–408. https://doi.
org/10.3109/00498259409043243
Srishailam K et al (2019) Investigation of torsional potentials, hindered
rotation, molecular structure and vibrational properties of some
biphenyl carboxaldehydes using spectroscopic techniques and
density functional formalism. J Mol Struct 1196:139–161
Sun Y-X et al (2009a) Experimental and density functional studies on
4-(4-cyanobenzylideneamino)antipyrine. Mol Phys 107:223–235.
https://doi.org/10.1080/00268970902769471
Liberta AE, West DX (1992) Antifungal and antitumor activity of het-
erocyclic thiosemicarbazones and their metal complexes: current
status. Biometals 5:121–126. https://doi.org/10.1007/BF01062223
Mohamed MS et al (2004) Synthesis of certain new 6-iodoquinazolines
as potential antitubercular agents. J Appl Sci 4:302–307. https://
doi.org/10.3923/jas.2004.302.307
Sun Y-X et al (2009b) Experimental and density functional studies on
4-(3,4-dihydroxybenzylideneamino) antipyrine and 4-(2,3,4-tri-
hydroxybenzylideneamino)antipyrine. J Mol Struct Theochem
904:74–82. https://doi.org/10.1016/j.theochem.2009.02.036
Tiwari AK et al (2007) Synthesis and biological properties of 4-(3H)-
quinazolone derivatives. Eur J Med Chem 42:1234–1238. https://
doi.org/10.1016/j.ejmech.2007.01.002
Monks A et al (1991) Feasibility of a high-fux anticancer drug screen
using a diverse panel of cultred human tumor cell lines. J Natl
Cancer Inst 83:757–766. https://doi.org/10.1093/jnci/83.11.757
Nakano M et al (2002) Theoretical study on second hyperpolarizabili-
ties of phenylacetylene dendrimer: toward an understanding of
structure-property relation in NLO responses of fractal antenna
dendrimers. J Am Chem Soc 124:9648–9655. https://doi.org/10.
1021/ja0115969
Tsuzuki S et al (1999) Torsional potential of biphenyl: ab initio calcu-
lations with the dunning correlation consisted basis sets. J Chem
Phys 11:2858–2861
Van Zyl EF (2001) A survey of reported synthesis of methaqualone and
some positional and structural isomers. Forensic Sci Int 122:142–
149. https://doi.org/10.1016/S0379-0738(01)00484-4
Padmapriya P et al (2016) Antiviral activity of thiosemicarbazones
derived from α-amino acids against Dengue virus. J Med Virol
89:546–552
West DX et al (1993) Structures of nickel(II) and copper(II) complexes
of 2-acetylpyridine azacyclothiosemicarbazones. Polyhedron
12:2489–2497. https://doi.org/10.1016/S0277-5387(00)83074-0
West DX et al (1994) Copper(II) and nickel(II) complexes of 2-for-
mylpyridine 3-piperidinyl-,3-hexamethyleneiminyl-and3azabi-
cyclo[3.2.2] nonylthiosemicarbazones. Transition Met Chem
19:553–558. https://doi.org/10.1007/BF00136373
Parr RJ, Szentpály LV, Liu S (1999) Electrophilicity Index. J Am Chem
Soc 121:1922–1924. https://doi.org/10.1021/ja983494x
Ramaiah K et al (2018) Synthesis, structural, biological evaluation,
molecular docking and DFT studies of Co(II), Ni(II), Cu(II),
Zn(II), Cd(II) and Hg(II) complexes bearing heterocyclic thio-
semicarbazone ligand. Appl Organometal Chem 32:4415–4433.
https://doi.org/10.1002/aoc.4415
West DX et al (1995) Copper(II) complexes of 2-benzoylpyridine
4N-substituted thiosemicarbazones. Polyhedron 14:2189–2200.
https://doi.org/10.1016/0277-5387(95)00010-P
Ramaiah K et al (2019) Synthesis, crystal and molecular structure,
and characterization of 2-((2-aminopyridin-3-yl)methylene)-N-
ethylhydrazinecarbothioamide using spectroscopic (1
Yousef TA et al (2013) Synthesis, characterization, optical band gap,
in vitro antimicrobial activity and DNA cleavage studies of some
metal complexes of pyridyl thiosemicarbazone. J Mol Struct
1035:307–317. https://doi.org/10.1016/j.molstruc.2012.10.058
H and 13C
NMR, FT-IR, FT-Raman, UV–Vis) and DFT methods and evalu-
ation of its anticancer activity. J Mol Struct 1184:405–417. https://
doi.org/10.1016/j.molstruc.2019.02.060
Reed AEL et al (1988) Intermolecular interactions from a natural bond
orbital, donar–acceptor viewpoint. Chem Rev 88:899–926
Sagdinc SG, Esme A (2010) Theoretical and vibrational studies of 4,
5-diphenyl-2-2 oxazole propionic acid (oxaprozin). Spectrochim
Acta A 75:1370–1376. https://doi.org/10.1016/j.saa.2010.01.004
Sajan D et al (2006) Structural and electronic contributions to hyper-
polarizability in methyl p-hydroxy benzoate. J Mol Struct 785:43–
53. https://doi.org/10.1016/j.molstruc.2005.09.041
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional afliations.
Sancho-García JC, Pérez-Jiménez AJ (2002) A theoretical study of the
molecular structure and torsional potential of styrene. J Phys B:
At Mol Opt Phys 35:1509–1523
1 3