Synthesis of Diphenyl Pyridazinone-based flexible system for conformational studies through weak noncovalent interactions: Application in DNA binding

Article abstract of DOI:10.1007/s12039-016-1059-3

This paper reports conformational studies of pyridazinone-based flexible dimer connected through diethylamine linker. The conformational studies have been done by X-ray crystal structure and DFT calculation. Further, after crystallization, the compound has shown two types of crystals, one is hydrated and another one is non-hydrated. The hydrated and non-hydrated crystals showed difference in their conformation due to the presence of water in crystal lattice of hydrated crystal. The difference in their conformation has been proved by crystallographic studies, DSC curves and detailed analysis of Hirshfeld surfaces and fingerprint plots facilitating a comparison of intermolecular interactions. Along with conformational studies, this compound also showed DNA binding, as revealed in docking simulation studies.

Full text of DOI:10.1007/s12039-016-1059-3

c
J. Chem. Sci. Vol. 128, No. 4, April 2016, pp. 555–564. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-016-1059-3
Synthesis of Diphenyl Pyridazinone-based flexible system for
conformational studies through weak noncovalent interactions:
Application in DNA binding
RANJEET KUMAR, PRAVEEN SINGH, ARCHANA GAURAV, PRATIMA YADAV,
RANJANA S KHANNA and ASHISH KUMAR TEWARI∗
Department of Chemistry (Centre of Advanced Studies), Institute of Science, Banaras Hindu University,
Varanasi, 221005, India
e-mail: ashishtewarichem@gmail.com
MS received 21 September 2015; revised 15 February 2016; accepted 16 February 2016
Abstract. This paper reports conformational studies of pyridazinone-based flexible dimer connected through
diethylamine linker. The conformational studies have been done by X-ray crystal structure and DFT calcula-
tion. Further, after crystallization, the compound has shown two types of crystals, one is hydrated and another
one is non-hydrated. The hydrated and non-hydrated crystals showed difference in their conformation due to
the presence of water in crystal lattice of hydrated crystal. The difference in their conformation has been proved
by crystallographic studies, DSC curves and detailed analysis of Hirshfeld surfaces and fingerprint plots facil-
itating a comparison of intermolecular interactions. Along with conformational studies, this compound also
showed DNA binding, as revealed in docking simulation studies.
Keywords. Single crystal structure; DFT calculation; Hirshfeld surfaces; fingerprint analysis; docking
simulation; DNA binding.
1. Introduction
pairs via the DNA minor groove, (vi) a threading inter-
calation mode, etc.16–18 Normally, binding mode of lig-
ands with DNA for most favourable free energy of com-
plex formation depends on structural features of flexible
ligands.17
This work deals with synthesis of symmetri-
cal diphenyl pyridazinone based flexible dimer,
namely, 2,2’-(azanediylbis(ethane-2,1-diyl))bis(3-oxo-
5,6-diphenyl-2,3-dihydropyridazine-4-carbonitrile) (3)
Several groups have quantified noncovalent interac-
tions to rationalize their observations across chemi-
cal sciences.1–4 The noncovalent interactions have been
exploited to prepare topologically complex molecules,
to control the enantioselectivity of reactions and for
asymmetric synthesis.5,6 In biological systems, nonco-
valent interactions have been identified as key factors
in determining the structural and molecular recogni- (scheme 1), linked through diethylamine spacer for con-
tion properties of nucleic acids, peptides and proteins formational studies through crystal structure in solid
as well as stabilization of DNA/RNA structures.7–10 state. The dimer 3 contained strong non-covalent sites
Further, noncovalent interactions is also applicable in and has enough flexibility to adjust the almost stable
the field of DNA binding with ligands.11 These non- folded conformation during crystallization using such
a long spacer. Therefore, molecule 3 has shown DNA
binding ability due to flexibility and intramolecular
folding. Normally, folding has been seen in propylene
spacer based molecules, which was quantified for the
first time by Leonard et al., between two hetero aro-
matic cores.19 Since 1995, extensive X-ray crystallo-
graphic studies by Avasthi et al., established the utility
of propylene linker, as suggested by Leonard et al.,19
in order to observe intramolecular folding between two
similar/different arene residues.1,20 But interestingly,
folding in the above mentioned systems was lost when
the ‘propylene linker’ was replaced by tetramethylene
linker21 or by pentamethylene linker.22
covalent interactions range from conventional strong
interactions (O-H· · · O, N-H· · · O) to unconventional
weak interactions (C–H· · · O, C–H· · · N) as well as π-
interactions (O-H· · · π, N-H· · · π, C-H· · · π), etc.12–15
The binding affinity of DNA with ligands through non-
covalent interaction occurs via several modes, such
as, (i) electrostatic attractions with the anionic sugar-
phosphate backbone of DNA, (ii) interactions with the
DNA major groove, (iii) interactions with the DNA
minor groove, (iv) intercalation between base pairs via
the DNA major groove, (v) intercalation between base
∗For correspondence
555

556
Ranjeet Kumar et al.
Scheme 1. Procedure for preparation of compound 3.
2. Experimental
CH2-N,), δ 4.42–4.46 (t, 4H, CH2-N py), 7.08–7.41
(m, 20H, Ar-H). 13C NMR (300 MHz, CDCl3): δ
45.78, 47.26, 113.32, 113.60, 128.17, 128.70, 128.95,
129.17, 130.38, 132.46, 134.17, 145,94, 150.93,
157.11, (m/z) = 415.24 (M+H) Anal. Calcd (%) for
C38H29N7O2C, 74.13; H, 4.74; N, 15.92: O, 5.2 Found
(%) 73.83; H, 4.94; N, 15.20: O, 5.72.
2.1 General
All reactions were monitored by thin layer chromatog-
raphy (TLC) over silica gel G UV active plates. The
melting points were recorded on an electrically heated
block and are uncorrected. The NMR spectra were
recorded on Jeol 300 MHz FT spectrometer equipped
with a 5 mm dual probe and a 6 mm multinuclear
inverse probe head with a Z-shielded gradient using
TMS as an internal reference [chemical shift in δ (parts
per million)].
2.3 X-ray Data Collection and Refinements
Single-crystal X-ray structure, space group, unit cell
dimensions, and intensity data were determined from
single crystal X-ray diffraction data collected at ambi-
ent temperature on Oxford Diffraction X-calibur CCD
diffractometer using graphite monochromated Mo Kα
radiation (λ = 0.71073 Å). The structures were deter-
mined by direct methods using SHELXS-97 and refined
on F2 by a full-matrix least-squares technique using
SHELXL-97.24 The packing diagrams were generated
using Mercury version 3.1. PLATON was used for the
analysis of bond lengths, bond angles, and other geo-
metrical parameters. Non-hydrogen atoms were refined
anisotropically, and hydrogen atoms were geometri-
cally fixed with thermal parameters equivalent to 1.2
times that of the atom to which they are bonded. Molec-
ular diagrams for all compounds were prepared using
ORTEP.25
2.2 Synthesis
Compounds 1 and 2 were synthesized according to
literature procedures.23
2.2a Synthesis of 2,2’-(azanediylbis(ethane-2,1-diyl))
bis(3-oxo-5,6-diphenyl-2,3-dihydropyridazine-4-car-
bonitrile) (3): In a 100 mL round-bottom flask, com-
pound 2 (0.5 g, 0.003 mol) was dissolved in dry DMF
and the mixture stirred for 15 min. Anhydrous potas-
sium carbonate (0.46 g, 0.003 mol) was added and
the mixture stirred for 2 h. Bis(2-chloroethyl)amine
hydrochloride (0.44 g, 0.002 mol) was added to the
mixture and stirred for 20 h. Completion of the reaction
was monitored by TLC. DMF was removed through
a rotary evaporator, and ice-cold water was added.
2.4 Theoretical Study
Precipitate was filtered with a Buchner funnel. The In order to investigate the conformational stability in
compound was recrystallized, which yielded an almost the gaseous state, single point and optimized energies
pure product: M.p.: 270-275◦C.Yield: (78%). 1H NMR have been calculated using the DFT-D method using
(300MHz, CDCl3): δ 2.16 (s, 1H), δ 3.25–3.27 (t, 4H, Gaussian 09.26

Conformational and DNA Binding Studies of Diphenyl Pyridazinone Dimer
557
2.5 Hirshfeld Surface Analysis
diphenyl pyridazinone-based flexible dimer, 2,2’-
(azanediylbis(ethane-2,1-diyl))bis(3-oxo-5,6-diphenyl-
2,3-dihydropyridazine-4-carbonitrile), are shown in
hydrated (3a) and non-hydrated (3b) crystals (figures 1
and S1 in Supplementary Information). The hydrated
crystal 3a was found to be P21/n monoclinic space
group with the following values: cell lengths are as
follows: a = 16.2553(12) Å, b = 9.4909(7) Å, c =
23.076(2) Å and cell angles (◦) are α = 90.00, β =
105.213 (8), γ = 90.00, Z = 4 and V = 3435.3 (5) Å
Non-hydrated crystal 3b was found to be monoclinic
with the space group the P21/c with the following val-
ues: cell lengths a = 17.046(3)Å, b = 9.3679(12) Å,
c = 20.873(4) Å and cell angles (◦) are α = 90.00, β =
106.887(18), γ = 90.00, Z = 4 and V = 3189.4(10) Å
(Table 1).
The crystal structure of molecule 3 (3a and 3b)
revealed that the molecule is in folded conformation,
which is controlled by a combination of intramolecu-
lar N-H· · · N, N-H· · · O, C-H· · · O, C-H· · · N and N-
H· · · π interactions.28,29 The intramolecular N-H· · · N,
N-H· · · O, C-H· · · O, C-H· · · N and N-H· · · π interac-
tions occurred between diethylene amine linker with
pyridazinone moieties, and another C-H· · · O and C-
H· · · N interaction occurred between phenyl hydrogen
of one pyridazinone moieties with oxygen and nitro-
gen atom of another pyridazinone moieties. The crys-
tal structure of 3a (hydrated) and 3b (non-hydrated)
also revealed that the conformation in both crystals are
different due to trapped water in their crystal lattice
of hydrated crystal 3a, as shown by variation in bond
distances, bond angles and torsions angles (Tables S1
The Hirshfeld surface emerged from an attempt to
define the space occupied by a molecule in a crystal
for the purpose of partitioning the crystal electron den-
sity into molecular fragments. Graphical tools based
on the Hirshfeld surface and the associated two-
dimensional (2D) fingerprint plot offered considerable
promise for exploring packing modes and intermolecu-
lar interactions in molecular crystals. Calculations were
performed using the Crystal Explorer package.27
2.6 Crystallization Experiments
The hydrated crystal of diphenyl pyridazinone-based
flexible dimer, 2,2’-(azanediylbis(ethane-2,1-diyl))bis(3-
oxo-5,6-diphenyl-2,3-dihydropyridazine-4-carbonitrile)
(3a) was crystallized in a mixture of chloroform and
methanol in ratio of (1:1) by slow evaporation at room
temperature.
The non-hydrated crystal of diphenyl pyridazinone-
based flexible dimer, 2,2’-(azanediylbis(ethane-2,1-diyl))
bis(3-oxo-5,6-diphenyl-2,3-dihydropyridazine-4-carbo-
nitrile) (3b) was crystallized in a mixture of ethanol
and ethyl acetate (1:2) by slow evaporation at room
temperature.
3. Results and Discussion
3.1 Crystallography Studies
In this section we shall discuss about crystallographic
studies of compound 3, particularly the intramolecular and S4 in SI).
interactions that stabilized the molecule in folded
Crystal packing of crystal 3a and 3b has been shown
U-shaped conformation. The compound 3 has two in figures 2 and 3. The figures 4 and 5 had shown the
crystals, which are 3a hydrated and 3b non-hydrated. intermolecular contact in molecular packing. Packing is
Hydrated crystal 3a and non-hydrated crystal 3b are stabilized by C–H· · ·O, C–H· · ·N, C–H· · · π and π · · · π
different in their conformation as water is trapped interactions. Iintermolecular π · · · π stacking interac-
in crystal lattice of 3a. The crystal structure of tions are observed only in crystal 3a, between cyano
Figure 1. Intramoleculer interactions of molecule 3 in (hydrated crystal 3a and non-hydrated crystal 3b).

558
Ranjeet Kumar et al.
group of one of the pyridazinone moiety and heteroaro- the molecular packing revealed that intermolecular
matic ring of another pyridazinone moiety. Moreover, C–H· · · O, C–H· · · N and C–H· · · π interaction dis-
the intermolecular π · · · π stacking interactions are tances are also different in 3a and 3b. These differences
stabilized by combination of C−H· · · π and C–H· · · O influenced by trapped water molecules in their crys-
interactions in both crystals that occur between cen- tal lattice, forming C–H· · · O and O· · · O interactions
troids of pyridazinone rings. The centroid to centroid between water molecules and pyridazinone moieties.
distance between pyridazinone moieties in crystal 3a Further, the intermolecular differences occur due to the
was found to be 3.75 Å and in crystal 3b it was found trapped water molecule in crystal lattice of 3a, which
to be 3.72 Å. This difference may be influenced by the influenced the packing pattern in crystal 3a compared to
fact that in crystal 3b, a large number of C–H· · · π crystal 3b. Thus, it can be concluded that both crystals
interactions are present compared to crystal 3a. Further, are different in their conformations.
Table 1. Crystallographic details of crystal (3a and 3b).
3.2 Computational Studies
Identification code
3a
3b
To further understand the conformation of molecule 3
(in 3a and 3b crystals), energy in the gaseous state,
crystal energy and optimized energy were calculated at
ω B97X-D level of theory with Gaussian 09 package
using the 6-31G (d, p) basis set. The crystal 3a was
optimized by removing water molecules from their
lattice. The ω B97X-D contains both exchange and
dispersion corrections that play important roles in
correctly describing both bond changes and weak
interactions.30,31 Conformations of molecule 3 (3a and
3b crystals) have already been proposed in solid state.
The crystal energies of 3a and 3b were found to
be -1253766.90 kcal/mol and -1253737.28 kcal/mol
(Table S2 in SI), respectively. The crystal energy of
3b was found to be 29.62 kcal/mol higher than 3a,
which revealed that the crystals are different in their
conformations. Further, optimization energy of 3a and
3b was also calculated for conformational studies by
considering the same molecular frame as the crystal
structure that showed nearly same energy and same
conformation. Table S3 (in SI) shows the compari-
son of crystallographic and computed intramolecular
Empirical formula
Formula weight
Crystal system
Space group
Cell length
a (Å)
C38H29N7O22(O)
647.68
C38H27N 7O2
615.67
Monoclinic
P 21/c
Monoclinic
P 21/n
16.2553 (12)
9.4909 (7)
23.076(2)
17.046(3)
9.3679(12)
20.873(4)
b (Å)
c (Å)
Cell angle
α(◦)
90.00
105.213(8)
90.00
3435.3(5)
1.252
90.00
106.887(18)
90.00
3189.4(10)
1.278
β(◦)
γ (◦)
Cell volume, V (Å3)
D calc (mg/m3)
F(000)
1352
4
0.084
1.252
1280
4
0.082
1.282
Z
μ (mm)
Dx,g cm−3
Index range
R-factor (%)
R int
9.8
0.068
9.61
0.097
GOF on F2
theta range (deg.)
CCDC No.
0.99
0.914
25.9◦–3.3◦
1018592
29.1◦–3.0◦
1041164
Figure 2. Packing of crystal 3a along a, b and c axis.

Conformational and DNA Binding Studies of Diphenyl Pyridazinone Dimer
559
Figure 3. Packing of crystal 3b along a, b and c axis.
Figure 4. (a) Alternate interaction for C− H· · · π, C−H· · · O, C−H· · · N and π · · · π interactions in crystal 3a; (b) showing
distances of intermolecular C−H· · · π interactions; (c) showing distances of intermolecular C−H· · · N and π · · · π interac-
tions; (d) and (e) showing intermolecular C−H· · · O interactions; and (f) showing intermolecular π · · · π interactions.

560
Ranjeet Kumar et al.
Figure 5. (a) Alternate interaction for C−H· · · π, C−H· · · O, C−H· · · N and π · · · π interactions in crystal 3b; (b) show-
ing distances of intermolecular C−H· · · N interactions; (c) showing distances of intermolecular C−H· · · π interactions; (d)
showing distance of C−H· · · O interactions; (e) showing intermolecular π · · · π interactions.
Figure 6. The DSC curves of molecule 3 for hydrated 3a and non-hydrated 3b crystals.

Conformational and DNA Binding Studies of Diphenyl Pyridazinone Dimer
561
H-bonded geometry parameters for crystals 3a and 3b mapped over dnorm, shape index and curvedness. Com-
in folded conformation. To avoid confusion and com- plementary regions are visible in the fingerprint plots
plexity in numbering, the numbering pattern for the where one molecule acts as the donor (de > di) and
optimized structure is used as a reference to crystal the other as an acceptor (de < di). The fingerprint plots
structure. The obtained geometries of both structures could be decomposed to highlight a particular atom
suggest that all noncovalent interactions like N-H· · · N, pair in close contacts. The two dimensional fingerprint
N-H· · · π, N-H· · · O, C-H· · · N and C-H· · · O are plots for molecule 3 revealed that both crystals illus-
responsible for the stabilization of the molecule in trate significant differences between the intermolecular
folded conformation (figure S2 in SI).
3.3 Differential scanning calorimetry (DSC)
Differential scanning calorimetry (DSC) is a fre-
quently preferred thermal analytical technique for
its ability to provide detailed information on both
the physical and energetic properties of a sub-
stance, especially on the purity of the compo-
nent and phase changes upon heating.32 Thus,
DSC measurements of molecule 3 for hydrated
3a and non-hydrated 3b crystals were carried out.
DSC analysis was performed with slower heating
rate, 5◦C min−1 under dry nitrogen atmosphere, allow-
ing better resolution in the overlap process as indi-
cated in the graph (figure 6). The temperature of range
was 35◦C-300◦C. For hydrated crystal 3a, DSC curve
showed three peaks at 106.59, 176.19 and 273.52◦C.
Weak endothermic peak at 106.59◦C stand obviously
for the process of dehydration, one strong exothermic
peak at 176.19◦C is attributed to solid–solid phase
transition, and the endothermic peak at 273.52◦C
is attributed to solid–liquid melting transition. Non-
hydrated crystal 3b showed one strong exothermic peak
at 180.81◦C for solid–solid phase transition, and a
strong endothermic peak at 278.22◦C for solid–liquid
melting transition. The differences in exothermic peaks
of solid–solid phase transitions and endothermic melt-
ing transition are due to the differences in their packing
pattern due to water molecules present in crystal lattice
of hydrated crystal 3a. Thus, DSC melting peak
revealed that both crystals are different in their confor-
mations.
3.4 Hirshfeld Surface Analysis
The application of Hirshfeld surface analysis could be
very valuable in the exploration of the packing modes
and intermolecular interactions in molecular crystals.
Hirshfeld surface analysis is particularly promising for
the visualisation of variations in the environments of the
molecules.27 The surfaces were shown as transparent to
allow visualization of the molecule 3 (3a and 3b crys-
tals) for which they were calculated. Both crystals are
illustrated in figure S3 (in SI), where surfaces are shown
Figure 7. Hirshfeld surface and two-dimensional finger-
print plots for molecule 3 (hydrated 3a and non-hydrated 3b
crystals).

562
Ranjeet Kumar et al.
interaction patterns, due to the significant differences in 3.5 Docking simulation for DNA binding
their conformations.
Prior to the simulations, all bound ligands, cofactors,
and water molecules were removed from the macro-
molecule (DNA). The macromolecule was checked for
polar hydrogen, and torsion bonds of the inhibitors
were selected and defined. Gasteiger charges were com-
puted, and the Auto Dock atom types were defined
using Auto Dock version 4.2 (the graphical user inter-
face of Auto Dock supplied by MGL Tools).33 The
Lamarckian genetic algorithm (LGA), considered one
of the best docking methods available in Auto Dock,
was employed.34,35 For docking simulations of mole-
cule 3, structures of 3a and 3b were docked onto
DNA d(CGCGAATTCGCG)2 and DNA (5’ D(GAAG-
CTTC)-3’) oligonucleotides retrieved from the Protein
Data Bank (PDB IDs: 1BNA and 173D), respec-
tively.36–38 To probe the detailed dynamics of the inter-
calation process as well as to validate force fields in
direct binding simulations, we docked the daunomycin
drugs using two well-studied DNA fragments.
The hydrated (3a) and non-hydrated (3b) crystals
had shown differences in their % of intermolecular
interactions due to the presence and absence of water
molecule in their crystal lattice. The Hirshfeld surface
and fingerprint analysis do not show a similar propor-
tion of intermolecular O· · · H interactions in the two
crystals, i.e., 17.4% in 3a and 9.8% in 3b. In both the
crystals, O· · · H interactions are represented by a spike
having the (de, di) regions of (1.12 Å, 1.4 Å). There
was a significant difference between the intermolecular
interactions in both crystals in terms of N· · · H interac-
tions 12.7% and 15.1% which are assigned as two long
spikes in 3a (de=1.1 Å, di=1.45 Å) and 3b (de=1.21
Å, di=1.6 Å), respectively in the fingerprint plots. In
Hirshfeld plot, another kind of intermolecular interac-
tion within both the crystals was also observed. The
decomposition of the fingerprint plot had shown C· · · H
contact 23.5% in 3a and 28.4% in 3b. These give rise
to characteristic wings in the region (de, di) in 3a (1.02
Å, 1.48 Å) and 3b (1.1 Å, 1.6 Å). The H· · ·H contact
comprises of 33.6% in 3a and 40.0% in 3b in the region
of (de, di) 3a (1.02 Å, 1.01 Å) and 3b (1.11 Å, 1.11 Å),
respectively, and these crystals had also shown many
contacts like C· · · C, N· · · N, O· · · N, O· · · C, O· · · O
and C· · · N (figure 7).
The DNA binding with compound 3 (3a and 3b struc-
tures) occurred through noncovalent interactions like
hydrogen bonding, π · · · π stacking and hydropho-
bic interaction in base pairs of minor groove of
DNA (figure 8). Table 2 shows the docking score of
Daunomycin and compound 3 (3a and 3b structures)
1BNA
173D
3b
3a
3b
3a
Figure 8. Best docked conformations for molecule 3 (hydrated 3a and non-hydrated 3b
structures) dockings with PDB IDs: 1BNA and 173D DNA fragments.

Conformational and DNA Binding Studies of Diphenyl Pyridazinone Dimer
563
Table 2. Docking Simulation results of molecule 3 (3a and 3b structures) for binding energy of interacting side chain
residues with 1BNA and 173D DNA fragments.
Name
1BNA
Interacting side
173D
Interacting side
Binding energy
(kcal/mol)
Binding energy
(kcal/mol)
Molecule
chain residues
chain residues
Daunomycin
3a
3b
−7.39
−6.11
−5.42
DC1, DG2 and DG24
DC3, DG24, DG22, DG4 and DA5
DA5, DG4, DG22, DC21, DT20 and DA8
−5.97
−6.04
−5.83
DT6, DT7, DC5 and DG6
DC13, DG12 and DT14
DG4 and DC5
within the minor groove of DNA. The compound 3 Supplementary Information (SI)
(3a and 3b structures) has shown lower binding affin-
Figures S1–S5 and Tables S1–S4 are shown in Sup-
plementary Information, available at www.ias.ac.in/
chemsci.
ity with DNA (1BNA) fragment and better binding
affinity with DNA (173D) fragments as compared to
Daunomycin. The conformation of hydrated crystal
3a has shown better binding affinity with both DNA
fragments having binding score −6.11 and −6.04 as
compared to non-hydrated crystal 3b conformation with
binding score of −5.42 and −5.83. The docking poses
for 3a have shown binding interactions with DC3,
DG24, DG22, DG4, and DA5 whereas 3b has shown
DA5, DG4, DG22, DC21, DT20, DA8, DG4 and DC5
within the DNA minor groove of both 1BNA and 173D
fragments.
Acknowledgements
AKT acknowledges DST India for Grant no. SR/S1/381
OC-42/2012 for financial assistance. Authors thank
Pedro Valerga (Departamento de Ciencia de los, Mate-
riales e Ingenieria Metalurgica, Facultad de Ciencias,
Campus Universitario del Rio San Pedro, 11510, Puerto
Real, Spain) for solved crystals.
4. Conclusions
References
The diphenyl pyridazinone-based flexible dimer of 3
has been synthesized for the first time for conforma-
tional studies in crystal in hydrated 3a and non-hydrated
3b forms. The crystallography studies have shown
that diphenyl pyridazinone-based flexible dimer gave
folded U shape conformation, seen in crystal structure
of 3 (3a and 3b crystals) in spite of long linker due to
intramolecular weak noncovalent interactions such as
C-H· · · π, N-H· · · π, N-H· · · N, N-H· · · O, C-H· · · O
and C-H· · · N. The docking simulations revealed that
molecule 3 has DNA binding ability due to flexibility
andintramolecularfolding. Therefore, thedesignofsuch
types of flexible molecules is of interest for structural
and medicinal chemists. Further, crystallographic stud-
ies have also revealed that from crystal structure of
molecule 3 is found as two crystals (3a and 3b), which
showed conformational differences due to the presence
and absence of water molecules in their crystal lat-
tice, supported by differences in bond distances, bond
angles, torsion angles and packing patterns. Moreover,
differences in conformation have been supported by
DFT calculations, DSC spectra, Hirshfeld surfaces and
two-dimensional fingerprint plots. Due to differences
in their conformation and torsion angles of 3a and 3b,
there was a variation in binding energy revealed in
docking simulation with DNA.
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