Design, synthesis, in silico analysis with PPAR-γ receptor and study of non-covalent interactions in unsymmetrical heterocyclic/phenyl fleximer

Article abstract of DOI:10.1002/jccs.202000215

This work deals with the design, synthesis, in silico analysis, crystallization, and the interpretation 2-cyano-3-{4-[2-(phthalimid-nyl)-propoxy]-phenyl}-acrylic acid ethyl ester (7). Analog 7 is designed based on rosiglitazone. The quantitative analysis

Full text of DOI:10.1002/jccs.202000215

Received: 21 May 2020
Revised: 1 August 2020
Accepted: 15 September 2020
DOI: 10.1002/jccs.202000215
A R T I C L E
Design, synthesis, in silico analysis with PPAR-γ receptor
and study of non-covalent interactions in unsymmetrical
heterocyclic/phenyl fleximer
Ved Prakash Singh1,2
| Jayanta Dowarah1 | Brilliant N. Marak1
|
Ashish Kumar Tewari2
1Department of Chemistry, School of
Physical Sciences, Mizoram University,
Aizawl, Mizoram, India
2Department of Chemistry, Institute of
Science, Banaras Hindu University,
Varanasi, Uttar Pradesh, India
Abstract
This work deals with the design, synthesis, in silico analysis, crystallization,
and the interpretation 2-cyano-3-{4-[2-(phthalimid-nyl)-propoxy]-phenyl}-
acrylic acid ethyl ester (7). Analog 7 is designed based on rosiglitazone. The
quantitative analysis of Compound 7 has been performed through single-
crystal X-Ray Diffraction (XRD) and Hirshfeld surface analysis. Fleximer 7 has
studied the role of flexibility in non-covalent interactions and binding affinity
with PPAR-γ receptors. Both phthalimide ring and phenyl rings are linked
with propylene linker. 2-cyano-3-{4-[2-(phthalimid-nyl)-propoxy]-phenyl}-
acrylic acid ethyl ester has Z = 8 in the crystal packing and stabilized by inter-
molecular non-covalent interactions like C H…O, C H…N, C H…л, and
л…л, and so forth.
Correspondence
Ved Prakash Singh, Department of
Chemistry, School of Physical Sciences,
Mizoram University, Aizawl 796004,
Mizoram, India and Department of
Chemistry, Institute of Science, Banaras
Hindu University, Varanasi-221 005, India.
Email: vpsingh@mzu.edu.in
Ashish kumar Tewari, Department of
Chemistry, Institute of Science,
Banaras Hindu University,
K E Y W O R D S
Varanasi-221 005, India.
crystal, docking, intra-molecular, fleximer, intermolecular, non-covalent interactions, PPAR-γ
Email: tashish2002@yahoo.com
Funding information
Department of Science and Technology,
Ministry of Science and Technology, India
is the DST funding agency.
1 | INTRODUCTION
facial stacking orientation of aromatic molecules are of
particular interest as loan pair–π interactions. These inter-
Non-covalent interactions are of fundamental importance for
understanding molecular recognition in biological systems,[1]
and physical and chemical properties of new materials.[2–6]
These play a vital role in influencing the assembly, confor-
mation, and spacing of aromatic dimer stacks.[7–9] The
understanding of the stack system about its orientation and
spacing and control of these non-covalent forces in stabiliz-
ing the supramolecular self-assembly process is indispensable
for the progress of crystal engineering.[10,11]
actions are intermolecular forces, which is very much sim-
ilar to hydrogen bonding, whose nature is still
undefined.[19] Arrangement of loan pair–π interactions
between aromatic rings can generally be distinguished into
two different situations: face-to-face, offset and slipped.[20]
A heterocyclic system is more favorable for aromatic
interactions; for example, if nitrogen introduced or an
electron-deficient ring is more prompt for aromatic interac-
tions. Unsymmetrical fleximers having aromatic and het-
eroaromatic rings are studied like pyridines,[21] pyrazolo
[3,4-d] pyrimidine, and so forth. Out of these studies, only
a few have shown intra and inter-molecular stacking
The acquisition of artificial nucleobases into DNA
helix can lead the bio-chemist designer to study the natu-
ral systems.[12–18] Among various weak interactions, the
J Chin Chem Soc. 2020;1–9.
http://www.jccs.wiley-vch.de
© 2020 The Chemical Society Located in Taipei & Wiley-VCH GmbH
1

2
SINGH ET AL.
interactions, whereas most of them show only inter-
molecular non-covalent aromatic interactions. Unsymmet-
rical dimer shows donor-acceptor type interactions of loan
pair–π lateral offset stacking in imidazolin-5-ones. These
studies show that how weak πꢀꢀꢀπ interactions are exploited
for tailoring supramolecular assemblies.[22] Consequently,
to study the role of non-covalent interactions, we synthe-
sized unsymmetrical flexible heterodimer, 2-cyano-
3-{4-[2-(phthalimid-nyl)-propoxy]-phenyl}-acrylic acid ethyl
ester (7) linked through methylene linkers.
rosiglitazone and its receptor PPARγ. Molecular recogni-
tion processes involving intermolecular interactions of
compound and PPARγ are carried out by in-silico studies.
2 | RESULTS AND DISCUSSION
The compound crystallized in ethyl acetate: hexane solu-
tion at room temperature by the slow evaporation
method. Only Z (7) isomer is obtained in the final step of
the synthesis. This reaction takes place through a ther-
modynamically controlled product pathway because Z is
thermodynamically more stable then E isomer.
The peroxisome proliferator-activated receptor
belongs to the family of nuclear receptors.[23] Peroxisome
proliferator-activated receptors (PPARs) are the group of
nuclear receptors that control the carbohydrate metabo-
lism by altering the expression of the genes involved.
Rosiglitazone Thiazolidinedione (TZD) is an anti-diabetic
drug of glitazone series. In general, the ligand is in a U-
shaped conformation; the TZD head group makes several
specific interactions with amino acids in H3, H4, H10,
and the AF-2 helix.[24] The carbonyl groups of the TZD
form hydrogen bonds with two histidine residues, H323
and H449. Y473 in the AF-2 helix forms a secondary
hydrogen bond with H323. The partly negatively charged
nitrogen of the TZD head group is within hydrogen-
bonding distance of the Y473 side chain. A buried lysine
residue, K367, forms another secondary hydrogen bond
with rosiglitazone. Next to the head group, the sulfur
atom of the TZD ring positioned in a hydrophobic region
of the PPAR-γ. The central benzene ring of the ligand
occupies a very narrow pocket between C285 and M364.
The bridging oxygen atom between the benzene ring and
the pyridine ring provides vital geometry for the pyridine
ring, which occupies the pocket between H3 and the b-
sheet. Substituted carboxylic acids can act as bio-isosteric
replacements for the TZD head group, maintaining high-
affinity binding and receptor activation.[24] All of these
hydrophobic carboxylic acids may become the key to
bind with PPAR. The main side effect of glitazones is
water retention leading to edema, with significant water
retention, leading to decompensation of potentially previ-
ously unrecognized heart failure. These side effects
require the development of new molecules with potent
anti-diabetic activities with the least side effects.
2.1 | Crystal structure analysis
The compound is an unsymmetrical fleximer linked with
a tri-methylene linker. One side of the dimer has
phthalimide substituent, while the other side p-substituted
phenyl ring is linked through oxygen atom (Table 1).
The phthalimide group selected for study due to its
polarized nature exhibited both donors and an acceptor
in intermolecular and intramolecular interactions. It is a
polarized bicyclic system due to the amide group in one
ring. Another part of the fleximer is a substituted phenyl
ring, an electron-rich moiety of the compound. Oxygen
linked to methylene linker and phenyl ring is also taking
part in intra-molecular interaction, which creates a new
conformation in molecules in the solid-state, and
C18 C20 exists in gauche conformation.
The cyano group's nitrogen taking part in intra-
molecular interaction with C13 H13 and angle of
C7 C9 N10 becomes 178.43ꢁ in place of 180ꢁ. This C
(13) H(13)ꢀ ꢀ ꢀN(10) weak bond forms seven-membered
rings of C7, C8, C9, C10, C11, C13, N10, H13 atoms, which
In the present work, compounds designed on the struc-
tural basis of rosiglitazone in Figure 1. In order to mini-
mize the side effects of rosiglitazone, the head portion was
replaced by one of its bio-isoester, dicarboxylic ester func-
tion. Cyano group was introduced to compensate for the
nitrogen of TZD. Efforts were made to modify the tail por-
tion of rosiglitazone by introducing phthalimide heterocy-
clic moieties rich in biological properties. The central
benzene ring is retained as it is essential for anti-diabetic
activities, confirmed from the crystal structure of
FIGURE 1 Similarity of Compound 7 with rosiglitazone

SINGH ET AL.
3
create an unsymmetrical bond angle between
C8 C11 C13 and C8 C11 C12, which is 117.16ꢁ and
125.38ꢁ, respectively. O17 is involved in weak interactions
with H19b. It is tilted toward C14, and the angle between
O17 C16 C14 becomes 115.61ꢁ, whereas O17 C16 O15
becomes 124.81ꢁ in place of 120ꢁ. Intra-molecular interac-
tions are summarized in Table 2 (Figure 2).
Crystal packing of molecules stabilized via various
non-covalent interactions. In the packing diagram, four
molecules arranged in two planes in two groups just per-
pendicular to the each other due to the presence of inter-
molecular edge to face C(29) H(29)ꢀ ꢀ ꢀπ Cg(C26 C31)
(3.130 Å), C(24) O(25)ꢀ ꢀ ꢀπ Cg(N22, C23 C27) (2.407 Å),
C(15) H(15)ꢀ ꢀ ꢀπ Cg(C11 C16) (3.045 Å) interaction
(Figure 3 and Table 3). These interactions are present
between a similar ring of two molecules. Means five-
membered ring interacts with a five-membered ring, and
a six-membered ring interacts with a six-membered ring
through loan pair interaction and C H л interactions.
Arene-arene interaction is also observed by expanding
the crystal network, which stabilizes the unsymmetrical
molecule in the opposite orientation, as observed in
CH π interactions. Aromatic loan pair–π interaction pre-
sent between bicyclic phthalimide ring and phenyl ring
Cg(C11 C16)πꢀ ꢀ ꢀπCg (N22, C23 C27) (3.448Aꢁ)
(Figure 4 and Table 3).
TABLE 1 Crystal data, data collection, and structure
refinement for Compound 7 (CCDC 1907144)
Empirical formula
Formula weight
Temperature
C23H20N2O5
404.42
296 (2) K
Crystal system, space
group
Monoclinic, P21/c
Unit cell dimensions
a = 22.2055(6) Å, α = 90ꢁ
b = 11.0555(3) Å, β = 91.312(2) ꢁ
c = 8.0619(2) Å, γ = 90ꢁ
1978.62(9) Å3
Volume
Z
8
There are two loan pair–π interactions between two
molecules from both the ends of the molecule. These aro-
matic CH π and loan pair–π interactions orient the mol-
ecules in opposite orientation into the ABAB pattern in
Figure 5.
ρcalc
1.3575 g/cm3
μ
0.097 mm−1
F(000)
Crystal size
Radiation
Index ranges
848.5
0.35 × 0.30 × 0.25 mm
Mo Kα (λ = 0.71073)
The Hirshfeld surface and fingerprint plots[27] of Com-
pound 7 are in Figure 6. Hirshfeld surface view exactly
explained the pattern of molecule conformation exists in
−26 ≤ h ≤ 29, −13 ≤ k ≤ 12,
−10 ≤ l ≤ 6
Reflections collected
8,243
Independent reflections
4,440 [Rint = 0.0168,
Rsigma = 0.0365]
Goodness-of-fit on F2
0.954
Final R indexes [I > =2σ R1 = 0.0366, wR2 = 0.0919
(I)]
Note: Computer programs: CrysAlis PRO, Oxford Diffraction Ltd.,
SHELXL2016/6[25] for first crystal, CrysAlis PRO, Oxford Diffrac-
tion Ltd., Version 1.171.33.41, olex2.solve,[26] olex2.refine.[26]
FIGURE 2 Intra-molecular interactions in Compound 7
TABLE 2 Intra-molecular interactions in Compound 7
S. No.
Interaction
d (Å)
2.513
2.490
2.656
2.406
2.407
2.696
D (Å)
2.914
2.887
3.172
2.803
2.688
3.523
C
H—N/O (o)
1.
2.
3.
4.
5
C(19) H(19b)ꢀꢀꢀO(17)
C(19) H(19b)ꢀꢀꢀO(21)
C(20) H(20b)ꢀꢀꢀO(25)
C(8) H(8)ꢀꢀꢀO(3)
C(2) H(2a)ꢀꢀꢀO(3)
C(13) H(13)ꢀꢀꢀN(10)
104.61
104.31
113.66
105.60
96.03
6.
148.52

4
SINGH ET AL.
the solid-state. Electronic distribution within the com-
pound also explained the existence of non-covalent inter-
actions (Figure 6). The principal weak interactions are
visible in the fingerprint plots. The surface coverage for
Compound 7 is H…H 39.8%, C…C 6.4%, N…H 7.7%, O…H
23.2%, C…H 16.1%, N…C 3.3%, C…O 3.1%, and other inter-
actions are less than 0.2%. The primary intermolecular
interactions are observable in the fingerprint plot. This
study gives the exact contribution of different types of
interactions like loan pair–π interaction contributes 6.4%,
whereas CH-л interactions contribution is 16.1%.
FIGURE 4 л…л interactions in the crystal of Compound 7
The 2D fingerprint plots represent the weak inter-
molecular interactions with the pair of contacts and
their percentage of contribution toward the 3D
Hirshfeld surface formation. The di and de in the finger-
print plots represent the distance between the nearest
internal element and external to the 3D molecular
Hirshfeld surface, respectively.[28] The yellowish-red bin
on the fingerprint plots also provided information about
the presence of weak л–л stacking in the crystal struc-
ture (Figure 6b). The spoke-like pattern in the finger-
print plots represents the C H…O interactions in the
FIGURE 5 Crystal network (a) and unit cell packing (b) of
FIGURE 3 CH-л, loan pair-л interactions in Compound 7
Compound 7
TABLE 3 Intermolecular
interactions in Compound 7
S. No.
Interaction
d (Å)
2.577
2.642
2.662
3.130
2.407
3.045
3.448
D (Å)
3.455
3.472
3.281
4.016
4.030
3.922
—
C
H—л/N/O (o)
1.
2.
3.
4.
5
C(18) H(18b)ꢀ ꢀ ꢀO(21)
C(12) H(12)ꢀ ꢀ ꢀO(25)
C(18) H(18a)ꢀ ꢀ ꢀO(17)
C(29) H(29)ꢀ ꢀ ꢀл Cg(C26 C31)
C(24) O(25)ꢀ ꢀ ꢀл Cg(N22, C23 C27)
C(15) H(15)ꢀ ꢀ ꢀл Cg(C11 C16)
Cg(C11 C16)лꢀ ꢀ ꢀлCg (N22, C23 C27)
150.60
149.07
122.06
159.99
152.40
157.80
—
6.
7.

SINGH ET AL.
5
crystal lattice in the region of di + de = 2.45–2.7 Å
(Figure 6b). The C H…л interactions can be seen as a
pair of unique blue colored wings in the region of di
+ de = 2.45–2.7 Å(Figure 6b). The C H…N pair of inter-
actions of contacts also reflected as two characteristic
wings occupied in the region of di + de = 2.45–2.7 Å
(Figure 6b).
Calculated interaction energy with non-covalent
interactions for Compound 7 is in Table 4. The
Hirshfeld surface analysis also shows different kinds
of weak non-covalent intermolecular interactions,
where loan pair–π stacking, C H…π interactions,
C H…N, and C H…O interactions of Compound 7 in
the crystal packing structure is in Figure 7. The dis-
persion component calculated for these interactions is
the major component, presumably a result of the aro-
matic electronic re-distribution in the compound.[29]
Another interaction of interest is these weak H-bonds
(C H…O and C H…N), making a non-covalent inter-
action among neighbor molecules. There should be a
significant electrostatic component, but the dispersion
component is a major one found in this calculation,
presumably a result of the charge distribution in the
ester functional group and cyano group and the polar-
ization of the phenyl ring by its substituents.
The Curvedness plots and the Shape index plots of 3D
Hirshfeld also reveal the various weak intermolecular
interactions in the crystal structure of Compound 7. The
yellow spots in the Curvedness plots represent the weak
interactions of Compound 7 in the crystal structure, shown
in Figure 8a. The Curvedness plots also give information
about the weak л-л stacking. The green-colored flat regions
in the Curvedness plots indicate the presence of weak л-л
stacking in the crystal structure of Compound 7.[29] The
red-colored spots in Curvedness plots show strong
hydrogen-bonding interactions in the crystal structure.
Red and blue areas represent the acceptor and the
donor property, respectively, in shape index of Com-
pound 7 (Figure 8b). Yellowish-red colored concave
regions indicate the presence of weak intermolecular
FIGURE 6 (a) Hirshfeld surfaces and (b) fingerprint plots of
Compound 7
TABLE 4 Interaction energies (kJ/mol) calculated for Compound 7
S. No.
D
H…A
E_ele
−3.8
−9.0
1.1
E_pol
−1.4
−3.5
−0.6
−0.4
−0.6
−3.6
E_dis
−9.2
E_rep
4.7
E_tot
−10.2
−21.2
−5.0
1
2
3
4
5
6
C1 H1b…N10, C1 H1b…O4,
C1 H1c…N10, C1 H1c…O4
C1 H1a…O3
−16.6
−7.4
8.7
1.2
C2 H2a…O4, C2 H2a…O3
−1.8
0.4
−9.1
1.8
−9.1
−5.6
3.4
−2.8
C19 H19a…O17, C13 H13a…C26C27C28C29C31C0aa,
C11C12C13C14C15C16…C23C24C26C27N22
−28.3
−127.1
76.5
−96.0
7
8
9
C15 H15…C11C12C13C14C15C16
C12 H12…O25, C18-H18b…O21
−12.9
−25.3
−8.5
−8.9
−6.7
−3.9
−62.6
−44.4
−44.7
43.2
31.6
25.4
−48.0
−50.9
−35.1
C12 H12…O21, C14 H14…O21, C0aa H0aa…O3,
C12-H12…C23, C12 H12…C26

6
SINGH ET AL.
FIGURE 8 (a) curvedness both side view, (b) shape index
both side view of Compound 7
Arm I, Arm II, and Arm III. Arm-I is mostly polar, and it
is located near H12; Arm II contains some polar residues.
However, it is predominantly hydrophobic and lies close
to the β-sheet of the surface. Whereas, the Arm III pocket
is also hydrophobic and located near the β-sheet but bur-
ied deeper near H5.[32] Compound 7 binds with PPAR-γ
receptor through C H…O, C H…N, C H…π, and π…π
non-covalent interactions in the same way as observed in
crystal analysis and Hirshfeld analysis. The donor and
acceptor region of crystal structure and Hirshfeld analysis
found similar as observed in the binding of Compound
7 with PPAR-γ receptor in docking analysis.
The binding mode of Compound 7 in the active site of
PPAR-γ was examined in depth using molecular docking
analysis. The analysis of docking results indicated that
Compound 7 has a high binding affinity in the active site
of PPAR-γ. It has a binding energy of 9.3 kcal/mol, higher
than the binding energy of rosiglitazone (8.3 kcal/mol).
Much like rosiglitazone, Compound 7 occupied Arm I and
Arm II of the ligand-binding pocket, and the arm-III pocket
remains unoccupied. The three-dimensional representation
FIGURE 7 (a) л-л stacking, (b) C H…л interactions,
(c) C H…O interactions of Compound 7 in Hirshfeld surface
analysis
interactions in the Shape index plots.[30,31] The red and
blue colored triangles on the surface of rings of the mole-
cule in the Shape index plots also indicated the presence
of weak л–л stacking in the crystal structure (Figure 8b).
Hirshfeld surface analysis gives evidence about weak
intermolecular interactions, and all these weak interac-
tions stabilize and strengthen the crystal packing struc-
ture of Compound 7.
2.2 | In silico analysis
The ligand-binding pocket of PPAR-γ has a sizable Y-
shaped cavity. It is comprised of three sub-pockets viz.

SINGH ET AL.
7
of Compound 7 in the binding cavity of PPAR-γ is illus-
trated in Figure 9. The more hydrophilic group of Com-
pound 7, that is, ethyl cyanoacrylate, occupied the most
polar pocket Arm I, whereas less polar group phthalimide
directed toward the Arm II pocket. The ethyl cyanoacrylate
established two strong hydrogen bonds with the residues
Ser289 and Tyr327 in the Arm I pocket. In contrast, the car-
bonyl oxygen of phthalimide exhibited one hydrogen bond
interaction with the residue Ser342 in the Arm II pocket. In
addition to hydrogen bond interactions, π-sulfur interac-
tions with the residues Cys285 and Met364, and π-alkyl
interactions with the residues Phe282, His499, Ile341,
Cys285, Arg288, and Leu330 largely contributed to its bind-
ing affinity in the ligand-binding domain of PPAR-γ.
3 | EXPERIMENTAL
3.1 | Synthesis of 2-cyano-
3-{4-[2-(phthalimid-nyl)-propoxy]-phenyl}-
acrylic acid ethyl ester (7)
In a 100 ml round bottom flask 4-(3-phthalimid-nyl-
propoxy) benzaldehyde (0.32 g, 1.02 mmol), ethyl cyano
acetic acid ethyl ester (0.1153 g, 1.02 mmol), piperidine
(0.005 g), and sodium acetate (0.008 g) were taken in tolu-
ene. Flask was attached to the dean stark apparatus. The
reaction mixture refluxed for 7 hr. Completion of the reac-
tion was monitored through thin layer chromatography.
The solvent was evaporated, and the residue was extracted
with chloroform (3 × 200 ml) and washed with water
(3 × 100 ml). The combined organic layer was dried by
anhydrous sodium sulfate. Chloroform was evaporated,
and crude was purified through column chromatography
using ethyl acetate and hexane as eluent. Pure compound
was collected from 22% EtOAc/Hexane, followed by
recrystallization in ethyl acetate and hexane. Single crystal
X-ray Ortep diagram of this compound confirms that these
reactions gave Z-isomer only (Scheme 1).
FIGURE 9 Illustrations of the binding mode of Compound 7 in
the ligand-binding domain of PPAR-γ. (a) The Y-shaped cavity of the
ligand-binding domain. (b) Molecular interactions of Compound
7 with PPAR-γ. (c) Overlay of Compound 7 with rosiglitazone
3.1.1 | 1HNMR 300 MHz, 25oC, Si(CH3)4,
(CDCl3), δ (ppm)
3.2 | Crystal structure determinations
1.37–1.41 (3H, t, CH3, J = 6.9 Hz, J = 7.2 Hz); 2.21–2.25
(2H, m, CH2); 3.90–3.95 (2H, t, NCH2, J = 6.6 Hz,
J = 6.6 Hz); 4.01–4.14 (2H, t, OCH2, J = 5.7 Hz,
J = 6.0 Hz); 4.33–4.39 (2H, q, CH2); 6.85–6.88 (2H, d,
ArH, J = 8.7 Hz); 7.93–7.96 (2H, d, ArH, J = 8.7 Hz);
7.71–7.85 (4H, m, ArH); 8.15 (1H, s, C C H). 13C NMR
(75 MHz, CDCl3): (δ): 14.09, 27.97, 35.16, 62.29, 66.02,
99.18, 114.97, 116.07, 123.15, 124.27, 131.93, 133.47,
133.93, 154.22, 162.76, 162.96, 168.20.
Single-crystal X-ray data for compounds 7 was collected
with an Oxford Diffraction Xcalibur CCD diffractometer.
Graphite monochromated Mo Kα (λ = 0.71073 Å) was
used as a radiation source. The structures were deter-
mined by direct methods using Olex-2.[25] It is refined on
F2 by a full-matrix least-squares technique.[25,26] Non-
hydrogen atoms were refined anisotropically, and hydro-
gen atoms were geometrically fixed with thermal parame-
ters equivalent to 1.2 times that of the atom to which

8
SINGH ET AL.
SCHEME 1 (7); Yield: 0.39 g, 94%.
M.p.: 129–132ꢁC
they bonded. All diagrams of the compounds were pre-
pared using Oak Ridge Thermal Ellipsoid Plot, and the
packing diagrams were generated using Mercury version
3.1.[33a] Ortep and Mercury were used to analyze bond
lengths, bond angles, and other geometrical
parameters.[33b]
Finally, the processed protein structure subjected to dock-
ing with the crystal structure of Compound 7. The docked
results were visualized using the pymol and Discovery
Studio.[39,40]
4 | CONCLUSIONS
3.3 | Hirshfeld surface and fingerprint
plots analysis
Cyano-3-{4-[2-(phthalimid-nyl)-propoxy]-phenyl}-acrylic
acid ethyl ester is a thermodynamically controlled prod-
uct Z isomer formed as a product. Crystal packing and its
network have stabilized by different types of intra-
molecular interactions (C H…O, C H…N), and inter-
molecular (C H…O, C H…π, and π…π) non-covalent
interactions. Non-covalent interactions orient the mole-
cule in opposite orientation in the solid-state due to
charge dispersion, polarization, and charge re-orientation
of conjugated π electrons. Charge re-organization due to
the neighbor molecule is very similar in the crystal struc-
ture, Hirshfeld surface analysis, and in the drug-receptor
analysis. The polarization of molecules defines the orien-
tation of molecules in the solid-state, taking part in drug-
receptor binding, as observed in docking analysis. Crystal
property can be utilized in the development of a new
drug by using its donor-receptor property. The flexibility
of Compound 7 gives a better conformation to fit the Y-
shaped cavity of the PPAR-γ receptor. Flexibility
enhances the selectivity and binding affinity of analogs.
This Compound 7 shows a potentially binding affinity
toward the PPAR-γ receptor even better than then
rosiglitazone standard drug. This compound maybe
becomes a better anti-diabetic drug as per docking analy-
sis. This Compound 7 can be further in vivo studied to
develop a new anti-diabetic drug.
Hirshfeld surfaces, fingerprint plots, interaction energies,
and energy frameworks were calculated using
CrystalExplorer17.5.[34] The interactions energy calcula-
tions also showed sufficient evidence about the different
kind of weak intermolecular interactions. The interaction
energies of Compound 7 calculated using the CE-
B3LYP/6-31G(d,p) functional/basis set combination.[35]
The interaction energy is broken down as
Etot = keleE0ele + kpolE0pol + kdisE0dis + krepE0rep ð1Þ
where the k values are scale factors, E0ele represents the
electrostatic component, E0pol the polarization energy,
E0dis the dispersion energy, and E0rep the exchange-
repulsion energy.[36]
3.4 | Molecular docking
Molecular docking analysis was carried using the
autodockVina.[37] It involves a series of steps like protein
selection from a protein data bank and its preparation,
grid generation, ligand preparation, and docking to the
receptor. PPAR-γ protein for docking retrieved from the
protein data bank (PDB id: 5YCP). The protein prepara-
tion was done in chimera[38] by deleting co-crystallized
ligand and embedded water molecules. It was further
processed by adding polar hydrogens and assigning partial
charges. The grid was generated to cover the ligand-biding
domain of PPAR-γ, and the exhaustiveness parameter for
analyzing the binding affinity. It was set to nine modes.
ACKNOWLEDGMENTS
Department of Chemistry, Banaras Hindu University,
Varanasi, INDIA is acknowledged for departmental facili-
ties. Department of Chemistry, Mizoram University,
Aizawl, Mizoram, India, acknowledged the other infra-
structure facilities. The author Jayanta Dowarah acknowl-
edged DST for Inspire fellowship for financial support.

SINGH ET AL.
9
[24] J. Dowarah, V. P. Singh, Bioorg. Med. Chem. 2020, 28(5),
115263(1–78). https://doi.org/10.1016/j.bmc.2019.115263.
[25] G. M. Sheldrick, Acta Crystallog. 2008, A64, 112.
[26] O. V. Dolomanovn, L. J. Bourhis, R. J. Gildea, J. A. K.
Howard, H. Puschmann, J. Appl. Cryst. 2009, 42, 339.
[27] C. F. Mackenzie, P. R. Spackman, D. Jayatilaka, M. A.
Spackman, IUCrJ. 2017, 4, 575.
CONFLICT OF INTEREST
The authors declare no potential conflict of interest.
ORCID
Ved Prakash Singh https://orcid.org/0000-0003-4401-
8379
[28] J. J. McKinnon, M. A. Spackman, A. S. Mitchell, Acta
Crystallogr. 2004, B60, 627.
REFERENCES
[29] V. P. Singh, J. Dowarah, D. K. G. Lalhruaizela, Cryst. Res.
[1] (i) V. P. Singh, Sci. Technol. J. 2015, 3(1), 42; (ii) A. K. Tewari,
P. Srivastava, V. P. Singh, P. Singh, R. S. Khanna, Res. Chem.
Intermed. 2013, 39(7), 2925.
[2] G. R. Desiraju, Crys. Eng. Des. Org. Solids. Elsevier Science
Publishers B. V., Amsterdam 1989.
[3] C. A. Hunter, J. K. M. Saunders, J. Am. Chem. Soc. 1990, 112,
5525.
[4] D. K. Muller, P. Hobza, Chem. Rev. 2000, 100, 143.
[5] G. R. Desiraju, T. Steiner, Weak Hyd. Bond Struc. Chem. Bio.
Oxford University Press, Oxford 2000.
[6] T. Steiner, Angew. Chem., Int. 2002, 41, 48.
[7] A. N. Sokolov, T. Frisˇcic, L. R. MacGillivray, J. Am. Chem.
Soc. 2006, 128, 2806.
[8] T. Seki, S. Yagai, T. Karatsu, A. Kitamura, J. Org. Chem. 2008,
73, 3328.
Technol. 2019, 55, 1900136(1–7).
[30] S. Shyamapada, M. Christoph, M. Samiran, Acta. Chim. Slov.
2016, 63, 129.
[31] K. M. Rahul, K. J. Amanpreet, A. Meenu, K. C. Sukhvinder,
J. Chem. Sci. 2015, 127, 849.
[32] J. Shang, R. Brust, S. A. Mosure, J. Bass, P. Munoz-Tello, H. Lin,
T. S. Hughes, M. Tang, Q. Ge, T. M. Kamenekca, D. J. Kojetin,
Elife 2018, 7, e43320(1–34). https://doi.org/10.7554/eLife.43320.
[33] (a)I. J. Bruno, J. C. Cole, P. R. Edgington, M. K. Kessler, C. F.
Macrae, P. McCabe, J. Pearson, R. Taylor, Acta Cryst. 2002,
B58, 389. (b) L. J. Farrugia, J. Appl. Cryst. 2012, 45, 849.
[34] J. J. McKinnon, M. A. Spackman, A. S. Mitchell, Acta-
Crystallogr 2004, B60, 627.
[35] S. F. Boys, F. Bernardi, Mol. Phys. 1970, 19, 553.
[36] M. J. Turner, S. Grabowsky, D. Jayatilaka, M. A. Spackman,
J. Phys. Chem. Lett. 2014, 5, 4249.
[9] K. Katagiri, T. Tohaya, H. Masu, M. Tominaga, I. Azumaya,
J. Org. Chem. 2009, 74, 2804.
[37] O. Trott, A. J. Olson, J. Comput. Chem. 2010, 31, 455. https://
doi.org/10.1002/jcc.21334.
[10] B. W. Gung, X. W. Xue, H. J. Reich, J. Org. Chem. 2005, 70(9),
3641.
[38] E. F. Pettersen, T. D. Goddard, C. C. Huang, G. S. Couch,
D. M. Greenblatt, E. C. Meng, T. E. Ferrin, J. Comput. Chem.
2004, 25, 1605.
[39] W. L. DeLano, The PyMOL Molecular Graphics System, Delano
Scientific, San Carlos, CA 2002.
[11] A. K. Tewari, V. P. Singh, C. Puerta, P. Valerga, Acta Cryst.
2007, E63, 1930.
[12] O. Baudoin, F. Gonnet, M. P. Teulade-Fichou, J. P. Vigneron,
J. C. Tabet, J. M. Lehn, Chem. A-Eur. 1999, J5, 2762.
[13] T. Benzing, T. Tjivikua, J. Wolfe, J. Rebek, Science. 1988,
242, 266.
[14] M. Sirish, H. J. Schneider, J. Am. Chem. Soc. 2000, 122, 5881.
[15] S. R. Waldvogel, R. FrThlich, C. A. Schalley, Angew. Chem.
2000, 112, 2580.
[16] J. N. Wilson, E. T. Kool, Org. Biomol. Chem. 2006, 4, 4265.
[17] A. T. Kruger, L. Haige, A. H. F. Lee, E. T. Kool, Acc. Chem.
Res. 2007, 40, 141.
[18] P. G. A. Janssen, S. Jabbari-Farouji, M. Surin, X. Vila, J.
Gielen, T. F. A. de Greef, M. R. J. Vos, P. Bomans, N. A. J. M.
Sommerdijk, P. C. M. Christianen, P. Leclère, R. Lazzaroni, P.
van der Schoot, E. W. Meijer, A. P. H. J. Schenning, J. Am.
Chem. 2009, 131, 1222.
[19] C. A. Hunter, Chem. Soc. Rev. 1994, 23, 101.
[20] S. Tsuzuki, Struct. Bond. (Berlin) 2005, 115, 149.
[21] F. N. Khan, S. M. Roopan, V. R. Hathwar, M. Akkurt, Acta
Cryst. 2010, E66, 1001.
[40] Accelrys Discovery Studio Visualizer v 3.5, Accelrys Software
Inc, San Diego, CA 2010. http://www.accelrys.com.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Singh VP, Dowarah J,
Marak BN, Tewari AK. Design, synthesis, in silico
analysis with PPAR-γ receptor and study of non-
covalent interactions in unsymmetrical
heterocyclic/phenyl fleximer. J Chin Chem Soc.
2020;1–9. https://doi.org/10.1002/jccs.202000215
[22] B. K. Rajbongshi, G. Ramanathan, J. Chem. Sci. 2009, 121, 973.
[23] V. P. Singh, Sci. Tech. J. 2016, 4, 113.