Structural chemistry and anti-inflammatory activity of flexible/restricted phenyl dimers

Article abstract of DOI:10.1007/s13738-020-01853-x

Three phenyl dimer compounds, namely 3,3′-Diformyldiphenoxyethane (C₁₆H₁₄O₄) (1), 1-(4-[2-(4-Acetyl-phenoxy)-ethoxy]-phenyl)-ethanone (C₁₇H₁₆N₂O₃) (2), 1-{4-[2-(4-Acetyl-phenoxymethyl)-benzyloxy]-phenyl}-ethanone (C₂₄H₂₂O₄) (3), were obtained and fully characterized, including their crystal structure determinations. The structural properties of two compounds 4, 4^′-(ethylenedioxy)dibenzaldehyde) (C₁₆H₁₄O₄) (Tewari et al. Acta Cryst. E63:o1930, 2007) [1] (4) and 4-(2-Phenoxy-ethoxy)-benzaldehyde (C₁₅H₁₄O₃) (Valgera et al. CCDC 710835, 2016) [2] (5) are discussed with the role of the substituent in crystal packing. In vivo, anti-inflammatory activities of all compounds were studied on Wistar strain albino rats. All the compounds exhibited anti-inflammatory activity except 5. Compounds 1, 2, 4 have shown moderate-to-intermediate effects on inhibitory properties. Compound (3) with restricted rotation in the compound-like SC-558 drug was shown to possess good inhibitory properties at 180?min. In silico analysis was performed and compared with experimental in vivo results.

Full text of DOI:10.1007/s13738-020-01853-x

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-020-01853-x
ORIGINAL PAPER
Structural chemistry and anti‑infammatory activity of fexible/
restricted phenyl dimers
Ved Prakash Singh1 · Jayanta Dowarah1 · Ashish Kumar Tewari2 · David K. Geiger3
Received: 21 August 2019 / Accepted: 2 January 2020
© Iranian Chemical Society 2020
Abstract
Three phenyl dimer compounds, namely 3,3′-Diformyldiphenoxyethane (C16H14O4) (1), 1-(4-[2-(4-Acetyl-phenoxy)-ethoxy]-
phenyl)-ethanone (C17H16N2O3) (2), 1-{4-[2-(4-Acetyl-phenoxymethyl)-benzyloxy]-phenyl}-ethanone (C24H22O4) (3), were
obtained and fully characterized, including their crystal structure determinations. The structural properties of two compounds
′
4, 4 -(ethylenedioxy)dibenzaldehyde) (C16H14O4) (Marriott et al. J Med Chem 42:3210, 1999) [1] (4) and 4-(2-Phenoxy-
ethoxy)-benzaldehyde (C15H14O3) (Hunter, Chem Soc Rev 23:101, 1994) [2] (5) are discussed with the role of the substituent
in crystal packing. In vivo, anti-infammatory activities of all compounds were studied on Wistar strain albino rats. All the
compounds exhibited anti-infammatory activity except 5. Compounds 1, 2, 4 have shown moderate-to-intermediate efects
on inhibitory properties. Compound (3) with restricted rotation in the compound-like SC-558 drug was shown to possess
good inhibitory properties at 180 min. In silico analysis was performed and compared with experimental in vivo results.
Keywords Weak interactions · Anti-infammatory activity · Docking · Interaction energy
Introduction
and selectivity, compounds should have key pharmacoph-
ore [3]. Several kinds of forces play an essential role in the
binding of a particular drug to particular receptors. Aromatic
interactions non-covalent interactions play a subtle role in
drug–receptor binding mechanisms. Since the majority of
biologically active compounds consists of aromatic and het-
ero-aromatic units, which provide an opportunity for weak
interactions such as C–H···π, and π–π types of non-conven-
tional H-bonds [4, 5]. Aromatic interactions are neither too
strong nor too weak by nature, but these are enough to retain
the stable drug–receptor complex [6–8]. Therefore, these
interactions are signifcant in drug design and development
of the drug.
Non-covalent interactions are signifcant in drug design and
the biological activity of compounds. It is also essential in
the strategic design of bioactive solid materials with desir-
able architectures. Structural biology and X-ray crystallogra-
phy had provided benefcial information in the development
of new drugs. It already established that for good activity
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-020-01853-x) contains
supplementary material, which is available to authorized users.
A literature survey revealed [9–11] that many 1,2 and
1,3-diaryl heterocycle feximers have found their clinical
application as NSAIDs, and are good COX-2 inhibitors [12,
13] Sometimes fve-membered rings link these and are situ-
ated at 1, 2 positions of fve-membered rings like SC-558.
According to the Gold hypothesis, two rings were inserted
in two pockets of COX-2 enzyme and interact with Tyr-355,
Arg-120, and Phe-518 as well as with one hydrogen bond
that involved the –SO2CH3 group with Tyr-115, Arg-513
[14]. According to the structure–activity relationship and
topology of the COX-2 active site, the inhibitors of the
* Ved Prakash Singh
vpsingh@mzu.edu.in
* Ashish Kumar Tewari
tashish2007@gmail.com
David K. Geiger
geiger@geneseo.edu
1
Department of Chemistry, School of Physical Sciences,
Mizoram University, Aizawl 796004, India
2
Department of Chemistry, Institute of Science, Banaras
Hindu University, Varanasi 221005, India
3
Department of Chemistry, College of Genesco, State
University of New York, Genesco, NY 4454, USA
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
enzyme should consist of at least an H bond acceptor, two
aromatic rings, and two hydrophobic groups [14].
the reaction mixture extracted with CHCl3. The CHCl3 layer
was dried with anhydrous Na2SO4 and fltered. The prod-
uct recovered from CHCl3, and the product was purifed via
crystallization. It was characterized as compound 2; it was
recrystallized via difusion of hexane into an ethyl acetate
at room temperature.
As per in silico analysis, the fexibility of the compound
can increase the compatibility of the compound to ft in the
pocket of the COX-2 enzyme [13]. Motivated by the fnd-
ings mentioned above, we have synthesized a series of diaryl
systems attached to C-1 and C-2 of the ethane nucleus and
substituted ethane system. These molecules are motivated
by the restricted rotation of SC-558 as well as fexible drugs
such as Rofecoxib and Porecoxib. In one of the compounds,
phenyl ring is introduced to reduce the fexibility of the
compound. In the rest of the compounds, fexibility is high
to make it more compatible to ft in the pocket of COX-2.
In this series of the compound, CHO and COCH3 groups
are introduced in the ring to make hydrogen bonding with
active site at COX-2 like SC-558. These groups are intro-
duced as a hydrogen bond acceptor. The position of CHO
groups varied from meta- to para-positions to observe the
most efective position in molecular binding with COX-2
active site. In one of the designed molecules, only one ring
is substituted with the –CHO group motivated by Rofecoxib
and Porecoxib [14].
O
O
R2
R1
OH
R3
K2CO3
DMF
R3
+
Br
Br
R1
R1
R2
R2
Compound 1
Compound 2
Compound 3
Compound 4
R1= H, R2= CHO, R3= -CH2CH2-
R1= COCH3, R2= H, R3= -CH2CH2-
R1= COCH3, R2= H, R3= o-CH2C6H5CH2-
R1= CHO, R2= H, R3= -CH2CH2-
General Scheme for compound 1-4
(1); Yield: 1.81 g, 49%. Mp.113-15°C.
1H NMR 300 MHz, 25 °C, Si(CH3)4, (CDCl3) (δ):
4.24 (4H, s, 2OCH2); 7.23 (2H, s, Ar-H), 7.45–7.49 (6H, d,
Ar-H, J=11.4 Hz) 9.98 (2H, s, –CHO). 13C NMR (75 MHz,
CDCl3): (δ): 64.67, 114.69, 114.99, 117.96, 130.22, 163.36,
163.62, 190.78. MS (m/z): 271 (M+ 1). Element Analy-
sis: (i). Calculated: C = 71.11%; H = 5.17%. (ii). Found:
C=71.15%; H=5.11%.
These compounds have diferent functional groups to
provide polarized structure to make C–H···π, π–π, and other
weak interactions as per requirement for drug action. These
analogs have fexibility as well as multiple sites to develop
proximity for weak interactions with receptor sites with good
potential. We have selected these compounds for screening
as anti-infammatory agents based on rationale celecoxib,
the 1,2-diaryl compound, which is COX-2 selective drug.
In the present series of the compound, we explore the struc-
tural property of fve compounds with diferent degrees of
freedom, which may be useful to study for binding of the
molecules with the target receptor in various conditions. The
results of the structural exploration of the diferent weak
interactions, including the Hirshfeld surface analysis, are
reported with in silico analysis and in vivo activity analysis
of all the feximers.
Synthesis of 1‑{4‑[2‑(4‑Acetyl‑phenoxy)‑ethoxy]‑phenyl}
‑ethanone (2)
In a 100-ml round-bottom fask, p-hydroxy acetophenone
(2 g, 0.015 mol) and potassium carbonate (2.3 g, 0.015 mol)
were taken in DMF and stirred for 20 min. After 20 min,
1,2-dibromoethane was added and stirred it for 12 h. Com-
pletion of the reaction was checked via TLC (20% EtOAc &
Hexane) in which one spot visualized. After completion of
the reaction, DMF removed under reduced pressure through
the rotary evaporator, and the reaction mixture was extracted
with CHCl3/ H2O (200/200 × 3 ml). The CHCl3 layer was
dried with anhydrous Na2SO4 and fltered. Chloroform was
removed, and the product was purifed via crystallization. A
single crystal was obtained via slow evaporation of a solu-
tion of the product in ethyl acetate at room temperature.
(2); Yield: 1.41 g, 67%.Mp.132-34 °C.
Experimental
Synthesis and crystallization
Synthesis of 3, 3′‑Diformyldiphenoxyethane (1)
1H NMR 300 MHz, 25 °C, Si(CH3)4, (CDCl3) (δ):
2.57 (6H, s, 2CH3); 4.42 (4H, s, OCH2); 6.87–6.90 (4H,
d, Ar-H, J =8.1 Hz); 7.92–7.95 (4H, d, Ar-H, J =8.1 Hz).
13C NMR (75 MHz, CDCl3): (δ): 26.20, 68.49, 111.48,
123.56, 130.69, 133.31, 162.36, 196.62. MS (m/z): 299.4
(M + 1).Element Analysis: (i). Calculated: C = 70.07%;
H = 6.57. (ii). Found: C = 69.99%; H = 6.59%.
In a 100-ml round-bottom fask, m-hydroxybenzaldehyde
(3 g, 0.025 mol) and potassium carbonate (3.4 g, 0.0025 mol)
were taken in DMF and stirred for 20 min. After 20 min, 1,
2-dibromoethane was added and stirred. The completion of
reaction was checked via TLC (20% EtOAc & Hexane), in
which one spot visualized. After completion of the reac-
tion, DMF removed under through rotary evaporator and
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Journal of the Iranian Chemical Society
Synthesis of 1‑{4‑[2‑(4‑Acetyl‑phenoxymethyl)‑benzyloxy]‑
phenyl}‑ethanone (3)
difractometer. Crystallographic details of compounds 1, 2,
and 3 are summarized in Table 1.
In a 100-ml round-bottom fask, p-hydroxy acetophenone
(2 g, 0.015 mol) and potassium carbonate were taken and
stirred for 20 min. After 20 min, 1,2-dibromoxylene was
added and stirred. The completion of reaction was checked
via TLC (20% EtOAc & Hexane), in which one spot visual-
ized. After completion of the reaction, DMF removed under
reduced pressure, and the reaction mixture was extracted
with CHCl3/H2O. The CHCl3 layer was dried and fltered.
The product was purifed via crystallization. A single crystal
was obtained via slow evaporation in ethyl acetate at room
temperature.
Hirshfeld Surface, fnger‑plot and weak interaction
energy analysis
The Hirshfeld surface analysis was performed by using
CrystalExplorer 17 [20] to explore the space occupied by a
molecule in the crystalline solid-state to know the electron
density into the molecule. The fngerprint plot of the mol-
ecules was used to explore the packing modes and non-cova-
lent interactions in the molecule. Interaction energies for
(3) were calculated employing the CE-B3LYP/6-31G(d,p)
functional/basis set combination and are corrected for basis
set superposition energy (BSSE) using the counterpoise
(CP) method [21]. The interaction energy is broken down as
(3); Yield: 1.80 g, 80%.Mp.141-43 °C.
1H NMR 300 MHz, 25 °C, Si(CH3)4, (CDCl3) (δ): (δ):
2.55 (6H, s, 2CH3); 5.23 (4H, s, 2OCH2); 6.97–7.00 (4H,
d, Ar-H, J =8.7 Hz), 7.39–7.42 (2H, m, Ar-H); 7.50–7.53
(2H, m, Ar-H); 7.90–7.93 (4H, d, Ar-H, J = 9.0 Hz). 13C
NMR (75 MHz, CDCl3): (δ): 26.27, 68.14, 114.38,
128.74, 129.16, 130.56, 130.69, 134.39, 162.28, 196.56.
MS (m/z): 374 (M + 1).Element Analysis: (i). Calcu-
lated: C = 77.01%; H = 5.88%. (ii). Found: C = 77.10%;
H =5.89%.
Etot = keleEe�le + kpolEp�ol + kdisEd�is + krepEr�ep
,
where the k values are scale factors, Eeꢀle represents the elec-
trostatic component, Epꢀol the polarization energy, Edꢀis the
dispersion energy, and Erꢀep the exchange–repulsion energy
[22, 23]. The C–H bond lengths converted to normalized
values based on neutron difraction results [24]. A prelimi-
nary analysis of important intermolecular interactions was
performed using PLATON [25].
Synthesis of 4, 4′‑Diformyldiphenoxyethane (4) [1]
.
Synthesis of 4‑(2‑Phenoxy‑ethoxy)‑benzaldehyde (5) [2]
OH
+
O
O
K2CO3
DMF
K2CO3
Br
DMF
OH
Br
O
Br
OHC
OHC
Scheme for compound 5
Crystal structure determination
and Hirshfeld surface analysis
COX‑2 interaction in silico analysis
and evaluation of the anti‑infammatory
efects of compounds (1)–(5)
X‑ray crystallography
In silico analysis
Single-crystal X-ray data for compounds (1) and (2) and 3
were collected with an Oxford Difraction Xcalibur CCD
The ability of compounds to interact with the COX-2 was
assessed by in silico studies. Here for docking, PDB ID 6cox
was used to dock each compound to study the binding and
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Journal of the Iranian Chemical Society
Table 1 Experimental detail
Compound crystal data
1 (CCDC 1906450)
2 (CCDC 1907007)
3(CCDC 1906456)
Chemical formula
Mr
Crystal color
Temperature
Wavelength
Crystal system, space group
a, b, c (Å)
C16H14O4
270.27
Yellowish
293(2) K
0.71073 Å
Monoclinic, P21/c
5.6289(3), 16.0475(8), 7.3064(3)
C18H18O4
298.32
Colorless
296(2) K
0.71073 Å
Monoclinic, P21/c
C24 H22 O4
374.41
Yellowish
293(2) K
0.71073 Å
Monoclinic, C2/c
9.1687(7), 5.5014(3), 15.1170(10) 13.0860(11), 10.4392(10),
14.3196(11)
α, β, γ
90.00°, 99.190(4), 90.00°
651.51(6) Å3
MoKα
90.00°, 100.586(7)°, 90.00°
749.53 (9) Å3
MoKα
90.00°, 92.465(7) 90.00°
1954.4(3)
MoKα
Cell volume, V
Radiation type
µ (mm−1
)
0.099
0.09
0.086
Data collection difractometer
Absorption correction
Tmin, Tmax
Bruker APEX-II CCD
Multi-Scan
0.95180, 1.00000
Bruker APEX-II CCD
Multi-Scan
0.981, 0.988
Bruker APEX-II CCD
Multi-Scan
0.940–1.000
No. of measured, independent and 2693, 1447, 1240
5176, 1759, 1261
4087, 2206, 1541
observed [I>2σ(I)] refections
No. of refections
No. of parameters
No. of restraints
H-atom treatment
F(000)
1447
92
0
1759
101
0
2206
128
0
H-atom parameters constrained
284
0.26×0.24×0.21 mm
H-atom parameters constrained
316
0.19×0.16×0.12 mm
H-atom parameters constrained
792.0
0.28×0.25×0.23 mm
Crystal size
Z
2
2
4
R factor (%)
Theta range for data collection
Limiting indices
3.33
2.538–28.801
3.78
2.26–28.78
4.14
2.490–28.696
−7≤h≤7, −20≤k≤19, −9≤l≤4 −14≤h≤9, −11≤k≤10,
−17≤h≤12, −13≤k≤13,
−20≤l≤13
−13≤l≤18
Melting point
352 K
0.010
0.678
0.033, 0.097, 1.09
408 K
0.015
0.678
0.038, 0.104, 1.07
417 K
0.14
0.677
0.041, 0.119, 1.05
Rint
(sin θ/λ)max (Å−1
)
Final R indices [F2 >2σ (F2)],
wR(F2), S
R indices (all data)
R1 =0.0830, wR2 =0.1650
0.29, −0.16
R1 =0.0548, wR2 =0.1044
0.15, −0.18
R1 =0.0623, wR2 =0.1192
0.18, −0.16
∆ρmax, ∆ρmin (e Å−3
)
Computer programs: Bruker APEX2 [15], Bruker SAINT [16], SHELXT 2014 [17], SHELXL2014 [18], Bruker SHELXTL, and publCIF [19]
active site of drugs with COX-2 [26]. All the compounds
were docked at the active site using Autodock-1.5.6, and
PyMOL is used for visualization of the docked ligand–pro-
tein complex.
45–55% relative humidity with the light–dark cycle in the
departmental animal room. Carrageenin-induced paw edema
[27] was used throughout the experiment.
Evaluation of the anti‑infammatory efects of com‑
pounds
Results and discussion
Compounds (1) and (2) crystallized in the monoclinic space
group P21/c with Z=2, and compound 4 crystallized in the
monoclinic space group Cc with Z=4, whereas compound
(5) crystallized in the monoclinic space group P21/n with
Z=4. Compound (3) (density 1.273) is also having a similar
kind of chemical environment with restricted rotation and
All experiments have been conducted on adult Wistar strain
albino rats, weighing between 150 and 200 g. The animals
were taken from the Central Animal House of the IMS,
B.H.U. They kept under identical housing conditions at an
ambient temperature of 25 °C 2 °C in colony cages and
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Journal of the Iranian Chemical Society
Fig. 1 Part of the crystal
structure of compound (1), a
(i) CH…π interactions, loan
pair…π interactions (ii) Crystal
packing view along a* and
CH…π interactions b showing
the formation of a hydrogen-
bonded sheet lying parallel
to (101) symmetry codes: (i)
−1+x,y,z, (ii) 1−x, −1/2+y,
1.5−z
crystallizes in the monoclinic, C2/c space group with Z=4.
Compounds (1), (2) and (4) are symmetrical feximers, but
substituted O-phenyl ring in compound s(1) and (2) are hav-
ing staggered conformation at substituted ethane (linker of
dimer), whereas compound (4) crystallized in gauche con-
formation due to intramolecular hydrogen bonding. Com-
pound (5) is an unsymmetrical phenyl dimer, but it is also
crystallized exactly like compound (4) in gauche conforma-
tion around the dimethylene linker. Compound (3) crystal-
lized like V shape, and both the phenyl rings were orientated
in the opposite face. Overall, the structure of compounds (1)
and (2) (both rings are in the same plane) is quite similar
in the crystalline phase. Compounds (4) and (5) both are
having similarity in molecular structure in solid-state that
is irrespective of symmetrical and unsymmetrical nature of
the dimer.
The hydrogen-bonding network for (1) and crystal pack-
ing is shown in Fig. 1. In compound (1), both formyl group
oxygens of the molecule are involved in hydrogen bonding,
whereas linker oxygens are not involved in any weak inter-
actions. In addition to C–H…O interactions in the extended
structure of compound (1) are having intermolecular
Table 2 Hydrogen-bond
D-H…A
D-H
H…A
D….A
D-H..A (°)
geometry (Å) for (1)
C2–H2…O2(i)
0.929
0.930
0.970
1.210
0.970
0.929
0.929
2.538
2.552
2.681
3.387
3.020
3.566
3.767
3.436
3.280
3.631
3.498
3.931
3.489
4.092
162.38
135.53
166.54
84.66
156.98
87.18
C3–H3…O2(ii)
C7–H7A…O2(iii)
C8O2…Cg (C3 C2 C1 C6 C5 C4)(iii)
C7–H7B…. Cg (C3 C2 C1 C6 C5 C4)(iv)
C8–H8…. Cg (C3 C2 C1 C6 C5 C4)(v)
C8–H8…. Cg (C3 C2 C1 C6 C5 C4)
63.30
Cg is the centroid of the ring
Symmetry codes: (i) −x, −1/2+y, ½−z (ii) −x, −1/2+y, 1/2−z (iii) 1−x, −1/2+y, 1/2−z (iv) 1−x,
−1/2+y, 1.5−z (v) −1+x,y,z
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Journal of the Iranian Chemical Society
Fig. 2 Hirshfeld and fngerprint
plots of compound (1)
Table 3 Interaction energies (kJ mol−1) calculated for (1)
close contacts in the Hirshfeld surfaces. These interactions
are displayed in the fngerprint 2D plot between di (di is
closest internal distance) and de (closest external distance).
Table 3 shows the results of the interaction energy calcu-
lations for (1). The strongest interaction energy involves a
pair of C–H…π interactions between molecules related by a
center of symmetry (Fig. 3). Another interaction of interest
is these weak H-bonds (C2–H2…O2 and C3–H3…O2) that
result in an R22(18) ring and ultimately to the sheets, as shown
in Fig. 1. The third interaction explored is an intriguing π…π
interaction involving the carbonyl group and the phenyl ring
system. Of particular interest is the large electrostatic com-
ponent calculated for this interaction, presumably a result
Interaction(s)
E′ele
E′pol
E′dis
E′rep
Etot
2 C7–H7B…Cg(1)
−11.8
−15.7
−1.8
−4.5
−46.6
−19.3
27.9
21.8
−37.2
−23.3
C2–H2…O2/
C3-H3…O2 [R2
2(18)]
C8–O8…Cg(1)
−7.1
−1.2
1.5
−2.0
−0.4
−0.6
−27.5
−18.5
−7.3
19.2
9.0
4.1
−21.1
−12.2
−2.7
Scale factors used to determine Etot:kele =1.057, kpol =0.740,
kdis =0.871, and krep =0.618 [16]. See “Hirshfeld surface, fnger-plot
and weak interaction energy analysis” for calculation details
loan-pair-π interactions between –CH=O and pi-electrons of
the ring. In this compound, C–H…π interactions are exhib-
ited in the crystal packing between C7H7b and pi-electrons
of the ring of the adjacent molecule (Table 2). The aromatic
ring is behaving as donor as well as an acceptor in C–H…π
and loan pair interactions, respectively [22].
Hirshfeld and fngerprint plots [16] for (1) are shown
in Fig. 2. Hirshfeld and fngerprint plots generated, and
all interactions are visible in the fngerprint plots. In the
Hirshfeld surface, close contacts are visible in a red color.
The fngerprint analysis of compound (1) shows that H–H
interactions are responsible for around 39.5%, C–H…O for
27.6%, C–H for 23.7%, C–O for 4.6, and C–C for 4% of the
Fig. 4 Partial packing diagrams of compound (2) view along the
b-axis. Symmetry code: 1+x, y , −1+z (H8A..O1), 1−x, 1/2−y,
−1/2−z
Fig. 3 a C(2)–H(2)…Cg(1) [2645.01] 2.99 136 3.7231(14) [2645]=1−X, −1/2+Y, 1/2−Z b C(8)–H(8B)…Cg(1) [2555.01] 2.91 150
3.7721(15) [2555]=−X, 1/2+Y, 1/2−Z
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Journal of the Iranian Chemical Society
Fig. 5 Partial packing diagrams
of compound (2) symmetry
code: 1+x, y, −1+z
Table 4 Hydrogen-bond geometry (Å) for (2)
C8 C9) π-electrons of the ring of the adjacent molecule
(Table 4). Compound 2 is having C–H…π aromatic interac-
tions as major non-covalent interactions, which shows the
involvement of electrostatic forces rather than dispersion
forces in aromatic interactions [23].
D–H…A
D–H
H…A D…A D–H…A (°)
C8–H8a…O1(i)
0.960 2.715 3.612 155.95
0.970 2.674 3.514 145.16
0.960 2.679 3.595 159.59
0.930 2.994 3.723 136.37
0.930 3.798 4.611 148.87
C9–H9a…O1(ii)
C8–H8c…O1(iii)
Hirshfeld and fngerprint plots [16] for (2) are shown in
Fig. 6. The fngerprint analysis of compound (2) shows that
H–H interactions are responsible for around 41.7%, C–H–O
for 25.6%, C–H for 30.8%, O–O for 1.2 and O–C for 0.3% of
the close contacts in the Hirshfeld surfaces. All interactions
are visible in the fngerprint 2D plot.
C2–H2… Cg (C1–C6)(iv)
C5–H5… Cg (C1–C6)(v)
C9–H9b… Cg (C1–C6)(vi) 0.970 3.436 4.296 148.91
Cg is the centroid of the ring. Symmetry codes: (i) 1−x, −y, z (ii)
1−x, −y, z (iii) x, −1/2−y, −1/2+z (iv) 1−x, −y, −z (v) 1−x, −y,
−z (vi) 1−x, −y, 1−z
The results obtained for the interaction energy calcula-
tions for (2) are shown in Table 5, in which the primary
of the charge distribution in the aldehyde functional group
and the polarization of the phenyl ring by its substituents.
Compound (2) is having COCH3 at the p position of the
ring, and again like compound (1), only carbonyl oxygen is
taking part in weak interactions. In an extensive hydrogen-
bonding network, terminal carbonyl oxygen is involved in
three weak interactions, and two were forming an eight-
membered R22 (8) and R22 (8) ring, in which C–H–O interac-
tions are involved. The partial packing diagram of the com-
pound is shown in Figs. 4 and 5.
Table 5 Interaction energies (kJ mol−1) calculated for (2)
Interaction(s)
E′ele
E′pol E′dis
E′rep Etot
C2–H2…Cg(1)
−12.9 −4.2 −44.2 25.8 −39.3
2 C8–H8C…O1 [R2 2(34)] −13.2 −3.6 −35.0 20.2 −34.5
C8–H8B…Cg(1)
−1.8 −1.2 −23.6 11.5 −16.2
2 C8–H8A…O1 [R2 2(8)]
−8.3 −2.4
−1.0 −0.1
−7.3
−4.5
7.7 −12.2
2.4 −3.6
Scale factors used to determine Etot:kele =1.057, kpol =0.740,
kdis =0.871, and krep =0.618 [16]. See “Hirshfeld surface, fnger-plot
and weak interaction energy analysis” section for calculation details
In this compound, C–H…π interactions are exhibited
in the crystal packing between C5H5–Cg (C1 C2 C4 C5
Fig. 6 Hirshfeld and fngerprint plots of compound (2)
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Journal of the Iranian Chemical Society
Fig. 7 a Diagram showing the architecture of packing diagrams b ring motif R22 (8) and R22 (18) of compound (3)
Table 6 Hydrogen-bond geometry (Å) for (3)
the carbonyl group results in an R22(34) motif and yields sig-
nifcant interaction energy between molecules related by a
translation along the b-axis. Another set of C–H…O interac-
tions involving the carbonyl group results in an R22(8) motif
between inversion center-related molecules.
D-H…A
D–H H…A D….A D–H…A (°)
C9–H9a…O1(i)
0.970 2.696 3.620 159.43
0.970 2.593 3.479 151.97
0.960 2.631 3.503 151.33
C9–H9b…O1(ii)
C1–H1A…O1(iii)
Compound (3) is having restrictions in the rotation due
to the linked phenyl ring. The molecular structure is sym-
metrical in the structure, like an open book. Terminal oxy-
gen of carbonyl is involved in an extended network struc-
ture to form R22 (8) and R22 (18) in ring, as shown in Fig. 7b.
This oxygen is trifurcated and involved in three hydrogen
bonding.
C8H8…Cg (C3–C8)(iv)
C5H5… Cg (C10–C12)(v)
C4H4… Cg (C10–C12)(vi)
C12H12… Cg (C3–C8)
Cg (C3–C8)…. Cg (C3–C8)
0.930 3.682 3.605
77.99
0.930 3.513 3.978 113.59
0.930 3.491 3.967 114.44
0.930 3.288 4.173 159.65
–
3.918
–
–
Cg is the centroid of the ring
In addition to C–H–O hydrogen bonding, the extended
structure of (3) in Fig. 7a exhibits C–H–π interactions
(Table 6) in which C12–H12-π interaction is the result of the
tilted structure of the aromatic ring concerning each other.
C4–H4-π and C5–H5-π interactions are exhibited for the
development of tilted structure in the crystal. Linked oxygen
is involved in an extended network structure to form R22 (8)
and R22 (18) ring (Fig. 7b). Finally, the superstructure exhib-
its a weak π–π interaction between adjacent molecules, with
a Cg (C3–C8)…Cg (C3–C8) distance of 3.918 Å (Table 5)
Symmetry codes: (i)1/2−x, −1/2+y, 1.5−z (ii) 1/2−x, −1/2−y,
1−z (iii) 1/2−x, −1.5−y, 1−z (iv) 1/2+x, 1/2−y, 1/2+z (v)
1/2−x, 1.5−y, 1−z (vi) 1/2−x, 1.5−y, 1−z
interactions are indicated for the strongest. There are no
signifcant π…π interactions [the closest Cg…Cg distance
is 4.9415 (8) Å]. Two C–H…pi interactions are responsible
for the strongest and the third strongest interaction between
molecular pairs results. A pair of weak H-bonds involving
Fig. 8 Hirshfeld and fngerprint
plots of compound (3)
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Journal of the Iranian Chemical Society
Table 7 Interaction energies (kJ mol−1) calculated for (3)
contacts in the Hirshfeld surfaces. All interactions are visible
in the fngerprint 2D plot.
Interaction(s)
E′ele
E′pol E′
E′rep Etot
The results obtained for the interaction energy calcula-
tions for (3) are shown in Table 7, in which the primary
interactions are indicated for the strongest. A π…π interac-
tion between phenyl rings containing C3 through C8 (related
by ½ − x, ½ − y, 1 − z) (Fig. 9a) leads to the strongest
calculated interaction energy. The molecular pair also has
two C9-H9A…O1 hydrogen bonds (Fig. 10a). The second
strongest interaction involves molecules having a C9-H9B…
O1 and two C–H…π interactions in which the π system is
from the six-membered ring comprised of C10 through C12
and the donors are C4–H4 and C5–H5 (Fig. 9b).
Cg(1)…Cg(1)/2 C9–H9…O1 −21.6 −4.7 −57.1 34.2 −54.9
C9–H9B…O1/C4–H4…
Cg(2)/C5–H5…Cg(2)
−10.8 −4.0 −27.7 15.7 −28.8
−1.1 −2.0 −36.8 21.7 −21.3
−2.0 −1.4 −30.8 16.8 −19.6
−3.0 −1.0 −21.6 7.3 −18.3
−8.4 −2.8 −8.7 10.5 −12.1
2 C12–H12…Cg(1)
2 C1–H1A…O1 [R22(8)]
Scale factors used to determine Etot:kele =1.057, kpol =0.740,
kdis =0.871, and krep =0.618 [16]. See “Hirshfeld surface, fnger-plot
and weak interaction energy analysis” section for calculation details
The fnal interaction explored is that of two molecules
participating in two C1–H1A…O1 hydrogen bonds result-
ing in an R22(18) motif. The last interaction, the one result-
ing in the ring formation, is the only one in which the
Hirshfeld and fngerprint plots [16] for (3) are shown in
Fig. 8. The fngerprint analysis of compound (3) shows that
H–H interactions are responsible for around 47%, C–H–O
for 21.4%, C–H for 27.8%, and C–C for 3.9 of the close
Fig. 9 a π···π interaction with symmetry code 1/2−x, 1/2−y, 1−z. The interaction also includes two weak C9–H9A···O1i hydrogen bonds b two
weak C–H···π interactions with symmetry code x, −1+y, z)
Fig. 10 a Partial packing
diagrams along the c-axis b
extended network of compound
4
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Journal of the Iranian Chemical Society
Table 8 Hydrogen-bond geometry (Å) for (4)
exhibited for the development of tilted geometry of aromatic
ring with respect to each other in the crystal packing. This
compound exhibits a weak π–π interaction between adja-
cent molecules, with Cg (C3–C8)….Cg (C3–C8) face to face
arene–arene interactions and distance of 3.918 Å (Table 7).
Hirshfeld and fngerprint plots [16] for (4) are shown in
Fig. 11. The fngerprint analysis of compound (4) shows that
H–H interactions are responsible for around 38.8%, C–H–O
for 28.1%, C–H for 21.7%, C–O for 3.9%, O–O for 1.3% and
C–C for 6.1% of the close contacts in the Hirshfeld surfaces.
All interactions are visible in the fngerprint 2D plot.
The results obtained for the interaction energy calcula-
tions for (4) are shown in Table 9, in which the primary
intermolecular interactions are indicated for the strongest
interaction energies. The strongest interaction energy results
from a pair of molecules involved in two C–H…π interac-
tions. A close second involves two molecules joined by two
C–H…O hydrogen bonds resulting in an R22(26) ring and
also contains a π…π interaction (Fig. 12a). The fnal molec-
ular pair explored is joined by single C–H…O hydrogen
(Fig. 12b). In the two strongest interactions explored, the
dispersion energy component is much larger than the elec-
trostatic energy component, consistent with the involvement
of the π electrons.
D–H…A
D–H H…A D….A D–H…A (°)
C7–H7…O4(i)
0.950 2.658 3.317 126.96
0.950 2.602 3.189 120.29
0.950 2.656 3.079 107.57
0.989 2.709 3.438 130.75
0.989 2.708 3.484 135.63
0.990 2.527 3.387 145.15
0.949 2.611 3.414 142.53
0.950 2.608 3.425 144.35
0.949 2.795 3.664 152.62
0.950 2.866 3.693 146.11
3.653
C14–H14…O2(ii)
C16–H16…O2(iii)
C9–H9b…O3(iv)
C8–H8b…O1(v)
C8–H8a…O4(vi)
C11–H11…O4(vii)
C2–H2…O2(viii)
C3–H3… Cg (C10–C15)(ix)
C6–H6… Cg (C1–C6)(x)
Cg (C1–C6)… Cg (C10–
C15)(xi)
Cg is the centroid of the ring
Symmetry codes: (i)−1+x, y, −2+z (ii)−1+x, y, −1+z
(iii))−1+x, 1−y, −1.5+z(iv) −x, 1−y, −1/2+z (v) x, 1−y,
−1/2+z (vi) −1/2+x, ½+y, −1+z (vii) −1/2+x, 1.5−y, −1/2+z
(viii) −1/2+x, 1.5−y, −1/2+z (ix) x, 1−y, −1/2+z (x) x, 1−y,
−1/2+z (xi) −1/2+x, 1.5−y, −1/2+z
electrostatic energy component is comparable to the disper-
sive component.
Compound (4) is an asymmetrical phenyl dimer, but the
orientation of the phenyl rings is not planer. The molecule
is having two terminals and two linked oxygens, and all are
involved in hydrogen bonding in the extended structure of
the molecule, unlikely (1) and (2) molecule. Linked oxy-
gen of compound is involved in extended network structure
to form R22 (8), R33 (20), R33 (21), R34 (16) and R22 (26) ring
(Fig. 10b). Terminal oxygen is trifurcated and involved in
the extended ring through hydrogen bonding (Table 8).
In addition to C-H–O hydrogen bonding, the extended
structure of (4) exhibits C–H–π as well as π–π interactions
(Table 8), in which the tilted structure of the aromatic ring
with respect to each other is the result of C3–H3-π interac-
tion (Fig. 10a). C4–H4-π and C5–H5-π interactions are also
Compound (5) is an unsymmetrical phenyl dimer, but ori-
entations of the phenyl rings are very similar to compound
(4). The molecule has one terminal and two linked oxygens,
and all are involved in hydrogen bonding in the extended
structure of the molecule, unlikely (1) and (2) molecule. Ter-
minal oxygen is involved in an extended network structure to
form the R22 (10) ring. Both linked oxygens are taking part in
hydrogen bonding (Table 10). The partial packing diagram
of the compound is shown in Fig. 13.
Hirshfeld and fngerprint plots [16] for (4) are shown in
Fig. 14. The fngerprint analysis of compound (4) shows that
H–H interactions are responsible for around 41.8%, C–H–O
for 21.9%, C–H for 32.9%, C–O for 2.9%, O–O for 0.1% and
Fig. 11 Hirshfeld and fngerprint plots of compound (4)
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Journal of the Iranian Chemical Society
Table 9 Interaction energies (kJ mol−1) calculated for (4)
at para-position, and the rest of the molecules are having
–CHO group in the ring. All compounds are having an elec-
tron-withdrawing group to polarize the electronic distribu-
tion in the ring. However, all of them are not having π–π
intermolecular interaction in the opposite orientation. Some
other intermolecular forces such as C–H…π, C–H…O, loan
pair…π interactions re-orient the molecule and neutralize
the polarization efect of CHO, COCH3 group. One com-
mon factor present in both compounds 3 and 4 is that elec-
tron-withdrawing groups are present at the para-position to
the linker group. It means CHO, COCH3 at para-positions
develop a uniform polarization in the ring, which suited for
intermolecular π…π interactions.
Interaction(s)
E′ele
E′pol
E′
E′rep
Etot
C6–H6…Cg(1)/
C15–H15…Cg(2)/
C9–H9B…O3/
C8–H8B…O1
Cg(1)…Cg(2)/
C2–H2…O2/
C11–H11…O4
[R2 2(26)]
−7.9
−5.2
−57.2
35.6
−40.1
−12.3
−4.0
−52.8
37.2
−39.0
C8–H8A…O4
−12.9
−7.6
−6.6
−3.7
2.0
−3.3
−2.9
−2.2
−1.1
−1.4
−16.0
−9.1
−9.5
−12.9
−13.1
13.4
9.1
8.5
7.5
7.1
−21.7
−12.5
−11.7
−11.3
−6.0
Docking analysis was performed for synthesized com-
pounds at the COX-2 enzyme active site and compared with
standard drug SC-558. The total score obtained is shown
in Table 12. The docking score (which refects the binding
capacity of drug with enzyme active site) for compound 3
was found to be −9.95, and for the rest of the compounds
1, 2, 4, 5 it was found to be − 7.72, − 8.05, − 8.1, − 7.27
(Table 11). Compound 3 docking score is slightly less than
that of SC-558 (− 10.78) standard drug, suggesting that
3 (Fig. 15) can be further studied to develop a new anti-
infammatory drug.
Scale factors used to determine Etot: kele =1.057, kpol =0.740,
kdis =0.871, and krep =0.618 [16]. See “Hirshfeld surface, fnger-plot
and weak interaction energy analysis” section for calculation details
C–C for 0.3% of the close contacts in the Hirshfeld surfaces.
All interactions are visible in the fngerprint 2D plot.
An analysis of close contacts reveals no signifcant π…π
interactions. The results obtained for the interaction energy
calculations for (5) are shown in Table 11, in which the pri-
mary intermolecular interactions are indicated for the strong-
est interaction energies. These interactions are containing
two C–H…π interactions. A molecular pair involving a
C–H…π and C–H…O bond gave the next strongest interac-
tion. Other notable interactions explored involve C–H…O
interactions, one set which results in an R22(10) ring motif,
and a C–H…π interaction. The molecular pair in which the
C–H…O interactions lead to the ring motif is the only inter-
action in this set in which the electrostatic energy component
outweighs the dispersive component.
The results of the present study have shown that com-
pound 3 had shown to possess maximum anti-infammatory
Table 10 Hydrogen-bond geometry (Å) for (5)
D–H…A
D–H
H…A D…A D–H…A (°)
C3–H3…O1(i)
0.950 2.444 3.317 126.96
0.950 2.459 3.189 120.29
0.945 2.758 3.335 119.96
0.950 2.545 4.262 134.23
C13–H13…O3(ii)
C15–H15…O2(iv)
C2–H2….Cg (C9–C14)
Aromatic interactions are present in all the compounds,
mainly C–H…π interactions, but π…π interactions are pre-
sent only in compounds 3 and 4. Compounds 1, 2 and 5 are
very similar to compound 4, but non-covalent interactions
are quite diferent irrespective of their molecular bonding.
C–H…π interactions are supported by Hirshfeld surface
analysis. There are prominent wings in all compound’s
fngerprint plot indicating the presence of C–H…π inter-
actions. Compounds 2 and 4 are having –COCH3 group
C8–H8b… Cg (C1–C6)(v) 0.990 2.692 3.495 138.48
C7–H7a… Cg (C9–C14)
C7–H7b… Cg (C9–C14)
0.990 3.687 3.470
0.991 2.551 3.470 154.13
69.88
C10–H10… Cg (C9–C14) 0.950 3.669 4.554 156.09
Cg is the centroid of the ring
Symmetry codes: (i) −x, −1+y, z (ii) 2−x, 2−y, −z (iii) 1/2−x,
1/2+y, 1/2−z (iv) 1/2−x, 1/2+y, 1/2−z (v) 1−x, −y, −z (vi) x,
1+y, z (v) 1/2−x, 1/2+y, 1/2−z
Fig. 12 a Cg(1)…Cg(2)xii
(xii=½+x, 3/2−y, ½+z) π···π
interactions b C–H…[C6–H6…
Cg(1)xiv and C15xiv–H15xiv
Cg(2), where xiv=x, 1−y,
½+z) interactions
…
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Journal of the Iranian Chemical Society
Fig. 13 Partial packing dia-
grams of compound (5) view
along the b-axis
Fig. 14 Hirshfeld and fnger-
print plots of compound (5)
Table 11 Interaction energies (kJ mol−1) calculated for (5)
efect at 180 min that is 12.7%, whereas standard drug inhib-
its up to 13.7% (Table 12). Other compounds, i.e., 2, 4, and
5, have shown intermediate efects on inhibitory properties
(Tables 13, 14). Compound 1 has shown a negligible efect.
Therefore, the results indicated that structurally similar
to SC-558, compound 3 is a potent inhibitor of infamma-
tion. Torsion angle of linker oxygen atoms of compound
1, 2 is having a maximum 180°, and compound 3 linker
carbons torsion angle is least 9.55°. The V shape structure
of compound 3 is very similar to SC-558, which is very
much suitable in binding with the active site as per docking
study with COX-2. Compound 3’s fexibility is reduced by
the phenyl ring to make it more compatible with binding
with COX-2. Compound 3 conformations exist in V shape
structure in both crystal structure as well as the most suitable
conformation in docking study for binding with COX-2. This
conformation favors binding with COX-2, which is observed
Interaction(s)
E′ele
E′pol E′dis
E′rep Etot
2 C8–H8B…Cg(1)
−19.3 −4.4 −49.7 32.8 −46.7
C7–H7B…Cg(2)/C3–H3…O1 −14.8 −3.7 −54.6 51.0 −34.5
−16.5 −3.6 −22.2 15.8 −29.7
C10–H10…O1/C11–H11…
−7.3 −1.7 −28.4 17.0 −23.2
O2
2 C13–H13…O3 [R22(10)]
−17.1 −5.1 −10.6 18.4 −19.7
−2.8 −1.1 −17.4 12.3 −11.4
−4.1 −1.0 −14.9 11.1 −11.2
−0.7 −0.8 −13.4 11.2 −6.1
−1.3 −0.1 −6.7 2.6 −5.7
−2.2 −1.0 −2.8 1.8 −4.4
C15–H15…Cg(1)
Scale factors used to determine Etot:kele=1.057, kpol =0.740,
kdis =0.871, and krep =0.618 [16]. See “Hirshfeld surface, fnger-plot
and weak interaction energy analysis” section for calculation details
Table 12 Compounds docking
Compound Score Hydrogen bonds
Other interactions (pi–pi stacking/hydrophobic, etc.)
scores, interactions compared
with SC-558
(SC-558)
10.78 GLN 192
PHE 518, LEU 352, VAL 349, ARG 120, SER 353,
GLY 526, VAL 523, ALA 527
1
2
3
−7.72 PHE 518, GLN 192, SER 530 SER 353, PHE 518, VAL 523, GLY 526, LEU 352
−8.05 PHE 518, GLN 192, TRP 387 SER 353, VAL 523, LEU 352,
−9.95 PHE 518
VAL 523, LEU 352, VAL 349, LEU 359, ARG 120,
ALA 527, GLY 526
4
5
−8.1 PHE 518
−7.27 PHE 518, GLN 192
SER 353, LEU 352, ALA 527, GLU 526, VAL 523
SER 353, VAL 523, MET 522, TRP 387
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Journal of the Iranian Chemical Society
Fig. 15 Binding of compound (3) with COX–
Table 13 Percentage of edema
Group
Percentage of edema growth relative to control at diferent time intervals (mean SEM)
growth of albino rat relative to
the control group
0 (min)
30 (min)
90 (min)
180 (min)
Control
Nimu-slide
100
100
100
0
0
0
130.2 6.45 (30.2)
113.7 2.88 (13.7)
138.5 4.45 (38.5)
123.5 3.27* (23.5)
122.3 5.22 (22.3)
113.7 4.25 (13.7)
1
2
3
4
5
116.33 5.61
128.18 3.73*
118.17 6.23
(16.33)
(28.18)
(18.17)
100
100
100
100
0
0
0
0
116.13 6.11
(16.13)
128.6 4.17*
(28.6)
115.19 3.90
(15.19)
113.62 3.78
125.49 7.21*
112.7 4.25
(13.62)
(25.49)
(12.7)
117.39 2.59**
(17.39)
126.2 3.98***
(26.2)
114.6 2.54**
(14.6)
116.8 5.60
125.6 4.86
114.1 5.86
(16.8)
(25.6)
(14.1)
N=6 Number of rats in each group. Results in parentheses indicate percentage change from the respective
control group
p-value<0.05=*; <0.01=**; <0.001=***
Table 14 Edema growth at
Group
Paw edema at diferent time intervals (ml/rat) (mean SEM)
diferent intervals of albino rat
0 (min)
30 (min)
90 (min)
180 (min)
Control
Nimu-slide
1
2
3
4
5
0.99 0.05
1.02 0.054
1.10 0.064
1.12 0.048
1.10 0.043
0.92 0.061
1.08 0.058
1.26 0.044**
1.16 0.065
1.28 0.058
1.30 0.061
1.25 0.048
1.08 0.063
1.26 0.059
1.35 0.06
1.26 0.038
1.41 0.065
1.44 0.053
1.38 0.061
1.16 0.055
1.35 0.049
1.21 0.072
1.15 0.045
1.30 0.073
1.29 0.062
1.24 0.054
1.05 0.067
1.23 0.061
Results are (mean SEM) of 6 rats in each group
p-value<0.05=*; <0.01=**; <0.001=***
in the in vivo study of compound 3, and it becomes most
potent. Only small changes in 1, 2, 4, and 5 are showing
functional activity diferences in a similar way as observed
in the weak interactions and most stable conformations.
As per the results, m-substituted phenyl rings compound
1 conformation is not well suited for binding with COX-2.
The crystal structure of compound 1 shows the most stable
conformation of the compound that is not similar to the most
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Journal of the Iranian Chemical Society
active conformation in docking analysis. It is found in in-
vivo results of compound 1, and it becomes the least potent
compound. Compounds 2, 3, 4, 5 are p-substituted phenyls
rings, which enter correctly in the pocket of the COX-2
active site to make a compatible binding. Compound 2 has
structural similarity with compound 1 in terms of the tor-
sion angle of linkers, but a p-substituted ring of compound
2 makes it better than 1 to bind with COX-2. It shows that
COX-2 pocket size is very much suitable for p-substituted
phenyl rings. Compounds 4 and 5 docking results show that
one of the –CHO groups is enough for anti-infammatory
activity. However, as per the in vivo study, two –CHO groups
increase the activity of compound 5. Only fexibility is not
enough to make a compatible ft in the COX-2 active site. It
shows that the torsion angle of the linker should be less to ft
in the pocket of the COX-2 active site. So, the overall torsion
angle in the crystal structure and docking study refects the
compatibility of a drug to bind with the active site.
may be helpful in drug design and the development of new
materials in the feld of crystal engineering.
Acknowledgements Department of Chemistry, Banaras Hindu Uni-
versity, Varanasi, India, is acknowledged for departmental facilities.
Department of Chemistry, Mizoram University, Aizawl, Mizoram,
India, is acknowledged the other infrastructure facilities. SAIF, Gauhati
University, Guwahati, India, is acknowledged for SCXRD facilities.
Institute of Medical Sciences, B.H.U, Varanasi, India, is acknowledged
for providing the space and facilities to perform biological analysis.
Jayanta Dowarah acknowledges DST, New Delhi, for DST-inspired
fellowship.
Compliance with ethical standards
Conflict of interest The authors declare that they have no confict of
interest.
References
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Non-covalent interactions are playing a vital role in stabiliz-
ing a particular conformation of compounds. Here in these
examples, intermolecular aromatic interactions are observed
in unsymmetrical compound 4. In contrast, in compounds 1
and 2, both rings are symmetrical in their packing as well as
the electronic environment in their crystals. There are small
modifcations in the structure of compounds by changing
position and number of donor groups, but it observed that
they difer a lot in its biological activity. Compound 1 is
having diferent conformation in docking study as well as
crystal structure. It shows that the crystal structure of the
compound, as well as the most stable conformation of the
compound, plays a signifcant role in its biological activity.
Sometimes fexibility becomes restrictions as observed in
compounds 1 and 2, but sometimes it enhances the activ-
ity as observed in compound 3. Both compounds 1 and 2
structural study shows a big diference with docking con-
formation. Both are having not good activity even they have
better fexibility then compound 3. We can conclude that
only fexibility is not enough in all cases to enhance the
activity. We can conclude that if structural conformation in
crystal and most suitable conformations of docking analysis
have similarity, then it will be more efective in biological
activity. In vivo as well as in silico analysis results have a
good agreement, and the only slight diference is observed
in the activity of compound 5. These are some excellent
examples of feximers to establish that weak attractive inter-
molecular interactions play an essential role in determining
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