Design, molecular docking study and synthesis of 3,6-bis(3'-substituted propoxy)xanthone derivatives as COX-2 inhibitors

Article abstract of DOI:10.14233/ajchem.2015.19293

New drug discovery is considered broadly in terms of two kinds of investigational activities such as exploration and exploitation. Docking of small molecules in the receptor binding site and estimation of binding affinity of the complex is a vital part of

Full text of DOI:10.14233/ajchem.2015.19293

Asian Journal of Chemistry; Vol. 27, No. 12 (2015), 4634-4640
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.19293
Design, Molecular Docking Study and Synthesis of
3,6-Bis(3'-substituted propoxy)xanthone Derivatives as COX-2 Inhibitors
1
2
3,*
BRAJESH SHANKAR , APAROOP DAS and PRATAP PARIDA
1
Department of Pharmaceutical Sciences, Sardar Bhagwan Singh Postgraduate Institute of Biomedical Sciences & Research, Dehradun-248 161,
India
2
Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh-786 004, India
Centre for Studies in Biotechnology, Dibrugarh University, Dibrugarh-786 004, India
3
*
Corresponding author: E-mail: pratapparida2007yahoo.com@gmail.com
Received: 27 April 2015; Accepted: 27 June 2015;
Published online: 29 August 2015;
AJC-17521
New drug discovery is considered broadly in terms of two kinds of investigational activities such as exploration and exploitation. Docking
of small molecules in the receptor binding site and estimation of binding affinity of the complex is a vital part of structure based drug
design. The current study deals with the evaluation of cyclooxygenase (COX) inhibitory activity of xanthone using in silico docking
studies. In silico docking studies were carried out using AutoDock 4.2, based on the Lamarckian genetic algorithm principle. Molecular
properties of the ligands were investigated by using Discovery Studio 3.1. The docking results showed that all the selected xanthone
derivatives having binding energy ranging between -6.61 to -15.46 kcal/mol when compared with that of the standard drug i.e. celecoxib
(-9.94 kcal/mol). All the 3,6-bis(3’-substituted propoxy)xanthone derivatives contributed cyclooxygenase inhibitory activity because of
its structural parameters. Molecular docking analysis of these compounds can lead to further development of potent cyclooxygenase
inhibitors for the treatment of inflammation. A further structure-based research methodology of virtual screening was employed to
analyze the selectivity of the 2 isozymes. After docking study these derivatives were successfully synthesized.
Keywords: Molecular docking, Structure activity relationship, Synthesis, Topo isomerase, Xanthone derivatives.
8
-10
and renal toxicities caused by mixed COX inhibitors
.
INTRODUCTION
Investigations of many naturally occurring xanthones as well
as their synthetic derivatives, show broad spectrum of anti-
inflammatory activity . The present research work was based
on in silico docking and to synthesize 3,6-bis(3’-substituted
propoxy)-xanthone derivatives the substitution is made on 3-
and 6-position by propane side chain with different nucleo-
philes to obtain a series of new xanthone derivatives. Docking
is done by autodock 4.2 to the active site of the COX-2. The
structures of the synthesized compounds were confirmed on
the basis of analytical and spectral data.
Prostaglandins are converted into arachdonic acid by
prostaglandin endoperoxide hydroxysynthases (PGHS). Two
11
main isoform PGHS-1 and PGHS-2, were referred to as COX-1
1
(
cyclooxygenase-1) and COX-2, respectively . The predomi-
nantly constitutive form of the enzyme COX-1, is expressed
throughout the body and performs a number of homeostatic
2,3
functions, whereas COX-2 is induced by cytokines or antigens .
Cyclooxygenase-1 (COX-1) is involved in gastric mucosa pro-
tection, platelet aggregation, ovary and breast cell carcinoma
4
develop-ment and renal blood regulation . In contrast, the indu-
cible form, COX-2 is expressed in response to inflammation
and is involved in the production of the prostaglandins that
EXPERIMENTAL
5
mediate pain and support the inflammatory process . The pain
Retrieval of 3D structure: The 3D structure of the protein
was downloaded from Research Collaboratory for Structural
Bioinformatics (RCSB), Protein Databank (PDB, http://
www.pdb.org). The PDB ID of the selected protein was found
to be 3LN1.
6
caused by inflammation is treated by COX-2 inhibition . In
addition, COX-2 mediating the vessel formation and prolife-
7
ration plays a crucial role in tumorigenesis . All the classic
NSAIDs (non-steroidal anti-inflammatory drugs) inhibit both
COX-1 and COX-2 at standard anti-inflammatory doses.
Therefore, molecular-based targeting strategies were employed
to develop specific COX-2 inhibitors to circumvent the gastric
Ligand preparation and optimization: The ligands were
TM
drawn using Moldraw tool of Exome Horizon in 2D and
were converted into 3D before submission for docking. The

Vol. 27, No. 12 (2015)
Design and Synthesis of 3,6-Bis(3'-substituted propoxy)xanthone Derivatives 4635
general structure was given in the Fig 1. The ligands optimi-
zation was performed using ADMET module of Accelrys
Discovery studio 3.1.
on top. Clusters are created based on the comparison of
conformations using RMSD values.
Synthesis: Synthesis of all the designed compounds (B1-
B9) involves three steps reactions.All the targeted compounds
were synthesized using laboratory grade chemicals and
solvents without further purification. Eaton’s reagent was
prepared by dissolving phosphorus pentoxide in methane
sulphonic acid in 1:10 ratio i.e. 10 g phosphorus pentoxide
was dissolved in 100 mL methane sulphonic acid. 100 mL of
Eaton’s reagent was added slowly to a mixture of resorcinol
O
X
O
O
O
X
Fig. 1. General structure of the proposed compounds
(60 mmol) and 2,4-dihydroxybenzoic acid (60 mmol). The
mixture was warmed up to 70 °C for 35 min under stirred.
Then cooled to room temperature and the reaction was poured
into an ice bath and stirred for 2 h. The resulting solid collected
by filtration, washed with water until pH 6 and dried at 60 °C.
Potassium carbonate (0.25 mmol) was added to a solution of
Ligand structure preparation, toxicity and drug likeness:
The data set of different 3,6-bis(3’-substituted propoxy)xanthone
derivatives, were generated ligand molecules. ChemAxon is a
freeware which developed by Advanced Chemistry Develop-
ment, Inc. was used for drawing and conversion of 2D chemical
structure of compound to 3D structures. It was also used for
optimization of the ligand molecules. Medchem Designer was
used for ADME/Tox screening of the selected ligands and the
results were recorded. In silico prediction biological activity
of the compounds were calculated such as molecular weight,
hydrogen bond donors/acceptors, log P and total polar surface
area (TPSA). Actelion (OSIRIS) [OSIRIS Property Explorer
3
,6-bis(3’-substituted propoxy)xanthone (0.2 mmol) and 1,3-
dibromopropane in acetone. The mixture was refluxed under
stirring for 24 h at 65 °C. Cooled the mixture, filtered and
concentrated the filtrate to obtain crude product. 3,6-bis(3’-
substituted propoxy)xanthone (10 mmol) and selected amine
(
20 mmol) was dissolved in 20 mL of acetone and stirred at
room temperature for 48 h (Scheme-I). The end of reaction
was confirmed by TLC with the formation of only one spot.
(
http://wwworganic-chemistryorg/prog/peo/)] property
1
4-17
The crude product was purified
.
explorer was used to screen the drug likeness. Toxicity risks
were evaluated by calculating mutagenic, tumorigenic,
irritant, reproductive effective, solubility, drug likeliness and
drug score.
Spectral data
3,6-Bis[3-(3-nitrophenylamino)propoxy]xanthone
(B1): UV-visible spectrum (λmax): 554 nm (DMSO); FT-IR
-1
Docking methodology: The Lamarckian genetic algo-
rithm (LGA) was employed for ligand conformational
searching, which is a hybrid of a genetic algorithm and a local
search algorithm. This algorithm first builds a population of
individuals (genes), each being a different random conformation
of the docked molecule. Each individual is then mutated to
acquire a slightly different translation and rotation and the
local search algorithm then performs energy minimizations
on a user-specified proportion of the population of individuals.
The individuals with the low resulting energy are transferred
to the next generation and the process is then repeated. Rapid
energy evaluation was achieved by precalculating atomic
affinity potentials for each atom in the ligand molecule. In the
AutoGrid procedure, the target enzyme was embedded on a
(KBr pellets, νmax, cm ): 3431.36 (2°amine), 2845.30 (C-C
str., alkyl), 1346.31 (C-N str., nitro compound), 1579.70 (N-
H benzene, 2°amine), 1622.13 (C=O str., Keto group), 1430
1
(C-C str., aromatic); H NMR δ: 3.436 (m, 2H, -CH
2
CH
-NH- aromatic), 3.03 (m,
-NH-aromatic), 1.983 (m, 1H, -NH aromatic), 6.768
2
CH
2
-
NH-aromatic), 1.98 (t, 2H, -CH
2H, -CH
(m, 3H-xanthone); C NMR δ: 63.188 (-CH
phenyl), 130 (4a, 4b xanthone), 149 (C=O xanthone), 130 (2C-
2
CH
2
2
1
3
2
CH
2
CH -NH-
2
phenyl); 40.004 (-CH
[M ].
2
-NH-phenyl); MS m/z (%): 586 (7.7 %),
+
3,6-Bis[3-(4-nitrophenylamino)propoxy]xanthone
(B2): UV-visible spectrum (λmax): 556 nm (DMSO); IR (KBr
-1
pellets, νmax, cm ): 3481.51 (2°amine), 2800.32 (CH str.,alkyl),
1631.78 (C=O str., keto group), 1475.54 (C-C str., aromatic),
12
three dimensional grid point . The energy of interaction of
each atom in the ligand was encountered. AutoDock was run
several times to get various docked conformations and used
to analyze the predicted docking energy. The binding sites for
these molecules were selected based on the ligand-binding
1307.74 (C-N str., nitro compound), 1595.13 (N-H ben.,
1
2°amine) H NMR δ: 1.28 (m, 2H, 6.8, -CH
2
CH
-NH-phenyl), 3.28 (t, 2H, -CH
NH-phenyl), 6.69 (d, 2H, 2-H-phenyl), 7.26 (t, 1H, 6-H-
2
CH -NH-
2
phenyl), 1.52 (m, 2H, -CH
2
CH
2
2
-
1
3
xanthone), 7.69 (d, 1H, 8-H-xanthone); C NMR δ: 24.01
(-CH CH CH NH-phenyl-), 27.48 (-CH CH NH-phenyl),
31.69 (-CH NH-phenyl), 112.58 (2-C-phenyl), 117.29 (5-C-
13
pocket of the templates . AutoDock Tools provide various
methods to analyze the results of docking simulations such
as, conformational similarity, visualizing the binding site and
its energy and other parameters like intermolecular energy and
inhibition constant. For each ligand, ten best poses were
2
2
2
2
2
2
xanthone), 119.33 (5-C-phenyl, 7-C-xanthone), 129.75 (8-C-
xanthone), 135.63 (4-C-phenyl), 155.62 (4a, 4b-C-xanthone),
+
160.20 (1, 3-C-xanthone); MS m/z (%): 585 (34.2 %), [M ].
14
generated and scored usingAutoDock 4.2 scoring functions .
The analogues were docked into the binding pocket. The
similarity of docked structures is measured by computing the
root-mean-square deviation (RMSD) between the coordinates
of selected molecular conformation with the molecular
conformation having lowest interaction energy which is ranked
3,6-[3-(2-Hydroxyphenylamino)propoxy]xanthone
(B3): UV-visible spectrum (λmax): 524 nm (DMSO); IR (KBr
-1
pellets, νmax, cm ): 3070 (2°amine), 1604.77 (C=O str., keto
group), 1431.18 (C-C str., aromatic), 1309.67 (OH ben.,
1
phenolic), 1502.55 (N-H ben., 2°amine); H NMR δ: 1.37 (m,
2
2H, -CH CH
2
CH -NH-phenyl), 5.87 (s, 1H, 2-H-phenyl), 6.06
2

4
636 Shankar et al.
Asian J. Chem.
-
1
O
OH
(
KBr pellets, νmax, cm ): 3045.60 (N-H str., 2°amine); 2970.38
Stirred with Eaton's reagent
at 70 °C for 35 min
(C-H str., alkyl); 1608.63 (C=O str., keto group); 1130.29 (C-O
str., alkyl ether); 1469.76 (C-C str., aromatic). NMR spectrum:
OH
+
Stirred with ice for 2 h
1
H NMR (DMSO-d
6
): 3.875 (s, 2H, -CH
CH -NH-cyclohexyl); 2.072
d, 1H, NH cyclohexyl); 7.505 (d, 1H, 6H xanthone); 1.44 (s,
2
CH
2
CH
2
-NH-
HO
OH
cyclohexyl); 1.641 (s, 2H, -CH
2
2
OH
O
(
1
2
13
H, cyclohexyl). C NMR (DMSO-d
7.48 (2-C-propane); 38.75 (2-C-cyclohexyl); 64.83 (1-C-
6
): δ23.20 (3-C-propane);
propane); 117.36 (5-C-xanthone); 120.27 (7-C-xanthone);
29.98 (8-C-xanthone); 131.43 (6-C-xanthone); 162.50 (1-C-
HO
O
OH
1
3
,6-Dihydroxy xanthone
K
2
CO
3
, Acetone
+
+
xanthone). Mass spectrum m/z (%): 503 (5.7); [M ].
,6-Bis(3'-indole propoxy)xanthone (B7): UV-visible
Br
Br
Stirred for 24 h at 65 °C
3
1
,3-Dibromo propane
spectrum (λmax): 345 nm (methanol); FT-IR spectrum (KBr
O
O
-1
pellets, νmax, cm ): 3047 (C-H str., aromatic); 2926 (C-H str.,
o
alkyl); 1334 (C-N str., 3 amine); 1488 (C-C str., aromatic);
1
1
105 (C-O str., 6 membered cyclic ether)NMR spectrum: H
Br
O
O
Br
NMR (MeOD): δ 6.417-6.425 (d, 1H, xanthone, H-1 & H-8,
J = 3.2 Hz); 6.291-6.317 (t, 1H, xanthone, J = 8.4 Hz, J = 2
Hz); 3.312-3.574 (t, 2H, H-3', J = 6.4 Hz); 4.100-4.114 (d,
3,6-Bis(3-bromopropoxy)-9H-xanthen-9-one
X
Stirred for 48 h at room temperature
2
H, H-1' J = 5.6 Hz); 6.964-7.001 (t, 1H, indole, H-5, J = 7.2
O
O
Hz, J = 7.6 Hz); 7.520-7.538 (d, 1H, indole, H-2, J =7.2 Hz);
7
1
indole, H-4 & H-7); C NMR (MeOD): δ 199.47 (C-9,
xanthone); 164.56 (C-1 and C-8); 168.61 (C-3 and C-6);
.195-7.202 (d, 1H, indole, H-3, J = 2.8 Hz); 7.056- 7.094 (t,
H, indole, H-6, J = 8.00 Hz, J =7.2); 7.324-7.375 (m, 1H,
1
3
X
O
O
X
3
,6-Bis(3'-substituted propoxy)xanthone
1
37.63 (C-5a & C-4a); 112.11 (C-2 and C-7); 104.64 (C-8a
and C-9a); 122.47 (C-4 and C-5); 125.46 (C-2, indole); 102.24
C-3, indole); 119.97 (C-4, indole); 121.16 (C-5, indole);
14.19 (C-6, indloe); 110.61 (C-7, indole); 135.50 (C-7a,
Scheme-I
(
1
(
4
s, 1H, 2-H-xanthone), 6.11 (d, 1H, 6-H-phenyl), 6.17 (s, 1H,
-H-xanthone), 7.12 (d, 1H, 5-H-xanthone), 7.16 (t, 1H, 7-H-
xanthone), 7.67 (d, 1H, 8-H-xanthone); C NMR δ: 92.50 (2-
C-xanthone), 5-C-xanthone), 120.17 (7-C-xanthone), 129.99
8-C-xanthone), 135.57 (6-C-xanthone), 157.12 (4a, s4b-C-
xanthone), 162.50 (1,3-C-xanthone), 171.78 (9-C-xanthone),
CH NH-phenyl). MS m/z (%): 529 (34.1); [M ].
,6-Bis[3-(ethyl(phenyl)propoxy]xanthone (B4): UV-
visible spectrum (λmax): 534 nm (DMSO); IR (KBr pellets,
max, cm ): 2927.94 (C-H str., alkyl), 1604.77 (C=O, keto group),
'
1
3
indole); 129.11 (C-3a); 49.69 (C-1'); 49.49 (C-3); 48.41 (C-
+
2
'); Mass spectrum m/z (%): 543 (38.7); [M ].
,6-Bis(3'-p-aminoacetophenone propoxy)xanthone
B8): UV-visible spectrum (λmax): 318 nm (methanol). FT-IR
3
(
(
-1
+
spectrum (KBr pellets, νmax, cm ): 3391 (N-H str., 2°amine);
921 (C-H str.,alkyl); 1630 (C=O str.,keto group); 1487 (C-C
str., aromatic); 1338 (C-N str., 2°amine); 1586 (N-H ben.,
°amine); 1100 (C-O str., 6 membered cyclic ether).NMR
3
9.693 (-CH
2
CH
2
2
2
3
-1
2
ν
1
1
1
spectrum: H NMR (MeOD): δ 3.175 (s, 1H, N-H); 2.309 (s,
H, CH ); 4.878 (s, 2H, H-3'); 7.592-7.613 (d, 1H, benzene,
463.97 (C-C str., aromatic) 1346.31 (C-N str., 3° amine); H
3
3
NMR δ: 4.129 (d, 2H, -CH
H, -CH CH -N-ethylaniline), 1.252 (d, 3H, CH
phenyl), 1.785 (s, 1H, 2Hphenyl), 7.309 (d, 1H, 8Hxanthone),
2
CH
2
CH
2
-N-ethylaniline), 8.63 (d,
H-3 and H-5, J = 8.4 Hz); 7.171-7.193 (d, 1H, benzene, H-2
and H-6, J = 8.8 Hz); 6.476-6.497 (d, 1H, xanthone, H-1 and
2
2
2
3
CH -3°amine
2
13
1
3
H-8, J = 8.4 Hz); 6.123-6.162 (m, 1H, xanthone). C NMR
MeOD): δ 199.37 (C-9); 199.11 (C=O); 135.49 (C-1, benzene);
32.21 (C-4, benzene); 126.85 (C-2 & C-6, benzene); 169.45
C-3 & C-6); 164.65 (C-1 & C-8); 114.51 (C-3 & C-5,
benzene); 110.40 (C-2 & C-7); 104.82 (C-8a & C-9a); 155.38
C-4a & C-5a); 113.51 (C-4 & C-5); 25.95 (CH ); 49.70 (C-1');
9.50 (C-3'); 48.44 (C-2'). Mass spectrum m/z (%): 580 (8.4);
3
.343 (s, 3H, -CH
2
-3°aminephenyl); C NMR 65.734 (3C,
methylphenyl), 162.673 (4a, 4b, phenyl)115.021 (2C, phenyl);
(
1
(
+
1
29.459 (3C-phenyl); MS m/z (%) : 538 (100); [M ].
-[5-(Furan-2-ylmethylamino)propoxy]hydroxy-
xanthone (B5): UV-visible spectrum (λmax): 537 nm (DMSO).
FT-IR spectrum (KBr pellets, νmax, cm ): 3143.97 (N-H str.,
°amine); 2800 (C-H str., alkyl); 1604.77 (C=O str., keto
3
-
1
(
4
3
2
+
1
[
M ].
group); 1465.90 (C-C str., aromatic). NMR spectrum: H NMR
400 MHz, D O): δ 4,098 (s, 2H, -CH CH CH -NH-furfuryl);
.942 (s, 2H, -CH CH -NH-furfuryl); 4.334 (s, 1H, -NH-
furfuryl); 1.99 (s, 1H, 2H furan); 7.652 (d, 1H, 8H, xanthone);
3
,6-Bis(3'-p-aminobenzoic acid propoxy)xanthone
(
1
2
2
2
2
(
B9): UV-visible spectrum (λmax): 346 nm (methanol). FT-IR
2
2
-1
spectrum (KBr pellets, νmax, cm ): 3391 (N-H str., 2°amine);
921 (C-H str.,alkyl); 1630 (C=O str.,keto group); 1487 (C-C
str., aromatic); 1338 (C-N str., 2°amine); 1586 (N-H ben.,
°amine); 1100 (C-O str., 6 membered cyclic ether)NMR
13
2
6
(
4
(
.503 (t, 1H, 1H xanthone). C NMR (100 MHz, D
3C, furfuryl); 62.795 (4C-furan); 98.909 (1C furan); 158 (4a,
b xanthone); 169.228 (C=O xanthone). Mass spectrum m/z
2
O): δ 65.930
2
1
+
spectrum: H NMR (MeOD): δ 7.758-7.777 (d, 1H, benzene,
H-3 and H-5, J = 7.6 Hz); 7.322-7.343 (d, 1H, benzene, H-2
and H-6, J = 8.4 Hz); 6.640-6.661 (d, 1H, xanthone, H-1 and
%) : 500.28 (5.9); [M ].
,6-Bis[3-(cyclohexylamino)propoxy]xanthone (B6):
UV-visible spectrum (λmax): 563 nm (DMSO). FT-IR spectrum
3

Vol. 27, No. 12 (2015)
Design and Synthesis of 3,6-Bis(3'-substituted propoxy)xanthone Derivatives 4637
H-8, J= 8.4 Hz); 6.312-6.336 (t, 1H, xanthone, J = 8.4 Hz, J =
Hz); 3.317 (s, 1H, N-H); 5.151-5.223 (d, 2H, H-3', J = 28.8
Hz). C NMR (MeOD): δ 176.30 (COOH); 132.09 (C-1,
benzene); 135.53 (C-4, benzene); 199.69 (C-9); 164.41 (C-1
and C-8); 168.20 (C-3 and C-6); 151.60 (C-5a and C-4a);
Docking study: The ligands were targeted to celecoxib
bound at the COX-2 active site. Here we observed that the
residue Leu 338 and Ser 339 are inhibited by celecoxib. All
the ligands successfully targeted to the active site of celecoxib.
The binding energy was observed in the range of -6.61 to
-15.46 kcal/mol. The binding energy of the selected ligands
were plotted in the graph and from the graph (Fig. 3) the
binding energy of all the ligands were observed among which
the best ligand which shows better activity in all the active site
was found to be B1 (-15.46 kcal/mol). According to the active
site analysis of celecoxib, it was observed that celecoxib formed
two hydrogen bonds with the aminoacid residues Ser 339 and
His 75 (Fig. 4). It also formed hydrophobic interaction with
several amino acids however the active side residue Leu 338
was also inhibited with a hydrophobic bond by celecoxib
2
1
3
1
11.38 (C-2 and C-7); 104.66 (C- 8a and C-9a); 114.93 (C-4
and C-5); 49.75 (C-1'); 49.53 (C-3'); 49.33 (C-2').Mass
+
spectrum m/z (%): 583 (36.7); [M ].
RESULTS AND DISCUSSION
The water molecules and ligands attached to the protein
were removed by using Swiss PDB Viewer. The Protein was
having 552 number of groups, 8851 number of atoms and 8987
number of bonds. The binding site of the protein were analyzed
and reported in Fig. 2. The molecular properties of all the
derived groups (X) such as total polar surface area (TPSA),
hydrogen bond donor (HBD), hydrogen bond acceptor (HBA),
number of rotatable bonds (nRB) were provided in Table-1.
(
Fig. 4). The validation of residue inhibition to the active site
of celecoxib was well observed by the xanthone derivatives.
The ligand b1 formed six hydrogen bonds with the aminoacids.
It was observed that, the residue Leu 338 and Ser 339 are
inhibited properly (Fig. 5). The ligand b3 also interacted with
the aminoacid Ser 339 (Fig. 6). Both the aminoacids are
forming hydrophobic interaction with the ligand b5 (Fig. 7).
0
1
2
3
4
5
6
7
8
9
-
2
-4
-6
-
6.61
-8
-
8.75
-
10
12
14
16
-
9.91
-
10.39
-
-
11.63 -11.96
-
12.93 -13.10 -12.66
-
-
-
15.46
-18
Fig. 3. Binding energy values for the proposed compounds (kcal/mol). The
compound 1 (b1), 3 (b3), 4 (b4), 5 (b5) showed better binding energy
than the control drug (celecoxib)
Ala502 CELECOXIB
Ile503
His75
Val509
Gly340
Leu338
Ser339
Fig. 2. Crystal structure of celecoxib bound at the COX-2 active site
Gln178
Val335
Toxicity and drug likeness: The pharmacokinetics and
pharmacodynamics properties of the ligands were calculated.
The rotatable bonds, rigid bonds, flexibility, hydrogen bond
donors, hydrogen bond acceptors, maximum rings, total
charge, heavy atoms, hetero atoms, Lipinki’s violation, oral
bioavailability were calculated. The compounds successfully
passed the Lipinkis rule. We observed that none of these
compounds produce toxicity or mutagenicity. ADMET
screening revealed that the ligands were non-toxic and passed
Lipinski’s rule and the Actelion property explorer revealed
that ligands were non-mutagenic, non-tumorigenic and non-
irritative with high solubility and drug likeness rule (Table-2).
Phe504
(a)
Leu517
Ser516
Ala513
Gly512
(
b)
Fig. 4. (a) The binding site of the drug celecoxib in pharmacophore model.
The green residues indicate lipophilic binding sites, the blue
symbolizes the hydrogen bond donor, the red denotes hydrogen
bond acceptor and the faded black directs the hydrogen residues.
(
b) The interacting amino acids with the protein. The green dotted
line indicates the hydrogen bond formation and the rest are amino
acids forming hydrophobic interaction

4
638 Shankar et al.
Asian J. Chem.
TABLE-1
CALCULATED MOLECULAR PROPERTIES OF THE COMPOUNDS
Total polar
surface area bond acceptor
Hydrogen
Hydrogen
bond donor
Number of
rotatable bonds
Ligand
Substituent (X)
m.w.
log P
NH2
B1
B2
555.97
3.8
131.04
6
0
14
O2N
NH2
555.97
3.8
131.04
6
0
14
NO2
NH2
HO
B3
B4
495.98
511.99
4.062
44.76
51.24
8
6
0
0
12
14
5.76
NH
NH2
B5
B6
471.98
463.99
2.254
5.096
63.22
44.76
8
6
0
0
14
12
O
NH2
NH
B7
B8
511.99
543.58
3.224
2.956
51.24
78.9
6
8
0
0
10
14
O
NH2
O
HO
B9
551.97
2.432
78.9
10
0
14
NH2

Vol. 27, No. 12 (2015)
Design and Synthesis of 3,6-Bis(3'-substituted propoxy)xanthone Derivatives 4639
TABLE-2
Phe49
b3
c log P, SOLUBILITY, DRUG LIKENESS AND DRUG-SCORE
ACCOUNTED BY OSIRIS PROPERTY EXPLORER
Leu65
Ligand
code
B1
B2
B3
B4
B5
B6
B7
B8
Drug
likeness
c log P
Solubility
Drug-score
Ser457
Pro69
3.32
3.32
4.47
6.47
2.35
4.86
4.24
4.76
1.95
2.24
-7.26
-7.26
-5.75
-6.9
-4.33
-6.48
-4.57
-6.47
-5.15
-3.83
-4.16
-9.92
1.08
4.36
1.28
-4.09
3.54
-2.84
0.94
-7.03
0.1
0.1
0.21
0.14
0.38
0.11
0.31
0.09
0.3
Val74
Tyr101
Glu510
Val509
Tyr341
B9
Celecoxib
(a)
0.39
Arg106
Val335
Ser339
Ala513
Leu65
b1
(b)
Leu345
Asn28
Fig. 6. (a) The binding site of the drug b3 in pharmacophore model. The
green residues indicate lipophilic binding sites, the blue symbolizes
the hydrogen bond donor, the red denotes hydrogen bond acceptor
and the faded black directs the hydrogen residues. (b) The interacting
amino acids with the protein. The green dotted line indicates the
hydrogen bond formation and the rest are amino acids forming
hydrophobic interaction
Lys68
Pro69
Tyr101
Arg106
Pro71
Clus510
Tyr341
b5
Arg106
Val74
Ala513
Ser339
Leu338
Glu51
0
Pro71 Pro69
(a)
Val509
Ser339
Val509
Val335
Trp373
(b)
41
Gln336
3
r
y
T
Val74
Lys68
Fig. 5. (a) The binding site of the drug b1 in pharmacophore model. The
green residues indicate lipophilic binding sites, the blue symbolizes
the hydrogen bond donor, the red denotes hydrogen bond acceptor
and the faded black directs the hydrogen residues. (b) The interacting
amino acids with the protein. The green dotted line indicates the
hydrogen bond formation and the rest are amino acids forming
hydrophobic interaction
Leu338
Ala513
Phe504
Leu65
Ser457
(a)
Lys454
(
b)
Asn28
The physio-chemical properties of the synthesized comp-
ounds are given in Table-3.
Fig. 7. (a) The binding site of the drug b5 in pharmacophore model. The
green residues indicate lipophilic binding sites, the blue symbolizes
the hydrogen bond donor, the red denotes hydrogen bond acceptor
and the faded black directs the hydrogen residues. (b) The interacting
amino acids with the protein. The green dotted line indicates the
hydrogen bond formation and the rest are amino acids forming
hydrophobic interaction.
Structure-activity correlation of the docked and synthesized
compounds revealed some interesting assumptions. It was seen
that the substitution of substituted primary or secondary
rd
th
aromatic amine into the 3 and 6 position of the xanthone
ring greatly enhances the PGHS-2 inhibitory activity. Electron
withdrawing group (EWG) like NO
in ligand B1 (binding energy:-15.46 kcal/mol) as the most
active member of this study. NO group is an EWG inductively
2
at meta position of aniline
as well as by resonance and so it is the strongest EWG reported.
Besides EWG substituted on an aromatic ring is always meta
2
directing and the NO group in B1 is in the meta position. This
2
TABLE-3
PHYSIO-CHEMICAL PROPERTIES OF THE SYNTHESIZED COMPOUNDS
Compound
State
Solid
Solid
Solid
Solid
Solid
Solid
Solid
Solid
Solid
Colour
Yellow
Light yellow
Brown
Black
Black
Light brown
Yellow
Yellow
Yield (%)
69.78
64.35
74.67
74.67
71.23
77.47
76.90
71.00
68.20
Solubility
DMSO, methanol
Acetone, ethanol, DMSO, methanol
Methanol, DMSO
m.p. (°C)
160-165
140
105-110
110-120
178-180
212-210
160-165
80-88
B1
B2
B3
B4
B5
B6
B7
B8
B9
Chloroform, DMSO
DMSO, chloroform
Ethanol, DMSO
Ethanol, ethyl acetate, methanol and DMSO
Ethanol, ethyl acetate, methanol and DMSO
Ethanol, ethyl acetate, methanol and DMSO
Yellow
190-195

4
640 Shankar et al.
Asian J. Chem.
corresponds to the higher activity of B1 with respect to docking
results of other ligands. On the other hand, EWG at para
position of aniline in ligand B2 produced lower binding energy
of effective hydrogen bond and π-cation interactions, which
was also supplemented through scoring parameters. In the light
of above observation, xanthone derivatives can act as a lead
towards the development of potential COX-2 inhibitors, these
compounds show excellent correlation between docking results
and synthetic data. A considerable amount of work is still
required in this direction and is in progress. It will be reported
subsequently in future. Further research can be carried out on
these compounds and used for testing in vivo antiinflammatory
activity.
(
-8.75 kcal/mol). Interestingly, our study involved docking of
only one ligand (B6) with an aliphatic ring cyclohexylamine
but this compound showed the lowest binding energy (-6.61
kcal/mol) of all the nine ligands. Hence, aliphatic substitution
in the xanthone nucleus may be considered to decrease the
anti-inflammatory activity. N-substituted aniline in ligand B4
also show relatively good binding energy (-13.10 kcal/mol).
Electron donating group (EDG) at ortho position in substituent
ACKNOWLEDGEMENTS
(
B3) decreased the activity slightly and EWG at para position
in substituent (B9) shows moderate binding efficacy. We
currently all marketed NSAIDs are inhibitors of both COX-1
and COX-2.The aspect of enzyme selectivity of NSAIDs
becomes important particularly under the point of view of low
risk NSAIDs with reduced side-effects. Therefore, the classic
NSAIDs are being pushed increasingly into the background,
whereas selective COX-2 inhibitors with an attractive
pharmacological profile and reduced side-effects are being
The authors gratefully acknowledge to Department of
Pharmaceutical Sciences, Dibrugarh University, Dibrugarh,
India for providing the research facilities.
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