Synthesis, anti-inflammatory activity and in silico studies of some novel morpholine based carboxamides

Article abstract of DOI:10.14233/ajchem.2020.22488

Two series of carboxamides were synthesized from 3-fluoro-4-morpholinoaniline and different substituted aromatic/heterocyclic carboxylic acids. All the compounds were characterized by IR, ¹H NMR, ¹³C NMR and mass spectral data. The n

Full text of DOI:10.14233/ajchem.2020.22488

Asian Journal of Chemistry; Vol. 32, No. 4 (2020), 901-906
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2020.22488
Synthesis, Anti-inflammatory Activity and in silico
Studies of Some Novel Morpholine Based Carboxamides
1,2
3
3
PREMANAND M. HONAVAR , VASANTHA KUMAR , NIKHIL P.4, NAVEEN KUMAR ,
S. SREENIVASA , VISHWANATHA P.3, BOJA POOJARY and B. SHIVARAMA HOLLA
2
4
3,*
1Department of Chemistry, Sri Dharmasthala Manjunatheshwara College ofArts, Science, Commerce, BBA and P.G. Centre, Honavar-581334, India
2Department of Studies and Research in Organic Chemistry, Tumkur University, Tumkur-572103, India
3Department of Chemistry, Sri Dharmasthala Manjunatheshwara College (Autonomous), Ujire-574240, India
4Department of Studies and Research in Chemistry, Mangalore University, Mangalagangotri-574199, India
*Corresponding author: E-mail: hollabs@gmail.com
Received: 8 October 2019;
Accepted: 5 December 2019;
Published online: 25 February 2020;
AJC-19810
Two series of carboxamides were synthesized from 3-fluoro-4-morpholinoaniline and different substituted aromatic/heterocyclic carboxylic
acids. All the compounds were characterized by IR, 1H NMR, 13C NMR and mass spectral data. The newly synthesized amide derivatives
were screened for anti-inflammatory activity by following carrageenan induced rat paw edema method. Among the compounds screened,
compound 6e was found to be highly potent. Molecular docking interaction of active compounds revealed that effective binding was
observed in the pocket of COX-I and COX-II proteins.
Keywords: Carboxamides, Morpholinyl, Pyridine, Antiinflammatory activity, Docking studies.
activities such as antimicrobial [10], anticonvulsant [11],
analgesic [12], anticancer [13] and anticoagulant activities [14].
They also involved as intermediates in the synthesis of biologi-
cally important molecules. Carboxamides with conjugation
of other aliphatic, aromatic and heterocyclic moieties produce
various types of biological activities. A number of amides of
aromatic and heterocyclic carboxylic acids have been synthe-
sized in search for new antagonists of excitatory amino acids
receptors with anticonvulsant activity. Amide functionality is
also an important functional group which is responsible for
binding with different protein molecules and as a result increases
its pharmacological activity [15].
Amide derivatives exhibited anti-inflammatory [16,17],
antimicrobial [18], antitubercular [19], anticancer [20] and
anticonvulsant [21] activities. In the current study, morpholine
containing aromatic amine and substituted aromatic/hetero-
cyclic carboxylic acids were combined to synthesize a new series
of amide derivatives and screened for in vivo anti-inflammatory
activities by carrageenan induced paw edema method. Molecular
docking studies was performed to understand the interaction
of the molecules with COX-I (PDB code: 2OYE) and COX-II
INTRODUCTION
Inflammation is referred as a complex biological process
that happens when body tissues are exposed to hazardous stimuli,
such as irritants and pathogens [1]. The process of inflamma-
tion threatens human health, and exaggerated and prolonged
inflammation may cause various diseases, including arthritis,
sepsis and even cancer [2]. Presently, 35% of the global medi-
cinal prescription for the treatment of inflammation are non-
steroidal anti-inflammatory drugs (NSAIDs) [3,4].Aspirin and
indomethacin are the common NSAIDs, that inhibit cyclo-
oxygenases (COX-1 and COX-2) [5,6], which are involved in
the catalyzation of converting arachidonic acid to prostaglandins.
Considering the significant toxicity of NSAIDs to the gastro-
intestinal tract and kidney [7], it is of great importance and
urgent need to develop new anti-inflammation drugs [8].
Morpholine based compounds occupy pivotal place in
medicinal chemistry owing their special features such as strong
basic nature and participation in donor acceptor type of inter-
action [9]. From the literature, it is observed that morpholine
moiety containing amide derivatives exhibited wide range of
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902 Honavar et al.
Asian J. Chem.
protein (PDB code: 4COX) that are responsible for exhibiting
anti-inflammatory activity.
N-(3-Fluoro-4-morpholinophenyl)thiophene-2-carbox-
amide (6b):Yield: 82 %; m.p.: 186-188 ºC; IR (KBr, νmax, cm-1):
3306 (N-H), 3086, 2952 (-C-H), 2848, 2820, 1633 (C=O), 1589
(C=C), 1116 (C-F); 1H NMR (400 MHz, DMSO-d6, δ in ppm):
10.22 (s, 1H, NHCO), 7.956 (d, 1H, J = 3.2 Hz, thiophene-H),
7.824 (d, 1H, J = 3.2Hz, thiophene-H), 7.635-7.591 (dd, 1H,
J = 2.4 Hz & 15.2Hz, Ar-H), 7.406-7.381 (dd, 1H, J = Hz, Ar-
H), 7.191 (t, 1H, J = 4.5 Hz, thiophene-H), 7.003 (t, 1H, J =
9.6 Hz, Ar-H), 3.702 (t, 3H, O-CH2), 2.935 (t, 4H, N-CH2);
13C NMR (100 MHz, DMSO-d6, δ in ppm): 160.1, 155.9, 153.5,
140.2, 136.0, 134.2, 132.3, 129.5, 128.4, 119.4, 116.7, 109.0,
66.6, 51.1; MS (m/z): calculated 306.0838, found: 306.9971.
5-Chloro-N-(3-fluoro-4-morpholinophenyl)thiophene-
2-carboxamide (6c):Yield: 84 %; m.p.: 194-196 ºC; IR (KBr,
EXPERIMENTAL
All the chemicals and solvents used were procured from
Spectrochem and Sigma-Aldrich make in the appropriate grade
and used without further purification; purity of the chemicals
and solvents received was confirmed by TLC. Melting points
were determined in open capillary and are uncorrected. IR
spectra were recorded on Bruker alpha series in KBr (cm-1).
1H and 13C NMR spectra were recorded on a BRUKERAV400,
Agilent 400MR using TMS as internal standard, Mass data was
recorded on Agilent Waters, USA and chemical shift values
are reported in δ ppm.
General procedure for the synthesis of 4-(2-fluoro-4-
nitrophenyl)morpholine (3): 3,4-Difluoronitrobenzene (10
mmol) was added dropwise to a mixture of morpholine (10
mmol) in dry dimethylformamide in presence of Hünig′s base
DIPEA (30 mmol) and then the contents of the reaction mixture
were heated at 90 ºC for 6 h. Reaction mass was poured to
crushed ice to get solid product, filtered, washed with water
and dried. The yellow solid obtained was recrystallized from
ethanol to get pure product.
General procedure for the synthesis of 3-fluoro-4-morp-
holinoaniline (4): 4-(2-Fluoro-4-nitrophenyl)morpholine (3)
(10 mmol) was taken in round bottom flask containing 10 mL
of 6 M HCl, stirred the mixture for 0.5 h, then (30 mmol) of
Sn granules were added during stirring. The stirring was con-
tinued for another 2.5 h and after completion of the reaction,
50 mL of distilled water was added with 20 % NaOH. The
product was extracted with ethyl acetate. The organic layer
was evaporated to dryness to get product 4.
General procedure for the synthesis of amide deriva-
tives (6a-e and 11a,b): To a solution of different acids 5a-e
(2.54 mmol) in DMF and N-methylmorpholine (7.64 mmol),
added 3.81 mmol of TBTU (N,N,N′,N′-tetramethyl-O-(benzo-
triazol-1-yl)uronium tetrafluoroborate). Reaction mass was
stirred at room temperature for 1 h.Added 3-fluoro-4-morpho-
linoaniline (4) (2.54 mmol) and stirring continued for 12 h.
Completion of the reaction was monitered by TLC (3:2 hexane:
ethyl acetate).After the completion, reaction mass was poured
onto crushed ice, solid obtained was filtered off, washed with
cold water and dried.All the products were recrystallized using
DMF.
ν
max, cm-1): 3291 (N-H), 2983, 2961 (-C-H), 1631 (C=O), 1576
(C=C), 1118 (C-F); 1H NMR (400 MHz, DMSO-d6, δ in ppm):
10.29 (s, 1H, NH), 7.843 (d, 1H, J = 4 Hz, thiophene-H), 7.572
(d, 1H, J = 16Hz, Ar-H), 7.359 (d, 1H, J = 9Hz, Ar-H), 7.230
(d, 1H, J = 4Hz, thiophene-H), 7.002 (t, 1H, J = 9Hz, Ar-H),
3.699 (t, 3H, J = 4Hz, O-CH2), 2.933 (t, 4H, J = 4.2Hz, N-CH2);
13C NMR (100 MHz, DMSO-d6, δ in ppm): 160, 155.9, 153.5,
139.3, 136.25, 134.3, 133.78, 129.4, 128.6, 119.5, 116.8, 109.1,
66.6, 51.1; MS (m/z): calculated 340.8003, found 340.9494
(M+) and 342.9491 (M+2).
5-Bromo-N-(3-fluoro-4-morpholinophenyl)furan-2-
carboxamide (6d): Yield: 78 %; m.p.: 190-192 ºC; IR (KBr,
νmax, cm-1): 3302 (N-H), 3129 (=C-H), 2961, 2887, 2845 (-C-H),
1654 (C=O), 1592 (C=C), 1120 (C-F); 1H NMR (400 MHz,
DMSO-d6, δ in ppm): 10.23 (s, 1H, NH), 7.622-7.580 (dd, 1H,
J = 2 & 14.2 Hz, Ar-H), 7.423-7.398 (dd, 1H, J = 1.4 & 8.6 Hz,
Ar-H), 7.308 9 (d, 1H, J = 3.6 Hz, furyl-H), 6.992 (t, 1H, J =
9 Hz, Ar-H), 6.801 (d, 1H, J = 3.2 Hz, furyl-H), 3.699 (t, 4H,
J = 4.4 Hz, O-CH2), 2.930 (t, 4H, J = 4.4 Hz, N-CH2); 13C NMR
(100 MHz, DMSO-d6, δ in ppm): 160.6, 160.1, 158.2, 154.3,
140.9, 138.5, 130.5, 124.12, 122.34, 121.6, 119.5, 113.9, 71.3,
55.8; MS (m/z): calculated 368.0172, found 368.9220 (M+)
and 370.9177 (M+2).
2-Chloro-N-(3-fluoro-4-morpholinophenyl)nicotin-
amide (6e):Yield: 85%; m.p.: 202-204 ºC; IR (KBr, νmax, cm-1):
3356 (N-H), 2946, 2917, 2846 (C-H), 1663 (C=O), 1611 (C=N),
1584 (C=C), 1115 (C-F); 1H NMR (400 MHz, DMSO-d6, δ in
ppm): 10.65 (s, 1H, NH), 8.50 (s, 1H, pyridyl-H), 8.03 (d, J =
6.4 Hz, 1H, pyridyl-H), 7.607-7.530 (m, 2H, Ar-H), 7.31 (d, J
= 7.6 Hz, pyridyl-H), 7.016 (t, 1H, J = 8.8 Hz, Ar-H), 3.703
(s, 4H, O-CH2), 2.932 (s, 4H, N-CH2); 13C NMR (100 MHz,
DMSO-d6, δ in ppm): 163.8, 156.0, 153.6, 151.0, 146.9, 138.6,
136.4, 134.1, 133.4, 123.6, 119.7, 116.1, 108.2, 66.6, 51.1;
MS (m/z): calculated 335.0837, found 335.9958 (M+) and
337.9890 (M+2).
Spectral data
3-Fluoro-N-(3-fluoro-4-morpholinophenyl)-4-methyl-
benzamide (6a):Yield: 86 %; m.p.: 178-180 ºC; IR (KBr, νmax
,
cm-1): 3292 (N-H), 2964 (-C-H), 1641 (C=O), 1592 (C=C),
1116 (C-F); 1H NMR (400 MHz, DMSO-d6, δ in ppm): 10.23
(s, 1H, N-H), 7.698-7.642 (m, 3H, Ar-H), 7.449-7.401 (m, 2H,
Ar-H), 7.026-6.980 (t, 1H, Ar-H, J = 9.2Hz), 3.715-3.694 (t,
4H, O-CH2, J = 4.2Hz), 2.946-2.925 (t, 4H, N-CH2, J = 4.2 Hz),
2.277(s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6, δ in ppm):
164.2, 161.9, 159.5, 155.9, 153.5, 136.0, 134.7, 134.5, 134.4,
132.1, 128.8, 128.6, 124.0, 119.4, 119.3, 116.8, 114.6 114.3,
109.1, 108.9, 66.6, 51.2, 14.6; MS (m/z): calculated: 332.1336,
found 333. 0410 (M+1).
6-(3,5-Difluorophenyl)-N-(3-fluoro-4-morpholino-
phenyl)-2-methylnicotinamide (11a):Yield: 76 %; m.p.: 212-
214 ºC; IR (KBr, νmax, cm-1): 3262 (N-H), 2968, 2918, 2845
(C-H), 1641 (C=O), 1118 (C-F); 1H NMR (400 MHz, DMSO-
d6, δ in ppm): 10.51 (s, 1H, NH), 8.035-7.964 (dd, 2H, J = 8.4
& 20 Hz,Ar-H), 7.862-7.840 (m, 2H, pyridyl-H), 7.665-7.622
(dd, 1H, J = 2.2 & 15Hz, Ar-H), 7.387-7.302 (m, 2H, Ar-H),
7.017 (t, 1H, J = 9.4Hz,Ar-H), 3.712 (t, 4H, J = 3.6Hz, O-CH2),
2.61 (s, 3H, CH3), 2.469 (t, 4H, J = 4.6 Hz, N-CH2); 13C NMR

Vol. 32, No. 4 (2020)
Synthesis, Anti-inflammatory Activity and in silico Studies of Some Novel Morpholine Based Carboxamides 903
(100 MHz, DMSO-d6, δin ppm): 166.4, 164.65, 162.1, 156.01,
153.6, 142.0, 137.2, 136.2, 134.5, 132.0, 119.5, 118.2, 116.1,
110.2, 108.38, 105.1, 66.6, 51.2, 23.3. MS (m/z): calculated
(427. 1508), found, 428.0576 (M+1).
where Vt is edema volume in drug treated group and Vc is
edema volume in the control group.
Molecular docking
Ligands preparation: The Chemdraw was used to draw
the structures of the synthesized compounds. Optimization of
the ligands was carried out using macromolecular force field
(MMF) followed by energy minimization protocol [23]. Several
ligand conformations were generated, based on CHARM energy,
bond energy, dihedral energy, initial potential energy, electro-
static energy values, the drug likeliness was evaluated using
the Lipinski rule of 5 via Lipinski drug filter protocol [24] these
studies were performed using Discovery studio 3.5 (Accelrys).
Protein preparation:In this study, COX-1, COX-2 proteins
(PDB ID: 2OYE, 4COX) were selected as target proteins for
anti-inflammatory activity [25,26]. The 3D structures were
retrieved from protein data bank to study the binding mode of
inhibitors. Prior to protein preparation, the inhibitors, other
ligand and water molecules were deleted from the protein to
obtain clean protein. The structures thus obtained were optimized
classically using CHARM force field implemented in theAuto-
dock suite [27], minimized with conjugate gradient energy
minimization protocol followed by convergence energy mini-
mization (0.001 kcal/mol) that arrange the structures for docking
and simulations.
6-(4-Chlorophenyl)-N-(3-fluoro-4-morpholinophenyl)-
2-methylpyridine-3-carboxamide (11b) :Yield: 80 %; m.p.:
224-226 ºC; IR (KBr, νmax, cm-1): 3268 (N-H), 2998, 2964,
2919, 2881 (C-H), 1643 (C=O); 1H NMR (400 MHz, DMSO-
d6, δ in ppm): 10.48 (s, 1H, NH), 8.14 (d, 2H, J = 8.4 Hz,Ar-H),
7.91-7.95 ( m, 2H, pyridyl-H), 7.64 (d, 1H, J = 14 Hz, Ar-H),
7.55 (d, 2H, J = 8.4 Hz, Ar-H), 7.38 ( d, 1H, J = 8.4Hz, Ar-H),
7.01 (t, 1H, J = 9 Hz, Ar-H), 3.71 (t, 4H, O-CH2), 2.94 (t, 4H,
N-CH2), 2.47 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6, δ
in ppm): 166.6 (C=O), 156.0, 155.8, 155.2,153.6, 137.2, 137.0,
136.2, 136.1, 134.7, 134.5, 134.4, 131.2, 129.4, 128.9, 119.5,
117.5, 116.2, 108.5, 108.2, 66.0, 51.1, 23.3; MS (m/z): calcu-
lated (425. 1306), found, 426.0310 (M+1) and 428.0305 (M+3)
Anti-inflammatory activity: The effect of test drug on
carrageenan induced paw edema in rats was studied as per the
method described by Winter et al. [22]. Wistar albino rats of
either sex weighing between 160-230 gwere selected for the
experimentation andthey were randomly divided into three
groups: Group 1: Water control, Group 2: Diclofenac -- (100
mg/kg), Group 3 to 16: CODED drugs.
To a first group, tap water was administered to serve as
control. Second group was taken as standard and administered
with the standard drug diclofenac (100 mg/kg) and group 3 to
16 would be treated with the test drugs. The test drug was admin-
istered once daily for seven consecutive days. On 7th day prior
to carrageenan injection the initial paw volume of left hind
paw was measured using a plethysmometer (Electronic-Orchid)
as follows: after 1 h, drug administration, paw edema would
be produced by injecting 0.1 mL freshly prepared 1 % carrag-
eenan in sterile saline solution to the sub-plantar aponeurosis
of the left hind limb. The rats was administered with the tap
water in the dose of 2 mL/100g body weight to ensure uniform
hydration. This is supposed to minimize the variation in edema
formation. The intensity of edema formation was recorded after
1, 3 and 6h after carrageenan injection. Results was expressed
as percentage increase in paw volume in comparison to the
initial values. Percentage increase in paw volumes was calcu-
lated by subtracting the initial paw volumes from the paw
volumes obtained after the injection of the phlogistic agent.
The figure was divided by the initial paw volume and multi-
plied by hundred.Also percentage of inhibition was calculated
by using the following equation:
For molecular docking studies, a flexible docking approach
was employed using the LeadIT software in which COX proteins
were considered as receptor proteins. The docking results for
receptor-ligand complex comprised intermolecular interaction
energies, namely, hydrogen bonding and hydrophobic and
electrostatic interaction. Receptor-ligand complex with least
binding energy was used to infer the best binding compound.
The best conformations were selected based on the least docking
energy value [28].
RESULTS AND DISCUSSION
Synthesis of N-(3-fluoro-4-morpholinophenyl) substituted
arylamides (6a-e) is depicted in Scheme-I. Initially, 3,4-difluoro-
nitrobenzene (1) was treated with morpholine in the presence
of DIPEA base in DMF solvent to yield compound 3. Nitro
group of compound 3 was then reduced with Sn in HCl to yield
amine 4. Finally, different carboxamides 6a-e were synthesized
by the condensation of amine 4 with substituted aromatic acids
(5a-e) using TBTU as coupling agent in the presence of NMM
base in DMF medium at room temperature.
Synthesis of N-(3-fluoro-4-morpholinophenyl)-2-methyl-
6-substituted-arylpyridine-3-carboxamides was depicted in
Scheme-II. Initially, substituted acetophenones (7a-b) were
reacted with N,N-dimethyl formamide dimethylacetal to yield
V
t
Inhibition (%) =1− ×100
V
c
O
Ar
NH
ii
iii
i
F
NO2
O
N
NH
O
N
NH2
+
O
N
NO2
O
F
F
F
F
2
1
6a-e
4
3
6a: 3-F-4-Me-phenyl, 6b: 2-Thienyl, 6c: 5-Cl-2-thienyl, 6d: 5-Br-2-furyl, 6e: 2-Cl-3-pyridyl
Scheme-I: Synthesis of N-(3-fluoro-4-morpholinophenyl)substituted arylamides (6a-e); Reagents and conditions: (i) DIPEA, DMF, 90 °C
(ii) Sn/conc. HCl (iii) Ar-CO2H (5a-e), HBTU, NMM, DMF, RT, 12 h

904 Honavar et al.
Asian J. Chem.
3-(dimethylamino)-1-aryllprop-2-en-1-ones (8a-b), which were
then subjected to cyclization with ammonium acetate and ethyl-
acetoacetate in ethanolic medium to yield ethyl-2-methyl-6-
arylpyridine-3-carboxylates (9a-b) [29]. These esters were then
hydrolyzed with aqueous NaOH in ethanol to obtain the corres-
ponding carboxylic acids (10a-b). These acids were then coupled
with 3-fluoro-4-morpholinobenzenamine (4) in the presence
of coupling agent (TBTU) in DMF medium and N-methylmor-
pholine base to yield compound 11a-b.
This compound has shown considerable inhibition from the
1st h to 24 h and is found to be equipotent to indomethacin drug.
However other two pyridine derivatives, 11a and 11b were found
to be less potent compared to compound 6e. Compound from
the thiophene series 6b and 6c were found to be active molecule
as they showed considerable inhibition at the end of 24 h.
Compound 6a with 3-fluoro-4-methylphenyl derivative was
emerged as second potent compound in the series with consi-
derable inhibition. Compound 6d with 5-bromofuryl substitu-
tion was least potent aming all the compounds. From the study
it is clear that, compound 6e emerged as highly promising
antiinflammatory compound.
Molecular docking: Molecular docking studies was per-
formed on COX-I (PDB code: 2OYE) and COX-II protein (PDB
code: 4COX) to understand the possible mode of action of the
potent compounds 6e and 6a. The results are depicted in Figs.
1 and 2, respectively. Fig. 1 shows the interaction of compounds
6a and 6e with the COX-I protein. The morpholine oxygen
involves in hydrogen bonding with ARG 67 residue. The N-H
and C=O of amide functionality involves in hydrogen bonding
with GLN106 and ASN143, respectively. The additional
H-bonding interaction in compound 6e appears between the
nitrogen of pyridine with GLN144. This could gives more stab-
ility to compound 6e in the pocket of 2OYE protein. Fig. 2
shows the interaction of compounds 6a and 6e with COX-II
All the compounds were characterized by IR, 1H & 13C
NMR and LC-MS spectral data. IR spectra of compounds 6a-e
and 11a-b showed a strong absorption band for the N-H stret-
ching in the range 3330-3260 cm-1 and a strong carbonyl stret-
ching band in the region 1650-1630 cm-1. The 1H NMR spectrum
of all the target compounds showed a broad singlet for the
N-H proton of the amide in the region 10.2-10.6 ppm, which
clearly indicated the formation of products. Also this is confir-
med by the presence of a carbony carbon signal in the 13C NMR
spectrum in the region 160-167 ppm. LC-MS spectrum of all
the target compounds is in agreement with the molecular weight
of the products.
The antiinflammatory activity of the synthesized comp-
ounds 6a-e and 11a-b is given in Table-1. It is clearly noted
that compound 6e, which is 2-chloro-3-pyridyl substituted
derivative emerged as highly potent candidate in the series.
O
O
O
O
CH3
O
(ii)
CH3
(i)
N
R1
R1
+
N
O
N
CH3
R1
7a,b
8a,b
9a,b
F
O
O
N
O
OH
(iii)
N
(iv)
N
H
R1
N
R1
10a,b
11a,b
11a: 3,5-F2; 11b: 4-Cl
Scheme-II: Synthesis of N-(3-fluoro-4-morpholinophenyl)-2-methyl-6-substituted-arylpyridine-3-carboxamides 11a,b; Reagents and
conditions: (i) Neat reflux (ii) Ethyl acetoacetate, ammonim acetate, EtOH, reflux (iii) 20 % NaOH, ethanol, reflux (iv) TBTU,
NMM, DMF, RT
TABLE-1
ANTIINFLAMMATORY ACTIVITY OF THE COMPOUNDS 6a-e AND 11a, b
Afetr 1 h
Afetr 2 h
Afetr 3 h
Afetr 24 h
Compd.
Inhibition
(%)
Inhibition
(%)
Inhibition
(%)
Inhibition
Swelling
Swelling
Swelling
Swelling
(%)
Cont.
6a
6b
6c
6d
6e
11a
18.95 1.56
27.55 3.83
22.00 3.43
35.66 10.98
35.89 8.15
10.95 1.73
41.58 11.02
36.61 8.78
19.34 3.17
–
22.88 1.66
20.15 3.80
18.63 3.29
32.83 9.72*
32.38 8.95
8.21 1.86
37.49 12.52
52.14 9.83*
11.42 3.09
–
26.68 1.34
14.79 3.64**
12.91 2.23**
19.66 5.53*
27.21 11.21
6.05 1.47**
33.57 11.20
36.65 5.53*
7.00 2.51**
–
22.31 2.17
5.91 3.22**
6.37 0.90**
6.88 1.06
20.85 15.73
2.15 1.60**
16.08 8.52
14.68 1.06
1.43 0.35**
–
-45.38
11.94
44.56
73.50
71.44
69.17
6.54
90.36
27.92
34.19
93.59
-16.09
-98.11
-89.39
42.22
-119.41
-93.19
-2.05
18.58
-43.48
41.52
51.61
26.32
-1.98
77.32
-25.82
-37.36
73.77
64.12
-63.85
-127.88
50.09
11b
Indomethacin

Vol. 32, No. 4 (2020)
Synthesis, Anti-inflammatory Activity and in silico Studies of Some Novel Morpholine Based Carboxamides 905
6a
6a
Interactions
van der Waal
Pi-Donor hydrogen bond
Pi-Pi T-shaped
Pi-Alkyl
Unfavourable furo
Conventional hydrogen bond
Carbon hydrogen bond
6e
6e
Interactions
van der Waal
Pi-Donor hydrogen bond
Pi-Pi T-shaped
Alkyl
Unfavourable furo
Conventional hydrogen bond
Carbon hydrogen bond
Halogen (Cl, Br, I)
Pi-Alkyl
Fig. 1. 3D and 2D docking poses of compounds 6a and 6e with COX-I protein 2OYE
6a
6a
Interactions
van der Waal
Pi-Donor hydrogen bond
Pi-Sigma
Pi-Pi T-shaped
Alkyl
Unfavourable furo
Conventional hydrogen bond
Halogen (Fluorine)
6e
6e
Interactions
van der Waals
Amide-Pi Stacked
Alkyl
Pi-Alkyl
Unfavourable furo
Conventional hydrogen bond
Halogen (Fluorine)
Fig. 2. 3D and 2D docking poses of compounds 6a and 6e with COX-II protein 4COX

906 Honavar et al.
Asian J. Chem.
TABLE-2
DOCKING RESULTS OF TARGET MOLECULES ON COX-I AND COX-II PROTEINS
PDB 2OYE
PDB 4COX
π-π
π-π
Compd.
Docking
score
Docking
score
Hydrogen bond interaction
residue
Hydrogen bond interaction residue
ARG67, ASN143, GLN106
ARG67, ARG86, SER88, SER90,
LYS109
interactionon
residues
interactionon
residues
-10.098
-11.203
PHE108
–
-12.146
-16.603
PHE699, VAL702
GLN695, VAL702, GLY695
PHE699
PHE699
6a
6b
-8.853
Indomethacin -30.583
ARG67, ASN143, GLN144, GLN106
PHE108
–
-10.898
-22.299
GLY695, CYS773
–
GLN695
–
6e
–
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based carboxamides with different aryl and heterocyclic units
in good yields were efficiently synthesized.Anti-inflammatory
activity of these compounds identified a highly potent com-
pound 6e, which is equipotent to indomethacin drug. Also,
compounds 6a and 6b emerged as good inhibitors of inflam-
mation. Docking score and binding of the most active comp-
ounds into the crystal structure of COX proteins is in compatible
with the in vivo antiinflammatory study.
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CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
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