Microwave assisted synthesis, characterization, molecular docking and antiinflammatory activity of p-methoxy cinnamic acid derivatives

Article abstract of DOI:10.14233/ajchem.2018.21302

All the title compounds benzamido-(4-methoxy)-N²-(arylidene)cinnamic acid hydrazide (1-13) were synthesized by the microwave irradiation of α-benzamido-(4-methoxy)cinnamalhydrazide (II) with different aromatic/hetero aromatic aldehydes and char

Full text of DOI:10.14233/ajchem.2018.21302

Asian Journal of Chemistry; Vol. 30, No. 8 (2018), 1781-1786
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2018.21302
Microwave Assisted Synthesis, Characterization, Molecular Docking and
Antiinflammatory Activity of p-Methoxy Cinnamic Acid Derivatives
*
M. SOUJANYA , A.V.L.S. RAMAKRISHNA, CH. PUSHYA RAGINI and V. JYOTHSNA
Department of Pharmaceutical Chemistry, Gokula Krishna College of Pharmacy, Sullurpeta-524 121, India
*Corresponding author: E-mail: soujipharma@gmail.com
Received: 23 February 2018;
Accepted: 21 April 2018;
Published online: 30 June 2018;
AJC-18974
All the title compounds benzamido-(4-methoxy)-N2-(arylidene)cinnamic acid hydrazide (1-13) were synthesized by the microwave
irradiation of α-benzamido-(4-methoxy)cinnamalhydrazide (II) with different aromatic/hetero aromatic aldehydes and characterized by
1
IR, H and 13C NMR, Mass spectral and elemental analysis. Furthermore, all the new derivatives were screened for antiinflammatory
activity by Carrageenan induced rat paw edema method. Compound 3, 6 and 12 exhibited highest activities, which are further supported
by molecular docking studies showed -9.7, -8.1 and -8.6 as dock scores respectively. All the title compounds obey the Lipinski rule of five
and devoid from toxicity assessed by Molinspiration and Osiris online predictors respectively.
Keywords: Cinnamamic acid derivatives, Microwave technique,Antiinflammatory activity, Molecular docking, Lipinski rule of five.
tion with less reaction time and screened for antiinflammatory
(in vivo and molecular docking studies against COX-2 protein
(pdb code: 3LN1)) activity. Further the study was continued
with the prediction of Lipinski rule of five, bioactive scores, drug
likeness score and toxicity profile of synthesized compounds.
INTRODUCTION
Inflammation is the body’s immune response to eliminates
the harmful stimuli and begin the healing process. NSAIDS
are the first drugs of choice to treat inflammation have several
side effects. To overcome these drawbacks different specific
COX-2 inhibitors were introduced. However these are also
withdrawn from the market due to their potential side effects
[1]. All these obstacles prompted us to introduce the newer
agents, which are devoid from the side effects. On the other
hand cinnamic acid and its derivatives possess wide range of
biological activities such as antiinflammatory [2,3], antimicro-
bial [4,5], antioxidant [6], cytotoxicity [7], antihyperlipidemic
[8.9] activities, etc. In addition to this, literature review more
and more focused on another versatile molecule acylhydrazone
exhibited number of biological activities which includes anti-
inflammatory [10,11], analgesic [12], antioxidant [13], anti-
microbial [14,15], anticancer [16], antituberculosis [17,18],
antiviral [19] and antiamoebic activities [20], etc. In the present
era microwave chemistry plays an important role in synthetic
chemistry and reduced the time from hours to minutes and
also enhances the purity and yields [21].
EXPERIMENTAL
All the melting points reported in this series were deter-
mined in open capillaries using Thermonik Pricision melting
point cum boiling point apparatus C-PMB and are uncorrected.
Homogeneity of the compounds was checked by using pre-
coated TLC plates. The IR spectra were recorded using KBr
1
pellets on a Perkin-Elmer 1760 spectrophotometer. H, 13C
NMR spectra were recorded on BrukerAdvance/Jeol 400 MHz
spectrophotometer, using tetramethyl silane as internal stan-
dard. Mass spectra were recorded on an Apex Mass spectro-
photometer, elemental analysis were performed using Flash
EA1112 CHNS analyzer. Microwave irradiation was carried
out in a domestic microwave oven (LGMS, 2.45 MHz). All
the solvents and chemicals were procured from SigmaAldrich
and used without purification.
In light of these facts we have planned to synthesize the
p-methoxy cinnamic acid derivatives by hybridization between
the two important pharmacophores such as cinnamic acid
and hydrazone moieties in order to enhance their multi-target
abilities. All the p-methoxy cinnamic acid derivatives were
synthesized by using microwave technique completes the reac-
Synthesis of 2-phenyl-4-(4-methyl phenyl)oxazol-5-one
(I): Synthesis of 2-phenyl-4-(4-methoxy phenyl)-oxazol-5-one
was done accordance with the previously reported method [22].
Synthesis of α-benzamido-(4-methoxy)cinnamahy-
drazide (II): 2-Phenyl-4-(4-methoxy phenyl)oxazol-5-one (2)
(0.02 mmol) was stirred with a solution of hydrazine hydrate

1782 Soujanya et al.
Asian J. Chem.
(0.04 mmol) in ethanol (30 mL) for 30 min. The bright yellow
colour of oxazolone immediately changed to light yellow
colour, which was filtered, washed, used in next step. Yield:
79 %; m.p. 155-157 °C; IR (KBr, νmax, cm–1): 3228, 3242 (NH2),
3073 (Ar C-H), 1651 (C=O), 1573 (C=C).
General procedure for the synthesis of benzamido-(4-
methoxy)-N2-(arylidene)cinnamic acid hydrazide (1-13):
Equimolar ratios of α-benzamido-(4-methoxy)-cinnamahydra-
zide (II) and different benzaldehydes (0.01 mol) in absolute
ethanol with few drops of glacial acetic acid were transferred
in to reaction flask and allowed to microwave irradiation at
210 watts with 30 s of interval for about 60-210 s. The reaction
was monitored by TLC and the mixture was allowed to cool at
room temperature, filter and purified by recrystallization from
methanol [23]. The physical data of all the p-methoxy cinnamic
acid derivatives (1-13) were given below.
1H, CONHN); Anal. calcd. for C24H21N3O4 (%): C, 69.39; H,
5.10; N, 10.11. Found: C, 69.43; H, 5.17; N, 10.23.
Benzamido-(4-methoxy)-N2-(3,4-dihydroxy benzyli-
dene)cinnamic acid hydrazide (6): Yield: 63 %; m.p. 196-
198 °C; IR (KBr, νmax, cm–1): 3365 (Ar-OH), 3274 (N-H), 3051
1
(Ar C-H), 1678 (C=O), 1594 (C=C); H NMR (400 MHz,
DMSO-d6) δ: 3.76 (s, 3H, -OCH3), 6.80-7.93 (m, 13H, Ar C-
H, HC=C), 8.13 (s, 1H, HC=N), 9.60 (s, 2H, Ar-OH), 10.00
(s, 1H, CONH), 11.37 (s, 1H, CONHN); 13C NMR (100 MHz,
DMSO-d6) δ 55.9, 114.2, 122.4, 127.4, 127.5, 128.9, 132.2,
134.2, 143.0, 147.4, 149.6, 163.6.Anal. calcd. for C24H21N3O5
(%): C, 66.81; H, 4.91; N, 9.74. Found: C, 66.74; H, 4.85; N,
9.70;
Benzamido-(4-methoxy)-N2-(4-chlorobenzylidene)-
cinnamic acid hydrazide (7): Yield: 76 %; m.p. 170-172 °C;
IR (KBr, νmax, cm–1): 3221 (N-H), 3091 (Ar C-H), 1665 (C=O),
1601 (C=C); 1H NMR (400 MHz, DMSO-d6) δ: 3.76 (s, 3H,
-OCH3), 7.01-8.24 (m, 14H, Ar C-H), 8.27 (s, 1H, HC=N),
10.17 (s, 1H, CO-NH), 11.48 (s, 1H, CO-NHN); 13C NMR
(100 MHz, DMSO-d6) δ 55.9, 114.2, 122.4, 127.4, 127.5,
127.8, 128.9, 129.0, 130.6, 131.9, 132.2, 134.2, 143.0, 159.9,
163.6, 168.0. EI-MS m/z; 433 (M+).Anal. calcd. for C24H20N3O3Cl
(%): C, 66.44; H, 4.65; N, 9.68. Found: C, 66.51; H, 8.21; N,
9.57.
Benzamido-(4-methoxy)-N2-(benzylidene)cinnamic
acid hydrazide (1) [24]: Yield: 71 %; m.p. 180-182 °C; IR
(KBr, νmax, cm–1): 3201 (N-H), 3044 (Ar C-H), 1634 (C=O),
1602 (C=C); 1H NMR (400 MHz, DMSO-d6) δ: 3.77 (s, 3H,
OCH3), 6.95-8.06 (m, 15H,Ar C-H, C=C), 8.42 (s, 1H, CH=N),
10.03 (s, 1H, CONH), 11.60 (s, 1H, CONHN); EI-MS m/z;
399 (M+). Anal. calcd. for C24H21N3O3 (%): C, 72.16; H, 5.30;
N, 10.52. Found: C, 72.25; H, 5.39; N, 10.30.
Benzamido-(4-methoxy)-N2-(4-methoxy benzylidene)-
cinnamic acid hydrazide (2) [23]:Yield: 73 %; m.p. 184-186
°C; IR (KBr, νmax, cm–1): 3244 (N-H), 3075 (Ar C-H), 1659
(C=O), 1599 (C=C); 1H NMR (400 MHz, DMSO-d6) δ: 3.77
(s, 3H, -OCH3), 3.80 (s, 3H, -OCH3), 6.95-8.05 (m, 14H, Ar-
C-H, C=CH), 8.33 (s, 1H, CH=N), 10.02 (s, 1H, CONH), 11.49
(s, 1H, CONHN); EI-MS m/z; 429 (M+). Anal. calcd. for
C25H23N3O4 (%): C, 69.92; H, 5.40; N, 9.78. Found: C, 69.88;
H, 5.48; N, 9.69
Benzamido-(4-methoxy)-N2-(2,4-dichlorobenzylidene)-
cinnamic acid hydrazide (8):Yield: 74 %; m.p. 207-209 °C;
IR (KBr, νmax, cm–1): 3234 (N-H), 3078 (Ar C-H), 1681 (C=O),
1603 (C=C); 1H NMR (400 MHz, DMSO-d6) δ:3.73 (s, 3H, -
OCH3), 7.10-8.13 (m, 13H, Ar C-H, HC=C), 8.26 (s, 1H,
HC=N), 10.36 (s, 1H, CONH), 11.51 (s, 1H, CONHN); Anal.
calcd. for C24H19N3O3Cl2 (%): C, 61.55; H, 4.09; N, 8.97.
Found: C, 61.62; H, 4.13; N, 8.90.
Benzamido-(4-methoxy)-N2-(3-nitrobenzylidene)-
cinnamic acid hydrazide (9):Yield: 78 %; m.p. 164-167 °C;
IR (KBr, νmax, cm–1): 3210 (N-H), 3061 (Ar C-H), 1656 (C=O),
1599 (C=C); 1H NMR (400 MHz, DMSO-d6) δ: 3.76 (s, 3H,
-OCH3), 7.11-8.21 (m, 14H, Ar C-H, HC=C), 8.28 (s, 1H,
HC=N), 10.21 (s, 1H, CONH), 11.65 (s, 1H, CONHN); 13C
NMR (100 MHz, DMSO-d6) δ55.9, 114.2, 122.4, 122.9, 126.2,
127.4, 127.5, 127.8, 128.9, 129.8, 132.2, 134.2, 134.7, 135.3,
143.0, 148.1, 163.6, 168, 169.9. Anal. calcd. for C24H20N4O5
(%): C, 64.86; H, 4.54; N, 12.61. Found: C, 64.84; H, 4.65; N,
12.48.
Benzamido-(4-methoxy)-N2-(3,4-dimethoxy benzyli-
dene)cinnamic acid hydrazide (3): Yield: 69 %; m.p. 197-
199 °C; IR (KBr, νmax, cm–1): 3262 (N-H), 3023 (Ar C-H), 1662
(C=O), 1603 (C=C); 1H NMR (400 MHz, DMSO-d6) δ: 3.77-
3.78 (s, 9H, -OCH3), 6.85-8.07 (m, 13H, Ar C-H, C=C), 8.21
(s, 1H, HC=N), 10.06 (s, 1H, CONH), 11.52 (s, 1H, CONHN);
13C NMR (100 MHz, DMSO-d6): δ 55.9, 56.2, 114.2, 114.4,
115.4, 122.4, 122.5, 127.1, 127.4, 127.5, 128.9, 132.2, 134.2,
143.0, 149.9, 152.1, 159.9, 163.6, 168.Anal. calcd. for C26H25N3O6
(%): C, 67.96; H, 5.48; N, 9.14. Found: C, 67.84; H, 5.37; N,
9.25.
Benzamido-(4-methoxy)-N2-(3,4-dimethoxy-4-hydroxy
benzylidene)cinnamic acid hydrazide (10): Yield: 65 %;
m.p. 214-216 °C; IR (KBr, νmax, cm–1): 3243 (N-H), 3031 (Ar
C-H), 1683 (C=O), 1603 (C=C); 1H NMR (400 MHz, DMSO-
d6) δ: 3.72-3.75 (s, 9H, OCH3), 6.90-8.13 (m, 12H, Ar C-H,
HC=C), 8.17 (s, 1H, HC=N), 9.46 (s, 1H, OH), 10.10 (s, 1H,
CO-NH), 11.48 (s, 1H, CONHN);Anal. calcd. for C26H25N3O6
(%): C, 65.67; H, 5.30; N, 8.84. Found: C, 65.80; H, 5.54; N,
8.61.
Benzamido-(4-methoxy)-N2-(3,4,5-trimethoxy benzyli-
dene)cinnamic acid hydrazide (4): Yield: 65 %; m.p. 211-
213 °C; IR (KBr, νmax, cm–1): 3278 (N-H), 3011 (Ar C-H), 1652
(C=O), 1598 (C=C); 1H NMR (400 MHz, DMSO-d6) δ: 3.78-
3.81 (s, 12H, -OCH3), 6.91-8.02 (m, 12H,Ar C-H), 8.28 (s, 1H,
HC=N), 10.01 (s, 1H, CONH), 11.38 (s, 1H, CONHN); EI-
MS m/z; 489 (M+). Anal. calcd. for C27H27N3O6 (%): C, 66.25;
H, 5.56; N, 8.58. Found: C, 66.36; H, 5.48; N, 8.48.
Benzamido-(4-methoxy)-N2-(4-hydroxy benzylidene)-
cinnamic acid hydrazide (5): Yield: 70 %; m.p. 189-191 °C;
IR (KBr, νmax, cm–1): 3207 (N-H), 3101 (Ar C-H), 1675 (C=O),
1612 (C=C); 1H NMR (400 MHz, DMSO-d6) δ: 3.74 (s, 3H,
Ar-OCH3), 6.91-8.20 (m, 14H, Ar C-H, C=C), 8.21 (s, 1H,
HC=N), 9.62 (s, 1H, Ar-OH), 10.12 (s, 1H, CONH), 11.42 (s,
Benzamido-(4-methoxy)-N2-(isopropyl benzylidene)-
cinnamic acid hydrazide (11): Yield: 66 %; m.p. 207-209 °C;
IR (KBr, νmax, cm–1): 3237 (N-H), 3027 (Ar C-H), 1680 (C=O),
1
1610 (C=C); H NMR (400 MHz, DMSO-d6) δ: 1.2 (d, 6H,
(CH3)2), 2.9 (s, 1H, CH(CH3)2), 3.73 (s, 3H, -OCH3), 6.90-
8.13 (m, 14H, Ar C-H, CH=C), 8.12 (s, 1H, CH=N), 10.09 (s,

Vol. 30, No. 8 (2018)
Synthesis, Molecular Docking and Antiinflammatory Activity of p-Methoxy Cinnamic Acid Derivatives 1783
1H, CO-NH), 11.52 (s, 1H, CONHN); Anal. calcd. for
C27H27N3O3 (%): C, 73.45; H, 6.16; N, 9.52. Found: C, 73.55;
H, 6.22; N, 9.78.




V
t
Inhibition (%) =100 1−

(1)
V

c
Benzamido-(4-methoxy)-N2-[(indol-3-yl)methylene]-
cinnamic acid hydrazide (12):Yield: 73 %; m.p. 161-163 °C;
IR (KBr, νmax, cm–1): 3310 (N-H), 3061 (Ar-CH), 1682 (C=O),
1608 (C=C); 1H NMR (400 MHz, DMSO-d6) δ: 3.76 (s, 3H,
-OCH3), 6.96- 8.32 (m, 15H, Ar CH, CH=C), 10.06 (s, 1H,
CO-NH), 10.51 (s, 1H, CO-NHN), 11.61 (s, 1H, NH); EI-MS
m/z; 439 (M+1)+. Anal. calcd. for C26H22N4O3 (%): C, 70.89;
H, 5.49; N, 12.72. Found: C, 70.61; H, 5.36; N, 12.71.
Benzamido-(4-methoxy)-N2-[(fur-2-yl)methylene]-
cinnamic acid hydrazide (13):Yield: 68 %; m.p. 177-179 °C;
IR (KBr, νmax, cm–1): 3256 (N-H), 3019 (Ar C-H), 1678 (C=O),
1588 (C=C); 1H NMR (400 MHz, DMSO-d6) δ: 3.78 (s, 3H,
-OCH3), 6.70-7.96 (m, 13H, Ar C-H, HC=C), 8.09 (s, 1H,
HC=N), 10.08 (s, 1H, CONH), 11.48 (s, 1H, CONHN); Anal.
calcd. for C22H19N3O4 (%): C, 67.86; H, 4.92; N, 10.79. Found:
C, 67.81; H, 4.88; N, 10.72.
where, Vc volume of the edema in the control group and Vt
volume of the edema in the treated group. Statistical signi-
ficance of the results was tested by Dunnet’s test.
Molecular docking: Molecular docking of compounds
1-13 with the 3D X-ray crystal structure of human COX-2
retrieved from the Protein Data Bank (PDB code: 3LN1) was
imported in to MCULE, the online drug discovery plat form.
The structure of title compounds were drawn using chem
sketch 12.0 software available in MCULE and run the docking
for a selected target. Consequently it generates the different
pose of ligands with the target and among those we can select
the best pose of ligand, which gained the good dock score.
Molecular property prediction: Molecular properties
like log P (lipophilicity), total polar surface area (TPSA),
number of hydrogen bond donors (HBD) and acceptors (HBA),
number of rotatable bonds and as well as prediction of
bioactivity score for the important drug targets like GPCR
ligands, kinase inhibitors, ion channel modulators, enzymes
and nuclear receptors were assessed by the online tool kit
Molinspiration (www.molinspiraton.com) [25]. The Osiris
Property Explorer is an integral part of Actelion’s in-house
substance registration system. It calculate the various drug
relevant properties such as log S (solubility), drug likeness
score and toxicity such as mutagenicity, tumorogenicity, irritant
and reproductive effects [26].
Pharmacological screening
in vivoAntiinflammatory activity [24]:The in vivo anti-
inammatory activity of all title compounds was evaluated using
carrageenan-induced rat paw edema in male albino rats (150-
180 g) of Wistar strain. The rats were divided into groups of
six animals. Control group received 0.5 % sodium carboxy
methylcellulose, the standard group received standard drug
indomethacin 5 mg/kg body weight and the test groups
received the title compounds at the dose of 100 mg/kg body
weight. The volume of paw was measured by plethysmograph
immediately after carrageenan injection. The paw volume was
again measured after 3 h. A mark was made at the lateral
malleolus and the foot was dipped to the same distance into
the arm of the plethysmograph. Average edema volumes for
test compound treated and positive control rats were compared
statistically and the percentage of edema inhibition was
calculated using the formula:
RESULTS AND DISCUSSION
All the p-methoxy cinnamic acid derivatives (1-13) were
synthesized by the reaction between the α-benzamido-(4-
methoxy)-cinnamalhydrazide (II) and aromatic/hetero
aromatic aldehydes under microwave irradiation with less
reaction time (60-210 s) and yields were good (63-78 %)
(Scheme-I). Compound II has been synthesized from
O
O
Cl
HO
N
HC
O
+
OH
H2N
H
+
STEP 1
O
O
O
a
STEP 2
O
O
O
NH2NH2
O
O
R
b
STEP 3
NH
c
O
STEP 4
HN
NH2
NH
N NH
O
R
O
N
O O
(II)
(1-13)
(I)
(a): (CH3CO)2 O/zinc oxide; (b): Absolute ethanol, stirring; (c): MW at 210 watts; R = Phenyl (1); 4-methoxy phenyl (2); 3,4,-Dimethoxy
phenyl (3); 3,4,5-Trimethoxy phenyl (4); 4-Hydroxy phenyl (5); 3,4-Dihydroxy phenyl (6); 4-Chloro phenyl (7); 2,4-Dichloro phenyl (8);
3-Nitro phenyl (9); 3,5-Dimethoxy-4-hydroxy phenyl (10); 4-Isopropyl phenyl (11); Indol-3-yl (12); 2-Furyl (13)
Scheme-I: General sequence of reactions for the synthesis of title compounds 1-13

1784 Soujanya et al.
Asian J. Chem.
TABLE-1
compound I by the action of hydrazine hydrate which attacks
the oxazole ring at the highly susceptible carbonyl site. Com-
pound I was prepared according to the procedure given in
literature. All the title compounds were characterized by the
in vivo ANTI-INFLAMMATORY ACTIVITY AND
MOLECULAR DOCK SCORES OF TITLE COMPOUNDS 1-13
Edema volume
SD)a
Edema
Dock score
(Kcal/mol)
S. No. Compd.
(
inhibition (%)c
1
spectral data IR, H NMR, 13C NMR, Mass and elemental
1
2
1
2
0.17 (0.10)
0.22 (0.04)
0.14 (0.04)
0.39 (0.02)
0.25 (0.05)
0.15 (0.04)
0.16 (0.08)
0.28 (0.22)
0.33 (0.10)
0.30 (0.01)
0.16 (0.12)
0.15 (0.06)
0.19 (0.03)
0.14 (0.02)
68.5 *
59.2
74.0 *
27.7 *
53.7
72.2*
70.3*
48.1
38.8
44.4 *
70.3
72.2 *
64.8*
-8.5
-8.0
-9.7
-6.6
-4.9
-8.6
-8.3
-7.8
-7.4
-7.7
-7.9
-8.1
-8.2
-8.7
analysis. The IR spectral data of title compounds (1-13)
revealed bands at 3278-3201 cm–1 and 1681-1634 cm–1 due to
the presence of NH and C=O peaks respectively. Appearance
of two more bands between 3101-3011 cm–1 and 1612-1588
cm–1 regions indicated the presence of aromatic -C-H, C=C-
groups in all the cinnamic acid hydrazides. 1H NMR spectra
data showed a singlet at δ 8.09-8.42 region due to CH=N
indicates the formation of title compounds. Appearance of
singlet at δ 10.00-10.36, δ 11.37-11.60 and δ 3.72-3.81 is due
to the CONHC-, CONHN- and aromatic OCH3 groups, respec-
tively. Singlet at δ 1.2 and multiplet at δ 6.70-8.32 region due
to the methyl (11) and aromatic protons of title compounds.
Additional support for the structures of title compounds was
provided by 13C NMR spectra revealed two peaks at δ 163-
169 and around δ 143-due to -CONH and HC=N, respectively.
Appearance of peaks between δ 114-159 due to the presence
of aromatic/heroaromatic carbons and also appearance of signal
around δ 55 indicated the presence of-OCH3. The mass spectral
data revealed the presence of molecular ion peaks at m/z 399,
429, 489, 433 and 439 indicates the formation of title compounds
1, 2, 4, 7 and 12, respectively.
Antiinflammatory activity: All the title compounds 1-13
screened for in vivo antiinflammatory activity by carrageenan
induced rat paw edema method and the results were given in
Table-1. Among all, compound 3 exhibited highest activity
which is equal to the standard drug indomethacin (74 %).
Compounds 6 and 12 showed equal activities (72 %) which
are comparable to the standard. The good activity of compound
12 might be due to the presence of additional electron rich
heterocyclic ring at the hydrazone end of the molecule. This
result is in accordance with the previous report stated that the
presence of indole moiety in the acylhydrazone framework
enhances the antiinflammatory activity [27,28]. Compounds
11 (4-isopropyl phenyl derivative), 7 (4-chloro phenyl deriva-
tive) and 1 (phenyl derivative) exhibited significant activities
3
3
4
4
5
5
6
6
7
7
8
8
9
9
10
11
12
13
14
10
11
12
13
Std
74.0*
a
Significant levels *p < 0.001 by Dunnet’s test; Edema volume was
measured 3 h after carrageenan injection and expressed as mean
standard deviation; Control edema volume = 0.54 0.03; At 100
mg/kg (p.o) percent edema inhibition was calculated by comparing
edema volume of test/std with that of the respective control animals
b
c
followed by 2-furyl, 4-methoxy and 4-hydroxy derivatives. The
results suggested that the type of substitution at the hydrazone
end played an important role such as presence of activating
groups on the aromatic ring (compounds such as 2, 3, 5 and
11) enhances the activity profile compared to the other substi-
tutions (compound 9, 13 and 7) [19]. It is interesting to note that
increases the number of methoxy group on the phenyl ring (at
the imine end) increases the activity up to dimethoxy groups
(compound 1 < 2 < 3 > 4 derivatives).
Molecular docking: Further all the title compounds 1-13
were docked into COX-2 (PDB code: 3LN1) protein and the
results were depicted in Table-1. Docking results revealed that
the aromatic substitution at the hydrazide end is responsible
for binding of ligand with the hydrophobic cavity of target
protein, which alters the activity profile of compounds. All
the derivatives showed good to moderate affinity towards the
target assessed by using one click molecular docking tool.
Among all compound 3 (-9.7) showed highest docking score
TABLE-2
MOLECULAR DESCRIPTORS OF TITLE COMPOUNDS 1-13
Compd.
log P
log S
TPSA
% ABS n-HBA n-HBD n-ROTB
MW
MUT
TUM
IRR
REPE
DL
1
2
3
4
5
6
7
8
9
10
11
12
13
4.7
4.6
4.6
4.5
4.4
4.0
5.3
5.9
4.1
4.0
5.9
4.0
3.9
-5.4
-5.5
-5.5
-5.5
-5.1
-5.8
-6.2
-6.9
-6.2
-4.8
-6.3
-5.6
-5.1
79.7
89.0
98.2
107.5
100.0
120.2
79.7
79.7
125.6
118.4
79.7
95.5
92.9
81.6
78.3
75.2
72.0
74.5
67.6
81.6
81.6
65.7
68.3
81.6
76.1
77.0
6
7
8
9
7
8
6
6
8
8
6
7
7
2
2
2
2
3
4
2
2
1
2
2
3
2
7
8
9
10
7
7
7
7
8
9
399
429
459
489
415
431
433
468
444
475
441
438
389
G
G
G
G
G
G
G
G
G
G
G
G
R
G
G
R
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
R
G
G
G
G
6.35
6.35
6.35
6.35
6.34
6.34
6.38
6.38
0.63
4.72
6.09
7.16
6.01
8
7
7
log P: Lipophilicity; log S: Solubility; TPSA: Total polar surface area; n-HBA: No of hydrogen bond acceptors; n-HBD: No of hydrogen bond
donors; n-VIO: n-Violations; n-ROTB: No of rotatable bonds; MW: Molecular weight; MUT: Mutagenic; TUM: Tumerigenic; IRR: Irritant; REPE:
Reproductive effect; DL: Drug-likeness score; G: No Risk; R: High Risk.

Vol. 30, No. 8 (2018)
Synthesis, Molecular Docking and Antiinflammatory Activity of p-Methoxy Cinnamic Acid Derivatives 1785
than standard indomethacin (-7.18) followed by compound 6 (-8.6),
1 (-8.5) and 7 (-8.3). Amino acids VAL 492, GLU493, GLY
495, ALA496, VAL 318, SER 322, LEU321, HIS 63, GLY 323,
TYR 359, THR 356, GLU161, ASN 484, LEU 353, HIS 320,
MET 491, LEU353, HIS 320, HER 322 and PHE 430 were found
at the active site of human COX-2 with title compounds and
illustrated in Figs. 1-4. Docking results of the active compounds
were further supported by in vivo antiinflammatory results.
Molecular properties predictions: The efficacy of any
drug depends on its high oral bioavailability in human beings.
For any compound to become a successful drug candidate it
should satisfy the Lipinski’s rule of five which stated that any
compound to become orally active drug, if it should have mole-
cular weight not more than 500, partition coefficient (log P)
below 5, number of hydrogen bond donors not more than 5 and
number of hydrogen bond acceptors not more than 10. Topolo-
gical polar surface area is another descriptor used to assess
the drug transporter properties. TPSA is the sum of surfaces
of polar atoms such as oxygen, nitrogen and attached hydrogen.
The % of absorbance was calculated by the following equation
[29]:
% ABS = (109-0.345) × TPSA
The predicted values revealed that log P, TPSA, % absor-
ption and log S found between 3.9 to 5.9; 79.2 to 125.6; 65.7
to 81.6 % and-4.82 to -6.90, respectively, Table-2. For a potent
compound to be orally effective it should show no more than
one violation of Lipinski’s rule of five. The bioactivity scores of
the title compounds 1-13 towards GPCR, kinase inhibitor,
protease inhibitor and enzyme inhibitor mechanisms were calcu-
lated using Molinspiration programme and depicted in Table-3.
If the bioactivity score for a molecule is more than 0 then it is
active; between -0.5 to 0 then moderately active [30]. The results
revealed that all the compounds displayed more selectivity towards
enzyme inhibition (in the range of -0.30 to -0.54), which gave
additional support to the result of predicted antiinflammatory
activities [31]. It is interesting to note that compound 12 exhibited
good affinity towards enzyme inhibition.
Fig. 1. Interaction of compound 3 with COX-2
TABLE-3
BIOACTIVE SCORES OF TITLE COMPOUNDS 1-13
Fig. 2. Interaction of compound 6 with COX-2
Compd. GPCRL
ICM
-0.77
-0.72
-0.70
-0.71
-0.70
-0.69
-0.75
-0.75
-0.75
-0.67
-0.70
-0.65
-0.86
KI
NRL
-0.82
-0.77
-0.74
-0.74
-0.70
-0.70
-0.81
-0.84
-0.83
-0.68
-0.71
-0.72
-1.07
PI
EI
-0.47
-0.44
-0.43
-0.42
-0.41
-0.41
-0.46
-0.47
-0.56
-0.41
-0.42
-0.28
-0.61
-0.54
-0.51
-0.49
-0.46
-0.48
-0.49
-0.54
-0.54
-0.60
-0.45
-0.52
-0.38
-0.73
-0.48
-0.45
-0.46
-0.45
-0.45
-0.45
-0.50
-0.52
-0.56
-0.43
-0.45
-0.42
-0.60
-0.41
-0.38
-0.37
-0.35
-0.35
-0.34
-0.42
-0.42
-0.47
-0.31
-0.37
-0.30
-0.54
1
2
3
4
5
6
7
8
9
10
11
12
13
Fig. 3. Interaction of compound 12 with COX-2
GPCRL: G protein coupled receptor ligand; ICM: Ion channel
modulators; KI: Kinase inhibitor; NRL: Nuclear receptor ligand; PI:
Protease inhibitor; EI: Enzyme inhibitor.
However, toxicity is also one of the important issue could
be addressed for all the lead compounds before its selection.
All the title compounds 1-13 free from risk of toxicity (muta-
genicity, tumorogenicy, irritability and reproductive effects)
except compounds 9 and 13predicted by OSIRIS. Drug likeness
score may be defined as a complex balance of various molecular
properties and structure features which determine whether
particular molecule is similar to the known drugs and positive
scores are desirable. All the title compounds showed positive
Fig. 4. Interaction of standard with COX-2

1786 Soujanya et al.
Asian J. Chem.
L.M. Lima, E.J. Barreiro, M. González and H. Cerecetto, Bioorg. Med.
Chem., 20, 2158 (2012);
https://doi.org/10.1016/j.bmc.2012.01.034.
drug likeness scores 0.63-7.16 and compound 12 scored the
highest drug likeness score assessed by OSIRIS tool.
13. G. Rajitha, N.Saideepa and Praneetha, Indian J. Chem., 50B, 729
(2011).
14. M.Soujanya and G.Rajitha, Int. J. Pharmaceut. Sci. Res., 8, 3786
(2017).
15. M.Soujanya and G.Rajitha, Derpharma chemica, 9, 10 (2017).
16. A.T. Mavrova, D. Wesselinova, N. Vassilev and J.A. Tsenov, Eur. J.
Med. Chem., 63, 696 (2013);
Conclusion
All the p-methoxy cinnamic acid derivatives (1-13) were
synthesized in good yields with less reaction time by using
microwave technique. Compound 3 exhibited good anti-
inflammatory activity, which is comparable to the standard
drug indomethacin. Further, the docking results of active
compounds were correlated with the molecular docking results.
Title compounds obey the Lipinski rule of five, good percen-
tage of oral absorption and free from toxicity accessed by using
different tools.
https://doi.org/10.1016/j.ejmech.2013.03.010.
17. E.Vavrikova, S. Polanc, M. Kocevar, K. Horvati, S. Bosze, J. Stolarikova,
K. Vavrova and J. Vinsova, Eur. J. Med. Chem., 46, 4937 (2011);
https://doi.org/10.1016/j.ejmech.2011.07.052.
18. J.D. Bhatt, C.J. Chudasama and K.D. Patel, Bioorg. Med. Chem., 23,
7711 (2015);
https://doi.org/10.1016/j.bmc.2015.11.018.
REFERENCES
19. J.Yinxue, T. Zhiwu and H. Meizi, Bioorg. Med. Chem., 12, 2135 (2010).
20. S.M. Siddiqui, A. Salahuddin and A. Azam, Eur. J. Med. Chem., 49,
411 (2012);
1. P. McGettigan and D. Henry, JAMA, 296, 1633 (2006);
https://doi.org/10.1001/jama.296.13.jrv60011.
2. E. Pontiki, D. Hadjipavlou-Litina, G. Geromichalos andA. Papageorgiou,
Chem. Biol. Drug Des., 74, 266 (2009);
https://doi.org/10.1111/j.1747-0285.2009.00864.x.
3. E. Pontiki and D. Hadjipavlou-Litina, Bioorg. Med. Chem., 15, 5819
(2007);
https://doi.org/10.1016/j.bmc.2007.06.001.
4. S. Naz, S. Ahmad, S. Ajaz Rasool, S. Asad Sayeed and R. Siddiqi,
Microbiol. Res., 161, 43 (2006);
https://doi.org/10.1016/j.micres.2005.05.001.
5. M. Sova, Mini Rev. Med. Chem., 12, 749 (2012);
https://doi.org/10.2174/138955712801264792.
https://doi.org/10.1016/j.ejmech.2012.01.030.
21. N. Karaman, E.E. Oruc-Emre, Y. Sicak, B. Çatikka, A. Karaküçük-
Iyidogan and M. Öztürk, Med. Chem. Res., 25, 1590 (2016);
https://doi.org/10.1007/s00044-016-1592-0).
22. G. Fareed, N. Afza, A. Versiani, N. Fareed, R. Mughal, A. Kalhoro, L.
Iqbal and M. Lateef, J. Serb. Chem. Soc., 78, 1127 (2013);
https://doi.org/10.2298/JSC120917126F.
23. M. Soujanya, M. Lakshmi narayana, T.Sarala devi, S. Anusha and G.
Rajitha, Int. J. Pharmacy Technol., 6, 6193 (2014).
24. C.A. Winter, E.A. Risley and G.W. Nuss, Proc. Soc. Exp. Biol. Med.,
111, 544 (1962);
https://doi.org/10.3181/00379727-111-27849.
6. E. Pontiki, D. Hadjipavlou-Litina, K. Litinas and G. Geromichalos,
Molecules, 19, 9655 (2014);
https://doi.org/10.3390/molecules19079655.
7. P. De, M. Baltas and F. Bedos-Belval, Curr. Med. Chem., 18, 1672
(2011);
25. Molinspiration cheminformatics [homepage on the internet], Available
from: http://www.molinspiration.com. [Cited 2013 March 3].
http://www.Molinspiration.Com/cgi-bin/properties.
26. P. Ertl, B. Rohde and P. Selzer, J. Med. Chem., 43, 3714 (2000);
https://doi.org/10.1021/jm000942e.;
27. M. Soujanya and G. Rajitha, Letts. Drug Design Discov., 14, (2017)(In
press).
28. S.M. Sondhi, M. Dinodia andA. Kumar, Bioorg. Med. Chem., 14, 4657
(2006);
https://doi.org/10.2174/092986711795471347.
8. L.Y. Zang, G. Cosma, H. Gardner, X. Shi, V. Castranova and A.
Vallyathan, J. Physiol. Cell Physiol., 279, C954 (2000);
https://doi.org/10.1152/ajpcell.2000.279.4.C954.
9. K. Mnafgui, A. Derbali, S. Sayadi, N. Gharsallah, A.S. Elfeki and N.
Allouche, J. Food Sci. Technol., 52, 4369 (2015);
https://doi.org/10.1007/s13197-014-1488-2.
10. M. Soujanya and G. Rajitha, Asian J. Chem., 29, 2479 (2017);
https://doi.org/10.14233/ajchem.2017.20785.
11. G. Rajitha, K.V.S.R.G. Prasad, A. Umamaheswari, D. Pradhan and K.
Bharathi, Med. Chem. Res., 23, 5204 (2014);
https://doi.org/10.1016/j.bmc.2006.02.014.
29. B. Vishwanathan, B.M. Gurupadayya and K.V. Sairam, Bangladesh J.
Pharmacol., 11, 67 (2015);
https://doi.org/10.3329/bjp.v11i1.23981.
30. A. Verma, Asian Pacific J. Trop. Biomed., 3, S1735 (2012).
31. A.R. Mullaicharam, N. Halligudi and H.S. Al-bahri, Int. J. Nutr.
Pharmacol. Neur. Diseases, 2, 156 (2012);
https://doi.org/10.1007/s00044-014-1091-0.
12. P. Hernández, M. Cabrera, M.L. Lavaggi, L. Celano, I. Tiscornia, T.
Rodrigues da Costa, L. Thomson, M. Bollati-Fogolín, A.L.P. Miranda,
https://doi.org/10.4103/2231-0738.95991.