Synthesis, in vitro and molecular docking studies of 1-(3,4-dimethoxy-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-penta-1,4-dien-3-one as new potential anti-inflammatory

Article abstract of DOI:10.14233/ajchem.2018.21297

Synthesis of new asymmetrical curcumin analogue of 1-(3,4-dimethoxy-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-penta-1,4-dien-3-one via condensation reaction between vanillinacetone and veratraldehyde in ethanol has been performed. The in vitro anti-inflammatory activities of the synthesized compounds showed excellent anti-inflammatory activity. In vitro anti-inammatory activity by using inhibition of albumin denaturation technique compared to standard dichlorofenac. Molecular docking studies were performed, where docking of the compound into 6COX active site suggested that it could exert its anti-inflammatory potential by cyclooxygenase inhibition.

Full text of DOI:10.14233/ajchem.2018.21297

Asian Journal of Chemistry; Vol. 30, No. 8 (2018), 1765-1770
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2018.21297
Synthesis, in vitro and Molecular Docking Studies of 1-(3,4-Dimethoxy-phenyl)-5-(4-hydroxy-
3-methoxy-phenyl)-penta-1,4-dien-3-one as New Potential Anti-inflammatory
2
2
MARIO ROWAN SOHILAIT1,2,*, HARNO DWI PRANOWO and WINARTO HARYADI
1Department of Chemistry, Faculty of Mathematics and Natural Sciences, Pattimura University, Jl.Ir.M. Putuhena, Kampus Poka, Ambon
97233, Indonesia
2Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Jl. Sekip Utara, Yogyakarta 55281,
Indonesia
*Corresponding author: E-mail: rio.rowan@gmail.com
Received: 20 February 2018;
Accepted: 26 April 2018;
Published online: 30 June 2018;
AJC-18971
Synthesis of new asymmetrical curcumin analogue of 1-(3,4-dimethoxy-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-penta-1,4-dien-3-one
via condensation reaction between vanillinacetone and veratraldehyde in ethanol has been performed. The in vitro anti-inflammatory
activities of the synthesized compounds showed excellent anti-inflammatory activity. In vitro anti-inammatory activity by using inhibition
of albumin denaturation technique compared to standard dichlorofenac. Molecular docking studies were performed, where docking of the
compound into 6COX active site suggested that it could exert its anti-inflammatory potential by cyclooxygenase inhibition.
Keywords: Curcumin analogues, Anti-inflammatory, Molecular docking, Synthesis, in vitro.
Curcumin, a well-known acyclic diarylheptanoid, has been
identified as the major constituent in turmeric and it has been
known for some time that curcuminoids have been used as a
natural food additive. It belongs to the group of β-diketones
and exhibits tautomerism between enol- and keto-structures.
It has attracted special attention due to its potent pharmo-
calogical activities such as to protect cells from β-amyloid
insult in Alzheimer’s disease [23] and cancer preventive
properties [24]. Biological activities of curcumin chelated to
metal ions as well as antioxidant effects of curcumin are also
well documented in literature [25]. The enol form is charac-
terized by a strong intra-molecular hydrogen bond. When the
enol group forms the intra-molecular hydrogen bond, the β-
diketone undergoes changes towards the total π-system
delocalization [26]. There is a strong correlation between the
π-system delocalization and the strengthening of the intra-
molecular hydrogen bond. Moreover, in solution curcumin can
form inter-molecular H-bonds with the solvent molecules and
this strongly influences its physicochemical properties. The
chemopreventive effects of curcumin have been attributed to
various biological properties, including neutralization of
carcinogenic free radicals [27] and anti-angiogenesis action,
which limits the blood supply to rapidly growing malignant
cells [28,29]. However, the nature of many biological pro-
perties of curcumin remains unclear; therefore the investigation
of the structure and reactivity of this prolific medicinal agent
INTRODUCTION
Inflammation is a localized physical condition with heat,
swelling, redness and usually pain. It is mediated by the release
of proinflammatory mediators (bradykinin and cytokines),
which in turn increases the rate of prostaglandin synthesis [1,2].
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the
biosynthesis of prostaglandins by inhibiting cyclooxygenases
(COXs). It exists in two isoforms i.e., a constitutive form (COX-1)
and an inducible form (COX-2) [3,4]. COX-1 enzyme is respon-
sible for maintenance of gastric integrity and kidney function
[5-7] whereas COX-2 is involved in the inflammation and pain
[8,9].All classical NSAIDs, such as aspirin and indomethacin
are non selective inhibitors for both COX-1 and COX-2, but
bind more tightly to COX-1. In order to prevent or decrease these
side effects, a current strategy consists of designing selective
COX-2 inhibitors with an improved gastric safety profile [10,11].
Curcuminoids exhibited many interesting biological
activities [12], for example, antioxidant activity [13,14], anti-
inflammatory activity [15,16], anticancer activity [13,17,18],
antiprotozoal activity [19] and anti-HIV activity [20]. On the
other hand, curcumin analogue such as modification of the
dienone functional group curcumin into monoketone and side
chain of aromatic ring with symmetrical or asymmetrical subs-
tituents possessed structural features which conferred potential
biological activity and pharmaceutical use [21,22].

1766 Sohilait et al.
Asian J. Chem.
is important. A photolysis study by Jovanovic et al. [30]
attributes the antioxidant mechanism of curcumin to intra-
molecular H-atom in the keto-enolic group.A theoretical study
by Balasubramanian suggests that the keto-enolic form of
curcumin may be responsible for the inhibition of β-amyloid
aggregation [31].
During the last decade, synthetic modifications of curcu-
min, which were aimed at enhancing its bioactivities, have
been intensively studied. One sustainable strategy for green
synthesis of organic compounds is microwave irradiation.
Since, microwaves will not affect molecular structure in the
excitation of molecules, the effect of microwave absorption is
purely kinetic. Compared to traditional methods, microwave
synthesis is more convenient to synthesize and can be carried
out in higher yields in short reaction times under mild reaction
conditions. In the present study, we report the synthesis of
asymmetrical curcumin analogues under microwave irra-
diation.
Molecular docking study further helped in supporting the
observed COX-2 selectivity. Molecular docking study of
5-nitro-2-(3,4,5-trimethoxybenzyl)-isoindoline-1,3-dione into
the active site of COX-2 revealed a similar binding mode to
SC-558, a selective COX-2 inhibitor. Docking study showed
that the methoxy moeities of 5-nitro-2-(3,4,5-trimethoxy-
benzyl)-isoindoline-1,3-dione inserted deep inside the 2°-
pocket of the COX-2 active site, where the O-atoms of such
groups underwent an H-bonding interaction with His90 (3.02
Å) and Arg513 (1.94, 2.83 Å) [32]. The interaction with amino
acid Ser530 is important for enzyme inhibitory activity and is
well exemplified by the binding interaction of aspirin with
COX-2 [33].Active site amino acid residues Ser530, Met522,
Tyr385, Arg513, Phe518, His90 and Arg120 surrounded the
phenyl rings of curcumin analogues [34]. The scoring function
and a number of hydrogen bondings formed with the surroun-
ding amino acids are used to predict their binding modes. The
level of COX-2 inhibition of compound prompted us to perform
molecular docking studies to understand the ligand-protein
interactions in detail.
The transformation of the β-diketone structure of curcu-
min as a monocarbonyl curcumin significantly increases
its stability. As a result, the design, synthesis and evaluation
of its pharmacological activity of single carbonyl curcumin
analogues has become a research focus. The reported mono-
carbonyl curcumin analogues are mainly about symmetric
curcumin analogues, rarely are about asymmetric monocar-
bonyl curcumin analogues. This paper described the synthesis
and anti-inflammatory activity of new asymmetric monocarbonyl
curcumin analogues and the molecular docking studies.
60 (E. Merck, 70-230 mesh). Chromatographic purity by
HPLC (Shimadzu LC-20AD prominence) was determined by
using area normalization method and the condition specified
in each case: column, mobile phase (range used), flow rate, detec-
tion wavelength and retention times. Microwave irradiation is
performed by a conventional (unmodified) domestic microwave
oven equipped with a turntable (SHARP, R-268R, 230-240 V
~ 50 Hz, 800 W, 2450 MHz).
Synthesis of 4-(4-hydroxy-3-methoxy-phenyl)-but-3-
en-2-one: A mixture of the vanillic aldehyde (0.2 mmol) and
acetone (0.6 mmol) in methanol (20 mL) was added potassium
hydroxide (1 M in water, 5 mL) and the the mixture was placed
in a microwave oven. The resulting precipitate was removed
by filtration, washed with cold ethanol and purified by recrysta-
llization from ethanol. Light yellow powder, yield 92 %, m.p.
128-130 °C; 1H NMR (CDCl3): δ 2.33 (s, 3H), 3.89 (s, 3H),
6.05 9 (s, 1H, OH), 6.57 (d, 1H, Ar), 6.91 (d, 1H, Ar), 7.02 (d,
1H, J = 6.4 Hz), 7.06 (d, 1H, Ar), 7,43 (d, 1H, J = 6.4 Hz); 13C
NMR (CDCl3): 27.47 (CH3), 56.14 (OCH3), 109.54 (Ar),
115.04 (Ar), 123.70 (Ar), 125.13 (Ar), 127.07 (CH=CH),
144.00 (CH=CH), 147.11 (C-OH), 148.51 (C-OCH3), 198,69
(C=O); HPLC 100 %, column: Shim-Pack VP-OPS (250 ×
4.6) mm, mobile phase: methanol/acetonitrile (70:30), flow rate
1.0 mL/min, UV 268 nm, retention time 6.013 min; C11H12O3:
m/z 192 [M+H]+.
Synthesis of 1-(3,4-dimethoxy-phenyl)-5-(4-hydroxy-
3-methoxy-phenyl)-penta-1,4-dien-3-one: A mixture of the
veratraldehyde (0.2 mmol) and the vanillinacetone (0.2 mmol)
were dissolved in 15 mL of ethanol. Into this solution 3 mL of
a 1 M KOH solution in water was then added drop wise over
several seconds and the mixture was placed in a microwave
oven. The precipitate was washed with cold ethanol and dried
in vacuum. The solid was purified by chromatography over silica
gel using CH2Cl2/CH3OH (9:1) as the eluent to yield com-
pounds.Yellow powder, yield 81 %, m.p. 189-191 °C; IR (KBr,
ν
max, cm-1): 3458 (-OH), 3005 (CH-aromatic), 2835 (CH-
aliphatic) 1643 (C=O), 1620 (C=C), 1581 (Ar-H), 1267
(-OCH3); 1H NMR (DMSO-d6): δ 3.39 (s, 3H), 3.85 (d, 6H),
4.12 (d, 1H), 6.84 (d, 1H, Ar), 7.01 (d, 1H, Ar), 7.20 (dd, 1H,
Ar), 7.29 (d, 1H, Ar), 7.40 (d, 1H, Ar), 7.66 (d, CH=CH, J =
16.2 Hz), 7.70 (d, CH=CH, J = 16.2 Hz), 8.01 (C=O); 13C
NMR (DMSO-d6): 48.64 (OCH3), 55.58 (OCH3), 55.63
(OCH3), 55.73 (Ar), 110.48 (Ar), 111.40 (Ar), 111.64 (Ar),
115.70 (Ar), 122.96 (Ar), 123.21 (Ar-CH=), 123.47 (Ar-CH=),
123.91 (CH=CH), 126.35 (CH=CH), 127.63 (OCH3), 142.41
(OCH3), 143.04 (OCH3), 148.01 (CAr -OH), 149.03 (CH=CH),
149.51 (CH=CH), 151.95 (C=O); HPLC 100 %, column: Shim-
PackVP-OPS (250 × 4.6) mm, mobile phase: methanol/aceto-
nitrile (70:30), flow rate 1.0 mL/min, UV 268 nm, retention
time 6.502 min; C20H20O4: m/z 324 [M+H]+.
EXPERIMENTAL
Melting points (°C) were recorded using a Fisher Scientific
Digital melting point apparatus and are uncorrected. Infrared
spectra were obtained on a Prestige-21 Shimadzu FTIR spec-
trophotometer. 1H and 13C NMR were recorded on a JEOL JNM-
ECZ 500R spectrophotometer at 500 and 125 MHz, respec-
tively in DMSO-d6 and CDCl3 as the solvent. Mass spectra
(MS) were obtained on a Shimadzu MS-QP 2010S. Column
chromatography purifications were carried out on silica gel
Anti-inflammatory activity: Methods of Priya et al. [35],
Suresh Kumar et al. [36] and Sahoo et al. [37] followed with
minor modification. The reaction mixture was consisting of
test compound at different concentrations and 1 mL of 1 mM
albumin solution in 0.2 M phosphate buffer. pH of the reaction
mixture was adjusted using small amount of 1 N HCl. The
samples were incubated at 37 °C for 15 min and then heated
at 70 °C for 15 min. After cooling the samples, the turbidity

Vol. 30, No. 8 (2018) Studies of 1-(3,4-Dimethoxy-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-penta-1,4-dien-3-one asAnti-inflammatory 1767
was measured spectrophotometrically at 660 nm. The experi-
ment was performed in triplicate. Per cent inhibition of protein
denaturation was calculated as follows:
points with a gridspace of 0.375 Å, centers of grid box: x =
23.049; y = 23.526; z = 46.984. Cluster analysis was performed
on the docked results using an RMS tolerance of 2.0 Å. Finally,
the more energetically favourable cluster poses were evaluated
by using Phyton MoleculeViewer (PMV ver.1.5.6) and PyMol
ver.1.7.4 (DeLano Scientific LLC).
Abssample − Abs
Inhibition (%) =
control ×100
Abssample
Molecular docking studies:Three-dimensional coordinates
COX-2 (pdb code 6-COX) were retrieved from Brookhaven
Protein Data Bank. The pdb file was submitted to “Build/check/
repair model” and “Prepare PDB file for docking programs”
modules where missing side chains were modelled in, a small
regularization was performed, water positions and symmetry
were corrected and hydrogens were added. Only chain A of
the repaired pdb file was evaluated and passed toAutodockTools
(ADT ver.1.5.6) for pdbqt file preparation. The ligands were
constructed with ChemSketch-12.01 program and these geo-
metries were optimized using theAustin Model 1 to the corres-
ponding mol2 file that was submitted to ADT for pdbqt file
preparation and docking with AutoDock4. The geometry of
built compound was optimized, partial charges were also calcu-
lated and saved as mol2 files that was passed, as usual, to
ADT for pdbqt file preparation. Autodock4 (ver. 4.2.6) [38-
40] was employed for docking simulations. Lamarckian
genetic algorithm with local search (GALS) was used as search
engine, with a total of 100 runs. The region of interest, used
by Autodock4 for docking runs and by Autogrid4 for affinity
grid maps preparation, was defined in such a way to comprise
the whole catalytic binding site using a grid of 40 × 40 × 40
Statistical analysis: The albumin denaturation measure-
ment results were subjected to statistical analysis using SPSS
software,Version 17 with significance at 0.05 level tested with
Duncan.
RESULTS AND DISCUSSION
The target compounds (Scheme-I) were obtained by
allowing ketones to react with aromatic aldehydes under basic
aldol condensation conditions. The synthesis by two steps of
base catalyzed Claisen condensation reaction. The first step
consisted of compound vanillin with excess acetone in the
presence of KOH (1 M) to afford the intermediate 4-(4-hydroxy-
3-methoxy-phenyl)-but-3-en-2-one. Then, the target comp-
ounds were prepared by Claisen condensation of 4-(4-hydroxy-
3-methoxy-phenyl)-but-3-en-2-one in good yield and veratral-
dehyde.
The site of curcumin anti-inflammatory activities is contro-
versial among scientists. Some studies focused on the two phenol
rings while others pointed it out that the β-diketone structure
might be involved in the anti-inflammatory action of curcumin
[41,42]. Previous studies have proven that the presence of bis-
α,β-unsaturated β-diketone, two methoxy groups, two phenolic
O
O
O
H3C
CH3
O
O
KOH, MeOH
H3C
CH3
H3C
H
Microwave irradiation,
30 s
HO
HO
4-(4-Hydroxy-3-methoxy-phenyl)-but-3-en-2-one
Vanillic aldehyde
O
O
KOH, EtOH
Microwave irradiation,
H3C
H3C
H
30 s
O
Veratraldehyde
O
O
O
O
CH3
H3C
CH3
HO
1-(3,4-Dimethoxy-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-penta-1,4-dien-3-one
Scheme-I: Synthetic routes for the asymmetric curcumin analogues

1768 Sohilait et al.
Asian J. Chem.
hydroxyl groups and two double-conjugated bonds to be
critical in the anti-inflammatory activities assigned to curcumin
[43]. The synthesized compounds based on the structure of
curcumin by eliminating the unstable β-diketone moiety and
modifying it into conjugated double bonds while preserving
the phenolic OH group. Curcumin is deemed to be a weak
Michael donor since the 1,3-diketone unit in it is bis-α,β-
conjugated, thereby decreasing the reactivity of its central
methylene unit. It is also comparatively less active as a Michael
acceptor since the electron releasing substituents in its phenyl
ring on both sides are in conjugation with the enone unit. The
compound 1-(3,4-dimethoxy-phenyl)-5-(4-hydroxy-3-methoxy-
phenyl)-penta-1,4-dien-3-one has no Michael donor group.
However, it is a good Michael acceptor due to its two cross-
conjugated to –CH=CH–CO– enone units [44]. Pharmacophore
modification of the dienone functional group curcumin into
monoketone and side chain of aromatic ring with asymmetrical
substituents give better activity and stability than the parent
compound.
Anti-inflammatory activity: In the present study the in
vitro anti-inflammatory effect of compound was evaluated
against the denaturation of egg albumin. The results are summa-
rized in Table-1. The present findings exhibited a concentration
dependent inhibition of protein (albumin) denaturation by the
test compound throughout the concentration range of 100 to
600 µg/mL. Dichlorofenac sodium was used as the reference
drug which also exhibited concentration dependent inhibition
of protein denaturation. However, the effect of dichlorofenac
sodium was found to be less as compared with that of the
compound.
TABLE-1
INHIBITION (%) OF 1-(3,4-DIMETHOXY-PHENYL)-5-(4-
HYDROXY-3-METHOXY-PHENYL)-PENTA-1,4-DIEN-3-ONE
Inhibition (%) (Mean SE)
Conc. (µg/mL)
Compound
Dichlorofenac sodium
100
200
400
600
34.96 0.263a*
62.27 0.522b*
68.68 0.185c*
87.99 0.682d*
25.30 0.173a*
53.62 1.160b*
69.70 0.057c*
85.43 0.124d*
*Means within two treatments that have the same letter are not signify-
cantly different by Duncan 0.05 test.
the compound and the reference drug dichlorofenac sodium.
It has been reported that one of the features of several non-
steroidal anti-inflammatory drugs is their ability to stabilize
(prevent denaturation) heat treated albumin at the physiological
pH [45].
Molecular docking studies: The level of COX-2 inhi-
bition of compound 1-(3,4-dimethoxy-phenyl)-5-(4-hydroxy-
3-methoxy-phenyl)-penta-1,4-dien-3-one prompted us to
perform molecular docking studies to understand the ligand-
protein interactions. For this study, the crystal structures of
COX-2 enzymes complexed with SC-558 were used for the
docking [46].
Fig. 1 shows the conformational superposition of SC-558
(1-phenylsulfonamide-3-trifluoromethyl-5-parabromophenyl-
pyrazole), a selective inhibitor of COX-2 from the X-ray crystal
structure of SC-558–COX-2 complex and that from the docking
calculation. The RMSD between the two conformations is only
0.860 Å, indicating that the parameter set for docking is capable
of reproducing the X-ray structure.
The percentage inhibition of the synthesized compounds
showed high activity against the denaturation of protein. The
compound showed significant in vitro anti-inflammatory
activity with % inhibition of albumin denaturation 34.96,
62.27, 68.68 and 87.99 % respectively.
The increments in absorbance of compound with respect
to control indicated stabilization of protein i.e., inhibition of
protein (albumin) denaturation or anti-denaturation effect by
The most stable docking model was selected according
to the best scored conformation predicted by the AutoDock
scoring function. The compound 1-(3,4-dimethoxy-phenyl)-
5-(4-hydroxy-3-methoxy-phenyl)-penta-1,4-dien-3-one was
found to dock into the active site of COX-2 protein (PDB code:
6COX) with interaction energy of -7.6 kcal/mol. The comp-
ound could dock into the active site of COX-2 successfully.
The compound produces a deep moving into the hydrophilic
(a)
(b)
Fig. 1. (a) Conformational comparison of SC-558, (b) Crystal structure of SC-558–COX-2 complex (green) and that from the docking
simulation (red)

Vol. 30, No. 8 (2018) Studies of 1-(3,4-Dimethoxy-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-penta-1,4-dien-3-one asAnti-inflammatory 1769
pocket of COX-2 with which the methoxy groups are able to
reach the hydrophilic pocket and is involved in hydrogen
bonding with His90 (2.2, 3.3 Å) and Arg120 (2.2, 2.3 Å). Such
interactions are almost essential for COX-2 inhibitory activity,
as exemplified by the binding interaction of SC-558, an analog
of celecoxib cocrystallized in the COX-2 active site [47,48].
Docking studies in COX-2 showed that the methoxy-
phenyl ring of compounds fitted into the hydrophobic cavity
formed by Met552, Arg513, Tyr385, His90, Tyr348 and Ser530. In
the crystal structure of COX-2, this hydrophobic cavity was
occupied by bromophenyl ring of SC-558. The compounds
were oriented so that their methoxyphenyl group fitted into
the adjunct pocket which is responsible for COX-2 inhibitory
activity. The oxygen atom of methoxy group of compounds
formed weak bonds with Arg513 and His90 approximately at
distances of 3.8 and 3.3 Å respectively. Furthermore, hydrogen
bonds were observed between Arg120 and C=O group of com-
pounds at distances of 2.2 and 2.3 Å respectively (Fig. 2).
showed good inhibitory anti-inflammatory activity against the
denaturation of protein method. The molecular docking results
showed that the compound possess anti-inflammatory property.
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