Tyrosinase Inhibitory Effects of Derivatives of (E)-2-(Substituted Benzylidene)-3,4-Dihydronaphthalen-1(2H)-One

Article abstract of DOI:10.1002/bkcs.12122

Tyrosinase plays an essential role in melanin biosynthesis, and as such it has received great attention as a key target for the treatment of pigmentation disorders. In our earlier studies, we explored analogs with the β-phenyl-α,β-unsaturated carbonyl tem

Full text of DOI:10.1002/bkcs.12122

Article
DOI: 10.1002/bkcs.12122
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I. Y. Ryu et al.
KOREAN CHEMICAL SOCIETY
Tyrosinase Inhibitory Effects of Derivatives of (E)-2-(Substituted
Benzylidene)-3,4-Dihydronaphthalen-1(2H)-One
Il Young Ryu,†,† Inkyu Choi,†,† Sultan Ullah,† Heejeong Choi,† Pusoon Chun,‡ and Hyung
†,
*
Ryong Moon
†Laboratory of Medicinal Chemistry, College of Pharmacy, Pusan National University, Busan 46241,
Republic of Korea. *E-mail: mhr108@pusan.ac.kr
‡College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University,
Gimhae, Gyeongnam 50834, Republic of Korea
Received August 10, 2020, Accepted September 27, 2020
Tyrosinase plays an essential role in melanin biosynthesis, and as such it has received great attention as a
key target for the treatment of pigmentation disorders. In our earlier studies, we explored analogs with the
β-phenyl-α,β-unsaturated carbonyl template, and the results obtained indicated that this template confers
potent tyrosinase inhibitory activity. Thus, in the present study, (E)-2-(substituted benzylidene)-3,-
4-dihydronaphthalen-1(2H)-one derivatives (compounds 1–6) with this template were synthesized and
investigated with respect to their mushroom tyrosinase inhibitory effects. Derivative 4 with a 3-hydroxy-
4-methoxyl substituent on the β–phenyl ring of the template inhibited mushroom tyrosinase fourfold more
than kojic acid (IC50 = 15.60 ꢀ 0.32 μM vs. 57.06 ꢀ 0.46 μM). In silico docking simulation supported
this potent inhibitory activity of compound 4 by demonstrating a binding energy of −6.4 kcal/mol at the
active site of mushroom tyrosinase. Kinetic results imply that 4 competitively inhibits mushroom
tyrosinase.
Keywords: Tyrosinase, (E)-2-Benzylidene-3,4-dihydronaphthalen-1(2H)-one, β-Phenyl-α,β-unsaturated
carbonyl, Tyrosinase inhibitor, Kojic acid
Introduction
In their presence, pheomelanin is produced, whereas in
their absence, eumelanin is biosynthesized. Tyrosinase
plays many important roles in microorganisms, plants, and
animals. It contributes to the defense systems of bacteria
and insects7 and to developmental functions in insects.8 In
plants, it oxidizes various phenolics and is responsible for
the browning of fruits and crops,9 and as mentioned above,
in vertebrates, it plays a key role in melanin synthesis.
Over the past 10 years, we have synthesized many com-
pounds to find potent tyrosinase inhibitors10-18 and have
shown that several derivatives with the β-phenyl-α,-
β-unsaturated carbonyl template are effective tyrosinase
inhibitors. The present study represents a continuation of
this work and involved the synthesis and an investigation
of the mushroom tyrosinase inhibitory activities of (E)-
Melanins are a family of dark macromolecular insoluble
pigments found widely in nature and are classified as
eumelanins, pheomelanins, neuromelanins, allomelanins,
and pyomelanins.1 Eumelanins and pheomelanins are ani-
mal pigments and are responsible for brown-black and a
yellow-red colors, respectively.2 In animals, melanins are
produced by melanocytes in the basal layer of dermis via a
series of oxidation and polymerization reactions of L-tyro-
sine.3 Although melanin protects skin from UV radiation,
toxic chemicals, and environmental toxicants,4 excessive
melanogenesis causes a variety of skin disorders such as
melasma, lentigo, age spots, freckles, and senile pigment
spots.5
2-benzylidene-3,4-dihydronaphthalen-1(2H)-one
deriva-
Tyrosinase (polyphenol oxidase, EC 1.14.18.1) has
received considerable attention because it catalyzes the
rate-determining step in melanin biosynthesis. Tyrosinase
catalyzes two steps, that is, the conversion of L-tyrosine to
L-3,4-dihydroxyphenylalanine (L-dopa) and of L-dopa to
L-dopaquinone, which is in turn, is converted to eumelanin
or pheomelanin by chemical and/or enzymatic processes,
depending on the participation of glutathione and cysteine.6
tives, which all contained the β-phenyl-α,β-unsaturated car-
bonyl template. Since chalcones have the above template,
the synthesized compounds can be classified as a group of
chalcone tyrosinase inhibitors.
Experimental Section
General. The chemicals were purchased and used directly.
TLC (thin column chromatography) plates (60F245) were
obtained from Merck and MP Silica (Darmstadt, Germany,
†Both the authors (I.Y. Ryu, and I. Choi) contributed equally to
this article.
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40–63 μm, 60 Å) were used for column chromatography.
Water was removed from solvents by distillation over
CaH2 or Na/benzophenone. Mass data in low resolution
was obtained in ESI negative mode via Expression CMS
(advion, NY 14850, USA). Nuclear magnetic resonance
(NMR) data were obtained through Varian Unity AS500
spectrometer (Agilent Technologies, Santa Clara, CA,
133.9, 133.8, 132.8, 129.0, 127.9, 127.6, 127.2, 123.6,
118.0, 116.4, 28.5, 27.4; LRMS (ESI-) m/z 265 (M-H)−.
(E)-2-(4-Hydroxy-3-methoxybenzylidene)-
3,4-dihydronaphthalen-1(2H)-one (3).
13C NMR
(100 MHz, CDCl3) δ 188.1, 146.6, 146.6, 143.3, 137.3,
133.8, 133.8, 133.3, 128.4, 128.4, 128.3, 127.2, 124.0,
114.6, 113.0, 56.2, 29.0, 27.5; LRMS (ESI-) m/z 279 (M-
H)−, 264 (M-H-CH3)−.
1
USA) or a Varian Unity INOVA 400 spectrometer for H
(E)-2-(3-Hydroxy-4-methoxybenzylidene)-
3,4-dihydronaphthalen-1(2H)-one (4).
(100 MHz, CDCl3) δ 188.1, 147.3, 145.6, 143.4, 136.9,
134.2, 133.8, 133.3, 129.5, 128.4, 128.3, 127.2, 123.5,
116.0, 110.7, 56.2, 29.0, 27.4; LRMS (ESI-) m/z 279 (M-
H)−, 264 (M-H-CH3)−.
NMR (500 MHz and 400 MHz) or on a Varian Unity
INOVA 400 spectrometer for 13C NMR (100 MHz).
DMSO-d6 and chloroform-d (CDCl3) solvents were used
13C NMR
1
for H and 13C NMR data recording. Coupling constants
and chemical shifts frequency were measured in Hz (hertz)
and ppm (parts per million), respectively. These abbrevia-
tions singlet (s), doublet (d), triplet (t) and multiplet
(m) were used in the analysis of 1H NMR data.
(E)-2-(4-Hydroxy-3,5-dimethoxybenzylidene)-
3,4-dihydronaphthalen-1(2H)-one (5).
13C NMR
(100 MHz, CDCl3) δ 187.9, 147.1, 143.2, 137.5, 136.0,
134.0, 133.8, 133.4, 128.4, 128.3, 127.3, 127.2, 107.5,
56.6, 29.0, 27.5; LRMS (ESI-) m/z 309 (M-H)−, 294 (M-H-
CH3)−, 279 (M-H-2CH3)−.
General Synthetic Procedure of (E)-2-(substituted
benzylidene)-3,4-dihydronaphthalen-1(2H)-one Analogs
(1–6). A solution of α-tetralone and an appropriate benzal-
dehyde (0.9 equiv.) in 1.0
M
HCl acetic acid
(E)-2-(3-Bromo-4-hydroxybenzylidene)-
3,4-dihydronaphthalen-1(2H)-one (6).
(0.5 mL/0.1 mL of α-tetralone) was stirred at room temper-
ature for 72–96 h. Water (5 mL/0.1 mL of α-tetralone) and
methanol (1 mL/0.1 mL of α-tetralone) were added to the
reaction mixture, and the mixture was stirred for 1 min.
The methanol was then removed in vacuo. The resulting
solid was filtered through a Buchner funnel and washed
with water and/or dichloromethane to give (E)-
2-(substituted benzylidene)-3,4-dihydronaphthalen-1(2H)-
one analogs 1–6 as solids in yields of 16.2–73.8%.
(E)-2-(4-Hydroxybenzylidene)-3,4-dihydronaphthalen-1
(2H)-one (1). 13C NMR (100 MHz, DMSO-d6) δ 187.2,
159.1, 143.8, 137.0, 133.9, 133.8, 133.0, 132.8, 129.0,
127.9, 127.6, 126.7, 116.2, 28.5, 27.4; LRMS (ESI-) m/z
249 (M-H)−.
13C NMR
(100 MHz, CDCl3) δ 187.2, 155.5, 143.9, 135.3, 134.5,
134.1, 133.6, 131.7, 129.1, 128.5, 128.0, 127.6, 116.9,
110.1, 28.4, 27.3; LRMS (ESI-) m/z 327 (M-H)−,
329 (M + 2-H)−.
1H NMR data for compounds 1–6 are presented in
Table 1.
Mushroom Tyrosinase Inhibition Assay. The tyrosinase
inhibitory effects of synthesized compounds 1–6 were
determined following the existing procedure with minor
modification.19 Briefly, tyrosinase solution (20 μL; 1000 U/
mL) and the synthesized compounds (1–6, 10 μL, 50 μM)
were added to 170 μL of a solution of 50 mM phosphate
buffer (pH 6.5) containing 293 μM of L-tyrosine in the
wells of a 96-well plate and then incubated for 0.5 h at 37
ꢁC. Percentage tyrosinase inhibitions were calculated by
(E)-2-(3,4-Dihydroxybenzylidene)-
3,4-dihydronaphthalen-1(2H)-one (2).
13C NMR
(100 MHz, DMSO-d6) δ 187.2, 147.6, 145.8, 143.8, 137.4,
Table 1. 1H NMR data for compounds 1–6.
1 (400 MHz,
DMSO-d6)
2 (500 MHz,
DMSO-d6)
3 (500 MHz,
CDCl3)
4 (500 MHz,
CDCl3)
5 (500 MHz,
CDCl3)
6 (500 MHz,
DMSO-d6)
position δH (J in Hz)
3
4
5
6
7
8
3.04, t (6.4)
2.88, t (6.4)
7.37–7.31, m
7.51, t (7.6)
7.37–7.31, m
7.89, d (7.6)
7.62, s
3.08, t (6.0)
2.92, t (6.0)
7.35, d (8.0)
7.54, t (7.5)
7.38, t (7.5)
7.92, d (8.0)
7.57, s
3.16, t (6.0)
2.96, t (6.0)
7.26, d (7.5)
7.49, t (7.5)
7.37, t (7.5)
8.13, d (7.5)
7.83, s
3.16, t (6.5)
2.95, t (6.5)
7.25, d (7.5)
7.49, t (7.5)
7.36, t (7.5)
8.13, d (8.0)
7.80, s
3.17, t (6.0)
2.96, t (6.0)
7.25, d (7.5)
7.49, t (7.5)
7.36, t (7.5)
8.12, d (7.5)
7.81, s
3.06, t (6.0)
2.92, t (6.0)
7.35, d (7.5)
7.55, t (7.5)
7.39, t (7.5)
7.93, d (7.5)
7.69, s
vinylic
20
30
40
50
60
7.38, d (7.6)
6.82, d (7.6)
9.91, s, OH
6.82, d (7.6)
7.38, d (7.6)
6.98, s
6.98–6.58, m
3.93, s, OCH3
5.87, s
6.98–6.58, m
7.06, d (8.0)
7.09, s
6.72, s
7.60, s
9.45 or 9.15, s, OH
9.45 or 9.15, s, OH
6.80, d (8.0)
6.88, d (8.0)
5.69, s, OH
3.94, s, OCH3
6.91, d (8.5)
7.01, d (8.5)
3.92, s, OCH3
5.77, s, OH
3.92, s, OCH3
6.72, s
10.75, s, OH
7.02, d (8.5)
7.40, d (8.5)
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Scheme 1. Synthesis of the (E)-2-(substituted benzylidene)-3,4-dihydronaphthalen-1(2H)-one derivatives 1–6 and details of the aldehydes
used. Reagents and conditions: (a) 1 M HCl acetic acid, rt., 72–96 h.
Figure 2. Tyrosinase inhibitory activities of compound 4 at con-
centrations of 6.25, 12.5, and 25 μM. The IC50 value of 4 was cal-
culated from these data.
4 concentrations of 6.25, 12.5, or 25 μM and kojic acid
concentrations of 12.5, 25, or 50 μM. Linear plots were
obtained by plotting Log percent inhibition versus concen-
tration, and IC50 values (defined as the concentration
corresponding to 50% inhibition) were calculated.
Figure 1. Mushroom tyrosinase inhibitory effects of (E)-
2-(substituted
benzylidene)-3,4-dihydronaphthalen-1(2H)-one
derivatives 1–6. Experiments were performed in triplicate at a
derivative concentration of 50 μM. Con: Control, KA: Kojic acid.
In silico Docking Simulation of the Interaction between
Compound 4 and Tyrosinase. Docking studies were con-
ducted using the Schrodinger Suite (release 2020–2).20,21
The protein structure of tyrosinase was obtained from the
Protein Data Bank of ID 2Y9X. With Maestro 12.4,
unwanted chains were removed from the protein structure
and hits were regenerated. In the receptor grid wizard,
receptor grid coordinates were generated in the ligand-
binding site of tyrosinase. The ligand structures of kojic
acid and compound 4 were then imported into the entry list
of Maestro project table in CDXML format and optimized
with LigPrep using the OPLS3e force field. Glide extra pre-
cision (XP) was used to determine docking scores and
protein-ligand interactions.
measuring optical densities at 475 nm using a shaking
microplate reader (VersaMax™, Molecular Devices, San
Jose, CA, USA). Kojic acid (50 μM) was used as the posi-
tive control. To ensure consistency in the results, all experi-
ments were performed three times and the percentage
inhibition was obtained by the following formula.
% Tyrosinase inhibition = [1−(A/B) × 100].
A is optical density of the treated compound while B the
optical density of the nontreated compound. Compound
4 exhibited greatest inhibitory activity and was subjected to
further study. Three concentration-dependent inhibition
experiments were carried out in triplicate at compound
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Table 2. IC50 values of kojic acid and compound 4.
Compound
Conc. (μM)
Tyrosinase inhibitiona (%)
IC50b (μM)
Kojic acid
4
—
—
57.06 ꢀ 0.46
15.60 ꢀ 0.32
6.25
12.5
25
28.19 ꢀ 1.51
45.11 ꢀ 0.71
70.42 ꢀ 0.75
a Results are the means ꢀ SEs of three experiments.
b 50% inhibitory concentration.
Figure 3. Binding interactions between tyrosinase (PDB ID = 2Y9X) and compound 4 or kojic acid. Pharmacophore results and binding
interactions with tyrosinase for the two compounds were obtained using maestro 12.4. Figure 3(a) and (b) are 2D and 3D representations
of tyrosinase-ligand interactions.
Kinetic Experiments of Tyrosinase Inhibition. To a
96-well plate, 20 μL of mushroom tyrosinase (1000 units/
mL) aqueous solution, and 170 μL containing L-tyrosine
(0, 2, 4, and 8 mM) as a substrate, and 50 mM potassium
phosphate buffer (pH 6.5) were added with or without com-
pound 4 (0, 7.5, 15, and 30 μM, each 10 μL). The initial
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at this concentration, its inhibitory effect was considerably
stronger than that of kojic acid (81.92% vs. 37.95%). Com-
pound 6 (33.10% inhibition) with a 3-bromo-4-hydroxyl
substituent on the β–phenyl ring inhibited tyrosinase to the
same extent as kojic acid, whereas compound 1 with a
4-hydroxyl substituent inhibited tyrosinase by 26.78%. The
other compounds (2, 3, and 5) inhibited mushroom tyrosi-
nase by less than 10%.
Because compound 4 exhibited greatest inhibitory activ-
ity, it was investigated in further detail. The IC50 value of
4 (15.60 ꢀ 0.32 μM) was fourfold less than that of kojic
acid (57.06 ꢀ 0.46 μM) (Table 2), and at concentrations of
6.25, 12.5, and 25 μM, it inhibited tyrosinase by 28.19%,
45.11%, and 70.42%, respectively (Figure 2).
In silico Docking Simulation. To investigate whether
compound 4 binds to the active site of tyrosinase, in silico
docking simulation was performed using Schrodinger Suite.
Kojic acid was used as the reference control. Compound
4 and kojic acid both occupied the same binding pocket of
mushroom tyrosinase (Figure 3(b)). The two-dimensional
(2D) figures of tyrosinase-ligand interactions showed that
compound 4 and kojic acid interacted with the amino acid
residues of tyrosinase (Figure 3(a)). The pyran-4-one of
kojic acid and the 3,4-dihydronaphthalenone of compound
4 both interacted with His263 via π-π stacking. Kojic acid
also formed a hydrogen bond with His263. Although com-
pound 4 did not form hydrogen bonds, it interacted via an
additional pi-pi stacking interaction (blue dashed lines) with
Phe264 of tyrosinase and formed several hydrophobic inter-
actions (yellow dashed lines) with amino acid residues in
the active site (Figure 3(b)). As a result of these additional
interactions compound 4 (−6.4 kcal/mol) showed higher
binding affinity for tyrosinase than kojic acid
(−5.3 kcal/mol).
Kinetic Studies. To investigate the mechanism of tyrosi-
nase inhibition, the initial rate of dopachrom production by
tyrosinase was measured at different concentrations (0, 7.5,
15, and 30 μM) of compound 4 in the presence of L-
tyrosine of various concentrations (0, 2, 4, and 8 mM). As
shown in Lineweaver-Burk plot of Figure 4, four lines with
different slops merged at one point on the y-axis, indicating
that compound 4 competitively inhibits mushroom tyrosi-
nase by noncovalently binding to the active site of the
enzyme.
Figure 4. Lineweaver-Burk plot of mushroom tyrosinase at four
different concentrations of 4. The plot is presented as average
values of 1/V of three times independent experiments with four
different L-tyrosine concentrations (0, 2, 4, and 8 mM).
rate of dopachrome generation was examined by measuring
the changes of optical density at 475 nm per minute
(ΔOD475/min). The optical density was measured using a
shaking microplate reader (VersaMax™, Molecular
Devices, San Jose, CA, USA). All kinetic experiments were
independently repeated three times.
Results and Discussion
Synthesis. Syntheses of (E)-2-(substituted benzylidene)-3,-
4-dihydronaphthalen-1(2H)-one derivatives 1–6 were
accomplished by condensing 3,4-dihydronaphthalen-1(2H)-
one with an appropriate benzaldehyde in 1 M HCl acetic
acid solution, as shown in Scheme 1. According to our
accumulated structure–activity relationship data, derivatives
with at least one hydroxyl group on the β–phenyl ring of
the β-phenyl-α,β-unsaturated carbonyl template exhibited
tyrosinase inhibitory activity, and thus, we used benzalde-
hydes with one or more hydroxyl groups. The structures of
1
the six derivatives produced were confirmed by H and 13C
NMR and mass spectroscopy. Compared to chalcones, the
synthesized compounds have two more carbons in their
structure, providing a higher lipophilicity. When these com-
pounds are used as whitening agents, the increased
lipophilicity can improve the absorption of these com-
pounds into the skin.
Conclusion
Tyrosinase Inhibition. The inhibitory effects of the six
Based on considerations of our accumulated structure–
(E)-2-(substituted
benzylidene)-3,4-dihydronaphthalen-1
activity
relationship
data,
we
synthesized
six
(2H)-one derivatives 1–6 on mushroom tyrosinase were
examined. Kojic acid was used as a positive reference con-
trol. The mushroom tyrosinase inhibitory activities of all
compounds were evaluated at 50 μM. The results are
shown in Figure 1. Of the six compounds, compound 4 with
a 3-hydroxy-4-methoxyl substituent on the β–phenyl ring
of the template exhibited the greatest inhibitory effect, and
(E)-2-(substituted
benzylidene)-3,4-dihydronaphthalen-1
(2H)-one derivatives 1–6 containing the β-phenyl-
α,β-unsaturated carbonyl template and then assayed their
mushroom tyrosinase inhibitory activities. Compound
4 showed much stronger tyrosinase inhibitory activity than
kojic acid, and this was supported by our docking simula-
tion results, which showed the binding energies of
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respectively. Kinetic studies have demonstrated that 4 is an
inhibitor that competes with tyrosinase substrates. Our
results also support the notion that the β-phenyl-α,-
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© 2020 Korean Chemical Society, Seoul & Wiley-VCH GmbH
www.bkcs.wiley-vch.de
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