New class of alkynyl glycoside analogues as tyrosinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2020.127276

A new series of alkynyl glycoside analogues were designed and synthesized from cheap and a commercially available sugar by introduction of various alkynyl and alkyl groups at C-1 and C-6 positions of the sugar ring. The inhibitory abilities of alkynyl gly

Full text of DOI:10.1016/j.bmcl.2020.127276

Journal Pre-proofs
New Class of Alkynyl Glycoside Analogues as Tyrosinase Inhibitors
Natthiya Saehlim, Anan Athipornchai, Uthaiwan Sirion, Rungnapha Saeeng
PII:
S0960-894X(20)30386-3
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127276
BMCL 127276
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
16 April 2020
16 May 2020
18 May 2020
Please cite this article as: Saehlim, N., Athipornchai, A., Sirion, U., Saeeng, R., New Class of Alkynyl Glycoside
Analogues as Tyrosinase Inhibitors, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://doi.org/
10.1016/j.bmcl.2020.127276
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1 New Class of Alkynyl Glycoside Analogues as Tyrosinase
2 Inhibitors
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4
Natthiya Saehlima, Anan Athipornchaia,b, Uthaiwan Siriona,b, Rungnapha Saeenga,b*
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a Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Burapha
University, Sangesook, ChonBuri 20131, Thailand
b The Research Unit in Synthetic Compounds and Synthetic Analogues from Natural Product for Drug
9
Discovery (RSND), Burapha University, Chonburi 20131, Thailand
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*E-mail: rungnaph@buu.ac.th
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Abstract: A new series of alkynyl glycoside analogues were designed and synthesized from
cheap and a commercially available sugar by introduction of various alkynyl and alkyl groups
at C-1 and C-6 positions of the sugar ring. The inhibitory abilities of alkynyl glycosides were
investigated in vitro on mushroom tyrosinase for the catalysis of L-Tyrosine and L-DOPA as
substrates and comparing with arbutin and kojic acid. Non-terminal alkyne compound 2d
showed excellent tyrosinase inhibitory activity (IC50 54.0 M) against L-Tyrosine comparable
to arbutin (IC50 1.46 mM) while 2b exhibited potent activities (IC50 34.3 M) against L- DOPA
higher than kojic acid (IC50 0.11 mM) and arbutin (IC50 13.3 mM). Kinetic studies revealed
that compound 2d was a non-competitive inhibitor with the best Ki value of 21 M and formed
an irreversible receptor complex with mushroom tyrosinase. The SARs results showed that the
type of alkyne and alkyl groups at position C-6 on sugar and the stereoisomer played an
important role in determining their inhibitory activities. The potent activity of alkynyl
glycosides identified in this study highlight the importance of this scaffold and these
compounds are very modestly potent to the development of new class for tyrosinase inhibitor.
OBn
L-Tyrosine
O
BnO
OR1
OH
BnO
OBn
R2
O
O
O
BnO
BnO
HO
HO
2d
, IC50 54.0 M
OBn
OH
CH3
O
n
OH
OBn
O
Me, Bn
38 Analogues
D-glucose
R1 = H, akyl, alkynyl
R2 = H, Me
BnO
BnO
L-DOPA
OBn
O
2b
, IC50 34.3 M
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27
Key words: Alkynyl glycoside; Tyrosinase inhibitors; alkyne; sugar
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1

1
2
Highlights
► A series of alkynyl glycoside derivatives were designed and synthesized.
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4
► A series of alkynyl glycoside analogues were evaluated against mushroom tyrosinase for
their catalysis in melanin synthesis.
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► Several synthetic derivatives show excellent activity which is higher than arbutin.
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► A kinetic mechanism was proposed that the compounds are non-competitive inhibitor of
mushroom tyrosinase.
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Tyrosinase or polyphenol oxidase (EC 1.14.18.1), is a multifunctional copper-
containing enzyme widely distributed in nature. It is a well known catalyst in the
transformation of L-tyrosine to melanin.1 The process of melanin synthesis is of considerable
importance in the coloring of skin, hair, eyes and in food browning.2,3 On the other hand, the
production of hyperpigmentation of melanin causes melasama, freckles and other
dermatological disorders.4 In addition, tyrosinase enzyme activity was found to be enhanced
in the insect molting process5 and influenced the neurodegeneration associated with
Parkinson’s disease.6,7 Based on this problem, the development of tyrosinase inhibitors or
skin whitening agents have become increasingly important in cosmetic, food and the medical
industry. In the cosmetic industry, skin whitening products such as kojic acid8 and arbutin9
have been extremely important however these compounds display side effects such as skin
toxicity and low clinical efficiency.10,11 Moreover, arbutin is now prohibited for use in several
countries. Therefore, the development of new non-toxic skin whitening agents is needed. In
the past decade, the biological activities of glycosylated products have been increasingly used
for the development of drug efficacy, pharmacokinetics and reduced side effects.12,13
Currently, a large number of natural and synthetic tyrosinase inhibitors as a family of
glycosides display potent inhibitory activity (Fig. 1).14-19 The relationship between these
sugars and bioactive aglycone has shed light on their biological significance, which could
lead to the development of novel inhibitors based on the chemical properties of aglycone.
2

HO
OH
CHO
O
OH
O
OH
OH
OH
O
O
O
HO
HO
HO
HO
HO
O
OH
OH
OH
HO
OH
Arbutin
Helicid
Hydroxystilbene
S
N
N
NH2
H
COOH
AcO
HO
O
MeOOC
O
O
HO
HO
AcO
AcO
O
OAc
Thiosemicarbazide
OH
OH
Triterpene
1
2
Fig. 1. Chemical structures of some known tyrosinase inhibitors.
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4
Acetylenic metabolites have been demonstrated to possess a number of interesting
pharmacophore in nature with potent biological activities such as anticancer, antibacterial,
anti-inflammatory, and other chemical and medicinal properties.20-22 However, to our
knowledge, the tyrosinase activity of acetylenic compounds have never been reported. In the
present study, we designed and synthesized a series of alkynyl glycosides to investigate the
influence of alkynyl groups on mushroom tyrosinase by modify at C-1 and C-6 positions of
sugar and evaluate their bioactivity with L-Tyrosine (monophenolase activity) and L-DOPA
(diphenolase activity) for develop to novel potent tyrosinase inhibitors.
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The glycoside analogues (1-9) were synthesized by the strategic pathway shown in
Schemes 1, 2 and 3. The alkynyl O-glycoside derivatives (1a-1d) were prepared by Fischer
glycosylation at the anomeric position of D-glucose with various carbon chain lengths of
alkynyl alcohols (a-d) in the presence of sulphuric acid immobilized on silica gel (H2SO4–
SiO2)23 (Scheme 1). O-Benzylation of D-glucose and alkynyl glycosides 1a-1d with benzyl
bromide under basic condition gave O-benzyl alkynyl glycosides 2a-2e. Selective
debenzylation at the C-6 position of compounds 2a-2e with trimethylsilyl
trifluoromethanesulfonate (TMSOTf), followed by O-acetylation using acetic anhydride
provided compounds 3a-3e. Removing of acetyl groups of 3a-3e by treatment with sodium
hydroxide furnished compounds 4a-4e.
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23
Compound 4f was prepared by O-silylation at C-6 of -methyl-D-glucose with
TBSCl, followed by O-benzylation and removal of the silyl moiety under acidic conditions.
Then, O-benzylation and O-acetylation at the C-6 position of 4f gave products 2f and 3f
3

1
2
3
4
respectively (Scheme 2). O-Methylation of compounds 4a-4f with MeI gave products 5a-5f.
To study the structure activity relationship (SAR) of alkyne at C-6, O-glycoside analogues
6a, 6d-6f and 7a, 7d-7f were prepared from reactions of 4a, 4d-4f with propargyl bromide
and 1-bromo-2-butyne in the presence of sodium hydride as a base in DMF respectively.
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6
7
8
9
In addition, to study the SAR at C-6, protection of diol at C-5 and C-6 of alkynyl
glycosides 1a-1b, 1d with benzaldehyde using ZnCl2 as a catalyst gave benzylidene acetal
compounds 8a-8b, 8d, followed by O-benzylation with benzyl bromide, afforded the
products 9a-9b, 9d. All the synthesized compounds have been characterized by FTIR, 1H
NMR, 13C NMR and mass spectroscopic data.
10
OH
OH
O
O
(i)
HO
HO
HO
HO
HO
HO
HO
a
b
c
d
OH
OH
OR
OH
D-Glucose
1a-1d
HO
e
CH3
(ii)
OH
OBn
OAc
(iv)
(iii)
O
O
O
BnO
BnO
BnO
BnO
BnO
BnO
OBn
OR
OBn
OBn
OR
OR
2a-2e
OH
3a-3e
OTBS
4a-4e
OH
(ii)
O
O
O
(v)
BnO
BnO
HO
HO
HO
HO
(vi)
OH
OBn
OMe
OH
OMe
OMe
4f
-methyl-D-glucose

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12
Scheme 1 Synthesis of compounds 1-4. Reagents and conditions: (i) H2SO4-SiO2,
acetylene alcohols (a-d), 60 °C, overnight, 60-78% (ii) NaH, BnBr, DMF, r.t., 3 h, 80-
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17
97% (iii) TMSOTf, Ac2O, CH3CN, 0 °C - r.t., 20 min., 64-88% (iv) NaOH, MeOH:H2O,
0 °C - r.t., 30 min., 83-99% (v) TBSCl, pyridine, 0 °C - r.t., 1 h. (vi) HCOOH/H2O (4:1),
THF, 0 °C - r.t., 3 h, 61% (3 steps).
4

OMe
O
(vii)
BnO
BnO
OH
O
OBn
OR
OR
OR
BnO
BnO
5a-5f
O
OBn
OR
OBn
4a-4e
(viii)
O
O
and
(x)
BnO
BnO
BnO
BnO
OH
OBn
OBn
OMe
O
2f
6a 6d-6f
,
BnO
BnO
O
OAc
OBn
(ix)
4f
OMe
H3C
O
O
BnO
BnO
(xi)
BnO
BnO
OBn
7a 7d-7f
OBn
OMe
3f
,
R =
Me
CH3
a
b
c
d
e
f
1
2
Scheme 2 Synthesis of compounds 5-7. Reagents and conditions: (vii) NaH, MeI, DMF, r.t.,
30 min., 70-93% (viii) NaH, propargyl bromide, DMF, r.t., 30 min., 93-98% (ix) NaH, 1-
bromo-2-butyne, DMF, r.t., 30 min., 93-97% (x) NaH, BnBr, DMF, r.t., 30 min., 98% (xi)
NaH, Ac2O, DMF, r.t., 30 min., 85%.
3
4
5
OH
O
Ph
O
O
(xii)
O
HO
HO
HO
OH
OH
OR
OR
1a-1b, 1d
8a-8b, 8d
(xiii)
R =
a:
b:
d:
O
Ph
O
O
BnO
OBn
CH3
OR
9a-9b, 9d
6
7
Scheme 3 Synthesis of compounds 8-9. Reagents and conditions: (xii) ZnCl2,
8
9
benzaldehyde, r.t., overnight, 65-82% (xiii) NaH, BnBr, DMF, r.t., 1 h, 90-95%.
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13
All alkynyl glycoside derivatives were evaluated in vitro on mushroom tyrosinase
using arbutin and kojic acid as reference standard according to the procedures reported in
literature.24 The IC50 values was summarized in Table 1. In this study, two types of substrate
were used to investigate the effect of competition against inhibitors catalyzed by tyrosinase.
5

1
2
Inhibitory effects of alkynyl O-glycoside derivatives on mushroom tyrosinase with
L-Tyrosine as substrate
3
4
The results indicated that -propargyl O-glycoside compound 2a and -isomer
2a showed diferent activity (Table 1). - propargyl O-glycoside showed strong tyrosinase
inhibitory activity with an IC50 value of 94.7 M while -isomer showed wek activity.
Interestingly, the mixture of both isomers (2a) exhibited potent activity (81.9 M), and the
activity was slightly reduced when the chain length of alkyne increased to butynyl 2b (IC50 =
150 M) and pentynyl 2c (IC50 = 105 M). Non-terminal alkyne compound 2d showed the
strongest inhibitory activity (IC50 = 54.0 M), indicating that the electron density of the
alkynyl moiety greatly influenced the inhibitory behavior against tyrosinase. A comparison of
the IC50 values of stereoisomers of compound 2d found that mixtures of isomers exhibited
more potent activity than single isomers, suggesting a synergistic effect. The IC50 values of
benzyl glycoside 2e and alpha methoxyl glycoside 2f showed weak inhibitory activitities.
This data suggested that the type of alkynyl moiety at C-1 plays a significant role in enabling
the binding with the active site of tyrosinase. Replacement of the benzyl group at the C-6
position of glycoside with acetoxyl (3d), hydroxyl (4d), methoxyl (5d), alkyne (6d,7d) and
benzylidene acetal (9d) led to a decrease in inhibitory activity, demonstrating that the benzyl
group at C-6 of 2d displayed a very important role in determining inhibitory behavior.
According on the results in Table 1, several synthetic glycoside derivatives showed
tyrosinase inhibitory activity greater than arbutin a whitening agent used in the cosmetic
industry.
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7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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27
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29
30
31
32
33
Inhibitory effects of alkynyl glycoside derivatives on mushroom tyrosinase with L-
DOPA as substrate
The alkynyl O-glycosides 2b and 2d showed excellent tyrosinase inhibitory
activity with IC50 values of 34.7 and 70.7 M respectively, which exhibited stronger activity
than kojic acid and arbutin. Changing the benzyl group at the C-6 position of 2d to hydroxyl,
4d exhibited slightly lower inhibition (IC50 = 80.4 M). In contrast, when the C-6 position of
2d was replaced with methoxyl, 5d showed strong inhibitory potency with an IC50 value of
45.4 M. The results suggested that with an alkynyl moiety at the C-1 and the benzyl group
at C-6 position of sugar, a significant increasing in activity was increased by interacting with
the active site of tyrosinase and L-DOPA as substrate.
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1
2
3
Table 1 The inhibitory effects of alkynyl glycoside derivatives on mushroom tyrosinase
activity
IC50 (M)
Tyrosine
81.9 ± 0.14
> 500
94.7 ± 0.43
150 ± 0.41 34.3 ± 0.40
105 ± 0.21 > 500
IC50 (M)
compd. R1 R2
n
compd. R1 R2
n
3
DOPA
> 500
> 500
> 500
Tyrosine
DOPA
2a
Bn
Bn
Bn
Bn
Bn
H
H
H
H
H
1
1
1
2
3
5c
Me H
> 500
> 500
5d
5e
5f
6a
Me Me 1
Me Bn
Me Me -
73.6 ± 0.10 45.4 ± 0.22
2a
2a
2b
-
> 500
> 500
> 500
435 ± 0.58
494 ± 1.8
> 500
2c
H
H
H
H
H
1
2d
Bn Me 1
Bn Me 1
Bn Me 1
54.0 ± 0.10 70.7 ± 0.31 6d
Me 1
Bn
Me -
> 500
205 ± 0.22
> 500
288 ± 1.2
> 500
> 500
6e
6f
7a
7d
7e
7f
321 ± 0.67
179 ± 0.16
> 500
191 ± 1.8
461 ± 0.94
268 ± 0.82
208 ± 1.1
219 ± 1.1
273 ± 0.52
> 500
> 500
> 500
> 500
> 500
> 500
> 500
> 500
-
2d
2d
2e
Bn Bn
-
Me H
Me Me 1
Me Bn
Me Me -
1
> 500
> 500
Bn Me -
72.0 ± 0.12
> 500
> 500
> 500
2f
3a
3b
Ac
Ac
Ac
H
H
H
1
2
3
-
274 ± 0.74
> 500
> 500
> 500
3c
8a
H
H
H
H
1
2
3d
3e
3f
4a
4b
4c
4d
4e
4f
5a
Ac Me 1
Ac Bn
Ac Me -
400 ± 0.35 8b
357 ± 1.9
> 500
463 ± 2.7
> 500
207 ± 0.26
> 500
-
8d
H
Me 1
9a
Bn
Bn
Bn
Bn
Bn
Bn
H
H
H
H
H
H
1
1
1
2
2
2
> 500
> 500
> 500
383 ± 1.5
431 ± 0.64
> 500
H
H
H
H
H
H
H
H
H
Me 1
Bn
Me -
1
2
3
> 500
> 500
9a
9a
9b
9b
9b
9d
> 500
> 500
> 500
> 500
> 500
> 500
257 ± 0.26
> 500
> 500
> 500
80.4 ± 0.17
> 500
-
> 500
> 500
> 500
> 500
Bn Me 1
Bn Me 1
Bn Me 1
> 500
> 500
Me H
Me H
1
2
> 500
> 500
> 500
> 500
9d
9d
5b
> 500
> 500
> 500
> 500
arbutin
1465 ± 3.3 13282 ± 23.0
12.8 ± 0.15 107 ± 0.20
Kojic acid
7

O
R1
Ph
R2
O
OR1
BnO
BnO
= (a-d)
R2
O
OBn
O
n
=
=
BnO
BnO
6-7
8-9
R2 Bn
R2 Me
(e)
(f)
= (a-d)
OBn
O
n
2-5
O
R2 Bn
O
=
(e)
(f)
O
R2 Me
R1O
=
R2
OR1
O
= (a-b, d)
n
1
2
3
4
5
6
7
The kinetic behaviour of the most active compounds 2d and 7d for the hydroxylation
of L-Tyrosine (Fig. 2) and 2b and 5d for the oxidation of L-DOPA (Fig. 3) were investigated
to determine the type of inhibition and inhibition constant (Ki) using Lineweaver–Burk plots.
The results showed that the plots of 1/V versus 1/S gave straight lines with different slopes
but same x-intercept points, which demonstrated that the Vmax values increased while Km
remains unchanged. This behavior indicated that all of selected compounds were a non-
competitive inhibitor of tyrosinase. The inhibition constant (Ki) of 2d and 7d were 21 and
32 M with L-tyrosine as substrate, while for 2b and 5d were 49 and 52 M with L-DOPA
as substrate, respectively. This result suggested that compound 2d had the most potent
inhibitory effect (see supporting data).
8
9
10
11
12
13
14
15
16
140
120
100
80
0.07 mM
100
80
60
40
20
0
0.03 mM
0.015 mM
0 mM
7d
2d
0.035 mM
0.0175 mM
0 mM
Linear (0.07 mM)
60
40
20
0
-1
-0.5
0
0.5
1
-1
-0.5
0
0.5
1
-20
-20
1/S (mM)-1
1/S (mM)-1
8

1
2
Fig. 2. Lineweaver-Burk plots for inhibition of selected compounds 2d and 7d against
mushroom tyrosinase for the catalysis of L-Tyrosine.
3
4
5
6
7
8
9
10
11
12
13
100
80
60
40
20
0
100
80
60
40
20
0
0.04 mM
0.02 mM
0 mM
0.04 mM
0.02 mM
0 mM
2b
5d
-0.8
-0.3
0.2
1/S (mM)-1
0.7
1.2
-0.8
-0.3
0.2
1/S (mM)-1
0.7
1.2
-20
-20
14
15
16
Fig. 3. Lineweaver-Burk plots for inhibition of selected compounds 2b and 5d against
mushroom tyrosinase for the catalysis of L-DOPA.
17
18
19
20
21
22
23
The inhibition mechanism of the inhibitors was determined by the relationship between
enzyme activity versus the concentration of enzyme at different inhibitor concentrations as
shown in Fig.4. The results of inhibitory effect of 2d and 7d on mushroom tyrosinase for the
hydroxylation of L-tyrosine showed that when increasing the concentrations of enzyme at
different concentrations of 2d, a family of parallel straight lines with the same slopes was
observed, indicating that 2d was an irreversible inhibitor. In contrast, 7d gave a family of
straight lines with all passed through the origin, demonstrating that 7d was a reversible
9

1
2
inhibitor. The behavior of 2b and 5d gave the same result as 7d, thus compounds 2b and 5d
were reversible inhibitors on mushroom tyrosinase for the oxidation of L-DOPA (Fig.5).
3
4
0.05
0.04
0.03
0.02
0.01
0.00
0.12
0.10
0.08
0.06
0.04
0.02
0.00
0 mM
0 mM
2d
7d
0.0075 mM
0.015 mM
0.03 mM
0.00875 mM
0.0175 mM
0.035 mM
0.07 mM
5
6
7
8
9
0.0
10.0
20.0
30.0
0.0
10.0
20.0
30.0
[E] µg/mL
[E] µg/mL
10
11
12
Fig. 4. The inhibitory effects of 2d and 7d on mushroom tyrosinase for the catalysis of
L-Tyrosine.
13
14
15
16
17
18
19
20
21
0.16
0.14
0.12
0.1
0.16
0.14
0.12
0.1
0 mM
0 mM
5d
2b
0.02 mM
0.04 mM
0.08 mM
0.16 mM
0.01 mM
0.02 mM
0.04 mM
0.08 mM
0.08
0.06
0.04
0.02
0
0.08
0.06
0.04
0.02
0
0.0
5.0
10.0
15.0
0.0
5.0
10.0
15.0
[E] µg/mL
[E] µg/mL
22
23
Fig. 5. The inhibitory effects of 2b and 5d on mushroom tyrosinase for the catalysis of
L-DOPA.
24
25
26
27
28
29
30
To investigate the binding modes of the most inhibitor (2d and 2b) with in the
active site of tyrosinase, docking simulations were performed using Autodock 4.2 software25
and the structure of mushroom tyrosinase was obtained from the Protein Data Bank (ID:
2Y9X)26 as shown in Fig. 6. Interestingly, compound 2d showed a good fit in the pocket site
of the protein molecular surface and had a binding energy of -7.80 kcal/mol. The three
hydrogen bond interactions was observed between all three oxygen groups of the 2d and the
His244 residue (bond distances: 1.8, 2.3 and 2.8 Å). In addition, the benzyl and alkyl group
10

1
2
of the 2d interacted with Val248, Asn281, His263 and His61 residues via π-alkyl
interactions, while benzyl group interacted with Phe264 via π-π interactions. In the same
way, the binding energy of 2b was calculated as -7.12 kcal/mol and displayed hydrogen bond
interaction with the Glu322 residue (bond distance: 3.5 Å). The alkynyl group of 2b
interacted with Val283 residues via π-alkyl interaction, while benzyl group was involved in
the π-alkyl and π-π interaction with Val248 and Phe264, respectively. Thus, on the basis of
the molecular docking results, we observe that the oxygen group was formed a strong
hydrogen bond against tyrosinase. Moreover, the benzene ring and alkynyl group were
important formed hydrophobic interactions with amino acid residues surrounding active site
of tyrosinase.
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2d
2b
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Fig. 6. Molecular docking results of 2d and 2b (Green) interacting with residues in the
active site of tyrosinase (PDB code: 2Y9X). Hydrogen bonds and hydrophobic interactions
were displayed as green and red dashed lines, respectively.
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In conclusion, a series of alkynyl O-glycoside derivatives were designed and
synthesized and study as a new class of tyrosinase inhibitor for the first time. Several of the
O-glycoside derivatives exhibited more potent tyrosinase inhibitory activities than arbutin a
widely used tyrosinase inhibitor. In particularly, compound 2b and 2d showed the most
potent activity with IC50 values of 34.3 and 54.0 M, respectively. The structure activity
relationships (SARs) suggested that the type of alkynyl moiety, benzyl group at C-6 position
of the sugar and stereoisomers at C-1 played a very important role in the tyrosinase inhibition
activity. Moreover, the kinetic analysis study indicated that 2d, the most potent tyrosinase
inhibitor was a non-competitive type inhibitor with a Ki value of 21 M and formed an
irreversible receptor complex against mushroom tyrosinase. Molecular docking showed a
good fit in the cavity of tyrosinase and had a binding energy of -7.80 kcal/mol. These
compounds will be of potential use for further development of drugs for the treatment of
tyrosinase-related disorders.
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Acknowledgements
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This work was supported by a Research Grant of Burapha University through National
Research Council of Thailand (39/2557), The Research Unit in Synthetic Compounds and
Synthetic Analogues from Natural Product for Drug Discovery (RSND), Burapha University
and the Center of Excellence for Innovation in Chemistry (PERCH-CIC). R.S. and N.S.
gratefully acknowledge the Royal Golden Jubilee (R.G.J.) Ph.D. program, (PHD/0165/2557)
for providing scholarships. The authors would like to thank Assistant Prof. Suchaya Pongsai,
Faculty of Science, Burapha University, for a helpful discussion on docking simulations
techniques. Special thanks to Prof. Dr Ron Beckett, Faculty of Science, Burapha University,
for his comments and English corrections.
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Declaration of interests
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☒ The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
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☐The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:
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Highlights
► A series of alkynyl glycoside derivatives were designed and synthesized.
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► A series of alkynyl glycoside analogues were evaluated against mushroom tyrosinase for
their catalysis in melanin synthesis.
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► Several synthetic derivatives show excellent activity which is higher than arbutin.
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► A kinetic mechanism was proposed that the compounds are non-competitive inhibitor of
mushroom tyrosinase.
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Graphical abstract
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OBn
L-Tyrosine
O
BnO
OR1
OH
BnO
OBn
R2
O
O
O
BnO
BnO
HO
HO
2d
, IC50 54.0 M
OBn
OH
CH3
O
n
OH
OBn
O
Me, Bn
38 Analogues
D-glucose
R1 = H, akyl, alkynyl
R2 = H, Me
BnO
BnO
L-DOPA
OBn
O
2b
, IC50 34.3 M
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