Synthesis and bioactivity of new chalcone derivatives as potential tyrosinase activator based on the click chemistry

Article abstract of DOI:10.1002/cjoc.201400820

A new series of (E)-1-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-3-phenylprop-2-en-1-one 1a(4-((1-benzyl-1H-1,2,3-triazol-4-yl) methoxy)phenyl)-1-phenylprop-2-en-1-one 1b-15b were designed, synthesized based on click chemistry, and biologically evaluated for their activity on tyrosinase. The result showed that most of prepared compounds 1a-15a have potent activating effect on tyrosinase, especially for 3a, 8a-10a and 14a-15a. Among them, compounds 10a and 14a demonstrated the best activity with EC₅₀=1.71 and 5.60 μmol·L^-1 respectively, even better than the positive control 8-MOP (EC₅₀=14.8 μmol·L^-1). Conversely, compounds 3b, 5b-6b, 9b-10b, and 15b induced enzymatic inhibition on tyrosinase.

Full text of DOI:10.1002/cjoc.201400820

FULL PAPER
DOI: 10.1002/cjoc.201400820
Synthesis and Bioactivity of New Chalcone Derivatives as Po-
tential Tyrosinase Activator Based on the Click Chemistry
Chao Niu,a,b Gen Li,a,b Adila Tuerxuntayi,a,b and Haji A. Aisa*,a,b
a Key Laboratory of Plant Resources and Chemistry of Arid Zone, Chinese Academy of Sciences, Urumqi, Xinjiang
830011, China
b State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical
Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, Xinjiang 830011, China
A new series of (E)-1-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-3-phenylprop-2-en-1-one 1a－15a
and (E)-3-(4-((1-benzyl-1H-1,2,3-triazol-4-yl) methoxy)phenyl)-1-phenylprop-2-en-1-one 1b－15b were designed,
synthesized based on click chemistry, and biologically evaluated for their activity on tyrosinase. The result showed
that most of prepared compounds 1a－15a have potent activating effect on tyrosinase, especially for 3a, 8a－10a
and 14a－15a. Among them, compounds 10a and 14a demonstrated the best activity with EC50＝1.71 and 5.60
μmol•L−1 respectively, even better than the positive control 8-MOP (EC50＝14.8 μmol•L−1). Conversely, com-
pounds 3b, 5b－6b, 9b－10b, and 15b induced enzymatic inhibition on tyrosinase.
Keywords enzyme, chalcone, heterocycles, synthesis, structure-activity relationship
OH
Introduction
OH
OH
OH
Tyrosinase (monophenol monooxygenase, EC:
1.14.18.1), also known as polyphenol oxidase,[1] is a
copper-containing enzyme widely distributed in nature.
Tyrosinase could catalyze the first two reactions in the
melanin synthesis, the two steps in the pathway are the
hydroxylation of monophenol to o-diphenol (monophe-
nolase or cresolase activity) and the oxidation of diphe-
nol to o-quinones (diphenolase or catecholase activity),
both using molecular oxygen followed by a series of
nonenzymatic steps resulting in the formation of mela-
nin,[2-4] which plays a crucial protective role against skin
photocarcinogenesis. Some dermatological disorders,
such as Vitiligo, arise from the destruction and disap-
pearance of melanocytes.
The Ver-nohia anthelmintica L. is a kind of plant
growing only in the high altitude localities of southern
Xinjiang and minority regions of Pakistan and India. Its
fruits extract is one of the most popular Uygur medi-
cines used for Vitiligo and initially recorded in ‘Yao
Yong Zong Ku’ around 300 years ago.[5-7] Some impor-
tant chalcone compounds were isolated from the plant
as well (Figure 1). It was believed that these compounds
played an important role in this treatment. since it may
activate tyrosinase and improve the melanin produc-
tion.[8,9]
HO
HO
OH
O
HO
OH
O
O
3,4,2',4',5'-pentahydroxy-6'-methoxy-
2-methylchalcone
Butein
OH
OH
OH
OH
HO
OH
HO
O
OH
O
Isoliquiritigenin
3,4,2',4',5'-pentahydroxychalcone
Figure 1 Structures of the chalcones in Vernonia anthelmintica
Wild.
spices, tea and soy based foodstuff are very versatile for
physiologically activity, such as antitumoral,[10,11] anti-
oxidant,[12] antimicrobial,[13] antibacterial,[14] anti-in-
flammatory[15,16] and anti-HIV.[17] Until now, most chal-
cones and their derivatives have been described as po-
tent inhibitors on tyrosinase.[18-20]
A few agonist of tyrosinase have been reported.
Currently, only four derivatives of carbazole substituted
chalcone urea[21] and 4'-(phenylurenyl/thiourenyl)chal-
cone derivatives[22] were discovered as activator of the
tyrosinase. Unfortunately, all these compounds bore a
Chalcones which are major classes of natural prod-
ucts with widespread distribution in fruits, vegetables,
*
E-mail: haji@ms.xjb.ac.cn, niuchao@ms.xjb.ac.cn
Received December 1, 2014; accepted January 17, 2015; published online March 30, 2015.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400820 or from the author.
486
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2015, 33, 486—494

Synthesis and Bioactivity of New Chalcone Derivatives as Potential Tyrosinase Activator
poor activity.
Our group has been interested in the chalcones with
NaOH as base, followed by deprotection with HCl in
ethanol.[32,33] After that, a' or b' was treated with
propargyl bromide to afford a or b according to the
known procedure,[34] which in the last step reacted with
compounds 1－15, catalyzed by CuSO4/Na-Ascorbate
to yield the desired compounds.
activator effect on tyrisinase all along.[23-26] Inspired by
above results and the literature, we introduced the
1,2,3-triazole group into chalcone ring A or B to im-
prove the activity. 1, 4-Linked triazoles possess a high
dipole moment and the nitrogen atoms at the 2 and 3
positions can act as hydrogenbond acceptors.[27,28] Thus,
a new series compounds of (E)-1-(4-((1-benzyl-
1H-1,2,3-triazole-4-yl)methoxy)phenylriazo)-3-phenyl-
prop-2-en-1-one 1a－15a and (E)-3-(4-((1-benzyl-
1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1-phenylprop-2-
en-1-one 1b－15b were synthesized and the effects of
them on tyrosinase have been evaluated in this letter.
The synthetic route of compounds 1－15, 1a－15a
and 1b－15b is outlined in Scheme 1. Compounds 1－
15 were obtained from substituted benzyl chloride or
benzyl bromide in DMSO with the presence of NaN3.[29]
The 1,2,3-triazole 1a－15a, 1b－15b were prepared in a
four-steps synthetic pathway based on click chemis-
try.[30,31] The hydroxyl-substituted chalcones were pre-
pared through the Claisen-Schmidt condensation of the
corresponding acetopheones and benzaldehydes with
Experimental
General
Reagents and solvents were purchased from Sigma,
Sodipro or VMR, and used without further purification.
Thin-layer chromatography (TLC) was carried out on
glass plates coated with silica gel (Qingdao Haiyang
Chemical Co., G60F-254) and visualized by UV light
(254 nm). The products were purified by column chro-
matography over silica gel (Qingdao Haiyang Chemical
Co., 200－300 mesh). Melting points were determined
on a Buchi B-540 apparatus and uncorrected. All the
NMR spectra were recorded with a Bruker AVANCE II
400 MHz spectrometer in CDCl3, using TMS as an in-
ternal standard. High-resolution mass spectra (HRMS)
were recorded on AB SCIEX QSTAR Elite quadrupole
Scheme 1 Synthesis of 1a－15a and 1b－15b
R
i
R
X
N3
1
15
－
HO
MOMO
MOMO
iv
ii
iii
+
H
O
a'
O
O
O
O
N
N
O
1
－
15
N
R
B
A
v
O
a
O
1a
－15a
OMOM
OH
OMOM
ii
iii
iv
+
H
O
O
O
O
b'
N
N
O
N
1
15
－
O
A
B
v
R
O
b
O
1b 15b
－
1, 1a, 1b: R = H
2, 2a, 2b: R = 2-Cl
3, 3a, 3b: R = 3-OCH3
4, 4a, 4b: R = 4-CH3
6, 6a, 6b: R = 4-NO2
7, 7a, 7b: R = 2-CF3
8, 8a, 8b: R = 3-Cl
9, 9a, 9b: R = 4-Cl
11, 11a, 11b: R = 2-CH3
12, 12a, 12b: R = 3-CH3
13, 13a, 13b: R = 2-F
14, 14a, 14b: R = 3-F
5 5a 5b
: R = 4-CN
10 10a 10b
15 15a 15b
: R = 4-F
,
,
,
,
: R = 3,4-Cl2
,
,
Regents and condition: (i) NaN3, DMSO, r.t.; (ii) 10% NaOH, ethanol, r.t.; (iii) 3 mol•L−1 HCl, ethanol, r.t.; (iv) propargyl bromide, K2CO3, DMF,
r.t.; (v) CuSO4/Na-Ascorbate, DCM/H2O, r.t.
Chin. J. Chem. 2015, 33, 486—494
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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487

Niu et al.
FULL PAPER
time-of-flight mass spectrometry. The IR data were re-
corded on a Thermo Fisher Scientific Nilolet 6700
FT-IR infrared spectrometer (KBr).
mmol) and K2CO3 (0.69 g, 5 mmol) were dissolved in 20
mL of DMF. This solution was stirred for 2 h at room
temperature, the progress of the reaction was monitored
by TLC. When the reaction was complete, 100 mL of
water was poured into the solution, the reaction mixture
was extracted with CHCl3 for three times. The organic
layer was separated and washed with distilled water and
dried over anhydrous MgSO4. The solvent was removed
at reduced pressure, and the residue was purified by a
silica gel column eluted with petroleum ether/ethyl ace-
tate (V∶V＝25∶1) to give the desired compounds a or
b.
Synthesis of compounds 1－15
Benzyl chloride or benzyl bromide (5 mmol) and
NaN3 (6 mmol) were dissolved in 10 mL DMSO, the
solution was stirred over night at room temperature until
the raw materials consumed, the mixture was extracted
with diethyl ether for three times, and washed with wa-
ter. The organic phase was dried with MgSO4, filtered,
and evaporated to afford the compounds 1－15.
(Azidomethyl)benzene (1): yield 79%, colourless oil;
IR (KBr) v: 2089 cm−1.
1
4'-Propargyloxy chalcone (a): yield 81%; H NMR
(400 MHz, CDCl3) δ: 8.05 (d, J＝8.7 Hz, 2H), 7.81 (d,
J＝15.7 Hz, 1H), 7.70－7.61 (m, 2H), 7.54 (d, J＝15.7
Hz, 1H), 7.41 (d, J＝4.2 Hz, 3H), 7.07 (d, J＝8.7 Hz,
2H), 4.78 (d, J＝2.4 Hz, 2H), 2.57 (t, J＝2.4 Hz, 1H).
1-(Azidomethyl)-2-chlorobenzene (2): yield 83%,
1
colourless oil; H NMR (400 MHz, CDCl3) δ: 7.45－
7.38 (m, 2H, aryl-H), 7.33－7.27 (m, 2H, aryl-H), 4.50
(s, 2H, CH2); 13C NMR (101 MHz, CDCl3) δ: 133.88,
133.42, 130.12, 129.88, 129.74, 127.26, 52.38; IR (KBr)
v: 2100 cm−1.
1
4-Propargyloxy chalcone (b): yield 85%; H NMR
(400 MHz, CDCl3) δ: 8.00 (d, J＝7.4 Hz, 2H), 7.77 (d,
J＝15.7 Hz, 1H), 7.60 (d, J＝8.7 Hz, 2H), 7.55 (d, J＝
7.4 Hz, 1H), 7.49 (t, J＝7.5 Hz, 2H), 7.42 (d, J＝15.7
Hz, 1H), 7.01 (d, J＝8.7 Hz, 2H), 4.73 (d, J＝2.4 Hz
2H), 2.55 (t, J＝2.4 Hz, 1H).
1-(Azidomethyl)-3-methoxybenzene (3): yield 82%,
1
colourless oil; H NMR (400 MHz, CDCl3) δ: 7.30 (t,
J＝7.8 Hz, 1H), 6.95－6.84 (m, 3H), 4.32 (s, 2H), 3.83
(s, 3H); 13C NMR (101 MHz, CDCl3) δ: 160.05, 136.98,
129.98, 120.50, 113.94 113.75, 55.36, 54.85; IR (KBr) v:
2092 cm−1.
Synthesis of compounds 1a－15a or 1b－15b
a or b (0.262 g, 1 mmol) and azide 1－15 ( 1 mmol)
were dissolved in 20 mL of dry DCM. When the solid
was dissolved completely, the solutions of anhydrous
CuSO4 (0.08 g, 0.5 mmol) and Vc-Na (0.5 g, 2.5 mmol)
in water were added separately. The solution was stirred
for 48 h. After the reaction was completed, 50 mL of
water was added and extracted with DCM for three
times. The combined organic phase was dried with
MgSO4, filtered, and evaporated to a residue that was
purified by a silica gel column eluted with petroleum
ether/ethyl acetate (V∶V , 3∶1－1∶1) to give the fi-
nal compounds 1a－15a or 1b－15b.
1-(4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-
phenyl)-3-phenyl-2-en-1-one (1a): white solid, yield
51%, m.p. 133－136 ℃; 1H NMR (400 MHz, CDCl3) δ:
8.03 (d, J＝9.0 Hz, 2H), 7.80 (d, J＝15.7 Hz, 1H),
7.67－7.62 (m, 2H), 7.53 (d, J＝15.6 Hz, 2H), 7.44－
7.36 (m, 6H), 7.31－7.27 (m, 2H), 7.06 (d, J＝9.0 Hz,
2H), 5.55 (s, 2H), 5.28 (s, 2H); 13C NMR (101 MHz,
CDCl3) δ: 188.73, 161.94, 144.16, 143.88, 135.03,
134.30, 131.60, 130.83, 130.40, 129.22, 128.95, 128.93,
128.39, 128.18, 122.78, 121.80, 114.64, 62.14, 54.37;
IR (KBr) v: 1653, 1596, 1335, 1218, 1180, 981 cm−1;
HRMS (ESI) calcd for C25H22N3O2 [M＋H]＋ 396.1712,
found 396.1690.
1-(Azidomethyl)-4-methylbenzene (4): yield 80%,
colourless oil; IR (KBr) v: 2080 cm−1.
1-(Azidomethyl)-4-cyanobenzene (5): yield 86%,
colourless oil; IR (KBr) v: 2096 cm−1.
1-(Azidomethyl)-4-nitrobenzene (6): yield 90%, red
solid; IR (KBr) v: 2100 cm−1.
1-(Azidomethyl)-2-trifluoromethylbenzene (7): yield
85%, colourless oil; IR (KBr) v: 2105 cm−1.
1-(Azidomethyl)-3-chlorobenzene (8): yield 76%,
colourless oil; IR (KBr) v: 2100 cm−1.
1-(Azidomethyl)-4-chlorobenzene (9): yield 80%,
colourless oil; IR (KBr) v: 2085 cm−1.
1-(Azidomethyl)-3,4-dichlorobenzene (10): yield
85%, colourless oil; IR (KBr) v: 2090 cm−1.
1-(Azidomethyl)-4-chlorobenzene (11): yield 80%,
colourless oil; IR (KBr) v: 2085 cm−1.
1-(Azidomethyl)-3-methylbenzene (12): yield 82%,
colourless oil; IR (KBr) v: 2091 cm−1.
1-(Azidomethyl)-2-fluorobenzene (13): yield 75%,
colourless oil; IR (KBr) v: 2095 cm−1.
1-(Azidomethyl)-2-fluorobenzene (14): yield 78%,
colourless oil; IR (KBr) v: 2100 cm−1.
1-(Azidomethyl)-4-fluorobenzene (15): yield 74%,
1
colourless oil; H NMR (400 MHz, CDCl3) δ: 7.34－
1-(4-((1-(2-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-3-phenyl-2-en-1-one (2a): white solid,
yield 63%, m.p. 162－165 ℃; H NMR (400 MHz,
CDCl3) δ: 8.03 (d, J＝8.9 Hz, 2H), 7.80 (d, J＝15.7 Hz,
1H), 7.68－7.62 (m, 3H), 7.53 (d, J＝15.7 Hz, 1H),
7.47－7.38 (m, 4H), 7.35－7.27 (m, 2H), 7.22 (dd, J＝
7.5, 1.8 Hz, 1H), 7.07 (d, J＝8.9 Hz, 2H), 5.68 (s, 2H),
5.28 (s, 2H); 13C NMR (101 MHz, CDCl3) δ: 188.73,
7.27 (m, 2H, aryl-H), 7.11－7.04 (m, 2H, aryl-H), 4.32
(s, 2H, CH2); 13C NMR (101 MHz, CDCl3) δ: 164.00,
161.54, 131.34, 130.12, 115.89, 54.16; IR (KBr) v: 2093
cm−1.
1
Synthesis of compounds a or b
4'-Hydroxychalcone or 4-hydroxychalcone (a' or b',
0.224 g, 1 mmol), propargyl bromide (0.214 mL, 2.4
488
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© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2015, 33, 486—494

Synthesis and Bioactivity of New Chalcone Derivatives as Potential Tyrosinase Activator
161.95, 144.16, 143.82, 135.04, 133.59, 132.20, 131.61,
130.84, 130.52, 130.43, 130.41, 130.02, 128.95, 128.40,
127.69, 123.17, 121.81, 114.66, 62.14, 51.60; IR (KBr)
v: 1651, 1594, 1336, 1219, 1173, 980 cm−1; HRMS (ESI)
calcd for C25H21ClN3O2 [M ＋ H] ＋ 430.1322, found
430.1335.
441.1563, found 441.1555.
1-(4-((1-(2-Trifluoromethylbenzyl)-1H-1,2,3-triazol-
4-yl)methoxy)phenyl)-3-phenyl-2-en-1-one (7a): white
1
solid, yield 52%, m.p. 126－130 ℃; H NMR (400
MHz, CDCl3) δ: 8.02 (d, J＝8.9 Hz, 2H), 7.79 (d, J＝
15.7 Hz, 1H), 7.73 (d, J＝7.6 Hz, 1H), 7.62－7.65 (m,
2H), 7.60 (s, 1H), 7.57－7.43 (m, 3H), 7.43－7.39 (m,
3H), 7.22 (d, J＝7.7 Hz, 1H), 7.06 (d, J＝8.9 Hz, 2H),
5.76 (s, 2H), 5.29 (s, 2H); 13C NMR (101 MHz, CDCl3)
δ: 188.80, 161.90, 144.23, 135.00, 132.80, 131.62,
130.85, 130.43, 130.28, 128.95, 128.92, 128.40, 128.19,
127.89, 126.29 (q, J＝5.6 Hz), 125.45, 123.31, 121.77,
114.64, 62.07, 50.84; IR (KBr) v: 1651, 1590, 1314,
1107, 989 cm−1; HRMS (ESI) calcd for C26H21F3N3O2
[M＋H]＋ 464.1586, found 464.1572.
1-(4-((1-(3-Methoxybenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-3-phenyl-2-en-1-one (3a): white solid,
1
yield 54%, m.p. 135－137 ℃; H NMR (400 MHz,
CDCl3) δ: 8.03 (d, J＝8.9 Hz, 2H), 7.80 (d, J＝15.7 Hz,
1H), 7.61－7.67 (m, 2H), 7.57 (s, 1H), 7.53 (d, J＝15.7
Hz, 1H), 7.44－7.37 (m, 3H), 7.9 (t, J＝8.0 Hz, 1H),
7.06 (d, J＝8.9 Hz, 2H), 6.92－6.83 (m, 2H), 6.81－
6.77 (m, 1H), 5.51 (s, 2H), 5.27 (s, 2H), 3.77 (s, 3H);
13C NMR (101 MHz, CDCl3) δ: 188.72, 161.94, 160.15,
144.15, 135.75, 135.03, 131.58, 130.83, 130.41, 130.29,
128.95, 128.40, 122.87, 121.79, 120.33, 114.64, 114.29,
113.79, 62.13, 55.33, 54.30; IR (KBr) v: 1660, 1602,
1253, 1216, 1167, 990 cm−1; HRMS (ESI) calcd for
C26H24N3O3 [M＋H]＋ 426.1818, found 426.1840.
1-(4-((1-(3-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-3-phenyl-2-en-1-one (8a): white solid,
yield 49%, m.p. 130－133 ℃; H NMR (400 MHz,
1
CDCl3) δ: 8.03 (d, J＝9.0 Hz, 2H), 7.80 (d, J＝15.7 Hz,
1H), 7.61－7.67 (m, 2H), 7.59 (s, 1H), 7.53 (d, J＝15.7
Hz, 1H), 7.44－7.39 (m, 3H), 7.35－7.26 (m, 3H), 7.16
(dt, J＝6.8, 1.7 Hz, 1H), 7.07 (d, J＝9.0 Hz, 2H),
5.53－5.51 (m, 2H), 5.31－5.27 (m, 2H); 13C NMR
(101 MHz, CDCl3) δ: 188.72, 161.89, 144.18, 136.28,
135.11, 135.02, 131.65, 130.84, 130.51, 130.41, 129.14,
128.95, 128.39, 128.17, 126.16, 122.81, 121.79, 114.64,
62.12, 53.61; IR (KBr) v: 3158, 1658, 1603, 1336, 1215,
1165, 975 cm−1; HRMS (ESI) calcd for C25H21ClN3O2
[M＋ H]＋ 430.1322, found 430.1335.
1-(4-((1-(4-Methylbenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-3-phenyl-2-en-1-one (4a): white solid,
1
yield 57%, m.p. 123－127 ℃; H NMR (400 MHz,
CDCl3) δ: 8.02 (d, J＝8.9 Hz, 2H), 7.79 (d, J＝15.7 Hz,
1H), 7.61－7.66 (m, 2H), 7.56－7.50 (m, 2H), 7.43－
7.39 (m, 3H), 7.18 (s, 4H), 7.05 (d, J＝8.9 Hz, 2H),
5.49 (s, 2H), 5.24 (s, 2H), 2.34 (s, 3H). 13C NMR (101
MHz, CDCl3) δ: 188.69, 161.99, 144.12, 143.84, 138.87,
135.02, 131.54, 131.31, 130.83, 130.42, 129.85, 128.96,
128.40, 128.24, 122.87, 121.79, 114.64, 62.12, 54.15,
21.20; IR (KBr) v: 3057, 2920, 1653, 1599, 1251, 1220,
1171, 1049, 995 cm−1; HRMS (ESI) calcd for
C26H24N3O2 [M＋H]＋ 410.1869, found 410.1886.
1-(4-((1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-3-phenyl-2-en-1-one (9a): white solid,
yield 60%, m.p. 153－155 ℃; H NMR (400 MHz,
1
CDCl3) δ: 8.03 (d, J＝8.9 Hz, 2H), 7.80 (d, J＝15.7 Hz,
1H), 7.67－7.60 (m, 2H), 7.58－7.50 (m, 2H), 7.38－
7.45 (m, 3H), 7.35 (d, J＝8.5 Hz, 2H), 7.22 (d, J＝8.6
Hz, 2H), 7.06 (d, J＝8.9 Hz, 2H), 5.51 (s, 2H), 5.27 (s,
2H); 13C NMR (101 MHz, CDCl3) δ: 188.71, 161.90,
144.19, 144.10, 135.01, 132.83, 131.64, 130.84, 130.42,
129.48, 129.43, 128.96, 128.40, 122.71, 121.77, 114.62,
62.10, 53.59; IR (KBr) v: 1656, 1601, 1337, 1219, 1174,
986 cm−1; HRMS (ESI) calcd for C25H21ClN3O2 [M＋
H]＋ 430.1322, found 430.1343.
1-(4-((1-(4-Cyanobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-3-phenyl-2-en-1-one (5a): white solid,
1
yield 61%, m.p. 153－155 ℃; H NMR (400 MHz,
CDCl3) δ: 8.01 (d, J＝8.9 Hz, 2H), 7.77 (d, J＝15.7 Hz,
1H), 7.68－7.58 (m, 5H), 7.51 (d, J＝15.7 Hz, 1H),
7.42－7.37 (m, 3H), 7.34 (d, J＝8.4 Hz, 2H), 7.04 (d,
J＝8.9 Hz, 2H), 5.60 (s, 2H), 5.26 (s, 2H); 13C NMR
(101 MHz, CDCl3) δ: 188.66, 161.85, 144.31, 144.23,
139.61, 134.93, 132.93, 131.64, 130.84, 130.49, 128.98,
128.48, 128.41, 123.17, 121.70, 118.13, 114.61, 112.84,
62.01, 53.51; IR (KBr) v: 3044, 2231, 1651, 1602, 1166,
994 cm−1; HRMS (ESI) calcd for C26H21N4O2 [M＋H]＋
421.1665, found 421.1651.
1-(4-((1-(3,4-Dichlorobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-3-phenyl-2-en-1-one (10a): light
yellow solid, yield 64%, m.p. 138－140 ℃; H NMR
1
(400 MHz, CDCl3) δ: 8.03 (d, J＝8.8 Hz, 2H), 7.80 (d,
J＝15.7 Hz, 1H), 7.61－7.66 (m, 2H), 7.60 (s, 1H), 7.53
(d, J＝15.7 Hz, 1H), 7.35－7.48 (m, 5H), 7.11 (dd, J＝
8.2, 2.0 Hz, 1H), 7.06 (d, J＝8.8 Hz, 2H), 5.50 (s, 2H),
5.28 (s, 2H); 13C NMR (101 MHz, CDCl3) δ: 188.70,
161.85, 144.32, 144.21, 135.00, 134.47, 133.42, 133.34,
131.67, 131.22, 130.85, 130.44, 129.98, 128.96, 128.40,
127.27, 122.81, 121.76, 114.62, 62.08, 53.02; IR (KBr)
v: 2360, 2342, 1648, 1588, 1336, 1218, 1033, 975 cm−1;
HRMS (ESI) calcd for C25H20Cl2N3O2 [M ＋ H] ＋
464.0933, found 464.0937.
1-(4-((1-(4-Nitrobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-3-phenyl-2-en-1-one
(6a):
light
1
yellow solid, yield 50%, m.p. 159－162 ℃; H NMR
(400 MHz, CDCl3) δ: 8.22 (d, J＝8.8 Hz, 2H), 8.02 (d,
J＝8.9 Hz, 2H), 7.78 (d, J＝15.7 Hz, 1H), 7.68 (s, 1H),
7.65－7.59 (m, 2H), 7.52 (d, J＝15.7 Hz, 1H), 7.44－
7.37 (m, 5H), 7.05 (d, J＝8.9 Hz, 2H), 5.66 (s, 2H),
5.29 (s, 2H); 13C NMR (101 MHz, CDCl3) δ: 190.52,
160.07, 148.13, 144.36, 141.42, 138.38, 132.68, 130.27,
128.67, 128.62, 128.43, 128.27, 124.37, 120.20, 115.19,
62.00, 53.26; IR (KBr) v: 3082, 2922, 1647, 1457, 1334,
978 cm−1; HRMS (ESI) calcd for C25H21N4O4 [M＋H]＋
1-(4-((1-(2-Methylbenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-3-phenyl-2-en-1-one (11a): white
Chin. J. Chem. 2015, 33, 486—494
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
489

Niu et al.
FULL PAPER
1
solid, yield 68%, m.p. 117－120 ℃; H NMR (400
MHz, CDCl3) δ: 8.01 (d, J＝8.9 Hz, 2H), 7.79 (d, J＝
15.7 Hz, 1H), 7.66－7.59 (m, 2H), 7.52 (d, J＝15.7 Hz,
1H), 7.45 (s, 1H), 7.43－7.38 (m, 3H), 7.32－7.14 (m,
4H), 7.05 (d, J＝8.9 Hz, 2H), 5.54 (s, 2H), 5.24 (s, 2H),
2.27 (s, 2H); 13C NMR (101 MHz, CDCl3) δ: 188.70,
161.97, 144.13, 136.98, 135.02, 132.26, 131.54, 131.12
130.83, 130.42, 129.51, 129.30, 128.96, 128.40, 126.74,
122.76, 121.78, 114.65, 62.13, 52.52, 21.93; IR (KBr) v:
3141, 2923, 2360, 2342, 1652, 1596, 1381, 1217, 980
cm−1; HRMS (ESI) calcd for C26H24N3O2 [M＋H]＋
410.1869, found 410.1876.
MHz, CDCl3) δ: 8.03 (d, J＝8.9 Hz, 2H), 7.80 (d, J＝
15.7 Hz, 1H), 7.63 (t, J＝6.5 Hz, 2H), 7.49－7.56 (m,
2H), 7.44－7.38 (m, 3H), 7.31－7.26 (m, 2H), 7.11－
7.03 (m, 4H), 5.52 (s, 2H), 5.28 (s, 2H); 13C NMR (101
MHz, CDCl3) δ: 188.72, 164.18, 161.91, 144.20, 144.04,
135.02, 131.63, 130.84, 130.42, 130.20 (d, J＝3.3 Hz),
130.11, 130.03, 128.96, 128.40, 122.62, 121.77, 116.36,
116.14, 114.62, 62.13, 53.60; IR (KBr) v: 1651, 1602,
1509, 1220, 1169, 1034, 976 cm−1; HRMS (ESI) calcd
for C25H21FN3O2 [M＋H]＋ 414.1618, found 414.1613.
3-(4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-
phenyl)-1-phenyl-2-en-1-one (1b): white solid, yield
57%, m.p. 132－134 ℃; 1H NMR (400 MHz, CDCl3) δ:
8.01 (d, J＝8.2 Hz, 2H), 7.77 (d, J＝15.7 Hz, 1H),
7.55－7.62 (m, 3H), 7.54 (s, 1H), 7.50 (t, J＝7.4 Hz,
2H), 7.45－7.35 (m, 4H), 7.30－7.27 (m, 2H), 7.01 (d,
J＝8.8 Hz, 2H), 5.54 (s, 2H), 5.23 (s, 2H); 13C NMR
(101 MHz, CDCl3) δ: 190.57, 160.21, 144.50, 144.08,
138.45, 134.36, 132.63, 130.25, 129.21, 128.91, 128.60,
128.44, 128.17, 122.73, 120.11, 115.23, 62.12, 54.34;
IR (KBr) v: 1630, 1507, 1220, 1172, 980 cm−1; HRMS
(ESI) calcd for C25H22N3O2 [M＋H]＋ 396.1712, found
396.1719.
1-(4-((1-(3-Methylbenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-3-phenyl-2-en-1-one (12a): white
1
solid, yield 50%, m.p. 123－126 ℃; H NMR (400
MHz, CDCl3) δ: 8.02 (d, J＝8.9 Hz, 2H), 7.79 (d, J＝
15.7 Hz, 1H), 7.65－7.59 (m, 2H), 7.57 (s, 1H), 7.53 (d,
J＝15.7 Hz, 1H), 7.42－7.37 (m, 3H), 7.25 (t, J＝7.5
Hz, 1H), 7.16 (d, J＝7.5 Hz, 1H), 7.10－7.02 (m, 4H),
5.48 (s, 2H), 5.25 (s, 2H), 2.32 (s, 3H); 13C NMR (101
MHz, CDCl3) δ: 188.64, 162.00, 144.09, 143.81, 139.03,
135.01, 134.31, 131.52, 130.83, 130.43, 129.62, 129.06,
128.96, 128.88, 128.41, 125.23, 122.98, 121.78, 114.65,
62.12, 54.30, 21.35; IR (KBr) v: 2360, 1654, 1596, 1335,
1217, 1174, 1047, 972 cm−1; HRMS (ESI) calcd for
C26H24N3O2 [M＋H]＋ 410.1869, found 410.1853.
3-(4-((1-(2-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-1-phenyl-2-en-1-one (2b): white solid,
1
yield 60%, m.p. 118－120 ℃; H NMR (400 MHz,
1-(4-((1-(2-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-3-phenyl-2-en-1-one (13a): white
solid, yield 55%, m.p. 127－130 ℃; H NMR (400
CDCl3) δ: 8.01 (d, J＝7.1 Hz, 2H), 7.77 (d, J＝15.6 Hz,
1H), 7.65 (s, 1H), 7.62－7.55 (m, 3H), 7.50 (t, J＝7.6
Hz, 2H), 7.38－7.47 (m, 2H), 7.33 (td, J＝7.6, 1.8 Hz,
1H), 7.28 (dd, J＝7.6, 1.2 Hz, 1H), 7.22 (dd, J＝7.6, 1.8
Hz, 1H), 7.03 (d, J＝8.7 Hz, 2H), 5.68 (s, 2H), 5.25 (s,
2H); 13C NMR (101 MHz, CDCl3) δ: 190.54, 160.23,
144.45, 144.02, 138.52, 133.59, 132.57, 132.28, 130.48,
130.38, 130.21, 130.01, 128.58, 128.43, 128.26, 127.66,
123.02, 120.24, 115.32, 62.19, 51.56; IR (KBr) v: 1655,
1598, 1447, 1216, 1047, 972 cm−1; HRMS (ESI) calcd
for C25H21ClN3O2 [M＋H]＋ 430.1322, found 430.1339.
3-(4-((1-(3-Methoxybenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-1-phenyl-2-en-1-one (3b): white solid,
1
MHz, CDCl3) δ: 8.03 (d, J＝9.0 Hz, 2H), 7.80 (d, J＝
15.7 Hz, 1H), 7.68－7.61 (m, 3H), 7.53 (d, J＝15.7 Hz,
1H), 7.45－7.39 (m, 3H), 7.39－7.34 (m, 1H), 7.30 (td,
J＝7.5, 1.5 Hz, 1H), 7.19－7.10 (m, 2H), 7.07 (d, J＝
9.0 Hz, 2H), 5.60 (s, 2H), 5.28 (s, 2H). 13C NMR (101
MHz, CDCl3) δ: 188.73, 161.95, 159.36, 144.15, 135.04,
131.60, 131.11 (d, J＝8.3 Hz), 130.84, 130.71 (d, J＝
3.1 Hz), 130.40, 128.95, 128.39, 124.93 (d, J＝3.7 Hz),
123.01, 121.81, 121.60, 116.03, 115.82, 114.64, 62.11,
47.90; IR (KBr) v: 1652, 1596, 1493, 1219, 1172, 997
cm−1. HRMS (ESI) calcd for C25H21FN3O2 [M＋H]＋
414.1618, found 414.1625.
1
yield 63%, m.p. 116－119 ℃; H NMR (400 MHz,
CDCl3) δ: 8.00 (d, J＝7.3 Hz, 2H), 7.77 (d, J＝15.7 Hz,
1H), 7.63－7.53 (m, 4H), 7.49 (t, J＝7.4 Hz, 2H), 7.41
(d, J＝15.7 Hz, 1H), 7.29 (t, J＝7.9 Hz, 1H), 7.01 (d,
J＝8.6 Hz, 2H), 6.93－6.82 (m, 2H), 6.79 (s, 1H), 5.50
(s, 2H), 5.23 (s, 2H), 3.77 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ: 190.53, 160.20, 160.14, 144.47, 144.05,
138.44, 135.79, 132.60, 130.25, 130.21, 128.57, 128.41,
128.14, 122.73, 120.29, 120.11, 115.23, 114.26, 113.76,
62.12, 55.31, 54.24; IR (KBr) v: 2360, 1586, 1508, 1251,
1053, 986 cm−1; HRMS (ESI) calcd for C26H24N3O3
[M＋H]＋ 426.1818, found 426.1827.
1-(4-((1-(3-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-3-phenyl-2-en-1-one (14a): white
1
solid, yield 52%, m.p. 131－133 ℃; H NMR (400
MHz, CDCl3) δ: 8.03 (d, J＝9.0 Hz, 2H), 7.80 (d, J＝
15.7 Hz, 1H), 7.66－7.61 (m, 2H), 7.58 (s, 1H), 7.53 (d,
J＝15.7 Hz, 1H), 7.44－7.39 (m, 3H), 7.32－7.39 (m,
1H), 7.10－7.03 (m, 4H), 6.99－6.94 (m, 1H), 5.54 (s,
2H), 5.29 (s, 2H); 13C NMR (101 MHz, CDCl3) δ:
188.73, 164.27, 161.89, 144.18, 136.70 (d, J＝7.4 Hz),
135.03, 131.65, 130.92, 130.84, 130.41, 128.95, 128.40,
123.62 (d, J＝3.1 Hz), 122.82, 121.78, 116.07, 115.86,
115.20, 114.98, 114.64, 62.13, 53.68; IR (KBr) v: 1655,
1593, 1334, 1253, 1170, 997 cm−1; HRMS (ESI) calcd
for C25H21FN3O2 [M＋H]＋ 414.1618, found 414.1605.
1-(4-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-3-phenyl-2-en-1-one (15a): white
3-(4-((1-(4-Methylbenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-1-phenyl-2-en-1-one (4b): white solid,
1
yield 65%, m.p. 166－168 ℃; H NMR (400 MHz,
CDCl3) δ: 8.01 (d, J＝7.0 Hz, 2H), 7.77 (d, J＝15.7 Hz,
1H), 7.62－7.55 (m, 3H), 7.54－7.47 (m, 3H), 7.41 (d,
J＝15.7 Hz, 1H), 7.18 (s, 4H), 7.01 (d, J＝8.8 Hz, 2H),
5.50 (s, 2H), 5.22 (s, 2H), 2.35 (s, 3H); 13C NMR (101
1
solid, yield 65%, m.p. 128－132 ℃; H NMR (400
490
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© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2015, 33, 486—494

Synthesis and Bioactivity of New Chalcone Derivatives as Potential Tyrosinase Activator
MHz, CDCl3) δ: 190.56, 160.21, 144.50, 143.91, 138.89,
138.44, 132.62, 131.27, 130.23, 129.85, 128.59, 128.43,
128.23, 128.14, 122.63, 120.09, 115.22, 62.09, 54.17,
21.18; IR (KBr) v: 1646, 1561, 1508, 1253, 1174, 996
cm−1; HRMS (ESI) calcd for C26H24N3O2 [M＋H]＋
410.1869, found 410.1868.
HRMS (ESI) calcd for C25H21ClN3O2 [M ＋ H] ＋
430.1322, found 430.1318.
3-(4-((1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-1-phenyl-2-en-1-one (9b): white solid,
1
yield 61%, m.p. 132－135 ℃; H NMR (400 MHz,
CDCl3) δ: 8.01 (d, J＝7.0 Hz, 2H), 7.77 (d, J＝15.7 Hz,
1H), 7.62－7.54 (m, 4H), 7.50 (t, J＝6.6 Hz, 2H), 7.42
(d, J＝15.6 Hz, 1H), 7.36 (d, J＝8.5 Hz, 2H), 7.22 (d,
J＝8.5 Hz, 2H), 7.01 (d, J＝8.8 Hz, 2H), 5.51 (s, 2H),
5.24 (s, 2H); 13C NMR (101 MHz, CDCl3) δ: 190.56,
160.15, 144.45, 144.30, 138.43, 135.00, 132.84, 132.64,
130.25, 129.47, 129.43, 128.60, 128.44, 128.22, 122.68,
120.17, 115.22 62.06, 53.60; IR (KBr) v: 1587, 1561,
1253, 1174, 995 cm−1; HRMS (ESI) calcd for
C25H21ClN3O2 [M＋H]＋ 430.1322, found 430.1235.
3-(4-((1-(3,4-Dichlorobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-1-phenyl-2-en-1-one (10b): light
3-(4-((1-(4-Cyanobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-1-phenyl-2-en-1-one (5b): white solid,
1
yield 53%, m.p. 146－150 ℃; H NMR (400 MHz,
CDCl3) δ: 8.00 (d, J＝7.0 Hz, 2H), 7.76 (d, J＝15.7 Hz,
1H), 7.67 (d, J＝8.5 Hz, 2H), 7.64－7.54 (m, 4H), 7.49
(t, J＝7.4 Hz, 2H), 7.42 (d, J＝15.7 Hz, 1H), 7.35 (d,
J＝8.6 Hz, 2H), 7.01 (d, J＝8.8 Hz, 2H), 5.61 (s, 2H),
5.25 (s, 2H); 13C NMR (101 MHz, CDCl3) δ: 190.52,
160.09, 144.37, 139.57, 138.39, 132.95, 132.68, 130.27,
128.62, 128.47, 128.43, 128.27, 123.01, 120.20, 118.09,
115.18, 112.92, 62.01, 53.53; IR (KBr) v: 2238, 1646,
1560, 1507, 1252, 1173, 995 cm−1; HRMS (ESI) calcd
for C26H21N4O2 [M＋H]＋ 421.1665, found 421.1658.
3-(4-((1-(4-Nitrobenzyl)-1H-1,2,3-triazol-4-yl)-
1
yellow solid, yield 66%, m.p. 120－123 ℃; H NMR
(400 MHz, CDCl3) δ: 8.00 (d, J＝8.5 Hz, 2H), 7.77 (d,
J＝15.7 Hz, 1H), 7.63－7.55 (m, 4H), 7.50 (t, J＝7.4
Hz, 2H), 7.47－7.35 (m, 3H), 7.11 (dd, J＝8.2, 2.1 Hz,
1H), 7.01 (d, J＝8.8 Hz, 2H), 5.50 (s, 2H), 5.25 (s, 2H);
13C NMR (101 MHz, CDCl3) δ: 190.56, 160.11, 144.43,
144.39, 138.45, 134.49, 133.43, 133.33, 132.62, 131.20,
130.23, 129.96, 128.59, 128.43, 128.29, 127.24, 122.74,
120.25, 115.24, 62.08, 53.01; IR (KBr) v: 2923, 1656,
methoxy)phenyl)-1-phenyl-2-en-1-one
(6b):
light
1
yellow solid, yield 48%, m.p. 148－150 ℃; H NMR
(400 MHz, CDCl3) δ: 8.22 (d, J＝8.8 Hz, 2H), 8.00 (d,
J＝7.0 Hz, 2H), 7.76 (d, J＝15.7 Hz, 1H), 7.66 (s, 1H),
7.62－7.53 (m, 3H), 7.49 (t, J＝7.4 Hz, 2H), 7.38－
7.45 (m, 3H), 7.01 (d, J＝8.8 Hz, 2H), 5.66 (s, 2H),
5.26 (s, 2H); 13C NMR (101 MHz, CDCl3) δ: 190.52,
160.07, 148.13, 144.36, 141.39, 138.35, 132.68, 130.27,
128.67, 128.62, 128.43, 128.27, 124.37, 120.20, 115.19,
62.00, 53.26; IR (KBr) v: 1655, 1592, 1510, 1252, 1174,
986 cm−1; HRMS (ESI) calcd for C25H21N4O4 [M＋H]＋
441.1563, found 441.1584.
1593, 1248, 1175, 1106, 986 cm−1; HRMS (ESI) calcd
＋
for C25H20Cl2N3O2 [M ＋ H]
464.0933, found
464.0942.
3-(4-((1-(2-Methylbenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-1-phenyl-2-en-1-one (11b): white
1
solid, yield 52%, m.p. 116－119 ℃; H NMR (400
3-(4-((1-(2-Trifluoromethylbenzyl)-1H-1,2,3-triazol-
4-yl)methoxy)phenyl)-1-phenyl-2-en-1-one (7b): white
solid, yield 50%, m.p. 122－124 ℃; H NMR (400
MHz, CDCl3) δ: 8.00 (d, J＝7.0 Hz, 2H), 7.77 (d, J＝
15.7 Hz, 1H), 7.61－7.54 (m, 3H), 7.49 (t, J＝7.4 Hz,
2H), 7.45－7.37 (m, 2H), 7.33－7.14 (m, 4H), 7.00 (d,
J＝8.8 Hz, 2H), 5.55 (s, 2H), 5.22 (s, 2H), 2.28 (s, 3H);
13C NMR (101 MHz, CDCl3) δ: 190.58, 160.21, 144.52,
143.83, 138.44, 136.99, 132.64, 132.26, 131.12, 130.24,
129.51, 129.29, 128.60, 128.44, 128.14, 126.73, 122.63,
120.09, 115.25, 62.10, 52.51, 19.00; IR (KBr) v: 3144,
2922, 1654, 1599, 1216, 1046, 974 cm−1; HRMS (ESI)
calcd for C26H24N3O2 [M ＋ H] ＋ 410.1869, found
410.1860.
1
MHz, CDCl3) δ: 8.00 (d, J＝7.0 Hz, 2H), 7.77 (d, J＝
15.7 Hz, 1H), 7.73 (d, J＝7.5 Hz, 1H), 7.63－7.45 (m,
8H), 7.42 (d, J＝15.6 Hz, 1H), 7.22 (d, J＝7.7 Hz, 1H),
13
7.02 (d, J＝8.8 Hz, 2H), 5.75 (s, 2H), 5.25 (s, 2H); C
NMR (101 MHz, CDCl3) δ: 190.54 (s), 160.16, 144.47,
138.43, 132.89 (d, J＝1.5 Hz), 132.78 (d, J＝0.9 Hz),
132.64, 130.25, 128.89, 128.60, 128.44, 128.21, 126.27
(q, J＝5.6 Hz), 125.45, 123.33, 122.73, 120.13, 115.24,
62.05, 50.29; IR (KBr) v: 1654, 1590, 1314, 1098, 993
cm−1; HRMS (ESI) calcd for C26H21F3N3O2 [M＋H]＋
464.1586, found 464.1592.
3-(4-((1-(3-Methylbenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-1-phenyl-2-en-1-one (12b): white
1
solid, yield 55%, m.p. 132－134 ℃; H NMR (400
3-(4-((1-(3-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-1-phenyl-2-en-1-one (8b): white solid,
yield 57%, m.p. 142－145 ℃; H NMR (400 MHz,
MHz, CDCl3) δ: 8.00 (d, J＝7.0 Hz, 2H), 7.77 (d, J＝
15.7 Hz, 1H), 7.61－7.55 (m, 3H), 7.54 (s, 1H), 7.50 (t,
J＝7.4 Hz, 2H), 7.41 (d, J＝15.6 Hz, 1H), 7.27 (t, J＝
7.9 Hz, 1H), 7.17 (d, J＝7.8 Hz, 1H), 7.11－7.05 (m,
2H), 7.01 (d, J＝8.8 Hz, 2H), 5.49 (s, 2H), 5.23 (s, 2H),
2.34 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 190.56,
160.23, 144.50, 144.01, 139.07, 138.45, 134.28, 132.63,
130.24, 129.63, 129.06, 128.88, 128.60, 128.44, 128.14,
125.23, 122.75, 120.10, 115.24, 62.13, 54.33, 21.35; IR
(KBr) v: 2360, 1659, 1591, 1512, 1253, 1215, 1015, 988
cm−1; HRMS (ESI) calcd for C26H24N3O2 [M＋H]＋
410.1869, found 410.1856.
1
CDCl3) δ: 8.03 (d, J＝7.0 Hz, 2H), 7.80 (d, J＝15.7 Hz,
1H), 7.65－7.57 (m, 4H), 7.52 (t, J＝7.4 Hz, 2H), 7.44
(d, J＝15.6 Hz, 1H), 7.37－7.28 (m, 3H), 7.18 (dt, J＝
6.9, 1.7 Hz, 1H), 7.04 (d, J＝8.8 Hz, 2H), 5.54 (s, 2H),
5.28 (s, 2H); 13C NMR (101 MHz, CDCl3) δ: 190.56,
160.14, 144.46, 144.36, 138.44, 136.30, 135.11, 132.64,
130.50, 130.25, 129.13, 128.60, 128.44, 128.23, 128.16,
126.15, 122.76, 120.16, 115.23, 62.10, 53.60; IR (KBr)
v: 2988, 1586, 1509, 1336, 1222, 1176, 1003, 984 cm−1;
Chin. J. Chem. 2015, 33, 486—494
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3-(4-((1-(2-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-1-phenyl-2-en-1-one (13b): white
solid, yield 50%, m.p. 116－120 ℃; H NMR (400
CDCl3) δ: 190.56, 160.17, 144.46, 144.22, 138.43,
132.65, 130.25, 130.10, 130.02, 128.61, 128.44, 128.20,
122.61, 120.15, 116.34, 116.12, 115.21, 62.08, 53.58;
IR (KBr) v: 2350, 1593, 1508, 1213, 1175, 1017, 987
cm−1; HRMS (ESI) calcd for C25H21FN3O2 [M＋H]＋
414.1618, found 414.1505.
1
MHz, CDCl3) δ: 8.00 (d, J＝7.0 Hz, 2H), 7.77 (d, J＝
15.7 Hz, 1H), 7.65 (s, 1H), 7.62－7.54 (m, 3H), 7.50 (t,
J＝7.4 Hz, 2H), 7.41 (d, J＝15.7 Hz, 1H), 7.38－7.33
(m, 1H), 7.29 (td, J＝7.5, 1.6 Hz, 1H), 7.18－7.09 (m,
2H), 7.02 (d, J＝8.8 Hz, 2H), 5.60 (s, 2H), 5.23 (s, 2H);
13C NMR (101 MHz, CDCl3) δ: 190.56, 160.21, 144.50,
144.06, 138.45, 132.63, 131.09 (d, J＝8.3 Hz), 130.70
(d, J＝3.1 Hz), 130.25, 128.60, 128.44, 128.17, 124.92
(d, J＝3.7 Hz), 122.97, 121.77, 121.62, 120.12, 116.02,
115.81, 115.23, 62.07, 47.83; IR (KBr) v: 2360, 1591,
1571, 1253, 1217, 1004 cm−1; HRMS (ESI) calcd for
C25H21FN3O2 [M＋H]＋ 414.1618, found 414.1607.
3-(4-((1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-1-phenyl-2-en-1-one (14b): white
Biological assay (Activity on tyrosinase)
Potassium phosphate buffer (0.06 mL, 50 mmol•L−1)
at pH 6.5, 0.04 mL tyrosinase (250 U/mL) and 2 μL of
the test compounds (0.5－300 μmol•L−1), dissolved in
DMSO were inserted into 96-well plates. After 5 min
incubation at 25－30 ℃, 0.1 mL of L-tyrosine (2
mmol•L−1) was added and incubated for additional 30
min. The optical density of the samples at 490 nm was
measured relative to control containing DMSO (2 μL)
and without inhibitor. The activity was expressed as the
sample concentration that gave a 50% effect in the en-
zyme activity (EC50).
1
solid, yield 56%, m.p. 127－129 ℃; H NMR (400
MHz, CDCl3) δ: 8.01 (d, J＝7.0 Hz, 2H), 7.77 (d, J＝
15.7 Hz, 1H), 7.62－7.55 (m, 4H), 7.50 (t, J＝7.4 Hz,
2H), 7.41 (d, J＝15.7 Hz, 1H), 7.39－7.32 (m, 1H),
7.09－6.99 (m, 4H), 6.99－6.94 (m, 1H), 5.54 (s, 2H),
5.25 (s, 2H); 13C NMR (101 MHz, CDCl3) δ: 190.56,
160.15, 144.46, 144.33, 138.44, 136.74 (d, J＝7.4 Hz),
132.64, 130.87 (d, J＝8.3 Hz), 130.25, 128.60, 128.44,
128.22, 123.61 (d, J＝3.0 Hz), 122.78, 120.16, 116.05,
115.84, 115.23, 114.97, 62.10, 53.64; IR (KBr) v: 1589,
1509, 1250, 1175, 986 cm−1; HRMS (ESI) calcd for
C25H21FN3O2 [M＋H]＋ 414.1618, found 414.1622.
3-(4-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)-
methoxy)phenyl)-1-phenyl-2-en-1-one (15b): white
Results and Discussion
Synthesis and structure
Dichloromethane (DCM) and tert-butyl alcohol
(TBA) were often used as solvent in click chemistry.
TBA was initially used in the preparation of compounds
1a－15a and 1b－15b, however, no product was ob-
tained after 48 h. So we tried to use DCM as the solvent
instead of TBA, the result was satisfactory. Click chem-
istry just finished in 2 h and there was no other
by-product.
1
solid, yield 60%, m.p. 134－136 ℃; H NMR (400
All new compounds were characterized by 1H NMR,
13C NMR, IR and HRMS (ESI). The aryl azides 1－15
were all identified by IR.
As showed in the Figure 2, the single crystals of the
compounds 8a, 10a and 15a (CCDC No. 1043285,
1043286 and 1043287) used for X-ray diffraction
MHz, CDCl3) δ: 8.00 (d, J＝7.0 Hz, 2H), 7.77 (d, J＝
15.7 Hz, 1H), 7.62－7.55 (m, 3H), 7.54 (s, 1H), 7.50 (t,
J＝7.4 Hz, 2H), 7.41 (d, J＝15.7 Hz, 1H), 7.30－7.26
(m, 2H), 7.07 (t, J＝8.6 Hz, 2H), 7.01 (d, J＝8.8 Hz,
2H), 5.51 (s, 2H), 5.23 (s, 2H); 13C NMR (101 MHz,
Figure 2 The crystal structures of the compounds 8a, 10a and 15a.
492
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Chin. J. Chem. 2015, 33, 486—494

Synthesis and Bioactivity of New Chalcone Derivatives as Potential Tyrosinase Activator
analysis were obtained by slow evaporation of ace-
tone-ethanol (V∶V＝1∶3) mixed solution at room
temperature.
As shown in Table 1, most of prepared compounds 1a－
15a showed good to excellent activating effect on ty-
rosinase. The potencies of compound 8a (EC50＝11.90
μmol•L−1), 10a (EC50＝1.71 μmol•L−1), 14a (EC50＝
5.60 μmol•L−1) and 15a (EC50＝14.56 μmol•L−1) were
better or comparative to the positive control 8-MOP, of
which EC50 was 14.8 μmol•L−1.
The position, number and nature of the substituent
on benzene ring were varied in order to identify the
most appropriate group. The compounds with halogen
(X) and trifluoromethyl (CF3) showed higher activity
compared with CH3, OCH3 and H, which suggested that
the electron-withdrawing group (EWG) may be favora-
ble to enhance the activity. However, the activity droped
rapidly when substituted with CN and NO2, indicating
that substituents with too strong electron-withdrawing
ability must have no benefit to the activity.
Among these halogenated compounds 2a, 8a－10a,
14a and 15a, the most important factor in their efficacy
was the location of the group. The shift of F substituent
from the meta (14a, EC50＝5.60 μmol•L−1) into the para
or ortho position led to 15a (EC50＝14.56 μmol•L−1),
which had a lower activity and 13a (EC50 ＝62.65
μmol•L−1), which was inactive. The similar result was
observed in compounds 2a, 8a and 9a which were sub-
stituted with Cl group as well. It became apparent that
the presence of a halogen group in the meta or para po-
sition of the phenyl ring was fundamental for activity.
The replacement of the Cl group with F contributed
no enhancement to the activity. Nevertheless, the num-
ber of the halogen atom on benzene made a great influ-
ence on activity. Introduction of a second Cl to the ben-
zene strongly increased activity. 3,4-Disubstituted
compound 10a exhibited a most promising activity than
any other compounds (EC50＝1.71 μmol•L−1).
Structure-activity relationship
The activities on tyrosinase of synthesized com-
pounds 1a－15a, 1b－15b were performed according to
a modified method,[35] with 8-MOP[36-39] and Kojic
acid[40] as positive control drug. The effects of the com-
pounds are summarized in Table 1 and Table 2.
Table 1 Activator effect on tyrosinase of compounds 1a－15a
Compd.
1a
Substrate
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
R
H
EC50a/(μmol•L−1)
＞100
2a
2-Cl
68.15±3.73
37.42±2.18
＞100
3a
3-OCH3
4-CH3
4-CN
4-NO2
2-CF3
3-Cl
4a
5a
＞100
6a
95.51±4.64
75.08±4.87
11.90±0.93
23.85±2.63
1.71±0.23
＞100
7a
8a
9a
4-Cl
10a
11a
12a
13a
14a
15a
8-MOP
3,4-Cl2
2-CH3
3-CH3
2-F
42.74±3.22
62.65±4.36
5.60±0.47
14.56±1.38
14.8±1.50
3-F
4-F
－
a
50% effective concentration, results are the mean±SD from
three independent experiments.
Table 2 Inbibitory effect on tyrosinase of compounds 1b－15b
Compared with the benzothiazole compounds (7b,
7d) in our previous research (Figure 3),[26] the active
1,2,3-triazole compounds in this work (3a, 8a－10a,
14a－15a) generally showed a better activity, which
may be influenced by the preferable solubility and the
characteristics of the triazole.
From the Table 2, all the compounds 1b－15b
slightly inhibited the tyrosinase, which was induced by
the shift of the same group from A ring into the B ring
of the chalcone. The result revealed that the same
1-benzyltriazol group on para-position of the chalcone
A ring may cause a great improvement on activating
effect on tyrosinase, but an inhibitor effect when it was
introduced to B ring.
Compd.
1b
Substrate
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
L-tyrosine
R
H
IC50a/(μmol•L−1)
＞100
2b
2-Cl
＞100
3b
3-OCH3
4-CH3
4-CN
4-NO2
2-CF3
3-Cl
85.76±3.17
＞100
4b
5b
66.52±2.32
43.18±1.43
＞100
6b
7b
8b
＞100
9b
4-Cl
35.64±0.71
24.10±0.52
＞100
10b
11b
12b
13b
14b
15b
Kojic acid
3,4-Cl2
2-CH3
3-CH3
2-F
＞100
＞100
R
N
Bz
S
3-F
＞100
4-F
31.43±0.86
10.78±0.38
O
－
7a: R = H, 7b: R = CH3, 7c: R = OCH3, 7d: R = Cl
a 50% inhibitory concentration, results are the mean±SD from
Figure 3 The Structure of the benzothiazole compounds.
three independent experiments.
Chin. J. Chem. 2015, 33, 486—494
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
493

Niu et al.
FULL PAPER
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This work was supported by the West Light Founda-
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