Synthesis of Novel Triazole Incorporated Thiazolone Motifs Having Promising Antityrosinase Activity through Green Nanocatalyst CuI-Fe3O4@SiO2 (TMS-EDTA)

Article abstract of DOI:10.1002/aoc.5962

In the present work, novel 5-((1-benzyl-1,2,3-triazol-4-yl)methoxybenzylidene)-2-(arylamino)thiazol-4-one thiazolone incorporated triazole derivatives have been designed as tyrosinase inhibitors. The compounds were synthesized through click reaction in good yield. Moreover, the antityrosinas activity of the synthesized derivatives was evaluated. In the search for establishing a click copper-catalyzed azide/alkyne cycloaddition (CuAAC) reaction under strict conditions, in terms of a novel air-stable, a recyclable and efficient magnetic catalyst was planned for new triazole derivatives as a well-organized copper iodide supported on the functionalized Fe₃O₄@SiO₂ core-shell (CuI/Fe₃O₄@SiO₂(TMS-EDTA) nanoparticles). The engineered nanocatalyst synthesized for the first time and characterized by different methods, including FT-IR spectroscopy, XRD, FESEM, EDX, TEM, TGA, and BET analysis. The excellent catalytic performance in ethanol with high surface area (351.7 m²g^?1) and short reaction time for diverse functional groups (120–200 min), no use of toxic solvents, reusability of the catalyst, and using eco-friendly conditions are the advantageous of this work. Moreover,the nanocatalyst can be used at least five times without any significant decrease in the yield of the reaction. The thiazolidine-triazole derivatives 9a, 9c, 9e, and 9 g showed promising tyrosinase inhibitory activity with IC₅₀ values in the range of 5.90–9.81 μM. The compounds were found to be considerably more potent tyrosinase inhibitors than the reference inhibitor kojic acid (IC₅₀ = 18.36 μM).

Full text of DOI:10.1002/aoc.5962

Received: 25 March 2020
DOI: 10.1002/aoc.5962
Revised: 21 July 2020
Accepted: 22 July 2020
F U L L P A P E R
Synthesis of Novel Triazole Incorporated Thiazolone Motifs
Having Promising Antityrosinase Activity through Green
Nanocatalyst CuI-Fe O @SiO (TMS-EDTA)
3
4
2
1
2
1
Mahdieh Darroudi
| Sara Ranjbar
| Mohammad Esfandiar
|
3
4
Mahsima Khoshneviszadeh
| Mahshid Hamzehloueian
|
3,5
1
Mehdi Khoshneviszadeh
| Yaghoub Sarrafi
1
Department of Organic Chemistry,
In the present work, novel 5-((1-benzyl-1,2,3-triazol-4-yl)methoxybenzylidene)-
-(arylamino)thiazol-4-one thiazolone incorporated triazole derivatives have
Faculty of Chemistry, University of
Mazandaran, Babolsar, 47416, Iran
2
2
Pharmaceutical Sciences Research
been designed as tyrosinase inhibitors. The compounds were synthesized
through click reaction in good yield. Moreover, the antityrosinas activity of the
synthesized derivatives was evaluated. In the search for establishing a click
copper-catalyzed azide/alkyne cycloaddition (CuAAC) reaction under strict
conditions, in terms of a novel air-stable, a recyclable and efficient magnetic
catalyst was planned for new triazole derivatives as a well-organized copper
Center, Shiraz University of Medical
Sciences, Shiraz, Iran
3
Medicinal and Natural Products
Chemistry Research Center, Shiraz
University of Medical Sciences, Shiraz,
Iran
4
Department of Chemistry, Jouybar
Branch, Islamic Azad University, Jouybar,
Iran
iodide supported on the functionalized Fe
O @SiO core-shell (CuI/Fe O @SiO
3 4 2 3 4 2
(TMS-EDTA) nanoparticles). The engineered nanocatalyst synthesized for the
5
Department of Medicinal Chemistry,
first time and characterized by different methods, including FT-IR spectroscopy,
School of Pharmacy, Shiraz University of
Medical Sciences, Shiraz, Iran
XRD, FESEM, EDX, TEM, TGA, and BET analysis. The excellent catalytic
2
−1
performance in ethanol with high surface area (351.7 m g ) and short reaction
time for diverse functional groups (120–200 min), no use of toxic solvents,
reusability of the catalyst, and using eco-friendly conditions are the advantageous
of this work. Moreover,the nanocatalyst can be used at least five times without
any significant decrease in the yield of the reaction. The thiazolidine-triazole
derivatives 9a, 9c, 9e, and 9 g showed promising tyrosinase inhibitory activity
with IC50 values in the range of 5.90–9.81 μM. The compounds were found to be
considerably more potent tyrosinase inhibitors than the reference inhibitor kojic
acid (IC50 = 18.36 μM).
Correspondence
Mehdi Khoshneviszadeh, Department of
Medicinal Chemistry, School of
Pharmacy, Shiraz University of Medical
Sciences, Shiraz, Iran.
Email: khoshnevim@sums.ac.ir
Yaghoub Sarrafi, Department of Organic
Chemistry, Faculty of Chemistry,
University of Mazandaran, 47416
Babolsar, Iran.
Email: ysarrafi@umz.ac.ir
K E Y W O R D S
click reaction, magnetic nanoparticle catalyst, novel Thiazolone-triazole, Tyrosinase inhibitor
1
| INTRODUCTION
Furthermore, the regioselectivity of cycloadducts is
[
23–26]
crucial
and it has been found that some 1,2,3-triazole
1
,2,3–Triazole and thiazolone scaffolds have shown
and thiazolone derivatives exhibited antityrosinase
[
1,2]
[23–26]
various biological activities including; antitumors,
anti-HIV, anti-allergy, antifungal,
anticancer, antiviral,
activity.
Tyrosinase, also known as polyphenol oxidase,
[
3]
[4]
[5–7]
[8,9]
anti-infection,
is a copper-containing enzyme abundantly distributed
in nature. This enzyme participates in the biosynthesis of
[10]
[11–13]
[14–22]
and antimicrobial properties.
Appl Organomet Chem. 2020;e5962.
wileyonlinelibrary.com/journal/aoc
© 2020 John Wiley & Sons, Ltd.
1 of 14
https://doi.org/10.1002/aoc.5962

2
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DARROUDI ET AL.
melanin by catalyzing the hydroxylation of L-tyrosine to
,4-dihydroxyphenylalanine, L-DOPA (mycophenolate
activity) and subsequently, oxidation of L-DOPA to
area, immobilization of metals and ligands, easy
preparation, adsorption, and also easy separation from
the reaction mixture through an external magnet.
3
[55–62]
[27]
dopaquinone (diphenolase activity). Tyrosinase inhibitors
are beneficial for the treatment of hyperpigmentation and
The core-shell supported CuI nanoparticles with high
specific surface area, small sizes, and reusability are
being used as click catalysts to improve the efficiency of
[28,29]
neurodegenerative disorders.
In addition, tyrosinase
[
63–71]
plays an important role in the oxidation of vegetables
and fruits phenolic compounds; hence, some tyrosinase
inhibitors have been applied in the food industry as
effective anti-browning agents preventing fruits and
the triazoles synthesis.
In this study, based on the antityrosinase effect of the
thiazolone and triazole heterocycles, the thiazolone-
triazole hybrid scaffold was designed. The 5-((1-benzyl-
1,2,3-triazol-4-yl)methoxybenzylidene)-2-(arylamino)
thiazol-4-one derivatives were synthesized via efficient
and simple CuAAC reactions. These 1,2,3-triazoles were
prepared in the presence of an CuI/Fe O @SiO (TMS-EDTA)
[30]
vegetable deterioration.
One of the most effective synthetic tools for the con-
venient preparation of hybrid structures of biologically
active scaffolds is the click reaction between an azide and
3
4
2
[31,32]
a terminal alkyne.
Accordingly, copper-catalyzed
nanoparticles as an efficient and recyclable magnetic
catalyst in ethanol at high yields while having very short
reaction time. It is pivotal to point out that, at the end of
the reaction, the catalyst was separated with a simple
method and reused in further reactions without any
significant catalytic activity loss. Finally the synthesized
compounds were evaluated for their inhibitory effect on
the diphenolase activity of mushroom tyrosinase enzyme.
azide/alkyne cycloaddition (CuAAC) reaction is known
as a utilized, reliable, and straightforward way for
[33–42]
triazole cycloadducts production (Scheme 1).
Until
now, different copper-containing catalysts such as
[
43,44]
[45,46]
[47]
CuSO4,
CuI,
Cu O, CuFe O nanoparticles,
2 2 4
[
48–50]
[49]
Cu/C, Cu/SiO2,
and polymer capped Cu/Cu O
2
have been used for the click reaction. Generally,
Cu(I) salt or in situ reductions of Cu (II) can be used as a
homogenous catalyst for the regioselective CuAAC
[45,48,50–53]
reactions.
However, homogeneous copper cata-
2 | EXPERIMENTAL
lysts have some problems, such as not-recyclability,
inconvenient separation, and environmental pollu-
2.1 | Materials and instruments
[54]
tion.
Through immobilization of copper, two-goal
lines are achieved, a) stabilization of copper species, b)
preparation of a new heterogeneous catalyst for novel
thiazolone-triazole scaffolds synthesis via click reaction
under green conditions. Among various supporting
materials being used for nanoparticles, the use of
functionalized magnetic nanoparticles (Fe O ) has
All the chemicals were purchased from Merck and
Sigma-Aldrich. The reactions were monitored by thin
layer chromatography (TLC). Melting points were
measured on an Electrothermal 9,100 apparatus. NMR
spectra were recorded with a Bruker DRX-400 AVANCE
1
13
instrument (400.1 MHz for H, 100.6 MHz for C) with
3
4
attracted much attention to the chemical community.
The magnetic nanoparticle offers unique advantages
making this support as a more sustainable catalyst
including readily available support with high surface
CDCl as a solvent. IR spectra were recorded on an FT-IR
3
Bruker vector 22 spectrometers. Mass spectra were
recorded on a Finnigan-Matt 8,430 mass spectrometer
operating at an ionization potential of 70 eV in Babolsar.
SCHEME 1 Preparation of
Cu/Fe O @SiO (TMS-EDTA)
3 4 2

DARROUDI ET AL.
3 of 14
[
23,24,77–79]
Elemental analyses were carried with a Perkin-Elmer
our previous studies.
Initially, stock solutions
2
400II CHNS/O Elemental Analyzer. X-ray diffraction
of test compounds in DMSO at 40 mM were prepared
and diluted to the required concentrations. Then after
10 ml of tyrosinase (0.5 mg/ml) was mixed with 160 ml of
phosphate buffer (50 mM, pH = 6.8) in 96-well plates
and 10 ml of the test compounds at different concentra-
tions were added to each well (in triplicate). The plates
(XRD) patterns were recorded on a Philips PW1730
diffractometer using Cu Kα radiation of wavelength
ꢀ
1.54056 A . Field Emmision Sanning Electron Microscopy
(FESEM) was recorded using a Tescan MIRA ΙΙΙ.
Thermogravimetric analysis (TGA) and differential thermal
analysis (DTA) were recorded on a Q600 (TA, USA) in
Tehran and Kashan.
ꢀ
were incubated at 28 C for 20 min, then 20 ml of
L-DOPA solution (0.5 mM) was added to the wells. Kojic
acid was used as a positive control, and the experiments
were done in three independent runs. The inhibitory
activity of the tested samples was stated in terms of IC ,
2
.2 | Preparation and characterization of
5
0
copper iodide Fe O @SiO (TMS-EDTA)
3
4
2
which is the concentration that inhibited 50% of the
enzyme activity. The percent inhibition ratio was
assessed according to the following equation:
The Fe O @SiO (TMS-EDTA) nanoparticle was pre-
pared according to the literature.
3
4
2
[72–76]
Afterward, the
resulting Fe O @SiO (TMS-EDTA) nanoparticle was
3
4
2
dispersed in copper (ΙΙ) sulfate solution (1 M, 25 ml in
deionized water) and stirred at 60 C for 15 hr. The
resulting hybrid was separated with a magnet and
washed successively with water (3 × 10 mL) and finally
dried in vacuum at room temperature to give the CuI
À
Á
ꢀ
Inhibition ð%Þ = 100 Abs
– Abscompound =Abscontrol
control
3 | RESULTS AND DISCUSSION
3.1 | Design strategy
supported-Fe O @SiO
(TMS-EDTA) nanoparticles.
Consequently, the CuI -Fe O @SiO (EDTA) catalyst
3
4
2
3
4
2
was prepared through a straightforward and green
procedure (Scheme 1).
Molecular hybridization is a powerful tool in drug design
and development that is based on the combination
of pharmacophoric fragments of biologically active
molecules. The target 5-((1-benzyl-1,2,3-triazol-4-yl)meth-
oxybenzylidene)-2-(arylamino)thiazol-4-one skeleton was
designed based on the structures of some tyrosinase inhib-
itors stated in our previous studies and other literature
(Figure 1). Some thiazolidine-2,4-dione derivatives (A in
2.3 | Mushroom tyrosinase
inhibition assay
Diphenolase activity of mushroom tyrosinase was deter-
mined using L-DOPA as the substrate, and by observing
the formation of dopachrome at 475 nm as reported in
FIGURE 1 Design of
proposed thiazolone-triazole
hybrids as tyrosinase inhibitors
using molecular hybridization
approach

4
of 14
DARROUDI ET AL.
FIGUR E 2 FT- IR spectra
of (a) Fe
b) Fe
and (c) CuI supported-Fe
SiO (TMS-EDTA)
3
O
4
@SiO
2
MNPs,
(
3
O
4
@SiO (TMS-EDTA)
2
3 4
O @
2
[
23]
Figure 1) have been reported to exhibit tyrosinase inhibi-
comparable to that of kojic acid (IC50 = 9.28 μM).
[26]
tory activity (IC s = 37.6–140.3 μM).
Furthermore, it
Considering these structural features, we designed a series
of thiazolone-triazole hybrids as tyroinase inhibitors by
applying hybridization approach.
50
has been found that two 2-(2,4-dimethoxy phenylamino)-5
methylene-4-thiazolinone derivatives (B in Figure 1) with
IC50 values of 34.1 and 52.6 μM were effective tyrosinase
[25]
inhibitors.
Our previous study indicated that two
phthalimide-1,2,3-trizole hybrid compounds (C in
Figure 1) showed less inhibitory activity on tyrosinase
3
.2 | Characterization of copper iodide
Fe O @SiO (TMS-EDTA)
3
4
2
(
(IC s = 26.2 and 26.5 μM) than the reference drug kojic
5
0
[24]
acid did.
Moreover, it was proved that benzimidazole-
The CuI supported-Fe O @SiO (TMS-EDTA) nanoparti-
3 4 2
1
,2,3-triazole hybrid compounds (D in Figure 1) exhibited
cle was synthesized for the first time and also character-
ized by FTIR, TGA, TEM, BET, BJH, XRD, EDAX and
FESEM analysis. In Figure 2, the IR spectra of
effective inhibitory activity comparable to that of kojic acid
with IC50 values of 9.42 and 10.34 μM which were
3 4 2
FIGURE 3 FESEM images of CuI/Fe O @SiO (TMS-EDTA) nanoparticles

DARROUDI ET AL.
5 of 14
3 4 3 4 2
FIGURE 4 TEM images of (a) Fe O @ SiO2(TMS-EDTA) nanoparticles and (b) CuI/Fe O @SiO (TMS-EDTA) nanoparticles
Fe O @SiO magnetic nanoparticle (a), Fe O @SiO
2
copper modified-nanoparticles was investigated by the
transmission electron microscopy (TEM) analysis. The
TEM images (Figure 4) of MNPs showed a well-defined
morphology of particles and confirmed nano-sized parti-
cles distributing in the catalyst matrix, which had a diam-
eter around 20–40 nm. The MNPs aggregation is due to
the preparation of the TEM sample throughout the sol-
3
4
2
3
4
(
(
TMS-EDTA) (b) and CuI/-Fe O @SiO (TMS-EDTA)
3 4 2
c) were demonstrated. As illustrated in the IR spectrum
of Fe O @SiO MNP in Figure 2(a), the characteristic
3
4
2
peaks at 551 cm− and 572 cm is related to Fe–O,
1
−1
which confirms the existence of Fe O . The FT-IR data
3
4
for Fe O @SiO (TMS-EDTA) (Figure 2b) displays two
3
4
2
-1,
[75,76]
peaks at 1660, and 1,385 cm which attributed to C=O
and C-N groups of ligand, respectively and stretching
vent evaporation the NPs aggregate on the grid.
The X-ray diffraction (XRD) pattern shows character-
istic peaks of copper, presenting all the phases of Cu, as
shown in Figure 5 (b). The XRD was investigated with
Philips PW1730 diffractometer with CuKα radiation
(λ = 1.5418 Å) within a range of Bragg angle 10-80 at
40 kV indicating the presence of nanoparticles such as
Fe O , SiO and Cu into the catalyst. As displayed, the
-
1
vibration of Si–O at 1050, 1110 cm are assignable for
the Fe O @SiO (TMS-EDTA). The FT-IR data for copper
3
4
2
complex-Fe O @SiO (TMS-EDTA) (Figure 2c) is the
3
4
2
−
1
appearance of a peak at 806.61 cm for Cu–O stretching
[
72]
vibration.
In order to prove some properties as the average parti-
cle size and morphology of catalyst structure, the field
emission scanning electron microscopy (FESEM) images
were used where clearly shows copper iodide homoge-
neously immobilized on the Fe O @SiO (TMS-EDTA)
3
4
2,
XRD pattern of CuI supported-Fe O @SiO (TMS-EDTA)
3
4
2
nanoparticle indicates some characteristic peaks at 2θ
values:74, 62, 56, 52, 43, 35, 30, and 25 corresponding
diffractions are in good agreement with those results for
3
4
2
[
72]
surface (Figure 3). Furthermore, the aggregation of this
Fe O @ SiO
2.
The diffraction peak shows a slight
3
4
3 4 2 3 4 2
FIGURE 5 XRD pattern of (a) Fe O @SiO and (b) CuI/-Fe O @SiO (TMS-EDTA)

6
of 14
DARROUDI ET AL.
3 4 2
FIGURE 6 EDAX of CuI/Fe O @ SiO (TMS-EDTA) nanoparticle
decline intensity along with peak expansion, which may
be attributed to decreasing of scattering contrast arises
from Fe O @SiO surface and the organic moiety
where the broadening radian is defined λ, obtaining from
the full width at half maximum, θ is the Bragg angle, and k
is the Scherrer constant (0.9 for Cu Kα radiation). The cal-
culated particle size through this equation is about 17.7 nm.
These results are supported by SEM data. Energy
dispersive spectroscopy analysis of X-rays (EDAX)
data for the CuI supported-Fe O @SiO (TMS-EDTA)
3
4
2
immobilized onto it (Figure 5 (a) and (b)).
The particles size was calculated by Scherrer equation (1)
Kλ
Kλ
Kλ
Kλ
Bcosθ
ð1Þ
3
4
2
L = Kλ=ðB cos θÞL =
L =
L =
L =
Bcosθ
Bcosθ
Bcosθ
FIGURE 8 N2 adsorption–desorption isotherms of
Fe @SiO MNPs, (b) Fe @SiO (TMS-EDTA) and (c) CuI
supported-Fe @ SiO (TMS-EDTA)
FIGURE 7 TGA copper supported of Fe
EDTA) nanoparticle
3
O
4
@ SiO
2
(TMS-
3
O
4
2
3
O
4
2
3
O
4
2

DARROUDI ET AL.
7 of 14
considered to the desorption of physically adsorbed water in
addition to dehydration of the surface –OH groups. The first
stage of the endothermic weight loss could be related to
ꢀ
the evaporation of water almost 170–210 C (3.7%), that
physically absorbed on the surface of the nanoparticle.
The second stage of the weight loss could be allocated to
the decomposition of O-containing functional groups.
ꢀ
Eventually, the major weight loss occurs above 300 C,
corresponding to the degradation of carbon skeletons within
apparent mass change (9.7%). Also, Fe O changed to Fe O
2 3
3
4
ꢀ
in temperature higher than 700 C. Moreover, relatively
slow weight loss at elevated temperatures can be related to
the disintegration of the silica. So, the TGA curves confirm
the successful grafting of organic groups onto the MNP.
The nitrogen adsorption–desorption isotherms and
the BJH pore size distribution (based on the adsorption
FIGURE 9 BJH pore size distribution curves of (a)
Fe
3
O
4
@SiO
2
MNPs, (b) Fe
3 4 2
O @SiO (TMS-EDTA) and (c) CuI
branch of the isotherms) for all samples Fe O @SiO
2
supported-Fe
3
O
4
@ SiO (TMS-EDTA)
2
3
4
MNPs, Fe O @SiO (TMS-EDTA) and CuI supported-
3
4
2
nanocatalyst was illustrated in Figure 6. The EDAX anal-
ysis confirms that the Cu is existing on the surface of the
matrix. This analysis proved that the Cu characteristic
peaks in 2.25% weight percentage. Also, The TGA curves
of copper iodide supported-Fe O @SiO (TMS-EDTA)
Fe O @ SiO (TMS-EDTA) are shown in Figure 8 and
3 4 2
Figure 9. Type IV characterizes the isotherms with
an H1-type hysteresis loop well-defined by IUPAC,
representing that the well-ordered arrangement of
Fe O @SiO has stayed. Table 1 presents the results for
3
4
2
3
4
2
shown in Figure 7.
three structural parameters of the samples, including
specific surface area (BET method), total pore volume,
and pore diameter (BJH method). Successful incorpora-
tion of functional organic materials into Fe O @SiO
2
The thermal stability of the synthesized NPs was exam-
ined by thermo-gravimetric analysis. The decomposition of
copper iodide supported-Fe O @SiO (TMS-EDTA) displays
3
4
2
ꢀ
3
4
the first weight loss below 200 C, and this can be
(TMS-EDTA) pores and the inclusion of Cu into this
TABLE 1
N
2
adsorption–desorption isotherms of (a)Fe
3
O
4
@SiO
2
MNPs, (b) Fe
3
O
4
@SiO
2
3 4
(TMS-EDTA) and (c) CuI supported-Fe O @
SiO (TMS-EDTA)
2
2
Pore Volume (cm g−1)
3
Material Type
Surface Area (m g−1)
Pore size (nm)
9.922
Fe
Fe
3
3
O
4
4
@SiO
@SiO
2
2
898
0.99
O
(TMS-EDTA)
(TMS-EDTA).
789
0.862
0.498
8.211
CuI-Fe
3
O
4
@ SiO
2
351.7
5.206
SCHEME 2 Preparation of starting
materials

8
of 14
DARROUDI ET AL.
SCHEME 3 Preparation of the
-arylamino-5-(propynyloxy)
2
benzylidene) 4-thiazolidinone
derivatives
[
80,81]
structure shifted the pore size to a smaller value and led
to declining in pore volume and surface area.
in accordance with the literature (Scheme 2a).
In the
following, compounds 5a-c were prepared from hydroxy
benzaldehyde 4a-c and propargyl bromide in the presence
of K CO3 by a known method (Scheme 2b).
Based on the obtained experimental results, it can be
predicted that the copper supported-Fe O @SiO
[82]
The
3
4
2
2
(
TMS-EDTA) could be used as a heterogeneous nanocatalyst
general procedure for the preparation of organic azides is
shown in Scheme 2c.
[
83]
with high catalytic activity in the 1,2,3-triazoles synthesis.
Therefore, the efficiency of copper iodide supported-
Fe O @SiO (TMS-EDTA) nanocatalyst was tested in the
thiazolone-triazole cycloadducts synthesis through a
straightforward and green procedure.
Then, dipolarophiles 8a-c were synthesized by the
reaction of thiazolone derivatives 3a-c with prop-
argylated hydroxyl benzaldehydes 5a-c in the presence
of malononitrile as a catalyst under reflux condition in
good yields. The active methylene in the thiazolones
3
4
2
3
a goes through nucleophilic addition reaction to
3
.3 | Thiazolone-1,2,3-triazole analogs
the double bond of arylidene malononitriles via a
Michael type addition reaction to give dipolarophile 8a
(Scheme 3).
As shown in Scheme 2, initially, 5-arylidene-4-thiazolone
derivatives 3a-c were synthesized as the tautomeric mixtures
SCHEME 4 CuAAC
reaction between alkyne and
benzyl azide

DARROUDI ET AL.
9 of 14
TABLE 2 Optimization of cycloaddition to generate 9a
Entry
Catalyst
Solvent
DMSO
Catalyst (mol%)
Yield, %
1
2
3
4
5
6
7
CuSO
CuSO
CuSO
4
4
4
5
5
80
90
65
78
78
97
93
DMSO-Water
Water
5
CuI-Fe
CuI-Fe
CuI-Fe
CuI-Fe
3
3
3
3
O
O
O
O
4
4
4
4
@SiO
@SiO
@SiO
@SiO
2
2
2
2
(TMS-EDTA)
(TMS-EDTA)
(TMS-EDTA)
(TMS-EDTA)
Water
5
Ethanol
Ethanol
Ethanol
10
5
10
As exhibited in Scheme 4, under the optimized condi-
tions, different substituted alkyne 8 and benzyl azide 7 were
used in this 32CA reaction (Table 2), and an array of novel
thiazolone triazoles was synthesized smoothly in good
yields in the presence of CuI/Fe O @SiO (TMS-EDTA)
scaffold and high yield of the reaction, the pure product
can be obtained through the addition of prepared
magnetic nanoparticle and also the catalyst separated
by an external magnet which there is no need to use of
toxic solvent.
3
4
2
nanoparticles and sodium ascorbate. The catalytically
active Cu(I) species which supported on the functionalized
Fe O @SiO (TMS-EDTA) nanoparticles can be generated
from Cu (II) salts using sodium ascorbate as the reducing
agent. These results are presented in Table 3.
The products of cycloaddition reaction exist as a
mixture of tautomeric cycloadduct 9a and 9a’ in ethanol
solution (Figure 10). The structure of the cycloadduct
9 was assigned by various spectroscopic techniques.
So, the IR spectrum of yellow solid 9a demonstrated
3
4
2
−1
In the presented work, due to biological properties
of novel synthesized thiazolone incorporated triazole
absorptions at 3354 cm , indicating the presence of an
NH group, 1,686 cm− of a CO group, 1,540 for imine
1
TABLE 3 Copper-catalyzed 1,3 dipolar cycloaddition of alkynes and azides
Entry
Ar
Y
Z
Yield
97%
75%
71%
82%
81%
85%
86%
58%
83%
79%
77%
70%
73%
72%
78%
80%
63%
65%
69%
73%
75%
9
9
9
9
9
9
9
9
1
1
1
1
1
1
1
1
1
1
1
1
1
a
b
c
d
e
f
Ph
H
H
Ph
H
3,4-Cl
4-Br
4-Br
2-Cl
H
Ph
H
Py
H
Py
H
Py
5-Br
H
g
Py
3,4-Cl
2-Cl
H
h
4-ClC
Ph
6
H
4
H
0a
0b
0c
H
Ph
H
3,4-Cl
H
Ph
3-OMe
3-OMe
3-OMe
3-OMe
H
0d
0e
0f
Ph
2-Cl
3,4-Cl
2-Cl
3,4-Cl
3,4-Cl
H
Ph
Py
0 g
0 h
0i
Py
Py
3-OMe
H
4-ClC
4-ClC
4-ClC
4-ClC
4-ClC
6
6
6
6
6
H
4
H
4
H
4
H
4
H
4
0j
3-OMe
3-OMe
H
2-Cl
H
0 k
0 l
0 m
2-Cl
3,4-Cl
3-OMe

10 of 14
DARROUDI ET AL.
FIGURE 10 Two regioisomers of 9a
FIGURE 11 Recyclability of the Cu-
Fe @ SiO (TMS-EDTA) nanoparticle in the
click reactions
3
O
4
2
−
1
13
group and at 1176 cm which corresponds to ether
The C NMR of 9 showed a peak at δ = 53.32 ppm owing
1
group. The H NMR spectrum of 9a exhibited a singlet at
to the CH group and a peak at δ = 62.13 ppm for the
2
δ = 7.90 for H , two singlet peaks of -CH groups at 5.26
CH attached to the oxygen group. The NMR spectral
d
2
2
and 5.30 ppm for Ha in 9a, and a singlet peak at
.63 ppm for H in OCH group, respectively. Two singlet
peaks at 8.30 ppm and 8.34 ppm of CH is referred to Hc
of methine group. Two signals at 11.54 and 12.34 of NH
represent the existence of a tautomeric mixture of 9a.
data of isolated product was in good agreement with the
assigned structure of 9a and 9a’. Mass spectra also con-
firmed the formation of the product. The mass spectrum
of 9a showed a molecular ion peak of 467.1 (M ).
This procedure was applied to a series of organic azides
5
b
2
+
TABLE 4 Assessment of the catalyst activity in comparison with previous work
Entry
Substrate of Benzyl
Benzyl bromide
Benzyl bromide
Benzyl bromide
Benzyl bromide
Benzyl bromide
Benzyl bromide
Benzyl azide
Catalyst
Conditions
Time (min)
Yield (%)
[
84]
1
2
3
4
5
6
7
8
9
Polymer supported CuI and azide
Reflux, Ethanol
60
92
92
92
93
98
90
99
95
ꢀ
[85]
CuCl
Cu/Al
CuNPs
CuNPs/C
Cu(I)-zeolite
CuSO -Chitosan
MnFe @GO@CS/Cu
2
/SiO
2
H
2
O, MW/70 C
10
[
[
86]
87]
2
O
3
Ball-mill
60
Methanol, r.t.
480
180
15
ꢀ
[87]
[88]
H
H
2
2
O, 70 C
ꢀ
O, 90 C
[89]
4
H2O, r.t.
2
H O/EtOH, 50 C
240
30
ꢀ
[90]
Benzyl azide
2
O
4
Benzyl azide
CuSO
CuSO
CuSO
4
4
4
DMSO
180
220
150
120
80 [this work]
90, [this work]
65, [this work]
97, [this work]
1
1
1
0
1
2
Benzyl azide
DMSO-Water
Water
Benzyl azide
Benzyl azide
CuI-Fe
3
O
4
@SiO
2
(TMS-EDTA)
Ethanol

DARROUDI ET AL.
11 of 14
and terminal alkynes under similar conditions to form
the corresponding triazole products in good yields
TABLE 5 Tyrosinase inhibitory activities of synthesized
compounds 9a-9 h, 10a-10 m and kojic acid
(Supporting information-Spectra: Fig 1-48, spectral
interpretation 3a-10m).
3.4 | Comparison of the catalyst
The result for CuI-Fe O @SiO (TMS-EDTA) catalyst
3
4
2
performance evaluation as well as the activity informa-
tion of the previously reported heterogeneous copper
particles are presented in Table 4. Consequently, the
synthesized catalyst has some beneficials, such as
stability, slightly less reaction time at room temperature,
separable magnetically, and the available commercial
materials at a suitable price.
[
a]
Compounds
X
Y
Z
IC50 (μM)
8.92 ± 1.65
9
9
9
9
9
a
b
c
d
e
H
H
H
H
H
3,4-Cl
4-Br
4-Br
2-Cl
H
47.23 ± 2.80
9.81 ± 2.20
H
H
3.5 | Recycling of the catalyst
[b]
Py
Py
Py
Py
4-Cl
H
H
ND
H
6.34 ± 0.87
>50
The heterogeneous catalysts recyclability is essential
from the economic perspective. The method of reusing
the CuI-Fe O @SiO (TMS-EDTA) catalyst was manipu-
9f
5-Br
H
3
4
2
9 g
3,4-Cl
2-Cl
H
5.90 ± 1.23
ND
lated for the click reaction of organic azides and termi-
nal alkynes upon optimized reaction conditions. After
the accomplishment of each cycle, the solid catalyst
was separated from the reaction mixture using an
external magnet and washed several times with ethanol
9
1
1
1
1
h
H
0a
0b
0c
0d
H
>50
H
H
3,4-Cl
H
49.4 ± 1.78
ND
H
3-OMe
3-OMe
3-OMe
3-OMe
H
H
2-Cl
3,4-Cl
2-Cl
3,4-Cl
3,4-Cl
H
>50
(5 ml), and after drying through vacuum overnight and
use again in a sequential run. The results in Figure 11
determine that the supported catalyst was highly
recyclable under the studied reaction conditions,
preserving almost unaltered its initial catalytic perfor-
mance after six uses.
10e
H
ND
1
1
1
1
1
0f
Py
Py
Py
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
H
ND
0 g
0 h
0i
>50
3-OMe
H
ND
ND
0j
3-OMe
3-OMe
H
2-Cl
H
ND
3
.6 | Anti-tyrosinase activity of the
10 k
10 l
ND
synthesized thiazolone -triazoles
2-Cl
3,4-Cl
H
ND
10 m
3-OMe
H
ND
The mushroom tyrosinase inhibitory potency of some
derivatives was assessed using kojic acid as the com-
mon inhibitor. Results in terms of IC50 values are
presented in Table 5. Compounds 9a , 9c , 9e and 9 g
Kojic Acid
18.36 ± 1.09
a
Values represent means ± SE of 3 independent experiments.
ND; Not determined.
b
with IC50 values of 8.92
±
1.95, 9.81
±
2.20,
6
.34 ± 0.87, 5.90 ± 1.23 μM, respectively, were found
to be considerably better tyrosinase inhibitors than the
positive control kojic acid (IC50 = 18.36 ± 1.09 μM).
Compounds 9b and 10b exhibited tyrosinase inhibition
with IC50 values of 47.23 ± 2.80 and 49.4 ± 1.78 μM,
respectively.
According to IC50 values in Table 5, it can be affirmed
that group 9 derivatives possessing 2-((1-aryl-1,2,3-
triazole-4-yl) methoxy) benzylidene moieties, were
considerably more potent tyrosinase inhibitors than their
counterparts in group 10 bearing 4-((1-aryl-1,2,3-triazole-
4-yl)methoxy)benzylidene moieties (comparing 9a, 9b
and 9 g, respectively, with 10a, 10b and 10 g).
Moreover, in group 9 compounds, the presence of a
pyridine ring substitution at the amino-phenyl group, as
in 9 g, would remarkably improve the activity as
compared to 9b.

12 of 14
DARROUDI ET AL.
4
| CONCLUSION
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AUTHOR CONTRIBUTIONS
Mahdieh Darroudi: Conceptualization; data curation;
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Sara Ranjbar: Formal analysis. Mohammad Esfandiar:
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How to cite this article: Darroudi M, Ranjbar S,
Esfandiar M, et al. Synthesis of Novel Triazole
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