Synthesis and anti-acetylcholinesterase activity of benzotriazinone-triazole systems

Article abstract of DOI:10.1007/s12039-016-1154-5

An approach for the construction of benzotriazinone-triazole system is described. The synthesis is based on diazonium chemistry and subsequent intramolecular heteroatom-heteroatom bond formation. The introduction of triazole moiety occurred via click reac

Full text of DOI:10.1007/s12039-016-1154-5

J. Chem. Sci. ꢀc Indian Academy of Sciences.
DOI 10.1007/s12039-016-1154-5
Synthesis and anti-acetylcholinesterase activity
of benzotriazinone-triazole systems
a
a
a
SETAREH MOGHIMI , FERESHTEH GOLI-GARMROODI , HEDIEH PILALI ,
b
b
c
MOHAMMAD MAHDAVI , LOGHMAN FIROOZPOUR , HAMID NADRI ,
ALIREZA MORADI , ALI ASADIPOUR , ABBAS SHAFIEE and ALIREZA FOROUMADI
Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center,
Tehran University of Medical Sciences, Tehran, Iran
Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
c
d
a
a,d,∗
a
b
c
Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences,
Yazd, Iran
d
Department of Medicinal Chemistry, Faculty of Pharmacy and Neuroscience Research Center, Institute of
Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
e-mail: aforoumadi@yahoo.com
MS received 15 March 2016; revised 23 July 2016; accepted 28 July 2016
Abstract. An approach for the construction of benzotriazinone-triazole system is described. The synthesis
is based on diazonium chemistry and subsequent intramolecular heteroatom-heteroatom bond formation. The
introduction of triazole moiety occurred via click reaction catalyzed by nano-sized copper, supported on modi-
fied silica mesopore KIT-5 leading to the desired products in excellent yield. Also, in vitro acetylcholinesterase
(AChE) inhibitory activities of the target compounds were screened by Ellman’s method.
Keywords. Triazole; benzotriazinone; diazonium chemistry; nanocatalyst; acetylcholinesterase.
1
. Introduction
become one of the well-studied reactions in modern
12
organic chemistry, The pharmacological properties
Nitrogen-containing heterocycles are key structural mo- which are depicted in triazole-containing molecules13
1
tifs in natural and synthetic bioactive agents. In the could be attributed to the stereochemical features and
library of six-membered heterocyclic frameworks, 1,2, the ability of this core in mimicking special bonds,
1
4
15
3
-benzotriazines which show exceptional bioactivity resulting in anti-allergic, antibacterial and anti-
16
are widely used in medicinal chemistry. In the benzotri- HIV activities. Due to the remarkable features of
2
azine class of compounds, 1,2,3-benzotriazine-4-one
benzotriazinone and triazole ring systems, we decided
is recognized as a core structure in molecules exhibit- to synthesize new benzotriazinones-triazoles hybrid
3
ing various biological effects including antiarthritic,
heterocycles.
4
5
6
7
anesthetic, diuretic, sedative, antitumor, and cho-
rismate inhibitory activities. The sustained interest in lytic organic reactions and in the synthesis of novel
Nanocatalysts have attracted interests in several cata-
8
17
18
triazine chemistry was not restricted to the applica- heterocyclic cores. Meanwhile, nanocatalysts espe-
tion of these compounds in pharmaceuticals and other cially those which are immobilized onto various sup-
bioactive molecules. There are also some reports rely- ports, are considered as a big achievement in the
ing on their application as a substrate, from which a sustainable construction of triazoles. As a result, we
wide variety of new heterocyclic frameworks could be decided to introduce nanoparticles copper iodide/
1
9
9
20
derived.
APTES-KIT-5 (CuI-AK) in water as a catalyst
for the synthesis of 3-(substituted-1,2,3-triazol-4-yl
methyl)benzo[d][1,2,3]triazin-4(3H)-ones, whereby we
could meet global concerns about environmental issues
along with the high yielding synthesis of new com-
pounds which were not reported before.
Considered as a unique class of five-membered N-hete-
rocycles, triazoles are mainly synthesized via the rapid
and potent pathway, copper-catalyzed azide-alkyne cyl-
coaddition (CuAAC).10 Due to the importance of tri-
azoles in diverse applied sciences,1 this reaction has
1
Herein, we report our investigation on the synthe-
sis of benzotriazinone-triazole system utilizing nano
copper catalyst in water. The reaction proceeded by
∗
For correspondence

Setareh Moghimi et al.
only three-steps and produced 3-(substituted-1H-1,2,3- Germany. In short, to determine IC values, 50 μL of
50
triazol-4-yl methyl)benzo[d][1,2,3]triazin-4(3H)-ones the five different concentration of the test compounds
in overall high yield.
that produced inhibition in the range of 20–80% was
added to the mixture of 3 mL phosphate buffer 0.1
M, pH = 8.0 and 100 μL of DTNB solution (0.1 M)
and 50 μL AChE. 10 μL solution of acetylthiocholine
iodide (0.15 M) as substrate was added following 10
2. Experimental
2.1 Materials and Methods
◦
min incubation at 25 C. The progress curve was plotted
by measuring the absorbance at 412 nm for 6 min.
The IC50 values were determined graphically from
inhibition curves (inhibitor concentration vs percent of
inhibition). UNICO double beam spectrophotometers
Melting points were taken on a Kofler hot-stage appara-
tus and are uncorrected. H and C NMR spectra were
recorded on a Bruker FT-500, using tetramethylsilane
1
13
(TMS) as an internal standard. The infrared (IR) spec-
2
100 was used for colorimetric measurements.
tra were obtained on a Nicolet Magna FT-IR 550 spec-
trophotometer (KBr disks). Mass spectra were recorded
on an Agilent Technology (HP) mass spectrometer
operating at an ionization potential of 70 eV. Elemen-
tal analysis were carried out with a Perkin-Elmer model
2.2 Spectral data of some of the products
2.2a 3-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)benzo
2
40-C apparatus.
[
d][1,2,3]triazin-4(3H)-one (5a): Pale yellow solid,
◦
[0.27 g, 86%]; M.p. 176–178 C; IR (KBr): 1678,
−1
1
2
.1a Biological activity assay: Colorimetric Ell- 1456, 1331, 1059, 784, 694 cm ; H NMR (500
21
man’s method was used to evaluate the inhibitory MHz, DMSO-d ): δ 5.56 (s, 2H), 5.64 (s, 2H), 7.30 (d,
6
potency of target compounds toward AChE. Acetyl- J = 8.0 Hz, 1H), 7.32–7.37 (m, 3H), 7.94 (t, J = 7.3
cholinesterase (AChE, E.C. 3.1.1.7, Type V-S, Hz, 1H), 8.09 (t, J = 7.3 Hz, 1H), 8.16–8.18 (m, 1H),
lyophilized powder, from Electric eel, 1000 unit) 8.19 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.25 (d, J = 8.0
ꢁ
13
was obtained from Sigma–Aldrich. 5, 5 -Dithiobis- Hz, 1H) ppm; C NMR (125 MHz, DMSO-d ): δ 44.6,
6
(2-nitrobenzoic acid) (DTNB), potassium dihydrogen 52.8, 119.3, 123.9, 124.5, 127.9, 128.0, 128.5, 128.6,
phosphate, dipotassium hydrogen phosphate, potassium 133.0, 135.4, 135.8, 142.2, 143.6, 154.4 ppm; MS: m/z
+
hydroxide, sodium hydrogen carbonate, and acetylthio- (%) = 318 (51, M ), 227 (29), 146 (100), 91 (22), 77
choline iodide were purchased from Fluka. Donepezil (39). Anal. Calcd. (%) for C H N O: C, 64.14; H,
17
14
6
hydrochloride was obtained from Merck, Darmstadt, 4.43; N, 26.40. Found (%): C, 64.21; H, 4.32; N, 26.51.
O
NH2
O
+
N
H
O
2
1
a
O
N
O
O
c
b
N
N
N
N
N
N
N
H
N
N
NH2
4
R
3
5
O O
Si
O O
O
Si
Si OH
O
O
O HO
OH
Si
O
Si
NH2
CuI
O
OH
Si
HO
Si OH
O
CuI
O
NH2
HO
NH2
CuI
A
Scheme 1. Reagents and conditions: (a) H2O, r.t.; (b) NaNO2, HCl (10%), acetone; (c) NaN3, benzyl bromides, CuI-AK,
H2O, reflux.

Synthesis and anti-acetylcholinesterase activity of benzotriazinone-triazoles
3
. Results and discussion
as the reaction medium, in response to green chemistry
principles.
3.1 Synthesis and characterization
To test the scope of the reaction, 10 different benzyl
bromide derivatives were effectively examined to syn-
thesize 5a–j in excellent yields (Table 1). In general,
the presence of methyl substitution gave higher yields.
Within our program for the synthesis of novel
22
heterocycles, herein, we started by stirring isatoic
anhydride and propargyl amine in water at room
temperature to obtain pure 2-amino-N-(prop-2-yn-
Electron-withdrawing groups like NO , F, Cl, and Br
2
also produced the desired products in good yields.
The Cu catalyst could be reused in click reaction,
while significant loss of activity was observed in fifth
run (Table 2).
1
-yl)benzamide 3 as a white solid in 85% yield
(
Scheme 1). In the following step, exposure of 3 to
◦
acidic solution of sodium nitrite at 0 C for 1 h, resulted
in intramolecular nitrogen-nitrogen bond formation. In
the final step, copper nanocatalyst on modified silica-
based KIT-5 (CuI-AK), catalyst A was used. So, triple Table 2. The recyclability of Cu nanoparticle in the for-
20
mation of 5a.
bond was subjected to click reaction in the presence
of NaN , different benzyl bromide derivatives and 0.04
g catalyst A in refluxing water. The desired products
Yield (%)a
3
Entry
Run
5
a–j were obtained after 3 h in good to excellent
1
2
3
4
5
1
2
3
4
5
86
85
83
82
71
yields. Water rich solvents like t-BuOH/H O (1:1.5)
and EtOH/H O (1:1.5) were also examined at reflux
temperature for the synthesis of 5a which produced
the desired product in same yields (86%, 84%,
respectively). Nevertheless, we decided to report water
2
2
a)
Isolated yields.
Table 1. Substrate scope of 1,2,3-triazol-benzo[d][1,2,3]
triazin-4(3H)-ones.
O
O
N
N
N
N
N
N
N
N
N
N
N
N
5
a, 86%a
5b, 88%
O
O
N
N
N
N
N
N
N
N
O
N
N
N N
N
O
F
Cl
Cl
5
c, 91%
5
d, 81%
N
Cl
Cl
Br
N
N
N
N
N
N
N
N
N
N
N
O
5e, 79%
5f, 83%
O
N
N
N
N
N
N
N
N
N
N
N
Cl
5
h, 83%
5g, 80%
Cl
O
N
O
N
N
N
N
N
N
N
N N
N
N
5
j, 81%
5i, 82%
NO
2
a
Isolated yields.

Setareh Moghimi et al.
Table 3. Acetylcholinesterase inhibitory activities of Supplementary Information (SI)
a
compounds 5a–5j.
1
13
Full experimental details and H, C NMR spectra are
provided in the supplementary information available at
www.ias.ac.in/chemsci.
Entry
Compound
IC50 (μ M)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
>25
1.88 ± 0.091
>25
Acknowledgements
3.97 ± 0.19
This study was funded and supported by Research
Council of Tehran University of Medical Sciences
(TUMS); Grant no. 93-03-45-29092 and Iran National
Science Foundation (INSF).
>25
>25
1.94 ± 0.077
5.85 ± 0.27
>25
>25
0.022 ± 0.002
5i
5j
10
1
1
Donepezil
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