Synthesis of novel benzimidazole and benzothiazole derivatives bearing a 1,2,3-triazole ring system and their acetylcholinesterase inhibitory activity

Article abstract of DOI:10.3184/174751917X14836231670980

A series of 20 novel benzimidazole and benzothiazole derivatives linked to a 1,2,3-triazole ring system was synthesised, characterised and evaluated for in vitro acetylcholinesterase (AChE) inhibitory activity. Several copper catalysts and solvents were screened to establish the optimal conditions for the preparation of the target compounds. Three different linkers were used to optimise the enzyme inhibitory effect. Out of the 20 compounds, 13 showed some AChE inhibition. The most potent compound, which showed 84% inhibition at 100 μM, contained a 1-(2-fluorobenzyl)-1,2,3-triazole linked to a benzimidazole group. A docking simulation study showed that the most active compound bound preferentially to the catalytic anionic subsite of the AChE enzyme.

Full text of DOI:10.3184/174751917X14836231670980

30 RESEARCH PAPER
VOL. 41 JANUARY, 30–35
JOURNAL OF CHEMICAL RESEARCH 2017
Synthesis of novel benzimidazole and benzothiazole derivatives bearing a
1,2,3-triazole ring system and their acetylcholinesterase inhibitory activity†
Laleh Farajia, Shiva Shahkaramib, Hamid Nadric, Alireza Moradic, Mina Saeedid, Alireza Foroumadia,
Ali Ramazanib, Ismaeil Haririane, Mohammad Reza Ganjalif, Abbas Shafieea and Mehdi Khoobia,e*
aDepartment of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
bDepartment of Chemistry, University of Zanjan, PO Box 45195-313, Zanjan, Iran
cDepartment of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
dMedicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
eDepartment of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
fCenter of Excellence in Electrochemistry, Faculty of Chemistry, University of Tehran, Tehran, Iran
A series of 20 novel benzimidazole and benzothiazole derivatives linked to a 1,2,3-triazole ring system was synthesised, characterised and
evaluated for in vitro acetylcholinesterase (AChE) inhibitory activity. Several copper catalysts and solvents were screened to establish
the optimal conditions for the preparation of the target compounds. Three different linkers were used to optimise the enzyme inhibitory
effect. Out of the 20 compounds, 13 showed some AChE inhibition. The most potent compound, which showed 84% inhibition at 100 µM,
contained a 1-(2-fluorobenzyl)-1,2,3-triazole linked to a benzimidazole group. A docking simulation study showed that the most active
compound bound preferentially to the catalytic anionic subsite of the AChE enzyme.
Keywords: acetylcholinesterase inhibitors, Alzheimer’s disease, benzimidazole, benzothiazole, 1,2,3-triazole
Heterocycles are enormously important compounds that are
ubiquitous in vital bioactive molecules and macromolecules.
Hybrids of different heterocyclic scaffolds has led to the
identification of novel lead compounds in medicinal chemistry.1
Among various heterocycles, benzimidazoles are important
bioactive molecules due to their versatile biological activities.2 In
this regard, benzimidazoles bearing a 2-methylenethio moiety
have shown remarkable bioactivities. For example, compounds
A–D (Fig. 1) have shown anti-parasitic,3 anti-microbial,4 anti-
protozoal/antibacterial,5 potent dual orexin receptor antagonist6
or anti-convulsant/anti-diabetic activities.7 Benzothiazoles also
have valuable biological properties.8 They have been reported
as anti-tumour agents,9 ABL kinase inhibitors,10 anti-larval
agents11 and carbonic anhydrase inhibitors.12
pathways in the central and peripheral nervous systems.20 It has
been revealed that loss of cholinergic transmission is one of the
most important causes of Alzheimer’s disease. Accordingly,
much research has been devoted to developing cholinesterase
inhibitors.21
Here, in continuation of our research on the synthesis
of novel heterocycles and bioactive compounds bearing
1,2,3-triazoles,22,23 we focus on the synthesis of novel
benzimidazole and benzothiazole derivatives linked to
1,2,3-triazole ring systems as anti-AChE agents.
Results and discussion
Chemistry
The ‘click chemistry’ concept described by Sharpless et al.13
and further modified procedures14 introduced new synthetic
routes for the preparation of 1,2,3-triazole derivatives. Their
cytotoxic,15 anti-tuberculosis,16 anti-platelet17 and anti-HIV-118
activities have been well documented in the literature. This
strategy has also been useful for the construction of anti-
acetylcholinesterase (AChE) inhibitors.19 AChE is an enzyme
that degrades choline-based esters in numerous cholinergic
Our synthetic route for the preparation of the target compounds
7 is shown in Scheme 1. In the first step, reaction of
2-mercaptobenzimidazole (1; R = H) or its 5-methyl derivative
(1; R = Me) with propargyl bromide 2 in the presence of
NaOH (4%) at room temperature for 5 h afforded 2-(prop-2-
yn-1-ylthio)-1H-benzo[d]imidazole (3; R = H) or its 5-methyl
derivative (3; R = Me). The reaction was conducted in various
solvents such as CH2Cl2 and DMF; however, the best result
O
H
O
S
N
N
N
N
N
N
N
S
NH
N
N
N
S
S
N
H
O
S
N
H
R3
O
N
H
B
O
R1
R2
A
C
R4
H
N
N
N
S
N
H
O
l
C
O
D
Fig. 1 Biologically active benzimidazoles A–D possessing a 2-methylenethio linker.
* Correspondent. E-mail: m-khoobi@tums.ac.ir; Mehdi.khoobi@gmail.com
† This work is dedicated to the memory of Professor Abbas Shafiee (1937–2016).

JOURNAL OF CHEMICAL RESEARCH 2016 31
was obtained in aqueous medium. Then, a click reaction of 3
and an in situ prepared benzyl azide 6 (from the reaction of
the appropriate benzyl halide derivative 4 and sodium azide 5)
led to the formation of products 7.24 To obtain the best reaction
conditions, a model reaction was comprehensively investigated.
For this purpose, 2-bromobenzyl bromide 4a and sodium azide
5 were reacted in the presence of different copper salts, such as
CuI, CuSO4 and Cu(OAc)2, as well as various bases, including
Na2CO3, K2CO3 and Et3N, in the presence of sodium ascorbate
in various solvents and the results are shown in Table 1. After
in situ generation of 1-(azidomethyl)-2-bromobenzene 6a,
2-(prop-2-yn-1-ylthio)-1H-benzo[d]imidazole 3a, catalyst and
base were added to the mixture to give product 7a. Our results
revealed that using Cu(OAc)2, ascorbic acid and Na2CO3 in EtOH
at 80 °C led to the formation of compound 7a in good yield. With
these results in hand, target products 7 were prepared using the
optimised conditions within 12–20 h (checked by TLC).
In
another
synthetic
pathway
(Scheme
2),
2-mercaptobenzimidazole or 2-mercaptobenzothiazole (8; X =
N, S) were reacted with 2-bromoethyl acetate 9 in the presence
of KOH in dry EtOH at 30 °C to give compound 10. Hydrolysis
of 10 using NaOH in MeOH/THF at room temperature gave
the corresponding acid 11, which reacted with propargylamine
12 in the presence of DCC in CH2Cl2 at room temperature
to yield amide 13. Finally, reaction of compound 13 and an in
situ prepared benzyl azide 6, as described for the formation of
product 7, gave product 14. For these reactions, the solvent was a
mixture of H2O/PEG, as demonstrated by reaction optimisation.
Synthesis of a third series of compounds 17 was performed as
shown in Scheme 3. 4-(Benzo[d]thiazol-2-yl)phenol 1525 was
reacted with propargyl bromide 2 in the presence of K2CO3 in
DMF at 80 °C for 16 h to form 2-(4-(prop-2-yn-1-yloxy)phenyl)
benzo[d]thiazole 16. A click reaction of 16 with an in situ
prepared benzyl azide 6 gave the title compounds 17. For these
reactions, benzyl halide derivatives 4 and sodium azide 5 were
reacted in the presence of CuSO4·5H2O and sodium ascorbate in
t-BuOH/H2O at room temperature for 1–2 h. Then, compound 16
was added and the reaction was continued for a further 20–24 h
to afford product 17.
Table 1 Optimisation of the reaction conditions (catalyst, base, solvent)
for the reaction of 4-bromobenzyl azide (6a; Ar = 2-Br–C6H4) (1 equiv.)
(formed in situ from 4-bromobenzyl bromide (4a; Ar = 2-Br–C H4) (1
equiv.) and sodium azide 5 (1.2 equiv.)) with the terminal alkyne 6(3; R =
H) to form the tetracyclic product (7a; Ar = 2-Br–C6H4) (Scheme 1)a
Entry Copper salt
Base
Solvent
CH3CN
DMSO
H2O/PEG
ethanol
ethanol
ethanol
ethanol
ethanol
Yield/%b
10
30
35
35
50
65
55
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
CuSO4/sodium ascorbate
Cu(OAc)2/sodium ascorbate Na2CO3
Cu(OAc)2/sodium ascorbate K2CO3
Cu(OAc)2/sodium ascorbate Et3N
Biological investigation
The in vitro anti-AChE activity of compounds 7a–e, 14a–e and
17a–j was evaluated using Ellman’s method26 and compared
with donepezil as the reference drug. The results are shown in
Table 2. As can be seen, most of the short series of compounds
7a–e showed relatively good activity. The best result, which was
obtained with compound 7e, which has a 2-fluorobenzyl group
55
aReaction conditions: A mixture of compound 4a, sodium azide 5, catalyst and base was
stirred in solvent (5 mL) at 80 °C for 30 min to form azide 6a. Then alkyne (3; R = H) was
added and stirring continued for 20 h.
bIsolated yields.
4
R
R
5
R
N
N
N
12-20 h
NaOH (4%)
r.t./5 h
N
+
Br
H
S
S
S
N
N
H
6
N
H
N
H
3
6
ArCH2N3
N
7
2
Ar
7
1
EtOH
Ascorbic acid
Na2CO3
R = H, Me
Cu(OAc)2
60-70 oC/30 min
ArCH2X
NaN3
+
5
4
Scheme 1
O
O
N
X
O
N
X
N
KOH/dry EtOH
30 oC
Br
NaOH
SH +
S
S
EtO
H
O
Et
O
MeOH/THF
r.t.
X
9
11
10
8
4
O
O
N
N
5
H2N
12
6 h
ArCH2N3
S
S
N
N
N
6
X
X
N
H
DCC/CH2Cl2/r.t.
H
6
7
13
14
N
Ar
Ascorbic acid
Na2CO3
H2O/PEG
CuOAc
X = N, S
70 oC/30 min
+
NaN3
ArCH2X
5
4
Scheme 2

32 JOURNAL OF CHEMICAL RESEARCH 2016
4
7
S
N
S
N
S
5
6
20-24 h
K2CO3
80 oC/DMF
16 h
N
r
B
O
O
OH +
N
6
ArCH2N3
N
N
2
Ar
16
15
17
t-BuOH/H2O
r.t./1-2 h
CuSO4 5H2O
.
Sodium ascorbate
+
NaN3
ArCH2X
5
4
Scheme 3
Table 2 Synthesisa (Schemes 1–3) and AChE inhibitory activity of
compounds 7a–e, 14a–e and 17a–j
Entry Compound
R
H
H
CH3
CH3
CH3
–
–
–
–
–
–
–
–
–
–
–
X
–
–
–
–
–
Ar
AChE inhibition at 100 µM/%
1
7a
2-BrC6H4
2-NO2C6H4
2-BrC6H4
4-BrC6H4
2-FC6H4
75
<20
79
<20
84
<20
<20
<20
<20
<20
45
42
38
44
26
27
48
30
30
2
7b
3
7c
4
7d
5
7e
6
7
8
9
14a
14b
14c
14d
14e
17a
17b
17c
17d
17e
17f
17g
17h
17i
17j
Donepezil
NH 4-BrC6H4
S
S
S
S
–
–
–
–
–
–
–
–
–
–
4-BrC6H4
4-OMeC6H4
4-MeC6H4
4-FC6H4
C6H5
10
11
12
13
14
15
16
17
18
19
20
21
2-FC6H4
3-FC6H4
4-FC6H4
3-BrC6H4
4-BrC6H4
3-ClC6H4
4-ClC6H4
3-MeC6H4
4-MeC6H4
Fig. 2 The binding mode of compound 7e in the active site of AChE.
their anti-AChE activity. Among the synthesised compounds,
benzimidazoles with a simple 2-methylenethio linker showed
better activity compared with the results for benzimidazoles
and benzothiazoles with acetamide or methoxyphenyl linkers.
–
–
–
–
46
100
Experimental
aReaction conditions: A mixture of benzyl azide 4 (formed in situ), a base, a copper
catalyst and an alkyne (3; R = H or Me) was stirred in EtOH (5 mL) at 80 °C for 12–20 h.
Chemistry
Melting points were taken on a Kofler hot stage apparatus and are
uncorrected. 1H NMR and 13C NMR spectra were recorded on a
Bruker FT-500 spectrometer (Germany), using TMS as an internal
standard. The IR spectra were obtained on a Nicolet Magna FTIR 550
spectrometer (KBr disks). The elemental analyses were performed
on an Elementar Analysensystem GmbH VarioEL CHNS mode
(Germany). Compounds 3, 10, 11 and 13 were prepared according to
the procedure described in the literature.27–29
connected to the 1,2,3-triazole system and a methyl group at the
5-position of the benzimidazole ring, was 84% inhibition at 100
µM. Compounds 7c and 7a depicted relatively good inhibitory
activity with 79 and 75% inhibition of AChE, respectively.
However, compounds 7b and 7d showed low inhibitory activity
(<20%). The in vitro AChE inhibitory activity of compounds
14 revealed that they are not potent inhibitors as all compounds
exhibited less than 20% inhibition of AChE. Compounds 17
showed moderate AChE inhibitory activity. Derivatives 17a,
17b, 17d, 17g and 17j showed 42–48% inhibition of AChE.
Compounds 17c, 17e, 17f, 17h and 17i showed low activity.
Synthesis of compounds 7; general procedure
A mixture of benzyl halide derivative 4 (0.5 mmol), sodium azide 5
(0.040 g, 0.6 mmol), Cu(OAc)2 (0.030 g, 0.15 mmol), ascorbic acid
(0.025 g, 0.14 mmol) and sodium carbonate (0.02 g, 0.19 mmol) was
stirred in EtOH (5 mL) at 60–70 °C for 30 min. Then, compound
3 (0.25 mmol) was added to the reaction mixture and the desired
product 7 was obtained after 12–20 h. After completion of the reaction
(checked by TLC), the mixture was filtered, the solvent was removed
and the crude product was obtained by extraction with ethyl acetate
(2 × 15 mL). All compounds were purified by column chromatography
using petroleum/ethyl acetate (1:1).
2-(((1-(2-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-1H-
benzo[d]imidazole (7a): Yellow solid; m.p. 192–194 °C; yield 55%;
IR (KBr) (cm–1): 3147, 3067, 2961, 1621, 1589, 1435; 1H NMR (500
MHz, DMSO-d6): δ 8.05 (s, 1H, triazole), 7.64 (d, J = 7.7 Hz, 1H, H4),
7.44–7.43 (m, 2H, H7, H3’), 7.32–7.25 (m, 2H, H5, H6), 7.13–7.11 (m, 2H,
H4’, H5’), 7.02 (d, J = 7.3 Hz, 1H, H6’), 5.61 (s, 2H, CH2), 4.60 (s, 2H,
CH2); 13C NMR (125 MHz DMSO-d6): δ 149.1, 143.3, 134.9, 132.8,
131.8, 130.3, 130.2, 128.2, 126.4, 124.2, 122.7, 122.5, 121.4, 115.8,
Docking study
To define the binding mode of the most active compound 7e, it
was docked and the best docking position was chosen in terms
of free energy of binding (Fig. 2). It is clear that compound 7e
occupied the catalytic anionic subsite in which Trp83 showed
T-shape π-stacking with the pendant 2-fluorobenzyl moiety. Also,
a hydrogen bond was formed between the 1,2,3-triazole ring and
Gly122. In addition, the benzimidazole ring was accommodated in
a hydrophobic pocket made up of Tyr333 and Phe329.
Conclusion
Novel benzimidazole and benzothiazole derivatives linked to a
1,2,3-triazole ring system were synthesised and evaluated for

JOURNAL OF CHEMICAL RESEARCH 2016 33
115.7, 52.8, 26.0. Anal. calcd for C17H14BrN5S: C, 51.01; H, 3.53; N,
17.50; found: C, 51.15; H, 3.48; N, 17.38%.
2-(Benzo[d]thiazol-2-ylthio)-N-((1-(4-bromobenzyl)-1H-1,2,3-
triazol-4-yl)methyl)acetamide (14b): White solid; m.p. 171–172
1
2-(((1-(2-Nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-1H-
benzo[d]imidazole (7b): Yellow solid; m.p. 204–205 ºC; yield 60%;
IR (KBr) (cm–1): 3141, 3068, 2964, 1615, 1436, 1550, 1350; 1H NMR
(500 MHz, DMSO-d6): δ 8.11 (dd, J = 7.8, 1.6 Hz, 1H, H3’), 8.09 (s,
1H, triazole), 7.64–7.58 (m, 2H, H4, H7), 7.42–7.43 (m, 2H, H4’, H5’),
7.13–7.10 (m, 2H, H5, H6), 6.87 (dd, J = 7.8, 1.6 Hz, 1H, H6’), 5.91 (s,
2H, CH2 ), 4.62 (s, 2H, CH2); 13C NMR (125 MHz, DMSO-d6): δ 149.2,
147.4, 143.7, 134.3, 133.3, 131.0, 129.6, 129.5, 128.1, 125.0, 124.5,
122.8, 121.4, 114.2, 113.9, 49.9, 25.8. Anal. calcd for C17H14N6O2S: C,
55.73; H, 3.85; N, 22.94; found: C, 55.60; H, 3.74; N, 23.10%.
°C; yield 65%; IR (KBr) (cm–1): 3236, 3145, 3065, 1666; H NMR
(500 MHz, DMSO-d6): δ 8.83 (t, J = 3.3 Hz, 1H, O=C–NH), 8.00
(d, J = 8.1 Hz, 1H, H4), 7.95 (s, 1H, triazole), 7.79 (d, J = 8.1 Hz, 1H,
H7), 7.54 (d, J = 8.3 Hz, 2H, H3’, H5’), 7.46 (t, J = 7.3 Hz, 1H, H6), 7.37
(t, J = 7.3 Hz, 1H, H5), 7.21 (d, J = 8.3 Hz, 2H, H2’, H6’) 5.52 (s, 2H,
CH2), 4.34 (d, J = 5.3 Hz, 2H, CH2), 4.16 (s, 2H, S–CH2); 13C NMR
(125 MHz, DMSO-d6): δ 166.3, 166.2, 152.5, 144.7, 135.4, 134.7, 131.6,
130.1, 126.4, 124.5, 123.1, 121.8, 121.4, 121.0, 51.9, 34.7, 34.6. Anal.
calcd for C19H16BrN5OS2: C, 48.10; H, 3.40; N, 14.76; found: C, 48.31;
H, 3.23; N, 14.48%.
2-(((1-(2-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-5-
methyl-1H-benzo[d]imidazole (7c): White solid; m.p. 161–163 °C;
2-(Benzo[d]thiazol-2-ylthio)-N-((1-(4-methoxybenzyl)-1H-1,2,3-
triazol-4-yl)methyl)acetamide (14c): Brown solid; m.p. 128–129
1
1
yield 60%; IR (KBr) (cm–1): 3156, 3090, 2949, 1625, 1443; H NMR
°C; yield 65%; IR (KBr) (cm–1): 3331, 3125, 3063, 1651; H NMR
(500 MHz, DMSO-d6): δ 12.43 (s, 1H, NH), 8.03 (s, 1H, triazole), 7.64
(d, J = 8.0, 1 Hz, 1H, H5’), 7.39 (d, J = 8.0, 1H, H3’), 7.32–7.23 (m, 2H,
H4’, H6’), 7.16 (s, 1H, H4), 7.31 (d, J = 7.0, 1H, H7), 6.94 (d, J = 7.0, 1H,
H6), 5.62 (s, 2H, CH2), 4.58 (s, 2H, CH2), 2.39 (s, 3H, CH3); 13C NMR
(125 MHz, DMSO-d6): δ 143.4, 134.9, 132.8, 130.9, 130.2, 130.1, 128.2,
124.2, 122.9, 122.7, 122.5, 117.4, 117.1, 110.3, 109.9, 52.8, 26.0, 21.2.
Anal. calcd for C18H16BrN5S: C, 52.18; H, 3.89; N, 16.90; found: C,
52.29; H, 3.64; N, 16.73%.
(500 MHz, DMSO-d6): δ 8.82 (t, J = 5.0 Hz, 1H, O=C–NH), 8.01 (d,
J = 8.3 Hz, 1H, H4), 7.88 (s, 1H, triazole), 7.80 (d, J = 8.3 Hz, 1H, H7),
7.47 (t, J = 7.5 Hz, 1H, H6), 7.37 (t, J = 7.5 Hz, 1H, H5), 7.24 (d, J = 8.5
Hz, 2H, H2’, H6’), 6.89 (d, J = 8.5 Hz, 2H, H3’, H5’), 5.44 (s, 2H, CH2),
4.35 (d, J = 5.5 Hz, 2H, CH2), 4.17 (s, 2H, CH2), 3.72 (s, 3H, CH3);
13C NMR (125 MHz, DMSO-d6): δ 166.3, 166.2, 159.1, 152.5, 144.7,
134.7, 129.6, 127.9, 126.4, 124.5, 122.6, 121.8, 121.0, 114.1, 55.1, 52.3,
36.4, 34.7. Anal. calcd for C20H19N5O2S2: C, 56.45; H, 4.50; N, 16.46;
found: C, 56.28; H, 4.71; N, 16.67%.
2-(Benzo[d]thiazol-2-ylthio)-N-((1-(4-methylbenzyl)-1H-1,2,3-
triazol-4-yl)methyl)acetamide (14d): White solid; m.p. 137–138 °C;
yield 58%; IR (KBr) (cm–1): 3252, 3141, 3079, 2950 1625, 1421;
1H NMR (500 MHz, DMSO-d6): δ 8.81 (t, J = 5.5 Hz, 1H, O=C–
NH), 8.01 (d, J = 8.0 Hz, 1H, H4), 7.89 (s, 1H, triazole), 7.79 (d,
J = 8.0 Hz, 1H, H7), 7.46 (t, J = 7.5 Hz, 1H, H6), 7.36 (t, J = 7.5 Hz,
1H, H5), 7.11–7.16 (m, 4H, H2’, H3’, H5’, H6’), 5.47 (s, 2H, CH2), 4.34 (d,
J = 5.5 Hz, 2H, CH2), 4.16 (s, 2H, CH2), 2.27 (s, 3H, CH3); 13C NMR
(125 MHz, DMSO-d6): δ 166.3, 166.2, 152.5, 144.6, 137.4, 134.7, 132.9,
129.2, 127.9, 126.4, 124.5, 122.8, 121.8, 121.0, 52.5, 36.4, 34.7, 20.7.
Anal. calcd for C20H19N5OS2: C, 58.66; H, 4.68; N, 17.10; found: C,
58.44; H, 4.41; N, 17.24%.
2-(((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-5-
methyl-1H-benzo[d]imidazole (7d): White solid; m.p. 151–152 °C;
1
yield 65%; IR (KBr) (cm–1): 3138, 3019, 2927, 1626, 1400; H NMR
(500 MHz, DMSO-d6): δ 8.05 (s, 1H, triazole), 7.48 (d, J = 8.5 Hz, 2H,
H3’, H5’), 7.32 (s, 1H, H4), 7.22 (s, 1H, H7), 7.16 (d, J = 8.5 Hz, 2H, H2’,
H6’), 6.5 (d, J = 8.0 Hz, 1H, H6) 5.53 (s, 2H, CH2), 4.56 (s, 2H, CH2),
2.39 (s, 3H, CH3); 13C NMR (125 MHz; DMSO-d6): δ 149.7, 148.6,
143.4, 142.6, 136.1, 131.6, 129.9, 123.7, 120.7, 117.6, 117.3, 109.4, 108.3,
51.9, 26.0, 21.2. Anal. calcd for C18H16BrN5S: C, 52.18; H, 3.89; N,
16.90; found: C, 52.39; H, 3.63; N, 16.75%.
2-(((1-(2-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-5-
methyl-1H-benzo[d]imidazole (7e): Yellow solid; m.p. 106–107 ºC;
1
yield 60%; IR (KBr) (cm–1): 3156, 3115, 2946, 1620, 1443; H NMR
(500 MHz, DMSO-d6): δ 12.50 (s, 1H, NH), 8.05 (s, 1H, triazole),
7.38–7.33 (m, 2H, H4, H7), 7.24–7.13 (m, 4H, H4’, H5’, H6’, H6), 6.94 (d,
J = 8.0 Hz, 1H, H3’), 5.60 (s, 2H, CH2), 4.58 (s, 2H, CH2), 2.38 (s, 3H,
CH3); 13C NMR (125 MHz, DMSO-d6): δ 160.0 (d, JC–F = 245.3 Hz),
148.6, 143.5, 134.4, 130.7, 130.6, 130.5, 124.8, 123.8, 122.8, 122.7,
122.1, 115.6 (d, JC–F = 7.0 Hz), 115.8, 110.3, 46.8, 25.9, 21.2. Anal. calcd
for C18H16FN5S: C, 61.17; H, 4.56; N, 19.82; found: C, 61.31 H, 4.38; N,
19.67%.
2-(Benzo[d]thiazol-2-ylthio)-N-((1-(4-fluorobenzyl)-1H-1,2,3-
triazol-4-yl)methyl)acetamide (14e): Green solid; m.p. 140–141 °C;
yield 70%; IR (KBr) (cm–1): 3226, 3145, 3063, 2955, 1630, 1450;
1H NMR (500 MHz, DMSO-d6): δ 8.83 (t, J = 5.3 Hz, 1H, O=C–NH),
8.01 (d, J = 8.0 Hz, 1H, H4), 7.95 (s, 1H, triazole), 7.79 (d, J = 8.0 Hz,
1H, H7), 7.46 (t, J = 7.7 Hz, 1H, H5), 7.37 (t, J = 7.7 Hz, 1H, H6),
7.34–7.32 (m, 2H, H2’, H6’), 7.17 (t, J = 9.0 Hz, 2H, H3’, H5’), 5.52 (s, 2H,
CH2), 4.34 (d, J = 5.0 Hz, 2H, CH2), 4.16 (s, 2H, CH2); 13C NMR (125
MHz, DMSO-d6): δ 166.3, 166.2, 162.0 (d, JC–F = 248.0 Hz), 152.6,
144.7, 134.7, 132.3, 130.2, 126.4, 124.5, 122.9, 121.8, 121.0, 115.5 (d,
JC–F = 21.2 Hz), 51.9, 36.4, 34.7. Anal. calcd for C19H16FN5OS2: C, 55.19;
H, 3.90; N, 16.94; found: C, 55.15; H, 3.92; N, 16.96%.
Synthesis of compounds 14; general procedure
A mixture of benzyl halide derivative 4 (0.5 mmol), sodium azide 5
(0.040 g, 0.6 mmol), Cu(OAc)2 (0.030 g, 0.15 mmol), ascorbic acid
(0.025 g, 0.14 mmol) and sodium carbonate (0.02 g, 0.19 mmol) was
added to a mixture of water and polyethylene glycol (10:1 wt%) and
heated at 70 °C for 30 min. Then, compound 13 (0.066 g, 0.25 mmol)
was added to the reaction mixture and the reaction was continued for
6 h. After completion of the reaction (checked by TLC), the mixture
was filtered and the crude product was obtained after extraction
with ethyl acetate (2 × 15 mL). Pure products 14 were obtained by
recrystallisation from a mixture of ethanol and ethyl acetate.
2-((1H-Benzo[d]imidazol-2-yl)thio)-N-((1-(4-bromobenzyl)-
1H-1,2,3-triazol-4-yl)methyl)acetamide (14a): Yellow solid; m.p.
183–185 °C; yield 55%; IR (KBr) (cm–1): 3282, 33141, 3052, 1660;
1H NMR (500 MHz, DMSO-d6): δ 12.59 (s, 1H, NH benzimidazole),
8.80 (t, J = 5.3 Hz, 1H, O=C–NH), 7.92 (s, 1H, triazole), 7.54 (d,
J = 8.3 Hz, 2H, H3’,H5’), 7.45 (d, J = 7.0 Hz, 1H, H6), 7.37 (d, J = 7.0 Hz,
1H, H5), 7.19 (d, J = 8.3 Hz, 2H, H2’,H6’), 7.06–7.15 (m, 2H, H4, H7), 5.50
(s, 2H, CH2), 4.33 (d, J = 5.5 Hz, 2H, CH2), 4.05 (s, 2H, CH2); 13C NMR
(125 MHz, DMSO-d6): δ 167.3, 144.9, 143.6, 135.4, 131.6, 131.4, 130.1,
125.6, 123.7, 122.9, 121.7, 121.3, 121.2, 118.8, 51.9, 34.8, 34.7. Anal.
calcd for C19H17BrN6OS: C, 49.90; H, 3.75; N, 18.38; found: C, 49.74; H,
3.51; N, 18.22%.
Synthesis of compounds 17; general procedure
Propargyl bromide 2 (1 mmol) was added to a solution of K2CO3
(2 mmol) and 4-(benzo[d]thiazol-2-yl)phenol (1 mmol) 1525 in DMF.
The mixture was stirred at 80 °C for at least 12 h. After completion of
the reaction (monitored by TLC), the mixture was diluted with EtOAc
(25 mL) and water (25 mL) and the organic layer was extracted with
EtOAc (2 × 25 mL). The organic phase was dried over anhydrous
Na2SO4 and the solvent was evaporated under reduced pressure to
afford the desired propargylated compounds 16, which were used for
further reaction without purification. Next, a solution of benzyl halide
derivative 4 (1.5 mmol), NaN3 5 (1.5 mmol) and Et3N (0.3 mmol) in
H2O/t-BuOH (1:1) was stirred at room temperature for 1–2 h. Then a
mixture of compound 16 (1 mmol), sodium ascorbate (0.2 mmol) and
CuSO4·5H2O (0.1 mmol) was added to the mixture and the reaction
was continued for 20–24 h. After completion of the reaction, the
mixture was extracted with ethyl acetate (2 × 20 mL), dried over
Na2SO4 and the solvent was evaporated under vacuum. The product
was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:1) as the eluent to afford pure products.

34 JOURNAL OF CHEMICAL RESEARCH 2016
1
2-(4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)benzo[d]
thiazole (17a): White solid; m.p. 197–198 °C; yield 90%; IR (KBr)
(cm–1): 3422, 2927, 2871, 1600, 1479; 1H NMR (500 MHz, DMSO-d6):
δ 8.3 (s, 1H, triazole), 8.15–7.85 (m, 4H, H7, H4, C6H4O), 7.57–7.15 (m,
9H, H6, H5, H2’, H3’, H5’, H6’, H4’, 2H C6H4O), 5.61 (s, 2H, CH2), 5.25
(s, 2H, CH2); 13C NMR (125 MHz, DMSO-d6): δ 166.6, 160.2, 153.9,
142.6, 134.0, 131.2, 128.7, 128.1, 127.8, 126.4, 125.0, 124.6, 122.6,
122.3, 121.9, 121.8, 115.4, 61.3, 52.8. Anal. calcd for C23H18N4OS: C,
69.32; H, 4.55; N, 14.06; found: C, 69.51; H, 4.36; N, 13.89%.
2-(4-((1-(2-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)
benzo[d]thiazole (17b): White solid; m.p. 185–187 °C; yield 87%; IR
(KBr) (cm–1): 3424, 2927, 1605, 1486; 1H NMR (500 MHz, DMSO-d6):
δ 8.3 (s, 1H, triazole), 8.20–7.84 (m, 4H, H7, H4, C6H4O), 7.61–7.08 (m,
8H, H6, H4’, H6’, H5, H3’, H5’, C6H4O), 5.68 (s, 2H, CH2), 5.25 (s, 2H,
CH2); 13C NMR (125 MHz, DMSO-d6): δ 167.2, 161.5 (d, JC–F = 245.0
Hz), 160.4, 153.6, 142.7, 134.2, 130.7, 128.8, 126.4, 125.8, 125.0, 124.6,
122.5, 122.4, 122.3, 122.1, 122.0, 115.7 (d, JC–F = 22.2 Hz), 115.4, 61.3,
46.9. Anal. calcd for C23H17FN4OS: C, 66.33; H, 4.11; N, 13.45; found:
C, 66.18; H, 3.91; N, 13.70%.
IR (KBr) (cm–1): 3424, 2927, 1604, 1604, 1477; H NMR (500 MHz,
DMSO-d6): δ 8.30 (s, 1H, triazole), 8.10 (d, J = 8.2 Hz, 1H, H7), 8.04
(d, J = 8.7 Hz, 2H, C6H4O), 8.02 (d, J = 8.2 Hz, 1H, H4), 7.52 (dt,
J = 8.2, 1.0 Hz, 1H, H6), 7.41–7.44 (m, 3H, H4’, H5’, H5), 7.40 (s, 1H,
H2’), 7.28–7.30 (d, J = 7.5 Hz, 1H, H6’), 7.23 (d, J = 8.7 Hz, 2H, C6H4O),
5.66 (s, 2H, CH2), 5.28 (s, 2H, CH2); 13C NMR (125 MHz, DMSO-d6):
δ 166.9, 160.4, 153.7, 142.6, 138.3, 134.2, 133.3, 130.6, 128.8, 128.1,
127.8, 126.6, 126.4, 125.8, 125.1, 124.9, 122.4, 122.1, 115.5, 61.3, 52.1.
Anal. calcd for C23H17ClN4OS: C, 63.81; H, 3.96; N, 12.94; found: C,
63.65; H, 4.18; N, 12.78%.
2-(4-((1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)
benzo[d]thiazole (17h): White solid; m.p. 168–169 °C; yield 89%; IR
(KBr) (cm–1): 3060, 2931, 1604, 1484; 1H NMR (500 MHz; DMSO-d6):
δ 8.3 (s, 1H, triazole), 8.10 (d, J = 8.3 Hz, 1H, H7), 8.04 (d, J = 9.0 Hz,
2H, C6H4O), 8.01 (d, J = 8.3 Hz, 1H, H4), 7.52 (t, J = 8.3 Hz, 1H, H6),
7.44 (d, J = 8.3 Hz, 2H, H2’, H6’), 7.42 (t, J = 8.3 Hz, 1H, H5), 7.35 (d,
J = 8.3 Hz, 2H, H3’, H5’), 7.22 (d, J = 9.0 Hz, 2H, C6H4O), 5.63 (s, 2H,
CH2), 5.26 (s, 2H, CH2); 13C NMR (125 MHz, DMSO-d6): δ 166.8,
160.4, 153.6, 142.6, 134.8, 134.2, 132.8, 129.8, 128.7, 128.6, 126.4,
125.8, 125.0, 124.7, 122.4, 122.1, 115.5, 61.3, 52.1. Anal. calcd for
C23H17ClN4OS: C, 63.81; H, 3.96; N, 12.94; found: C, 63.64; H, 3.78;
N, 13.18%.
2-(4-((1-(3-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)
benzo[d]thiazole (17c): White solid; m.p. 187–188 °C; yield 94%;
1
IR (KBr) (cm–1): 3131, 2924, 2871, 1600, 1483; H NMR (500 MHz,
DMSO-d6): δ 8.36 (s, 1H, triazole), 8.1 (d, J = 7.5 Hz, 1H, H7),
7.99–8.04 (m, 3H, C6H4O, H4), 7.51 (t, J = 7.5 Hz, 1H, H6), 7.42 (m,
2H, H4’, H5), 7.22 (d, J = 8.2 Hz, 2H, C6H4O), 7.15 (m, 3H, H2’, H5’, H6’),
5.65 (s, 2H, CH2), 5.26 (s, 2H, CH2); 13C NMR (125 MHz, DMSO-d6):
δ 167.3, 161.8 (d, JC–F = 245.0 Hz), 160.5, 153.6, 142.6, 134.3, 130.8,
130.7, 128.8, 126.5, 125.6, 125.1, 124.9, 124.0, 122.4, 122.12, 115.5,
115.1 (d, JC–F = 25.5 Hz), 114.8 (d, JC–F = 22.5 Hz), 61.4, 52.2. Anal.
calcd for C23H17FN4OS:C, 66.33; H, 4.11; N, 13.45; found: C, 66.54; H,
4.28; N, 13.28%.
2-(4-((1-(3-Methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)
benzo[d]thiazole (17i): White solid; m.p. 162–163 °C; yield 94%; IR
(KBr) (cm–1): 2924, 2848, 1603, 1477;1H NMR (500 MHz, DMSO-d6):
δ 8.3 (s, 1H, triazole), 8.10 (d, J = 8.0 Hz, 1H, H7), 8.03 (d, J = 9.0 Hz,
2H, C6H4O), 8.01 (d, J = 8.0 Hz, 1H, H4), 7.52 (dt, J = 8.0, 1.0 Hz, 1H,
H6), 7.42 (dt, J = 8.0, 1.0 Hz, 1H, H5), 7.25 (d, J = 7.5 Hz, 1H, H6’),
7.22 (d, J = 9.0 Hz, 2H, C6H4O), 7.11–7.14 (m, 3H, H2’, H4’, H5’), 5.57 (s,
2H, CH2), 5.26 (s, 2H, CH2), 2.28 (s, 3H, CH3); 13C NMR (125 MHz,
DMSO-d6): δ 166.8, 160.4, 153.6, 142.5, 137.9, 135.7, 134.2, 128.7,
128.7, 128.6, 128.4, 126.4, 125.8, 125.0, 124.9, 124.7, 122.4, 122.1,
115.5, 61.3, 52.8, 20.8. Anal. calcd for C24H20N4OS: C, 69.88; H, 4.89;
N, 13.58; found: C, 69.71; H, 4.66; N, 13.35%.
2- (4- ((1- (4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)
phenyl)benzo[d]thiazole (17d): White solid; m.p. 155–156 °C; yield
1
91%; IR (KBr) (cm–1): 3126, 2915, 1605, 1480; H NMR (500 MHz,
DMSO-d6): δ 8.32 (s, 1H, 1H triazole), 8.10 (d, J = 7.7 Hz, 1H, H7),
8.04 (d, J = 9.0 Hz, 2H, C6H4O), 8.01 (d, J = 7.7 Hz, 1H, H4), 7.52 (dt,
J = 7.7, 1.1 Hz, 1H, H6), 7.39–7.44 (m, 3H, H5, H2’, H6’), 7.19–7.23 (m,
4H, H3’, H5’, C6H4O), 5.62 (s, 2H, CH2), 5.26 (s, 2H, CH2); 13C NMR
(125 MHz, DMSO-d6): δ 166.9, 161.4 (d, JC–F = 250.0 Hz), 160.4,
153.6, 142.6, 134.2, 130.3, 130.2, 128.8, 126.4, 125.8, 125.0, 124.6,
122.4, 122.1, 115.6, 115.4 (d, JC–F = 22.0 Hz), 61.3, 52.0. Anal. calcd for
C23H17FN4OS: C, 66.33; H, 4.11; N, 13.45; found: C, 66.17; H, 4.38; N,
13.23%.
2-(4-((1-(4-Methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)
benzo[d]thiazole (17j): White solid; m.p. 163–164 °C; yield 90%; IR
(KBr) (cm–1): 3458, 2923, 1606, 1483; 1H NMR (500 MHz, DMSO-d6):
δ 8.26 (s, 1H, triazole), 8.10 (d, J = 8.0 Hz, 1H, H7), 8.03 (d, J = 8.7
Hz, 2H C6H4O), 8.00 (d, J = 8.0 Hz, 1H, H4), 7.51 (t, J = 8.0 Hz, 1H,
H6), 7.42 (t, J = 8.0 Hz, 1H, H5), 7.22 (d, J = 7.7 Hz, 2H, H2’, H6’), 7.21
(d, J = 8.7 Hz, 2H, C6H4O), 7.17 (d, J = 7.7 Hz, 2H, H3’, H5’), 5.56 (s,
2H, CH2), 5.24 (s, 2H, CH2), 2.27 (s, 3H, CH3); 13C NMR (125 MHz,
DMSO-d6): δ 166.6, 160.4, 153.6, 142.5, 137.4, 134.4, 132.8, 129.2,
128.7, 127.9, 126.4, 125.6, 125.0, 124.5, 122.4, 122.1, 115.5, 61.3, 52.6,
20.61. Anal. calcd for C24H20N4OS: C, 69.88; H, 4.89; N, 13.58; found:
C, 70.11; H, 4.65; N, 13.67%.
2-(4-((1-(3-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)
benzo[d]thiazole (17e): White solid; m.p. 176–177 °C; yield 91%;
1
IR (KBr) (cm–1): 3146, 3064, 2929, 1604, 1427; H NMR (500 MHz,
DMSO-d6): δ 8.36 (s, 1H, triazole), 8.10 (d, J = 8.3 Hz, 1H, H7), 8.04 (d,
J = 9.0 Hz, 2H, C6H4O), 8.01 (d, J = 8.3 Hz, 1H, H4), 7.05–7.55 (m, 3H,
H6, H5’, H6’), 7.42 (dt, 1H, J = 8.3, 1.3 Hz, H5), 7.32–7.36 (m, 2H, H2’, H4’),
7.23 (d, J = 9.0 Hz, 2H, C6H4O), 5.65 (s, 2H, CH2), 5.28 (s, 2H, CH2);
13C NMR (125 MHz, DMSO-d6): δ 166.8, 160.4, 153.6, 142.6, 138.4,
134.2, 130.9, 130.8, 130.6, 128.7, 127.0, 126.4, 125.8, 125.0, 124.9, 122.4,
122.1, 121.7, 115.4, 61.3, 51.9. Anal. calcd for C23H17BrN4OS:C, 57.87; H,
3.59; N, 11.74; found: C, 57.62; H, 3.70; N, 11.59%.
Biology
Acetylcholinesterase (AChE, E.C. 3.1.1.7, Type V-S, lyophilised
powder, from electric eel, 1000 unit) was obtained from Sigma-
Aldrich. 5,5-Dithiobis-(2-nitrobenzoic acid) (DTNB), potassium
dihydrogen phosphate, dipotassium hydrogen phosphate, potassium
hydroxide, sodium hydrogen carbonate and acetylthiocholine iodide
were purchased from Fluka. The solutions of synthesised compounds
were prepared in a mixture of DMSO (1 mL) and methanol (9 mL) and
diluted in 0.1 M KH2PO4/K2HPO4 buffer (pH = 8.0) to obtain the stock
solution of the test compounds. Each compound was tested at 3320 µM
to yield the final concentration of 100 µM. All inhibition assays
were performed in triplicate and the average inhibition percent was
reported. The temperature was held at 25 °C during all experiments.
The assay medium was composed of 0.1 M phosphate buffer pH = 8.0
(3 mL), 0.01 M DTNB (100 µL) and 100 µL of 2.5 unit mL−1 enzyme
solution (AChE, E.C. 3.1.1.7, Type V-S, lyophilised powder, from
electric eel). 100 µL of each test compound was added to the assay
tube and incubated at 25 °C for 15 min prior to adding 20 µL of
substrate (acetylthiocholine iodide). The rate of absorbance change
was measured at 412 nm for 6 min on the baseline obtained by blank
reading of the solutions with non-enzymatic hydrolysis. The blank
2-(4-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)
benzo[d]thiazole (17f): White solid; m.p. 190–191 °C; yield 88%;
1
IR (KBr) (cm–1): 3129, 3089, 2923, 1604, 1483; H NMR (500 MHz,
DMSO-d6): δ 8.33 (s, 1H, triazole), 8.10 (d, J = 7.8 Hz, 1H, H7), 8.04 (d,
J = 8.7 Hz, 2H, C6H4O), 8.01 (d, J = 7.8 Hz, 1H, H4), 7.58 (d, J = 8.5 Hz,
2H, H3’, H5’), 7.52 (dt, J = 7.8, 1.0 Hz, 1H, H6), 7.43 (dt, J = 7.8, 1.0
1Hz, 1H, H5), 7.28 (d, J = 8.5 Hz, 2H, H2’, H6’), 7.22 (d, J = 8.7 Hz,
2H, C6H4O), 5.62 (s, 2H, CH2), 5.26 (s, 2H, CH2); 13C NMR (125 MHz,
DMSO-d6): δ 166.9, 160.4, 153.6, 142.6, 135.3, 134.2, 131.6, 130.4,
130.1, 128.8, 126.4, 125.0, 124.8, 122.4, 122.1, 121.4, 115.5, 61.3, 52.1.
Anal. calcd for C23H17BrN4OS: C, 57.87; H, 3.59; N, 11.74; found: C,
57.62; H, 3.33; N, 11.58%.
2-(4-((1-(3-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)
benzo[d]thiazole (17g): White solid; m.p. 173–174 °C; yield 94%;

JOURNAL OF CHEMICAL RESEARCH 2016 35
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30 H. Nadri, M. Pirali-Hamedani, A. Moradi, A. Sakhteman, A. Vahidi, V.
Sheibani, A. Asadipour, N. Hosseinzadeh, M. Abdollahi, A. Shafiee and A.
Foroumadi, Daru, 2013, 21, 15.
The 3D structure of compound 7e was obtained from HyperChem 7 (by
Hypercube, Inc.) after energy minimisation (convergence criterion of
0.05 kcal (mol A˚)−1 and a maximum of 1000 interactions). Autodock
4.0 was used for docking 7e in the aromatic gorge of AChE co-
crystallised with N-saccharinohexyl-galanthamine (PDB ID: 3I6Z).
The geometric centre of the ligand was used to define the active site
interaction points. The docking result was analysed using the PLIP
(Protein Ligand Interaction Profiler) web server.31
Acknowledgements
This research was supported by grant from the Research
Council of Tehran University of Medical Sciences and Iran
National Science Foundation (INSF; Grant no. 92037263).
Received 27 October 2016; accepted 12 December 2016
Paper 1604398 doi: 10.3184/174751917X14836231670980
Published online: 19 January 2017
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