Synthesis and biological evaluation of new benzimidazole-1,2,3-triazole hybrids as potential α-glucosidase inhibitors

Article abstract of DOI:10.1016/j.bioorg.2019.103482

In this study, a series of benzimidazole-1,2,3-triazole hybrids 8a-n as new α-glucosidase inhibitors were designed and synthesized. In vitro α-glucosidase inhibition activity results indicated that all the synthesized compounds (IC₅₀ values ranging from 25.2 ± 0.9 to 176.5 ± 6.7 μM) exhibited more inhibitory activity in comparison to standard drug acarbose (IC₅₀ = 750.0 ± 12.5 μM). Enzyme kinetic study on the most potent compound 8c revealed that this compound was a competitive inhibitor into α-glucosidase. Moreover, the docking study was performed in order to evaluation of interaction modes of the synthesized compounds in the active site of α-glucosidase and to explain structure-activity relationships of the most potent compounds and their corresponding analogs.

Full text of DOI:10.1016/j.bioorg.2019.103482

Journal Pre-proofs
Synthesis and biological evaluation of new benzimidazole-1,2,3-triazole hy-
brids as potential α-glucosidase inhibitors
Nafise Asemanipoor, Maryam Mohammadi-Khanaposhtani, Shahram Moradi,
Mahbobeh Vahidi, Mehdi Asadi, Mohammad Ali Faramarzi, Mohammad
Mahdavi, Mahmood Biglar, Bagher Larijani, Haleh Hamedifar, Mir Hamed
Hajimiri
PII:
S0045-2068(19)31556-1
DOI:
https://doi.org/10.1016/j.bioorg.2019.103482
YBIOO 103482
Reference:
To appear in:
Bioorganic Chemistry
Received Date:
Revised Date:
Accepted Date:
24 September 2019
24 November 2019
25 November 2019
Please cite this article as: N. Asemanipoor, M. Mohammadi-Khanaposhtani, S. Moradi, M. Vahidi, M. Asadi, M.
Ali Faramarzi, M. Mahdavi, M. Biglar, B. Larijani, H. Hamedifar, M. Hamed Hajimiri, Synthesis and biological
evaluation of new benzimidazole-1,2,3-triazole hybrids as potential α-glucosidase inhibitors, Bioorganic
Chemistry (2019), doi: https://doi.org/10.1016/j.bioorg.2019.103482
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Synthesis and biological evaluation of new benzimidazole-1,2,3-triazole hybrids as potential
α-glucosidase inhibitors
Nafise Asemanipoora,1, Maryam Mohammadi-Khanaposhtanib,1, Shahram Moradia, Mahbobeh
Vahidic, Mehdi Asadid, Mohammad Ali Faramarzic, Mohammad Mahdavie,*, Mahmood Biglare,
Bagher Larijanie, Haleh Hamedifarf, Mir Hamed Hajimirig,*
a Department of Chemistry Tehran North Branch, Islamic Azad University Tehran Iran
b Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of
Medical Sciences, Babol, Iran
c
Department of Pharmaceutical Biotechnology, Faculty of Pharmacy and Biotechnology
Research Center, Tehran University of Medical Sciences, Tehran, Iran
d Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences
Research Center, Tehran University of Medical Sciences, Tehran, Iran
e
Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical
Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
f
CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences,
Karaj, Iran
g Nano Alvand Company, Avicenna Tech Park, Tehran University of Medical Sciences, Tehran
1439955991, Iran
* Corresponding authors.
1

E-mail addresses: momahdavi@tums.ac.ir (M. Mahdavi) and h.hajimiri@nanoalvand.com (M.H.
Hajimiri)
1 These authors contributed equally to this work.
Abstract
In this study, a series of benzimidazole-1,2,3-triazole hybrids 8a-n as new α-glucosidase inhibitors
were designed and synthesized. In vitro α-glucosidase inhibition activity results indicated that all
the synthesized compounds (IC50 values ranging from 25.2 ± 0.9 to 176.5 ± 6.7 μM) exhibited
more inhibitory activity in comparison to standard drug acarbose (IC50 = 750.0 ± 12.5 μM).
Enzyme kinetic study on the most potent compound 8c revealed that this compound was a
competitive inhibitor into α-glucosidase. Moreover, the docking study was performed in order to
evaluation of interaction modes of the synthesized compounds in the active site of α-glucosidase
and to explain structure-activity relationships of the most potent compounds and their
corresponding analogs.
Keywords: α-Glucosidase inhibitor, Molecular docking, Benzimidazole, 1,2,3-Triazole
1. Introduction
Diabetes mellitus (DM) is a metabolic disorder which has two main type 1 and type 2: in the type
1 of DM, the body does not produce enough insulin and in the type 2 of this disease, insulin is
sufficient, but the cells cannot use it efficiently [1]. The common treatment for type 1 diabetes is
injectable insulin while the main medications for type 2 diabetes are oral blood glucose-lowering
drugs that acted with various mechanisms such as enhances the effect of insulin, reduce intestinal
glucose absorption, increased glucosuria through the inhibition of sodium/glucose cotransporter 2
(SGLT2) in the kidney, and reduce insulin resistance through the stimulation of peroxisome
2

proliferator-activated receptors (PPARs) [2]. As was mentioned above, one of the most important
of these mechanisms is reduce intestinal glucose absorption that occurs through inhibition of the
carbohydrate-hydrolysing enzymes such as α-glucosidase and α-amylase [3]. Blocking the activity
of the latter enzymes led to a decrease in the decomposition of carbohydrates to glucose and
reduces level of this metabolite in the blood. Today, α-glucosidase inhibitors such as acarbose,
miglitol, and voglibose have been developed to treat of type 2 diabetes. Although these agents
have certain therapeutic effect on type 2 diabetes, taking them is associated with gastrointestinal
adverse reactions such as bloating, diarrhea, abdominal pain, and etc [4]. Therefore, it is urgent to
develop new efficient and potent α-glucosidase inhibitors with low side effects for treatment of the
type 2 diabetes.
Benzimidazole ring is an attractive pharmacophore for the medicinal chemists that widely used for
design and development of new biological active compounds [5]. Several benzimidazole
derivatives with α-glucosidase inhibitory activity have been reported (Fig. 1, A) [6-8]. Another
one of the useful pharmacophores for design new potent α-glucosidase inhibitors is 1,2,3-triazole
ring [9-11]. In this regard, recently, Wang et al. have been reported xanthone-triazole hybrids B
with high anti-α-glucosidase activities (Fig. 1) [12].
Keeping in view of the above mentioned importance of benzimidazole and 1,2,3-triazole moieties
in the design of new α-glucosidase inhibitors, herein, we designed, synthesized, and screened novel
benzimidazole-1,2,3-triazole hybrids 8a-n for their α-glucosidase inhibitory activity (Fig. 1).
Kinetic and docking studies of these compounds in order to evaluation of their interactions with
α-glucosidase were performed.
3

O
O
OH
N
R1
N
O
O
N
N
H
N
O
R2
A
Compound
B
Compouinds
HN
Molecular Hybridization
N
N
O
N
N
O
N
R
N
n
H
H
8a-n
Designed bhybrids
Fig. 1. Design strategy for benzimidazole-1,2,3-triazole hybrids 8a-n as new α-glucosidase
inhibitors.
2. Results and discussion
2.1. Chemistry
The synthetic route for the synthesis of benzimidazole-1,2,3-triazoles 8a-n has been depicted in
Scheme 1. This route was started from the reaction of o-phenylenediamine 1 and 4-(prop-2-
ynyloxy)benzaldehyde 2 in the presence of Na2S2O5 in DMF at 100 °C to give 2-(4-(prop-2-
ynyloxy)phenyl)-1H-benzo[d]imidazole 3. On the other hand, amines 4a-n reacted with
chloroacetyl chloride 5 in DMF at room temperature (RT), to give N-phenyl (or benzyl)-2-
chloroacetamides 6. In order to produce the appropriate molecules to participate in the click
4

reaction, N-phenyl (or benzyl)-2-chloroacetamides 6a-n and sodium azide reacted in the mixture
of H2O and t-BuOH (1:1) in the presence of triethylamine (Et₃N) at RT [13]. Then, mixture of 2-
(4-(prop-2-ynyloxy)phenyl)-1H-benzo[d]imidazole 3, sodium ascorbate, and copper(II) sulfate
(CuSO4) was added to the freshly prepared azide derivatives 7a-n and the reaction was continued
at RT for 24-48 h to give the target compounds 8a-n.
O
NH2
n
Cl
+
R
Cl
4a-n
5
n = 0, 1
R = H, 4-CH3, 4-CH2CH3, 4-
OCH3, 2-Cl, 2,3-Dichloro, 2,6-
Dichloro, 4-Cl, 3-Br, 4-Br, 2-NO2,
4-NO2, 4-F
(b)
O
Cl
N
n
+
NaN3
H
R
6a-n
(c)
NH2
NH2
O
N3
N
(a)
+
O
OHC
N
n
O
+
R
H
N
H
7a-n
1
3
2
(d)
N
N
O
N
N
O
N
R
N
n
H
H
8a-n
Scheme 1. Reagents and conditions for the synthesis of benzimidazole-1,2,3-triazoles 8a-n: (a)
DMF, Na2S2O5, 100 °C, 2 h; (b) DMF, RT, 30 min; (c) Et₃N, H2O/t-BuOH, RT, 1 h; (d)
CuSO4.5H2O, sodium ascorbate, RT, 24-48 h.
2.2. In vitro α-glucosidase inhibitory activity
5

The synthesized compounds 8a–n were screened for their in vitro α-glucosidase inhibition against
yeast α-glucosidase. The obtained IC50 values of the N-phenylacetamide derivatives 8a-l and N-
benzylacetamide derivatives 8m-n showed that all these compounds are more potent than standard
drug acarbose (IC50 = 750.0 ± 12.5 μM) and among them, the most potent compounds were
compounds 8c, 8k, 8b, 8a, and 8f with IC50 values 25.2 ± 0.9, 35.0 ± 1.0, 43.1 ± 1.5, 51.5 ± 1.8,
and 56.6 ± 2.1 μM, respectively. Moreover, the remaining compounds with the IC50 values ranging
from 63.0 ± 2.5 to 176.5 ± 6.7 μM exhibited α-glucosidase inhibitory activities around 12–4 folds
more than acarbose.
In the N-phenylacetamide derivatives 8a-l, the most potent compound was 4-ethyl derivative 8c.
Removing the ethyl substituent or replace it with methyl substituent, led to a slightly decrees in
the inhibitory activity as observed in the compounds 8a and 8b, respectively. Moreover, replacing
of ethyl substituent with methoxy, bromo, or nitro substituents, as in compounds 8d, 8j, and 8l,
respectively, caused to a significant decrease in the anti-α-glucosidase activity. Among the halo-
substituted derivatives 8e-j, compound 8f with 2,3-dichlorophenyl moiety was the most potent
compound. Removing the 3-chloro substituent, as in compound 8e, led to slightly decrease in the
activity while movement of 3-chloro to 6-position, as in compound 8g, led to a significant decrease
in the activity. Among the synthesized compounds, the less active compound was N-4-
bromophenylacetamide 8j. Replacement of bromo with chloro substituent or changing the position
of the bromine atom in the phenyl ring from 4-position to 3-position, producing compound 8h and
8i, dramatically increased the inhibitory activity. The second most potent compounds among the
synthesized compounds was 2-nitro derivative 8k while it 4-nitro analog 8l was one of the weakest
compounds synthesized against α-glucosidase. From the activity pattern of N-phenylacetamide
derivatives 8a-l it can be ascertain that the position of the substitutions on phenyl ring of N-
6

phenylacetamide moiety as well as their electron property play important role in the obtained anti-
α-glucosidase activity.
Inhibitory activity of N-benzylacetamide derivative 8m is 2.3-fold less than that of it corresponding
analog 8a of N-phenylacetamide series. The introduction of 4-fluoro substituent on benzyl group
improved inhibitory activity against α-glucosidase as observed in compound 8n.
Table 1. In vitro inhibitory activities of compounds 8a-n against α-glucosidase.
N
a'
d'
a
a
b
b
N
N
O
N
b'
c'
O
2
N
R
3
N
H
n
H
6
4
5
Compound
n
0
0
0
0
0
0
0
0
0
0
0
R
IC50 (μM)a
51.5 ± 1.8
43.1 ± 1.5
25.2 ± 0.9
112.5 ± 5.3
70.6 ± 2.6
56.6 ± 2.1
133.7 ± 6.0
91.6 ± 3.0
85.2 ± 2.8
176.5 ± 6.7
35.0 ± 1.0
8a
8b
8c
8d
8e
8f
H
4-CH3
4-CH2CH3
4-OCH3
2-Cl
2,3-Dichloro
2,6-Dichloro
4-Cl
8g
8h
8i
3-Br
8j
4-Br
8k
2-NO2
7

8l
8m
0
1
1
-
4-NO2
107.3 ± 5.1
121.1 ± 5.5
63.0 ± 2.5
H
4-F
-
8n
Acarbose
750.0 ± 12.5
a Data are expressed as mean ± S.E. of at least three different experiments.
2.3. Kinetic study
In order to gain the interaction mechanism between the synthesized compounds and α-glucosidase,
the most potent compound 8c was selected to study the inhibition kinetic. As shown in Fig. 2a, it
was revealed that compound 8c is a competitive α-glucosidase inhibitor. Moreover, the inhibitory
constant (Ki) of this compound was 23 µM (Fig. 2b).
a)
b)
7
6
5
4
3
2
1
0
20
15
10
5
Concentration of 8c
0 µM
11 µM
18 µM
25 µM
0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1/[S](PNPG, mM-1)
-5
-10
-15
-30
-20
-10
0
10
20
30
Compound (8c)
Fig. 2. The inhibition type and Ki of the most potent compound 8c.
2.4. Molecular docking study
In order to gain an insight of the interaction modes in the active site of α-glucosidase and also
explain the different activities of the synthesized compounds, molecular docking studies were
8

conducted using AutodockTools (version 1.5.6) on modeled α-glucosidase [14]. Interaction modes
of the selected analogs 8b-c, 8k-l, 8a and 8m, and 8e-f were showed in the Figs. 3-6 and details of
their interactions in the active site were listed in Tables 2-5. In each table, green entries showed
the same interactions between comparative analogs and the active site.
The comparison of interaction modes of the most potent compound 8c and it analog 8b (the third
most potent compound) (Fig. 3 and Table 2) showed that N-(4-ethylphenyl)acetamide moiety of
the compound 8c formed three interactions with Phe300 and Phe157 by 4-ethyl substituent,
pendant phenyl ring, and NH unit of amide moiety and N-(4-methylphenyl)acetamide moiety the
compound 8b established three interactions with Phe158, Arg312, Phe311 by 4-methyl substituent,
pendant phenyl ring, and carbonyl unit of amide moiety. Furthermore, 1,2,3-triazol ring of the
compound 8c interacted with His239 via a - interaction and a -cation interaction while this
ring of the compound 8b showed only a hydrogen bond with His279. Moreover, additional
interactions between middle phenyl and benzimidazole moieties of the compound 8c and Glu304
in comparison to the compound 8b can be also seen. Other interactions are the same in the both
compound 8b and 8c.
(8b)
(8c)
9

Fig. 3. Interaction modes of compounds 8b and 8c in the active site of α-glucosidase.
Table 2. Interaction mode details of the compounds 8b and 8c.
Compound
Interaction
Interacting unit of the
ligand
Amino
acid
Compound
Interaction
Interacting unit of the ligand
Amino
acid
8b
Hydrophobic
Hydrophobic
H-bond
H-bond
Hydrophobic
H-bond
4-Methyl
Pendant phenyl
NH-CO
1,2,3-triazol
Phe158
Arg312
Phe311
His279
Pro309
Thr307
Val305
Pro309
8c
Hydrophobic
-
4-Ethyl
Pendant phenyl
NH-CO
1,2,3-triazol
1,2,3-triazol
Phe300
Phe157
Phe157
His239
His239
Glu304
Pro309
Thr307
Glu304
Glu304
Val305
Pro309
H-bond
-
-cation
-anion
Hydrophobic
H-bond
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Middle phenyl
NH unit of benzimidazole
Benzimidazole
Benzimidazole
Middle phenyl
Middle phenyl
NH unit of benzimidazole
Benzimidazole
Benzimidazole
Benzimidazole
Benzimidazole
Hydrophobic
Hydrophobic
The second most potent compound 8k (IC50 = 35.0 ± 1.0 µM) with 2-nitro-phenyl group in comparison
to it regioisomer 8l (IC50 = 107.3 ± 5.1 µM) with 4-nitro-phenyl group showed additional interactions
with Phe157, His239, His279, Pro309 through amide group, 1,2,3-triazol ring, and benzimidazole moiety
as can be seen in the Fig.4 and Table 3. Moreover, an additional hydrophobic interaction between
benzimidazole moiety of the compound 8k and Glu304 was observed.
10

(8k)
(8l)
Fig. 4. Interaction modes of compounds 8k and 8l in the active site of α-glucosidase.
Table 3. Interaction mode details of the compounds 8k and 8l.
Compound
Interaction
Interacting unit of the ligand Amino Compound
acid
Interaction
Interacting unit of the ligand
Amino
acid
8k
Hydrophobic
H-bond
H-bond
-cation
-
-cation
-anion
Hydrophobic
H-bond
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Pendant phenyl
NH-CO
NH-CO
1,2,3-triazol
1,2,3-triazol
1,2,3-triazol
Arg312
Phe157
His239
His239
His279
His279
Glu304
Pro309
Thr307
Glu304
Glu304
Val305
Pro309
8l
Hydrophobic
-cation
-anion
Hydrophobic
H-bond
Hydrophobic
Hydrophobic
Hydrophobic
Pendant phenyl
1,2,3-triazol
Middle phenyl
Arg312
His279
Glu304
Pro309
Thr307
Glu304
Val305
Pro309
Middle phenyl
NH unit of benzimidazole
Benzimidazole
Middle phenyl
Middle phenyl
NH unit of benzimidazole
Benzimidazole
Benzimidazole
Benzimidazole
Benzimidazole
Benzimidazole
Benzimidazole
As can be seen in the Fig. 5 and Tables 1 and 4, insertion of a methylene unit between amid group and
pendant phenyl ring in the compound 8a (IC50 = 51.5 ± 1.8 µM), as in compound 8m (IC50 = 121.1 ±
5.5 µM), led to a significant decrease in the inhibitory activity and changes in interaction of amide group
with the active site. Amide group of the compound 8a formed two hydrogen bonds with Asp408 (NH
11

unit) and Asn412 (carbonyl unit) while this moiety of the compound 8m established only a hydrogen
bond with Phe157 (NH unit). Other interactions are the same in the both compound 8a and 8m.
(8a)
(8m)
Fig. 5. Interaction modes of compounds 8k and 8l in the active site of α-glucosidase.
Table 4. Interaction mode details of the compounds 8a and 8m in the active site of α-
glucosidase.
Compound
Interaction
Interacting unit of the ligand Amino Compound
acid
Interaction
Interacting unit of the ligand
Amino
acid
8a
H-bond
H-bond
-
NH-CO
NH-CO
1,2,3-triazol
Asp408
Asn412
His239
Arg312
Glu304
Pro309
Thr307
Glu304
Pro309
Pro309
8m
H-bond
-
NH-CO
1,2,3-triazol
1,2,3-triazol
Middle phenyl
Middle phenyl
Phe157
His239
Arg312
Glu304
Pro309
Thr307
Glu304
Pro309
Pro309
Hydrophobic
Hydrophobic
1,2,3-triazol
-anion
Hydrophobic
H-bond
H-bond
Hydrophobic
Hydrophobic
Middle phenyl
Middle phenyl
NH unit of benzimidazole
NH unit of benzimidazole
Benzimidazole
Benzimidazole
-anion
Hydrophobic
H-bond
H-bond
Hydrophobic
Hydrophobic
NH unit of benzimidazole
NH unit of benzimidazole
Benzimidazole
Benzimidazole
N-(2,3-dichlorophenyl)acetamide moiety of the most potent halogenated compound 8f (IC50 = 56.6 ± 2.1
µM) showed hydrophobic interactions with Tyr313 and Arg312 through chloro substituents and pendant
phenyl ring and a hydrogen bond with Phe157 through NH unit of amide group while it 2-chlorophenyl
analog 8e (IC50 = 70.6 ± 2.6 µM) as the second most potent halogenated derivative formed a hydrophobic
interaction with Tyr313 through 2-chloro substituent and two hydrogen bonds with Asp408 and Asn412
12

through amide group (Fig. 6 and Table 5). Moreover, 1,2,3-triazole ring of the compound 8f interacted with
residues His239 and His279 via -interactions while this ring of the compound 8e only formed a
hydrophobic interaction with Arg312. Middle phenyl moieties of these compounds showed the same
interactions with the active site. On the other hand, NH unit of benzimidazole moiety of compound 8e
formed two additional hydrogen bonds with Glu304 and Thr307 in comparison with the compound 8f.
Finally, benzimidazole moiety of the compound 8f formed four hydrophobic interactions with Glu304 (two
interactions), Val305, and Pro309 while this moiety of the compound 8e only two hydrophobic interactions
established with Pro309.
(8e)
(8f)
Fig. 6. Interaction modes of the compounds 8e and 8f in the active site of α-glucosidase.
Table 5. Interaction mode details of the compounds 8e and 8f in the active site of α-glucosidase.
13

Compound
Interaction
Interacting unit of the ligand Amino Compound
acid
Interaction
Interacting unit of the ligand
Amino
acid
8e
Hydrophobic
H-bond
H-bond
Hydrophobic
-anion
Hydrophobic
H-bond
H-bond
H-bond
Hydrophobic
Hydrophobic
2-Cl
NH-CO
NH-CO
Tyr313
Asp408
Asn412
Arg312
Glu304
Pro309
Thr307
Thr307
Glu304
Pro309
Pro309
8f
Hydrophobic
Hydrophobic
Hydrophobic
H-bond
-
-
-cation
-anion
2-Cl
3-Cl
Pendant phenyl
NH-CO
1,2,3-triazol
1,2,3-triazol
Tyr313
Tyr313
Arg312
Phe157
His279
His239
His239
Glu304
Pro309
Glu304
Thr307
Glu304
Glu304
Val305
Pro309
1,2,3-triazol
Middle phenyl
Middle phenyl
NH unit of benzimidazole
NH unit of benzimidazole
NH unit of benzimidazole
Benzimidazole
Benzimidazole
1,2,3-triazol
Middle phenyl
Middle phenyl
NH unit of benzimidazole
NH unit of benzimidazole
Benzimidazole
Benzimidazole
Benzimidazole
Benzimidazole
Hydrophobic
H-bond
H-bond
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
2.5. α-Amylas inhibition assay
Another strategy for the reduction of released glucose from carbohydrates is inhibition of α-
amylase [15]. In this regard, anti-α-amylase activity (against porcine pancreatic α-amylase) of
the most active α-glucosidase inhibitors 8c, 8k, and 8a was evaluated. Obtained results revealed
that the latter compounds were inactive against α-amylase (at 300 μM) when compared with
acarbose as a standard α-amylase inhibitor (IC50 =108 ± 0.71 μM).
3. Conclusion
In conclusion, a series of novel benzimidazole-1,2,3-triazole hybrids 8a-n were designed and
synthesized via click reaction. In vitro anti-α-glucosidase activity evaluation of title compounds
revealed that all the synthesized derivatives exhibited excellent inhibitory potency compared with
acarbose. The evaluation of inhibition mechanism revealed that the most active compound 8c
inhibited α-glucosidase in a competitive mode. Moreover, docking studies of the most potent
compounds and their corresponding analogs in the active site of modeled α-glucosidase were also
performed in order to evaluate of interaction modes and structure-activity relationships. α-Amylas
14

inhibition assay of the most potent compounds demonstrated that these compounds at 300 µM do
not exhibit activity.
4. Experimental
The melting points of benzimidazole-1,2,3-triazoles 8a-n were determined on a Kofler hot stage
apparatus and uncorrected. 1H and 13C NMR spectra of these derivatives were recorded on a Bruker
FT-500 in DMSO-d6 with tetramethylsilane as an internal standard. Nicolet Magna FTIR 550
spectrophotometer was used to record IR spectra of the synthesized compounds by using KBr
disks. Elemental analysis of title compounds 8a-n was performed on an Elementar Analysen
system GmbH VarioEL CHNS mode.
4.1. General Procedure for the Synthesis of 2-(4-(prop-2-ynyloxy)phenyl)-1H-benzo[d]imidazole
3
A mixture of o-phenylenediamine 1 (1 mmol), 4-(prop-2-ynyloxy)benzaldehyde 2 (1 mmol), and
Na2S2O5 (1.1 mmol) in DMF (15 mL) was stirred at 100 °C for 2 h. Then, the reaction mixture was
poured in the water and obtained product 3 was filtered off.
4.2. General Procedure for the Synthesis of N-phenyl (or benzyl)-2-chloroacetamides 6a-n
A solution of amines 4a-n (1mmol) and chloroacetyl chloride 5 (1.1 mmol) in DMF (15 mL) was
stirred at RT for 30 min. Then, the mixture was diluted with cold water, poured into ice, and the
obtained precipitates were filtered off. The residue was washed with water to obtain pure N-phenyl
(or benzyl)-2-chloroacetamide 6a-n.
4.3. General Procedure for the Synthesis of azide derivatives 7a-n
15

In order to do a click reaction, azide derivatives 7a-n were prepared in situ of reaction between N-
phenyl (or benzyl)-2-chloroacetamide 6a-n (1.1 mmol), sodium azide (0.9 mmol), and Et3N (1.3
mmol) in the mixture of H2O and t-BuOH(10 mL, 1:1) at RT for 1 h.
4.4. General Procedure for the Synthesis of benzimidazole-1,2,3-triazole-acetamides 8a-n
A mixture of 2-(4-(prop-2-ynyloxy)phenyl)-1H-benzo[d]imidazole 3 (1 mmol), sodium ascorbate,
and CuSO4.5H2O (7 mol %) was added to the azide derivatives 7a-n, and obtained mixture was
stirred at RT for 18-24 h. After that, reaction mixture was poured into crushed ice and precipitated
products 8a-n were filtered off, washed with water, and purified by recrystallization in ethyl
acetate.
4.4.1.
2-(4-((4-(1H-benzo[d]imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-
phenylacetamide 8a
White powder; Yield: 77%; mp =166–168 °C. IR (KBr): 3698, 1702, 1602 cm-1. 1H NMR (500
MHz, DMSO-d6): 5.28 (2H, s, CH2-O), 5.37 (2H, s,CH2), 7.15-7.19 (3H, m, Hα, H4), 7.24 (2H, d,
J = 8.5Hz, H3, H5), 7.34 (2H, dd, J = 7.5, 6 Hz, Hb', Hc'), 7.58 (2H, d, J = 7.5 Hz, H2, H6), 7.62
(2H, d, J = 6 Hz, Ha', Hd'), 8.12 (2H, d, J = 8 Hz, Hβ), 8.31 (1H, s, H-triazole), 10.49 (1H, s, NH),
12.75 (1H, s, NH).13C NMR (125 MHz, DMSO-d6): 58.2, 66.7, 111.3, 1116.7, 121.6, 126.3, 127.6,
128.5, 128.7, 129.1, 130.3, 130.4, 131.0, 132.5, 135.2, 135.7, 142.9, 150.8, 157.3, 163.5. Anal.
Calcd for C24H20N6O2: C, 67.91; H, 4.75; N, 19.80. Found: C, 67.83; H, 4.68; N, 19.92.
4.4.2.
2-(4-((4-(1H-benzo[d]imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(p-
tolyl)acetamide 8b
White powder; yield: 80%; mp =164–166 °C. IR (KBr): 3398, 3766, 1709, 1605 cm-1. 1H NMR
(500 MHz, DMSO-d6): 2.59 (3H, s, CH3), 5.28 (2H, s, CH2-O), 5.38 (2H, s, CH2), 7.13 (2H, d, J
16

= 8.5 Hz, Hα), 7.18 (2H, m, , Hb', Hc'), 7.25 (2H, d, J = 7 Hz, H3, H5), 7.47 (2H, d, J = 8 Hz, H2,
H6), 7.57 (2H, m, Ha', Hd'), 8.13 (2H, d, J = 8Hz, Hβ), 8.30 (1H, s, H-triazole), 10.4 (1H, s, NH),
10.64 (1H, s, NH). 13C NMR (125 MHz, DMSO-d6): 20.0, 58.1, 65.5, 113.5, 114.9, 116.1, 118.7,
124.5, 126.3, 127.5, 128.1, 128.2, 129.4, 131.8, 134.2, 136.9, 143.1, 150.7, 157.1, 165.0. Anal.
Calcd for C25H22N6O2: C, 68.48; H, 5.06; N, 19.17. Found: C, 68.57; H, 7.92; N, 19.27.
4.4.3.
2-(4-((4-(1H-benzo[d]imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-
ethylphenyl)acetamide 8c
Cream powder; yield: 75%; mp =151–153 °C. IR (KBr): 3298, 38764, 1702, 1562 cm-1. 1H NMR
(500 MHz, DMSO-d6): 1.15 (3H, t, J = 6 Hz, CH3), 2.56 (2H, m, CH2), 5.28 (2H, s, CH2-O), 5.35
(2H, s, CH2), 7.17 (4H, m, Hα, H3, H5), 7.24 (2H, d, J = 7 Hz, Hb', Hc'), 7.48 (3H, m, H2, H6,
Hd' or Ha' ), 7.62 (1H, d, J = 7 Hz, Ha' or Hd'), 8.12 (2H, d, J = 7Hz, Hβ), 8.30 (1H, s, H-triazole),
13
10.42 (1H, s, NH), 12.77 (1H, s, NH). C NMR (125 MHz, DMSO-d6): 16.4, 28.6, 56.3, 63.2,
115.4, 116.7, 118.8, 122.4, 122.8, 124.3, 125.3, 126.6, 128.5, 129.4, 132.0, 133.0, 139.7, 141.6,
149.4, 157.8, 166.4. Anal. Calcd for C26H24N6O2: C, 69.01; H, 5.35; N, 18.57. Found: C, 68.89;
H, 5.43; N, 18.71.
4.4.4.
2-(4-((4-(1H-benzo[d]imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-
methoxyphenyl)acetamide 8d
White powder; yield: 83%; mp =170–172 °C. IR (KBr): 3198, 3866, 1708, 1602 cm-1. 1H NMR
(500 MHz, DMSO-d6): 3.74 (3H,s, -OCH3), 5.28 (2H, s, CH2-O), 5.38 (2H, s, CH2), 7.18 (2H, bs,
Hα), 7.25 (2H, d, J = 7.5 Hz, H3, H5), 7.50 (2H, d, J = 8 Hz, H2, H6 ), 7.57 (2H, bs, Ha', Hd'),
8.13 (2H, d, J = 7.5Hz, Hβ), 8.30 (1H, s, H-triazole), 10.87 (1H, s, NH), 10.64 (1H, s, NH). 13C
17

NMR (125 MHz, DMSO-d6): 55.2, 56.2, 65.4, 111.4, 116.3, 118.7, 120.7, 122.6, 125.8, 126.3,
126.6, 127.6, 128.2, 128.8, 129.3, 129.6, 134.3, 139.9, 141.8, 150.9, 157.0, 158.5, 164.8. Anal.
Calcd for C25H22N6O3: C, 66.07; H, 4.88; N, 18.49. Found: C, 66.16; H, 4.72; N, 18.63.
4.4.5.
2-(4-((4-(1H-benzo[d]imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-
chlorophenyl)acetamide 8e
Pale yellow powder; yield: 72%; mp =190–192 °C. IR (KBr): 3392, 3566, 1708, 1602 cm-1. 1H
NMR (500 MHz, DMSO-d6): 5.28 (2H, s, CH2-O), 5.48 (2H, s, CH2-), 7.18 (3H, m, Hα, H6), 7.23
(3H, m, Hb', Hc', H4 ), 7.35 (1H, dd, J = 8, 6 Hz, H5 ), 7.53 (2H, d, J = 8 Hz, Ha', Hd'), 7.74 (1H,
d, J = 8.5 Hz, H6), 8.12 (2H, d, J = 9Hz, Hβ ), 8.31(1H, s, H-triazole), 10.11 (1H, s, NH), 12.73
(1H, s, NH). 13C NMR (125 MHz, DMSO-d6): 56.3, 65.9, 111.6, 112.6, 117.1, 119.2, 122.9, 126.6,
127.1, 128.9, 129.5, 129.9, 132.2, 135.4, 135.8, 139.1, 143.1, 149.7, 157.4, 165.5. Anal. Calcd for
C24H19ClN6O2: C, 62.81; H, 4.17; N, 18.31. Found: C, 62.98; H, 4.23; N, 18.52.
4.4.6.
2-(4-((4-(1H-benzo[d]imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2,3-
dichlorophenyl)acetamide 8f
White powder; yield: 75%; mp =150–152 °C. IR (KBr): 3776, 1701, 1630 cm-1. 1H NMR (500
MHz, DMSO-d6): 5.29 (2H, s, CH2-O), 5.50 (2H, s,CH2), 7.18 (2H, m, Hα), 7.25 (2H, d, J = 8 Hz,
Hb', Hc',), 7.38 (1H, dd, J = 8.5, 8 Hz, H3), 7.50 (1H, d, J = 7.5 Hz, H4), 7.56 (2H, m, Ha', Hd' ),
7.74 (1H, d, J = 8 Hz, H2), 8.13 (2H, d, J = 8.5 Hz, Hβ ), 8.31 (1H, s, H-triazole), 10.27 (1H, s,
NH), 12.69 (1H, s, NH). 13C NMR (125 MHz, DMSO-d6): 55.6, 64.9, 111.4, 116.8, 118.8, 121.5,
122.3, 123.3, 124.6, 126.5, 126.6, 128.1, 128.6, 129.0, 129.4, 131.5, 132.0, 133.2, 139.7, 142.5,
149.5, 157.2, 164.2. Anal. Calcd for C24H18Cl2N6O2: C, 58.43; H, 3.68; N, 17.03. Found: C, 58.32;
H, 3.51; N, 17.11.
18

4.4.7.
2-(4-((4-(1H-benzo[d]imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2,6-
dichlorophenyl)acetamide 8g
1
Cream powder; yield: 74%; mp =199–201 °C. IR (KBr): 3744, 1680 cm-1. H NMR (500 MHz,
DMSO-d6): 5.28 (2H, s, CH2-O), 5.41 (2H, s, CH2), 7.17 (2H, m, Hα), 7.24 (2H, d, J = 8.5 Hz,
Hb', Hc'), 7.34 (1H, m, H4 ), 7.57 (2H, m, H3, H5), 7.64 (2H, m, Ha', Hd' ), 8.13 (2H, d, J = 8.5
Hz, Hβ), 8.31 (1H, s, H-triazole), 10.86 (1H, s, NH), 12.77 (1H, s, NH). 13C NMR (125 MHz,
DMSO-d6): 58.9, 65.8, 111.3, 116.5, 116.9, 124.0, 126.2, 127.6, 128.4, 128.6, 129.2, 130.9, 133.1,
135.1, 135.2, 135.7, 137.1, 143.2, 151.3, 158.8, 163.4. Anal. Calcd for C24H18Cl2N6O2: C, 58.43;
H, 3.68; N, 17.03. Found: C, 58.54; H, 3.73; N, 16.91.
4.4.8.
2-(4-((4-(1H-benzo[d]imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-
chlorophenyl)acetamide 8h
White powder; yield: 69%; mp =176–178 °C. IR (KBr): 3398, 3766, 1718, 1610 cm-1. 1H NMR
(500 MHz, DMSO-d6): 5.28 (2H, s, CH2-O), 5.38 (2H, s,CH2), 7.19 (2H, m, H α), 7.24 (2H, d, J
= 7 Hz, Hb', Hc'), 7.40 (2H, d, J = 8 Hz, H3, H5 ), 7.56 (2H, m, H2, H6 ), 7.61 (2H, d, J = 7.5 Hz,
Ha', Hd'), 8.13 (2H, d, J = 8 Hz, Hβ), 8.31(1H, s, H-triazole), 9.95 (1H, s, NH), 10.64 (1H, s, NH).
13C NMR (125 MHz, DMSO-d6): 58.5, 64.5, 113.9, 114.9, 115.6, 118.8, 122.4, 125.0, 126.6,
127.2, 128.4, 128.9, 129.4, 131.2, 131.9, 133.0, 137.1, 139.7, 143.0, 149.5, 157.2, 164.8. Anal.
Calcd for C24H19ClN6O2: C, 62.81; H, 4.17; N, 18.31. Found: C, 62.72; H, 4.05; N, 18.22.
4.4.9.
2-(4-((4-(1H-benzo[d]imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(3-
bromophenyl)acetamide 8i
Yellow powder; yield: 74%; mp =182–184 °C. IR (KBr): 3198, 3866, 1708, 1600 cm-1. 1H NMR
(500 MHz, DMSO-d6): 5.28 (2H, s, CH2-O), 5.39 (2H, s,CH2), 7.17 (2H, m, Hα), 7.24 (2H,d, J =
19

7.5 Hz, H5, H6), 7.30 (3H, m, Hb', Hc'), 7.49 (2H, m, H4, Ha' or Hd'), 7.62 (1H, d, J = 7 Hz, Ha'
or Hd'),7.93 (1H, s, H2), 8.12 (2H, d, J = 8.5 Hz, Hβ), 8.3 (1H, s, H-triazole), 10.68 (1H, s, NH),
12.73 (1H, s, NH). 13C NMR (125 MHz, DMSO-d6): 56.1, 65.5, 111.4, 116.3, 116.7, 118.7, 122.8,
123.9, 125.2, 126.4, 127.6, 128.0, 128.3, 128.9, 129.4, 130.0, 130.8, 134.2, 139.8, 141.7, 150.4,
166.3. Anal. Calcd for C24H19BrN6O2: C, 57.27; H, 3.80; N, 16.70. Found: C, 57.15; H, 3.68; N,
16.84.
4.4.10.
2-(4-((4-(1H-benzo[d]imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-
bromophenyl)acetamide 8j
White powder; yield: 75%; mp =194–196 °C. IR (KBr): 3760, 3292, 1717, 1560 cm-1. 1H NMR
(500 MHz, DMSO-d6): 5.28 (2H, s, CH2-O), 5.38 (2H, s,CH2), 7.17 (2H, m, Hα), 7.24 (2H, d, J =
8.5 Hz, Hb', Hc' ), 7.52-7.57 (6H, m, H2, H3, H5, H6, Ha', Hd'), 8.12 (2H, d, J = 8Hz, Hβ), 8.33
(1H, s, H-triazole), 10.61(1H, s, NH), 12.78 (1H, s, NH). 13C NMR (125 MHz, DMSO-d6): 55.5,
64.6, 111.3, 116.9, 118.8, 121.6, 123.2, 124.6, 126.3, 127.5, 128.2, 128.3, 129.0, 129.4, 134.4,
139.9, 142.5, 150.7, 156.2, 166.6. Anal. Calcd for C24H19BrN6O2: C, 57.27; H, 3.80; N, 16.70.
Found: C, 57.33; H, 3.96; N, 16.57.
4.4.11.
2-(4-((4-(1H-benzo[d]imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-
nitrophenyl)acetamide 8k
Pale yellow powder; yield: 88%; mp =187–189 °C. IR (KBr): 3766, 1704, 1562 cm-1. 1H NMR
(500 MHz, DMSO-d6): 5.28 (2H, s, CH2-O), 5.476 (2H, s,CH2), 7.17 (2H, m, Hα ), 7.23 (2H, d, J
= 9 Hz, Hb', Hc' ), 7.33 (2H, dd, J = 9, 7.5 Hz, H4, H5), 7.50 (1H, m, Ha' or Hd'), 7.69 (1H, d, J =
7.5 Hz, Ha' or Hd' ), 7.75 (1H, dd, J = 7.5, 6 Hz, H3), 8.00 (1H, d, J = 8 Hz, H6), 8.12 (2H, d, J =
8 Hz, Hβ), 8.28 (1H, s, H-triazole), 10.78 (1H, s, NH), 12.76 (1H, s, NH). 13C NMR (125 MHz,
20

DMSO-d6): 55.8, 64.1, 111.3, 113.4, 116.8, 116.9, 118.7, 122.3, 123.6, 124.2, 126.5, 128.2,
129.01, 132.0, 132.2, 133.2, 139.7, 142.3, 149.4, 158.3, 165.5. Anal. Calcd for C24H19N7O4: C,
61.40; H, 4.08; N, 20.89. Found: C, 61.57; H, 4.17; N, 20.78.
4.4.12.
2-(4-((4-(1H-benzo[d]imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-
nitrophenyl)acetamide 8l
Yellow powder; yield: 90%; mp =156–158 °C. IR (KBr): 3746, 1702 cm-1. 1H NMR (500 MHz,
DMSO-d6): 5.29 (2H, s, CH2-O), 5.47 (2H, s, CH2), 7.18 (2H, bs, Hα), 7.25 (2H, d, J = 8.5 Hz,
Hb', Hc'), 7.57 (2H, m, Ha', Hd'), 7.83 (2H, d, J = 8.5 Hz, H2, H6), 8.13 (2H, d, J = 8 Hz, Hβ),
8.26 (2H, d, J = 9 Hz, H3, H5), 8.33 (1H, s, H-triazole), 11.1 (1H, s, NH), 12.80 (1H, s, NH). 13C
NMR (125 MHz, DMSO-d6): 55.6, 65.4, 111.3, 116.5, 116.7, 118.7, 123.6, 124.1, 124.4, 126.3,
127.5, 128.2, 129.0, 129.3, 134.4, 139.8, 142.2, 150.6, 157.3, 164.7. Anal. Calcd for C24H19N7O4:
C, 61.40; H, 4.08; N, 20.89. Found: C, 61.29; H, 3.94; N, 20.97.
4.4.13.
2-(4-((4-(1H-benzo[d]imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-
benzylacetamide 8m
Cream powder; yield: 83%; mp =155–158 °C. IR (KBr): 3396, 3566, 1700, 1607 cm-1. 1H NMR
(500 MHz, DMSO-d6): 4.32 (2H, s, CH2), 5.20 (2H, s, CH2-O), 5.25 (2H, s, CH2-), 7.16 (2H, m,
Hα), 7.22 (2H, d, J = 8 Hz, H2, H6 ), 7.26-7.29 (3H, m, Hb', Hc',H4 ), 7.33 (2H, m, H3, H5), 7.48
(1H, bs, Ha' or Hd' ), 7.61 (1H, bs, Ha' or Hd' ), 8.11 (2H, d, J = 8 Hz, Hβ), 8.25 (1H, s, H-triazole),
8.89 (1H, s, NH), 12.7 (1H, s, NH), 10.64 (1H, s, NH). 13C NMR (125 MHz, DMSO-d6): 400, 56.3,
65.5, 111.6, 115.9, 118.8, 120.7, 122.2, 122.9, 125.9, 126.5, 126.7, 128.4, 129.1, 129.3, 131.8,
21

133.0, 139.8, 142.1, 149.4, 157.7, 165.0. Anal. Calcd for C25H22N6O2: C, 68.48; H, 5.06; N, 19.17.
Found: C, 68.56; H, 5.17; N, 19.31.
4.4.14.
2-(4-((4-(1H-benzo[d]imidazol-2-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-
fluorobenzyl)acetamide 8n
White powder; yield: 74%; mp =175–177 °C. IR (KBr): 3700, 1703, 1562 cm-1. 1H NMR (500
MHz, DMSO-d6): 4.32 (2H,s, CH2), 5.20 (2H, s, CH2-O), 5.26 (2H, s, CH2), 7.15-7.18 (4H, m, H
α, H3, H4), 7.23 (2H, d, J = 8 Hz, Hb', Hc') 7.32-7.34 (2H, m, H2, H6), 7.49 (1H, d, J = 6.5 Hz ,
Ha' or Hd'), 7.62 (1H, d, J = 8.5 Hz, Ha' or Hd' ), 8.12 (2H, d, J = 8 Hz, Hβ),8.25 (1H, s, triazole),
8.85 (1H, s, H-triazole), 12.75 (1H, s, NH). 13C NMR (125 MHz, DMSO-d6): 42.0, 52.1, 61.4,
1111.4, 113.4, 115.4, 115.5, 115.6, 118.9, 121.8, 122.5, 123.4, 126.6, 128.4, 129.8, 129.9, 135.1,
135.3, 142.4, 144.3, 151.6, 159.8, 160.5, 162.5, 165.8. Anal. Calcd for C25H21FN6O2: C, 65.78; H,
4.64; N, 18.41. Found: C, 65.66; H, 4.51; N, 18.62.
4.5. α-Glucosidase inhibition assay
The anti-α-glucosidase effects of benzimidazole-1,2,3-triazoles 8a-n were screened according to the
previously reported method [12]. Firstly, 135 µL of potassium phosphate buffer, 20 µL of target compounds
8a-n with various concentrations, and 20 µL of α-glucosidase solution were added and incubated in the 96-
well microtiter plate for 10 min at 37 °C. Then, p-nitrophenyl glucopyranoside as substrate (25 µL, 4 mM)
was added to the incubated mixture and incubation was continued at 37 °C for 20 min. Finally, absorbance
was measured at 405 nm by spectrophotometer (Gen5, Power wave xs2, BioTek, USA), and IC50 values of
target compounds were calculated using the nonlinear regression curve (logit method).
4.6. Kinetics of enzyme inhibition
22

A kinetic analysis was conducted to determine the type of inhibition of the most potent compound
8c. To this end, 20 μL of the α-glucosidase solution (1 U/mL) was incubated with concentrations
0, 11, 18, and 25 μM of inhibitor 8c for 10 min at 37 °C. After that, the enzymatic reaction was
initiated by adding concentrations 1–4 mM of the substrate. Changes in absorbance were measured
at 405 nm for 20 min on a microtiter plate reader (Gen5, Power wave xs2, BioTek, USA).
4.7. Docking study
The docking study of the selected compounds 8b-c, 8k-l, 8a and 8m, and 8e-f in the active site of
modeled α-glucosidase was performed by AutoDock Tools, according to previously described
method [14]. For this propose, modeled α-glucosidase was constructed based on SWISS-MODEL.
After that, the PDBQT coordinate of the modeled α-glucosidase, acarbose, and the selected
compounds (as input files for the AutoGrid program) were produced using the AutoDock Tools.
In AutoGrid program for each atom type of the inhibitors, maps were determined with 0.375 Å
spacing between grid box with center box: x = 12.5825, y = 7.8955, z = 12.519 and the dimensions:
40 × 40 × 40 Å. Flexible ligand dockings for the each of selected inhibitor were accomplished.
Each docked system was carried out by 50 runs, and the best pose of each inhibitor was selected
for analyzing the interactions in the active site. The obtained results were visualized using
Discovery Studio 4.0 Client.
4.8. In vitro α-amylase inhibition assay
The anti-α-amylase activity of the compounds 8c, 8k, and 8a was determined based on the
colorimetric method, according to described method by Taha et al. [16].
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Dear Editor
There is no conflict of interest in this research article
Graphical abstract
Synthesis and biological evaluation of new benzimidazole-1,2,3-triazole hybrids as potential
α-glucosidase inhibitors
Nafise Asemanipoor, Maryam Mohammadi-Khanaposhtani, Shahram Moradi, Mahbobeh
Vahidi, Mehdi Asadi, Mohammad Ali Faramarzi, Mohammad Mahdavi,*, Hossein Adibi,
Hossein Rastegar, Mahmood Biglar, Bagher Larijani, Haleh Hamedifar, Mir Hamed Hajimiri,*
a)
20
Concentration of 8c
15
10
5
0 µM
11 µM
18 µM
25 µM
0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1/[S](PNPG, mM-1
)
-5
-10
-15
Kinetic study
H
N
N
N
N
O
N
H
N
N
N
O
O
α-glucosidase
N
R
N
H
n
N
O
H
N
inhibition
Compound 8c
Designed hybrids 8a-n
Docking study
27

A novel series of benzimidazole-1,2,3-triazole hybrids 8a-n was were synthesized by click
chemistry and evaluated as potent α-glucosidase inhibitors. All the synthesized compounds
showed anti-α-glucosidase activity more than standard inhibitor acarbose.
Highlights

A novel series of benzimidazole-1,2,3-triazole-acetamide hybrids 8a-n was synthesized and evaluated as
potent α-glucosidase inhibitors.




These compounds were synthesized by click reaction.
All the title compounds showed α-glucosidase inhibition superior to standard drug acarbose.
Compound 8c with N-4-ethylphenylacetamide was the most active compound (IC50 = 25.2 ± 0.9).
This compound was a competitive inhibitor against α-glucosidase (Ki = 23 μM).
28