Design and synthesis of 4,5-diphenyl-imidazol-1,2,3-triazole hybrids as new anti-diabetic agents: in vitro α-glucosidase inhibition, kinetic and docking studies

Article abstract of DOI:10.1007/s11030-020-10072-8

Abstract: Fourteen novel 4,5-diphenyl-imidazol-1,2,3-triazole hybrids 8a–n were synthesized with good yields by performing click reaction between the 4,5-diphenyl-2-(prop-2-yn-1-ylthio)-1H-imidazole and various benzyl azides. The synthesized compounds 8a–n were evaluated against yeast α-glucosidase, and all these compounds exhibited excellent inhibitory activity (IC₅₀ values in the range of 85.6 ± 0.4–231.4 ± 1.0?μM), even much more potent than standard drug acarbose (IC₅₀ = 750.0?μM). Among them, 4,5-diphenyl-imidazol-1,2,3-triazoles possessing 2-chloro and 2-bromo-benzyl moieties (compounds 8g and 8i) demonstrated the most potent inhibitory activities toward α-glucosidase. The kinetic study of the compound 8g revealed that this compound inhibited α-glucosidase in a competitive mode. Furthermore, docking calculations of these compounds were performed to predict the interaction mode of the synthesized compounds in the active site of α-glucosidase. Graphic abstract: A novel series of 4,5-diphenyl-imidazol-1,2,3-triazole hybrids 8a–n was synthesized with goodyields by performing click reaction between the 4,5-diphenyl-2-(prop-2-yn-1-ylthio)-1Himidazoleand various benzyl azides. The synthesized compounds 8a–n were evaluated againstyeast α-glucosidase and all these compounds exhibited excellent inhibitory activity (IC50 valuesin the range of 85.6 ± 0.4-231.4 ± 1.0 μM), even much more potent than standard drug acarbose(IC50 = 750.0 μM).[Figure not available: see fulltext.]

Full text of DOI:10.1007/s11030-020-10072-8

Molecular Diversity
https://doi.org/10.1007/s11030-020-10072-8
ORIGINAL ARTICLE
Design and synthesis of 4,5‑diphenyl‑imidazol‑1,2,3‑triazole hybrids
as new anti‑diabetic agents: in vitro α‑glucosidase inhibition, kinetic
and docking studies
Mohammad Sadegh Asgari1 · Maryam Mohammadi‑Khanaposhtani2 · Zeinab Sharaf3 · Mohammad Ali Faramarzi4 ·
Hossein Rastegar5 · Ensieh Nasli Esfahani6 · Fatemeh Bandarian6 · Parviz Ranjbar Rashidi1 · Rahmatollah Rahimi7 ·
Mahmood Biglar8 · Mohammad Mahdavi8 · Bagher Larijani8
Received: 24 April 2019 / Accepted: 9 March 2020
© Springer Nature Switzerland AG 2020
Abstract
Fourteen novel 4,5-diphenyl-imidazol-1,2,3-triazole hybrids 8a–n were synthesized with good yields by performing click
reaction between the 4,5-diphenyl-2-(prop-2-yn-1-ylthio)-1H-imidazole and various benzyl azides. The synthesized com-
pounds 8a–n were evaluated against yeast α-glucosidase, and all these compounds exhibited excellent inhibitory activity (IC50
values in the range of 85.6 0.4–231.4 1.0 μM), even much more potent than standard drug acarbose (IC50 =750.0 μM).
Among them, 4,5-diphenyl-imidazol-1,2,3-triazoles possessing 2-chloro and 2-bromo-benzyl moieties (compounds 8g and
8i) demonstrated the most potent inhibitory activities toward α-glucosidase. The kinetic study of the compound 8g revealed
that this compound inhibited α-glucosidase in a competitive mode. Furthermore, docking calculations of these compounds
were performed to predict the interaction mode of the synthesized compounds in the active site of α-glucosidase.
Graphic abstract
A novel series of 4,5-diphenyl-imidazol-1,2,3-triazole hybrids 8a–n was synthesized with goodyields by performing click
reaction between the 4,5-diphenyl-2-(prop-2-yn-1-ylthio)-1Himidazoleand various benzyl azides. The synthesized compounds
Mohammad Sadegh Asgari and Maryam Mohammadi-
Khanaposhtani contributed equally to this work.
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11030-020-10072-8) contains
supplementary material, which is available to authorized users.
5
* Mohammad Mahdavi
Food and Drug Research Institute, Food and Drug
Administration, MOHE, Tehran, Iran
Mahdavi_chem@yahoo.com
6
* Bagher Larijani
Diabetes Research Center, Endocrinology and Metabolism
Clinical Sciences Institute, University of Medical Sciences,
Tehran, Iran
emrc@tums.ac.ir
1
School of Chemistry, College of Science, University
7
8
Department of Chemistry, Iran University of Science
and Technology, Tehran, Iran
of Tehran, Tehran, Iran
2
Cellular and Molecular Biology Research Center, Health
Endocrinology and Metabolism Research Center,
Endocrinology and Metabolism Clinical Sciences Institute,
Tehran University of Medical Sciences, Tehran, Iran
Research Institute, Babol University of Medical Sciences,
Babol, Iran
3
Razi Herbal Medicines Research Center, Lorestan University
of Medical Sciences, Khorramabad, Iran
4
Department of Pharmaceutical Biotechnology, Faculty
of Pharmacy and Biotechnology Research Center, Tehran
University of Medical Sciences, Tehran, Iran
Vol.:(0123456789)
1 3

Molecular Diversity
8a–n were evaluated againstyeast α-glucosidase and all these compounds exhibited excellent inhibitory activity (IC50 val-
uesin the range of 85.6 0.4-231.4 1.0 μM), even much more potent than standard drug acarbose(IC50=750.0 μM).
Keywords Anti-diabetic agents · Kinetic study · α-Glucosidase · Molecular docking · 4,5-Diphenyl-imidazol,1,2,3-triazole
1,2,3-Triazole ring has a undeniable importance in
medicinal chemistry due to having unique features such as
metabolic stability, high dipole moment, and capability to
form hydrogen bonds [8, 9]. The construction of this ring by
click chemistry as an efcient method has led to increasing
the development of biological active compounds contain-
ing 1,2,3-triazole ring [10]. The antibacterial, anticancer,
antifungal, antitubercular, anti-acetylcholinesterase, and
anti-HIV activities of 1,2,3-triazole derivatives have been
well documented [10–16]. Furthermore, several hybrid
scafolds containing 1,2,3-triazole ring with high inhibitory
activity against α-glucosidase have been reported (Fig. 1a,
b) [17, 18]. In this regard, recently, we reported the synthe-
sis and α-glucosidase inhibitory activity of 1,2,3-triazole-
quinazolinone hybrids C (Fig. 1) [19]. On the other hand,
several derivatives of imidazole with excellent α-glucosidase
Introduction
α-Glucosidase (EC 3.2.1.20) is a carbohydrate-hydrolyz-
ing enzyme that catalytic activity of it resulted in cleavage
of poly- and disaccharides to glucose. Therefore, inhibi-
tion of this enzyme decreases postprandial blood glucose
level. Several efective glucosidic-based α-glucosidase
inhibitors such as acarbose [1], voglibose [2], miglitol [3],
and nojirimycin, [4] are clinically used for the treatment
of type 2 diabetes. These agents sufer from side efects
such as fatulence, meteorism, abdominal distension, and
diarrhea [5]. Recently, the design and development of non-
glucosidic-based α-glucosidase inhibitors have received
attention in order to achieve more effective and safer
α-glucosidase inhibitors [6, 7].
1 3

Molecular Diversity
Fig. 1 Several potent α-glucosidase inhibitors containing 1,2,3-triazole (a–c) or imidazole (e–d) and designed derivatives 8a–n as new
α-glucosidase inhibitors
inhibitory activity have been reported (Fig. 1) [20]. For
example, 2,4,5-triarylimidazoles D and 2,4,5-triarylimida-
zole-1,2,3-triazole hybrids E are potent inhibitors against
α-glucosidase (Fig. 1) [21]. Based on the mentioned points
and in continuation of our interest in the synthesis of new
α-glucosidase inhibitors, herein, we reported the design of
a novel series of 4,5-diarylimidazole-1,2,3-triazole hybrids
8a–n [22–24]. These compounds were synthesized by click
reaction and evaluated against α-glucosidase. Furthermore,
kinetic and docking studies were also performed to under-
stand the inhibition modes of these compounds against
α-glucosidase.
azide reacted in the presence of Et3N in the mixture of
H2O/t-BuOH at room temperature for 1 h. Finally, mix-
ture of 4,5-diphenyl-2-(prop-2-yn-1-ylthio)-1H-imidazole
5, CuSO4, and sodium ascorbate was added to the freshly
prepared azide derivatives 7 and the reaction was contin-
ued at room temperature for 24 h to give the corresponding
compounds 8a–n.
Biological study
In vitro α‑glucosidase inhibitory activity
The synthesized compounds 8a–n were screened for their
in vitro inhibitory activities against α-glucosidase in com-
parison with the standard inhibitor acarbose. The obtained
results were expressed as mean S.E. of three independ-
ent experiments. The IC50 values of the target compounds
demonstrated that all the synthesized compounds showed
signifcant inhibition against α-glucosidase at concentra-
tions less than 231.4 1.0 µM, while acarbose showed
IC50 =750.0 1.5.
Results and discussion
Chemistry
The synthetic route for the synthesis of 4,5-diphenyl-imida-
zol-1,2,3-triazole hybrids 8a–n is depicted in Scheme 1. It
was started from the reaction between 2-hydroxy-1,2-diphe-
nylethanone 1 and thiourea 2 in DMF at 100 °C for 3 h to
give 4,5-diphenyl-1H-imidazole-2-thiol 3. The latter com-
pound reacted with propargyl bromide 4 in the presence
of potassium carbonate in acetone at 0–10 °C for 5 min to
give 4,5-diphenyl-2-(prop-2-yn-1-ylthio)-1H-imidazole 5.
On the other hand, diferent benzyl halides 6 and sodium
In order to obtain an optimized α-glucosidase inhibi-
tor, the substituent was altered on the pendant phenyl moi-
ety. The most active compounds were 2-chloro, 2-bromo,
2-fuoro, 2-methyl derivatives (the compounds 8g, 8i, 8d,
and 8b, respectively) with IC50 values≤95.2 0.4 µM.
1 3

Molecular Diversity
Scheme 1 Synthesis of
4,5-diphenyl-imidazol-1,2,3-
triazole hybrids 8a–n
The IC50 value of the un-substituted compound 8a was
173.4 0.7. The introduction of methyl, fuoro, chloro, and
bromo substituents on the 2-position of the pendant phe-
nyl group led to around twofold increase in the inhibitory
activity, as observed in the compounds 8b, 8d, 8g, and 8i.
Movement of the mentioned substituents to the 3 or 4-posi-
tion on the pendant phenyl group, as in the compounds 8e,
8f, 8h, 8j, and 8k, led to a decrease in the inhibitory activity
in comparison with their 2-substituted regioisomers. Inter-
estingly, the inhibitory activities of the 3-substituted com-
pound 8c with the electron-donating group (methoxy) and
8m with the electron-withdrawing group (nitro) were more
than those of the un-substituted compound 8a. On the other
hand, the weakest compounds among the synthesized com-
pounds were 2-nitro and 4-nitro derivatives 8l and 8n. From
the obtained results, it can be ascertained that the type and
position of the substituents in the pendant phenyl group play
a signifcant role in the inhibitory activity of the synthesized
compounds.
Kinetic study
The kinetic study of the most active compound 8g against
α-glucosidase was performed in order to determine the
inhibition mode of the synthesized compounds. As can be
observed in Fig. 2a, the Lineweaver–Burk plot showed that
(a)
(b)
Fig. 2 Kinetic study of compound 8g against α-glucosidase. a The Lineweaver–Burk plot in the absence and presence of diferent concentrations
of compound 8g; b the secondary plot between Km and various concentrations of compound 8g
1 3

Molecular Diversity
with increase in the concentration of the compound 8g, the
Km gradually increased, while Vmax remained unchanged.
This fnding demonstrated that the compound 8g was a
competitive inhibitor to α-glucosidase. The Ki value of this
compound was calculated as 85 μM through the secondary
re-plot of the obtained Lineweaver–Burk plots (Fig. 2b).
acarbose interacted with Thr307 via a hydrogen bond and an
unfavorable interaction while compound 8g interacted with
this amino acid via a hydrogen bond, (2) acarbose interacted
with His279 via a hydrophobic interaction while compound
8g interacted with this amino acid via a π-cation interac-
tion, (3) acarbose interacted with Glu304 via a hydrogen
bond, while compound 8g interacted with this amino acid
via a π-anion interaction, and (4) acarbose formed a hydro-
gen bond and an unfavorable interaction with Arg312, while
compound 8g, in addition to forming a hydrogen bond, cre-
ates three interactions with this amino acid. Further studies
on binding energies of acarbose and compound 8g revealed
that compound 8g has a lower binding energy (−9.74 kcal/
mol) than acarbose (− 4.04 kcal/mol) and therefore binds
easily to α-glucosidase than does acarbose.
Molecular modeling study
To clarify the interaction mode of the synthesized com-
pounds in the active site of α-glucosidase and explain the
diferent activities of these compounds, molecular mod-
eling studies were conducted using Auto Dock Tools (ver-
sion 1.5.6) on the modeled α-glucosidase [25]. Acarbose as
a standard inhibitor and compounds 8d–e, and 8g–i were
docked in the modeled α-glucosidase. The superposed struc-
ture of acarbose and the most potent compound 8g in the
active site of enzyme is shown in Fig. 3. Molecular modeling
of the standard inhibitor acarbose predicted that this drug
interacted with Asn241, His279, Thr301, Glu304, Thr307,
Ser308, Pro309, Arg312, and Gln322 residues (Fig. 4) [25].
The 2-chloro substituent of the most active compound
8g formed hydrophobic interactions with Phe311, Tyr313,
and Arg312 (Fig. 4). The latter residue also created a hydro-
phobic interaction with pendant phenyl ring, an interaction
with sulfur atom, and two interaction with 1,2,3-triazol
ring (a hydrogen bond and a hydrophobic interaction). In
addition, 1,2,3-triazol also interacted with His239 through
a π–π interaction and a π-cation interaction. Imidazole moi-
ety formed a hydrogen bond with Thr307 and a π-anion
with Glu304. Moreover, one of the phenyl rings attached
to imidazole moiety interacted with residue His279 via a
π-cation interaction. Comparison of interaction modes of
acarbose and compound 8g in the active site showed that
both compounds interacted with four amino acids Thr307,
Arg312, His279, and Glu304. However, there are diferences
in the interactions of these compounds with active site: (1)
Movement of the chloro substituent into 4-position, as
in the compound 8h, caused a signifcant decrease in the
potency and number of interactions with the active site in
comparison with the 2-substituted compound 8g. In this
regard, as can be observed in Fig. 4, the compound 8h inter-
acted with two important residues (Arg312 and Glu304),
while the compound 8g interacted with four important resi-
dues (His279, Glu304, Thr307, and Arg312). The detailed
binding mode of the compound 8h showed that 4-chloro
substituent and phenyl ring of the benzyl moiety formed
a hydrophobic interaction with Asp408 and a hydrophobic
interaction with Arg312, respectively. 1,2,3-triazole ring of
this compound created a hydrogen bond and a hydrophobic
interaction with Arg312 and a weak hydrophobic interaction
with Pro309. The latter amino acid established two weak
hydrophobic interactions with 5-phenyl and imidazole rings.
Moreover, the imidazole ring of compound 8h interacted
with Glu304 via a π-anion (Fig. 4). The values of the bind-
ing energies of the compounds 8g and 8h were −9.74 and
−9.19, respectively. This fnding showed that the compound
8g was more stable than the compound 8h inside the active
site.
As can be observed in Table 1, the 2-chloro substituted
compound 8g and 2-bromo substituted compound 8i showed
approximately same inhibitory activity against AChE.
2-Bromo substituent and imidazole moiety of the compound
8i, like the compound 8g, interacted with Arg312, Phe311,
Tyr313, Thr307, and Glu304 (Fig. 4). The 1,2,3-triazole ring
of the compound 8i interacted with Arg312 and His239,
while this moiety in the compound 8i only interacted
with His239. In addition, the sulfur atom and phenyl ring
attached to the imidazole ring in the compound 8i, unlike
the compound 8g, could not interact with the active site. It
is worthy to note that the binding energy of the compound
8i (-10.12 kcal/mol) was better than that of the compound
8g (−9.74 kcal/mol).
The interaction mode of the third most potent compound
8d showed that the pendant 2-fuoro phenyl ring of this
Fig. 3 Acarbose (cyan) and most potent compound 8g (pink) super-
imposed in the active site pocket
1 3

Molecular Diversity
Fig. 4 Interactions of the standard inhibitor acarbose and compounds 8g, 8h, and 8i in the active site amino acid residues of the modeled
α-glucosidase
compound formed a π-anion interaction with Asp408 and a
hydrophobic interaction with Arg312 (Fig. 5). Interactions
of the 1,2,3-triazole and imidazole rings of the compound
8d were similar to those of the compound 8i. Changing the
position of the fuorine atom on the pendant phenyl ring
from 2-position to 3-position led to a slight decrease in the
inhibitory activity and minor changes in interaction mode
(Table 1 and Fig. 5). The pendant 3-fuorophenyl ring of the
compound 8e, unlike the compound 8d, could not interact
with the active site. Interactions of the imidazole ring of the
compound 8e were similar to those of the compound 8d.
1,2,3-Triazole ring of compound 8e only formed a π-cation
interaction with His239. The values for the binding energies
of the compounds 8d and 8e were −9.49 and −9.43 kcal/
mol, respectively.
ADME and toxicity studies
ADME/T properties of the most potent compounds 8b, 8d,
8g, and 8i were calculated using PreADMET as an online
software, and the results are presented in Table 2 [26].
As can be seen in this Table, the most potent compounds
have good Caco-2 cell permeability, human oral absorp-
tion (HIA), and skin permeability. On the other hand, blood
1 3

Molecular Diversity
Table 1 In vitro α-glucosidase inhibitory activities of compounds
8a–n
Conclusion
We synthesized a new series of 4,5-diphenyl-imidazol-1,2,3-
triazole hybrids 8a–n in good yields with the use of the click
reaction by coupling an 4,5-diphenyl–1H-imidazole con-
taining a terminal alkyne with various benzyl azides. These
molecules were screened in vitro for their α-glucosidase
inhibition. In general, the synthesized compounds showed
excellent α-glucosidase inhibitory activities in comparison
with acarbose as the standard drug. Among the synthesized
compounds, the 2-chloro and 2-bromo derivatives 8g and 8i
showed the highest α-glucosidase inhibitory activity. The
compound 8g could inhibit α-glucosidase in a competitive
mode. The docking study of these compounds confrmed
that they were well ftted in the active site of α-glucosidase.
Compound
R
IC50 (µM) Compound
R
IC50 (µM)
8a
H
2-CH3
3-OCH3 121.0 0.4 8j
2-F
3-F
4-F
2-Cl
–
173.4 0.7 8h
95.2 0.4 8i
4-Cl
2-Br
3-Br
4-Br
159.8 0.9
88.0 0.5
168.1 0.7
128.1 0.9
8b
8c
8d
93.3 0.6 8k
103.3 0.9 8l
125.2 1.3 8m
85.6 0.4 8n
750.0 1.5 Acarbose
8e
2-NO2 213.8 1.1
3-NO2 136.9 1.0
4-NO2 231.4 1.0
8f
Experimental
8g
Acarbose
–
750.0 1.5
Chemistry
brain permeability (BBB) of these compounds was not in the
acceptable range. Predicting the toxicity of the most potent
compounds 8b, 8d, 8g, and 8i by PreADMET Toxicity
server demonstrated that these compounds were non-muta-
genic (Ames_test) and medium cardiotoxic (hERG_inhibi-
tion). All test compounds, with the exception of compound
8i which may have a carcinogenic efect in rat, carcinogenic
efect had not on mouse and rat.
The melting points of 4,5-diphenyl-imidazol-1,2,3-triazole
hybrids 8a–n were determined on a Kofer hot-stage appa-
ratus. The 1H and 13C NMR spectra of the title compounds
were determined on a Bruker FT-500 using TMS as an inter-
nal standard. The IR spectra were recoded using KBr disks
on a Nicolet Magna FTIR 550 spectrophotometer. Elemental
analysis was carried out with an Elementar Analysen system
GmbH VarioEL CHN mode.
Fig. 5 Interaction modes of compounds 8d and 8e with the active site residues of modeled α-glucosidase
1 3

Molecular Diversity
Table 2 ADME/T profle of the
most potent compounds 8b, 8d,
8g, and 8i
ADME/T propertiesa
Compound
8b
8d
8g
8i
Caco2
HIA
BBB
36.2378
96.022248
2.9484
52.9295
95.942170
2.41331
56.1878
96.265681
3.53386
53.5177
96.410695
3.75894
Skin_Permeability
Ames_test
hERG_inhibition
Carcino_Mouse
Carcino_Rat
−2.14579
Non-mutagen
Medium risk
Negative
−2.42795
Non-mutagen
Medium risk
Negative
−2.31292
Non-mutagen
Medium risk
Negative
−2.33852
Non-mutagen
Medium risk
Negative
Negative
Negative
Negative
Positive
aThe recommended ranges for Caco2:<25 poor,>500 great, HIA:>80% is high<25% is poor,
BBB=−3.0 to 1.2, and Skin_Permeability=−8.0 to 1.0
General procedure for the preparation of 4,5‑diphe‑
nyl‑1H‑imidazole‑2‑thiol 3
cold water, and purifed by recrystallization in ethanol to
give the corresponding derivatives 8a–n.
A mixture of 2-hydroxy-1,2-diphenylethanone 1 (1 mmol,
0.2 g) and thiourea 2 (1 mmol, 0.07 g) in DMF (15 mL) was
heated at 100 °C for 3 h. Then, the mixture was poured into
ice-cold water and the obtained precipitate was fltered of
and recrystallized in ethanol to obtain 4,5-diphenyl-1H-im-
idazole-2-thiol 3 [27].
1‑Benzyl‑4‑(4,5‑diphenyl‑1H‑imidazol‑2‑ylsulfanylmethyl)
‑1H‑[1,2,3]triazole (8a)
Cream powder; yield: 87% (0.37 g), mp 158–160; IR (KBr,
υ): 3373, 1463, 771 cm−1; 1H NMR (500 MHz, DMSO-d6) δ
12.62 (s, 1H, NH), 8.01 (s, 1H, Triazole), 7.46 (d, J=7.7 Hz,
1H, Ph), 7.43–7.36 (m, 4H, Ph), 7.35–7.32 (m, 2H, Ph),
7.32–7.25 (m, 6H, Ph), 7.23 (s, 1H, Ph), 5.57 (s, 2H, CH2),
4.41 (s, 2H, S-CH2); 13C NMR (125 MHz, DMSO-d6) δ
144.20, 139.61, 137.75, 136.40, 131.12, 129.14, 129.11,
128.62, 128.51, 128.30, 128.24, 128.10, 127.48, 127.02,
123.94, 53.22 (S-CH2), 28.14 (CH2). Anal. Calcd for
C25H21N5S: C, 70.90; H, 5.00; N, 16.54. Found: C, 71.05;
H, 5.16; N, 16.68.
General procedure for the preparation of 4,5‑diphe‑
nyl‑2‑(prop‑2‑yn‑1‑ylthio)‑1H‑imidazole 5
A mixture of 4,5-diphenyl-1H-imidazole-2-thiol 3 (1 mmol,
0.25 g), propargyl bromide 4 (1.2 mmol, 0.15 mL), and
potassium hydroxide (1.2 mmol, 0.06 g) in acetone (10 mL)
was stirred at 0–10 °C for 5 min. After completion of the
reaction (checked by TLC), the reaction mixture was cooled
down to room temperature and poured into cold water. Sub-
sequently, the precipitated product was fltered of to give
pure 4,5-diphenyl-2-(prop-2-yn-1-ylthio)-1H-imidazole 5
[28].
4‑(4,5‑Diphenyl‑1H‑imidazol‑2‑ylsulfanylmethyl)‑1‑(2‑meth
yl‑benzyl)‑1H‑[1,2,3]triazole (8b)
General procedure for the synthesis of 4,5‑diphenyl‑imi‑
dazol‑1,2,3‑triazole hybrids 8a–n
Cream powder; isolated yield: 94% (0.41 g), mp 167–169;
1
IR (KBr, υ): 3375, 1460, 778 cm−1; H NMR (500 MHz,
DMSO-d6) δ 12.65 (s, 1H, NH), 7.85 (s, 1H, Triazole), 7.43
(d, J = 7.6 Hz, 2H, Ph-H), 7.39 (d, J = 7.8 Hz, 1H, H3),
7.38–7.35 (m, 3H, Ph), 7.33 (d, J= 6.7 Hz, 1H, Ph), 7.27
(d, J = 7.5 Hz, 2H, Ph), 7.22 (d, J = 7.3 Hz, 1H, Ph), 7.19
(dd, J=7.3, 1.4 Hz, 1H, H6), 7.15 (d, J=7.3 Hz, 1H, H5),
7.09 (dd, J=7.3, 1.5 Hz, 1H, H4), 7.06–7.01 (m, 1H, H3),
5.56 (s, 2H, CH2), 4.41 (s, 2H, S-CH2), 2.22 (s, 3H, CH3);
13C NMR (125 MHz, DMSO-d6) δ 143.59, 139.04, 137.18,
136.14, 134.65, 133.77, 130.49, 130.24, 128.55, 128.50,
128.16, 128.01, 127.60, 127.50, 126.91, 126.45, 126.05,
123.30, 50.84 (S-CH2), 27.47 (CH2), 18.38 (CH3). Anal.
Calcd for C26H23N5S: C, 71.37; H, 5.30; N, 16.01. Found:
C, 71.51; H, 5.45; N, 16.19.
At frst, benzyl azide derivatives 7 were prepared in situ. For
this purpose, the mixture of benzyl halides 6 (1.1 mmol) and
sodium azide (0.9 mmol) in the presence of Et3N (1.3 mmol)
and the mixture of water/t-BuOH (8 mL, 1:1) was stirred
at room temperature for 1 h [19]. Subsequently, the mix-
ture of 4,5-diphenyl-2-(prop-2-yn-1-ylthio)-1H-imidazole 5
(1 mmol, 0.3 g), CuSO4 .5H2O (7 mol%, 0.3 g), and sodium
ascorbate (15 mol%, 0.13 g) was added to the freshly pre-
pared benzyl azide derivative 7 and stirred at room tempera-
ture for 24-48 h. Upon completion of the reaction (monitored
by TLC), the reaction mixture was poured into crushed ice.
Then, the precipitated product was fltered of, washed with
1 3

Molecular Diversity
4‑(4,5‑Diphenyl‑1H‑imida‑
zol‑2‑ylsulfanylmethyl)‑1‑(3‑methoxy‑benzyl)‑1H‑[1,2,3]
triazole (8c)
(CH2). Anal. Calcd for C25H20FN5S: C, 68.01; H, 4.57; N,
15.86. Found: C, 68.14; H, 4.32; N, 15.78.
4‑(4,5‑Diphenyl‑1H‑imidazol‑2‑ylsulfanylmethyl)‑1‑(4‑fuor
o‑benzyl)‑1H‑[1,2,3]triazole (8f)
Cream powder; isolated yield: 92% (0.42 g), mp 172–174;
1
IR (KBr, υ): 3379, 1466, 762 cm−1; H NMR (500 MHz,
DMSO-d6) δ 12.66 (s, 1H, NH), 8.02 (s, 1H, Triazole),
7.49–7.43 (m, 2H, Ph), 7.41–7.35 (m, 4H, Ph), 7.32–7.25
(m, 3H, Ph), 7.24–7.17 (m, 2H,Ph, H5), 6.90–6.84 (m,
2H, H2,6), 6.80 (s, 1H, H4), 5.54 (s, 2H, CH2), 4.44 (s,
2H, S-CH2), 3.69 (s, 3H, OCH3); 13C NMR (125 MHz,
DMSO-d6) δ 159.40, 143.78, 139.26, 137.36, 134.84,
130.71, 129.91, 129.86, 128.63, 128.17, 127.76, 127.60,
127.06, 126.73, 126.57, 123.50, 119.93, 113.68, 113.45,
55.04 (OCH3), 52.72 (S-CH2), 27.64 (CH2). Anal. Calcd
for C26H23N5S: C, 68.85; H, 5.11; N, 15.44. Found: C,
68.91; H, 5.25; N, 15.59.
Cream powder; isolated yield: 85% (0.37 g), mp 169-171;
1
IR (KBr, υ): 3370, 1466, 769 cm−1; H NMR (500 MHz,
DMSO-d6) δ 12.67 (s, 1H, NH), 7.99 (s, 1H, Triazole), 7.46
(d, J=7.7 Hz, 2H, H3, H5), 7.38 (d, J=5.3 Hz, 4H, Ph), 7.33
(dt, J=8.4, 3.6 Hz, 3H, Ph), 7.27 (d, J=7.5 Hz, 2H, Ph), 7.22
(t, J=7.1 Hz, 1H, Ph), 7.09 (t, J=8.8 Hz, 2H, H2, H6), 5.56 (s,
2H, CH2), 4.43 (s, 2H, S-CH2); 13C NMR (125 MHz, DMSO-
d6) δ 162.83, 160.88, 143.91, 139.21, 137.39, 134.86, 132.18,
130.69, 130.24, 130.18, 128.70, 128.22, 127.81, 127.71,
127.10, 126.66, 123.46, 115.64, 115.47, 52.02 (SCH2), 27.77
(CH2). Anal. Calcd for C25H20FN5S: C, 68.01; H, 4.57; N,
15.86. Found: C, 67.94; H, 4.69; N, 15.94.
4‑(4,5‑Diphenyl‑1H‑imidazol‑2‑ylsulfanylmethyl)‑1‑(2‑fuor
o‑benzyl)‑1H‑[1,2,3]triazole (8d)
1‑(2‑Chloro‑benzyl)‑4‑(4,5‑diphenyl‑1H‑imidazol‑2‑ylsulfan
ylmethyl)‑1H‑[1,2,3]triazole (8g)
Cream powder; isolated yield: 90% (0.40 g), mp 159–161;
Cream powder; isolated yield: 89% (0.41 g), mp 162–164;
IR (KBr, υ): 3365, 1467, 777 cm−1; H NMR (500 MHz,
IR (KBr, υ): 3378, 1462, 779 cm−1; H NMR (500 MHz,
1
1
DMSO-d6) δ 12.67 (s, 1H, NH), 8.02 (s, 1H, Triazole),
7.96 (d, J = 19.9 Hz, 1H, H3), 7.55 (d, J = 7.2 Hz, 1H,
H4), 7.45–7.35 (m, 7H, Ph), 7.30–7.25 (m, 3H, Ph), 7.19
(t, J = 9.6 Hz, 2H, H6), 7.12 (t, J = 7.6 Hz, 1H, H5), 5.61
(s, 2H, CH2), 4.41 (s, 2H, S-CH2); 13C NMR (125 MHz,
DMSO-d6) δ 160.99, 159.03, 148.25, 143.84, 139.26,
137.99, 137.37, 134.73, 130.69, 130.62, 130.60, 130.57,
129.55, 128.70, 128.61, 128.23, 128.12, 127.71, 127.08,
126.59, 124.75, 124.72, 123.55, 122.73, 122.62, 115.61,
115.44, 46.84 (S-CH2), 27.62 (CH2). Anal. Calcd for
C25H20FN5S: C, 68.01; H, 4.57; N, 15.86. Found: C, 68.16;
H, 4.37; N, 15.71.
DMSO-d6) δ 12.66 (s, 1H, NH), 7.97 (s, 1H, Triazole),
7.49–7.15 (m, 14H, Ph, H3, H4, H5, H6), 5.67 (s, 2H, CH2),
4.43 (s, 2H, S-CH2); 13C NMR (125 MHz, DMSO-d6) δ
143.77, 139.15, 137.33, 134.86, 133.16, 132.58, 130.68,
130.39, 130.15, 129.55, 128.62, 128.15, 127.76, 127.62,
127.05, 126.56, 123.81, 50.57 (SCH2), 27.61 (CH2). Anal.
Calcd for C25H20ClN5S: C, 65.56; H, 4.40; N, 15.29. Found:
C, 65.38; H, 4.53; N, 15.12.
1‑(4‑Chloro‑benzyl)‑4‑(4,5‑diphenyl‑1H‑imidazol‑2‑ylsulfan
ylmethyl)‑1H‑[1,2,3]triazole (8h)
Cream powder; isolated yield: 88% (0.40 g), mp 193–195;
1
IR (KBr, υ): 3371, 1462, 776 cm−1; H NMR (500 MHz,
4‑(4,5‑Diphenyl‑1H‑imidazol‑2‑ylsulfanylmethyl)‑1‑(3‑fuor
o‑benzyl)‑1H‑[1,2,3]triazole (8e)
DMSO-d6) δ 12.62 (s, 1H, NH), 7.98 (s, 1H, Triazole),
7.44 (d, J = 7.7 Hz, 2H, H3, H5), 7.41–7.35 (m, 4H, Ph),
7.33–7.20 (m, 8H, Ph, H2, H6), 5.57 (s, 2H, CH2), 4.41
(s, 2H, S-CH2); 13C NMR (125 MHz, DMSO-d6) δ 144.32,
139.52, 137.77, 135.42, 135.29, 133.24, 131.12, 130.20,
130.18, 129.13, 129.13, 128.64, 128.24, 128.13, 128.12,
127.49, 127.07, 127.04, 124.02, 123.98, 52.39 (SCH2),
28.18 (CH2). Anal. Calcd for C25H20ClN5S: C, 65.56; H,
4.40; N, 15.29. Found: C, 65.64; H, 4.27; N, 15.16.
Cream powder; isolated yield: 97% (0.43 g), mp 163–165; IR
(KBr, υ): 3375, 1455, 776 cm−1; 1H NMR (500 MHz, DMSO-
d6) δ 12.66 (s, 1H, NH), 8.06 (s, 1H, Triazole), 7.54–7.45 (m,
2H, Ph), 7.44–7.41 (m, 1H, H5), 7.41–7.35 (m, 3H, Ph), 7.33
(d, J=7.6 Hz, 2H, Ph), 7.30–7.24 (m, 2H, Ph), 7.24–7.20 (m,
1H, Ph), 7.14 (t, J=10.0 Hz, 2H, H2, H6), 7.09 (d, J=8.0 Hz,
1H, H4), 5.59 (s, 2H, CH2), 4.44 (s, 2H, S-CH2); 13C NMR
(125 MHz, DMSO-d6) δ 163.06, 161.12, 143.92, 139.23,
138.60, 138.54, 137.34, 134.78, 130.76, 130.70, 130.64,
128.61, 128.12, 127.74, 127.61, 127.08, 126.57, 123.90,
123.88, 123.64, 115.01, 114.84, 114.67, 52.10 (SCH2), 27.69
1‑(2‑Bromo‑benzyl)‑4‑(4,5‑diphenyl‑1H‑imidazol‑2‑ylsulfan
ylmethyl)‑1H‑[1,2,3]triazole (8i)
Cream powder; isolated yield: 93% (0.47 g), mp 180–182;
1
IR (KBr, υ): 3379, 1468, 773 cm−1; H NMR (500 MHz,
1 3

Molecular Diversity
DMSO-d6) δ 12.65 (s, 1H, NH), 7.94 (s, 1H, Triazole), 7.64
(dd, J=11.5, 9.8 Hz, 1H, H3), 7.47–7.21 (m, 12H, Ph, H4,
H5), 7.11 (d, J=6.9 Hz, 1H, H6), 5.62 (s, 2H, CH2), 4.42
(s, 2H, S-CH2); 13C NMR (125 MHz, DMSO-d6) δ 143.75,
139.15, 137.33, 135.04, 134.77, 132.84, 130.63, 130.38,
130.34, 128.64, 128.18, 128.16, 127.76, 127.64, 127.06,
126.59, 123.87, 122.83, 52.90 (SCH2), 27.60 (CH2). Anal.
Calcd for C25H20BrN5S: C, 59.76; H, 4.01; N, 13.94. Found:
C, 59.53; H, 4.13; N, 14.05.
139.04, 134.22, 130.87, 129.79, 129.49, 128.61, 128.16,
127.74, 127.01, 126.52, 124.97, 124.23, 49.89 (S-CH2),
27.67 (CH2). Anal. Calcd for C25H20N6O2S: C, 64.09; H,
4.30; N, 17.94. Found: C, 64.17; H, 4.51; N, 17.87.
4‑(4,5‑Diphenyl‑1H‑imidazol‑2‑ylsulfanylmethyl)‑1‑(3‑nitro
‑benzyl)‑1H‑[1,2,3]triazole (8m)
Cream powder; isolated yield: 95% (0.44 g), mp 168-170;
1
IR (KBr, υ): 3378, 1462, 771 cm−1; H NMR (500 MHz,
1‑(3‑Bromo‑benzyl)‑4‑(4,5‑diphenyl‑1H‑imidazol‑2‑ylsulfan
ylmethyl)‑1H‑[1,2,3]triazole (8j)
DMSO-d6) δ 12.63 (s, 1H, NH), 8.23 (s, 1H, H2), 8.15
(d, J = 8.1, 2.3 Hz, 1H, H4), 8.11 (s, 1H, Triazole), 7.69
(d, J = 7.7 Hz, 1H, H6), 7.57 (t, J= 8.0, 2.1 Hz, 1H, H5),
7.47–7.20 (m, 10H, Ph), 5.76 (s, 2H, CH2), 4.46 (s, 2H,
S-CH2); 13C NMR (125 MHz, DMSO-d6) δ 147.80, 144.01,
139.15, 138.04, 137.32, 134.83, 134.57, 130.66, 130.29,
128.63, 128.14, 127.74, 127.62, 127.01, 126.72, 126.56,
123.77, 123.05, 122.80, 51.73 (S-CH2), 27.64 (CH2). Anal.
Calcd for C25H20N6O2S: C, 64.09; H, 4.30; N, 17.94. Found:
C, 63.92; H, 4.22; N, 17.85.
Cream powder; isolated yield: 94% (0.47 g), mp 174-176;
1
IR (KBr, υ): 3379, 1468, 770 cm−1; H NMR (500 MHz,
DMSO-d6) δ 12.64 (s, 1H, NH), 8.06 (s, 1H, Triazole), 7.54
(d, J = 1.9 Hz, 1H, H4), 7.52–7.49 (m, 1H, H2), 7.46 (d,
J=7.3 Hz, 2H, Ph), 7.41–7.35 (m, 5H, Ph), 7.34–7.31 (m,
1H, Ph), 7.30–7.26 (m, 2H, Ph), 7.24 (d, J = 5.1 Hz, 2H,
H5, H6), 5.59 (s, 2H, CH2), 4.44 (s, 2H, S-CH2); 13C NMR
(125 MHz, DMSO-d6) δ 148.27, 143.88, 139.17, 138.56,
137.27, 134.82, 130.97, 130.88, 130.71, 129.57, 128.89,
128.73, 128.64, 128.26, 128.17, 127.96, 127.76, 127.63,
127.04, 126.93, 126.57, 123.64, 121.81, 51.92 (SCH2),
27.63 (CH2). Anal. Calcd for C25H20BrN5S: C, 59.76; H,
4.01; N, 13.94. Found: C, 59.83; H, 4.11; N, 13.84.
4‑(4,5‑Diphenyl‑1H‑imidazol‑2‑ylsulfanylmethyl)‑1‑(4‑nitro
‑benzyl)‑1H‑[1,2,3]triazole (8n)
Cream powder; isolated yield: 89% (0.42 g), mp 189–191;
1
IR (KBr, υ): 3375, 1461, 775 cm−1; H NMR (500 MHz,
DMSO-d6) δ 12.63 (s, 1H, NH), 8.10 (d, J = 8.7 Hz, 2H,
H5, H3), 8.04 (s, 1H, Triazole), 7.43 (dt, J = 8.7, 2.7 Hz,
4H, Ph), 7.39–7.29 (m, 5H, Ph), 7.27 (t, J = 7.5 Hz, 2H,
H2, H6), 7.23–7.17 (m, 1H, Ph), 5.75 (s, 2H, CH2), 4.43
(s, 2H, S-CH2); 13C NMR (125 MHz, DMSO-d6) δ 147.57,
144.50, 143.90, 139.41, 137.79, 135.25, 131.09, 129.26,
129.18, 129.10, 128.62, 128.22, 128.14, 127.45, 127.06,
124.39, 124.26, 52.28 (S-CH2), 28.21 (CH2). Anal. Calcd
for C25H20N6O2S: C, 64.09; H, 4.30; N, 17.94. Found: C,
63.95; H, 4.43; N, 17.81.
1‑(4‑Bromo‑benzyl)‑4‑(4,5‑diphenyl‑1H‑imidazol‑2‑ylsulfan
ylmethyl)‑1H‑[1,2,3]triazole (8k)
Cream powder; isolated yield: 92% (0.46 g), mp 197–199;
1
IR (KBr, υ): 3379, 1462, 774 cm−1; H NMR (500 MHz,
DMSO-d6) δ 12.64 (s, 1H, NH), 7.99 (s, 1H, Triazole),
7.45 (t, J = 7.5 Hz, 4H, Ph, H2, H6), 7.41–7.35 (m, 4H,
Ph), 7.33 (d, J = 6.5 Hz, 1H, Ph), 7.29 (t, J = 7.4 Hz, 2H,
Ph), 7.23 (d, J = 7.1 Hz, 1H, Ph), 7.19 (d, J = 8.2 Hz, 2H,
H2, H6), 5.55 (s, 2H, CH2), 4.42 (s, 2H, S-CH2); 13C NMR
(125 MHz, DMSO-d6) δ 148.28, 143.87, 139.06, 138.01,
137.32, 135.36, 134.83, 131.60, 130.66, 130.02, 129.59,
128.66, 128.28, 128.18, 127.78, 127.67, 127.03, 126.60,
123.56, 121.34, 52.00 (S-CH2), 27.74 (CH2). Anal. Calcd
for C25H20BrN5S: C, 59.76; H, 4.01; N, 13.94. Found: C,
59.62; H, 3.96; N, 14.08.
Biological assays
In vitro α‑glucosidase inhibition assay
Enzyme (α-glucosidase from Saccharomyces cerevisiae,
EC3.2.1.20, 20 U/mg) and substrate (p-nitrophenyl glu-
copyranoside) were prepared from Sigma-Aldrich. An
appropriate concentration of enzyme was prepared by potas-
sium phosphate bufer (pH 6.8, 50 mM), and the 4,5-dia-
rylimidazole-1,2,3-triazole hybrids 8a–n were dissolved
in DMSO (10% fnal concentration). The enzyme (20 μL),
diferent concentrations of the title compounds (20 μL),
and potassium phosphate bufer (135 μL) were added to a
96-well plate and incubated at 37 °C for 10 min [17–25].
Then, a substrate (25 μL, 4 mM) was added to each well of
the plate and allowed to be incubated at 37 °C for 20 min.
4‑(4,5‑Diphenyl‑1H‑imidazol‑2‑ylsulfanylmethyl)‑1‑(2‑nitro
‑benzyl)‑1H‑[1,2,3]triazole (8l)
Cream powder; isolated yield: 86% (0.40 g), mp 175–177;
1
IR (KBr, υ): 3378, 1462, 776 cm−1; H NMR (500 MHz,
DMSO-d6) δ 12.65 (s, 1H, NH), 8.11 (s, 1H, Triazole), 8.02
(s, 1H, H3), 7.64–7.51 (m, 2H, H4, H5), 7.48–7.20 (m, 10H,
Ph), 7.01–6.88 (m, 1H, H6), 5.95 (s, 2H, CH2), 4.49 (s, 2H,
S-CH2); 13C NMR (125 MHz, DMSO-d6) δ 147.43, 143.94,
1 3

Molecular Diversity
5. Hollander P (1992) Safety profle of acarbose, an α-glucosidase
inhibitor. Drugs 44:47–53. https://doi.org/10.2165/00003495-
199200443-00007
Finally, the change in the absorbance was measured at
405 nm by using the Gen5 spectrophotometer (Power wave
xs2, BioTek, America). DMSO as control and acarbose as
the standard inhibitor were used. The percentage of inhibi-
tion for the synthesized compounds 8a–n, control, and acar-
bose was calculated by using the following formula:
6. Adisakwattana S, Sookkongwaree K, Roengsumran S, Petsom A,
Ngamrojnavanich N, Chavasiri W, Deesamer S, Yibchok-anun
S (2004) Structure–activity relationships of trans-cinnamic acid
derivatives on α-glucosidase inhibition. Bioorg Med Chem Lett
14:2893–2896. https://doi.org/10.1016/j.bmcl.2004.03.037
7. Sou S, Mayumi S, Takahashi H, Yamasaki R, Kadoya S, Sodeoka
M, Hashimoto Y (2000) Novel α-glucosidase inhibitors with a
tetrachlorophthalimide skeleton. Bioorg Med Chem Lett 10:1081–
1084. https://doi.org/10.1016/S0960-894X(00)00161-X
8. Abboud JL, Foces-Foces C, Notario R, Trifonov RE, Volovodenko
AP, Ostrovskii VA, Alkorta I, Elguero J (2001) Basicity of N-H-
and N-methyl-1,2,3-triazoles in the gas phase, in solution, and in
the solid state—an experimental and theoretical study. Eur J Org
Chem 16:3013–3024. https://doi.org/10.1002/1099-0690(20010
8)2001:16%3c3013:AID-EJOC3013%3e3.0.CO;2-Y
[
]
%Inhibition = (Abs control Abs sample)∕Abs control × 100
The IC50 values of the tested agents were determined
from the nonlinear regression curve using the Logit method.
Kinetic study
The α-glucosidase solution (1 U/mL, 20 μL) was incubated
with diferent concentrations of the compound 8g (0, 45, 60,
and 85 µM) for 15 min at 30 °C. The enzymatic reaction was
initiated by adding various concentrations of p-nitrophenyl
glucopyranoside as substrate (1–10 mM). Then, change
in the absorbance was determined for 20 min at 405 nm
by using the spectrophotometer (Gen5, Power wave xs2,
BioTek, America).
9. Vatmurge NS, Hazra BG, Pore VS, Shirazi F, Chavan PS,
Deshpande MV (2008) Synthesis and antimicrobial activity
of β-lactam–bile acid conjugates linked via triazole. Bioorg
Med Chem Lett 18:2043–2047. https://doi.org/10.1016/j.
bmcl.2008.01.102
10. Thirumurugan P, Matosiuk D, Jozwiak K (2013) Click chemistry
for drug development and diverse chemical–biology applications.
Chem Rev 113:4905–4979. https://doi.org/10.1021/cr200409f
11. Aufort M, Herscovici J, Bouhours P, Moreau N, Girard C (2008)
Synthesis and antibiotic activity of a small molecules library of
1,2,3-triazole derivatives. Bioorg Med Chem Lett 18:1195–1198.
https://doi.org/10.1016/j.bmcl.2007.11.111
Docking study
12. Kumar A, Ahmad I, Chhikara BS, Tiwari R, Mandal D, Parang
K (2011) Synthesis of 3-phenylpyrazolopyrimidine-1,2,3-triazole
conjugates and evaluation of their Src kinase inhibitory and anti-
cancer activities. Bioorg Med Chem Lett 21:1342–1346. https://
doi.org/10.1016/j.bmcl.2011.01.047
Building the homology model of α-glucosidase and dock-
ing studies of the selected compounds 8d–e and 8g–i in the
active site of this enzyme were conducted using the previ-
ously described method [25].
13. Lima-Neto RG, Cavalcante NN, Srivastava RM, Mendonça Junior
FJ, Wanderley AG, Neves RP, dos Anjos JV (2012) Synthesis of 1,
2, 3-triazole derivatives and in vitro antifungal evaluation on Can-
dida strains. Molecules 17:5882–5892. https://doi.org/10.3390/
molecules17055882
In silico ADME/T study
14. Shanmugavelan P, Nagarajan S, Sathishkumar M, Ponnuswamy
A, Yogeeswari P, Sriram D (2011) Efcient synthesis and in vitro
antitubercular activity of 1,2,3-triazoles as inhibitors of Mycobac-
terium tuberculosis. Bioorg Med Chem Lett 21:7273–7276. https
://doi.org/10.1016/j.bmcl.2011.10.048
In silico ADME-Tox study of the most potent compounds
8b, 8d, 8g, and 8i was performed using the PreADMET
online server (http://preadmet.bmdrc.org/) [26].
15. Mohammadi-Khanaposhtani M, Mahdavi M, Saeedi M, Sabourian
R, Safavi M, Khanavi M, Foroumadi A, Shafee A, Akbarzadeh T
(2015) Design, synthesis, biological evaluation, and docking study
of acetylcholinesterase inhibitors: new acridone-1,2,4-oxadia-
zole-1,2,3-triazole hybrids. Chem Biol Drug Des 86:1425–1432.
https://doi.org/10.1111/cbdd.12609
Acknowledgements This project was fnancially supported by the
National Institute for Medical Research Development (NIMAD) (the
Grant Number: 977073).
16. Brik A, Alexandratos J, Lin YC, Elder JH, Olson AJ, Wlodawer
A, Goodsell DS, Wong CH (2005) 1,2,3-Triazole as a peptide sur-
rogate in the rapid synthesis of HIV-1 protease inhibitors. Chem-
BioChem 6:1167–1169. https://doi.org/10.1002/cbic.200500101
17. Iqbal S, Khan MA, Javaid K, Sadiq R, Fazal-ur-Rehman S, Choud-
hary MI, Basha FZ (2017) New carbazole linked 1,2,3-triazoles
as highly potent non-sugar α-glucosidase inhibitors. Bioorg Chem
74:72–81. https://doi.org/10.1016/j.bioorg.2017.07.006
References
1. Schmidt DD, Frommer W, Junge B, Müller L, Wingender W,
Truscheit E, Schäfer D (1997) α-Glucosidase inhibitors. Natur-
wissenschaften 64:535–536. https://doi.org/10.1007/BF00483561
2. Matsuo T, Odaka H, Ikeda H (1992) Efect of an intestinal disac-
charidase inhibitor (AO-128) on obesity and diabetes. Am J Clin
Nutr 55:314S–317S. https://doi.org/10.1093/ajcn/55.1.314s
3. Scott LJ, Spencer CM (2000) Miglitol Drugs 59:521–549. https
://doi.org/10.2165/00003495-200059030-00012
18. Wang G, Peng Z, Wang J, Li X, Li J (2017) Synthesis, in vitro
evaluation and molecular docking studies of novel triazine-tria-
zole derivatives as potential α-glucosidase inhibitors. Eur J Med
Chem 125:423–429. https://doi.org/10.1016/j.ejmech.2016.09.067
19. Saeedi M, Mohammadi-Khanaposhtani M, Pourrabia P, Razzaghi
N, Ghadimi R, Imanparast S, Faramarzi MA, Bandarian F, Esfa-
hani EN, Safavi M, Rastegar H (2019) Design and synthesis of
4. Asano N, Oseki K, Tomioka E, Kizu H, Matsui K (1994)
N-containing sugars from Morus alba and their glycosidase
inhibitory activities. Carbohydr Res 259:243–255. https://doi.
org/10.1016/0008-6215(94)84060-1
1 3

Molecular Diversity
novel quinazolinone-1,2,3-triazole hybrids as new anti-diabetic
agents: in vitro α-glucosidase inhibition, kinetic, and docking
study. Bioorg Chem 83:161–169. https://doi.org/10.1016/j.bioor
g.2018.10.023
as potent antidiabetic agents. New J Chem 42:17268–17278. https
://doi.org/10.1039/C8NJ02495B
25. Adib M, Peytam F, Rahmanian-Jazi M, Mahernia S, Bijanzadeh
HR, Jahani M, Mohammadi-Khanaposhtani M, Imanparast S,
Faramarzi MA, Mahdavi M, Larijani B (2018) New 6-amino-
pyrido [2,3-d] pyrimidine-2,4-diones as novel agents to treat
type 2 diabetes: a simple and efcient synthesis, α-glucosidase
inhibition, molecular modeling and kinetic study. Eur J Med Chem
155:353–363. https://doi.org/10.1016/j.ejmech.2018.05.046
26. Seul, South Corea: Bioinformatics and Molecular Design
Research Center; 2004. PreADMET program. http://preadmet.
bmdrc.org
20. Yar M, Bajda M, Shahzad S, Ullah N, Gilani MA, Ashraf M,
Rauf A, Shaukat A (2015) Organocatalyzed solvent free an
efcient novel synthesis of 2,4,5-trisubstituted imidazoles for
α-glucosidase inhibition to treat diabetes. Bioorg Chem 58:65–71.
https://doi.org/10.1016/j.bioorg.2014.11.006
21. Wang G, Peng Z, Wang J, Li J, Li X (2016) Synthesis and bio-
logical evaluation of novel 2,4,5-triarylimidazole-1,2,3-triazole
derivatives via click chemistry as α-glucosidase inhibitors.
Bioorg Med Chem Lett 26:5719–5723. https://doi.org/10.1016/j.
bmcl.2016.10.057
27. Maduskuie TP, Wilde RG, Billheimer JT, Cromley DA, Germain
S, Gillies PJ, Higley CA, Johnson AL, Pennev P, Shimshick EJ,
Wexler RR (1995) Design, synthesis, and structure-activity rela-
tionship studies for a new imidazole series of J774 macrophage
specifc acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors.
J Med Chem 38:1067–1083. https://doi.org/10.1021/jm00007a00
4
22. Adib M, Peytam F, Shourgeshty R, Mohammadi-Khanaposhtani
M, Jahani M, Imanparast S, Faramarzi MA, Larijani B, Mogh-
adamnia AA, Esfahani EN, Bandarian F (2019) Design and
synthesis of new fused carbazole-imidazole derivatives as anti-
diabetic agents: in vitro α-glucosidase inhibition, kinetic, and in
silico studies. Bioorg Med Chem Lett 29:713–718. https://doi.
org/10.1016/j.bmcl.2019.01.012
28. Veltri L, Mancuso R, Altomare A, Gabriele B (2015) Divergent
multicomponent tandem palladium-catalyzed aminocarbonyla-
tion-cyclization approaches to functionalized imidazothiazinones
and imidazothiazoles. ChemCatChem 7:2206–2213. https://doi.
org/10.1002/cctc.201500213
23. Mohammadi-Khanaposhtani M, Yahyavi H, Barzegaric E, Iman-
parast S, Heravi MM, Ali Faramarzi M, Foroumadi A, Adibi H,
Larijani B, Mahdavi M (2018) New biscoumarin derivatives as
potent α-glucosidase inhibitors: synthesis, biological evaluation,
kinetic analysis, and docking study. Polycycl Aromat Comp 5:1–2.
https://doi.org/10.1080/10406638.2018.1509359
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional afliations.
24. Adib M, Peytam F, Rahmanian-Jazi M, Mohammadi-Khana-
poshtani M, Mahernia S, Bijanzadeh HR, Jahani M, Imanparast S,
Faramarzi MA, Mahdavi M, Larijani B (2018) Design, synthesis
and in vitro α-glucosidase inhibition of novel coumarin-pyridines
1 3