Bioorganic & Medicinal Chemistry 27 (2019) 115148

Contents lists available at ScienceDirect

Bioorganic & Medicinal Chemistry

journal homepage: www.elsevier.com/locate/bmc

Design, synthesis, in vitro, and in silico studies of novel diarylimidazole-1,2, T

3-triazole hybrids as potent α-glucosidase inhibitors
Mina Saeedia,b, Maryam Mohammadi-Khanaposhtanic, Mohammad Sadegh Asgarid,
Nafiseh Eghbalnejade, Somaye Imanparastf, Mohammad Ali Faramarzif, Bagher Larijanig,
Mohammad Mahdavig, , Tahmineh Akbarzadehh,b,
⁎ ⁎

a
Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
b
Persian Medicine and Pharmacy Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
c
Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
d
School of Chemistry, College of Science, University of Tehran, Tehran, Iran
e
Faculty of Pharmacy, International Campus (TUMS-IC), Tehran University of Medical Sciences, Tehran, Iran
f
Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran 1417614411, Iran
g
Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
h
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

ARTICLE INFO ABSTRACT

This paper is dedicated to our unique teacher in In this work, new derivatives of diarylimidazole-1,2,3-triazole 7a-p were designed, synthesized, and evaluated
chemistry and medicinal chemistry, Professor for their in vitro α-glucosidase inhibitory activity. All compounds showed potent inhibitory activity in the range
Abbas Shafiee (1937–2016) of IC50 = 90.4–246.7 µM comparing with acarbose as the standard drug (IC50 = 750.0 µM). Among the syn-
thesized compounds, compounds 7b, 7c, and 7e were approximately 8 times more potent than acarbose. The
Keywords: kinetic study of those compounds indicated that they acted as the competitive inhibitors of α-glucosidase.
Diarylimidazole Molecular docking studies were also carried out for compounds 7b, 7c, and 7e using modeled α-glucosidase to
Docking study
find the interaction modes responsible for the desired inhibitory activity.
α-Glucosidase inhibitors
Kinetic study
1,2,3-triazole

1. Introduction
α-Glucosidase is an intestinal enzyme which catalyzes the breakage
of the 1,4-α glycosidic bonds of polysaccharides and some disaccharides
converting them into the absorbable glucose.1 This enzyme is involved
in various carbohydrate-related diseases such as diabetes, viral infec-
tions, cancer, and pompe disease.2–5 In this regard, various α-glucosi-
dase inhibitors such as acarbose (Glucobay), miglitol (Glyset), and vo-
glibose (Volix, Basen) are currently prescribed for the treatment of
patients with non-insulin-dependent (type 2) diabetes. The above
mentioned α-glucosidase inhibitors contain sugar moieties and their
synthesis need complicated multistep procedures.6 On the other hand,
administration of these inhibitors can bring undesirable side effects
including serious gastrointestinal disorders such as diarrhea and flatu-
lence.7 Thus, the development of efficient small molecules possessing
potent α-glucosidase inhibitory activity has recently attracted a great
attention.8–10
Imidazole and its derivatives are one of the most important nitrogen
containing heterocyclic scaffolds in medicinal chemistry11 possessing
versatile biological properties including anticancer, analgesic, anti-
tubercular, anti-inflammatory, anti-Alzheimer’s, antiviral, and antic-
onvulsant activities.12–18 Also, recent studies have confirmed α-gluco-
sidase inhibitory activity of imidazole derivatives,19–21 e.g. 2-(4,5-
diphenyl-1H-imidazol-2-yl)phenol A showed good α-glucosidase in-
hibitory activity (IC50 = 74.3 μM) comparing with acarbose
(IC50 = 38.2 μM).19 1,2,3-Triazole and its derivatives have been also
found as privileged scaffolds for drug discovery developments due to
stable metabolism, less adverse, high selectivity, and user-friendly
synthesis via click reaction.22 In recent years, several hybrid derivatives
containing 1,2,3-triazole ring23–26 such as chalcone-1,2,3-triazole B
(IC50 = 67.8 μM comparing with acarbose IC50 = 23.9 μM) possessing
α-glucosidase inhibitory activity have been reported.23
Molecular hybridization has been a strong tool for design and synthesis
of new bioactive compounds. It is expected that combination of various

⁎
Corresponding authors at: Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran (T. Akbarzadeh).
E-mail addresses: momahdavi@tums.ac.ir (M. Mahdavi), akbarzad@tums.ac.ir (T. Akbarzadeh).

https://doi.org/10.1016/j.bmc.2019.115148
Received 21 May 2019; Received in revised form 8 September 2019; Accepted 1 October 2019
Available online 15 October 2019
0968-0896/ © 2019 Elsevier Ltd. All rights reserved.
M. Saeedi, et al. Bioorganic & Medicinal Chemistry 27 (2019) 115148

Fig. 1. Design of diarylimidazole-1,2,3-triazole hybrids.

pharmacophores with different mechanisms of action can be helpful for
inducing favorite biological activity. In this respect, in view of α-glucosi-
dase inhibitory activity of compounds A and B, a novel series of diaryli-
midazole-1,2,3-triazole hybrids were designed and synthesized as potent
α-glucosidase inhibitors (Fig. 1). Apart from in vitro assessment of target
compounds, their possible mode of interaction with α-glucosidase was
investigated through kinetic and docking studies.
2. Results and discussion
derivative 1, ammonium acetate 2, and 4-(prop-2-ynyloxy) benzaldehyde
derivative 3 in acetic acid was heated at reflux for 1 h to afford compound
4. Next, 1,2,3-triazole scaffold was constructed via click reaction and for
this purpose, various benzyl halides 5 reacted with sodium azide in the
mixture of H2O and t-BuOH (1:1) in the presence of Et3N at room tem-
perature to produce benzyl azides 6 in situ. Then, the mixture of compound
4, sodium ascorbate, and CuSO4·5H2O was added to the freshly prepared
azides 6 and the reaction was continued at room temperature for 24–48 h
to give the target compounds 7a-p.

2.1. Chemistry 2.2. In vitro α-glucosidase inhibitory activity

The synthetic route for the preparation of diarylimidazole-1,2,3-tria- In vitro α-glucosidase inhibitory activity of synthesized diarylimi-
zoles 7a-p has been depicted in Scheme 1. Initially, a mixture of benzil dazole-1,2,3-triazole hybrids was assayed according to the literature27

Scheme 1. Reagents and conditions for the synthesis of compounds 7a-p: (a) AcOH, reflux, 1 h and (b) CuSO4·5H2O, sodium ascorbate, rt, 24–48 h.

2
M. Saeedi, et al. Bioorganic & Medicinal Chemistry 27 (2019) 115148

Table 1 benzyl ring deteriorated inhibitory activity in such a manner that

In vitro α-glucosidase inhibitory activity of compounds 7. compound 7c showed much better activity, approximately two times,
than compounds 7d and 7i.
Further investigation comes back to compounds 7j-l possessing two
4-methoxyaryl groups connected to imidazole moiety. Comparing the
corresponding inhibitory activity with those analogues (compounds 7a,
7c, and 7f, respectively) revealed that better activity was only obtained
by compound 7j (IC50 = 129.5 µM) comparing with compound 7a
(IC50 = 199.0 µM). In the case of halogenated compounds 7k
Entry Compound 7 R1 R2 R3 IC50 (µM)a
(IC50 = 179.0 µM) and 7l (IC50 = 143.6 µM), introduction of methoxy
1 7a H H 2-CH3 199.0 ± 0.4 groups did not induce higher activity.
2 7b H H 3,5-diCH3 90.4 ± 0.5 The last part of discussion is related to the series of compounds 7m-
3 7c H H 4-F 100.0 ± 0.5 p which possessed methoxy group connected to the phenoxy moiety. In
4 7d H H 4-Cl 246.7 ± 0.7
this respect, compound 7o containing 4-chlorobenzyl group connected
5 7e H H 2,3-diCl 97.7 ± 0.7
6 7f H H 3,4-diCl 106.0 ± 0.8 1,2,3-triazole ring showed the best activity (IC50 = 150.2 µM).
7 7g H H 2-Br 118.7 ± 0.6 Replacement of Cl by F, derivatives 7m (IC50 = 162.9 µM) and 7n
8 7h H H 3-Br 135.4 ± 0.8 (IC50 = 188.5 µM) at the 2- or 4- position led to lower inhibitory ac-
9 7i H H 4-Br 204.3 ± 0.6 tivity. It seems that the presence of 4-chlorobenzyl moiety was effective
10 7j OCH3 H 2-CH3 129.5 ± 1.2
in this series of compounds. Finally, the presence of an electron-with-
11 7k OCH3 H 4-F 179.0 ± 1.0
12 7l OCH3 H 3,4-diCl 143.6 ± 1.0 drawing group (NO2) not only did not improve inhibitory activity but
13 7m H OCH3 2-F 162.9 ± 1.0 also decreased activity against α-glucosidase (IC50 = 201.6 µM).
14 7n H OCH3 4-F 188.5 ± 1.0 It can be concluded that the substituents on the benzyl moiety
15 7o H OCH3 4-Cl 150.2 ± 0.9
connected to the 1,2,3-triazole ring played a remarkable role in in vitro
16 7p H OCH3 4-NO2 201.6 ± 1.1
17 Acarboseb 750.0 ± 1.5
α-glucosidase inhibitory activity and the efficacy of methoxy groups
either on the aryl groups connected to imidazole moiety or phenoxy
a
Data are expressed as mean ± SE (three independent experiments). link is generally depended on those substituents. In this regard, α-glu-
b
IC50 values for α-glucosidase inhibitory activity of 1-deoxynojirimycin and cosidase inhibitory activity of compounds 7c, 7k, and 7n possessing 4-
miglitol have been reported as IC50 = 192.0 μM28 and 59.76 μg/mL, respec- fluorobenzyl group revealed that the introduction of methoxy groups
tively in the literature.29 into the aryl or linker moieties led to lower activity (7c > 7k > 7n).
Similarly, in the case of compounds 7f and 7l possessing 3,4-di-
comparing with acarbose as the reference drug (Table 1). To obtain the chlorobenzyl group, the absence of methoxy group led to better activity
best insight into the role of the presence and position of substituents on (7f > 7l). In different manner, compound 7a showed lower activity
the aryl ring connected to imidazole and 1,2,3-triazole moieties as well than compound 7j. Both compounds contained 2-methylbenzyl moiety
as phenoxy linker in the inhibitory activity, a wide variety of com- but the absence and presence of methoxy depicted different activity
pounds 7 were synthesized. In this regard, synthesized compounds were comparing with compounds 7f/7l and compounds 7c/7k/7n. Also, in
considered in three categories of 7a-i (Table 1, R1 = H and R2 = H), 7j- the case of compounds 7d and 7o having 4-chlorobenzyl group, the
l (Table 1, R1 = OCH3 and R2 = H), and 7m-p (Table 1, R1 = H and presence of methoxy group was found to be effective for inducing de-
R2 = OCH3). sired inhibitory activity.
It is worth mentioning that all compounds 7 demonstrated much
better inhibitory activity at least 3 times than acarbose. The best ac- 2.3. Kinetic study
tivity was obtained by compound 7b (IC50 = 90.4 µM) which was ap-
proximately 8 times more potent than acarbose (IC50 = 750.0 µM). It The kinetic analysis of α-glucosidase inhibition by compounds 7b,
contained two phenyl groups connected to imidazole ring, phenoxy 7c, and 7e was performed according to our previous report.27 The
linker with no substituent, and two methyl groups at the 3- and 5- mechanism of inhibition and Ki values for those compounds were de-
positions of benzyl moiety connected to 1,2,3-triazole ring. Changing termined by Lineweaver–Burk plots and secondary re-plot of these
the position and number of methyl group led to the reduction of activity plots, respectively (Figs. 2–4).
of the analogue of 7b, compound 7a (IC50 = 199.0 µM) possessing 2- As can be seen in Figs. 2a–4a, with increasing the concentration of
methylbenzyl group connected to 1,2,3-triazole moiety. In the first the inhibitor, the values of Vmax remained constant and the values of Km
category of compounds 7a-i, counterparts of compound 7b, compounds increased. It indicated that compounds 7b, 7c, and 7e acted as com-
7c-i possessing halobenzyl connected to 1,2,3-triazole ring showed α- petitive inhibitors of α-glucosidase binding to the enzyme active site in
glucosidase inhibitory activity generally depending on the number and competition with substrate. Furthermore, the plot of Km versus different
position of halogens. In this series of compounds (7c-i), compound 7e concentrations of inhibitors gave an estimate of the inhibition constant,
containing two Cl groups at the 2- and 3- positions of aryl ring showed Ki values of 87.0, 109.0, and 100.4 µM for compounds 7b, 7c, and 7e,
very good activity against α-glucosidase (IC50 = 97.7 µM). respectively.
Interestingly, changing the position of chlorine groups to 3- and 4- led
to a slight decrease in the inhibitory activity of compound 7f 2.4. Docking study
(IC50 = 106.0 µM). It should be noted that compound 7d possessing a
chlorine group at the 4- position of aryl ring showed lower activity than Molecular docking simulations were applied to distinguish interac-
compounds 7e and 7f. As can be seen in Table 1, the presence of tions between the synthesized compounds and α-glucosidase. Due to
fluorobenzyl moiety led to a good in vitro α-glucosidase inhibitory ac- the lack of crystallographic structure of α-glucosidase from S. cerevisiae,
tivity as compound 7c was found to be a relatively potent inhibitor homology model of this enzyme was built according to our pervious
(IC50 = 100.0 µM). Finally, compounds 7g-i containing bromobenzyl study.27 The superposed structure of acarbose and the most potent
moiety depicted versatile inhibitory activity affected by the position of compound 7b in the active site of α-glucosidase is shown in Fig. 5 (left).
bromine. The order of activity for compounds 7g-i, was found to be Acarbose formed hydrogen bonding interactions with residues Asn241,
7g > 7h > 7i (IC50s = 118.7, 135.4, and 204.3 µM, respectively). It is Pro309, Thr301, Glu304, Thr307, Ser308, Arg312, Gln322, and a hy-
clear that the presence of halogen except fluorine at the 4-position of drophobic interaction with His279 (Fig. 5, right).27

3
M. Saeedi, et al. Bioorganic & Medicinal Chemistry 27 (2019) 115148

a) b)
80
8
Concentration of Inhibitor
0 µM

1/V(∆ PNP 405 nm/min) -1

40 µM 60
6
65 µM
90 µM

Km
40 4

20 2

0
0
-100 -80 -60 -40 -20 0 20 40 60 80 100
-2 -1 0 1 2
-1
1/[S](PNPG, mM ) [I], µM
-2

Fig. 2. (a) Lineweaver–Burk plots for the inhibition of α-glucosidase by compound 7b. (b) The secondary plot between Km and various concentrations of compound
7b (b).

Detailed binding modes of compounds 7b, 7c, and 7e were also
shown in Figs. 6–8. As can be seen in those figures, the following in-
teractions were mutual for three studied compounds: (1) hydrophobic
interactions of Val316 and Ala326 with phenyl groups attached to the
imidazole moiety, (2) a π-anion interaction between Glu304 and phe-
noxy moiety, (3) hydrophobic interactions of Pro309 with imidazole
and phenoxy moieties, and (4) hydrophobic interactions of Arg312 with
1,2,3-triazole ring and benzyl group.
The most potent compound 7b made further interactions as de-
scribed above. Two hydrogen bonding interactions were formed be-
tween NH of imidazole moiety and Thr307 as well as nitrogen of 1,2,3-
triazole ring and Arg312. Also, two hydrophobic interactions were
distinguished between 3,5-dimethylbenzyl moiety and Phe300 and
Arg439 (Fig. 6). As can be seen in the Figs. 6 and 7, comparing the
interaction mode of compound 7b with that of compound 7c revealed
that compound 7c formed only a hydrogen bond interaction with the
active site (between NH of imidazole moiety and Thr307) while com-
pound 7b established two hydrogen bonding interactions. On the other
hand, 1,2,3-triazole ring of the compound 7c formed additional inter-
actions with His239 (a hydrophobic interaction, a π-π interaction, and a
π-cation interaction). Also, 4-fluorobenzyl moiety of compound 7c in-
teracted with Asp408 via a π-anion interaction (Fig. 7).
Compound 7e unlike compounds 7b and 7c, established no hy-
drogen bonding interaction with the active site of enzyme (Figs. 6–8).
2,3-Dichlorobenzyl moiety of compound 7e formed interactions with
Asp408, Phe157, and Phe158 (Fig. 8).
The binding energy values for compounds 7b (−11.17 kcal/mol),
7c (−11.22 kcal/mol), and 7e (−11.46 kcal/mol) revealed that they
bound more readily to the active site than the standard drug acarbose
(−4.04 kcal/mol)27 which was in good agreement with those results
obtained in in vitro assay.
3. Conclusion
In conclusion, we synthesized a new series of diarylimidazole-1,2,3-
triazole derivatives 7a-p as potent α-glucosidase inhibitors comparing
with acarbose as the reference drug. Among them, compounds 7b, 7c,
and 7e with inhibitory activity approximately 8 times more potent than
acarbose were found to be the most active compounds. Also, their ki-
netic studies indicated competitive inhibitory activity toward α-gluco-
sidase. It is worth mentioning that docking study of compounds 7b, 7c,
and 7e revealed that they well fitted in the active site of α-glucosidase
with the binding energies less than acarbose.

a) b)
7

Concentration of Inhibitor 30
6
-1

0 µM
1/V(∆ PNP 405 nm, min)

40 µM
70 µM 5
20
100 µM
4
Km

10 3

0 1
-1.5 -1.0 -0.5 0.0 0.5 1.0 1.5
0
1/[S](PNPG, mM-1 )
-150 -100 -50 0 50 100 150
-10
-1 [I], µM

Fig. 3. (a) Lineweaver–Burk plots for the inhibition of α-glucosidase by compound 7c. (b) The secondary plot between Km and various concentrations of compound
7c.

4
M. Saeedi, et al. Bioorganic & Medicinal Chemistry 27 (2019) 115148

a) b)

50 7

Concentration of Inhibitor

-1
6

1/V(∆ PNP 405 nm, min)

40
0 µM 5
37 µM
67 µM 30
97 µM 4

Km
20 3

2
10

1
0
-1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 0
-150 -100 -50 0 50 100 150
-10 1/[S](PNPG, mM-1 )
[I], µM

Fig. 4. (a) Lineweaver–Burk plots for the inhibition of α-glucosidase by compound 7e. (b) The secondary plot between Km and various concentrations of compound
7e.

Fig. 5. Acarbose (cyan) and the most potent compounds 7b (pink) superimposed in the active site pocket of modeled α-glucosidase. (For interpretation of the
references to color in this figure legend, the reader is referred to the web version of this article.)

4. Experimental 4.2. General procedure for the synthesis of diarylimidazole-1,2,3-triazole

Melting points of synthesized compounds 7a-p were determined on
a Kofler hot stage apparatus. 1H and 13C NMR spectra were determined
on a Bruker and Varian FT-500, using TMS as an internal standard. IR
spectra were recorded using KBr disks on a Nicolet Magna FTIR 550
spectrophotometer. Elemental analysis was carried out with an
Elemental Analyzer system GmbH VarioEL CHN mode. Compound 3
was prepared according to the procedure described in the literature.30
4.1. General procedure for the preparation of 4,5-diaryl-2-(4-(prop-2-
ynyloxy)phenyl)-1H-imidazole derivatives 4
A mixture of benzil derivative 1 (1 mmol), ammonium acetate 2
(10 mmol), and 4-(prop-2-ynyloxy) benzaldehyde derivative 3
(1 mmol) in acetic acid was heated at reflux for 1 h. Upon completion of
the reaction (checked by TLC), the reaction mixture was poured into
water, the precipitate was filtered off, and washed with water to afford
compound 4.
hybrids 7a-p
A mixture of benzyl halid derivative 5 (1.1 mmol) and sodium azide
(0.9 mmol) in the presence of Et3N (1.3 mmol) in water/t-BuOH (8 mL,
1:1) was stirred at room temperature for 1 h. Subsequently, the mixture
of compound 4 (1 mmol), CuSO4·5H2O (7 mol%), and catalytic amounts
of sodium ascorbate was added to the freshly prepared benzyl azide
derivative 6 and stirred at room temperature for 24–48 h. Upon com-
pletion of the reaction (monitored by TLC), the reaction mixture was
poured into crushed ice. Then, the precipitate was filtered off, washed
with cold water, and purified by recrystallization from ethanol to give
the corresponding derivatives 7a-p.
4.2.1. 4-((4-(4,5-Diphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1-(2-
methylbenzyl)-1H-1,2,3-triazole 7a
White powder, Yield: 75%, mp = 203–205 °C. IR (KBr): 3418, 3062,
1610 cm−1. 1H NMR (500 MHz, CDCl3): δ = 2.25 (s, 3H, CH3), 5.11 (s,
2H, CH2), 5.50 (s, 2H, CH2), 6.93 (d, J = 8.5 Hz, 2H, H2, H6), 7.13 (d,

5
M. Saeedi, et al. Bioorganic & Medicinal Chemistry 27 (2019) 115148

Fig. 6. Docked conformer of compound 7b in the active site of α-glucosidase.

J = 7.5 Hz, 1H, H3′), 7.19–7.29 (m, 9H, H4′, H5′, H6′, Ph), 7.39 (s, 1H, 126.3, 126.6, 127.0, 127.5, 128.0, 128.2, 128.5, 135.6, 136.7, 137.8,
triazole), 7.42–7.62 (m, 4H, Ph), 7.78 (d, J = 8.5 Hz, 2H, H3, H5), 9.91 142.8, 145.4, 158.1. Anal Calcd for C33H29N5O: C, 77.47; H, 5.71; N,
(s, 1H, NH). 13C NMR (125 MHz, CDCl3): δ = 20.7, 52.4, 62.0, 115.1, 13.69. Found C, 77.20; H, 5.85; N, 13.51.
122.5, 123.5, 126.7, 126.9, 127.9, 128.2, 128.8, 129.2, 129.5, 131.1,
132.3, 134.9, 136.9, 138.0, 138.1, 144.1, 146.1, 158.7. Anal Calcd for
C32H27N5O: C, 77.24; H, 5.47; N, 14.07. Found C, 77.50; H, 5.21; N, 4.2.3. 4-((4-(4,5-Diphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1-(4-
14.25. fluorobenzyl)-1H-1,2,3-triazole 7c
White powder, Yield: 65%, mp = 180–182 °C. IR (KBr): 3415, 3065,
1615 cm−1. 1H NMR (500 MHz, CDCl3): δ = 5.21 (s, 2H, CH2), 5.53 (s,
4.2.2. 1-(3,5-Dimethylbenzyl)-4-((4-(4,5-diphenyl-1H-imidazol-2-yl)
2H, CH2), 7.02–7.06 (m, 4H, H2, H6, H3′, H5′), 7.30–7.68 (m, 14H,
phenoxy)methyl)-1H-1,2,3-triazole 7b
2 × Ph, H3, H5, H2′, H6′), 8.31 (s, 1H, triazole), 11.96 (s, 1H, NH). 13C
White powder, Yield: 75%, mp = 203–205 °C. IR (KBr): 3415, 3065,
NMR (125 MHz, CDCl3): δ = 52.8, 61.5, 114.4, 115.4 (JC-F = 22.5 Hz),
1615 cm−1. 1H NMR (500 MHz, CDCl3): δ = 2.24 (s, 6H, 2 × CH3),
122.5, 123.8, 124.0, 125.4, 126.7, 127.5, 127.7, 127.9, 129.4, 135.9,
5.20 (s, 2H, CH2), 5.52 (s, 2H, CH2), 6.93–6.96 (m, 3H, H2′, H4′, H6′),
139.2, 142.5, 144.3, 158.0, 161.1 (JC-F = 251.2 Hz). Anal Calcd for
7.13 (d, J = 8.5 Hz, 2H, H2, H6), 7.21–7.55 (m, 10H, 2 × Ph), 8.01 (d,
C31H24FN5O: C, 74.24; H, 4.82; N, 13.96. Found C, 74.55; H, 4.62; N,
J = 8.5 Hz, 2H, H3, H5), 8.26 (s, 1H, triazole), 12.50 (s, 1H, NH). 13C
14.20.
NMR (125 MHz, CDCl3): 20.7, 52.8, 61.1, 114.8, 123.4, 124.5, 125.6,

Fig. 7. Docked conformer of compound 7c in the active site of α-glucosidase.

6
M. Saeedi, et al.
Fig. 8. Docked conformer of compound 7e in the active site of α-glucosidase.
4.2.4. 1-(4-Chlorobenzyl)-4-((4-(4,5-diphenyl-1H-imidazol-2-yl)phenoxy)
methyl)-1H-1,2,3-triazole 7d
Cream powder, Yield: 83%, mp = 206–208 °C. IR (KBr): 3420,
2855, 1675, 1580 cm−1. 1H NMR (500 MHz, DMSO‑d6): δ = 5.22 (s,
2H, CH2), 5.64 (s, 2H, CH2), 7.15 (d, J = 8.8 Hz, 2H, H2, H6),
7.22–7.50 (m, 10H, 2 × Ph), 7.52 (d, J = 8.0 Hz, 2H, H2′, H6′), 7.56 (d,
J = 8.0 Hz, 2H, H3′, H5′), 8.02 (d, J = 8.8 Hz, 2H, H3, H5), 8.34 (s, 1H,
triazole), 12.55 (s, 1H, NH). 13C NMR (125 MHz, DMSO‑d6) δ = 52.9,
61.6, 115.4, 123.9, 125.2, 126.9, 127.1, 127.5, 128.0, 128.1, 128.6,
128.8, 129.1, 129.2, 130.4, 131.7, 133.3, 135.4, 135.7, 137.2, 143.4,
146.0, 158.6. Anal Calcd for C31H24ClN5O: C, 71.88; H, 4.67; N, 13.52.
Found C, 71.70; H, 4.52; N, 13.38.
4.2.5. 1-(2,3-Dichlorobenzyl)-4-((4-(4,5-diphenyl-1H-imidazol-2-yl)
phenoxy)methyl)-1H-1,2,3-triazole 7e
White powder, Yield: 80%, mp = 191–193 °C. IR (KBr): 3416, 3060,
1609 cm−1. 1H NMR (500 MHz, DMSO‑d6): δ = 5.22 (s, 2H, CH2), 5.79
(s, 2H, CH2), 7.14 (d, J = 8.5 Hz, 2H, H2, H6), 7.18 (d, J = 7.5 Hz, 1H,
H6′), 7.21 (t, J = 7.5 Hz, 1H, H5′), 7.28–7.65 (m, 10H, 2 × Ph), 7.66
(d, J = 7.5 Hz, 1H, H4′), 8.01 (d, J = 8.5 Hz, 2H, H3, H5), 8.30 (s, 1H,
triazole), 12.49 (s, 1H, imidazole). 13C NMR (125 MHz, DMSO‑d6):
δ = 51.1, 61.1, 114.9, 125.1, 126.3, 126.6, 127.0, 127.5, 128.0, 128.2,
128.5, 128.9, 130.5, 131.1, 132.2, 135.2, 135.7, 136.7, 142.8, 145.6,
158.1. Anal Calcd for C31H23Cl2N5O: C, 67.40; H, 4.20; N, 12.68. Found
C, 67.15; H, 4.43; N, 12.41.
4.2.6. 1-(3,4-Dichlorobenzyl)-4-((4-(4,5-diphenyl-1H-imidazol-2-yl)
phenoxy)methyl)-1H-1,2,3-triazole 7f
White powder, Yield: 80%, mp = 198–200 °C. IR (KBr): 3426, 3055,
1607 cm−1. 1H NMR (CDCl3, 500 MHz): δ = 5.14 (s, 2H, CH2), 5.42 (s,
2H, CH2), 6.93 (d, J = 8.5 Hz, 2H, H2, H6), 7.05 (d, J = 8.0 Hz, 1H,
H5′), 7.33 (s, 1H, H2′), 7.41 (d, J = 8.0 Hz, 1H, H6′), 7.28–7.52 (m,
10H, 2 × Ph), 7.55 (s, 1H, triazole), 7.78 (d, J = 8.5 Hz, 2H, H3, H5).
13
C NMR (125 MHz, CDCl3): δ = 52.9, 62.0, 115.2, 122.8, 122.9, 123.6,
126.9, 127.2, 127.8, 128.5, 128.9, 129.9, 131.0, 131.2, 131.5, 134.5,
135.0, 141.0, 144.7, 146.0, 158.6. Anal Calcd for C31H23Cl2N5O: C,
67.40; H, 4.20; N, 12.68. Found C, 67.58; H, 4.40; N, 12.80.
4.2.7. 1-(2-Bromobenzyl)-4-((4-(4,5-diphenyl-1H-imidazol-2-yl)phenoxy)
methyl)-1H-1,2,3-triazole 7g
White powder, Yield: 80%, mp = 205–207 °C. IR (KBr): 3416, 3060,
1609 cm−1. 1H NMR (500 MHz, DMSO‑d6): δ = 5.22 (s, 2H, CH2), 5.71
(s, 2H, CH2), 7.14 (d, J = 8.5 Hz, 2H, H2, H6), 7.17–7.23 (m, 3H, H4′,
H5′, H6′), 7.27–7.54 (m, 10H, 2 × Ph), 7.69 (d, J = 7.5 Hz, 1H, H3′),
7
Bioorganic & Medicinal Chemistry 27 (2019) 115148
8.01 (d, J = 8.5 Hz, 2H, H3, H5), 8.27 (s, 1H, triazole), 12.49 (s, 1H,
NH). 13C NMR (125 MHz, DMSO‑d6): δ = 52.9, 61.1, 114.9, 122.8,
123.4, 125.0, 126.3, 126.6, 127.0, 127.5, 128.0, 128.2, 128.3, 128.5,
130.3, 130.4, 132.8, 136.7, 142.7, 145.8, 158.1. Anal Calcd for
C31H24BrN5O: C, 66.20; H, 4.30; N, 12.45. Found C, 66.54; H, 4.44; N,
12.25.
4.2.8. 1-(3-Bromobenzyl)-4-((4-(4,5-diphenyl-1H-imidazol-2-yl)phenoxy)
methyl)-1H-1,2,3-triazole 7h
Cream powder, Yield: 91%, mp = 223–225 °C. IR (KBr): 3425,
2955, 2825, 1670, 1585 cm−1. 1H NMR (500 MHz, DMSO‑d6): δ = 5.23
(s, 2H, CH2), 5.65 (s, 2H, CH2), 7.17 (d, J = 8.7 Hz, 2H, H2, H6),
7.22–7.58 (m, 14H, 2 × Ph, H2′, H4′, H5′, H6′), 8.06 (d, J = 8.5 Hz,
2H, H3, H5), 8.37 (s, 1H, triazole), 12.56 (s, 1H, NH). 13C NMR
(125 MHz, DMSO‑d6): δ = 61.2, 52.0, 114.9, 121.9, 123.5, 124.9,
125.1, 126.7, 127.1, 127.4, 128.2, 128.3, 130.7, 130.9, 131.1, 135.3,
136.8, 138.6, 143.0, 145.6, 158.2. Anal Calcd for C31H24BrN5O: C,
66.20; H, 4.30; N, 12.45. Found C, 66.34; H, 4.46; N, 12.68.
4.2.9. 1-(4-Bromobenzyl)-4-((4-(4,5-diphenyl-1H-imidazol-2-yl)phenoxy)
methyl)-1H-1,2,3-triazole 7i
Cream powder, Yield: 87%, mp = 218–219 °C. IR (KBr): 3425,
2855, 1675, 1565 cm−1. 1H NMR (500 MHz, DMSO‑d6): δ = 5.23 (s,
2H, CH2), 5.63 (s, 2H, CH2), 7.16 (d, J = 8.4 Hz, 2H, H2, H6), 7.23 (d,
J = 7.5 Hz, 2H, H2′, H6′), 7.29–7.61 (m, 12H, 2 × Ph, H3′, H5′), 8.04
(d, J = 8.3 Hz, 2H, H3, H5), 8.34 (s, 1H, triazole), 12.58 (s, 1H, NH).
13
C NMR (125 MHz, DMSO): δ = 52.1, 61.2, 114.9, 121.4, 124.8,
126.4, 126.7, 127.1, 127.6, 128.1, 128.3, 128.6, 130.2, 131.7, 135.4,
136.8, 143.0, 145.6, 158.2. Anal Calcd for C31H24BrN5O: C, 66.20; H,
4.30; N, 12.45. Found C, 66.34; H, 4.52; N, 12.62.
4.2.10. 4-((4-(4,5-bis(4-Methoxyphenyl)-1H-imidazol-2-yl)phenoxy)
methyl)-1-(2-methylbenzyl)-1H-1,2,3-triazole 7j
White powder, Yield: 70%, mp = 102–105 °C. IR (KBr): 3430, 2934,
1612 cm−1. 1H NMR (500 MHz, CDCl3): δ = 2.26 (s, 3H, CH3), 3.80 (s,
6H, 2 × OMe), 5.14 (s, 2H, CH2), 5.51 (s, 2H, CH2), 6.83 (d, J = 8.0 Hz,
4H, 2 × 4-methoxyaryl), 6.94 (d, J = 8.5 Hz, 2H, H2, H6), 7.14 (d,
J = 7.0 Hz, 1H, H6′), 7.19–7.28 (m, 2H, H4′, H5′), 7.41–7.44 (m, 5H,
2 × 4-methoxyaryl, H3′), 7.78 (d, J = 8.5 Hz, 2H, H3, H5), 7.98 (s, 1H,
triazole). 13C NMR (125 MHz, CDCl3): δ = 20.5, 52.4, 55.3, 62.1, 114.0,
115.1, 122.5, 123.7, 126.7, 126.8, 129.1, 129.2, 129.5, 129.8, 130.0,
131.1, 132.5, 135.8, 144.0, 145.5, 146.5, 158.6, 158.9. Anal Calcd for
C34H31N5O2: C, 73.23; H, 5.60; N, 12.56. Found C, 73.54; H, 5.41; N,
12.34.
M. Saeedi, et al.
4.2.11. 4-((4-(4,5-bis(4-Methoxyphenyl)-1H-imidazol-2-yl)phenoxy)
methyl)-1-(4-fluorobenzyl)-1H-1,2,3-triazole7k
White powder, Yield: 75%, mp = 170–172 °C. IR (KBr): 3425, 3037,
1608 cm−1. 1H NMR (500 MHz, DMSO‑d6): δ = 3.75 (s, 3H, OMe), 3.80
(s, 3H, OMe), 5.20 (s, 2H, CH2), 5.61 (s, 2H, CH2), 6.86 (d, J = 8.5 Hz,
2H, 4-methoxyaryl), 6.99 (d, J = 8.5 Hz, 2H, 4-methoxyaryl), 7.11 (d,
J = 8.5 Hz, 2H, H2, H6), 7.21 (t, J = 8.5 Hz, 2H, H3′, H5′), 7.39–7.45
(m, 6H, 2 × 4-methoxyaryl, H2′, H6′), 7.97 (d, J = 8.5 Hz, 2H, H3, H5),
8.29 (s, 1H, triazole), 12.30 (s, 1H, NH). 13C NMR (125 MHz,
DMSO‑d6): δ = 57.0, 59.9, 60.1, 18.5, 119.0, 120.5 (JC-F = 21.2 Hz),
126.0, 128.0, 128.6, 129.5, 131.0, 131.4, 133.0, 134.5, 135.2, 141.2,
148.0, 149.7, 156.0, 157.3, 161.9 (JC-F = 245.0 Hz). Anal Calcd for
C33H28FN5O2: C, 70.58; H, 5.03; N, 12.47. Found C, 70.74; H, 4.86; N,
12.21.
4.2.12. 4-((4-(4,5-bis(4-Methoxyphenyl)-1H-imidazol-2-yl)phenoxy)
methyl)-1-(3,4-dichlorobenzyl)-1H-1,2,3-triazole 7l
White powder, Yield: 70%, mp = 102–104 °C. IR (KBr): 3430, 2999,
1613 cm−1. 1H NMR (500 MHz, DMSO‑d6): δ = 3.75 (s, 3H, OMe), 3.80
(s, 3H, OMe), 5.21 (s, 2H, CH2), 5.65 (s, 2H, CH2), 6.87–6.99 (m, 5H,
2 × 4-methoxyaryl, H6′), 7.12 (d, J = 7.0 Hz, 2H, H2, H6), 7.30 (d,
J = 7.0 Hz, 1H, H5′), 7.41–7.45 (m, 4H, 2 × 4-methoxyaryl), 7.64 (s,
1H, H2′), 7.97 (d, J = 7.0 Hz, 2H, H3, H5), 8.34 (s, 1H, triazole), 12.33
(s, 1H, NH). 13C NMR (125 MHz, DMSO‑d6): δ = 51.4, 55.0, 61.1,
113.5, 114.0, 123.6, 124.7, 126.5, 128.1, 128.3, 129.5, 130.0, 130.9,
132.3, 133.5, 136.8, 137.8, 140.5, 140.8, 143.0, 149.9, 157.9. Anal
Calcd for C33H27Cl2N5O2: C, 64.71; H, 4.44; N, 11.43. Found C, 64.51;
H, 4.67; N, 11.25.
4.2.13. 4-((4-(4,5-Diphenyl-1H-imidazol-2-yl)-2-methoxyphenoxy)
methyl)-1-(2-fluorobenzyl)-1H-1,2,3-triazole 7m
Cream powder, Yield: 88%, mp = 214–216 °C. IR (KBr): 3350,
2950, 2825, 1680, 1575 cm−1. 1H NMR (500 MHz, DMSO‑d6): δ = 3.82
(s, 3H, OCH3), 5.17 (s, 2H, OCH2), 5.70 (s, 2H, OCH2), 7.20–7.67 (m,
15H, 2 × Ph, H6, H3′, H4′, H5′, H6′), 7.65 (d, J = 8.0 Hz, 1H, H5), 7.67
(s, 1H, H3), 8.29 (s, 1H, triazole), 12.56 (s, 1H, NH). 13C NMR
(125 MHz, DMSO): δ = 61.6, 55.5, 46.9, 109.0, 113.7, 115.6 (d, JC-
F = 20.0 Hz), 117.7, 122.8 (d, JC-F = 13.7 Hz), 123.8, 124.8 (d, JC-
F = 3.7 Hz), 126.4, 127.0, 127.7, 128.1, 128.6 (d, JC-F = 30.0 Hz),
130.8, 131.2, 135.2, 136.8, 142.8, 145.6, 147.6, 149.1, 161.1 (d, JC-
F = 245.0 Hz). Anal Calcd for C32H26FN5O2: C, 72.30; H, 4.93; N, 13.17.
Found C, 72.33; H, 4.88; N, 13.14.
4.2.14. 4-((4-(4,5-Diphenyl-1H-imidazol-2-yl)-2-methoxyphenoxy)
methyl)-1-(4-fluorobenzyl)-1H-1,2,3-triazole 7n
Cream powder, Yield: 86%, mp = 247–249 °C. IR (KBr): 3420,
2965, 2850, 1690, 1585 cm−1. 1H NMR (500 MHz, DMSO‑d6): δ = 3.83
(s, 3H, OCH3), 5.18 (s, 2H, OCH2), 5.62 (s, 2H, OCH2), 7.22–7.69 (m,
13H, 2 × Ph, H6, H3′, H5′), 7.53 (dd, J = 8.0, 5.0 Hz, 2H, H2′, H6′),
7.66 (d, J = 8.0 Hz, 1H, H5), 7.69 (s, 1H, H3), 8.31 (s, 1H, triazole),
12.58 (s, 1H, NH). 13C NMR (125 MHz, DMSO): δ = 52.0, 61.7, 55.5,
109.0, 113.8, 115.6 (d, JC-F = 21.2 Hz), 117.8, 123.8, 124.8, 126.4,
127.1, 127.7, 128.2, 128.4, 128.7, 130.3, 130.4, 131.3, 132.3, 135.3,
136.8, 142.9, 145.6, 147.6, 149.1, 161.9 (d, JC-F = 242.5 Hz). Anal
Calcd for C32H26FN5O2: C, 72.30; H, 4.93; N, 13.17. Found C, 72.12; H,
4.72; N, 13.42
4.2.15. 1-(4-Chlorobenzyl)-4-((4-(4,5-diphenyl-1H-imidazol-2-yl)-2-
methoxyphenoxy)methyl)-1H-1,2,3-triazole 7o
Cream powder, Yield: 84%, mp = 228–230 °C. IR (KBr): 3420,
2855, 1670, 1589 cm−1. 1H NMR (500 MHz, DMSO‑d6): δ = 3.83 (s,
3H, OCH3), 5.19 (s, 2H, OCH2), 5.64 (s, 2H, OCH2), 7.21–7.47 (m, 11H,
2 × Ph, H6), 7.51 (d, J = 8.0 Hz, 2H, H2′, H6′), 7.56 (d, J = 8.0 Hz, 2H,
H3′, H5′), 7.65 (d, J = 8.0 Hz, 1H, H5), 7.69 (s, 1H, H3), 8.32 (s, 1H,
triazole), 12.57 (s, 1H, NH). 13C NMR (125 MHz, DMSO): δ = 52.5,
56.0, 62.2, 109.4, 114.3, 118.20, 124.3, 125.4, 126.9, 127.5, 128.1,
8
Bioorganic & Medicinal Chemistry 27 (2019) 115148
128.6, 128.8, 128.9, 129.1, 129.2, 130.4, 131.7, 133.3, 135.4, 135.7,
137.2, 143.4, 146.0, 148.0, 149.6. Anal Calcd for C32H26ClN5O2: C,
70.13; H, 4.78; N, 12.78. Found C, 70.38; H, 4.59; N, 12.62.
4.2.16. 4-((4-(4,5-Diphenyl-1H-imidazol-2-yl)-2-methoxyphenoxy)
methyl)-1-(4-nitrobenzyl)-1H-1,2,3-triazole 7p
Cream powder, Yield: 95%, mp = 233–235 °C. IR (KBr): 3450,
2955, 2850, 1690, 1585 cm−1. 1H NMR (500 MHz, DMSO‑d6): δ = 3.84
(s, 3H, OCH3), 5.22 (s, 2H, CH2), 5.83 (s, 2H, CH2), 7.23–7.57 (m, 13H,
2 × Ph, H6, H2′, H6′), 7.68 (d, J = 8.5 Hz, 1H, H5), 7.71 (s, 1H, H3),
8.26 (d, J = 8.3 Hz, 2H, H3′, H5′), 8.40 (s, 1H, triazole), 12.60 (s, 1H,
NH). 13C NMR (125 MHz, DMSO): δ = 52.1, 55.7, 61.9, 109.2, 114.0,
118.0, 123.9, 124.0, 124.1, 125.5, 126.6, 127.2, 127.9, 128.3, 128.6,
128.8, 129.2, 131.3, 135.4, 136.9, 143.3, 143.5, 145.8, 147.4, 147.8,
149.3. Anal Calcd for C32H26N6O4: C, 68.81; H, 4.69; N, 15.05. Found
C, 68.66; H, 4.58; N, 14.94.
4.3. In vitro α-glucosidase inhibition assay
A mixture containing phosphate buffer saline (135 µL, pH 6.8,
50 mM), test compound (20 µL) dissolved in DMSO (10% final con-
centration), and solution of α-glucosidase (Saccharomyces cerevisiae,
EC3.2.1.20, 20 U/mg, 20 µL) was pre incubated at 37 °C for 10 min in a
96-well plate. In order to initiate the enzyme-catalyzed reaction, 25 µL
of substrate (p-nitrophenyl-α-D-glucopyranoside, 4 mM) was added to
each well and the absorbance change was recorded at 400 nm within
20 min at 37 °C. The percentage of inhibition for tested compounds 7a-
p, control, and acarbose as positive control was calculated using the
following formula:
% Inhibition = [(Abs control − Abs sample)/Abs control] × 100.
IC50 values were calculated from the nonlinear regression curve using
the Logit method.
4.4. Kinetic study
The α-glucosidase solution (1 U/mL, 20 μL) was incubated with
different concentrations of 0, 40, 65, and 90 μM of the most potent
compound 7b (20 μL) for 15 min at 30 °C. Then, the enzymatic reaction
was initiated by adding various concentrations of p-nitrophenyl gluco-
pyranoside as substrate (1–4 mM). Finally, change in the absorbance
was recorded at 405 nm for 20 min using spectrophotometer (Gen5,
Power wave xs2, BioTek, America).
A Lineweaver–Burk plot was generated to identify the type of in-
hibition and the Michaelis–Menten constant (Km) value was determined
from plot between reciprocal of the substrate concentration (1/[S]) and
reciprocal of enzyme rate (1/V) over various inhibitor concentrations.
Experimental inhibitor constant (Ki) value was constructed by sec-
ondary plots of the inhibitor concentration [I] versus Km.
Also, the same procedure was conducted for compounds 7c and 7e
with different concentrations of 0, 40, 70, and 100 µM for compound 7c
and 0, 37, 67, and 97 µM for compound 7e.
4.5. Docking study
Docking studies of the most potent compounds 7b, 7c, and 7e were
performed exactly based on our previous report.27
Declaration of Competing Interest
There is no conflict of interest.
Acknowledgements
This work was supported by Research Council of Tehran University
of Medical Sciences and International Campus (TUMS-IC) with project
No. 94-01-169-28719.
M. Saeedi, et al.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bmc.2019.115148.
References
1. Scheen AJ. Is there a role for α-glucosidase inhibitors in the prevention of type 2
diabetes mellitus? Drugs. 2003;63:933–951.
2. Baron AD. Postprandial hyperglycaemia and α-glucosidase inhibitors. Diabetes Res
Clin Pract. 1998;40:S51–S55.
3. Howe JD, Smith N, Lee MR, et al. Novel imino sugar α-glucosidase inhibitors as
antiviral compounds. Bioorg Med Chem. 2013;21:4831–4838.
4. Pili R, Chang J, Partis RA, Mueller RA, Chrest FJ, Passaniti A. The α-glucosidase I
inhibitor castanospermine alters endothelial cell glycosylation, prevents angiogen-
esis, and inhibits tumor growth. Cancer Res. 1995;55:2920–2926.
5. Shimada Y, Nishimura E, Hoshina H, et al. Proteasome inhibitor bortezomib en-
hances the activity of multiple mutant forms of lysosomal α-glucosidase in pompe
disease. JIMD Rep. 2015;18:33–39.
6. Park SH, Kim JY, Kim JS, Jung C, Song DK, Ham WH. 1,3-Oxazine as a chiral building
block used in the total synthesis of (+)-1-deoxynojirimycin and (2R,5R)-dihydrox-
ymethyl-(3R,4R)-dihydroxypyrrolidine. Tetrahedron Asymmetry. 2015;26:657–661.
7. Hollander P. Safety profile of acarbose, an α-glucosidase inhibitor. Drugs.
1992;44:47–53.
8. Wardrop DJ, Waidyarachchi SL. Synthesis and biological activity of naturally oc-
curring α-glucosidase inhibitors. Nat Prod Rep. 2010;27:1431–1468.
9. Xie W, Tanabe G, Xu J, et al. Research progress of synthesis and structure-activity
relationship studies on sulfonium-type α-glucosidase inhibitors isolated from Salacia
genus plants. Mini-Rev Org Chem. 2013;10:141–159.
10. Saeedi M, Hadjiakhondi A, Nabavi SM, Manayi A. Heterocyclic compounds: effective
α-amylase and α-glucosidase inhibitors. Curr Top Med Chem. 2017;17:428–440.
11. Zhang L, Peng XM, Damu GL, Geng RX, Zhou CH. Comprehensive review in current
developments of imidazole-based medicinal chemistry. Med Res Rev.
2014;34:340–437.
12. Wang XQ, Liu LX, Li Y, et al. Design, synthesis and biological evaluation of novel
hybrid compounds of imidazole scaffold-based 2-benzylbenzofuran as potent antic-
ancer agents. Eur J Med Chem. 2013;62:111–121.
13. Nath M, Saini PK, Kumar A. New di- and triorganotin (IV) complexes of tripodal
Schiff base ligand containing three imidazole arms: Synthesis, structural character-
ization, anti-inflammatory activity and thermal studies. J Organomet Chem.
2010;695:1353–1362.
14. Pandey J, Tiwari VK, Verma SS, et al. Synthesis and antitubercular screening of
imidazole derivatives. Eur J Med Chem. 2009;44:3350–3355.
Bioorganic & Medicinal Chemistry 27 (2019) 115148
15. Almirante L, Polo L, Mugnaini A, et al. Murmann W. Derivatives of imidazole. I.
Synthesis and reactions of imidazo[1,2-a]pyridines with analgesic, antiin-
flammatory, antipyretic, and anticonvulsant activity. J Med Chem. 1965;8:305–312.
16. Sameem B, Saeedi M, Mahdavi M, Shafiee A. A review on tacrine-based scaffolds as
multi-target drugs (MTDLs) for Alzheimer's disease. Eur J Med Chem.
2017;128:332–345.
17. Sharma D, Narasimhan B, Kumar P, et al. Synthesis, antimicrobial and antiviral
evaluation of substituted imidazole derivatives. Eur J Med Chem.
2009;44:2347–2353.
18. Karakurt A, Dalkara S, Özalp M, Özbey S, Kendi E, Stables JP. Synthesis of some 1-(2-
naphthyl)-2-(imidazole-1-yl)ethanone oxime and oxime ether derivatives and their
anticonvulsant and antimicrobial activities. Eur J Med Chem. 2001;36:421–433.
19. Yar M, Bajda M, Shahzad S, et al. Organocatalyzed solvent free an efficient novel
synthesis of 2,4,5-trisubstituted imidazoles for α-glucosidase inhibition to treat
diabetes. Bioorg Chem. 2015;58:65–71.
20. Chaudhry F, Choudhry S, Huma R, et al. Hetarylcoumarins: synthesis and biological
evaluation as potent α-glucosidase inhibitors. Bioorg Chem. 2017;73:1–9.
21. Chaudhry F, Naureen S, Huma R, et al. In search of new α-glucosidase inhibitors:
Imidazolylpyrazole derivatives. Bioorg Chem. 2017;71:102–109.
22. Agalave SG, Maujan SR, Pore VS. Click chemistry: 1,2,3-triazoles as pharmacophores.
Chem Asian J. 2011;6:2696–2718.
23. Chinthala Y, Thakur S, Tirunagari S, et al. docking and ADMET studies of novel
chalcone triazoles for anti-cancer and anti-diabetic activity. Eur J Med Chem.
2015;93:564–573.
24. da Rocha DR, Santos WC, Lima ES, Ferreira VF. Synthesis of 1,2,3-triazole glyco-
conjugates as inhibitors of α-glucosidases. Carbohydr Res. 2012;350:14–19.
25. Wang G, Peng Z, Wang J, Li J, Li X. Synthesis and biological evaluation of novel
2,4,5-triarylimidazole-1,2,3-triazole derivatives via click chemistry as α-glucosidase
inhibitors. Bioorg Med Chem Lett. 2016;26:5719–5723.
26. Saeedi M, Mohammadi-Khanaposhtani M, Pourrabia P, et al. Design and synthesis of
novel quinazolinone-1,2,3-triazole hybrids as new anti-diabetic agents: In vitro α-
glucosidase inhibition, kinetic, and docking study. Bioog Chem. 2019;83:161–169.
27. Adib M, Peytam F, Rahmanian-Jazi M, et al. New 6-amino-pyrido[2,3-d]pyrimidine-
2,4-diones as novel agents to treat type 2 diabetes: a simple and efficient synthesis, α-
glucosidase inhibition, molecular modeling and kinetic study. Eur J Med Chem.
2018;155:353–363.
28. Zhang XQ, Mou XF, Mao N, et al. Design, semisynthesis, α-glucosidase inhibitory,
cytotoxic, and antibacterial activities of p-terphenyl derivatives. Eur J Med Chem.
2018;146:232–244.
29. Mauldina MG, Sauriasari R, Elya B. α-Glucosidase inhibitory activity from ethyl
acetate extract of Antidesma bunius (L.) Spreng stem bark containing triterpenoids.
Pharmacogn Mag. 2017;13:590–594.
30. Mahdavi M, Ashtari A, Khoshneviszadeh M, et al. Synthesis of new benzimidazole-
1,2,3-triazole hybrids as tyrosinase inhibitors. Chem Biodiversity. 2018;15:e1800120.