A new series of Schiff base derivatives bearing 1,2,3-triazole: Design, synthesis, molecular docking, and α-glucosidase inhibition

Article abstract of DOI:10.1002/ardp.201900034

A series of new Schiff bases bearing 1,2,3-triazole 12a?o was designed, synthesized, and evaluated as α-glucosidase inhibitors. All the synthesized compounds showed promising inhibition against α-glucosidase and were more potent than the standard drug aca

Full text of DOI:10.1002/ardp.201900034

Received: 31 January 2019
Revised: 18 April 2019
Accepted: 1 May 2019
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DOI: 10.1002/ardp.201900034
F U L L P A P E R
A new series of Schiff base derivatives bearing
1,2,3‐triazole: Design, synthesis, molecular docking, and
α‐glucosidase inhibition
Ensieh Nasli‐Esfahani1
Yaghoub Sarrafi4 Zeinab Sharafi5
Haleh Hamedifar7
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Maryam Mohammadi‐Khanaposhtani2
Nasser Samadi6 Mohammad Ali Faramarzi6
Bagher Larijani8 Mirhamed Hajimiri9
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Sepideh Rezaei3
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Fatemeh Bandarian1
Mohammad Mahdavi8
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1Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
2Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
3School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
4Faculty of Chemistry, University of Mazandaran, Babolsar, Iran
5Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
6Department of Pharmaceutical Biotechnology, Faculty of Pharmacy and Biotechnology Research Center, Tehran University of Medical Sciences, Tehran, Iran
7CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj, Iran
8Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
9Nano Alvand Company, Avicenna Tech Park, Tehran University of Medical Sciences, Tehran, Iran
Correspondence
Abstract
Dr. Mirhamed Hajimiri, Nano Alvand
Company, Avicenna Tech Park, Tehran
A series of new Schiff bases bearing 1,2,3‐triazole 12a‒o was designed,
University of Medical Sciences, Tehran
synthesized, and evaluated as α‐glucosidase inhibitors. All the synthesized
1439955991, Iran.
Email: h.hajimiri@nanoalvand.com
compounds showed promising inhibition against α‐glucosidase and were more
potent than the standard drug acarbose. The kinetic study on the most potent
compound 12n showed that this compound acted as a competitive α‐glucosidase
inhibitor. The docking study revealed that the synthesized compounds interacted
with the important residues in the active site of α‐glucosidase.
Dr. Mohammad Mahdavi, Endocrinology and
Metabolism Research Center, Endocrinology
and Metabolism Clinical Sciences Institute,
Tehran University of Medical Sciences, Tehran
71877, Iran.
Email: momahdavi@tums.ac.ir
K E Y W O R D S
1,2,3‐triazole, antidiabetic activity, molecular docking, Schiff base, α‐glucosidase
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1
INTRODUCTION
mediated diseases such as cancer, Alzheimer’s, hepatitis, and viral
infections.[4–6] Therefore, the design and development of new
The α‐glucosidase is one of the most important hydrolase enzymes, which
exist in the human intestinal cells. This enzyme is essential for the
hydrolysis of poly‐ and disaccharides into glucose monomers, which are
absorbed into the blood.[1] In type 2 diabetes, in which the body becomes
resistant to insulin, the use of α‐glucosidase inhibitors can be useful to
reduce postprandial hyperglycemia.[2] Available α‐glucosidase inhibitors
such as acarbose and miglitol cause diarrhea and other intestinal
disturbances.[3] In contrast, there are several reports showing that
α‐glucosidase inhibitors can be useful for the treatment of carbohydrate‐
α‐glucosidase inhibitors with high efficacy and low side effect are
attractive for medicinal chemists.[7–9]
A Schiff base unit is a valuable pharmacophore that has been found in
numerous biologically active compounds such as analgesic, antioxidant,
antileishmanial, and antidiabetic agents.[10–13] Recently, several series of
α‐glucosidase inhibitors containing Schiff bases such as compounds A, B,
and C have been reported (Figure 1).[14–16] In contrast, 1,2,3‐triazoles are
an important class of heterocycles, which have a wide spectrum of
pharmaceutical applications. 1,2,3‐Triazole derivatives exhibit various
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Arch Pharm Chem Life Sci. 2019;e1900034.
wileyonlinelibrary.com/journal/ardp © 2019 Deutsche Pharmazeutische Gesellschaft
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FIGURE 1 Design strategy of novel Schiff base derivatives bearing 1,2,3‐triazole 12a–o as new α‐glucosidase inhibitors based on molecular
hybridization of pharmacophoric units of reported α‐glucosidase inhibitors A–D
biological activities such as antibacterial, antifungal, anticancer,
antidiabetic potentials.[17–20] Some of these derivatives have also shown
significant inhibitory activity against α‐glucosidase.[21–23] In this regard,
we have recently reported a series of 1,2,3‐triazole derivatives D with
high α‐glucosidase inhibitory activity (Figure 1).[24]
chlorides 2, and triethylamine (NEt3) in ethanol was stirred at
room temperature for 12 hr. After that, acetic anhydride was
added to the solution, and stirring was continued for another
12 hr at room temperature to afford 2‐phenyl‐4H‐benzo[d][1,3]‐
oxazin‐4‐ones 3. Compounds 3 easily reacted with hydrazine 4 at
room temperature and afforded 2‐benzamidobenzohydrazides 5.
In contrast, 3‐methoxy‐4‐(prop‐2‐ynyloxy)benzaldehyde 8 was
prepared by the reaction between 4‐hydroxy‐3‐methoxybenzal-
dehyde 6 and propargyl bromide 7 in the presence of K2CO3 in
dimethylformamide (DMF) at room temperature. In the next step,
2‐benzamidobenzohydrazides 5 reacted with 3‐methoxy‐4‐(prop‐
2‐ynyloxy)benzaldehyde 8 in ethanol at room temperature to
produce (E)‐N′(4‐(prop‐2‐ynyloxy)benzylidene)‐2‐benzamidoben-
zohydrazides 9. The latter compounds participated in a click
reaction. For this purpose, different benzyl halide derivatives 10
and sodium azide reacted in the presence of Et3N in the mixture
of H2O and tert‐butyl alcohol (t‐BuOH; 1:1) at room temperature.
Then, the mixture of compounds 9, CuSO4·5H2O, and sodium
ascorbate was added to the freshly prepared azide derivatives
11 and the reaction was continued at room temperature for
24–48 hr to produce the target compounds 12a–o.
Herein, in view of the α‐glucosidase inhibitory activities of
compounds containing Schiff base or 1,2,3‐triazole and in
continuation to our interest in the discovery of potent
α‐glucosidase inhibitors, we reported the design and synthesis of
a series of new Schiff bases bearing 1,2,3‐triazole 12a–o.[25–27] All
the synthesized derivatives 12a–o were screened for their in vitro
α‐glucosidase inhibitory activities. Moreover, kinetic and docking
studies were also performed to further evaluate of interactions of
these compounds in the active site of α‐glucosidase.
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2
RESULTS AND DISCUSSION
Chemistry
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2.1
The designed compounds 12a–o were synthesized according to
Scheme 1. First, a solution of 2‐aminobenzoic acid 1, benzoyl

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X = Cl, Br
SCHEME 1 Reagents and conditions for the synthesis of compounds 12a–o. (a) NEt3, ethanol, room temperature, 12 hr. (b) Acetic anhydride, room
temperature, 12 hr. (c) Ethanol, room temperature, 12 hr. (d) K2CO3, DMF, room temperature, 3 hr. (e) Ethanol, room temperature, 24 hr. (f) NaN3, NEt3,
H2O/t‐BuOH, 1 hr; (g) CuSO4·5H2O, sodium ascorbate, room temperature, 24‐48 hr. DMF, dimethylformamide; t‐BuOH, tert‐butyl alcohol
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2.2
Biology
methoxy substituent as an electron‐donating group or chlorine atom
as an electron‐withdrawing substituent onto the 2‐position of the
pendant phenyl group led to a significant decrease in the inhibitory
activity, as observed in the compounds 12b and 12c, respectively. By
comparing the IC50 values of the 2‐chloro derivative 12c with the
2,3‐dichloro derivative 12d or 2,6‐dichloro derivative 12e, it could
be concluded that the introduction of second chlorine atom onto the
3‐position of the pendant phenyl group significantly increased
inhibitory activity. Interestingly, the 3‐chloro derivative 12f showed
the most potent activity in unsubstituted benzamide series while
the 2‐chloro derivative 12c was the less active halo‐substituted
compound. Replacement of the 3‐chloro substituent of the compound
12f with the 3‐bromo substituent, as in the compound 12g, decreased
inhibitory activity. Moreover, the translocation of bromine atom of
3‐ to 4‐position of the pendant phenyl ring had no significant effect on
inhibitory activity (compound 12g vs. 12h).
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2.2.1
In vitro α‐glucosidase inhibitory activity
The synthesized compounds 12a–o were evaluated for their in vitro
α‐glucosidase inhibition, in comparison to the standard drug
acarbose. The obtained results are summarized in Table 1. All the
synthesized compounds displayed excellent α‐glucosidase inhibitory
activity with IC50 values in the range of 107.1 1.4 to 374.7 1.3 µM,
as compared with acarbose (IC50 = 750.0 1.5 µM).
Structurally, the synthesized compounds 12a–o were divided into
two series based on the structure of 2‐benzamide moiety: unsubstituted
benzamide derivatives 12a–h and 4‐methoxybenzamide derivatives
12i–o. In each series, the substituents on the pendant benzyl group
were altered to optimize the α‐glucosidase inhibitory activity.
In the first series, the compound 12a with a pendant unsubstituent
phenyl group showed good inhibitory activity. Introduction of the

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TABLE 1 In vitro α‐glucosidase inhibitory activity of compounds 12a–o
Compounds
12a
R1
H
H
H
H
H
H
H
H
R2
IC50 (µM)a
208.1 1.0
374.7 1.3
275.7 1.5
160.0 1.7
243.0 1.2
122.0 1.5
217.0 1.2
209.0 1.2
Compounds
12i
R1
R2
IC50 (µM)a
178.0 1.0
154.7 1.8
189.2 0.7
147.5 0.8
204.5 1.0
107.1 1.4
131.6 1.3
750.0 1.5
H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
–
H
12b
2‐OCH3
2‐Cl
12j
4‐CH3
2‐Cl
2,3‐Cl2
2,6‐Cl2
3‐Cl
4‐Br
–
12c
12k
12d
2,3‐Cl2
2,6‐Cl2
3‐Cl
12l
12e
12m
12f
12n
12g
3‐Br
12o
12h
4‐Br
Acarbose
aValues are the mean SD. All experiments were performed at least three times
The observed IC50 values of the second series 12i–o against
α‐glucosidase revealed that the better result was obtained with the
3‐chloro substituent (compound 12n). Similar to the unsubstituted
benzamide series, the 2,3‐dichloro derivative 12l was more active
than the 2‐chloro derivative 12k while the 2,6‐dichloro derivative
12m, unlike the first series, was less active than the 2‐chloro
The comparison of IC50 values of the first series derivatives with
their analogs of the second series revealed that the introduction of a
methoxy group onto the 4‐position of 2‐benzamide led to a significant
increase in inhibitory activity against α‐glucosidase (Table 1).
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2.2.2
Enzyme kinetic study
derivative 12k. The presence of electron‐donating methyl or an
electron‐withdrawing bromo substituent instead of hydrogen on the
4‐position of the pendant benzyl group led to the increase of
inhibitory activity, as demonstrated in the compounds 12i, 12j, and
12o in the order of Br > CH3 > H.
To gain further insight into the mechanism of action of the Schiff bases
bearing 1,2,3‐triazole 12a–o, a kinetic study of the compound 12n as
the most potent compound against α‐glucosidase was performed
(Figure 2). This study revealed that no change was observed in Vmax
(a)
(b)
FIGURE 2 Kinetics of α‐glucosidase inhibition by compound 12n. (a) The Lineweaver–Burk plot in the absence and presence of different
concentrations of compound 12n. (b) The secondary plot between Km and various concentrations of compound 12n

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FIGURE 3 Acarbose (cyan) and the most potent compounds 12n (pink) and 12f (yellow) superimposed in the active site pocket
values by increasing the concentration of the compound 12n while Km
values increased (Figure 2a). Therefore, this compound was
residues Asn241, His279, Thr301, Pro309, Ser308, Glu304, Thr307,
Arg312, and Gln322 in this modeled α‐glucosidase.[27]
a
competitive inhibitor against α‐glucosidase. On the basis of the obtained
results, the Ki value of the compound 12n was 113 μM (Figure 2b).
The theoretical binding mode between the most potent
compound 12n and α‐glucosidase is shown in Figure 4a. The NH
unit of the compound 12n formed three hydrogen bonds with Glu304
(2.634 Å), Thr307 (2.272 Å), and Ser308 (2.733 Å) and nitrogen atom
of the 1,2,3‐triazole ring established a hydrogen bond with Arg312
(2.141 Å). A π–anion interaction can be observed between the
3‐chlorophenyl group and Asp408. Furthermore, the compound 12n
showed several weak hydrophobic interactions with residues Thr301,
Val305, Pro309, and Arg312.
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2.3
Docking study
To expose the interaction modes of the synthesized compounds and
Saccharomyces cerevisiae α‐glucosidase enzyme at the molecular level, a
docking study was performed by AutoDock Tools (version 1.5.6). Since,
the crystallographic structure of this form of enzyme has not been so far
published, a homology model of S. cerevisiae α‐glucosidase was built
according to previous research.[27] The superposed structures of acarbose
(the standard inhibitor) and the most potent compounds 12n and 12f in
the active site of α‐glucosidase are shown in Figure 3. Acarbose as a
standard drug with binding energy = −4.04 kcal/mol interacted with
Elimination of the 4‐methoxy substituent of the 2‐benzamide moiety
from the compound 12n, as in the compound 12f, changed the interaction
mode (Figure 4a vs. 4b). The NH unit of the compound 12f, unlike the
compound 12n, could not interact with the active site of enzyme. In the
case of the compound 12f, a hydrogen bond can be observed between
nitrogen atom of the 1,2,3‐triazole ring and Arg312 (2.071 Å). It is worthy
FIGURE 4 The interaction modes of compounds (a) 12n and (b) 12f in the active site pocket

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to note that this hydrogen bond is stronger than the hydrogen bond of
compound 12n with Arg312. In contrast, the most potent compound 12n
formed more hydrophobic interactions (with Thr301, Val305, Pro309,
and Arg312) with the active site of enzyme when compared with the
second most potent compound 12f (Pro309 and Arg312). In contrast, the
compound 12f interacted with the important residue His279 via a π–π
and a π–cation interaction. Furthermore, a π–cation interaction between
3‐methoxybenzylidene and His239, as well as a hydrophobic interaction
between 3‐chloro substituent and Arg439, was also observed (Figure 4b).
Further studies on the binding energies of the compounds 12n and
12f showed that theoretically the compound 12n with binding
energy = −10.44 kcal/mol bound easily to the target enzyme compared
with the compound 12f with binding energy = −9.31 kcal/mol. These
findings confirmed the results obtained through in vitro assays.
12 hr. After that, the reaction mixture was poured into crushed
ice and filtered off. Then, the precipitated product was purified
by recrystallization in ethanol to obtain pure 2‐phenyl‐4H‐benzo[d][1,3]‐
oxazin‐4‐ones 3.[28]
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4.1.3
General procedure for the synthesis
of 2‐benzamidobenzohydrazides 5
A mixture of 2‐phenyl‐4H‐benzo[d][1,3]oxazin‐4‐ones 3 (1 mmol) and
hydrazine
4 (1 mmol) in ethanol (15 ml) was stirred at room
temperature for 12 hr. After that, the reaction mixture was
poured into crushed ice. The obtained white precipitate was
filtered off and purified using recrystallization from ethanol to obtain
pure 2‐benzamidobenzohydrazides 5.[29]
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4.1.4
General procedure for the synthesis
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3
CONCLUSION
of 3‐methoxy‐4‐(prop‐2‐ynyloxy)benzaldehyde 8
A suspension of 4‐hydroxy‐3‐methoxybenzaldehyde 6 (1 mmol) and
K2CO3 (1 mmol) in DMF (5 ml) was stirred at room temperature for
1 hr. Then, it was added to a solution of propargyl bromide 7
(1.2 mmol) in DMF (10 ml) in a dropwise manner and the reaction
mixture was stirred at room temperature for 2 hr. Subsequently, the
reaction mixture was poured into crushed ice and the obtained
precipitate was filtered off. The precipitate was then recrystallized in
ethanol to obtain 3‐methoxy‐4‐(prop‐2‐ynyloxy)benzaldehyde 8.[30]
In summary,
a series of new Schiff base derivatives bearing
1,2,3‐triazole 12a–o was synthesized and evaluated as α‐glucosidase
inhibitors. In vitro assay revealed that all the synthesized compounds
were more potent than the standard drug acarbose. These compounds
showed a two‐ to sevenfold higher activity than acarbose. The kinetic
study of the most potent compound 12n demonstrated that this
compound could inhibit α‐glucosidase in a competitive manner. Docking
simulations of the synthesized compounds confirmed that they well
interacted with the active site residues of α‐glucosidase.
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4.1.5
General procedure for the synthesis
of (E)‐N′‐(4‐(prop‐2‐ynyloxy)benzylidene)‐2‐
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4
EXPERIMENTAL
Chemistry
benzamidobenzohydrazides 9
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4.1
A mixture of 2‐benzamidobenzohydrazides 5 (1 mmol) and 3‐methoxy‐4‐
(prop‐2‐ynyloxy)benzaldehyde 8 (1 mmol) was stirred at room tempera-
ture for 24 hr. Then, it was poured into crushed ice and the participated
product was filtered off and recrystallized in ethanol to obtain pure (E)‐
N′‐(4‐(prop‐2‐ynyloxy)benzylidene)‐2‐benzamidobenzohydrazides 9.
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4.1.1
General
Melting points of the target compounds 12a–o were measured on a
Kofler hot stage apparatus and were uncorrected. 1H and 13C nuclear
magnetic resonance (NMR) spectra of the synthesized compounds
were determined on a Bruker FT‐500, using TMS as an internal
standard. 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.
The NMR spectra of the investigated compounds are provided as
Supporting Information. The InChI codes of the investigated
compounds together with some biological activity data are also
provided as Supporting Information.
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4.1.6
General procedure for the synthesis of
compounds 12a–o
At first, benzyl azide derivatives 11 were prepared in situ.
For this purpose,
a solution of benzyl halides 10 (1.1 mmol),
sodium azide (0.9 mmol), and Et3N (1.3 mmol) in the mixture of
water/t‐BuOH (8 ml, 1:1) was stirred at room temperature for 1 hr.
Subsequently, the mixture of (E)‐N′‐(4‐(prop‐2‐ynyloxy)benzylidene)‐
2‐benzamidobenzohydrazides 9 (1 mmol), CuSO4·5H2O (7 mol %),
and sodium ascorbate was added to the freshly prepared benzyl
azide derivatives 11 and stirred at room temperature for 24–48 hr.
Upon completion of the reaction (monitored by thin‐layer chromato-
graphy), the obtained reaction mixture was diluted with cold water
and poured into crushed ice. Then, the precipitated products 12a–o
were filtered off, washed with cold water, and purified by
recrystallization in ethanol.
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4.1.2
General procedure for the synthesis
of 2‐phenyl‐4H‐benzo[d][1,3]oxazin‐4‐ones 3
A solution of 2‐aminobenzoic acid 1 (1 mmol), benzoyl chlorides 2
(1 mmol), and NEt3 (1 mmol) in ethanol (15 ml) was stirred at room
temperature for 12 hr. Then, acetic anhydride (3 ml) was added to the
solution, and stirring was continued at room temperature for a further

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(E)‐N′‐(4‐((1‐Benzyl‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐3‐methoxyben-
zylidene)‐2‐benzamidobenzohydrazide (12a)
J = 8.4 Hz, 1H), 11.93 (s, 1H, NH), 12.03 (s, 1H, NH). 13C NMR
(100 MHz, DMSO‐d6): δ 51.63, 55.91, 62.04, 108.98, 113.71, 121.16,
121.53, 122.52, 123.62, 126.01, 127.51, 127.68, 129.07, 129.12,
129.40, 129.48, 131.06, 131.22, 132.58, 132.70, 132.96, 134.89,
136.31, 139.70, 143.03, 149.73, 149.80, 150.03, 165.02, 165.22.
Anal. calcd. for C32H26Cl2N6O4: C, 61.06; H, 4.16; N, 13.35. Found: C,
61.16; H, 4.29; N, 13.43.
Pale yellow crystals; yield, 72%; mp, 196–198°C. IR (KBr, cm−1):
3312, 3302, 3103, 1653, 1644. 1H NMR (400 MHz, deuterated
dimethyl sulfoxide [DMSO‐d6]): δ 3.80 (s, 3H, OMe), 5.19 (s, 2H, CH2),
5.62 (s, 2H, CH2), 7.23 (s, 2H), 7.27–7.29 (m, 1H), 7.31–7.40 (m, 6H),
7.58–7.65 (m, 4H), 7.89 (d, J = 7.2 Hz, 1H), 7.96 (d, J = 6.8 Hz, 2H),
8.30 (s, 1H), 8.39 (s, 1H), 8.56 (d, J = 8 Hz, 1H), 11.92 (s, 1H, NH),
12.02 (s, 1H, NH). 13C NMR (100 MHz, DMSO‐d6): δ 53.30, 55.94,
62.07, 108.93, 113.59, 121.17, 151.53, 122.53, 123.63, 125.43,
127.52, 127.61, 128.46, 128.65, 129.07, 129.25, 129.41, 132.58,
132.96, 134,89, 136.45, 139.69, 143.10, 149.73, 149.76, 150.07,
165.02, 165.20. Analytically calculated (Anal. calcd.) for C32H28N6O4:
C, 68.56; H, 5.03; N, 14.99. Found: C, 65.39; H, 5.16; N, 15.08.
(E)‐N′‐(4‐((1‐(2,6‐Dichlorobenzyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐3‐
methoxybenzylidene)‐2‐benzamidobenzohydrazide (12e)
Pale yellow crystals; yield, 73%; mp, 221–223°C. IR (KBr, cm−1):
3316, 3306, 3107, 1649, 1640. 1H NMR (400 MHz, DMSO‐d6): δ
3.80 (s, 3H, OMe), 5.17 (s, 2H, CH2), 5.82 (s, 2H, CH2), 7.23 (s, 2H),
7.25–7.29 (m, 1H), 7.36 (s, 1H), 7.46–7.50 (m, 1H), 7.58–7.65 (m, 6H),
7.90 (d, J = 8 Hz, 1H), 7.95 (d, J = 8 Hz, 2H), 8.27 (s, 1H), 8.39 (s, 1H),
8.56 (d, J = 8 Hz, 1H), 11.92 (s, 1H, NH), 12.02 (s, 1H, NH). 13C NMR
(100 MHz, DMSO‐d6): δ 49.09, 55.94, 61.89, 108.93, 113.55, 121.16,
121.52, 122.51, 123.62, 125.73, 127.51, 127.61, 129.07, 129.40,
129.47, 130.80, 132.15, 132.58, 132.95, 134.89, 136.40, 139.70,
142.61, 149.73, 150.07, 165.02, 165.21. Anal. calcd. for
C32H26Cl2N6O4: C, 61.06; H, 4.16; N, 13.35. Found: C, 60.94; H,
4.05; N, 13.27.
(E)‐N′‐(4‐((1‐(2‐Methoxybenzyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐3‐
methoxybenzylidene)‐2‐benzamidobenzohydrazide (12b)
Pale yellow crystals; yield, 78%; mp, 200–202°C. IR (KBr, cm−1):
3311, 3308, 3098, 1651, 1646. 1H NMR (400 MHz, DMSO‐d6): δ 3.73
(s, 3H, OMe), 3.80 (s, 3H, OMe), 5.19 (s, 2H, CH2), 5.58 (s, 2H, CH2),
6.87–6.90 (m, 2H), 6.91 (s, 1H), 7.23 (s, 2H), 7.27–7.31 (m, 2H), 7.38
(s, 1H), 7.58–7.65 (m, 4H), 7.89 (d, J = 7.2 Hz, 1H), 7.96 (d, J = 6.8 Hz,
2H), 8.30 (s, 1H), 8.38 (s, 1H), 8.55 (d, J = 8 Hz, 1H), 11.91 (s, 1H, NH),
12.01 (s, 1H, NH). 13C NMR (100 MHz, DMSO‐d6): δ 53.21, 55.53,
55.58, 62.06, 108.94, 113.57, 113.98, 114.21, 120.52, 121.18,
121.53, 122.53, 123.63, 125.46, 127.51, 129.06, 129.41, 130.25,
130.40, 132.58, 132.96, 134.89, 137.88, 139.69, 143.09, 149.76,
150.06, 159.90, 165.02, 165.19. Anal. calcd. for C33H30N6O5:
C, 67.11; H, 5.12; N, 14.23. Found: C, 67.21; H, 5.03; N, 14.19.
(E)‐N′‐(4‐((1‐(3‐Chlorobenzyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐3‐
methoxybenzylidene)‐2‐benzamidobenzohydrazide (12f)
Pale yellow crystals; yield, 79%; mp, 205–207°C. IR (KBr, cm−1):
3313, 3308, 3109, 1653, 1643. 1H NMR (400 MHz, DMSO‐d6): δ 3.81
(s, 3H, OMe), 5.20 (s, 2H, CH2), 5.65 (s, 2H, CH2), 7.23 (s, 2H), 7.36 (s,
1H), 7.40–7.42 (m, 3H), 7.58–7.65 (m, 4H), 7.89 (d, J = 7.2 Hz, 1H),
7.96 (d, J = 8 Hz, 2H), 8.35 (s, 1H), 8.39 (s, 1H), 8.56 (d, J = 8.4 Hz, 1H),
11.93 (s, 1H, NH), 12.02 (s, 1H, NH). 13C NMR (100 MHz, DMSO‐d6):
δ 52.51, 55.96, 62.07, 108.96, 113.62, 121.20, 121.52, 122.52,
123.62, 125.61, 127.21, 128.36, 128.65, 129.07, 129.41, 131.20,
132.58, 132.95, 133.75, 134.90, 138.83, 139.70, 143.21, 149.72,
149.78, 150.03, 165.03, 165.21. Anal. calcd. for C32H27ClN6O4: C,
64.59; H, 4.57; N, 14.12. Found: C, 64.41; H, 4.66; N, 14.20.
(E)‐N′‐(4‐((1‐(2‐Chlorobenzyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐3‐
methoxybenzylidene)‐2‐benzamidobenzohydrazide (12c)
Pale yellow crystals; yield, 76%; mp, 203–205°C. IR (KBr, cm−1):
3311, 3309, 3109, 1649, 1641. 1H NMR (400 MHz, DMSO‐d6): δ
3.80 (s, 3H, OMe), 5.19 (s, 2H, CH2), 5.73 (s, 2H, CH2), 7.23 (s, 2H),
7.24–7.28 (m, 2H), 7.36–7.41 (m, 3H), 7.53 (d, 1H), 7.58–7.65 (m, 4H),
7.89 (d, J = 6.8 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 8.27 (s, 1H), 8.38 (s,
1H), 8.54 (d, J = 8 Hz, 1H), 11.90 (s, 1H, NH), 12.03 (s, 1H, NH). 13C
NMR (100 MHz, DMSO‐d6): δ 51.09, 55.96, 62.00, 108.96, 113.66,
121.21, 121.57, 122.54, 123.67, 125.86, 127.51, 127.63, 128.22,
129.05, 129.41, 130.12, 130.79, 131.05, 132.60, 132.97, 133.12,
133.65, 134.86, 139.64, 142.94, 149.75, 149.77, 150.03, 165.05,
165.23. Anal. calcd. for C32H27ClN6O4: C, 64.59; H, 4.57; N, 14.12.
Found: C, 64.75; H, 4.62; N, 14.25.
(E)‐N′‐(4‐((1‐(3‐Bromobenzyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐3‐
methoxybenzylidene)‐2‐benzamidobenzohydrazide (12g)
Pale yellow crystals; yield, 76%; mp, 211–213°C. IR (KBr, cm−1):
3311, 3307, 3106, 1659, 1646. 1H NMR (400 MHz, DMSO‐d6): δ 3.79
(s, 3H, OMe), 5.19 (s, 2H, CH2), 5.64 (s, 2H, CH2), 7.22 (s, 2H),
7.25–7.28 (m, 1H), 7.30–7.37 (m, 3H), 7.53–7.63 (m, 6H), 7.90 (d,
J = 7.6 Hz, 1H), 7.96 (d, J = 7.2 Hz, 2H), 8.35 (s, 1H), 8.39 (s, 1H), 8.55
(d, J = 8.4 Hz, 1H), 11.92 (s, 1H, NH), 12.04 (s, 1H, NH). 13C NMR
(100 MHz, DMSO‐d6): δ 52.47, 55.87, 62.03, 108.95, 113.58, 121.15,
121.55, 122.33, 122.59, 123.65, 125.60, 127.51, 127.59, 127.63,
129.04, 129.40, 131.21, 131.46, 131.55, 132.59, 132.98, 134.85,
139.03, 139.67, 143.21, 149.76, 150.02, 165.04, 165.25. Anal. calcd.
for C32H27BrN6O4: C, 60.10; H, 4.26; N, 13.14. Found: C, 60.16; H,
4.35; N, 13.05.
(E)‐N′‐(4‐((1‐(2,3‐Dichlorobenzyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐3‐
methoxybenzylidene)‐2‐benzamidobenzohydrazide (12d)
Pale yellow crystals; yield, 75%; mp, 206–208°C. IR (KBr, cm−1):
3308, 3307, 3105, 1645, 1643. 1H NMR (400 MHz, DMSO‐d6): δ
3.81 (s, 3H, OMe), 5.21 (s, 2H, CH2), 5.79 (s, 2H, CH2), 7.18 (d,
J = 7.6 Hz, 1H), 7.23 (s, 2H), 7.27–7.30 (m, 1H), 7.36 (s, 1H), 7.38–7.42
(m, 1H), 7.58–7.65 (m, 3H), 7.67 (d, J = 7.2 Hz, 2H), 7.90 (d, J = 8 Hz,
1H), 7.96 (d, J = 7.2 Hz, 2H), 8.31 (s, 1H), 8.39 (s, 1H), 8.56 (d,

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(E)‐N′‐(4‐((1‐(3‐Bromobenzyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐3‐
methoxybenzylidene)‐2‐benzamidobenzohydrazide (12h)
21.46, 51.09, 55.88, 62.00, 108.96, 113.65, 120.92, 121.42, 122.57,
123.49, 125.84, 127.53, 127.65, 128.21, 129.03, 129.93, 130.12,
130.78, 131.05, 132.05, 132.97, 133.13, 133.64, 139.81, 142.72,
142.95, 149.77, 150.03, 164.93, 165.30. Anal. calcd. for
Pale yellow crystals; yield, 73%; mp, 209–211°C. IR (KBr, cm−1):
3311, 3309, 3114, 1657, 1645. 1H NMR (400 MHz, DMSO‐d6): δ
3.80 (s, 3H, OMe), 5.19 (s, 2H, CH2), 5.61 (s, 2H, CH2), 7.23 (s, 2H),
7.27–7.30 (m, 3H), 7.36 (s, 1H), 7.58–7.65 (m, 6H), 7.90 (d, J = 7.2 Hz,
1H), 7.96 (d, J = 8 Hz, 2H), 8.31 (s, 1H), 8.39 (s, 1H), 8.56 (d, J = 8.4 Hz,
1H), 11.93 (s, 1H, NH), 12.02 (s, 1H, NH). 13C NMR (100 MHz,
DMSO‐d6): δ 52.54, 55.90, 62.07, 108.98, 113.62, 121.18, 121.53,
121.94, 122.51, 123.63, 125.49, 127.52, 127.65, 129.07, 129.41,
130.73, 132.18, 134.90, 135.85, 139.70, 143.16, 149.72, 149.77,
150.05, 165.02, 165.21. Anal. calcd. for C32H27BrN6O4: C, 60.10; H,
4.26; N, 13.14. Found: C, 60.13; H, 4.17; N, 13.23.
C33H29ClN6O5: C, 63.41; H, 4.68; N, 13.44. Found: C, 63.52; H,
4.73; N, 13.51.
(E)‐N′‐(4‐((1‐(2,3‐Dichlorobenzyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐3‐
methoxybenzylidene)‐2‐(4‐methoxybenzamido)benzo-
hydrazide (12l)
Pale yellow crystals; yield, 75%; mp, 221–223°C. IR (KBr, cm−1):
3315, 3308, 3100, 1663, 1644. 1H NMR (400 MHz, DMSO‐d6): δ
2.39 (s, 3H, OMe), 3.80 (s, 3H,OMe), 5.20 (s, 2H, CH2), 5.78 (s, 2H,
CH2), 7.23 (s, 2H), 7.27–7.30 (m, 1H), 7.36 (s, 1H), 7.38–7.42 (m, 1H),
7.58–7.65 (m, 3H), 7.67 (d, J = 7.2 Hz, 2H), 7.86 (d, J = 8 Hz, 2H), 7.95
(d, J = 7.2 Hz, 1H), 8.30 (s, 1H), 8.38 (s, 1H), 8.55 (d, J = 8 Hz, 1H),
11.90 (s, 1H, NH), 12.03 (s, 1H, NH). 13C NMR (100 MHz, DMSO‐d6):
δ 51.64, 55.96, 62.00, 108.96, 113.69, 121.20, 121.43, 122.56,
123.66, 126.02, 127.53, 127.66, 129.03, 129.13, 129.41, 129.52,
131.08, 131.24, 132.60, 132.70, 132.97, 134.85, 136.27, 139.79,
143.01, 149.75, 149.79, 150.02, 165.05, 165.29. Anal. calcd. for
C33H28Cl2N6O5: C, 60.10; H, 4.28; N, 12.74. Found: C, 60.18;
H, 4.31; N, 12.83.
(E)‐N′‐(4‐((1‐Benzyl‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐3‐methoxyben-
zylidene)‐2‐(4‐methoxybenzamido)benzohydrazide (12i)
Pale yellow crystals; yield, 76%; mp, 204–206°C. IR (KBr, cm−1):
3311, 3309, 3114, 1657, 1645. 1H NMR (400 MHz, DMSO‐d6): δ
2.40 (s, 3H, OMe), 3.80 (s, 3H, OMe), 5.19 (s, 2H, CH2), 5.62 (s, 2H,
CH2), 7.23 (s, 2H), 7.25–7.29 (m, 1H), 7.32–7.41 (m, 8H), 7.36 (s, 1H),
7.60–7.64 (m, 1H), 7.85 (d, J = 8 Hz, 2H), 7.90 (d, J = 8 Hz, 1H), 8.30 (s,
1H), 8.39 (s, 1H), 8.57 (d, J = 8 Hz, 1H), 11.91 (s, 1H, NH), 12.01 (s, 1H,
NH). 13C NMR (100 MHz, DMSO‐d6): δ 21.49, 53.30, 55.93, 62.08,
108.92, 113.58, 120.90, 121.39, 122.55, 123.44, 125.43, 127.53,
127.63, 128.46, 128.64, 129.05, 129.24, 129.92, 132.09, 132.96,
136.45, 139.86, 142.69, 143.11, 149.76, 150.07, 164.90, 165.26.
Anal. calcd. for C33H30N6O5: C, 67.11; H, 5.12; N, 14.23. Found: C,
67.22; H, 5.21; N, 14.16.
(E)‐N′‐(4‐((1‐(2,6‐Dichlorobenzyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐3‐
methoxybenzylidene)‐2‐(4‐methoxybenzamido)benzo-
hydrazide (12m)
Pale yellow crystals; yield, 74%; mp, 224–226°C. IR (KBr, cm−1):
3312, 3303, 3105, 1659, 1643. 1H NMR (400 MHz, DMSO‐d6): δ 2.39
(s, 3H, OMe), 3.80 (s, 3H, OMe), 5.16 (s, 2H, CH2), 5.82 (s, 2H, CH2),
7.23 (s, 2H), 7.25–7.28 (m, 1H), 7.37 (s, 1H), 7.39 (d, J = 8 Hz, 2H),
7.46–7.50 (m, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.59–7.64 (m, 1H), 7.85 (d,
J = 8 Hz, 2H), 7.88 (d, J = 6.8 Hz, 1H), 8.27 (s, 1H), 8.38 (s, 1H), 8.55 (d,
J = 8 Hz, 1H), 11.89 (s, 1H, NH), 12.03 (s, 1H, NH). 13C NMR
(100 MHz, DMSO‐d6): δ 21.51, 49.08, 55.87, 61.85, 108.91, 113.52,
120.92, 121.42, 122.56, 123.49, 125.75, 127.53, 127.60, 129.03,
129.47, 129.93, 130.77, 132.05, 132.16, 132.98, 136.40, 139.80,
142.60, 142.73, 149.72, 149.75, 150.06, 164.93, 165.28. Anal. calcd.
for C33H28Cl2N6O5: C, 60.10; H, 4.28; N, 12.74. Found: C, 60.01; H,
4.19; N, 12.86.
(E)‐N′‐(4‐((1‐(4‐Methylbenzyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐3‐
methoxybenzylidene)‐2‐(4‐methoxybenzamido)benzohydrazide (12j)
Pale yellow crystals; yield, 81%; mp, 207–209°C. IR (KBr, cm−1):
3313, 3310, 3108, 1660, 1641. 1H NMR (400 MHz, DMSO‐d6): δ 2.28
(s, 3H, CH3), 2.40 (s, 3H, OMe), 3.80 (s, 3H, OMe), 5.18 (s, 2H, CH2),
5.56 (s, 2H, CH2), 7.18 (d, J = 8 Hz, 2H), 7.19–7.29 (m, 4H), 7.36 (s,
1H), 7.40 (d, J = 8 Hz, 2H), 7.60–7.64 (m, 1H), 7.85 (d, J = 8 Hz, 2H),
7.89 (d, J = 8 Hz, 1H), 8.26 (s, 1H), 8.39 (s, 1H), 8.57 (d, J = 8 Hz, 1H),
11.90 (s, 1H, NH), 12.02 (s, 1H, NH). 13C NMR (100 MHz, DMSO‐d6):
δ 21.18, 21.52, 53.10, 55.88, 62.06, 108.92, 113.58, 116.82, 120.91,
121.40, 122.53, 123.45, 125.28, 127.53, 127.61, 128.51, 129.77,
129.93, 132.09, 132.97, 133.44, 138.00, 139.85, 142.70, 143.06,
149.76, 150.07, 164.90, 165.25. Anal. calcd. for C34H32N6O5: C,
67.54; H, 5.33; N, 13.90. Found: C, 67.39; H, 5.41; N, 14.01.
(E)‐N′‐(4‐((1‐(3‐Chlorobenzyl)‐1H‐1,2,3‐triazol‐4‐yl)-
methoxy)‐3‐methoxybenzylidene)‐2‐(4‐methoxybenzamido)benzo-
hydrazide (12n)
(E)‐N′‐(4‐((1‐(2‐Chlorobenzyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐3‐
methoxybenzylidene)‐2‐(4‐methoxybenzamido)benzohydrazide (12k)
Pale yellow crystals; yield, 76%; mp, 211–213°C. IR (KBr, cm−1):
3317, 3306, 3102, 1656, 1649. 1H NMR (400 MHz, DMSO‐d6): δ 2.39
(s, 3H, OMe), 3.80 (s, 3H, OMe), 5.20 (s, 2H, CH2), 5.73 (s, 2H, CH2),
7.23 (s, 2H), 7.24–7.28 (m, 2H), 7.35–7.42 (m, 5H), 7.46–7.50 (m, 1H),
7.52 (d, J = 8.8 Hz, 1H), 7.60–7.64 (m, 1H), 7.85 (d, J = 8 Hz, 2H), 7.89
(d, J = 8 Hz, 1H), 8.27 (s, 1H), 8.38 (s, 1H), 8.56 (d, J = 8 Hz, 1H), 11.90
(s, 1H, NH), 12.03 (s, 1H, NH). 13C NMR (100 MHz, DMSO‐d6): δ
Pale yellow crystals; yield, 81%; mp, 203–205°C. IR (KBr, cm−1):
3307, 3306, 3115, 1664, 1645. 1H NMR (400 MHz, DMSO‐d6): δ 2.39
(s, 3H, OMe), 3.81 (s, 3H, OMe), 5.20 (s, 2H, CH2), 5.65 (s, 2H, CH2),
7.23 (d, 2H), 7.27–7.30 (m, 2H), 7.37 (s, 1H), 7.39–7.42 (m, 5H),
7.60–7.64 (m, 1H), 7.86 (d, J = 8 Hz, 2H), 7.90 (d, J = 8 Hz, 1H), 8.35 (s,
1H), 8.39 (s, 1H), 8.57 (d, J = 8 Hz, 1H), 11.92 (s, 1H, NH), 12.02 (s, 1H,
NH). 13C NMR (100 MHz, DMSO‐d6): δ 21.48, 52.51, 55.94, 62.07,
108.92, 113.61, 120.91, 121.39, 122.55, 123.44, 125.59, 127.20,
127.53, 127.66, 128.35, 128.64, 129.05, 129.92, 131.19, 132.10,

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132.96, 133.76, 138.82, 139.86, 142.69, 143.21, 149.73, 149.78,
150.03, 164.90, 165.27. Anal. calcd. for C33H29ClN6O5: C, 63.41;
H, 4.68; N, 13.44. Found: C, 63.52; H, 4.56; N, 13.62.
concentrations. The experimental inhibitor constant (Ki)
value was constructed by secondary plots of the inhibitor
concentration [I] versus Km.
(E)‐N′‐(4‐((1‐(4‐Bromobenzyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐
3‐methoxybenzylidene)‐2‐(4‐methoxybenzamido)benzo-
|
4.3
Docking study
hydrazide (12o)
Building the homology model of α‐glucosidase and docking study of
the most potent compounds 12n and 12f in the active site of the
modeled α‐glucosidase was performed by AutoDock Tools, according
to the previously described method.[27]
Pale yellow crystals; yield, 78%; mp, 222–226°C; IR (KBr, cm−1):
3319, 3305, 3109, 1668, 1646. 1H NMR (400 MHz, DMSO‐d6): δ 2.39
(s, 3H, OMe), 3.81 (s, 3H, OMe), 5.19 (s, 2H, CH2), 5.61 (s, 2H, CH2),
7.23 (s, 2H), 7.25–7.30 (m, 3H), 7.37 (s, 1H), 7.40 (d, J = 8 Hz, 2H),
7.59 (d, J = 8 Hz, 2H), 7.61–7.64 (m, 1H), 7.86 (d, J = 8 Hz, 1H), 7.90 (d,
J = 8 Hz, 2H), 8.31 (s, 1H), 8.39 (s, 1H), 8.57 (d, J = 8 Hz, 1H), 11.91 (s,
1H, NH), 12.02 (s, 1H, NH). 13C NMR (100 MHz, DMSO‐d6): δ 21.52,
52.54, 55.94, 62.07, 108.94, 113.60, 120.90, 121.39, 121.94, 122.53,
123.44, 125.49, 127.53, 127.65, 129.04, 129.92, 130.72, 132.09,
132.18, 132.96, 135.85, 139.86, 142.69, 143.16, 179.77, 150.05,
164.90, 165.26. Anal. calcd. for C33H29BrN6O5: C, 59.20;
H, 4.37; N, 12.55. Found: C, 59.16; H, 4.42; N, 12.63.
ORCID
Mohammad Mahdavi
http://orcid.org/0000-0002-4171-7310
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4.2.1
α‐Glucosidase inhibition assay
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4.2.2
Kinetic study
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A Lineweaver–Burk plot
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SUPPORTING INFORMATION
Additional supporting information may be found online in the
Supporting Information section.
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https://doi.org/10.1002/ardp.201900034