Synthesis, in vitro evaluation, and molecular docking studies of novel hydrazineylideneindolinone linked to phenoxymethyl-1,2,3-triazole derivatives as potential α-glucosidase inhibitors

Article abstract of DOI:10.1016/j.bioorg.2021.104869

In this work, a novel series of hydrazineylideneindolinone linked to phenoxymethyl-1,2,3-triazole derivatives were designed, synthesized, and evaluated for their anti-α-glucosidase activity due to an urgent need to develop effective anti-diabetic agents.

Full text of DOI:10.1016/j.bioorg.2021.104869

Bioorganic Chemistry 111 (2021) 104869
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Synthesis, in vitro evaluation, and molecular docking studies of novel
hydrazineylideneindolinone linked to phenoxymethyl-1,2,3-triazole
derivatives as potential
α
-glucosidase inhibitors
,
Diba Shareghi-Boroujenia, Aida Irajib c, Somayeh Mojtabavid, Mohammad Ali Faramarzid,
Tahmineh Akbarzadeha, Mina Saeedie
,f,*
a Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
b Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
c Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
d Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran 1417614411, Iran
e Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
f Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran
A R T I C L E I N F O
A B S T R A C T
Keywords:
In this work, a novel series of hydrazineylideneindolinone linked to phenoxymethyl-1,2,3-triazole derivatives
Click reaction
Docking study
Diabetes
were designed, synthesized, and evaluated for their anti-α-glucosidase activity due to an urgent need to develop
effective anti-diabetic agents. Among tested 15 compounds, 8 derivatives (9a, 9b, 9c, 9d, 9e, 9f, 9h, and 9o)
demonstrated superior potency compared to that of positive control, acarbose. Particularly, compound 9d
α
-Glucosidase inhibitors
possessed the best anti-α-glucosidase activity with around a 46-fold improvement in the inhibitory activity.
Hydrazineylideneindolinone
1,2,3-Triazole
Additionally, 9d showed a competitive type of inhibition in the kinetic study and the molecular docking study
demonstrated that it well occupied the binding pocket of the catalytic center through desired interactions with
residues, correlating to the experimental results.
1. Introduction
process produces absorbable monosaccharides (single
α
-glucose) which
increase plasma glucose levels and postprandial hyperglycemia [8].
Diabetes mellitus (DM) is one of the most health problems of the
present era, affecting millions of people worldwide [1]. According to the
World Health Organization (WHO), more than 420 million people suffer
from diabetes all around the world and the number would be expected to
increase to 642 million in 2040 [2]. DM commonly referred as diabetes,
is a group of metabolic disorders of carbohydrate metabolism charac-
terized by the uncontrolled and inappropriately high blood sugar (hy-
perglycemia) [3]. Diabetes is classified as type I (insulin-dependent),
type II (noninsulin-dependent), gestational, and other uncommon di-
abete types based on its pathogenesis [4,5]; however type II is the most
common form of DM, accounting for around 90%- 95% of all diabetes
cases [6]. Current therapeutic approaches to treat type II DM include
Evidence has shown that α-glucosidase enzyme is a promising thera-
peutic target against type II DM and its complications especially obesity,
neuropathy, and vascular diseases [9] due to its high efficacy in
decreasing fasting and postprandial insulin levels with limiting the
systemic side effects.
In the past few decades, various natural, semisynthetic, and synthetic
α
-glucosidase inhibitors have been reported with sugar mimic [10],
chalcone [11,12], alkaloid [13,14], xanthone[15], azole [16], steroid
[17,18], and peptide structure [7]. Currently, acarbose, miglitol,
voglibose, and emiglitate are four α-glucosidase inhibitors prescribed as
drugs [15]. Acarbose, an oral anti-diabetic drug launched in 1990 is
currently used in the treatment of type II DM [19]. However, various
side effects including flatulence and abdominal pain are related to
acarbose. With the drastic increase in the incidence and prevalence of
DM without significant progress in the field of anti-diabetic drug de-
velopments, there is an urgent need to discover new efficient and potent
α
-glucosidase inhibitors, glucagon-like peptide-1 agonists, and dipep-
tidyl peptidase-IV (DPP-IV) inhibitors [7]. -Glucosidase (EC 3.2.1.20) is
the enzyme, located in the brush border of the small intestine and cleave
(1 → 4) bonds from the non-reducing side in carbohydrates. This
α
α
* Corresponding author at: Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
E-mail address: m-saeedi@tums.ac.ir (M. Saeedi).
https://doi.org/10.1016/j.bioorg.2021.104869
Received 29 November 2020; Received in revised form 2 February 2021; Accepted 24 March 2021
Available online 29 March 2021
0045-2068/© 2021 Elsevier Inc. All rights reserved.

D. Shareghi-Boroujeni et al.
Bioorganic Chemistry 111 (2021) 104869
α
-glucosidase inhibitors.
toxicity towards normal fibroblast cells. The IC50 values were ranging
from 13.0 to 75.5 ± 7.0 µM (compound C as the most potent compound
was depicted in Fig. 1) [39]. Compound D (Fig. 1) as the hybrid de-
rivatives of phenoxy-benzimidazole and aryl-1,2,3-triazole exhibited
much higher inhibitory activity than its parental compounds with
outstanding potential [31].
Isatin is one of the most important heterocycles having various
biological and pharmacological activities including antimicrobial [20],
antiviral [21], anticonvulsant [22], anticancer [23,24], and anti-
diabetic [25,26] properties. Isatin has attracted much attention as a
core structure in targeting α-glucosidase [25,27]. Various types of syn-
thetic isatin-based
α-glucosidase inhibitors have been recently intro-
From the synthetic point of view, isatine was used as an initiator with
duced [25,28–30]. 1,2,3-triazole ring has also been fully developed in
excellent α-glucosidase inhibitory potency. Based on the previous study,
the field of medicinal chemistry and drug development by the intro-
we also examined the introduction of the aromatic bromobenzyl group
into the X position of the isatin ring to evaluate the inhibitory activities.
On the other hand, different Y-substituted phenoxymethyl-1,2,3-triazole
was applied in the central core of the molecule as a suitable electron-rich
moiety with the potential to participate in the interactions with the
active site. Derivatization of the hybridized backbone was performed at
the Z position through a multi-component click reaction. Therefore, it
seems that hybridization of these three scaffolds in a single molecule can
improve pharmacological activity. In this direction, a novel series of
hydrazineylideneindolinone linked to phenoxymethyl-1,2,3-triazoles
duction of click reaction. Specifically, promising anti-α-glucosidase po-
tency has reported for derivatives bearing 1,2,3-triazole moiety
[31–34]. On the other hand, the 1,2,3-triazole ring is constructed via
multicomponent azide-alkyne click reaction which permits the synthesis
of adducts in a time and cost-effective manner.
In continuation of our ongoing research on designing novel com-
pounds with bioactivity against α-glucosidase [8,35]; herein, we report
the design and synthesis of new hydrazineylideneindolinone linked to
different phenoxymethyl-1,2,3-triazole derivatives. In the hybrid series
9a-o, various electronic and lipophilic environments were introduced to
study their impact on the in vitro inhibitory activity. In addition, kinetic
were rationally designed, synthesized, and evaluated as α-glucosidase
inhibitors. Kinetic study as well as in silico evaluations were performed
evaluation as well as in silico
α
-glucosidase inhibitory potentials were
on the synthesized hybrids.
performed.
2.2. Chemistry
2. Results and discussion
The synthesis of compounds 9 has been schematically shown in
Scheme 1.
2.1. Designing
Isatin or it 4-bromobenzyl derivative 1 reacted with hydrazine hy-
drate 2 in methanol under reflux conditions to obtain hydrazineylide-
neindolinone derivative 3. Then, compound 3 reacted with aldehyde 4
in the presence of catalytic amounts of SiO2-H2SO4 or acetic acid (HOAc)
under microwave irradiation (700 W) for 10–12 min to prepare prop-2-
Isatin (indole-2,3-dione) is known as an important biological and
pharmacological heterocyclic system with two cyclic rings. The six-
membered ring has an aromatic character, whereas the five-membered
one possesses an anti-aromatic character [36]. Recent studies showed
that isatin has attracted much attention as a core structure in targeting
yn-1-yloxybenzylidene-hydrazineylideneindolinone
derivatives
5.
α
-glucosidase [25]. Various types of synthetic isatin-based
inhibitors were introduced [25,28,29]. Rahim et al. reported isatin schiff
base derivatives (compound A, Fig. 1.) as a strong -glucosidase inhib-
M for the most active analog among the
α-glucosidase
Finally, click reaction of compound 5 and azides 8 (prepared by the
reaction of benzyl chloride/bromide derivative 6 and sodium azide 7)
led to the formation of products 9. The structure of all compounds was
confirmed using NMR and IR spectroscopy as well as elemental analysis.
NMR characterization indicated the presence of two conformers anti and
syn due to hydrazone moiety.
α
itor with IC50 = 2.2 ± 0.25
μ
series. From the docking viewpoint, it can be seen that compound A fits
well into the catalytic active site making interactions with the Arg212,
His239, Glu276 and Thr307 [27]. Recently, chromone-isatin derivative
as a promising α-glucosidase inhibitor was synthesized. Based on SAR
2.3. In vitro
α-glucosidase enzymatic assay
evaluations, compound B (Fig. 1) was regarded as the most potent
compound with an IC50 value of 3.18 ± 0.12 μM due to the presence of 4-
The results of the
α-glucosidase inhibitory assay were shown in
bromobenzyl pendant group [37].
Table 1. In this series, compound 9d bearing ortho-fluorobenzyl showed
exceptionally high potency against -glucosidase with an IC50 value of
16.43 M which is significantly lower than that of acarbose as the pos-
itive control (IC50 = 750.0 ± 10.0 M). Based on biological results, the
structure–activity relationship (SAR) was constructed for the designed
The recent findings on α-glucosidase inhibitors showed that phenoxy
α
linked to 1,2,3-triazole could effectively inhibit the enzyme [32,38]. In
particular, the modified phenoxy-1,2,3-triazole series reversibly
μ
μ
inhibited the α-glucosidase enzyme in a competitive manner without
Fig. 1. Novel hydrazineylideneindolinone linked to phenoxymethyl-1,2,3-triazoles by hybridization of isatine and phenoxymethyl-1,2,3-triazole.
2

D. Shareghi-Boroujeni et al.
Bioorganic Chemistry 111 (2021) 104869
Scheme 1. Synthesis of compounds 9a-o.
value of 16.43 µM followed by 9e (Z = 4-F) with an IC50 value of 86.8 ±
0.12 µM.
Table 1
α
-Glucosidase
inhibitory
activity
of
compounds
9a-o.
4. Evaluating the effect of Z moiety on
hydrazineylideneindolinone derivatives (X ¼ H and Y ¼ OMe)
From the screening data of 9f-j, it was revealed that 9f as unsub-
stituted derivative in this set might be considered as the moderate
α
-glucosidase inhibitor with IC50 = 215.42 ± 0.08 μM. Although the
presence of para methyl as an electron-donating group (9 h, IC50
110.59 ± 0.44 M) led to around two-fold improvement of -glucosidase
inhibitory activity comparing with un-substituted one (9f), the inhibi-
tory potency was not improved in 9g bearing ortho methyl group (IC50
=
Entry
Compound
X
Y
Z
IC50
(
μ
M) [a]
μ
α
1
9a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
100.47 ± 0.22
96.03 ± 0.06
43.51 ± 0.15
16.43 ± 0.01
86.8 ± 0.12
215.42 ± 0.08
>750
2
9b
2-Me
4-Me
2-F
>
3
9c
750 μM). Unexpectedly, there was a dramatic reduction in α-glucosidase
4
9d
5
9e
4-F
inhibitory activity via introducing fluorobenzyl moiety as an electron-
withdrawing group at Z (9i, Z = 2-F with IC50 > 750 and 9j, Z = 4-F
with IC50 > 750).
6
9f
OMe
OMe
OMe
OMe
OMe
H
H
7
9 g
9 h
9i
2-Me
4-Me
2-F
8
110.59 ± 0.44
>750
9
10
11
12
13
14
15
16
9j
4-F
>750
5. Evaluating the effect of Z moiety on 4-bromobenzyl-hydrazi-
9 k
9 l
4-Br-C6H4-CH2
H
>750
neylideneindolinone derivatives (X ¼ 4-bromobenzyl and Y ¼ H)
4-Br-C6H4-CH2
4-Br-C6H4-CH2
4-Br-C6H4-CH2
4-Br-C6H4-CH2
H
2-Me
4-Me
2-F
>750
9 m
9n
H
>750
To further improve anti-α-glucosidase activity, the impact of 4-bro-
H
>750
mobenzyl substitution on the indolin-2-one at X position was explored
(9 k-o). Disappointingly, 9k as the un-substituted derivative in this set
did not improve potency compared to 9a and 9f or even the positive
control. Also, methyl substitutions on the benzyl ring (9l Z = 2-Me with
9o
H
4-F
96.89 ± 0.26
750.0 ± 10.0
Acarbose
[a]
Data represented in terms of mean ± SD.
IC50 > 750 and 9m Z = 4-Me with IC50 > 750) displayed no α-glucosi-
scaffold. In order to better understand the SAR, synthetic compounds
were divided into three groups.
dase inhibitory property in the whole range of concentrations studied.
Investigation of the fluorinated derivatives showed that unlike the other
sets, in this category 4-F (9o, Z = 4-F with IC50 = 96.89 ± 0.26
μ
M)
M) at Z po-
-glucosidase inhibitory activity.
3. Evaluating the effect of Z moiety on
comparing with that of 2-F (9n, Z = 2-F with IC50 > 750
sition led to an improvement of
μ
hydrazineylideneindolinone derivatives (X ¼ H and Y ¼ H)
α
In cases of 9a-e, it can be seen that the unsubstituted compound (9a)
demonstrated an IC50 value of 100.47 µM with around 7 times
improvement in potency compared to that of acarbose as a positive
control. As can be seen in compounds 9b (Z = 2-Me) and 9c (Z = 4-Me),
the introduction of the methyl group as electron-donating moiety had a
6. SAR assessments regarding the potential of all sets it can be
understood that
• In most cases, the target hydrazonoindolin-2-one derivatives had
superior inhibitory activity toward α-glucosidase compared to 4-bro-
positive effect on
unsubstituted one. Substitution of small electron-withdrawing groups
such as fluoro at Z played a significant role in -glucosidase inhibition.
In detail, 9d as the top potent -glucosidase inhibitor generated via
introducing 2-F into the benzyl moiety at Z position showed an IC50
α-glucosidase inhibitory activity compared with the
mobenzyl-hydrazonoindolin-2-one counterpart. This may be due to
the bulkiness of the bromobenzyl on hydrazonoindolin-2-one ring
which cannot properly enter the active site and hinders the in-
teractions with the residues of the mentioned area.
α
α
3

D. Shareghi-Boroujeni et al.
Bioorganic Chemistry 111 (2021) 104869
• The substitution of MeO as a bulky electron donating group at Y
α
-glucosidase active site were documented in Table 2.
position led to decrease in the potency comparing with the unsub-
Fig. 5 showed the docking interactions of the most potent compound
stituted counterpart. This trend can be seen in compound 9f (IC50
=
9d (IC50 = 16.43 ± 0.01 μM). Docking evaluation depicted two pi-pi,
215.42 ± 0.08
μ
M) and 9a (IC50 = 100.47 ± 0.22
μM) or 9j (IC50
>
two pi-alkyl, and one pi-sulfur interaction with the indolinone ring as
well as two hydrogen bound interactions between Asp518 and Met519
with NH of indolinone. Another hydrogen bonding interaction was
750) and 9d (IC50 = 215.42 ± 0.08 μM).
• Mostly, introduction of para methyl group into the benzyl pendant at
Z position compared to ortho methyl had a positive effect on anti-
–
–
generated between C O of the indolinone ring and Arg600. On the
α
-glucosidase activity.
other side of the molecule, 2-fluorobenzyl made a pi-pi stacking with
Phe525 amino acid. The 1,2,3-triazole ring also constructed two pi-alkyl
interactions with leu283 and Ala555 plus pi-sulfur interaction with
Asp282. Another hydrogen bonding and pi-alkyl interactions were
generated between phenoxy moiety and Ala284.
• Overall, it seems that compounds possessing fluoride at Z induced
better
α-glucosidase inhibitory activity compared to other de-
rivatives. In another study done by Xie et al, the same trend was
observed so that among different derivatives, the derivative pos-
sessing 2-fluorobenzyl substituent displayed the highest inhibitory
activity [40].
3D interaction pattern of compound 9n (Fig. 6) showed two pi-alkyl
interactions between Leu766 and 4-bromobenzyl group. The mentioned
ring also participated in pi-pi interactions with Trp376. The indolinone
fused ring made two pi-pi, two pi-sulfur, and one pi-anion interactions
with Trp481, Met519, and Asp616, respectively. Terminal 2-fluoroben-
zyl participated in pi-pi interactions with Arg527 and Ala555. Also, the
phenoxy linker was fixed through pi-anion interaction with Asp282.
The summary of the SAR to improved
tivity was depicted in Fig. 2.
α-glucosidase inhibitory ac-
6.1. Enzyme kinetic studies
Although this compound showed interactions within the α-glucosidase
enzyme, low ChemScore value and no hydrogen bond interactions be-
According to results obtained from the kinetic study of compound 9d
and the related Lineweaver-Burk plot (Fig. 3), the Km gradually
increased and Vmax remained unchanged with increasing inhibitor
concentration which indicated a competitive inhibition. The results
showed that compound 9d bound to the active site of the enzyme and
competed with the substrate for binding to the active site. Furthermore,
the plot of the Km versus different concentrations of inhibitor gave an
estimate of the inhibition constant, Ki of 16.33 µM (Fig. 3).
tween 9n and enzyme could justify its low potency.
7. Conclusion
Following our expertise in the rational design of
α-glucosidase in-
hibitors [35,41]; herein, we designed, synthesized, and evaluated highly
potent
α-glucosidase inhibitors from the hydrazineylideneindolinone
linked to phenoxymethyl-1,2,3-triazoles. In this regard, 15 derivatives
were designed and synthesized. The SAR data obtained by the anti-
6.2. Docking analyses
α
-glucosidase screening of synthesized compounds showed a promising
inhibitory effect of derivatives containing hydrazineylideneindolinone
moiety comparing with 4-bromobenzyl-hydrazineylideneindolinone
counterparts. The most active compound 9d bearing 2-fluorobenzyl
The docking analysis of 9d as the most active and 9n as the least
potent compounds against the α-glucosidase enzyme has been achieved
using Gold software with ChemScore fitness function. To evaluate the
accuracy of docking, the redocking process of acarbose (as a crystallo-
graphic ligand) with human lysosomal acid-alpha-glucosidase (PDB ID:
5NN8) was performed. Alignment of the best pose of acarbose in the
group (IC50 = 16.43 ± 0.01 μM) showed 47 times better inhibitory ef-
fect than acarbose. The gold score determined via in silico study for the
designed compounds were strongly correlated with the experimentally
α
-glucosidase inhibitory activity. Molecular docking studies of 9d into
active site of α-glucosidase and crystallographic ligand was shown in
α
-glucosidase active site revealed that this molecule completely fit into
Fig. 4. Both shared a common binding mode which confirming the
reliability and accuracy of the used method for in silico studies. Next, the
docking assessments of the two mentioned compounds were done based
on the same protocol performed on the standard drug. The ChemScore
fitness value of 9d and 9n plus their interactions with residues in the
the
α-glucosidase pockets and formed hydrogen bond, pi-pi, pi-aryl, pi-
anion, and pi-sulfur interactions. Thus, the tested hybrid appears as a
good candidate for initiating lead drug discovery program.
Fig. 2. Summary of the SAR for the indolinone substituted phenoxy-methyltriazole derivatives.
4

D. Shareghi-Boroujeni et al.
Bioorganic Chemistry 111 (2021) 104869
Fig. 3. Kinetic study of inhibitor 9d against
α
-glucosidase. Lineweaver-Burk plot (left) and double reciprocal Lineweaver-Burk plot (right) are shown.
Table 2
Docking scores and interactions of compounds against the
ID: 5NN8
α
-glucosidase (PDB
Amino acid
Compound
ChemScore
Type of Interactions
9d
71.46
Hydrogen bond
Hydrogen bond
Hydrogen bond
Hydrogen bond
pi-pi
Ala284
Arg600
Met519
Asp518
Phe525
Trp481
Trp481
Ala555
Leu283
Ala284
Met519
Leu405
Asp282
Met519
Trp481
Trp481
Trp376
Ala555
Arg527
Leu677
Trp376
Asp282
Asp616
Met519
pi-pi
pi-pi
pi-alkyl
pi-alkyl
pi-alkyl
pi-alkyl
pi-alkyl
pi-anion
pi-sulfur
pi-pi
9n
55.20
pi-pi
pi-pi
Fig. 4. Depiction of crystallographic ligand (yellow) and docked acarbose
pi-alkyl
pi-alkyl
pi-alkyl
pi-alky
(green) in the active site of α-glucosidase enzyme. (For interpretation of the
references to colour in this figure legend, the reader is referred to the web
version of this article.)
pi-anion
pi-anion
pi-anion
8. Experimental
8.1. Chemistry
8.1.1. Synthesis of hydrazineylideneindolinone derivatives 3
A mixture of isatine or its derivative 1 (1 mmol) and hydrazine hy-
drate 2 (1 mmol) in methanol (10 mL) was refluxed for 4 h. After
completion of reaction (checked by TLC), the precipitated product was
filtered off, washed with cold methanol, and used for further reaction.
8.1.2. Synthesis of prop-2-yn-1-yloxybenzylidene-
hydrazineylideneindolinone derivatives 5
A mixture of compound 3 (1 mmol) and aldehyde derivative 4 [42]
(1 mmol) in methanol (10 mL), in the presence of catalytic amounts of
SiO2-H2SO4 [43] was reacted under microwave irradiation at 700 W for
10–12 min (1 min interval). After completion of the reaction (checked
by TLC), the catalyst was filtered off, the filtrate let to be cooled down,
and the precipitates were filtered off to afford compound 5. It should be
noted that the reaction could be achieved in the presence of a few drops
of acetic acid.
Synthesis of compounds 9: Synthesis of the title compounds 9 was
achieved by the click reaction of compound 5 and in situ prepared azides
8. The reaction was initiated by stirring the mixture of benzyl chloride/
Fig. 5. 3D interaction pattern of compounds 9d in the α-glucosidase active site.
5

D. Shareghi-Boroujeni et al.
Bioorganic Chemistry 111 (2021) 104869
H5′, H2′′, H3′′, H5′′, H6′′), 6.89 (d, J = 8.0 Hz, 1H, H7), 5.57 (s, 2H,
CH2), 5.26 (s, 2H, CH2), 5.21 (s, 2H, CH2), 2.25 (s, 3H, CH3) ppm.
13CNMR (125 MHz, DMSO‑d6) (two isomers): 165.3, 162.5, 161.8,
161.0, 160.8, 151.3, 145.3, 138.0, 134.0, 133.3, 131.5, 130.4, 129.8,
129.4, 128.5, 126.8, 126.7, 125.4, 122.8, 117.1, 115.9, 115.6, 111.2,
61.8, 53.2, 21.1 ppm. Anal. calcd. for C26H22N6O2: C, 69.32; H, 4.92; N,
18.66. Found: C, 69.20; H, 5.20; N, 18.52.
8.1.6. 3-((4-((1-(2-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)
benzylidene)hydrazineylidene)indolin-2-one 9d
Yield: 46%, mp = 157–160 ◦C. IR (KBr): 3231, 2850, 1735, 1609,
1539, 1511 cmꢀ 1. 1HNMR (500 MHz, DMSO‑d6) (two isomers): 10.82 (s,
1H, NH), 8.63 (s, 1H, CH), 8.31 (s, 1H, triazole), 8.29 (s, 1H, triazole),
8.03 (d, J = 7.9 Hz, 1H, H4), 7.95 (d, J = 8.6 Hz, 2H, H2′, H6′), 7.80 (d, J
= 9.0 Hz, 1H, H4), 7.42–7.25 (m, 7H, H6, H3′, H5′, H3′′, H4′′, H5′′,
H6′′), 7.14 (d, J = 9.0 Hz, 1H, H7), 7.03 (t, J = 7.9 Hz, 1H, H5), 6.89 (d,
J = 7.9 Hz, 1H, H7), 5.68 (s, 2H, CH2), 5.26 (s, 2H, CH2), 5.21 (s, 2H,
CH2). 13CNMR (125 MHz, DMSO‑d6) (two isomers): 165.2, 162.4, 161.8,
160.9, 160.6 (d, JC-F = 243.0 Hz), 151.2, 145.3, 143.1, 133.9, 131.3,
Fig. 6. 3D interaction pattern of compound 9n in the active site of the
131.2 (d, JC-F = 30.7 Hz), 130.4, 129.3, 126.8, 125.5, 125.3 (d, JC-F
=
α
-glucosidase enzyme.
16.7 Hz), 123.2 (d, JC-F = 14.5 Hz), 122.8, 117.1, 115.9 (d, JC-F = 20.7
Hz), 115.9, 115.6, 111.2, 61.7, 47.4 ppm. Anal. calcd. for C25H19FN6O2:
C, 66.07; H, 4.21; N, 18.49. Found: C, 65.86; H, 4.40; N, 18.22.
bromide derivative 6 (1.1 mmol) and sodium azide 7 (0.06 g, 0.9 mmol)
in the presence of triethylamine (0.13 g, 1.3 mmol) in water (4 mL) and
tert-butyl alcohol (4 mL) at room temperature for 30 min. Next, com-
pound 5 (0.5 mmol) and CuSO4⋅5H2O (7 mol%) were added to the re-
action mixture and it was continued for 24–48 h. After completion of the
reaction as checked by TLC, the mixture was poured on crushed ice, the
precipitates were filtered off and washed with water. In the case of some
compounds, they were purified using plate chromatography eluting
with ethyl acetate and petroleum ether.
8.1.7. 3-((4-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)
benzylidene)hydrazineylidene)indolin-2-one 9e
Yield: 66%, mp = 164–167 ◦C. IR (KBr): 3415, 2815, 1730, 1606,
1541, 1509 cmꢀ 1. 1HNMR (500 MHz, DMSO‑d6) (two isomers): 10.80 (s,
1H, NH), 8.62 (s, 1H, CH), 8.31 (s, 1H, triazole), 8.28 (s, 1H, triazole),
8.04 (d, J = 8.0 Hz, 1H, H4), 7.94 (d, J = 8.5 Hz, 2H, H2′, H6′),
7.40–7.17 (m, 7H, H6, H3′, H5′, H2′′, H3′′, H5′′, H6′′), 7.03 (t, J = 8.0
Hz, 1H, H5), 6.89 (d, J = 8.0 Hz, 1H, H7), 5.61 (s, 2H, CH2), 5.25 (s, 2H,
CH2), 5.21 (s, 2H, CH2) ppm. 13CNMR (125 MHz, DMSO‑d6): 165.2,
162.4, 162.1, 160.8 (d, JC-F = 250.0 Hz), 151.3, 145.4, 138.2, 133.8,
131.4, 130.7, 129.9, 129.8, 129.3, 126.8, 125.8, 125.2, 117.1, 116.0 (d,
JC-F = 25.7 Hz), 110.8, 61.7, 52.6 ppm. Anal. calcd. for C25H19FN6O2: C,
66.07; H, 4.21; N, 18.49. Found: C, 66.30; H, 4.35; N, 18.66.
8.1.3. 3-((4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)benzylidene)
hydrazineylidene)indolin-2-one 9a
Yield: 55%, mp = 153–155 ◦C. IR (KBr): 3394, 1732, 2825, 1606,
1537, 1508 cmꢀ 1. 1HNMR (500 MHz, DMSO‑d6) (two isomers): 10.83 (s,
1H, NH), 8.64 (s, 1H, CH), 8.34 (s, 1H, triazole), 8.04 (d, J = 7.5 Hz, 1H,
H4), 7.96 (d, J = 9.0 Hz, 2H, H2′, H6′), 7.38–7.33 (m, 6H, H6, H2′′, H3′′,
H4′′, H5′′, H6′′), 7.23 (d, J = 9.0 Hz, 2H, H3′, H5′), 7.04 (t, J = 7.5 Hz,
1H, H5), 6.90 (d, J = 7.5 Hz, 1H, H7), 5.63 (s, 2H, CH2), 5.27 (s, 2H,
CH2), 5.22 (s, 2H, CH2) ppm. 13CNMR (125 MHz, DMSO‑d6) (two iso-
mers): 165.2, 162.4, 161.2, 151.2, 145.3, 143.0, 136.4, 134.0, 131.5,
130.4, 129.4, 129.2, 128.6, 128.4, 126.8, 125.4, 122.8, 117.1, 116.5,
116.0, 111.2, 61.8, 53.4 ppm. Anal. calcd. for C25H20N6O2: C, 68.80; H,
4.62; N, 19.25. Found: C, 68.58; H, 4.44; N, 19.50.
8.1.8. 3-((4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-3-
methoxybenzylidene)hydrazineylidene)indolin-2-one 9f
Yield: 30%, mp = 198–200 ◦C. IR (KBr); 3403, 2923, 2853, 1727,
1616, 1540, 1504 cmꢀ 1
.
1HNMR (500 MHz, DMSO‑d6) (two isomers):
10.84 (s, 1H, NH), 8.63 (s, 1H, CH), 8.56 (s, 1H, CH), 8.32 (s, 1H, tri-
azole), 8.00 (d, J = 7.8 Hz, 1H, H4), 7.56–7.33 (m, 8H, H6, H2′, H6′,
H2′′, H3′′, H4′′, H5′′, H6′′), 7.04 (t, J = 7.8 Hz, 1H, H5), 6.90–6.89 (m,
2H, H7, H5′), 5.62 (s, 2H, CH2), 5.24 (s, 2H, CH2), 5.20 (s, 2H, CH2),
3.83 (s, 3H, OCH3), 3.78 (s, 3H, OCH3). 13CNMR (125 MHz, DMSO‑d6)
(two isomers): 165.2, 161.8, 161.2, 153.3, 151.5, 151.0, 149.8, 149.7,
145.3, 143.0, 136.4, 133.9, 129.2, 128.6, 128.4, 127.0, 126.1, 125.5,
124.1, 123.7, 122.8, 117.0, 113.8, 113.5, 113.2, 111.3, 111.2, 110.3,
62.1, 55.9, 53.3 ppm. Anal. calcd. for C26H22N6O3: C, 66.94; H, 4.75; N,
18.02. Found: C, 67.22; H, 4.59; N, 17.85.
8.1.4. 3-((4-((1-(2-Methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)
benzylidene)hydrazineylidene)indolin-2-one 9b
Yield: 75%, mp = 135–138 ◦C. IR (KBr): 3419, 2827, 1739, 1603,
1432 cmꢀ 1. 1HNMR (500 MHz, DMSO‑d6) (two isomers): 10.84 (s, 1H,
NH), 10.66 (s, 1H, NH), 8.64 (s, 1H, CH), 8.24 (s, 1H, triazole),
8.01–7.80 (m, 3H, H4, H2′, H6′), 7.40–6.91 (m, 9H, H5, H6, H7, H3′,
H5′, H3′′, H4′′, H5′′, H6′′), 5.63 (s, 2H, CH2), 5.27 (s, 2H, CH2), 5.23 (s,
2H, CH2), 2.30 (s, 3H, CH3) ppm. 13CNMR (125 MHz, DMSO‑d6): 165.2,
162.0, 161.1, 151.7, 145.6, 145.3, 142.2, 136.7, 134.5, 134.0, 132.2,
131.5, 130.9, 130.4, 129.1, 128.8, 126.7, 125.6, 116.0, 115.6, 115.6,
61.8, 51.5, 19.1 ppm. Anal. calcd. for C26H22N6O2: C, 69.32; H, 4.92; N,
18.66. Found: C, 69.51; H, 5.18; N, 18.80.
8.1.9. 3-((3-Methoxy-4-((1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)
methoxy)benzylidene)hydrazineylidene)indolin-2-one 9 g
Yield:24%, mp = 140–143 ◦C. IR (KBr): 3431, 2925, 2854, 1724,
1620, 1539, 1506 cmꢀ 1
.
1HNMR (500 MHz, DMSO‑d6) (two isomers):
10.96 (s, 1H, NH), 8.64 (s, 1H, CH), 8.58 (s, 1H, CH), 8.23 (s, 1H, tri-
azole), 8.01 (d, J = 7.5 Hz, 1H, H4), 7.57–7.19 (m, 7H, H6, H2′, H6′,
H3′′, H4′′, H5′′, H6′′), 7.09 (d, J = 7.5 Hz, 1H, H5′), 7.04 (t, J = 7.5 Hz,
1H, H5), 6.91 (d, J = 7.5 Hz, 1H, H7),
8.1.5. 3-((4-((1-(4-Methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)
benzylidene)hydrazono)indolin-2-one 9c
Yield: 50%, mp = 173–176 ◦C. IR (KBr): 3442, 2924, 1730, 1606,
1544, 1509 cmꢀ 1. 1HNMR (500 MHz, DMSO‑d6) (two isomers): 10.84 (s,
1H, NH), 8.64 (s, 1H, CH), 8.61 (s, 1H, CH), 8.31 (s, 1H, triazole), 8.29
(s, 1H, triazole), 8.03 (d, J = 8.0 Hz, 1H, H4), 7.94 (d, J = 9.0 Hz, 2H,
H2′, H6′), 7.80 (d, J = 8.0 Hz, 1H, H4), 7.38–7.03 (m, 8H, H5, H6, H3′,
5.63 (s, 2H, CH2), 5.45 (s, 2H, CH2), 5.25 (s, 2H, CH2), 5.20 (s, 2H,
CH2), 3.84 (s, 3H, OCH3), 3.79 (s, 3H, OCH3). 13CNMR (125 MHz,
DMSO‑d6): 164.7, 161.2, 151.0, 150.5, 150.2, 149.3 144.9, 142.4,
136.3, 134.1, 133.5, 130.4, 128.8, 128.7, 128.3, 126.6, 126.2, 125.1,
122.3, 117.0, 116.6, 113.5, 110.8, 61.7, 55.5, 51.0, 19.2 ppm. Anal.
6

D. Shareghi-Boroujeni et al.
Bioorganic Chemistry 111 (2021) 104869
calcd. for C27H24N6O3: C, 67.49; H, 5.03; N, 17.49. Found: C, 67.66; H,
5.21; N, 17.20.
8.1.14. 1-(4-Bromobenzyl)-3-((4-((1-(2-methylbenzyl)-1H-1,2,3-triazol-
4-yl)methoxy)benzylidene)hydrazono)indolin-2-one 9 l
Yield: 30%, mp = 172–177 ◦C. IR (KBr): 3350, 2922, 2852, 1729,
8.1.10. 3-((3-Methoxy-4-((1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)
methoxy)benzylidene)hydrazineylidene)indolin-2-one 9 h
1603, 1531, 1510 cmꢀ 1
.
1HNMR (500 MHz, DMSO‑d6) (two isomers):
8.70 (s, 1H, CH), 8.63 (s, 1H, CH), 8.25 (s, 1H, triazole), 8.21 (s, 1H,
triazole), 8.13 (d, J = 7.8 Hz, 1H, H4), 7.98 (d, J = 8.7 Hz, 2H, H2′, H6′),
7.54 (d, J = 8.5 Hz, 2H, 4-bromobenzyl), 7.41 (t, J = 7.8 Hz, 1H, H6),
7.34 (d, J = 8.5 Hz, 2H, 4-bromobenzyl), 7.25–7.08 (m, 5H, H5, H3′′,
H4′′, H5′′, H6′′), 7.01 (d, J = 7.8 Hz, 1H, H7), 5.63 (s, 2H, CH2), 5.27 (s,
2H, CH2), 5.22 (s, 2H, CH2), 4.96 (s, 2H, CH2), 2.31 (s, 3H, CH3) ppm.
13CNMR (125 MHz, DMSO‑d6): 164.1, 163.1, 162.5, 162.0, 150.2,
145.3, 142.8, 136.8, 135.8, 134.6, 133.8, 132.1, 131.6, 130.8, 130.0,
129.4, 129.2, 129.0, 126.7, 125.5, 123.7, 121.2, 116.7, 116.0, 110.4,
62.4, 51.4, 19.1 ppm. Anal. calcd. for C33H27BrN6O2: C, 63.98; H, 4.39;
N, 13.57. Found: C, 64.18; H, 4.60; N, 13.33.
Yield: 27%, mp = 13–136 ◦C. IR (KBr); 3449, 2923, 2853, 1727,
1616, 1541, 1504 cmꢀ 1
.
1HNMR (500 MHz, DMSO‑d6) (two isomers):
10.91 (s, 1H, NH), 8.57 (s, 1H, CH), 8.56 (s, 1H, CH), 8.28 (s, 1H, tri-
azole), 7.98 (d, J = 7.5 Hz, 1H, H4), 7.55–6.92 (m, 7H, H5, H6, H7, H2′,
H5′, H6′, H2′′, H3′′, H5′′, H6′′), 5.55 (s, 2H, CH2), 5.22 (s, 2H, CH2), 5.19
(s, 2H, CH2), 3.83 (s, 3H, OCH3), 3.78 (s, 3H, OCH3). 13CNMR (125 MHz,
DMSO‑d6) (two isomers): 161.1, 160.9, 150.6, 149.2, 145.1, 143.8,
142.5, 140.2, 137.4, 133.4, 132.9, 129.3, 128.7, 128.0, 126.5, 124.9,
123.6, 122.2, 116.9, 113.4, 113.1, 110.9, 110.7, 61.7, 55.5, 52.6, 20.7
ppm. Anal. calcd. for C27H24N6O3: C, 67.49; H, 5.03; N, 17.49. Found: C,
67.20; H, 4.81; N, 17.70.
8.1.15. 1-(4-Bromobenzyl)-3-((4-((1-(4-methylbenzyl)-1H-1,2,3-triazol-
4-yl)methoxy)benzylidene)hydrazono)indolin-2-one 9 m
8.1.11. 3-((4-((1-(2-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-
methoxybenzylidene)hydrazineylidene)indolin-2-one 9i
Yield: 30%, mp = 185–188 ◦C. IR (KBr): 3355, 2922, 2853, 1711,
Yield: 28%, mp = 193–196 ◦C. IR (KBr); 3483, 2923, 2853, 1732,
1618, 1594, 1538, 1505 cmꢀ 1. 1HNMR (500 MHz, DMSO‑d6) (two iso-
mers): 10.95 (s, 1H, NH), 8.64 (s, 1H, CH), 8.58 (s, 1H, CH), 8.32 (s, 1H,
triazole), 8.01 (d, J = 7.5 Hz, 1H, H4), 7.57–7.23 (m, 8H, H6, H2′, H5′,
H6′, H3′′, H4′′, H5′′, H6′′), 7.04 (t, J = 7.5 Hz, 1H, H5), 6.91 (d, J = 7.5
Hz, 1H, H7), 5.70 (s, 2H, CH2), 5.25 (s, 2H, CH2), 5.20 (s, 2H, CH2), 3.84
(s, 3H, OCH3), 3.79 (s, 3H, OCH3). 13CNMR (125 MHz, DMSO‑d6):
164.7, 164.0, 161.2, 160.1 (d, JC-F = 235.0 Hz), 151.0, 150.6, 149.4,
1603, 1539, 1510 cmꢀ 1
.
1HNMR (500 MHz, DMSO‑d6) (two isomers):
8.70 (s, 1H, CH), 8.62 (s, 1H, CH), 8.30 (s, 1H, triazole), 8.13 (d, J = 8.0
Hz, 1H, H4), 7.98 (d, J = 8.5 Hz, 2H, H2′, H6′), 7.54 (d, J = 8.5 Hz, 2H,
4-bromobenzyl), 7.41 (t, J = 8.0 Hz, 1H, H6), 7.33 (d, J = 8.5 Hz, 2H, 4-
bromobenzyl), 7.24–7.21 (m, 4H, H2′′, H3′′, H5′′, H6′′), 7.17 (d, J = 8.5
Hz, 2H, H3′, H5′), 7.11 (t, J = 8.0 Hz, 1H, H5), 7.00 (d, J = 8.0 Hz, 1H,
H7), 5.56 (s, 2H, CH2), 5.26 (s, 2H, CH2), 5.21 (s, 2H, CH2), 4.96 (s, 2H,
CH2), 2.27 (s, 3H, CH3) ppm. 13CNMR (125 MHz, DMSO‑d6): 164.1,
163.2, 161.9, 150.3, 147.7, 147.5, 145.1, 143.0, 137.9, 136.1, 133.8,
133.5, 132.1, 131.6, 130.0, 129.7, 128.5, 126.7, 125.4, 121.2, 116.7,
116.1, 115.1, 62.7, 53.1, 21.1 ppm. Anal. calcd. for C33H27BrN6O2: C,
63.98; H, 4.39; N, 13.57. Found: C, 64.25H, 4.15; N, 13.70.
142.5, 133.5, 130.8, 128.8, 126.6, 125.2, 124.9, 123.6, 122.8 (d, JC-F
=
15.6 Hz), 122.3, 120.5, 116.6, 115.6 (d, JC-F = 20.8 Hz), 113.4, 113.3,
110.8, 61.6, 54.9, 46.9 ppm. Anal. calcd. for C26H21FN6O3: C, 64.46; H,
4.37; N, 17.35. Found: C, 64.22; H, 4.18; N, 17.22.
8.1.12. 3-((4-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-
methoxybenzylidene)hydrazineylidene)indolin-2-one 9j
8.1.16. 1-(4-Bromobenzyl)-3-((4-((1-(2-fluorobenzyl)-1H-1,2,3-triazol-
4-yl)methoxy)benzylidene)hydrazono)indolin-2-one 9n
Yield: 25%, mp = 158–161 ◦C. IR (KBr): 3385, 2925, 2854, 1732,
Yield: 17%, mp = 158–161 ◦C. IR (KBr): 3350, 2922, 2852, 1727,
1602, 1462 cmꢀ 1. 1HNMR (500 MHz, DMSO‑d6) (two isomers): 8.70 (s,
1H, CH), 8.63 (s, 1H, CH), 8.33 (s, 1H, triazole), 8.13 (d, J = 8.0 Hz, 1H,
H4), 7.98 (d, J = 8.6 Hz, 2H, H2′, H6′), 7.54 (d, J = 8.5 Hz, 2H, 4-bro-
mobenzyl), 7.43–7.23 (m, 6H, H6, H3′, H5′, H3′′, H4′′, H5′′, H6′′), 7.12
(t, J = 8.0 Hz, 1H, H5), 7.01 (d, J = 8.0 Hz, 1H, H7), 5.69 (s, 2H, CH2),
5.27 (s, 2H, CH2), 5.22 (s, 2H, CH2), 4.96 (s, 2H, CH2) ppm. 13CNMR
(125 MHz, DMSO‑d6) (two isomers): 164.0, 162.1 (d, JC-F = 255.9 Hz),
162.0, 161.7, 161.6, 150.3, 149.6, 148.2, 147.3, 145.1, 142.8, 136.0,
133.7, 132.1, 131.7, 131.3, 130.0, 129.2, 126.9, 125.7, 125.3, 123.4,
121.1, 121.0, 116.9, 116.1, 115.9 (d, JC-F = 15.5 Hz), 110.4, 62.0, 47.9
ppm. Anal. calcd. for C32H24BrFN6O2: C, 61.65; H, 3.88; N, 13.48.
Found: C, 61.84; H, 3.60; N, 13.20.
1620, 1539, 1508 cmꢀ 1
.
1HNMR (500 MHz, DMSO‑d6) (two isomers):
10.93 (s, 1H, NH), 8.64 (s, 1H, CH), 8.58 (s, 1H, CH), 8.34 (s, 1H, tri-
azole), 8.31 (s, 1H, triazole), 8.00 (d, J = 7.5 Hz, 1H, H4), 7.57–7.21 (m,
8H, H6, H2′, H5′, H6′, H2′′, H3′′, H5′′, H6′′), 7.03 (t, J = 7.5 Hz, 1H, H5),
6.90 (d, J = 7.5 Hz, 1H, H7), 5.62 (s, 2H, CH2), 5.43 (s, 2H, CH2), 5.24 (s,
2H, CH2), 5.19 (s, 2H, CH2), 3.84 (s, 3H, OCH3), 3.79 (s, 3H, OCH3).
13CNMR (125 MHz, DMSO‑d6) (two isomers): 164.7, 162.9, 162.3,
161.2, 160.6 (d, JC-F = 224.6 Hz), 151.1, 150.6, 150.2, 149.3, 149.2,
148.0, 144.9, 144.0, 142.7, 133.4, 132.2, 131.6, 131.1, 130.3 (d, JC-F
=
8.6 Hz), 128.8, 127.2, 126.6, 124.9, 123.6, 123.0, 122.3, 116.6, 115.6
(d, JC-F = 21.4 Hz), 113.4, 113.2, 110.8, 63.0, 61.2, 55.9, 52.4 ppm.
Anal. calcd. for C26H21FN6O3: C, 64.46; H, 4.37; N, 17.35. Found: C,
64.60; H, 4.51; N, 17.15.
8.1.17. 1-(4-Bromobenzyl)-3-((4-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-
4-yl)methoxy)benzylidene)hydrazono)indolin-2-one 9o
8.1.13. 3-((4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)benzylidene)
hydrazono)-1-(4-bromobenzyl)indolin-2-one 9 k
Yield: 18%, mp = 174–178 ◦C. IR (KBr): 3355, 2922, 2852, 1715,
1604, 1543, 1504, 1463 cmꢀ 1. 1HNMR (500 MHz, DMSO‑d6) (two iso-
mers): 8.70 (s, 1H, CH), 8.63 (s, 1H, CH), 8.35 (s, 1H, triazole), 8.13 (d,
J = 7.8 Hz, 1H, H4), 7.98 (d, J = 8.8 Hz, 2H, H2′, H6′), 7.54 (d, J = 8.5
Hz, 2H, 4-bromobenzyl), 7.42–7.40 (m, 3H, H6, H2′′, H6′′), 7.33 (d, J =
8.5 Hz, 2H, 4-bromobenzyl), 7.25–7.19 (m, 4H, H3′, H5′, H3′′, H5′′),
7.11 (t, J = 7.8 Hz, 1H, H5), 7.01 (d, J = 7.8 Hz, 1H, H7), 5.62 (s, 2H,
CH2), 5.27 (s, 2H, CH2), 5.21 (s, 2H, CH2), 4.96 (s, 2H, CH2). 13CNMR
Yield: 50%, mp = 182–185 ◦C. IR (KBr): 3350, 2923, 2852, 1726,
1604, 1532, 1509, 1463 cmꢀ 1. 1HNMR (500 MHz, DMSO‑d6) (two iso-
mers): 8.70 (s, 1H, CH), 8.63 (s, 1H, CH), 8.34 (s, 1H, triazole), 8.32 (s,
1H, triazole), 8.13 (d, J = 8.0 Hz, 1H, H4), 7.98 (d, J = 8.8 Hz, 2H, H2′,
H6′), 7.54 (d, J = 8.4 Hz, 2H, 4-bromobenzyl), 7.42–7.32 (m, 8H, H6,
H2′′, H3′′, H4′′, H5′′, H6′′, 4-bromobenzyl), 7.24 (d, J = 8.8 Hz, 2H, H3′,
H5′), 7.11 (t, J = 8.0 Hz, 1H, H5), 7.01 (d, J = 8.0 Hz, 1H, H7), 5.63 (s,
2H, CH2), 5.27 (s, 2H, CH2), 5.22 (s, 2H, CH2), 4.96 (s, 2H, CH2) ppm.
13CNMR (125 MHz, DMSO‑d6) (two isomers): 164.2, 163.1, 162.2,
160.3, 150.3, 146.4, 145.3, 143.1, 136.5, 136.1, 133.8, 132.1, 131.6,
130.0, 129.2, 128.4, 127.2, 126.5, 126.4, 125.7, 124.6, 123.7, 123.6,
121.3, 116.6, 116.0, 106.9, 62.0, 53.5 ppm. Anal. calcd. for
(125 MHz, DMSO‑d6) (two isomers): 164.0, 162.6, 162.0 (d, JC-F
=
250.0 Hz), 162.2, 162.0, 150.4, 145.4, 143.1, 136.0, 133.9, 133.8,
132.8, 132.7, 132.1, 131.7, 131.6, 130.9, 130.8, 130.0, 126.7, 125.3,
123.6, 121.0, 116.7, 116.0, 115.7 (d, JC-F = 15.5 Hz), 111.8, 62.0, 52.5
ppm. Anal. calcd. for C32H24BrFN6O2: C, 61.65; H, 3.88; N, 13.48.
Found: C, 61.38; H, 3.71; N, 13.60.
C
32H25BrN6O2: C, 63.48; H, 4.16; N, 13.88. Found: C, 63.21; H, 4.33; N,
13.60.
7

D. Shareghi-Boroujeni et al.
Bioorganic Chemistry 111 (2021) 104869
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with the lowest IC50, was investigated against an α-glucosidase activity
with different concentrations of p-nitrophenyl
α-D-glucopyranoside
Analogues of xanthones——Chalcones and bis-chalcones as α-glucosidase
(2–10 mM) as the substrate in the absence and presence of compound 9d
at different concentrations (0, 8, 16, and 33 µM). A Lineweaver–Burk
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Declaration of Competing Interest
[24] Y.-O. Teng, H.-Y. Zhao, J. Wang, H. Liu, M.-L. Gao, Y. Zhou, K.-L. Han, Z.-C. Fan,
Y.-M. Zhang, H. Sun, Synthesis and anti-cancer activity evaluation of 5-(2-
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The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
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Acknowledgment
This work was supported by financial support from Tehran Univer-
sity of Medical Sciences with project No. 98-01-159-41836.
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Appendix A. Supplementary data
molecular docking studies of novel coumarin-isatin derivatives as α-glucosidase
inhibitors, Chem. Biol. Drug Des. 89 (3) (2017) 456–463.
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A. Wadood, N. Uddin, M. Nawaz, S.A.A. Shah, K.M. Khan, Isatin based
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bioorg.2021.104869.
thiosemicarbazide derivatives as potential inhibitor of α-glucosidase, synthesis and
their molecular docking study, J. Mol. Struct. 1222 (2020), 128922.
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