Synthesis, biological evaluation, and molecular docking studies of novel isatin-thiazole derivatives as α-glucosidase inhibitors

Article abstract of DOI:10.3390/molecules22040659

A series of novel isatin-thiazole derivatives were synthesized and screened for their in vitro α-glucosidase inhibitory activity. These compounds displayed a varying degree of α-glucosidase inhibitory activity with IC₅₀ ranging from 5.36 ± 0.13 to 35.76 ± 0.31 μm as compared to the standard drug acarbose (IC₅₀ = 817.38 ± 6.27 μm). Among the series, compound 6p bearing a hydroxyl group at the 4-position of the right phenyl and 2-fluorobenzyl substituent at the N1-positions of the 5-methylisatin displayed the highest inhibitory activity with an IC₅₀ value of 5.36 ± 0.13 μm. Molecular docking studies revealed the existence of hydrophobic interaction, CH-π interaction, arene-anion interaction, arene-cation interaction, and hydrogen bond between these compounds and α-glucosidase enzyme.

Full text of DOI:10.3390/molecules22040659

molecules
Article
Synthesis, Biological Evaluation, and Molecular
Docking Studies of Novel Isatin-Thiazole Derivatives
as α-Glucosidase Inhibitors
Zhenzhen Xie, Guangcheng Wang *, Jing Wang, Ming Chen, Yaping Peng, Luyao Li, Bing Deng,
Shan Chen and Wenbiao Li
College of Chemistry and Chemical Engineering, Hunan Engineering Laboratory for Analyse and Drugs
Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, China;
xiezz1993@126.com (Z.X.); wangjingjsu@sina.com (J.W.); mingchen940517@163.com (M.C.);
yapingpeng17@163.com (Y.P.); liluyao15@yeah.net (L.L.); dengbingfish@163.com (B.D.);
chenshan20142014@163.com (S.C.); liwenbiao0926@yeah.net (W.L.)
* Correspondence: wanggch123@163.com; Tel.: +86-743-8563-911
Academic Editor: Derek J. McPhee
Received: 29 March 2017; Accepted: 18 April 2017; Published: 20 April 2017
Abstract: A series of novel isatin-thiazole derivatives were synthesized and screened for their in vitro
α
-glucosidase inhibitory activity. These compounds displayed a varying degree of
inhibitory activity with IC50 ranging from 5.36 0.13 to 35.76 0.31 m as compared to the standard
drug acarbose (IC50 = 817.38 6.27 m). Among the series, compound 6p bearing a hydroxyl
group at the 4-position of the right phenyl and 2-fluorobenzyl substituent at the N1-positions of
the 5-methylisatin displayed the highest inhibitory activity with an IC50 value of 5.36 0.13 m.
Molecular docking studies revealed the existence of hydrophobic interaction, CH- interaction,
α-glucosidase
±
±
µ
±
µ
±
µ
π
arene-anion interaction, arene-cation interaction, and hydrogen bond between these compounds and
α-glucosidase enzyme.
Keywords: α-glucosidase inhibitor; molecular docking; isatin; thiazole; diabetic
1. Introduction
Diabetes mellitus is a group of metabolic disorders of carbohydrate metabolism characterized
by high blood glucose levels (hyperglycemia), resulting from defects in insulin secretion, insulin
action, or both [1]. Currently, there are an estimated 422 million people have diabetes mellitus
in the world, according to the latest 2016 data from the World Health Organization (WHO) [
2].
In diabetic patients, untreated and chronic hyperglycemia can cause serious complications, such as
heart disease, stroke, blindness, high blood pressure, kidney disease, and nervous system disease [3].
α-Glucosidase is a membrane-bound enzyme at the epithelium of the small intestine and hydrolyzes
terminal non-reducing 1–4 linked
is mainly responsible to cause hyperglycemia [
carbohydrate absorption and have been used as one of the therapeutic approaches for the treatment of
diabetes [ ]. Some -glucosidase inhibitors (acarbose, miglitol, and voglibose) have been approved
for clinical use and also used as anticancer [ ], anti-HIV [ ], and anti-hepatitis agents [ ]. Therefore,
-glucosidase inhibitors is an important research area in
α
-glucose residues to release monomeric glucose molecules which
4
]. Inhibition of -glucosidase activity can delay
α
4,5
α
6
7
8
design and synthesis of small molecules as
medicinal chemistry.
α
Isatin (1H-indole-2,3-dione,
nitrogen-containing aromatic heterocyclic compounds, which have been found in many plants and
human blood and tissue [ ]. Isatin has emerged as a promising nucleus and attracted increasing
I) is the reference compound of an important class of
9
Molecules 2017, 22, 659; doi:10.3390/molecules22040659
www.mdpi.com/journal/molecules

Molecules 2017, 22, 659
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attention in medicinal chemistry and drug discovery over the past decade [10]. Previous literature
reports indicated that isatin and its derivatives have diverse types of biological activity, including
anticancer [11], antibacterial [12], antiviral [13], anticonvulsant [14], anti-inflammatory [15], and
antifungal activity [16]. Notably, some isatin derivatives have been approved for clinic use such
as sunitinib, toceranib, and nintedanib. Furthermore, Rahim et al. reported the synthesis of isatin
based Schiff bases II (Figure 1) which showed excellent inhibitory potential many fold better than
the standard acarbose [17]. Sun et al. reported the synthesis of tetracyclic oxindole derivatives III
(Figure 1) and the most active compound (IC50 = 0.7 µm) was about 170 times as active as acarbose [18].
Recently, we have also synthesized a series of coumarin-isatin derivatives IV (Figure 1), and some of
the obtained compound exhibited excellent α-glucosidase inhibition activity [19].
Figure 1. The chemical structures of the reported α-glucosidase inhibitors containing isatin or thiazole moiety.
On the other hand, thiazole derivatives are considered as another important class of heterocyclic
compounds, which displayed a wide range of pharmacological activities such as anti-inflammatory [20],
anticancer [21], anticonvulsant [22], and antibacterial [23]. It is interesting that numerous studies
pointed out thiazole could be used as a useful moiety in the design of potent
inhibitors [24 28]. For example, compound series 25], VI 28], and VII 26] displayed potent
α-glucosidase inhibitory activity (Figure 1).
Over the years, molecular hybrid-based approaches had been exploited by researchers to discover
some promising chemical architectures which containing two or more bioactive pharmacophores [29,30]
α-glucosidase
–
V
[
[
[
.
Using this approach, and as part of our ongoing effort to develop potent α-glucosidase inhibitors [31–35]
herein we report the design and synthesis of a series of novel isatin-thiazole derivatives containing
isatin and thiazole moieties. The synthesized compounds were evaluated for their inhibitory activity
,
against
α-glucosidase. Furthermore, molecular docking was also performed to investigate the
interaction of inhibitors with enzymes.
2. Results and Discussion
2.1. Chemistry
The synthesis of isatin-thiazole derivatives 6a–6p was shown in Scheme 1. Reaction of
commercially available isatins
1
with various alkyl halides in the presence of K2CO3 in DMF provided
◦
N-alkyl isatins . Isatins ( and
2
1
2) were stirred with thiosemicarbazide in ethanol at 45 C for 3 h

Molecules 2017, 22, 659
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to provide the isatin thiosemicarbazones
3. Various substitutions of acetophenone
4
were treated
with NBS in the presence of p-toluenesulfonic acid in acetonitrile to give
-bromoacetophenone , with appropriate isatin thiosemicarbazones , was condensed in refluxing
ethanol for 2 h to afford the corresponding isatin-thiazole derivatives 6a 6p in moderate to high yield
α-bromoacetophenone 5.
α
5
3
–
(52.4–78.4%). All of the title compounds 6a–6p have not yet been reported in the literature.
◦
Scheme 1. Reagents and conditions: (
a
) R2X, K2CO3, DMF, room temperature, 2 h; (
b
) EtOH, 45 C, 3 h;
(c) p-MeC6H4SO3H, NBS, CH3CN, reflux, 2 h; (d) EtOH, reflux, 2 h.
1
The structures of all of the title compounds 6a–6p were characterized by H-NMR spectra.
1
The H-NMR spectrum of 6a exhibited two singlet signals at 11.36 and 13.33 ppm, attributed to
the protons of NH-indolin-2-one and =NNH group, respectively. Two doublet signals at 6.97 ppm
(J = 8.4 Hz) and 7.52 ppm (J = 2.0 Hz) were attributed to C7-H and C4-H of isatin ring, respectively.
The double-double peak of C6-H of the isatin ring was observed at 7.36 ppm with a coupling constant
of 8.4 Hz and 2.0 Hz. Two double peaks at 7.61 and 7.85 ppm with coupling constant of 8.4 Hz were
attributed to the aromatic protons of C3,5-H and C2,6-H, respectively. The hydrogen atom of thiazole
ring appeared as a singlet signal at 7.74 ppm. The 1H-NMR spectrum of all new compounds consistent
with their structures. Moreover, in their 13C-NMR spectra, the number of signals equals the number of
different carbons in the molecule (Supplementary Materials).
2.2. α-Glucosidase Inhibition Assay
All the synthetic compounds 6a
activity (Table 1). The results were shown that all the tested compounds displayed potent to moderate
-glucosidase inhibitory activity with IC50 ranging from 5.36 0.13 to 35.76 0.31 m more potent
than the standard drug acarbose (IC50 = 817.38 6.27 m [17 36]). Among the series, compounds 6a
6g 6h 6i 6j 6l 6m 6n, and 6p displayed potent inhibitory activity with IC50 values of 6.87
5.98 0.12, 6.12 0.15, 7.51 0.17, 6.51 0.13, 8.33 0.18, 7.17 0.15, 6.36 0.12, and 5.36
m. In particular, compound 6p (IC50 = 5.36 0.13
–6p were screened for their in vitro α-glucosidase inhibitory
α
±
±
µ
±
µ
,
,
,
,
,
,
,
,
±
±
0.14,
0.13
±
±
±
±
±
±
±
µ
±
µ
m) with a hydroxyl group at the 4-position of
the right phenyl ring and methyl and 2-fluorobenzyl groups at 5- and N1-positions of the isatin ring,
was found to be the most active compound. In comparison to compound 6p, a decrease in activity
was observed for 6i (IC50 = 7.51
at N1-positions of the isatin ring. Compounds 6c
IC50 value 10.34 0.17, 15.68 0.24, and 11.78 0.21 µ
±
0.17) in which 2-fluorobenzyl groups is replaced with hydrogen
6k, and 6o also displayed good inhibition with
m, respectively. Other compounds displayed
,
±
±
±

Molecules 2017, 22, 659
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low α-glucosidase inhibitory activity. The binding interactions of the most active compounds with
α-glucosidase were confirmed through molecular docking studies.
Table 1. α-Glucosidase inhibitory activity of novel isatin-thiazole derivatives (6a–6p).
Compound
R1
R2
R3
IC50 (µm) a
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
5-Cl
5-Me
5-Me
H
H
H
H
Br
Me
MeO
Me
F
MeO
Cl
Br
OH
F
Me
Me
F
F
Me
OH
6.87 ± 0.14
35.76 ± 0.31
10.34 ± 0.17
32.17 ± 0.29
33.20 ± 0.24
24.17 ± 0.28
5.98 ± 0.12
6.12 ± 0.15
7.51 ± 0.17
6.51 ± 0.13
15.68 ± 0.24
8.33 ± 0.18
7.17 ± 0.15
6.36 ± 0.12
11.78 ± 0.21
5.36 ± 0.13
817.38 ± 6.27
2-F-benzyl
2-F-benzyl
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
5.7-Me2
5-Me
5.7-Me2
5.7-Me2
5-F
5-F
H
H
5-Me
6o
6p
Acarbose
2-F-benzyl
a
Acarbose is standard for α-glucosidase inhibition activity.
2.3. Homology Model
The crystallographic structure of Saccharomyces cerevisiae
α
-glucosidase enzyme has not been
reported. To understand the ligand-enzyme interactions, the 3D structure of
means of modeller 9.15 homology modeling software (http://salilab.org/modeller/). The sequence in
FASTA format of -glucosidase was retrieved from UniProt (access code P53341). The crystallographic
α-glucosidase was built by
α
structure of Saccharomyces cerevisiae isomaltase (PDB ID: 3AJ7, Resolution 1.30 Å) with 72.4% of
sequence identity with the target was selected as the template for homology modeling [37]. The
quality of homology model was verified by PROCHECK (http://services.mbi.ucla.edu/PROCHECK/).
The result was shown that the model could be used to study the interactions between this class of
compounds and the active site of α-glucosidase [35].
2.4. Molecular Docking
The theoretical binding mode between 6i and Saccharomyces cerevisiae
in Figure 2. Compound 6i adopted a “V-shaped” conformation in the pocket of the
α
-glucosidase was shown
-glucosidase.
α
The indolin-2-one scaffold of 6i located at the hydrophobic pocket, surrounded by the residues
Phe-157, Leu-176, Pro-240, Phe-300, and Leu-218, forming a stable hydrophobic binding. Detailed
analysis showed that the indolin-2-one scaffold of 6i formed CH-
π interaction with the residue Phe-157.
In addition, the 4-hydroxylphenyl group of 6i formed CH- interactions with the residues Phe-158
π
and Tyr-71, and arene-anion interactions with the residues Asp-68 and Asp-349. Also, the arene-cation
interactions were observed between the 4-hydroxylphenyl group of 6i and the residues Arg-439 and
Arg-443. It was shown that the residues Thr-215 (bond length: 3.3 Å) and Asp-68 (length: 2.1 Å)
formed two hydrogen bonds with 6i, which was the main interaction between 6i and
On the other hand, molecular docking study of the standard drug acarbose with -glucosidase was
also performed (Figure 2B). The results were shown that compound 6i (binding energy was about
α-glucosidase.
α
−
9.2 kcal mol−1) has a similar binding affinity as compared to standard drug acarbose (binding energy
was about −6.8 kcal mol−1).

Molecules 2017, 22, 659
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Figure 2. Compound 6i
cerevisiae α-glucosidase.
(A) and acarbose (B) was docked to the binding pocket of the Saccharomyces
To explain the activity order of 6i and 6p against
further docked into the binding pocket of -glucosidase, and the theoretical binding mode between 6p
and -glucosidase was shown in Figure 3A. The interaction between 6p and -glucosidase was nearly
α-glucosidase in the molecular level, 6p was
α
α
α
the same as the compound 6i (Figure 3B). The main difference was that the 2-fluorophenyl group of 6p
formed extra hydrophobic interactions with the residues Phe-157, Leu-176, Pro-240, and Leu-218, and
formed two extra hydrogen bonds with the residue Glu-276 (length: 2.4 Å) and Asp-68 (length: 2.4 Å),
which made 6p was more active than 6i against
α
-glucosidase (Figure 3B). In addition, the estimated
10.1 kcal mol−1 for 6p, respectively, which was
binding energies were
−
9.2 kcal mol−1 for 6i and
−
consistent with the results of the in vitro α-glucosidase inhibitory activity.
Figure 3. (A) Compound 6p was docked to the binding pocket of the Saccharomyces cerevisiae α-glucosidase
;
(B) Compounds 6i and 6p were docked to the binding pocket of the Saccharomyces cerevisiae
α-glucosidase (overlapped).
To explain the activity order of 6b and 6p against
α
-glucosidase in the molecular level, 6b was
further docked into the binding pocket of
6b and -glucosidase was shown in Figure 4A. Compound 6b adopted a ‘V-shaped’ conformation
in the pocket of the -glucosidase. The 2-fluorophenylindolin-2-one group of 6b stretched into the
α-glucosidase, and the theoretical binding mode between
α
α
hydrophobic pocket that consisted of Phe-157, Leu-176, Pro-240, Phe-300, and Leu-218, forming a
stable hydrophobic binding. Detailed analysis showed that the indolin-2-one scaffold of 6b formed

Molecules 2017, 22, 659
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CH-π interaction with the residue Phe-157. In addition, the 4-methylphenyl group of 6b formed CH-π
interactions with the residues Phe-158 and Tyr-71, and arene-anion interactions with the residues
Asp-68 and Asp-349, respectively. Also, the arene-cation interactions were observed between the
4-methylphenyl group of 6b and the residues Arg-439 and Arg-443. It was shown that the residues
Thr-215 (bond length: 3.2 Å) and Glu-276 (length: 2.4 Å) formed two hydrogen bonds with 6b
which was the main interaction between 6b and -glucosidase. The interaction between 6p and
-glucosidase was nearly the same as the compound 6b (Figure 4B). The main difference was that the
4-methoxyphenyl group of 6p formed an extra hydrogen bond with the residue Asp-68 (length: 2.4 Å),
which made 6p was more active than 6b against -glucosidase (Figure 4B). In addition, the estimated
binding energies were
9.5 kcal mol−1 for 6b and 10.1 kcal mol−1 for 6p, respectively, which was
,
α
α
α
−
−
consistent with the results of the in vitro α-glucosidase inhibitory activity.
Figure 4. (A) Compound 6b was docked to the binding pocket of the Saccharomyces cerevisiae α-glucosidase
;
(B) Compounds 6b and 6p were docked to the binding pocket of the Saccharomyces cerevisiae
α-glucosidase (overlapped).
3. Experimental Section
3.1. General
All starting materials and reagents were purchased from commercial suppliers. TLC was
performed on 0.20 mm Silica Gel 60 F254 plates (Qingdao Ocean Chemical Factory, Shandong, China).
1H- and 13C-NMR spectra were recorded were recorded on a Bruker spectrometer (400 MHz) with
TMS as an external reference and reported in parts per million.
3.2. General Procedures for the Synthesis of 6a–6p
A mixture of
the completion of the reaction, the precipitates that formed were collected by filtration and washed
with ethanol (3 10 mL) to give the desired products 6a 6p. The spectroscopic and analytical data of
compounds are as follows:
3 (1.0 mmol) and 5 (1.2 mmol) in EtOH (10 mL) was stirred at reflux for 2 h. After
×
–
(Z)-3-(2-(4-(4-Bromophenyl)thiazol-2-yl)hydrazono)-5-chloroindolin-2-one (6a). Orange solid, yield 77.5%,
1H-NMR (d6-DMSO, 400 MHz)
: 6.97 (d, 1H, J = 8.4 Hz, ArH), 7.36 (dd, 1H, J = 8.4 Hz, 2.0 Hz, ArH),
7.52 (d, 1H, J = 2.0 Hz, ArH), 7.61 (d, 2H, J = 8.4 Hz, ArH), 7.74 (s, 1H, CH-thiazole), 7.85 (d, 2H,
J = 8.4 Hz, ArH), 11.36 (s, 1H, NH), 13.33 (s, 1H, NH); 13C-NMR (d6-DMSO, 100 MHz)
: 108.6, 113.0,
δ
δ
119.8, 121.5, 121.9, 127.1, 128.1, 128.2, 130.3, 131.6, 132.1, 132.2, 133.6, 140.4, 150.4, 163.4, 166.5.
(Z)-1-(2-Fluorobenzyl)-5-methyl-3-(2-(4-(p-tolyl)thiazol-2-yl)hydrazono) indolin-2-one (6b). Red solid, yield
52.5%, 1H-NMR (d6-DMSO, 400 MHz)
δ: 2.33 (s, 6H, CH3), 5.06 (s, 2H, CH2), 6.93 (d, 1H, J = 8.4 Hz,

Molecules 2017, 22, 659
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ArH), 7.14–7.19 (m, 2H, ArH), 7.23–7.26 (m, 3H, ArH), 7.32–7.37 (m, 2H, ArH), 7.44 (s, 1H, ArH), 7.58
(s, 1H, ArH), 7.79 (d, 2H, J = 8.0 Hz, ArH), 13.22 (s, 1H, NH); 13C-NMR (d6-DMSO, 100 MHz)
: 21.0,
δ
21.3, 37.4, 106.6, 110.3, 115.9 (d, 1C, J = 20.9 Hz), 119.7, 120.6, 122.9, 123.0, 125.2 (d, 1C, J = 3.4 Hz), 126.0,
126.1, 129.7, 129.9, 130.0, 130.1, 130.3 (d, 1C, J = 8.1 Hz), 131.2, 131.4, 131.8, 132.9, 137.8, 139.7, 151.7,
159.4 (d, 1C, J = 243.9 Hz), 161.8, 166.3; MS (ESI, m/z): 457.11 [M + H]+.
(Z)-1-(2-Fluorobenzyl)-3-(2-(4-(4-methoxyphenyl)thiazol-2-yl)hydrazono)-5-methylindolin-2-one (6c). Red
solid, yield 77.2%, 1H-NMR (d6-DMSO, 400 MHz)
δ: 2.32 (s, 3H, CH3), 3.79 (s, 3H, OCH3), 5.06 (s, 2H,
CH2), 6.92 (d, 1H, J = 8.0 Hz, ArH), 6.98 (d, 2H, J = 8.0 Hz, ArH), 7.13–7.18 (m, 2H, ArH), 7.22–7.26 (m,
1H, ArH), 7.32–7.37 (m, 2H, ArH), 7.43 (s, 1H, ArH), 7.48 (s, 1H, CH-thiazole), 7.83 (d, 2H, J = 8.0 Hz,
ArH), 13.21 (s, 1H, NH); 13C-NMR (d6-DMSO, 100 MHz)
δ: 21.0, 37.4, 55.6, 105.3, 110.3, 114.5, 114.7,
115.9 (d, 1C, J = 20.9 Hz), 119.7, 120.5, 122.9, 123.0, 125.2 (d, 1C, J = 3.5 Hz), 127.3, 127.6, 130.0, 130.1,
130.3 (d, 1C, J = 8.1 Hz), 131.2, 131.3, 132.8, 139.7, 151.5, 159.4 (d, 1C, J = 243.9 Hz), 159.6, 161.7; MS
(ESI, m/z): 473.09 [M + H]+.
(Z)-1-Methyl-3-(2-(4-(p-tolyl)thiazol-2-yl)hydrazono)indolin-2-one (6d). Red solid, yield 75.4%, 1H-NMR
(d6-DMSO, 400 MHz)
J = 8.0 Hz, ArH), 7.44 (t, 1H, J = 8.0 Hz, ArH), 7.57 (s, 1H, CH-thiazole), 7.57 (d, 1H, J = 8.0 Hz, ArH),
7.79 (d, 2H, J = 8.0 Hz, ArH), 13.26 (s, 1H, NH); 13C-NMR (d6-DMSO, 100 MHz)
: 21.3, 26.2, 106.4,
δ: 2.33(s, 3H, ArCH3), 3.27 (s, 3H, NCH3), 7.15–7.19 (m, 2H, ArH), 7.23 (d, 2H,
δ
110.2, 119.5, 119.9, 123.3, 126.1, 129.7, 130.8, 131.6, 131.8, 137.8, 143.0, 151.6, 161.8, 166.3.
(Z)-3-(2-(4-(4-Fluorophenyl)thiazol-2-yl)hydrazono)-1-methylindolin-2-one (6e). Orange solid, yield 70.3%,
1H-NMR (d6-DMSO, 400 MHz)
δ: 3.27 (s, 3H, NCH3), 7.15–7.18 (m, 2H, ArH), 7.26 (t, 2H, J = 8.8 Hz,
ArH), 7.44 (t, 1H, J = 8.0 Hz, ArH), 7.57 (d, 1H, J = 8.0 Hz, ArH), 7.62 (s, 1H, CH-thiazole), 7.93 (dd, 2H,
J = 8.8 Hz, 5.6 Hz, ArH), 13.25 (s, 1H, NH); 13C-NMR (d6-DMSO, 100 MHz) δ: 26.2, 107.1, 110.3, 115.9
(d, 1C, J = 21.5 Hz), 119.5, 120.0, 123.4, 128.2 (d, 1C, J = 8.1 Hz), 130.9, 131.0 (d, 1C, J = 2.9 Hz), 131.1,
131.9, 143.1, 150.5, 161.1 (d, 1C, J = 243.7 Hz), 161.8, 166.6.
(Z)-3-(2-(4-(4-Methoxyphenyl)thiazol-2-yl)hydrazono)-1-methylindolin-2-one (6f). Red solid, yield 69.9%,
1H-NMR (d6-DMSO, 400 MHz)
δ
: 3.27 (s, 3H, NCH3), 3.80 (s, 3H, OCH3), 6.98 (d, 2H, J = 8.8 Hz,
ArH), 7.15–7.19 (m, 2H, ArH), 7.44 (t, 1H, J = 8.0 Hz, ArH), 7.48 (s, 1H, CH-thiazole), 7.58 (d, 1H,
J = 7.2 Hz, ArH), 7.83 (d, 2H, J = 8.8 Hz, ArH), 13.26 (s, 1H, NH); 13C-NMR (d6-DMSO, 100 MHz)
δ:
26.2, 55.6, 105.2, 110.3, 114.5, 114.7, 119.5, 119.9, 123.4, 127.3, 127.5, 127.6, 130.8, 131.6, 143.0, 151.5, 159.6,
161.8, 166.3.
(Z)-3-(2-(4-(4-Chlorophenyl)thiazol-2-yl)hydrazono)indolin-2-one (6g). Orange solid, yield 66.9%, 1H-NMR
(d6-DMSO, 400 MHz) δ: 6.96 (d, 1H, J = 8.8 Hz, ArH), 7.10 (t, 1H, J = 8.8 Hz, ArH), 7.35 (t, 1H, J = 8.8 Hz,
ArH), 7.47 (d, 2H, J = 8.8 Hz, ArH), 7.54 (d, 1H, J = 8.8 Hz, ArH), 7.70 (s, 1H, CH-thiazole), 7.92 (d, 2H,
J = 8.8 Hz, ArH), 11.26 (s, 1H, NH-indolin-2-one),13.35 (s, 1H, NH); 13C-NMR (d6-DMSO, 100 MHz)
δ:
108.0, 111.5, 120.2, 120.3, 122.9, 127.9, 129.1, 131.0, 132.7, 132.9, 133.3, 141.8, 150.3, 163.6, 166.7.
(Z)-3-(2-(4-(4-Bromophenyl)thiazol-2-yl)hydrazono)-5,7-dimethylindolin-2-one (6h). Orange solid, yield
64.4%, 1H-NMR (d6-DMSO, 400 MHz)
: 2.21 (s, 3H, ArCH3), 2.29 (s, 3H, ArCH3), 6.99 (s, 1H, ArH),
7.19 (s, 1H, ArH), 7.61 (d, 2H, J = 8.8 Hz, ArH), 7.71 (s, 1H, CH-thiazole), 7.85 (d, 2H, J = 8.8 Hz, ArH),
11.22 (s, 1H, NH-indolin-2-one), 13.40 (s, 1H, NH); 13C-NMR (d6-DMSO, 100 MHz)
: 16.3, 20.9, 107.9,
δ
δ
118.1, 119.9, 120.6, 121.4, 128.2, 131.9, 132.0, 132.9, 133.2, 133.7, 138.2, 150.3, 164.2, 166.7.
(Z)-3-(2-(4-(4-Hydroxyphenyl)thiazol-2-yl)hydrazono)-5-methylindolin-2-one (6i). Orange solid, yield 52.4%,
1H-NMR (d6-DMSO, 400 MHz)
δ
: 2.33 (s, 3H, ArCH3), 6.80 (d, 2H, J = 8.8 Hz, ArH), 6.85 (d, 1H,
J = 8.0 Hz, ArH), 7.15 (d, 1H, J = 8.0 Hz, ArH), 7.36 (s, 2H, CH-thiazole and ArH), 7.71 (d, 2H, J = 8.8 Hz,
ArH), 11.16 (s, 1H, NH-indolin-2-one), 13.35 (s, 1H, NH); 13C-NMR (d6-DMSO, 100 MHz)
: 21.0, 104.2,
δ
111.3, 115.6, 115.9, 120.2, 120.6, 125.6, 127.6, 129.9, 131.4, 131.9, 132.7, 139.5, 151.5, 157.9, 163.7, 166.3.
(Z)-3-(2-(4-(4-Fluorophenyl)thiazol-2-yl)hydrazono)-5,7-dimethylindolin-2-one (6j). Orange solid, yield
59.6%, 1H-NMR (d6-DMSO, 400 MHz)
δ: 2.21 (s, 3H, ArCH3), 2.29 (s, 3H, ArCH3), 6.99 (s, 1H, ArH),

Molecules 2017, 22, 659
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7.19 (s, 1H, ArH), 7.26 (t, 2H, J = 8.8 Hz), 7.61 (s, 1H, CH-thiazole), 7.93 (d, 2H, J = 8.8 Hz, 5.6 Hz, ArH),
11.22 (s, 1H, NH-indolin-2-one), 13.39 (s, 1H, NH); 13C-NMR (d6-DMSO, 100 MHz)
: 16.3, 20.9, 106.8,
δ
115.8 (d, 1C, J = 21.5 Hz), 118.1, 119.9, 120.6, 128.2 (d, 1C, J = 8.1 Hz), 131.1 (d, 1C, J = 2.7 Hz), 131.8,
132.8, 133.1, 138.2, 150.5, 161.1 (d, 1C, J = 243.7 Hz), 164.2, 166.6.
(Z)-5,7-Dimethyl-3-(2-(4-(p-tolyl)thiazol-2-yl)hydrazono)indolin-2-one (6k). Orange solid, yield 62.1%,
1H-NMR (d6-DMSO, 400 MHz)
δ
: 2.21 (s, 3H, ArCH3), 2.29 (s, 3H, ArCH3), 2.34 (s, 3H, ArCH3), 6.99
(s, 1H, ArH), 7.20 (s, 1H, ArH), 7.23 (d, 2H, J = 8.0 Hz, ArH), 7.55 (s, 1H, CH-thiazole), 7.79 (d, 2H,
J = 8.0 Hz, ArH),11.22 (s, 1H, NH-indolin-2-one), 13.39 (s, 1H, NH); 13C-NMR (d6-DMSO, 100 MHz)
δ:
16.3, 20.9, 21.3, 106.2, 118.1, 119.9, 120.6, 126.1, 129.7, 131.9, 132.8, 133.0, 137.7, 138.2, 151.6, 164.2, 166.4.
(Z)-5-Fluoro-3-(2-(4-(p-tolyl)thiazol-2-yl)hydrazono)indolin-2-one (6l). Orange solid, yield 60.8%, 1H-NMR
(d6-DMSO, 400 MHz) δ: 2.24 (s, 3H, ArCH3), 6.96 (dd, 1H, J = 8.4 Hz, 4.4 Hz, ArH), 7.19 (dt, 1H,
J = 8.4 Hz, 2.4 Hz, ArH), 7.23 (d, 2H, J = 8.0 Hz, ArH), 7.35 (dd, 1H, J = 8.4 Hz, 2.4 Hz, ArH), 7.59 (s,
1H, CH-thiazole), 7.79 (d, 2H, J = 8.0 Hz, ArH), 11.28 (s, 1H, NH-indolin-2-one), 13.39 (s, 1H, NH);
13C-NMR (d6-DMSO, 100 MHz)
δ: 21.3, 106.7, 107.1, 107.4, 112.5 112.6, 117.0 (d, 1C, J = 24.5 Hz), 121.4
(d, 1C, J = 8.9 Hz), 125.9, 126.1, 129.7, 129.9, 131.7, 131.9 (d, 1C, J = 3.1 Hz), 137.8, 137.9, 151.7, 157.6 (d,
1C, J = 236.4 Hz), 163.8, 166.1.
(Z)-5-Fluoro-3-(2-(4-(4-fluorophenyl)thiazol-2-yl)hydrazono)indolin-2-one (6m). Orange solid, yield 57.7%,
1H-NMR (d6-DMSO, 400 MHz)
δ: 6.95 (dd, 1H, J = 8.4 Hz, 4.4 Hz, ArH), 7.19 (dt, 1H, J = 8.4 Hz,
2.4 Hz, ArH), 7.25 (d, 2H, J = 8.8 Hz, ArH), 7.35 (dd, 1H, J = 8.4 Hz, 2.4 Hz, ArH), 7.66 (s, 1H,
CH-thiazole), 7.94 (dd, 2H, J = 8.8 Hz, 5.6 Hz, ArH), 11.28 (s, 1H, NH-indolin-2-one), 13.39 (s, 1H, NH);
13C-NMR (d6-DMSO, 100 MHz)
δ: 107.2, 107.4, 107.4, 112.5, 112.6, 115.9 (d, 1C, J = 21.4 Hz), 116.2 (d,
1C, J = 21.5 Hz), 117.1, 117.3, 121.4, 121.5, 128.2, 128.3, 128.4, 131.0 (d, 1C, J = 2.9 Hz), 132.0 (d, 1C,
J = 3.6 Hz), 138.0, 150.5, 157.6 (d, 1C, J = 236.3 Hz), 161.1 (d, 1C, J = 243.6 Hz), 163.8, 166.3.
(Z)-3-(2-(4-(4-Fluorophenyl)thiazol-2-yl)hydrazono)indolin-2-one (6n). Orange solid, yield 78.4%, 1H-NMR
(d6-DMSO, 400 MHz) δ: 6.97 (d, 1H, J = 8.0 Hz, ArH), 7.10 (t, 1H, J = 8.0 Hz, ArH), 7.26 (d, 2H, J = 8.8 Hz,
ArH), 7.36 (t, 1H, J = 8.0 Hz, ArH), 7.54 (d, 1H, J = 8.0 Hz, ArH), 7.62 (s, 1H, CH-thiazole), 7.94 (dd, 2H,
J = 8.8 Hz, 5.6 Hz, ArH), 11.27 (s, 1H, NH-indolin-2-one), 13.35 (s, 1H, NH); 13C-NMR (d6-DMSO, 100
MHz) δ: 117.0, 111.5, 115.9 (d, 1C, J = 21.4 Hz), 120.2, 120.3, 122.9, 128.2 (d, 1C, J = 8.1 Hz), 130.9, 131.1
(d, 1C, J = 2.9 Hz), 132.6, 141.8, 150.5, 161.1(d, 1C, J = 243.6 Hz), 163.6, 166.6.
(Z)-3-(2-(4-(p-Tolyl)thiazol-2-yl)hydrazono)indolin-2-one (6o). Red solid, yield 73.3%, 1H-NMR (d6-DMSO,
400 MHz) δ: 2.34 (s, 3H, ArCH3), 6.97 (d, 1H, J = 8.0 Hz, ArH), 7.10 (t, 1H, J = 8.0 Hz, ArH), 7.23 (d,
2H, J = 8.0 Hz, ArH), 7.35 (t, 1H, J = 8.0 Hz, ArH), 7.54–7.56 (m, 2H, CH-thiazole and ArH), 7.79 (d,
2H, J = 8.4 Hz, ArH), 11.27 (s, 1H, NH-indolin-2-one), 13.35 (s, 1H, NH); 13C-NMR (d6-DMSO, 100
MHz) δ: 21.3, 106.3, 111.5, 120.2, 120.3, 122.9, 126.1, 129.7, 129.8, 130.9, 131.8, 132.5, 137.8, 141.7, 151.6,
163.7, 166.4.
(Z)-1-(2-Fluorobenzyl)-3-(2-(4-(4-hydroxyphenyl)thiazol-2-yl)hydrazono)-5-methylindolin-2-one (6p). Red
solid, yield 53.1%, 1H-NMR (d6-DMSO, 400 MHz)
δ
: 2.33 (s, 3H, ArCH3), 5.07 (s, 2H, ArCH2), 6.81 (d,
2H, J = 7.2 Hz, ArH), 6.93 (d, 1H, J = 7.2 Hz, ArH), 7.12–7.25 (m, 3H, ArH), 7.36–7.44 (m, 3H), 7.72 (d,
2H, J = 7.2 Hz, ArH), 9.62 (s, 1H, OH), 13.21 (s, 1H, NH); 13C-NMR (d6-DMSO, 100 MHz)
: 21.0, 37.4,
δ
104.4, 110.3, 115.9, 115.9 (d, 1C, J = 23.0 Hz), 119.8, 120.5, 122.9, 123.0, 125.2, 125.8, 127.6, 130.0, 130.2 (d,
1C, J = 8.1 Hz), 131.1, 132.8, 139.6, 151.9, 157.9, 159.4 (d, 1C, J = 237.9 Hz), 166.0; MS (ESI, m/z): 459.06
[M + H]+.
3.3. In Vitro Assay of α-Glucosidase Inhibitory Activity
According to the literature procedure [36], α-Glucosidase inhibitory activity was assayed by
using 0.1 M phosphate buffer (pH 6.8) at 37 ◦C. The enzyme (0.1 U/mL) in phosphate buffer saline
◦
was incubated with various concentrations of test compounds at 37 C for 15 min. Then 1.25 mM

Molecules 2017, 22, 659
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p-nitrophenyl α-D-glucopyranoside was added to the mixture as a substrate, after further incubation
at 37 ◦C for 30 min. The absorbance was measured spectrophotometrically at 405 nm. The sample
solution was replaced by DMSO as a control. Acarbose was used as a positive control. All experiments
were carried out in triplicates. The % inhibition has been obtained using the formula: inhibition (%) =
(1 − ∆Asample/
∆
Acontrol)
×
100%. IC50 value is defined as a concentration of samples inhibiting
50% of α-glucosidase activity under the stated assay conditions.
3.4. Molecular Docking
Molecular docking studies were performed to investigate the binding mode between the
compounds 6b
were obtained by ChemBioDraw Ultra 14.0 and ChemBio3D Ultra 14.0 softwares. The AutoDockTools
1.5.6 package was employed to generate the docking input files [39 40]. The search grid of -glucosidase
was identified as center_x: 19.676, center_y: 7.243, and center_z: 21.469 with dimensions size_x:
, 6i, 6p, and α-glucosidase using Autodock vina 1.1.2 [38]. The 3D structures of 6i and 6p
,
α
−
−
−
15, size_y: 15, and size_z: 15. The value of exhaustiveness was set to 20. For Vina docking, the default
parameters were used if it was not mentioned. The best-scoring poses as judged by the Vina docking
score were chosen and visually analyzed using PyMOL 1.7.6 software (Schrödinger®, New York, NY,
USA) (http://www.pymol.org/).
4. Conclusions
In conclusion, we designed and synthesized a novel series of
the molecular hybrid-based approaches. All the target compounds displayed potent to moderate
-glucosidase inhibitory activity with IC50 ranging from 5.36 0.13 to 35.76 0.31 m as compared
to the standard drug acarbose (IC50 = 817.38 6.27 m). Among the series, compound 6p bearing a
hydroxyl group at the 4-position of the right phenyl and 2-fluorobenzyl substituent at the N1-positions
of the 5-methylisatin displayed the highest inhibitory activity with an IC50 value of 5.36 0.13 m.
Furthermore, molecular docking studies revealed the existence of hydrophobic interaction, CH-
α-glucosidase inhibitor based on
α
±
±
µ
±
µ
±
µ
π
interaction, arene-anion interaction, arene-cation interaction, and hydrogen bond between these
compounds and α-glucosidase enzyme.
Supplementary Materials: Supplementary materials are available online.
Acknowledgments: This work was supported by Hunan Provincial Natural Science Foundation of China
(2015JJ3099), Scientific Research Fund of Hunan Provincial Education Department (15B194); The college students’
research learning and innovative experiment plan project of Jishou University and Hunan Province (Zhenzhen Xie).
Author Contributions: Guangcheng Wang designed and wrote the paper; Zhenzhen Xie, Jing Wang, Ming Chen,
Yaping Peng, Luyao Li, Bing Deng, Shan Chen, and Wenbiao Li carried out the experiments. All authors have
read and approved the final manuscript.
Conflicts of Interest: The authors confirm that this article content has no conflict of interest.
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Sample Availability: Samples of the compounds 6a–6p are available from the authors.
©
2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).