Benzoxazolyl linked benzylidene based rhodanine and analogs as novel antidiabetic agents: synthesis, molecular docking, and in vitro studies

Article abstract of DOI:10.1007/s00044-021-02781-y

Benzoxazolyl linked meta- and para-substituted new chemical entities (5a–5h) featuring thiazolidinedione, rhodanine, hydantoin, and thiohydantoin moieties were synthesized and characterized by ¹H NMR, ¹³C NMR, FT-IR, and HRMS spectra

Full text of DOI:10.1007/s00044-021-02781-y

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research (2021) 30:1905–1914
https://doi.org/10.1007/s00044-021-02781-y
ORIGINAL RESEARCH
Benzoxazolyl linked benzylidene based rhodanine and analogs as
novel antidiabetic agents: synthesis, molecular docking, and in vitro
studies
Varinder Singh1 Amanjot Singh Gagandeep Singh Raman K. Verma Rajiv Mall2
1 ●
1 ●
1 ●
●
Received: 22 May 2021 / Accepted: 9 August 2021 / Published online: 25 August 2021
©
The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021
Abstract
Benzoxazolyl linked meta- and para-substituted new chemical entities (5a–5h) featuring thiazolidinedione, rhodanine,
1
13
hydantoin, and thiohydantoin moieties were synthesized and characterized by H NMR, C NMR, FT-IR, and HRMS
spectral studies. In addition, all compounds were screened for α-glucosidase inhibitory activity and further supported by
molecular docking studies carried out at the active site of α-glucosidase (PDB code: 3TOP) in comparison to acarbose used
as a standard drug. Out of eight tested compounds, 5d was found as the most active inhibitor of α-glucosidase (IC = 9.48 ±
5
0
0
.36 µM), having rhodanine moiety substituted at meta-position of the phenyl ring.
Graphical Abstract
N
O
N
O
X
NH
NH
H
N
O
S
NH
X
N
H
O
(
5a-5d)
(5e-5h)
X = O : 5a, 5c, 5e, 5g and X = S : 5b, 5d, 5f, 5h
para-substituted : a and e, b and f
meta-substituted : c and g, d and h
●
●
●
Keywords Benzoxazole Molecular docking α-Glucosidase Antidiabetic
Introduction
Diabetes mellitus is the most common metabolic disorder
growing at alarming rates in developed as well as devel-
oping countries. According to the International Diabetes
Federation, the number of patients suffering from the dis-
ease is expected to increase up to 693 million by 2045 [1].
Increased blood glucose level characterized by hypergly-
cemia is either because sufficient insulin is not produced by
the pancreas or the insulin receptor does not act in response
to the secreted insulin [2]. Diabetes is also the primary
cause of morbidity and mortality associated with many
complications such as heart disease, neuropathy, nephro-
pathy, stroke, and vascular diseases [3]. Therefore, there is
an urgent need to develop newer therapeutic approaches
for the prevention and management of diabetes. Various
Supplementary information The online version contains
supplementary material available at https://doi.org/10.1007/s00044-
0
21-02781-y.
*
Rajiv Mall
rajivmall@pbi.ac.in
1
Synthetic Organic and Medicinal Chemistry Laboratory,
Department of Chemistry, Punjabi University, Patiala 147002
Punjab, India
2
Department of Basic and Applied Sciences, Punjabi University,
Patiala 147002 Punjab, India

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Medicinal Chemistry Research (2021) 30:1905–1914
NO2
NH
2
Scheme 1 (a) CH3COONH4,
CH3COOH, reflux 15 h. (b)
SnCl2.H2O, EtOH, reflux 4 h. (c)
EtOH, MW, 15 min
X
X
S
b
b
S
X
S
NH
NH
NH
CHO
O
O
O
a
O N
2
(2a-2d)
(3a-3d)
O
H
N
NO2
NH2
1
X
N
H
O
O
NH
NH
N
H
N
H
X
X
(
2e-2h)
(3e-3h)
N
O
X
NH
X
NH
S
S
O
NH
2
H N
N
O
O
(
5a-5d)
c
Cl
NH
2
O
4
NH
N
X
H
N
O
NH
H
N
O
X
N
H
(
5e-5h)
X = O : 2a, 2c, 2e, 2g and X = S : 2b, 2d, 2f, 2h
X = O : 3a, 3c, 3e, 3g and X = S : 3b, 3d, 3f, 3h
X = O : 5a, 5c, 5e, 5g and X = S : 5b, 5d, 5f, 5h
para-substituted : a and e, b and f
meta-substituted : c and g, d and h
therapeutic strategies to treat diabetes include increasing
insulin secretion from pancreatic β cells, intensification of
insulin action, reduction in the production of hepatic glu-
cose, or inhibition of glucosidase digestive enzyme [4].
Increased blood glucose levels in the body can be controlled
by inhibiting the enzymes α-amylase and α-glucosidase,
which are involved in hydrolyzing carbohydrates [5]. The
α-amylase enzyme firstly breakdown the long chains pre-
sent in the polysaccharides, and the enzyme α-glucosidase
finally helps to convert the disaccharides and starch to
glucose. Thus, inhibition of enzymes α-amylase and α-
glucosidase is a favorable therapeutic measure to treat dia-
betes mellitus, which helps to delay the absorption process
of glucose after taking meals. Presently, a few inhibitors of
these enzymes, such as voglibose, acarbose, and miglitol,
are being used clinically for the treatment of type II diabetes
[6, 7]. Furthermore, inhibitors of α-glucosidase are also
used as anti-HIV, anticancer, and antihepatitis agents
[8–10]. Therefore, the development of new inhibitors of
α-glucosidase enzymes is emerging as a thrust area of
research in medicinal chemistry. Thaizolidine-2,4-diones,
rhodanine, and their derivatives are recently studied as a
new class of α-glucosidase inhibitors in the field of med-
icinal chemistry [11, 12]. On the other hand, the literature
revealed that compounds with a benzoxazole heterocyclic
system are promising pharmacophores that exhibited anti-
diabetic activities [13]. In continuation of our interest in
designing and synthesizing new chemical entities [14–16],
we are reporting, the synthesis of novel benzoxazole deri-
vatives (5a–5h) featuring thiazolidinedione rhodanine,
hydantoin, and thiohydantoin moieties as antidiabetic
agents for the management of type II diabetes, in the present

Medicinal Chemistry Research (2021) 30:1905–1914
1907
Fig. 1 Hydrogen bond interactions and distances of the standard drug acarbose and benzoxazole derivatives with the amino acid residues of the
active site of α-glucosidase (PDB code: 3TOP). a Acarbose. b 5a. c 5b. d 5e. e 5f. f 5c. g 5d. h 5g. i 5h
study. The targeted molecules thus synthesized were
screened for their in vitro α-glucosidase inhibitory activity
and which is further supported, with the help of molecular
docking studies using SYBYL 7.3 at the active site of the
crystal structure of the α-glucosidase (PDB: 3TOP), to
predict binding affinities in terms of Gold score (G score)
and hydrogen-bonding interactions.
predicted Z configuration, whereas hydantoin- and
thiohydantoin-based compounds 2e–2h were assigned E
configuration [17]. The methine proton appeared as one
proton singlet at δ 6.52–6.45 ppm. The downfield shift of
methine protons in isomers (2a–2d) with Z configuration
has been reported due to the deshielding effect of the
adjacent carbonyl group [18, 19].
Reduction of nitrobenzylidene-based compounds (2a–2h)
with tin(II) chloride dihydrate in ethanol as solvent under
reflux gave corresponding aminobenzylidene-based com-
pounds (3a–3h). The completion of reduction of the nitro
Result and discussion
Chemistry
group to amino was evident from the presence of two proton
1
broad singlet of NH protons at δ 4.06–6.17 ppm in H NMR
2
The synthetic strategy designed begins with the prepara-
tion of nitrobenzylidene-based compounds (2a–2h)
through “Knoevenagel condensation” of 4-nitrobenzalde-
hyde/3-nitrobenzaldehyde with active methylene contain-
ing moieties such as thiazolidinedione, rhodamine,
hydantoin, and thiohydantoin using ammonium acetate in
acetic acid under reflux (Scheme 1). Z isomer was found
the only isomer in compounds 2a–2d, whereas compounds
spectrum along with the broad band in the range
3471–3414 cm− characteristic of bonded N–H stretch of
1
–NH group in their IR Spectra. The presence of a molecular
2
ion peak in the GC-MS spectra of all these compounds further
confirmed the structure assigned. The 2-chlorobenzoxazole
(4) required in the synthetic sequence was prepared by
chlorination of the corresponding 2-mercaptobenzoxazole
according to the literature procedure via displacement of thiol
group present in 2-mercaptobenzoxazole by the chloro group
substituent using POCl /PCl reagent [20].
2
e–2h formed as single isomers with E configuration. The
configuration thus assigned was established through the
3
5
presence of one proton singlet for the methine proton in
the H NMR spectrum of compounds 2a–2d and 2e–2h.
The downfield one proton singlet at δ 7.92–7.70 ppm in
thiazolidinedione- and rhodanine-based compounds 2a–2d
Targeted compounds (5a–5h) were finally synthesized
by the coupling of aminobenzylidenes (3a–3h) with
2-chlorobenzoxazole (4) in ethanol under microwave irra-
diations (340 W) as shown in Scheme 1. A characteristic
1

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Medicinal Chemistry Research (2021) 30:1905–1914
singlet signal corresponding to NH of linker at δ
to their para-substituted counterparts (5a, 5b, and 5e),
except compounds (5f and 5h) featuring thiohydantoin
moiety. Acarbose forms eleven hydrogen bonds with α-
glucosidase, whereas numbers of hydrogen bonds were
found lesser in synthesized ligands. It was also observed
that all compounds are interacting within the same region of
the active site (Fig. 1) with similar amino acid residues as
that of acarbose. The Hydrogen bond distances in Å
between the ligands and amino acid residues found in the
range. In most cases, distances are shorter than the distances
observed in the case of acarbose. Generally, the carbonyl
group, –NH group of the polar heads, and –NH of the linker
of the ligands are found to involve in the formation of
hydrogen bonds. It was further observed and analyzed that
the docking and in vitro studies results showed a good
correlation.
1
1
1.07–10.33 ppm was found in the respective H NMR
spectrum of compounds 5a–5h, whereas the absence of
broad singlets for NH at δ 4.06–6.17 ppm which appeared
2
in corresponding aminobenzylidenes (3a–3h) strongly
1
3
indicated the formation of 5a–5h via coupling reaction. C
1
3
peaks in the C NMR spectrum were found at their
expected chemical shift positions corresponding to all
intermediates and final targeted compounds. Further, the
+
presence of [M + H] as a base peak in their respective
HRMS spectrum of 5a–5h provides additional support to
the structures assigned.
Molecular docking studies in the active site of
α-glucosidase (PDB code: 3TOP)
Docking studies were performed to explore the G score
values, binding conformations and affinities, and various
hydrogen-bonding interactions with different amino acid
residues in the active site of α-glucosidase. The hydrogen
bond interactions and distances for compounds (5a–5h)
with the amino acid residues of α-glucosidase protein
compared to the standard drug acarbose are shown in Fig. 1.
All the targeted compounds were docked using SYBYL 7.3
In vitro studies
All the synthesized compounds (5a–5h) were subjected to
in vitro analysis to evaluate their potential as inhibitors of
the α-glucosidase enzyme using acarbose as a standard drug
(IC = 15.01 ± 1.90 µM, Table 2). All these compounds
5
0
(5a–5h) have shown good potential toward inhibition of α-
glucosidase activity having IC50 values ranging from 9.48 ±
0.36 to 28.47 ± 0.52 µM. The rhodanine-based meta-sub-
stituted compound 5d (IC = 9.48 ± 0.36 µM) showed the
(
Tripose Inc. software available in our in silico Drug Design
Lab) by using the C-terminal domain of protein α-glucosi-
dase PDB: 3TOP [14–16]. Acarbose was found to have
binding affinity in terms of its G score value −160.51. It
binds α-glucosidase by making hydrogen bonds with
ASP1526, ASP1279, ASP1157, HIS1584, ARG1510, and
LYS1460 amino acids in the active site of α-glucosidase
5
0
best α-glucosidase inhibition potential among all the syn-
thesized compounds in the series (5a–5h). The corre-
sponding rhodanine-based para-substituted compound 5b
(IC = 16.17 ± 0.60) and thiazolidinedione-based com-
5
0
(
Table 1). It was observed from the comparison of the
pounds 5a (IC = (18.40 ± 0.20 µM) and 5c (IC =
50 50
results of the docking studies that meta-substituted com-
pound 5d (−185.75) and a para-substituted compound 5b
17.50 ± 0.50 µM) were found with less but comparable
inhibition potential to that of the standard drug acarbose
(IC = 15.01 ± 1.90 µM) as shown in Table 2. It has been
(
−167.64) having rhodanine as the polar head group
5
0
showed higher binding affinities in comparison to acarbose
and form hydrogen bonds with ASP1157, ASP1279, and
ASP1526, ASP1279 amino acid residues, respectively,
through –NH of the linker and –NH of rhodanine moiety.
Thiazolidinedione-based meta-substituted compound 5c
found that the hydantoin and thiohydantoin-based com-
pounds 5e, 5f, 5g, and 5h with IC50 values 20.07 ± 0.28,
21.03 ± 0.24, 20.93 ± 0.66, and 28.47 ± 0.52 µM, respec-
tively, (Table 2) exhibited much lesser inhibitory potential
in comparison to acarbose (15.01 ± 1.90 µM). The results of
α-glucosidase inhibition studies have also been additionally
supported by the results of molecular docking studies in
terms of G scores and various binding interactions in the
active site of the α-glucosidase in comparison to acarbose.
The overall analysis of the results depicted a good corre-
lation between the in vitro α-glucosidase inhibition and the
molecular docking studies of the final compounds while
(
−155.39) and para-substituted compound 5a (−142.03)
showed comparable binding affinities but less than that of
acarbose (−160.51) and are found to interact with
ARG1510, ASP1420, and ASP1279 through the –NH and
CO group of thiazolidinedione ring. Hydantoin-based
compound 5e (−112.16) and 5g (−133.07) along with
thiohydantoin-based compound 5f (−128.51) and 5h
2
(
−94.18) were showing much lesser binding affinities
displaying a good correlation coefficient (R = 0.883)
compared to acarbose while interacting with ASP1526,
TRP1523 ARG1510, TRP1418, ASP1420, HIS1584, and
ASP1279.
between the IC50 values and G scores values (Fig. 2).
The analysis thus demonstrated that hydrogen-bonding
parts (thiazolidinedione, rhodanine, hydantoin, and thiohy-
dantoin) and the position of the hydrogen-bonding parts of
the benzoxazole derivatives played an important role in the
In general, it was found that meta-substituted compounds
(
5c, 5d, and 5g) showed higher binding affinities compared

Medicinal Chemistry Research (2021) 30:1905–1914
Table 1 Docking results of the
1909
Compound G score H-bonding interactions between the ligands and the active site amino acid (AA)
compounds (5a–5h) as
residues
compared to acarbose (standard
drug) at the active site of α-
glucosidase protein
Atoms of ligandsa
AA residues Bond distance
(Å)
No. of
hydrogen bonds
(
PDB: 3TOP)
Acarbose
−160.51 OH
ASP1279
HIS1584
ASP1526
ASP1526
ARG1510
ARG1510
ARG1510
ASP1157
ASP1157
ASP1157
LYS1460
1.99
1.95
2.65
1.85
2.41
2.63
2.08
1.91
1.85
2.75
2.59
11
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
5a
5b
5e
−142.03 NH of thiazolidinedione ASP1279
NH of thiazolidinedione ASP1279
2.73
2.09
2
2
3
−167.64 NH of linker
NH of rhodanine
ASP1526
ASP1279
1.73
1.98
−112.16 3-NH of hydantoin
ASP1420
ARG1510
TRP1418
1.89
2.27
2.66
4
-CO of hydantoin
2
-CO of hydantoin
5
f
−128.51 1-NH of thiohydantoin
ASP1279
ASP1279
HIS1584
2.20
2.59
2.16
3
2
1
-NH of thiohydantoin
3
-NH of thiohydantoin
5
c
−155.39 4-CO of
thiazolidinedione
NH of thiazolidinedione
−185.75 NH of linker
ARG1510
ASP1420
2.02
2.73
5
d
g
ASP1157
ASP1279
2.26
2.61
2
3
NH of rhodanine
5
−133.07 3-NH of hydantoin
NH of linker
ASP1526
ASP1526
TRP1523
2.61
1.79
2.59
2
-CO of hydantoin
5
h
−94.18 NH of linker
ASP1526
1.86
1
aThe particular atom of the ligands involved in H-bonding has been indicated by boldface
Table 2 α-glucosidase inhibitory activity of the synthesized
compounds
y = -0.1702x + 42.754
R² = 0.8839
3
0
Compounds
IC50 (µM)
25
5
5
5
5
5
5
5
5
a
b
e
18.40 ± 0.20
16.17 ± 0.60
20.07 ± 0.28
21.03 ± 0.24
17.50 ± 0.50
9.48 ± 0.36
2
1
0
5
f
c
10
5
d
g
h
20.93 ± 0.66
28.47 ± 0.52
15.01 ± 1.09
0
Acarbose
1
00
120
140
160
180
200
G score
α-glucosidase inhibition potential. It was observed that
compound 5d having rhodanine group substituted at the
meta-position to the phenyl moiety displayed the best
inhibitory potential among all the other benzoxazole deri-
vatives. Replacing the position of the rhodanine moiety
Fig. 2 Correlation graph between the G score values and IC50 values
from meta to para decreased the inhibitory activity, whereas
replacement of the rhodanine moiety with other cyclic
analogs such as thiazolidinedione, hydantoin, and

1910
Medicinal Chemistry Research (2021) 30:1905–1914
thiohydantoin drastically decreased the inhibitory potential.
The information thus obtained from this structure–activity
relationship will provide a better tool and be helpful for the
future scope of structural optimization.
spectrometer and XEVO G2-XS Q-TOF, respectively. The
spectral data of all intermediates and final compounds are
provided in Supplementary Data.
General procedure for the synthesis of compounds (2a–2h)
Conclusions
To the stirred suspension of 4-nitrobenzaldehyde/3-nitro-
benzaldehyde (13.24 mmol) and active methylene com-
pound, thiazolidinedione/rhodanine/hydantoin/thiohydantoin
(19.87 mmol) in 20 mL glacial acetic acid, ammonium
acetate (26.49 mmol) was added, and the reaction mixture
refluxed for 15 h. Then, the solution was cooled and the
residue filtered off, washed with warm water, and dried.
All the reported compounds 5a–5h prepared in excellent
yield via microwave-assisted synthetic strategy. The results
of comparative in vitro α-glucosidase inhibition studies
demonstrated that compound 5d (IC = 9.48 ± 0.36 µM)
displayed the best α-glucosidase inhibition potential in
comparison to acarbose (IC = 15.01 ± 1.90 µM) among all
50
50
the compounds of this series. Compounds 5b, 5c, and 5a
have also shown IC50 values very close to that of acarbose.
The results of the docking/scoring study of the targeted
compounds in the active site of α-glucosidase (PDB code:
(5Z)-5-(4-nitrobenzylidene)-1,3-thiazolidine-2,4-dione (2a)
−
1
Yield: 81%; mp: 275–277 °C; FT-IR (KBr, cm ): 3424,
1
3195 (NH), 1752(C=O), 1714(C=O); H NMR (400 MHz,
3
TOP) and those of the in vitro analysis also showed a good
DMSO-d ): δ = 12.80 (1H, br s, NH), 8.36 (2H, dt, J =
6
2
correlation (R = 0.883).
2.44 Hz and 8.84 Hz, Ar-H), 7.91 (1H, s, benylidene), 7.87
1
3
The pharmacophoric features incorporated in the
designed new chemical entities rendered this scaffold to
inhibit α-glucosidase enzyme—responsible for prolonged
hyperglycemia leading to oxidative stress and subsequent
cardiac artery disease. The information thus obtained
through structure–activity relationship will provide a better
tool for the future scope in structural optimization and may
direct in the design and future studies with this and similar
scaffolds to be developed for the management of T2D.
(2H, dt, J = 2.40 Hz and 8.80 Hz, Ar-H); C NMR
(100 MHz, DMSO-d ): δ = 167.35(C=O), 167.01(C=O),
6
147.38, 139.31, 130.86(2C), 129.01, 127.99, 124.19(2C);
+
GC-MS (m/z): 250 [M] .
(5Z)-5-(4-nitrobenzylidene)-2-thioxo-1,3-thiazolidin-4-one (2b)
−
1
Yield: 92%; mp: 255–257 °C; FT-IR (KBr, cm ): 3427,
1
3050 (NH), 1717(C=O), 1318, 1191 (C=S); H NMR
(
400 MHz, DMSO-d ): δ = 13.86 (1H, br s, NH), 8.32 (2H,
6
d, J = 8.76 Hz, Ar-H), 7.79 (2H, d, J = 8.84 Hz, Ar-H),
1
3
Material and methods
7.70 (1H, s, benylidene); C NMR (100 MHz, DMSO-d6):
δ = 194.45 (C=S) 168.98(C=O), 147.36, 139.13, 130.93
(2C), 129.94, 128.23, 123.99(2C); GC-MS (m/z): 266 [M] .
+
Chemistry
All the chemicals used in the reported work were purchased
from Sigma-Aldrich and SD Fine Chemicals without further
purification. The melting/boiling points reported here were
recorded using an open concentrated sulfuric acid bath and
are uncorrected. TLC analysis was carried out on glass
plates coated with silica gel-GF254 (Loba Chemie), and
spots were visualized using a UV cabinet (Perfit India).
Column chromatography was performed using silica gel
(5E)-5-(4-nitrobenzylidene)imidazolidine-2,4-dione (2e)
−
1
Yield: 72%; mp: 311–313 °C; FT-IR (KBr, cm ): 3333,
1
3196 (NH), 1779(C=O), 1744(C=O); H NMR (400 MHz,
DMSO-d ): δ = 11.38 (1H, br s, NH), 10.96 (1H, br s, NH),
6
8.20 (2H, d, J = 8.88 Hz, Ar-H), 7.85 (2H, d, J = 8.84 Hz,
1
3
Ar-H), 6.49 (1H, s, benylidene); C NMR (100 MHz,
DMSO-d6): δ = 165.22(C=O), 155.74(C=O), 146.15,
139.97, 130.81, 130.09(2C), 123.68(2C), 105.12; GC-MS
6
0–120 mesh (Loba Chemie). The Infrared spectra were
+
recorded on Perkin Elmer Spectrum RX FT-IR Spectro-
(m/z): 233 [M] .
1
13
photometer, USA. H, C, NMR spectra were recorded on
a Bruker AVANCE II 400 (400.13, 100.62 MHz) NMR
spectrometer, Bruker BioSpin, Switzerland. Chemical shifts
were reported in ppm (δ) with reference to the internal
standard TMS. The signals were designated as: br broad, s
singlet, d doublet, t triplet, and m multiplet. The GC-MS
spectra of intermediates and HRMS of final compounds
were recorded on Shimadzu GCMS-QP2010 Plus mass
(5E)-5-(4-nitrobenzylidene)-2-thioxoimidazolidin-4-one (2f)
−
1
Yield: 80%; mp: 284–286 °C; FT-IR (KBr, cm ): 3300,
1
3209 (NH), 1743 (C=O), 1175 (C=S); H NMR (400 MHz,
DMSO-d ): δ = 12.40 (1H, br s, NH), 12.25 (1H, br s, NH),
6
8.15 (2H, d, J = 8.84 Hz, Ar-H), 7.85 (2H, d, J = 8.84 Hz,
1
3
Ar-H), 6.46 (1H, s, benylidene); C NMR (100 MHz,

Medicinal Chemistry Research (2021) 30:1905–1914
1911
DMSO-d6): δ = 179.93(C=S), 165.48(C=O), 146.49,
refluxed for 4 h. The solvent was evaporated under
1
39.05, 130.54(2C), 130.12, 123.39(2C), 107.70 GC-MS
reduced pressure and the residue obtained was dissolved in
+
(
m/z): 249 [M] .
100 mL saturated aqueous NaHCO solution. The product
3
was extracted with hot ethyl acetate (5 × 50 mL) and
combined organic extract washed with brine (2 × 50 mL),
dried over Na SO , and the solvent was removed under
(
5Z)-5-(3-nitrobenzylidene)-1,3-thiazolidine-2,4-dione (2c)
2
4
−
1
Yield: 83%; mp: 260–262 °C; FT-IR (KBr, cm ): 3418,
3
reduced pressure to obtain 3a–3h.
1
164 (NH), 1746(C=O), 1693 (C=O); H NMR (400 MHz,
DMSO-d ): δ = 12.70 (1H, br s, NH), 8.41 (1H, t, J =
(5Z)-5-(4-aminobenzylidene)-1,3-thiazolidine-2,4-dione (3a)
6
1
7
.88 Hz, Ar-H), 8.28–8.26 (1H, m, Ar-H), 7.97(1H, d, J =
.96 Hz), 7.92 (1H, s, benylidene), 7.78 (1H, t, J = 8.04 Hz,
−
1
Yield: 77%; mp: 246–248 °C; FT-IR (KBr, cm ): 3471,
1
3
1
Ar-H);
C NMR (100 MHz, DMSO-d ): δ = 166.87
3373 (NH ), 3241 (NH), 1708(C=O), 1669 (C=O); H
6
2
(
1
C=O), 166.79(C=O), 148.11, 135.30, 134.75, 130.47,
29.20, 126.59, 124.10, 124.03; GC-MS (m/z): 250[M] .
NMR (400 MHz, DMSO-d ): δ = 12.36 (1H, br s, NH),
6
+
7.65 (1H, s, benylidene), 7.34 (2H, d, J = 8.64 Hz, Ar-H),
13
6.71 (2H, d, J = 8.64 Hz, Ar-H), 6.16 (2H, s, NH2);
C
(5Z)-5-(3-nitrobenzylidene)-2-thioxo-1,3-thiazolidin-4-one (2d)
NMR (100 MHz, DMSO-d ): δ = 168.08(C=O), 167.54
6
(
C=O), 151.09, 133.13, 132.15(2C), 120.23, 115.28,
−
1
+
Yield: 95%; mp: 235–237 °C; FT-IR (KBr, cm ): 3430,
3
113.97(2C); GC-MS: 220 [M] .
1
248 (NH), 1693 (C=O), 1172 (C=S); H NMR (400 MHz,
DMSO-d ): δ = 13.90 (1H, br s, NH), 8.42 (1H, t, J =
(5Z)-5-(4-aminobenzylidene)-2-thioxo-1,3-thiazolidin-4-one (3b)
6
1
7
.84 Hz, Ar-H), 8.30–8.28 (1H, m, Ar-H), 7.98 (1H, d, J =
.84 Hz), 7.80 (1H, t, J = 7.80 Hz, Ar-H), 7.77 (1H, s,
−
1
Yield: 88%; mp: 250–252 °C; FT-IR (KBr, cm ): 3460,
1
3
1
benylidene); C NMR (100 MHz, DMSO-d ): δ = 194.70
3364 (NH ), 3036 (NH), 1676 (C=O), 1198 (C=S); H
6
2
(
1
C=S), 169.16(C=O), 148.20, 135.63, 134.68, 130.69,
28.66, 124.47, 124.34; GC-MS (m/z): 266 [M] .
NMR (400 MHz, DMSO-d ): δ = 13.21 (1H, br s, NH),
6
+
7.44 (1H, s, benylidene), 7.26 (2H, d, J = 8.72 Hz, Ar-H),
13
6.67 (2H, d, J = 7.00 Hz, Ar-H), 6.17 (2H, br s, NH2);
C
(
5E)-5-(3-nitrobenzylidene)imidazolidine-2,4-dione (2 g)
NMR (100 MHz, DMSO-d ): δ = 194.95(C=S), 169.46
6
(
C=O), 152.28, 133.48, 133.19(2C), 119.83, 116.70,
−
1
+
Yield: 78%; mp: 265–267 °C; FT-IR (KBr, cm ): 3491,
3
114.02(2C); GC-MS: 236 [M] .
1
204 (NH), 1779(C=O), 1737 (C=O); H NMR (400 MHz,
DMSO-d ): δ = 10.94 (2H, br s, NH), 8.29 (1H, t, J =
6
1
7
.80 Hz, Ar-H), 8.06–8.03 (1H, m, Ar-H), 7.90 (1H, d, J =
.88 Hz), 7.57 (1H, t, J = 8.00 Hz, Ar-H), 6.45 (1H, s,
(5E)-5-(4-aminobenzylidene)imidazolidine-2,4-dione (3e)
1
3
−1
benylidene); C NMR (100 MHz, DMSO-d ): δ = 165.08
Yield: 90%; mp: 236–238 °C; FT-IR (KBr, cm ): 3414,
6
(
1
C=O), 155.70(C=O), 148.08, 134.86, 134.78, 130.04,
29.55, 123.39, 122.09, 105.34; GC-MS (m/z): 233 [M] .
3337 (NH ), 3243, 3051 (NH), 1746(C=O), 1705 (C=O);
2
+
1
H NMR (400 MHz, DMSO-d ): δ = 10.89 (1H, s, NH),
6
10.08 (1H, s, NH), 7.30 (2H, d, J = 8.56 Hz, Ar-H), 6.60
(
5E)-5-(3-nitrobenzylidene)-2-thioxoimidazolidin-4-one (2h)
(2H, d, J = 8.52 Hz, Ar-H), 6.30 (1H, s, benylidene), 5.54
1
3
(
2H, br s, NH2); C NMR (100 MHz, DMSO-d ): δ =
6
−1
Yield: 85%; mp: 278–280 °C; FT-IR (KBr, cm ):
3
165.65(C=O), 155.40 (C=O), 149.13, 130.92(2C), 123.46,
1
+
168,3079 (NH), 1717 (C=O), 1314, 1193 (C=S); H NMR
120.46, 113.90(2C), 110.67; GC-MS: 203 [M] .
(
400 MHz, DMSO-d ): δ = 12.17 (2H, br s, NH), 8.46 (1H,
6
t, J = 1.60 Hz, Ar-H), 8.14–8.12 (1H, m, Ar-H), 8.05 (1H, d,
J = 7.80 Hz), 7.62 (1H, t, J = 8.00 Hz, Ar-H), 6.52 (1H, s,
(5E)-5-(4-aminobenzylidene)-2-thioxoimidazolidin-4-one (3f)
1
3
benylidene); C NMR (100 MHz, DMSO-d ): δ = 179.97
6
−
1
(
1
C=S), 165.67(C=O), 148.08, 135.56, 134.25, 130.34,
29.49, 123.98, 122.64, 107.92; GC-MS (m/z): 249 [M] .
Yield: 87%; mp: 225–227 °C; FT-IR (KBr, cm ): 3440,
+
3341 (NH ), 3218 (NH), 1715 (C=O), 1379, 1178(C=S);
2
1
H NMR (400 MHz, DMSO-d ): δ = 10.94 (1H, br s, NH),
6
General procedure for the synthesis of compounds (3a–3h)
To the stirred suspension of compound 2a/2b/2c/2d/2e/2f/
10.11 (1H, br s, NH) 7.30 (2H, d, J = 8.56 Hz, Ar-H), 6.57
(
2H, d, J = 8.56 Hz, Ar-H), 6.28 (1H, s, benylidene), 5.63
1
3
(2H, s, NH2); C NMR (100 MHz, DMSO-d ): δ = 165.63
6
2
g/2h (8 mmol) in 25 mL ethanol, Tin(II) chloride dihy-
(C=S), 155.39(C=O), 149.53, 131.02(2C), 123.28, 120.10,
113.71(2C), 110.72; GC-MS: 219 [M] .
+
drate (32 mmol) was added and the reaction mixture was

1912
Medicinal Chemistry Research (2021) 30:1905–1914
(
5Z)-5-(3-aminobenzylidene)-1,3-thiazolidine-2,4-dione (3c)
filtered and washed with 5 mL of ethanol to get the targeted
compound (5a–5h).
−
1
Yield: 83%; mp: 204–206 °C; FT-IR (KBr, cm ): 3461,
375 (NH ), 3159 (NH), 1739(C=O), 1678 (C=MR
3
(
(5Z)-5-[4-(1,3-benzoxazol-2-ylamino)benzylidene]-1,3-
thiazolidine-2,4-dione (5a)
2
400 MHz, DMSO-d ): δ = 12.05 (1H, br s, NH), 7.59 (1H,
6
s, benylidene), 7.14 (1H, t, J = 7.80 Hz, Ar-H), 6.77 (1H, t,
J = 1.80 Hz, Ar-H), 6.73–6.69 (2H, m, Ar-H), 5.31(2H, br
−
1
Yield: 89%; mp: 257–259 °C; FT-IR (KBr, cm ): 3355,
1
3
1
s, NH2); C NMR (100 MHz, DMSO-d ): δ = 167.93
3312 (NH), 1723 (C=O), 1686 (C=O); H NMR (400 MHz,
6
(
1
C=O), 167.26(C=O), 148.66, 133.38, 132.74, 129.40,
22.28, 118.29, 116.36, 114.58; GC-MS: 220 [M] .
DMSO-d ): δ = 12.44 (1H, s, NH), 10.99 (1H, s, NH of
linker), 7.94 (2H, d, J = 8.76 Hz), 7.74 (1H, s, benzylidene),
6
+
7
.58 (2H, d, J = 8.76 Hz), 7.47–7.44 (2H, m, Ar-H),
13
(
(
5Z)-5-(3-aminobenzylidene)-2-thioxo-1,3-thiazolidin-4-one
3d)
7.25–7.21 (1H, m, Ar-H), 7.17–7.13 (1H, m, Ar-H);
C
NMR (100 MHz, DMSO-d ): δ = 167.96 (C=O), 167.39
6
(
C=O), 157.28, 146.99, 142.02, 140.69, 131.65, 131.46(2C),
−
1
Yield: 92%; mp:185–187 °C; FT-IR (KBr, cm ): 3450,
126.50, 124.17, 122.17, 120.62, 117.79(2C), 116.94, 109.16;
HRMS (m/z): 338.0594 (calcd. for C H N O S 338.0599).
1
3
346 (NH ), 3140 (NH), 1689 (C=O), 1176 (C=S); H
2
17 12 3 3
NMR (400 MHz, DMSO-d ): δ = 12.54 (1H, br s, NH), 7.65
6
(
(
(
1
1
1H, s, benylidene), 7.21 (1H, t, J = 7.92 Hz, Ar-H), 6.78
(5Z)-5-[4-(1,3-benzoxazol-2-ylamino)benzylidene]-2-thioxo-
1,3-thiazolidin-4-one (5b)
2H, d, J = 7.52 Hz, Ar-H), 6.74–6.71 (1H, m, Ar-H), 5.46
2H, br s, NH2); 13C NMR (100 MHz, DMSO-d ): δ =
6
−
1
95.84(C=S), 169.35(C=O), 149.29, 133.34, 132.65,
Yield: 91%; mp: 261–263 °C; FT-IR (KBr, cm ): 3307,
+
1
29.67, 124.29, 119.01, 116.68, 114.17; GC-MS: 236 [M] .
3249 (NH), 1684 (C=O), 1180 (C=S); H NMR (400 MHz,
DMSO-d ): δ = 13.68 (1H, s, NH), 11.07 (1H, s, NH of
6
(
5E)-5-(3-aminobenzylidene)imidazolidine-2,4-dione (3g)
linker), 7.95 (2H, d, J = 8.80 Hz), 7.59 (2H, d, J =
8
.76 Hz), 7.59 (1H, s, benzylidene), 7.48–7.44 (2H, m, Ar-
−
1
13
Yield: 95%; mp: 173–175 °C; FT-IR (KBr, cm ): 3414,
337 (NH ), 3242, 3051 (NH), 1747 (C=O), 1707 (C=O);
H), 7.28–7.22 (1H, m, Ar-H), 7.18–7.14 (1H, m, Ar-H); C
NMR (100 MHz, DMSO-d ): δ = 195.48 (C=S), 169.41
(C=O), 157.19, 146.99, 141.98, 141.08, 132.07(2C),
131.74, 126.42, 124.21, 122.50, 122.24, 117.91(2C),
117.00, 109.20; HRMS (m/z): 354.0370 (calcd. for
C H N O S 354.0371).
3
2
6
1
H NMR (400 MHz, DMSO-d ): δ = 10.27 (1H, s, NH),
.36 (1H, s, NH), 6.18 (1H, t, J = 7.80 Hz, Ar-H), 5.94 (1H,
t, J = 1.80 Hz, Ar-H),5.89 (1H, d, J = 7.76 Hz, Ar-H)
6
9
5
.72–5.69 (1H, m, Ar-H), 5.39 (1H, s, benylidene), 4.06
1
7
12
3
2 2
(
2H, br s, NH2); 13C NMR (100 MHz, DMSO-d ): δ =
6
1
1
64.65(C=O), 154.67(C=O), 147.71, 132.43, 128.27,
26.49, 116.69, 113.62, 108.50; GC-MS: 203 [M] .
(5E)-5-[4-(1,3-benzoxazol-2-ylamino)benzylidene]
imidazolidine-2,4-dione (5e)
+
−
1
(
5E)-5-(3-aminobenzylidene)-2-thioxoimidazolidin-4-one (3h)
Yield: 90%; mp: 242–244 °C; FT-IR (KBr, cm ): 3275,
3
1
198 (NH), 1774 (C=O), 1725 (C=O); H NMR (400 MHz,
DMSO-d ): δ = 11.11 (1H, s, NH), 10.77 (1H, s, NH),
10.39 (1H, s, NH of linker), 7.81 (2H, d, J = 8.68 Hz), 7.60
(2H, d, J = 8.72 Hz), 7.46–7.41 (2H, m, Ar-H), 7.24–7.20
(1H, m, Ar-H), 7.14–7.10 (1H, m, Ar-H), 6.41 (1H, s,
−
1
Yield: 91%; mp: 210–212 °C; FT-IR (KBr, cm ): 3419,
160 (NH ), 3039 (NH), 1719 (C=O), 1334, 1183 (C=S);
6
3
2
1
H NMR (400 MHz, DMSO δ ppm): 12.23 (1H, br s,
NH),11.75 (1H, br s, NH) 7.07 (1H, t, J = 7.80 Hz, Ar-H),
1
3
6
.96 (1H, s, Ar-H), 6.85(1H, d, J = 8.16 Hz), 6.66–6.63
benzylidene); C NMR (100 MHz, DMSO-d ): δ = 165.50
6
(
1H, m, Ar-H) 6.34 (1H, s, benylidene), 4.89 (2H, s, NH );
C NMR (100 MHz, DMSO):178.78(C=S), 165.67(C=O),
(C=O), 157.49 (C=O),155.55, 146.97, 142.24, 138.79,
2
1
3
130.18(2C), 126.63, 126.32, 123.80, 121.61, 117.53,
+
1
1
48.40, 132.63, 129.09, 127.21, 118.70, 115.40, 114.81,
116.63, 108.71(2C), 108.60; [M + H] ; HRMS (m/z):
+
12.55; GC-MS: 219 [M] .
321.0980 (calcd. for C H N O 321.0988).
1
7
13
4
3
General procedure for the synthesis of compounds (5a–5h)
(5E)-5-[4-(1,3-benzoxazol-2-ylamino)benzylidene]-2-
thioxoimidazolidin-4-one (5f)
A solution of 2-chlorobenzoxazole (1.63 mmol) and amine
−
1
3
a/3b/3c/3d/3e/3f/3g/3h(1.63 mmol) in 10 mL ethanol was
Yield: 92%; mp: 214–216 °C; FT-IR (KBr, cm ): 3160
1
irradiated in microwave (320 W) for 15 min. The reaction
mixture was cooled and the precipitates obtained were
(NH), 1719 (C=O), 1185 (C=S); H NMR (400 MHz,
DMSO-d ): δ = 11.22 (1H, s, NH), 10.88 (1H, s, NH),
6

Medicinal Chemistry Research (2021) 30:1905–1914
1913
1
0.47 (1H, s, NH of linker), 7.78 (2H, d, J = 5.84 Hz), 7.65
116.68, 108.99; HRMS (m/z): 321.0996 (calcd. for
(
(
2H, d, J = 8.80 Hz), 7.49 (2H, d, J = 7.60 Hz), 7.26–7.24
1H, m, Ar-H), 7.17–7.15 (1H, m, Ar-H), 6.40 (1H, s,
C H N O 321.0988).
1
7
13
4
3
1
3
benzylidene); C NMR (100 MHz, DMSO-d ): δ = 179.57
(
(5Z)-5-[3-(1,3-benzoxazol-2-ylamino)benzylidene]-2-
thioxoimidazolidin-4-one(5h)
6
C=S), 165.73(C=O), 161.74, 150.24, 141.52, 135.75,
1
1
30.79(2C), 128.93, 127.39, 126.16, 125.78, 125.02,
19.90, 111.00(2C), 109.76; HRMS (m/z): 337.0754(calcd.
−
1
Yield: 87%; mp: 208–210 °C; FT-IR (KBr, cm ): 3403,
1
for C H N O S 337.0759).
3251 (NH), 1728 (C=O), 1178(C=S); H NMR (400 MHz,
1
7
13
4
2
DMSO-d ): δ = 12.42 (1H, s, NH), 12.05 (1H, s, NH),
6
(
5Z)-5-[3-(1,3-benzoxazol-2-ylamino)benzylidene]-1,3-
10.65 (1H, s, NH of linker), 7.89 (1H, s, Ar-H), 7.83–7.80
thiazolidine-2,4-dione (5c)
(1H, m, Ar-H), 7.51 (2H, m, Ar-H), 7.45–7.42 (2H, m, Ar-
H),7.25–7.21 (1H, m, Ar-H) 7.16–7.12 (1H, m, Ar-H), 6.46
−
1
13
Yield: 88%; mp: 198–200 °C; FT-IR (KBr, cm ): 3314,
3
(1H, s, benzylidene); C NMR (100 MHz, DMSO-d ): δ =
6
1
184 (NH), 1737 (C=O), 1692 (C=O); H NMR (400 MHz,
DMSO-d ): δ = 12.63 (1H, br s, NH), 10.94 (1H, s, NH of
linker), 8.14 (1H, s, Ar-H), 7.87–7.84 (1H, m, Ar-H), 7.80
179.30 (C=S), 165.66 (C=O), 157.89, 147.01, 142.27,
139.04, 132.95, 129.44, 128.36, 124.04, 123.42, 121.75,
119.39, 118.48, 116.74, 111.33, 109.00; HRMS (m/z):
337.0769 (calcd. for C H N O S 337.0759).
6
(
(
(
1H, s, benzylidene), 7.58–7.50 (3H, m, Ar-H), 7.33–7.27
1
7
13
4
2
13
2H, m, Ar-H), 7.22–7.18 (1H, m, Ar-H); C NMR
100 MHz, DMSO-d ): δ = 168.09 (C=O), 167.34 (C=O),
Molecular docking methods
6
1
1
1
3
57.65, 146.94, 142.12, 139.52, 133.58, 131.66, 129.94,
24.38, 124.11, 123.93, 121.94, 119.38, 117.53, 116.72,
09.06; HRMS (m/z): 338.0597 (calcd. for C H N O S
The crystal structure of the C-terminal domain of human
intestinal α-glucosidase (PDB code: 3TOP) was used as a
molecular target. The crystal structure complexed with
acarbose (original ligand) was downloaded from RCSB
Protein Data Bank (PDB). Hydrogen atoms were added,
whereas water molecules were removed from the structure
of the enzyme and energy was minimized using
Gasteiger–Huckel charges and tripos force field in the Sybyl
software suit. Benzoxazole-based compounds were assigned
Gasteiger–Huckel charges and subsequently minimized via
Powel method using SYBYL 7.3 software. The energy-
optimized sketched compounds were subjected to docking
run at the ligand-binding site of α-glucosidase by the Surflex
dock in SYBYL 7.3 [21]. Docking analysis was conducted
using the Surflex dock module to predict and examine the
binding modes of the synthesized derivatives at the active
site of α-glucosidase. The hydrogen-bonding interactions
(amino acid residues and bond distances) of the synthesized
molecules at the respective active sites were also compared
to standard inhibitor acarbose (Table 1 and Fig. 1).
17
12
3
3
38.0599).
(
1
5Z)-5-[3-(1,3-benzoxazol-2-ylamino)benzylidene]-2-thioxo-
,3-thiazolidin-4-one (5d)
−
1
Yield: 95%; mp: 180–182 °C; FT-IR (KBr, cm ): 3309,
1
3
189 (NH), 1690 (C=O), 1187 (C=S); H NMR (400 MHz,
DMSO-d ): δ = 13.64 (1H, br s, NH), 10.83 (1H, s, NH of
linker), 8.01 (1H, s, Ar-H), 7.75–7.73 (1H, m, Ar-H), 7.51
6
(
(
1H, s, benzylidene), 7.45–7.41 (2H, m, Ar-H), 7.39–7.37
1H, m, Ar-H), 7.22–7.15 (2H, m, Ar-H), 7.10–7.06 (1H, m,
1
3
Ar-H);
C NMR (100 MHz, DMSO-d ): δ = 195.99
6
(
C=S), 169.41 (C=O), 157.62, 146.94, 142.11, 139.63,
1
1
33.46, 131.42, 130.03, 125.93, 125.14, 124.11, 121.95,
19.62, 117.57, 116.66, 109.08; HRMS (m/z): 354.0379
(
calcd. for C H N O S 354.0371).
17 12 3 2 2
(
5Z)-5-[3-(1,3-benzoxazol-2-ylamino)benzylidene]
imidazolidine-2,4-dione (5g)
In vitro enzymatic starch digestion assay
−
1
Yield: 93%; mp: 179.181 °C; FT-IR (KBr, cm ): 3275,
3
in vitro enzymatic starch digestion method with some
modifications was followed [22]. One hundred milligrams
of corn starch was gelatinized in 3 mL distilled water with
or without test compound or acarbose (a standard drug
used). To this solution, 4 µg α-amylase was added, vor-
texed, and then the mixture was incubated at 80 °C for
20 min. After 20 min incubation, 3 mL of the mixture was
diluted to 10 mL by adding distilled water. Then, 1 mL of
the above solution was taken and added to 2 mL of 0.1 M
sodium acetate buffer (pH = 4.75). To this 3 mL mixture,
1
197 (NH), 1775 (C=O), 1727 (C=O); H NMR (400 MHz,
DMSO-d ): δ = 11.20 (1H, s, NH), 10.98 (1H, br s, NH),
0.33 (1H, s, NH of linker), 7.84 (1H, s, Ar-H), 7.77–7.53
1H, m, Ar-H), 7.45 (d, 1H, J = 7.40 Hz), 7.41–7.36 (2H,
m, Ar-H),7.29, (d, 1H, J = 7.80 Hz) 7.22–7.18 (1H, m, Ar-
H), 7.13–7.09 (1H, m, Ar-H), 6.41 (1H, s, benzylidene);
NMR (100 MHz, DMSO-d ): δ = 165.41 (C=O), 165.35
C=O), 157.93, 155.61, 147.02, 142.27, 139.04, 134.20,
33.58, 129.41, 128.56, 124.01, 121.73, 118.95, 117.72,
6
1
(
1
3
C
6
(
1

1914
Medicinal Chemistry Research (2021) 30:1905–1914
3
0 µg of α-glucosidase was added, and the mixture was
9. Mehta A, Zitzmann N, Rudd PM, Block TM, Dwek RA. Alpha-
glucosidase inhibitors as potential broad-based anti-viral agents.
FEBS Lett. 1998;430:17–22. https://doi.org/10.1016/s0014-5793
again incubated at 60 °C for 30 min. Control samples were
having neither acarbose nor test compound. Following
equation was used to calculate the rate of inhibition of the
test compounds on enzymatic starch digestion:
(98)00525-0.
1
0. Zitzmann N, Mehta AS, Carrouee S, Butters TM, Platt FM,
McCauley J, et al. Imino sugars inhibit the formation and secretion
of bovine viral diarrhea virus, a pestivirus model of hepatitis C
virus: implications for the development of broad spectrum anti-
hepatitis virus agents. Proc Natl Acad Sci USA.
1999;96:11878–82. https://doi.org/10.1073/pnas.96.21.11878.
(
%) inhibition of enzymatic starch digestion = [A − A /
o i
A ] × 100, where A = absorbance of the control sample
and A = Absorbance given by test compound.
o
o
i
IC50 values (in µM) were determined by plotting the
graph between percentage inhibition of starch digestion
versus different concentrations of test compounds.
11. Chinthala Y, Domatti AK, Sarfaraz A, Singh SP, Arigari NK,
Gupta N, et al. Synthesis, biological evaluation and molecular
modeling studies of some novel thiazolidinediones with triazole
ring. Eur J Med Chem. 2013;70:308–14. https://doi.org/10.1016/j.
ejmech.2013.10.005.
1
1
1
2. Wang G, Peng Y, Xie Z, Wang J, Chen M. Synthesis, α-gluco-
sidase inhibition and molecular docking studies of novel thiazo-
lidine-2,4-dione or rhodanine derivatives. Med Chem Commun.
Acknowledgements The authors are highly thankful to Punjabi Uni-
versity Patiala authorities for providing the necessary research facil-
ities. The authors also submit their sincere thanks to the Director and
Mr. Avtar Singh of Sophisticated Analytical Instrumentation Facility
2
017;8:1477–84. https://doi.org/10.1039/C7MD00173H.
3. Wang G, Peng Z, Wang J, Li J, Li X. Synthesis, biological eva-
luation and molecular docking study of N-arylbenzo[d]oxazol-2-
amines as potential α-glucosidase inhibitors. Bioorg Med Chem.
(
SAIF), Panjab University, Chandigarh, for extending facilities for
spectral analysis. Furthermore, VS acknowledges the University
Grants Commission (UGC) for providing the Maulana Azad National
Fellowship (Award number: MANF-2015-17-PUN-60098).
2
016;24:5374–9. https://doi.org/10.1016/j.bmc.2016.08.061.
4. Singh G, Singh A, Verma RK, Mall R, Azeem U. Synthesis,
biological evaluation and molecular docking studies of novel
benzimidazole derivatives. Comp Biol Chem. 2018;72:45–52.
https://doi.org/10.1016/j.compbiolchem.2017.12.010.
Compliance with ethical standards
Conflict of interest The authors declare no competing interests.
15. Singh V, Singh A, Singh G, Verma RK, Mall R. Novel benzox-
azole derivatives featuring rhodanine and analogs as anti-
hyperglycemic agents: synthesis, molecular docking, and
biological studies. Med Chem Res. 2018;27:735–43. https://doi.
org/10.1007/s00044-017-2097-1.
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
1
6. Kaur J, Singh A, Singh G, Verma RK, Mall R. Novel indolyl
linked para-substituted benzylidene-based phenyl containing
thiazolidinediones and their analogs as α-glucosidase inhibitors:
synthesis, in vitro and molecular docking studies. Med Chem Res.
2018;27:903–14. https://doi.org/10.1007/s00044-017-2112-6.
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