Dibenzazepine-linked isoxazoles: New and potent class of α-glucosidase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2021.127979

α-Glucosidase inhibition is a valid approach for controlling hyperglycemia in diabetes. In the current study, new molecules as a hybrid of isoxazole and dibenzazepine scaffolds were designed, based on their literature as antidiabetic agents. For this, a series of dibenzazepine-linked isoxazoles (33–54) was prepared using Nitrile oxide-Alkyne cycloaddition (NOAC) reaction, and evaluated for their α-glucosidase inhibitory activities to explore new hits for treatment of diabetes. Most of the compounds showed potent inhibitory potency against α-glucosidase (EC 3.2.1.20) enzyme (IC₅₀ = 35.62 ± 1.48 to 333.30 ± 1.67 μM) using acarbose as a reference drug (IC₅₀ = 875.75 ± 2.08 μM). Structure-activity relationship, kinetics and molecular docking studies of active isoxazoles were also determined to study enzyme-inhibitor interactions. Compounds 33, 40, 41, 46, 48–50, and 54 showed binding interactions with critical amino acid residues of α-glucosidase enzyme, such as Lys156, Ser157, Asp242, and Gln353.

Full text of DOI:10.1016/j.bmcl.2021.127979

Bioorg. Med. Chem. Lett. 40 (2021) 127979
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Dibenzazepine-linked isoxazoles: New and potent class of
α
-glucosidase inhibitors
,
,
Umm-E-Farwaa, Saeed Ullahb, Maria Aqeel Khana *, Humaira Zafarc *, Atia-tul-Wahabc,
Munisaa Younusa, M. Iqbal Choudharyb
e, Fatima Z. Bashab
,
c,
d
,
,*
a Third World Center for Science and Technology (TWC), H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of
Karachi, 75270 Karachi, Pakistan
b H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, 75270 Karachi, Pakistan
c Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences, University of Karachi, 75270
Karachi, Pakistan
d Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21412, Saudi Arabia
e Department of Chemistry, Faculty of Science and Technology, Universitas Airlangga, Komplek, Campus C, Surabaya 60115, Indonesia
A R T I C L E I N F O
A B S T R A C T
Keywords:
α
-Glucosidase inhibition is a valid approach for controlling hyperglycemia in diabetes. In the current study, new
Dibenzazepine
molecules as a hybrid of isoxazole and dibenzazepine scaffolds were designed, based on their literature as
Isoxazoles
antidiabetic agents. For this, a series of dibenzazepine-linked isoxazoles (33–54) was prepared using Nitrile
Nitrile oxide–alkyne cycloaddition
oxide-Alkyne cycloaddition (NOAC) reaction, and evaluated for their
α-glucosidase inhibitory activities to
α
-Glucosidase inhibitors
explore new hits for treatment of diabetes. Most of the compounds showed potent inhibitory potency against
Diabetes
α
-glucosidase (EC 3.2.1.20) enzyme (IC50 = 35.62 ± 1.48 to 333.30 ± 1.67 µM) using acarbose as a reference
drug (IC50 = 875.75 ± 2.08 µM). Structure-activity relationship, kinetics and molecular docking studies of active
isoxazoles were also determined to study enzyme-inhibitor interactions. Compounds 33, 40, 41, 46, 48–50, and
54 showed binding interactions with critical amino acid residues of
α-glucosidase enzyme, such as Lys156,
Ser157, Asp242, and Gln353.
Diabetes mellitus (DM) is portrayed as a condition with increased
associated problems, is increasing at an alarming rate in most of the
countries. It is estimated that about 451 million people, with the age
between 20 and 79 years, have diabetes, and by 2045, it is predicted to
rise up to 693 million.11,12 In addition, the prevalence of diabetes and
prediabetes is getting much higher than previously found in Pakistan.13
Therefore, comprehensive strategies need to be developed for the pre-
vention and treatment of diabetes.
glucose levels (hyperglycemia) in blood than the normal.1 This happens
due to lack of insulin production, lowering in the corresponding hor-
mone’s action, or sometimes both.2 Insufficient insulin secretion or its
resistance to the body, categorized the metabolic disorder, diabetes, into
two kinds: type-I and -II, respectively. Former type is controlled by
taking insulin externally. However, later condition is controlled by
medications, including biguanides,
α
-glucosidase inhibitors (AGIs),
Among numerous approaches for controlling high glucose levels in
dipeptidyl peptidase-4 (DPP-4) inhibitors, etc.3–7
blood, inhibition of α-glucosidase enzyme is a valid approach. This
The disorder is associated with numerous changes in protein and
lipid metabolism as well as with numerous vascular problems. In
particular, when proteins are exposed to increased glucose levels, a
cascade of reactions takes place that leads to the gradual collection of
advanced glycation end products (AGEs) in body tissues along with
various other complications (impaired wound healing, cataract, ne-
phropathy and neuropathy). It is also a risk factor for obesity and car-
diovascular diseases.8–10 The metabolic disturbance, diabetes along with
enzyme, located in jejunum, is involved in the breakdown of poly-
saccharides into monosaccharides, and resulted in a hyperglycemic
condition. Using AGIs, the risk of hyperglycemia is reduced in diabetic
patients by competing for binding with enzymes, or via slowing down
the carbohydrate metabolism.14 Currently several AGIs are available for
managing the hyperglycemia, including miglitol, acarbose, and vogli-
bose, however, they have low efficacy and caused diarrhea, abdominal
discomfort, and flatulence.15,16 Therefore, there is a need to design new,
* Corresponding authors.
E-mail addresses: markhan883@gmail.com (M.A. Khan), hamramalik@gmail.com (H. Zafar), bashafz@gmail.com (F.Z. Basha).
https://doi.org/10.1016/j.bmcl.2021.127979
Received 23 November 2020; Received in revised form 5 March 2021; Accepted 16 March 2021
Available online 22 March 2021
0960-894X/© 2021 Published by Elsevier Ltd.

Umm-E-Farwa et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127979
safe and effective inhibitors for controlling the diabetes and related
disorders.
nitrile oxides in situ via chlorination/dehydrochlorination. Then, nitrile
oxides (31) underwent copper-catalyzed 1,3-dipolar cycloaddition re-
action with the alkynyl part of compound 2 to afford regioselective 5-
membered heterocyclic ring, isoxazole. Other regioisomer 32 was not
formed in this reaction. Literature precedence revealed that Cu-
catalyzed cycloaddition lead to 3,5-disubstituted compounds,22 which
was further supported by computational studies in the literature.23
Later, different conditions were explored for this reaction, as depicted in
Table 1. 0.2 Equivalences of copper sulphate pentahydrate with DMF
and water as solvents were found to be optimum conditions (yield: 60%)
(entry 3, Table 1). Structure of compound was confirmed by spectro-
scopic analysis. HREI-MS also confirmed the formation of product,
which corresponds to m/z 368.1300 for molecular ion peak (M+) with
molecular formula of C24H17FN2O (theoretical mass: 368.1325). The 1H
NMR spectrum of isoxazole (36) showed the characteristic isoxazolyl
peak for H-4′ at δ 6.68 ppm. Comparison of spectra with precursor
molecule 2 showed disappearance of proton for acetylenic moiety at δ
2.20 ppm, which in turn reappeared as isoxazolyl proton in the product.
Aromatic protons from 4′′-fluorophenyl ring appeared as a multiplet for
H-3′′ and H-5′′ in the region of δ 7.51–7.46 ppm and a doublet of doublet
for H-2′′ and H-6′′ at δ 8.06 ppm. Olefinic protons for dibenzazepine
scaffold appeared at δ 7.24 ppm (s, H-10/-11), while rest of the aromatic
protons appeared at δ 7.66 (tt, H-3/-7), 7.44 (td, H-2/-8), 7.53 (dd, H-4/-
6), and 7.51–7.46 ppm (m, H-1/-9). Methylene protons appeared as a
singlet at δ 5.50 ppm. Confirmation for 3,5-disubstituted analogue for-
mation was confirmed via comparing 13C NMR value to literature values
Based on our previous report17 on
α-glucosidase inhibition of
dibenzazepine-linked triazoles (I), new hybrid molecules were designed
with dibenzazepine connected to another heterocycle ring. Isoxazole is
chosen as a heterocyclic scaffold, as it already has few reports on anti-
diabetic properties, including compounds II-IV (Fig. 1).8–20 In the cur-
rent study, a new series of dibenzazepine-linked isoxazoles was syn-
thesized, and screened for their α-glucosidase inhibitory activities to
discover novel leads for the management of diabetes. To the best of our
knowledge, all the synthesized isoxazole analogues are new, and this is
the first report for their α-glucosidase inhibitory activity.
A library of dibenzazepine-linked isoxazoles (33–54) was prepared
according to synthetic route, illustrated in Scheme 1. Dibenzazepine (1)
was converted into its corresponding propargyl derivative 2 under base-
◦
catalyzed alkylation reaction with propargyl bromide at 60 C (yield:
93%).21 Compound 2 acts as a dipolarophile in the last synthetic step.
Oximes, will be later on converted in situ into corresponding nitrile ox-
ides 31, which will act as dipolar molecules in the last step. Oximes
(4–21 and 26–29) were prepared as E/Z mixture via condensation of
substituted benzaldehydes (3a and 22–25) with hydroxyl amine, and
was used as a mixture in the next step (combined yields: 40–99%). The
stereochemistry of oximes did not affect the outcome of product in the
last step. Few alkoxybenzaldehydes (22–25) were prepared via alky-
lating hydroxy-substituted benzaldehydes (3b) with ethyl and benzyl
halides (yields: 60–96%).
In the last step, dibenzazepine-linked isoxazoles (33–54) were pre-
pared via nitrile oxide–alkyne cycloaddition reaction between propargyl
dibenzazepine (2) and nitrile oxides (31) (yields: 42–79%). In this re-
action, oximes (4–21 and 26–29) were first converted to corresponding
of 3,5-disubstituted isoxazole,22 and interpreting 2D-NMR spectra. 13
C
NMR value for isoxazolyl carbon C-4′ in compound 36 was found to δ
100.5 ppm, which corresponds to 3,5-disubstituted isoxazole. Further,
NOESY spectra revealed that methylene protons showed correlations
Fig. 1. Designing of dibenzazepine-linked isoxazoles.
2

Umm-E-Farwa et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127979
Scheme 1. Synthetic route for dibenzazepine-linked isoxazoles (33–54).
acarbose, with IC50 ranging between 35.62 ± 1.48 to 333.30 ± 1.67 µM.
Among them, isoxazole 46 (IC50 = 35.62 ± 1.48 µM) was the most
potent analogue. Compounds 44, 52 and 53 were found inactive.
Structure-activity relationship (SAR) studies for synthesized
dibenzazepine-linked isoxazoles (33–54) were done on the basis of re-
sults, depicted in Table 2. Results revealed that unsubstituted congener
33 (IC50 = 77.90 ± 1.14 µM) was found to be 10-fold better in activity
than the standard drug acarbose. Comparison with other analogues
showed that replacing different substituents on phenyl ring changed the
inhibitory potency. Among the fluorinated compounds, 3′′-substitued
analogue 35 (IC50 = 114.23 ± 0.81 µM) was comparatively significant in
activity than 2′′-substitued analogue 34 (IC50 = 154.86 ± 2.07 µM) and
4′′-substitued analogue 36 (IC50 = 160.62 ± 1.24 µM). Comparison
among chloro-substituted compounds showed that compound 38 (IC50
= 98.62 ± 0.94 µM) with chloro group at 3′′-position, was found to be
more active than other isomers, compound 37 (IC50 = 106.82 ± 0.43
µM) and 39 (IC50 = 231.16 ± 1.62 µM). In contrast, comparing com-
pound 37 (3′′-chloro) with compound 54 (3′′-chloro-4′′-N,N-dimethyla-
mino) (IC50 = 109.75 ± 1.74 µM) showed only slight decrease in the
activity. However, drastic change in activity was observed, while
comparing compound 39 (4′′-chloro) with compound 53 (3′′-ethoxy-4′′-
chloro), as activity for compound 53 was completely diminished.
Comparing brominated compounds with other halogenated analogues
Table 1
Optimization of nitrile oxide–alkyne cycloaddition reaction.
S. no.
Catalyst
Catalyst loading
(eq.)
Solvent system
Time
(h)
Yield
(%)
1.
2.
3.
4.
5.
6.
7.
8.
9.
CuI
0.2
0.2
0.2
0.1
0.3
0.2
0.2
0.2
0.2
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMSO/H2O
ACN/H2O
BuOH/H2O
iPrOH/H2O
3 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
22
24
60
38
21
0
CuBr
CuSO4⋅5H2O
CuSO4⋅5H2O
CuSO4⋅5H2O
CuSO4⋅5H2O
CuSO4⋅5H2O
CuSO4⋅5H2O
CuSO4⋅5H2O
29
27
9
CuI = Copper iodide; CuBr = Copper bromide; CuSO4⋅5H2O = Copper sulphate
pentahydrate; DMF
= N,N-Dimethylformamide; H2O = Water; DMSO =
Dimethyl sulfoxide; iPrOH = Isopropanol; BuOH = Butanol; ACN = Acetonitrile.
with isoxazolyl proton H-4′ (at δ 6.68 ppm), dibenazepine aromatic
protons H-4/-6 (at δ 7.54–7.42 ppm) and H-3/-7 (at δ 7.66 ppm), and
also with phenyl protons H-2′′/H-6′′ (at δ 8.06 ppm). The isoxazolyl
correlations with methylene protons as well as with phenyl protons H-
2′′/H-6′′ indicated that it exists as 3,5-disubstituted regioisomer (Fig. 2).
Synthesized dibenzazepine-linked isoxazoles (33–54) were then
screened for their potency as the inhibitors of
α-glucosidase (EC
revealed that compounds 40 (IC50 = 64.86 ± 1.03 µM) and 41 (IC50
=
3.2.1.20) enzyme in vitro, using acarbose (IC50 = 875.75 ± 2.08 µM) as a
71.17 ± 1.34 µM) were found to be most potent among all the haloge-
nated compounds, and were found to be 14-fold better in activity than
the standard.
standard compound. Results (Table 2) for α-glucosidase inhibitory ac-
tivity revealed that most of the compounds 33–43, 45–51, and 54 were
found potent and multiple-fold better in activity than the standard drug
Among isoxazoles with electron-donating groups (methyl, ethoxy,
and benzyloxy), compound 46 (3′′-benzyloxy) (IC50 = 35.62 ± 1.48 µM)
was potent among the series, and showed 25-fold better activity than the
standard drug. Comparison among methylated analogues showed that
compound 43 (3′′-methyl) (IC50 = 142.23 ± 2.03 µM) was better than
compound 42 (2′′-methyl) (IC50 = 333.30 ± 1.67 µM), while compound
44 (4′′-methyl) was found to be inactive. Replacing ethoxy group with
benzyloxy group at 4′′-position, disclosed that activity was increased
from IC50 value of 214.79 ± 3.21 to 165.71 ± 0.74 µM. Further,
substituting benzyloxy group from 4′′- to 3′′-position, showed drastic
increase in activity from IC50 value of 165.71 ± 0.74 to 35.62 ± 1.48 µM.
Evaluation of isoxazoles with electron-withdrawing groups (cyano, and
nitro) revealed that compounds 48 (IC50 = 52.16 ± 1.56 µM) and 49
(IC50 = 46.62 ± 0.79 µM) with cyano group at 3′′- and 4′′-position,
Fig. 2. NOESY correlation of compound 36.
3

Umm-E-Farwa et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127979
Table 2
Yields (%) and biological activities of synthesized dibenzazepine-linked isoxazoles (33–54).
Compd. #
R
Yield
(%)
α
-Glucosidase inhibition
Lipase inhibition
Carbonic anhydrase inhibition
IC50 ± SDa
Ki ± SDa
Mode of inhibition
IC50 ± SDa
IC50 ± SDa
(µM)
(µM)
(µM)
(µM)
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
–
H
60
58
59
50
49
52
70
65
59
63
72
65
70
79
64
56
50
42
54
52
46
62
–
77.90 ± 1.14
154.86 ± 2.07
114.23 ± 0.81
160.62 ± 1.24
106.82 ± 0.43
98.62 ± 0.94
231.16 ± 1.62
64.86 ± 1.03
71.17 ± 1.34
333.30 ± 1.67
142.23 ± 2.03
Inactive
85.84 ± 0.01
Non-competitive
259.61 ± 0.79
169.23 ± 0.81
178.26 ± 1.09
162.85 ± 2.31
408.23 ± 1.59
415.04 ± 2.46
281.42 ± 2.14
inactive
121.10 ± 1.71
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
–
2′′-F
–
–
3′′-F
–
–
4′′-F
–
–
2′′-Cl
–
–
3′′-Cl
–
–
4′′-Cl
–
–
2′′-Br
55.57 ± 0.01
Non-competitive
3′′-Br
76.35 ± 0.01
Non-competitive
142.85 ± 2.03
inactive
2′′-Me
–
–
3′′-Me
–
–
inactive
4′′-Me
–
–
inactive
4′′-OEt
3′′-OBn
4′′-OBn
3′′-CN
214.79 ± 3.21
35.62 ± 1.48
165.71 ± 0.74
52.16 ± 1.56
46.62 ± 0.79
85.42 ± 0.38
189.51 ± 0.73
Inactive
–
–
287.84 ± 3.06
inactive
31.14 ± 0.01
Mixed
–
–
398.78 ± 1.73
289.90 ± 0.94
301.62 ± 1.34
139.12 ± 0.81
283.85 ± 1.43
274.37 ± 1.53
269.34 ± 1.45
181.89 ± 1.43
–
59.37 ± 0.00
Non-competitive
4′′-CN
54.76 ± 0.01
Non-competitive
2′′-NO2
3′′-NO2
4′′-NO2
3′′-OEt-4′′-Cl
3′′-Cl-4′′-NMe2
Acarboseb
Orlistatc
Acetazolamided
94.04 ± 0.01
Non-competitive
–
–
–
–
Inactive
–
–
109.75 ± 1.74
875.75 ± 2.08
–
115.37 ± 0.01
Non-competitive
–
–
–
–
–
–
–
–
0.01 ± 0.13
–
–
–
–
–
0.12 ± 0.00
a SD = Standard Deviation; b Standard drug for
α
-glucosidase inhibition; c Standard drug for lipase inhibition; d Standard drug for carbonic anhydrase inhibition;
Synthesized compounds 33–54 were found to be inactive in cytotoxicity assay as well as anti-glycation and DPPH inhibitory activity.
respectively, was found to be more active, and showed 19-fold better
than the reference drug. Comparatively, -glucosidase inhibitory activ-
interactions (see Supplementary Material, Fig. 9). Compound 40 with Br
α
at 2′′-position showed similar interactions to compound 33 (see Sup-
plementary Material, Fig. 10), and showed H-bonds with Lys156,
Ser157, Ser311, Asp242, and Gln353. Arg315 interacted with Br-
ity of nitro-substituted compounds was decreased, as this group was
switched from 2′′- (compound 50) to 3′′-position (compound 51). While,
compound 52 with nitro group at 4′′-position was found to be inactive.
Further, kinetic studies of dibenzazepine-linked isoxazoles 33, 40,
41, 46, 48, 49, 50 and 54 were done to investigate their mode of inhi-
bition (see Supplementary Material, Figs. 1–8). For this, various kinetic
parameters, such as, Vmax (enzyme’s maximum velocity) and Km ([S]
when enzyme’s velocity is half of the maximum) were examined using
different kinetic plots (Lineweaver-Burk plot, its secondary replots, and
Dixon plots). Lineweaver-Burk plot can be defined as the reciprocal of
reaction rate against reciprocal of substrate concentration [S]), while it´s
secondary replot is the plot of slope vs inhibitor concentration [I]. Dixon
plot was defined as a reciprocal of enzyme’s maximum velocity (Vmax) vs
inhibitor concentration [I].
substituted phenyl ring via π-cationic interactions, while Tyr158 inter-
acted via π-π stacking interactions. Change in position of Br group form
2′′- to 3′′-position in compound 41 resulted in a different docked pose
(see Supplementary Material, Fig. 11). Compound was able to retain the
H-bonds with Lys156, Ser157, Asp242, Asp352, and Ser311, while
π
-cationic, and π-π stacking interactions were lost. This was in accor-
dance with the kinetics results that showed a better Ki value for com-
pound 40 (Ki = 55.57 ± 0.01 µM), in comparison to compound 41 (Ki =
76.35 ± 0.01 µM).
Compound 46 with benzyloxy group showed a completely different
docked pose and resulted in H-bonding interactions with Ser157,
Asp242, Pro312, Gln353, and Glu411 (see Supplementary Material, Fig
.12). Compound 48 (3′′-substituted CN group) showed Ser240, Asp242,
Isoxazole 46 showed a mixed-type of inhibition (see Supplementary
Material, Fig. 1) with Ki = 31.14 ± 0.01 µM (Table 2). In this mode, Vmax
decreased, nevertheless, Km value either decreased or increased. How-
ever, isoxazoles 33 (Ki = 85.84 ± 0.01 µM), 40 (Ki = 55.57 ± 0.01 µM),
41 (Ki = 76.35 ± 0.01 µM), 48 (Ki = 59.37 ± 0.00 µM), 49 (Ki = 54.76 ±
0.01 µM), 50 (Ki = 94.04 ± 0.01 µM), and 54 (Ki = 115.37 ± 0.01 µM)
showed a non-competitive type of inhibition (see Supplementary Ma-
terial, Figs. 2–8). In this mode, Vmax was decreased whereas, apparent
Asp352, Gln353, and π-π stacking interactions (blue dotted line) with
Phe303 (see Supplementary Material, Fig. 13). Compound 49 (4′′-
substituted CN group) showed H-bonding interactions with Lys156,
Ser157, Asp242, Ser311, and Glu411 and π-π stacking interactions (blue
dotted line) with Tyr158 (see Supplementary Material, Fig. 14).
Compound 50 with NO2 group at 2′′-position showed H-bonds (red-
dotted line) with Ser157, Asp352. Arg315 interacted via π-cation and
K
m was not affected.
salt bridge formation (see Supplementary Material, Fig. 15). Compound
54 with Cl group at 3′′- and dimethylamino group at 4′′-position showed
H-bonding interactions with Pro312, Asn350, Gln353, and Glu411 (see
Supplementary Material, Fig. 16).
Compounds 33, 40, 41, 46, 48–50, and 54 with significant in vitro
α
-glucosidase inhibitory activity, were then preceded for ligand-
receptor interaction studies via molecular docking studies. All the
compounds showed binding interactions with critical amino acid resi-
Synthesized dibenzazepine-linked isoxazoles (33–54) were also
screened for other biological activities (Table 2), such as antiglycation
using rutin (IC50 = 55.80 ± 0.00 µM), DPPH inhibitory activity using N-
acetyl-L-cysteine (IC50 = 96.90 ± 0.66 µM) and gallic acid (IC50 = 21.80
± 1.03 µM) as reference compounds, respectively. But all compounds
were found to be inactive. Results for carbonic anhydrase inhibitory
activity of isoxazoles (33–54) using acetazolamide (IC50 = 0.12 ± 0.00
µM), showed unsubstituted derivative 33 as only and weakly active
dues of α-glucosidase enzyme. All the compounds (except compound 46)
were found to be non-competitive inhibitors via kinetic studies. There-
fore, sitemap analysis was performed to identify the best allosteric site in
α
-glucosidase enzyme.
Unsubstituted congener 33 (IC50 = 77.90 ± 1.14 µM; Ki = 85.84 ±
0.01 µM) showed H-bonding interactions with Lys156, Ser157, Asp352,
Ser311 and Glu411, while it interacted with Tyr158 via π-π stacking
4

Umm-E-Farwa et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127979
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Isoxazoles (33–54) were also evaluated for their lipase inhibitory
activity (Table 2). Orlistat was utilized as a reference inhibitor with IC50
= 0.01 ± 0.13 µM. Most of the compounds 33–39, 41, 45, and 47–54
showed weak inhibition with IC50 values between 139.12 ± 0.81 and
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respectively. Compounds 40, 42–44 and 46 were found to inactive.
Furthermore, synthesized isoxazoles (33–54) were investigated for their
cytotoxicity against 3T3-mouse fibroblast 3T3 cell lines using cyclo-
heximide as a standard. Compounds were found to be safe, when
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α
-glucosidase inhibitory activity revealed that most of the compounds
33–43, 45–51, and 54 (IC50 = 35.62 ± 1.48 to 333.30 ± 1.67 µM) were
found to be potent than the standard acarbose. Among them, isoxazole
46 (IC50 = 35.62 ± 1.48 µM) was the most active analogue. Compounds
30, 40, 41, 46, 48–50, and 54 also showed significant binding in-
10 Kelkar A, Kelkar J, Mehta H, Amoaku W. Cataract surgery in diabetes mellitus: a
systematic review. Indian J Ophthalmol. 2018;66:1401–1410. https://doi.org/
10.4103/ijo.IJO_1158_17.
11 Centers for Disease Control and Prevention. National Diabetes Statistics Report,
2020. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statist
ics-report.pdf, 2020.
teractions with amino acid residues of
α-glucosidase in molecular
docking studies. Results of lipase inhibitory activity showed compounds
as weak inhibitors, but can be helpful in controlling problem-associated
with diabetes, such as obesity. Thus, these molecules can act on multiple
targets for controlling the disease. These results proposed that activity
can be modified via varying different substitutions in these types of
molecules, and may help in designing new and less toxic anti-diabetic
agents with potency to control associated problems, such as obesity
and oxidative stress.
12 Cho N, Shaw JE, Karuranga S, et al. IDF Diabetes Atlas: Global estimates of diabetes
prevalence for 2017 and projections for 2045. Diabetes Res Clin Prac. 2018;138:
271–281.
13 Aamir AH, Ul-Haq Z, Mahar SA, et al. Diabetes Prevalence Survey of Pakistan (DPS-
PAK): Prevalence of type 2 diabetes mellitus and prediabetes using HbA1c: A
population-based survey from Pakistan. BMJ Open. 2019;9:e025300. https://doi.
org/10.1136/bmjopen-2018-025300.
14 Taha M, Rahim F, Imran S, et al. Synthesis, α-glucosidase inhibitory activity and in
silico study of tris-indole hybrid scaffold with oxadiazole ring: as potential leads for
the management of type-II diabetes mellitus. Bioorg Chem. 2017;74:30–40. https://
doi.org/10.1016/j.bioorg.2017.07.009.
15 Reuser AJJ, Wisselaar HA. An evaluation of the potential side-effects of α-glucosidase
Declaration of Competing Interest
inhibitors used for the management of diabetes mellitus. Eur J Clin Investig. 1994;24:
19–24. https://doi.ord/10.1111/j.1365-2362.1994.tb02251.x.
16 Ali F, Khan KM, Salar U, et al. Hydrazinyl arylthiazole based pyridine scaffolds:
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.
Synthesis, structural characterization, in vitro α-glucosidase inhibitory activity, and in
silico studies. Eur J Med Chem. 2017;138:255–272. https://doi.org/10.1016/j.
ejmech.2017.06.041.
17 Khan MA, Javaid K, Wadood A, et al. In vitro α-glucosidase inhibition by non-sugar
based triazoles of dibenzoazepine, their structure-activity relationship, and
molecular docking. Med Chem. 2017;13. https://doi.org/10.2174/
1573406413666170726142949.
Acknowledgement
18 Kumar A, Maurya RA, Sharma S, et al. Design and synthesis of 3,5-diarylisoxazole
derivatives as novel class of anti-hyperglycemic and lipid lowering agents. Bioorg
Med Chem. 2009;17:5285–5292. https://doi.org/10.1016/j.bmc.2009.05.033.
19 Joseph L, George M. Anti-bacterial and in vitro anti-diabetic potential of novel
isoxazole derivatives. J Pharm Res Int. 2016;9:1–7.
Authors are thankful to the Higher Education Commission, Pakistan
for providing financial assistance.
Appendix A. Supplementary data
20 Kumar A, Maurya RA, Sharma S, et al. Design and synthesis of 3, 5-diarylisoxazole
derivatives as novel class of anti-hyperglycemic and lipid lowering agents. Bioorg
Med Chem. 2009;17:5285–5292.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.127979.
21 Yousuf S, Khan M, Fazal S, Butt M, Basha FZ. 5-(Prop-2-ynyl)-5H-dibenzo[b, f]
azepine. Acta Cryst E. 2012;68.
22 Rammah M, Gati W, Mtiraoui H, et al. Synthesis of isoxazole and 1,2,3-triazole
isoindole derivatives via silver-and copper-catalyzed 1, 3-dipolar cycloaddition
reaction. Molecules. 2016;21:307. https://doi.org/10.3390/molecules21030307.
23 Himo F, Lovell T, Hilgraf R, et al. Copper (I)-catalyzed synthesis of azoles. DFT study
predicts unprecedented reactivity and intermediates. J Am Chem Soc. 2005;127:
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