Evaluation and docking of indole sulfonamide as a potent inhibitor of α-glucosidase enzyme in streptozotocin –induced diabetic albino wistar rats

Article abstract of DOI:10.1016/j.bioorg.2021.104808

We have synthesized new hybrid class of indole bearing sulfonamide scaffolds (1–17) as α-glucosidase inhibitors. All scaffolds were found to be active except scaffold 17 and exhibited IC₅₀ values ranging from 1.60 to 51.20 μM in comparison with

Full text of DOI:10.1016/j.bioorg.2021.104808

Bioorganic Chemistry 110 (2021) 104808
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Bioorganic Chemistry
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Evaluation and docking of indole sulfonamide as a potent inhibitor of
α
-glucosidase enzyme in streptozotocin –induced diabetic albino wistar rats
Muhammad Tahaa *, Syahrul Imranb, Mohammed Salahuddina, Naveed Iqbalc, Fazal Rahimd,
Nizam Uddine, Adeeb Shehzada, Rai Khalid Farooqf, Munther Alomarig,
Khalid Mohammed Khanh
,
a Department of Clinical Pharmacy Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 31441,
Dammam, Saudi Arabia
b Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia
c Department of Chemistry University of Poonch, Rawalakot, AJK, Pakistan
d Department of Chemistry, Hazara University, Mansehra 21300, Khyber Pakhtunkhwa, Pakistan
e Department of Chemistry, University of Karachi, Karachi 75270, Pakistan
f Department of Neuroscience Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam
31441, Saudi Arabia
g Department of Stem Cell Biology, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam
31441, Saudi Arabia
h H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
A R T I C L E I N F O
A B S T R A C T
Keywords:
We have synthesized new hybrid class of indole bearing sulfonamide scaffolds (1–17) as α-glucosidase inhibitors.
α
-Glucosidase inhibitors
All scaffolds were found to be active except scaffold 17 and exhibited IC50 values ranging from 1.60 to 51.20 µM
in comparison with standard acarbose (IC50 = 42.45 µM). Among the synthesized hybrid class scaffolds 16 was
Indole analogs
SAR
the most potent analogue with IC50 value 1.60 μM, showing many folds better potency as compared to standard
Molecular docking
In vivo
acarbose. Whereas, synthesized scaffolds 1–15 showed good
α-glucosidase inhibitory potential. Based on
α
-glucosidase inhibitory effect, Scaffold 16 was chosen due to highest activity in vitro for further evaluation of
antidiabetic activity in Streptozotocin induced diabetic rats. The Scaffold 16 exhibited significant antidiabetic
activity. All analogues were characterized through 1H, 13CNMR and HR MS. Structure-activity relationship of
synthesized analogues was established and confirmed through molecular docking study.
1. Introduction
synthesis of
decrease blood glucose level that in turn result to decrease glucose ab-
sorption [12–14]. -Glucosidase inhibitors do not show life threatening
condition and its overdose does not show weight gain or hyperglycemic
effects in body [15]. Beside diabetes, -glucosidase inhibitors showed
α-glucosidase inhibitors that possess catalytic potency to
To maintain healthy activities of body the
α
-glucosidase enzyme
α
catalyzes carbohydrates. Some serious problems to human health are
associated with higher activity of
blood glucose level [1–4]. In type-2 diabetes various
hibitors are used to maintain the sugar level of blood [5,6]. So far
α
-glucosidase that leads to increase in
α
α
-glucosidase in-
meaningful application in obesity and in other medical therapeutics
[16] and in case of HIV infections showed remarkable proliferation that
result to block viral infections [17,18]. Due to these aspects, we have
synthesized hybrid indole bearing sulfonamide as new class of
inhibitors.
various clinically used α-glucosidase inhibitors are acarbose, miglitol
and voglibose etc [7,8]. Inhibitors are usually administered orally that
leads to carbohydrates digestion and absorption delay, resulting to
maintain the glucose level [9–11]. Medicinal chemists focused on the
Indoles are a heterocyclic analogue that occurs in various natural
products as secondary metabolites such as alkaloids, marine secondary
metabolites and fungal secondary metabolites etc [19,20]. A lot of
synthesis of new α-glucosidase inhibitors as these inhibitors had various
side effects. Pharmaceutical community takes keen interest in the
* Corresponding author.
E-mail address: mtaha@iau.edu.sa (M. Taha).
https://doi.org/10.1016/j.bioorg.2021.104808
Received 19 January 2021; Received in revised form 25 February 2021; Accepted 2 March 2021
Available online 10 March 2021
0045-2068/© 2021 Elsevier Inc. All rights reserved.

M. Taha et al.
Bioorganic Chemistry 110 (2021) 104808
indole scaffolds showed its consideration in medicinal chemistry as well
as in organic synthesis. Indole and its scaffolds showed broad range of
biological potential such as antibacterial [21], anticancer [22], anti-
malarial [23], anti-ulcerative [24], anti-leishmanial [25], anti-platelet
[26], anti-rheumatoid [27], antioxidant [28], anti-viral [19], anti-HIV
[29], thymidine phosphorylase, as well as inhibitors of β-glucuroni-
dase [30,31].
biologically active scaffold the sulfonamide functional group showed its
great potency e.g, Alzheimer’s disease associated butyrylcholinesterase
(BChE) enzyme potent inhibitors have been synthesized from its previ-
ously marketed lead scaffold of sulfonamide that exhibited excellent
potency at low concentration [34,35]. Similarly, sulfonamide scaffolds
from the decades have been extensively used against certain disease that
are multifarious than bacterial infections like AD, diabetes [36], psy-
chosis [37], central nervous system (CNS) disorders [38], tumors [39]
and different cancer treatments [40].
In the synthesis of various groups of drugs sulfonamides moiety act
as a basic skeleton that are also names as sulpha drugs or sulfa drugs
[32,33]. To produce new effect/action in the previously synthesized
Our research group had previously synthesized different
Table 1
Synthesized hybrid indole bearing sulfonamide scaffolds (1–17).
S. No
R
IC50
(
μ
M)
S. No
10
R
IC50 (μM)
1
7.30 ± 0.20
4.70 ± 0.20
51.20 ± 1.10
8.20 ± 0.50
21.30 ± 0.30
28.50 ± 0.20
31.30 ± 0.50
35.80 ± 0.60
2
3
4
11
12
13
5
6
8.40 ± 0.010
14.30 ± 0.20
14
15
41.20 ± 0.20
41.90 ± 0.80
7
8
9
15.20 ± 0.30
16.70 ± 0.30
21.10 ± 0.40
16
17
1.60 ± 0.010
N.A.
Standard Acarbose
42.45 ± 1.05
2

M. Taha et al.
Bioorganic Chemistry 110 (2021) 104808
heterocycles as well as their hybrid analogues and evaluated against
different biological potential [41]. Keeping in view, the biological
importance of indole as well as sulfonamide scaffold we plan to design,
synthesis of new hybrid class of indole bearing sulfonamide scaffolds
that might show promising results upon comparison with individual
scaffolds.
antidiabetic activity in rats was designed and carried out. Acute toxicity
study was carried out at dose of 1000 mg/kg body weight and no toxicity
was found. Hence, three scalar doses 10, 25, & 50 mg/kg body weight
were selected for preliminary screening of Scaffold 16 for hypoglycemic
effect, and similar approach has been reported earlier [49]. The com-
pound was administered orally, and blood glucose level measured up to
6 h duration and the compound was found to be effective till 4 h
duration and reduced the blood glucose level significantly (***p <
0.001), as compared to the diabetic control group. Scaffold 16 signifi-
cantly decreases the blood glucose level at 2 h (17%) and 4 h (24%) at a
dose of 50 mg/kg, as compared to the values of 30 min and diabetic
control group. Whereas, at 25 mg/kg dose, scaffold 16 reduces 17% of
blood glucose level, as compared to values at 1 h and diabetic control
group (Fig. 1). No significant changes were observed in the blood
glucose level of animals treated with Scaffold16- 10 mg/kg body weight.
After 4 h of duration, the blood glucose levels in scaffold 16 treated
groups started inclined towards the higher values.
1.1. Result and discussion
1.1.1. Chemistry
The indole-based sulfonamide scaffolds (1–17) were synthesized by
treating 2-(1H-indol-3-yl) ethanamine with various aryl sulfonyl chlo-
ride in the presence of pyridine. The reaction completion was confirmed
by monitoring TLC. All synthesized compounds were recrystallized in
methanol. The purity of compounds was confirmed by proton NMR as
well as HR MS. All compounds were fully characterized different spec-
troscopy method (Table 1) Scheme 1.
1.1.3.2. Effects of sacaffold 16 on fasting blood glucose and body weight.
To find out the long-term beneficial effects of Scaffold 16 on fasting
blood glucose levels and body weights of animals, two scalar doses were
selected based on results of acute hypoglycemic effects (Fig. 1). These
doses of the compound were administered at a dose of 25 and 50 mg/kg
body orally for 28 days. On every 7th day interval, fasting blood glucose
and body weights were measured. Standard drug, Glibenclamide was
given at a dose of 5 mg/kg body weight for the same duration. It has
been found that the fasting blood glucose level of Scaffold 16 treated
group decreases significantly (***p < 0.001), as compared to the values
of 1st day and diabetic control group. The fasting blood glucose level of
the group treated with scaffold 16 at dose 25 mg/kg body was reduced
to 317.83 mg/dl on day 28 from the initial level of 440 mg/dl on day 1
(decrease of 28%). Higher reduction of fasting blood glucose level was
observed with the dose of 50 mg/kg, which reduced the initial blood
glucose level of 511 mg/dl to 241 mg/dl on 28th day (reduction of 53%)
(Fig. 2). Significant effect (***p < 0.001) was observed in the group
treated with standard drug Glibenclamide, which reduced 41% of fast-
ing blood glucose level on day 28, as compared to day 1.
1.1.2.
α
-Glucosidase inhibition
The synthesized hybrid indole bearing sulfonamide scaffolds (1–17)
were for their
α
-glucosidase inhibitory potential [42–44]. All scaffolds
were found active except scaffold 17. Different inhibitory potential was
exhibited by scaffolds1-15 with IC50 value ranging between 1.60 ±
0.010–51.20 ± 1.10
μM upon comparison with standard acarbose
(42.45 ± 1.05 μM). Scaffold 16 exhibited IC50 value 1.60 ± 0.010 many
folds better than standard acarbose and is the most potent scaffold
among the synthesized derivatives. Similarly scaffold 1, 2, 4 and 5
exhibited IC50 values ranging 4.70–8.40 μM showing 10 to 5 folds more
potency than standard.
The methyl substituted scaffolds 6, 9, 11 are the ortho, para and meta
substituted scaffolds that showed IC50 value 14.30 ± 0.20, 21.10 ± 0.40
and 28.50 ± 0.20 respectively. From IC50 values of enzyme inhibition
pattern it was confirm that ortho substituted > para substituted > meta
substituted scaffold.
Scaffold 4, 5, which are mono and dichloro substituted derivatives
exhibited IC50 value 8.20 ± 0.50 and 8.40 ± 0.010, respectively. It was
observed that addition of chloro as substitutent might be responsible for
slight decrease in potency.
Every week, body weight of all groups of animals were measured in
order to know the effect of Scafffold 16 treatment, and was compared to
normal, diabetic control and standard group. It has been found that
there is significant (***p < 0.001) improvement on day 28 in the body
weight of the animals treated with Scaffold 16 (25 and 50 mg/kg body
weight), as compared to body weight of animals on day 14 (Fig. 3).
Initial treatment of Scaffold 16 for 14 days failed to show any protection
on loss of body weight. Body weight of animals treated with Gliben-
clamide was improved significantly and was more stable throughout
study, as compared to the diabetic control and Scaffold 16 treated group.
The bromo substituted scaffolds 3, 13 are the ortho, para substituted
scaffolds that showed IC50 value 51.20 ± 1.10, 35.80 ± 0.60 respec-
tively, while scaffold 17 meta substituted was found inactive. From IC50
values of the scaffold it was confirmed that ortho substituted scaffold
showed greater potential as compared to para substituted and meta
substituted scaffold was the inactive as compared to ortho and para
substituted scaffold.
It was confirmed that type, number/s and position of substitutent/s
might play a role in slight increase or decrease in
tory potency.
α-glucosidase inhibi-
1.1.3.3. Effect of Scaffold-16 on oral glucose tolerance test (OGTT). On
28th day of the study, OGTT was carried out in fasted diabetic rats. The
animals were observed for 120 min duration, after administration of
Scaffold 16 at doses of 25 and 50 mg/kg body weight. There was sig-
nificant increase in the blood glucose levels of all the groups at 0.5 h of
1.1.3. Results of animals study
1.1.3.1. Hypoglycemic effect of Scaffold 16. Based on the excellent re-
sults of in vitro and molecular docking study showed by Scaffold 16,
Scheme 1. The indole-based sulfonamide scaffolds (1–17) were synthesized.
3

M. Taha et al.
Bioorganic Chemistry 110 (2021) 104808
Fig. 1. Hypoglycemic Effects of Scaffold-16. Values are expressed as the mean ± standard error of the mean (n = 6). ***P < 0.001 Compared to Diabetic control and
1 h (25 mg /kg); ***P < 0.001 Compared to Diabetic control and 0.5 h (50 mg /kg).
Fig. 2. Effect of Scaffold-16 on Fasting Blood Glucose Levels Values are expressed as the mean ± standard error of the mean (n = 6). ***P < 0.001 Compared to
Diabetic control and Day 1.
Fig. 3. Effect of Scaffold-16 on Body weight of Animals. Values are expressed as the mean ± standard error of the mean (n = 6). ***P < 0.001 Compared to Diabetic
control and Day 14.
OGTT, as compared to the level of 0 h. The glucose response failed in
diabetic control group of animals, whereas the animals treated with
scaffold 16 showed significant tolerance after 1 h of duration. After 2 h
of administration Scaffold 16, the blood glucose levels were reduced to
below initial blood glucose levels (Fig. 4).
1.1.4. Docking study
The docking results the most active compound 16 displayed inter-
action involving extended aromatic ring bearing chloro at ortho position.
The chloro substituent at ortho position interacts with the backbone of
Arg312 through hydrophobic alkyl interaction at 3.91 Å. Besides that,
the backbone of Arg312 also played an important role in making sure
that the extended aromatic ring is stable in the active site by interacting
The changes in the blood glucose level was used to calculated area
under the curve. As compared to level at 0.5 h, Scaffold 16 at a dose of
25 mg/kg bod weight reduced the areas under the curve (AUC) for
glucose by 36.90% and 43.30% at 50 mg/kg, whereas, Glibenclamide
reduces 20.62%, after 2 h of administration (Fig. 5). Area under curve
for Scaffold 16 at 25 and 50 mg/kg body weight was 55,765 and 53,408,
as compared to the 63,677 of Diabetic control group. Area under curve
was calculated by using Gaphpad Prism 8.0.1.
with the π-orbital of the aromatic ring through a π-alkyl interaction at
4.32 Å. On the other hand, some hydrogen bonds were observed as well.
It was observed that one of the oxygens of sulfonamide moiety forms a
conventional hydrogen bonding with the backbone (HD) of Asn241 at
1.88 Å. While another hydrogen bonding was observed between
hydrogen of amino group with the backbone (Nε2) of His279 at 2.06 Å
4

M. Taha et al.
Bioorganic Chemistry 110 (2021) 104808
Fig. 4. Oral Glucose Tolerance Test. Values are expressed as the mean ± standard error of the mean (n = 6). ***P < 0.001 Compared to Diabetic control and 0.5 h.
Fig. 5. Area Under Curve Values are expressed as the mean ± standard error of the mean (n = 6). ***P < 0.001 Compared to Diabetic control and 0.5 h.
Fig. 6. Interaction of most active compound 16 with residues in the active site.
(Fig. 6).
one of the nitrogen (Nε2) on imidazole ring of His279 further stabilizes
In the case of the second most active compound 2, it was observed
the interaction by acting as a hydrogen bond acceptor and interacts with
hydrogen (H36) on amino group of the sulfonamide moiety at a distance
that the extended aromatic ring can interact with various residues with
the active site. The results showed that one of the oxygen atoms of the
nitro group is forming a conventional hydrogen bonding with the
of 2.25 Å. It was also observed that oxygen (Oε2) on Glu304 can form
two electrostatic interactions with nitrogen (N23) of nitro substituent
and -orbital of the extended aromatic ring. Glu304 forms an
hydrogen (H
ε
1) on the backbone of His279 at 2.99 Å. On the other hand,
π
5

M. Taha et al.
Bioorganic Chemistry 110 (2021) 104808
electrostatic attractive charge interaction with nitro substituent at 4.20
Å while on the extended aromatic ring, Glu304 forms an electrostatic
J = 6.4 Hz, 1H), 7.02 (t, J = 6.1 Hz, 1H), 6.88–6.83 (m, 2H), 3.94 (t, J =
6.5 Hz, 2H), 3.03 (t, J = 6.5 Hz, 2H);13C NMR (100 MHz, DMSO‑d6): δ
162.1, 136.1, 132.6 (d, J = 182, C-F), 129.3, 127.0, 122.8, 121.4, 119.5,
118.5, 118.0, 112.5, 111.0, 110.0, 102.5, 55.5 (OCH3), 43.5, 27.6;
HREI-MS: m/z 348.0935; [(M+1)+ Calcd for C17H17FN2O3S 348.0943.
π
-anion interaction at 3.60 Å. It was observed that one of the oxygens of
sulfonamide moiety forms a conventional hydrogen bonding with the
backbone (HD22) of Asn241 at 2.09 Å (Fig. 7).
For the third most active compounds 1, hydrogen (H39) on methoxy
substituent interacts with Thr307 backbone oxygen at 2.81 Å through
carbon hydrogen bond (Fig. 8). Oxygen (O23) of methoxy substituent
interacts with the backbone of Thr301 (HG1) through a conventional
hydrogen bond at 2.05 Å. Extended aromatic ring is stabilized by elec-
2.1.2. N-(2-(1H-indol-3-yl)ethyl)-2-chloro-5-nitrobenzenesulfonamide (2)
1H NMR (400 MHz DMSO‑d6): δ 1H NMR (400 MHz DMSO‑d6): δ
14.13 (s, 1H, NH), 10.92 (s, 1H, NH), 8.33 (d, J = 2.1 Hz, 1H), 8.02 (d, J
= 6.0 Hz, 1H), 7.62 (d, J = 6.7 Hz, 1H), 7.36 (d, J = 6.4 Hz, 1H), 7.19 (d,
J = 2.4 Hz, 1H) 7.09 (t, J = 6.3 Hz, 1H), 6.99 (t, J = 6.1 Hz, 1H), 6.57 (d,
trostatic
π
-anion interaction with backbone of Glu304 (O
ε
1) at 3.44 Å
and also a hydrophobic
π
-alkyl interaction with Arg312 at a distance of
J = 7.3, Hz, 1H), 3.95 (t, J = 6.2 Hz, 2H), 3.15 (t, J = 6.2 Hz, 2H);13
C
4.15 Å. On the other hand, some hydrogen bonds were observed as well.
It was observed that both oxygens of sulfonamide moiety can form
conventional hydrogen bonds. One of the oxygens of sulfonamide moi-
ety forms a hydrogen bonding withAsn241 (HD22) at 213 Å while the
NMR (100 MHz, DMSO‑d6): δ 152.0,145.0, 136.1, 132.6, 129.1, 127.0,
124.4, 122.8, 122.0, 121.4, 119.5, 118.5, 112.5, 111.0, 43.5, 27.6;
HREI-MS: m/z 379.0381; [(M+1)+ Calcd for C16H14ClN3O4S 379.0393.
other oxygen atom forms a hydrogen bonding with His239 (H
ε
1) at 2.96
2.1.3. N-(2-(1H-indol-3-yl)ethyl)-2-bromobenzenesulfonamide (3)
1H NMR (400 MHz DMSO‑d6): δ 1H NMR (400 MHz DMSO‑d6): δ
11.56 (s, 1H, NH), 10.53 (s, 1H, NH), 7.88 (t, J = 6.7 Hz, 1H), 7.65–7.62
(m, 2H), 7.57 (d, J = 6.9 Hz, 1H), 7.36–7.32 (m, 2H), 7.19 (d, J = 2.4 Hz,
1H) 7.13 (t, J = 6.2 Hz, 1H), 7.07 (t, J = 6.2 Hz, 1H), 3.93 (t, J = 6.3 Hz,
2H), 3.14 (t, J = 6.3 Hz, 2H); 13C NMR (100 MHz, DMSO‑d6):): δ), 142.2,
136.1, 134.4, 130.2, 129.2, 127.8, 127.0, 122.8, 121.4, 120.3, 119.5,
118.5, 112.5, 111.0, 43.5, 27.6; HREI-MS: m/z 378.0023; [(M+1)+
Calcd for C16H15BrN2O2S 378.0037].
Å. While another hydrogen bonding was observed between hydrogen of
amino group with the backbone (N 2) of His279 at 2.10 Å. Phe157 is
ε
potentially involved in two hydrophobic π- πstaking interactions with
indole moiety at 4.51 and 5.17 Å, which may have resulted in better
complex stability.
2. Experimental
2.1. Synthesis procedure for hybrid indole bearing sulfonamide
2.1.4. N-(2-(1H-indol-3-yl)ethyl)-4-chlorobenzenesulfonamide (4)
1H NMR (400 MHz DMSO‑d6): δ 12.09 (s, 1H, NH), 11.12 (s, 1H, NH),
7.90 (d, J = 6.7 Hz, 2H), 7.54 (d, J = 6.9 Hz, 1H), 7.33 (d, J = 6.4 Hz,
2H), 7.15–7.05 (m, 3H), 3.90 (t, J = 6.2 Hz, 2H), 3.11 (t, J = 6.2 Hz, 2H);
13C NMR (100 MHz, DMSO‑d6): δ 143.0, 137.0, 136.1, 129.0, 129.0,
128.5, 128.5, 127.0, 122.8, 121.4, 119.5, 118.5, 112.5, 111.0, 43.5,
27.6; HREI-MS: m/z 334.0530; [(M+1)+ Calcd for C16H15ClN2O2S
334.0522.
The synthesis of indole-based sulfonamide was carried out by
reacting 2-(1H-indol-3-yl) ethanamine (1 mmol) with various aryl sul-
fonyl chloride (1.1 mmol each) in the presence of pyridine (10 mL). The
reaction was remained on stirring overnight. The confirmation of
completion of reaction was monitored by TLC. After completion of re-
action the mixture was poured in dilute solution of HCl to kill pyridine.
The ppt formed was filtered and washed with cold water. The crude
products were recrystallized in methanol to afford pure indole-based
sulfonamide scaffolds (1–17) in good yields. The purity of compounds
was confirmed by proton NMR as well as HR MS (Fig. 9) general figure of
compounds (1–17).
2.1.5. N-(2-(1H-indol-3-yl)ethyl)-2,5-dichlorobenzenesulfinamide (5)
1H NMR (400 MHz DMSO‑d6): δ 13.81 (s, 1H, NH), 10.8 (s, 1H, NH),
7.57 (d, J = 6.7 Hz, 1H), 7.47 (t, J = 2.4 Hz, 2H), 7.34–7.31 (m, 2H),
7.14 (t, J = 2.4 Hz, 2H), 7.07 (t, J = 6.3 Hz, 1H), 6.98 (t, J = 6.1 Hz, 1H),
6.88 (t, J = 7.5 Hz, 2H), 3.90 (t, J = 6.2 Hz, 2H), 3.11 (t, J = 6.2 Hz, 2H);
13C NMR (100 MHz, DMSO‑d6): δ 138.1, 137.5, 136.1, 132.6), 130.5,
130.0, 127.5, 127.0, 122.8, 121.4, 119.5, 118.5, 112.5, 111.0, 43.5,
27.6; HREI-MS: m/z 368. 0530; [(M+1)+ Calcd for C16H14Cl2N2O2S
368.0153.
2.1.1. N-(2-(1H-indol-3-yl)ethyl)-2-fluoro-4-methoxybenzenesulfonamide
(1)
1H NMR (400 MHz DMSO‑d6): δ 1H NMR (400 MHz DMSO‑d6): δ
12.70 (s, 1H, NH), 10.92 (s, 1H, NH), 7.87 (t, J = 6.7 Hz, 1H), 7.58 (d, J
= 6.9 Hz, 1H), 7.34 (d, J = 6.5 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H) 7.06 (t,
Fig. 7. Interaction of second most active compound 2 with residues in the active site.
6

M. Taha et al.
Bioorganic Chemistry 110 (2021) 104808
Fig. 8. Interaction of third most active compound 1 with residues in the active site.
119.5, 118.5, 112.5, 111.0, 43.5, 27.6, 21.4 (CH3); HREI-MS: m/z
314.1073; [(M+1)+ Calcd for C17H18N2O2S 314.1089].
2.1.10. N-(2-(1H-indol-3-yl)ethyl)-3-iodo-5-methoxybenzenesulfonamide
(10)
1H NMR (400 MHz DMSO‑d6): δ 12.21 (s, 1H, NH), 10.88 (s, 1H, NH),
7.76 (t, J = 6.3 Hz, 1H), 7.71 (t, J = 6.2 Hz, 1H), 7.47–7.42 (m, 2H), 7.24
(t, J = 6.1 Hz, 2H), 7.08 (t, J = 2.4 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 3.85
(t, J = 6.4 Hz, 5H), 3.07 (t, J = 6.0 Hz, 2H);13C NMR (100 MHz,
DMSO‑d6): δ 162.0, 142.0, 136.1, 127.0, 126.1, 124.5, 122.8, 121.4,
119.5, 118.5, 112.5, 111.0, 110.0, 95.4, 55.5 (OCH3), 43.5, 27.6; HREI-
MS: m/z 455.9989; [(M+1)+ Calcd for C17H17IN2O3S 456.0004].
Fig. 9. General Figure of indole-based sulfonamide analogs (1–17).
2.1.11. N-(2-(1H-indol-3-yl)ethyl)-3-methylbenzenesulfonamide (11)
1H NMR (400 MHz DMSO‑d6): δ 11.76 (s, 1H, NH), 10.76 (s, 1H, NH),
7.60 (t, J = 6.1 Hz, 2H), 7.49 (d, J = 6.2 Hz, 1H), 7.39 (d, J = 6.3 Hz, 1H)
7.15 (t, J = 7.2 Hz, 1H), 7.20 (t, J = 6.4 Hz, 1H), 7.04 (t, J = 6.3 Hz, 1H),
6.74 (t, J = 6.2 Hz, 2H), 3.85 (t, J = 4.6 Hz, 5H), 3.09 (t, J = 6.3 Hz, 2H),
2.14 (s, 3H, CH3); 13C NMR (100 MHz, DMSO‑d6): δ 139.5, 138.4, 136.1,
132.5, 128.5, 127.0, 126.5, 124.1, 122.8, 121.4, 119.5, 118.5, 112.5,
111.0, 43.5, 27.6, 21.5 (CH3); HREI-MS: m/z 314.1073; [(M+1)+ Calcd
for C17H18N2O2S 314.1089].
2.1.6. N-(2-(1H-indol-3-yl)ethyl)-2-methylbenzenesulfonamide (6)
1H NMR (400 MHz DMSO‑d6): δ 1H NMR (400 MHz DMSO‑d6): δ
13.38 (s, 1H, NH), 10.52 (s, 1H, NH), 7.93 (t, J = 6.4 Hz, 1H), 7.69–7.66
(m, 2H), 7.60 (d, J = 64 Hz, 1H), 7.39–7.35 (m, 2H), 7.22 (d, J = 2.2 Hz,
1H) 7.17 (t, J = 6.7 Hz, 1H), 7.10 (t, J = 6.4 Hz, 1H), 3.96 (t, J = 6.7 Hz,
2H), 3.12 (t, J = 6.7 Hz, 2H) 2.10 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO‑d6): δ 138.5, 136.1, 135.6, 131.1, 131.5, 129.5, 127.0, 122.8,
121.4, 120.3, 119.5, 118.5, 112.5, 111.0, 43.5, 27.6, 21.5 (CH3); HREI-
MS: m/z 314.1073; [(M+1)+ Calcd for C17H18N2O2S 314.1089.
2.1.12. N-(2-(1H-indol-3-yl)ethyl)-3,5-dimethoxybenzenesulfonamide
(12)
2.1.7. N-(2-(1H-indol-3-yl)ethyl)-2-hydroxynaphthalene-1-sulfonamide
(7)
1H NMR (400 MHz DMSO‑d6): δ 11.98 (s, 1H, NH), 10.73 (s, 1H, NH),
7.75 (dd, J = 2.3, 2.4 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.44 (d, J = 6.1
Hz, 1H) 7.42 (t, J = 6.2 Hz, 1H), 7.39 (t, J = 6.1 Hz, 1H), 7.09 (t, J = 6.6
Hz, 1H), 6.98 (t, J = 6.2 Hz, 2H), 6.82 (t, J = 2.0 Hz, 1H), 3.95 (t, J = 6.4
Hz, 2H), 3.82 (s, 6H, 2xCH3), 3.06(t, J = 6.4 Hz, 2H); 13C NMR (100
MHz, DMSO‑d6): δ 161.2, 161.2, 142.0, 136.1, 127.0, 122.8, 121.4,
119.5, 118.5, 112.5, 111.0, 103.5, 103.0, 103.0, 55.5 (OCH3), 55.5
(OCH3), 43.5, 27.6; HREI-MS: m/z 360.1131; [(M+1)+ Calcd for
1H NMR (400 MHz DMSO‑d6): δ 14.04 (s, 1H, NH), 10.93 (s, 1H, NH),
9.03(s, 1H, OH), 7.95 (t, J = 6.7 Hz, 1H), 7.62–7.58 (m, 2H), 7.54 (d, J
= 6.3 Hz, 1H), 7.33–7.29 (m, 2H), 7.19 (d, J = 2.4 Hz, 1H) 7.14 (t, J =
6.3 Hz, 1H), 7.07 (t, J = 6.2 Hz, 1H), 7.00 (t, J = 6.6 Hz, 1H), 6.66 (d, J
= 6.3 Hz, 1H), 3.93 (t, J = 6.7 Hz, 2H), 3.08 (t, J = 6.7 Hz, 2H); 13C NMR
(100 MHz, DMSO‑d6): δ 148.1, 137.5, 136.1, 127.5, 127.0, 126.6, 126.3,
126.0, 124.0, 122.8, 122.5, 122.1, 121.4, 119.5, 119.1, 118.5, 112.5,
111.0, 43.5, 27.6; HREI-MS: m/z 366.1029; [(M+1)+ Calcd for
C20H18N2O3S 366.1038.
C18H20N2O4S 360.1143].
2.1.13. N-(2-(1H-indol-3-yl)ethyl)-4-bromobenzenesulfonamide (13)
1H NMR (400 MHz DMSO‑d6): δδ 11.22 (s, 1H, NH), 9.56 (s, 1H, NH),
7.73 (t, J = 6.5 Hz, 1H), 7.49 (d, J = 7.2 Hz, 2H), 7.43 (d, J = 6.1 Hz,
1H), 7.25 (d, J = 7.2 Hz, 2H), 7.01–6.96 (m, 2H), 3.93 (t, J = 6.6 Hz,
2H), 3.13 (t, J = 6.6 Hz, 2H); 13C NMR (100 MHz, DMSO‑d6): δ 143.1,
136.1, 131.3, 131.3, 129.0, 129.0, 127.0, 126.0, 122.8, 121.4, 119.5,
118.5, 112.5, 111.0, 43.5, 27.6; HREI-MS: m/z 378.0023; [(M+1)+
Calcd for C16H15BrN2O2S 378.0037].
2.1.8. N-(2-(1H-indol-3-yl)ethyl)-3-chlorobenzenesulfonamide (8)
1H NMR (400 MHz DMSO‑d6): δ 12.13 (s, 1H, NH), 10.83 (s, 1H, NH),
7.64 (t, J = 6.6 Hz, 2H), 7.53 (d, J = 6.4 Hz, 1H), 7.42 (d, J = 6.7 Hz, 1H)
7.19 (t, J = 6.2 Hz, 2H), 7.14 (t, J = 6.1 Hz, 1H), 7.02 (t, J = 6.2 Hz, 1H),
7.00 (t, J = 6.6 Hz, 1H), 6.76 (t, J = 6.2 Hz, 1H), 3.88 (t, J = 6.4 Hz, 2H),
3.06 (t, J = 6.4 Hz, 2H); 13C NMR (100 MHz, DMSO‑d6): δ 141.0, 136.1,
134.1, 132.5, 130.3, 127.0, 126.1, 125.1, 122.8, 121.4, 119.5, 118.5,
112.5, 111.0, 43.5, 27.6; HREI-MS: m/z 334.0532; [(M+1)+ Calcd for
C
16H15ClN2O2S 334.0542].
2.1.14. N-(2-(1H-indol-3-yl)ethyl)naphthalene-1-sulfonamide (14)
1H NMR (400 MHz DMSO‑d6): δδ 10.81 (s, 1H, NH), 9.04 (s, 1H, NH),
8.87 (d, J = 6.7 Hz, 1H), 7.72 (t, J = 6.1 Hz, 2H), 7.55 (d, J = 6.7 Hz,
1H), 7.36–7.30 (m, 2H), 7.22 (t, J = 6.3 Hz, 1H), 7.06–7.02 (m, 2H),
3.91 (t, J = 6.2 Hz, 2H), 3.09 (t, J = 6.2 Hz, 2H); 13C NMR (100 MHz,
DMSO‑d6): δ 137.4, 136.5, 136.1, 134.3, 129.1, 128.0, 128.0, 127.0,
126.3, 125.5, 123.5, 123.5, 122.8, 121.4, 119.5, 118.5, 112.5, 111.0,
2.1.9. N-(2-(1H-indol-3-yl)ethyl)-4-methylbenzenesulfonamide (9)
1H NMR (400 MHz DMSO‑d6): δ 12.64 (s, 1H, NH), 10.92 (s, 1H, NH),
7.89 (t, J = 6.3 Hz, 1H), 7.72 (t, J = 6.1 Hz, 2H), 7.55 (d, J = 6.7 Hz, 1H),
7.36–7.30 (m, 2H), 7.22 (t, J = 6.3 Hz, 1H), 7.06–7.02 (m, 2H), 3.91 (t, J
= 6.2 Hz, 2H), 3.09 (t, J = 6.2 Hz, 2H);13C NMR (100 MHz, DMSO‑d6): δ
137.5, 137.0, 136.1, 129.0, 129.0, 128.1, 128.1, 127.0, 122.8, 121.4,
7

M. Taha et al.
Bioorganic Chemistry 110 (2021) 104808
43.5, 27.6; HREI-MS: m/z 350.1076; [(M+1)+ Calcd for C20H18N2O2S
was measured at 405 nm spectrophotometrically (SpectraMax®
plus384) for 5 min after incubation with substrate. Individual blanks for
test samples were prepared to correct background absorbance where
350.1089].
2.1.15. N-(2-(1H-indol-3-yl)ethyl)-2-bromo-4,5-
substrate was replaced with 50
μL of buffer. Control sample contained
dimethoxybenzenesulfonamide (15)
10 μL DMSO in place of test samples. Percentage of enzyme inhibition
1H NMR (400 MHz DMSO‑d6): δ 12.64 (s, 1H, NH), 10.92 (s, 1H, NH),
8.89 (t, J = 6.3 Hz, 1H), 8.01–7.97 (m, 3H), 7.68–7.64 (m, 3H), 7.52 (t, J
= 6.7 Hz, 1H), 7.32 (d, J = 6.4 Hz, 1H), 7.19 (d, J = 6.3 Hz, 1H),
was calculated as (1-B/A) × 100 where A represents absorbance of
control without test samples, and B represents absorbance in presence of
test samples. Data found was used for the calculation of IC50 values
(concentration at which there is 50% enzyme inhibition)
7.04–7.01 (m, 3H), 3.91 (t, J = 6.2 Hz, 2H), 3.09 (t, J = 6.2 Hz, 2H); 13
C
NMR (100 MHz, DMSO‑d6): δ 153.1, 149.3, 136.1, 135.6, 127.0, 122.8,
121.4, 119.5, 118.5, 118.2, 114.2, 113.0, 112.5, 111.0, 55.7 (OCH3),
55.7 (OCH3), 43.5, 27.6; HREI-MS: m/z 438.0233; [(M+1)+ Calcd for
Enzyme unit Definition: The amount of enzyme required to release
one µmole of glucose per minute from maltose (10 mg/mL) in sodium
acetate buffer (100 mM), pH 4.5 at 40 ◦C.
C
18H19BrN2O4S 438.0248].
2.4. In vivo antidiabetic study
2.1.16. N-(2-(1H-indol-3-yl)ethyl)-2-chloro-5-fluorobenzenesulfonamide
(16)
Albino Wistar rats were obtained from IRMC animal house. The
animals were fed standard diet along with water. The experiments were
carried out as per IAU guidelines of Animal Care and Use applicable to
animal study and the study was approved by the ethical committee
(Ethics Review ID: IRB-2021-300).
1H NMR (400 MHz DMSO‑d6): δ 13.41 (s, 1H, NH), 10.83 (s, 1H, NH),
7.58 (d, J = 6.5 Hz, 1H), 7.34 (d, J = 6.7 Hz, 1H), 7.27 (dd, J = 7.3, 2.4
Hz, 1H) 7.18–7.14 (m, 2H), 7.07 (t, J = 6.0 Hz, 1H), 6.98 (t, J = 6.2 Hz,
1H), 6.88 (dd, J = 6.0, 6.2 Hz, 1H), 3.90 (t, J = 5.8 Hz, 2H), 3.08 (t, J =
5.8 Hz, 2H); 13C NMR (100 MHz, DMSO‑d6): 167.1 (d, J = 174, C-F),
136.1, 135.0, 132.7, 130.0, 127.0, 122.8, 121.4, 119.5, 118.5, 117.4,
113.5, 112.5, 111.0, 43.5, 27.6; HREI-MS: m/z 352.0436; [(M+1)+
Calcd for C16H14ClFN2O2S 352.0448.
2.4.1. Acute oral toxicity study
Synthesized Scaffold 16 was administered to Wistar rats at a dose of
1000 mg/kg body weight to observe the toxicity or lethality of the
compound.
2.1.17. N-(2-(1H-indol-3-yl)ethyl)-3-bromobenzenesulfonamide (17)
1H NMR (400 MHz DMSO‑d6): δ 12.23 (s, 1H, NH), 11.73 (s, 1H, NH),
7.53 (t, J = 6.3 Hz, 2H), 7.41 (d, J = 6.3 Hz, 1H), 7.30 (d, J = 6.5 Hz, 1H)
7.07 (t, J = 7.5 Hz, 1H), 6.99 (t, J = 6.3 Hz, 1H), 6.94 (t, J = 6.4 Hz, 1H),
6.83 (t, J = 6.6 Hz, 2H), 3.85 (t, J = 4.6 Hz, 5H), 3.09 (t, J = 6.3 Hz, 2H);
13C NMR (100 MHz, DMSO‑d6): δ 142.0, 136.1, 134.5, 130.0,
129.3,127.0, 126.1, 123.2, 22.8 , 121.4, 119.5, 118.5, 112.5, 111.0,
43.5, 27.6; HREI-MS: m/z 378.0023; [(M+1)+ Calcd for C16H15BrN2O2S
378.0037].
2.4.2. STZ induced diabetes
For the present study, albino male wistar rats weighing 170–220 gm
were used. To induce the diabetes, 16 h fasted rats were injected
intraperitoneally 60 mg/kg Streptozotocin (MOLECULE-ON CAS
number 18883-66-4) dissolved in cold citrate buffer of pH 4.5. After
injecting the STZ, to prevent the hypoglycaemia, 5% glucose solution
will be given per oral for a period of two days. After 5 days of injection,
blood glucose level was measured by using glucometer (Accu-chek,
Roche), rats with blood glucose level above 200 mg/dL were considered
as diabetics and used in the experiments. Animals could access normal
food and water during entire study, except prior to the collection of
blood sample (fasted blood glucose was measured) [47–49].
2.2. Molecular docking protocol
Molecular docking was performed on the active compounds to
identify possible binding modes that explained the reason for their po-
tency. The method used for molecular docking was as mentioned in our
previous paper with slight modifications [45]. The molecular docking
2.4.3. Hypoglycemic study
Since there was no information on effective dose of synthesized
Scaffold 16 and the compound was found to be safe at a dose of 1000
mg/kg, hence we have selected scalar doses 10, 25, and 50 mg/kg body
weight. The effect of these Scaffold doses on fasting blood glucose levels
was determined by administering orally and blood glucose level was
measured by using glucometer (Accu-chek, Roche) at the interval of 0 ,
0.5 , 1 , 2 , 4 and 6 h following treatment by tail vein method under mild
sevoflurane anaesthesia [47–49]. Each group was consisting of 6 ani-
mals (n = 6).
study was conducted using a homology model for α-glucosidase. The
structures of all compounds were prepared using Chem3D by Cam-
bridgeSoft. The geometry and energy of the structures were optimized
using MMFF94. GOLD was used to identify the binding modes of the
active compounds responsible for the activity. The Chemscore fitness
function with default settings was employed in this study. The protein
sequence for Baker’s yeast
uniprot (http://www.uniprot.org). A homology model for Saccharo-
myces. cerevisiae glucosidase was built using the crystal structure of -D-
glucose-bound isomaltase from S. cerevisiae (PDB ID: 3A4A), which
shares a 72% identical and 85% similar sequence to -glucosidase. The
α-glucosidase (MAL12) was obtained from
α
2.4.4. Effects of Sacaffold-16 on blood glucose and body weight
The animals were grouped as follows and each group was consisting
of 6 animals (n = 6):
α
sequence alignment and homology modeling were performed using
Swiss-Model, which is a fully automated homology modeling pipeline
(SWISS-MODEL) managed by the Swiss Institute of Bioinformatics. The
docking results were visualized using Discovery Studio visualizer 3.5
and PyMol. The homology model was evaluated using PROCHECK.
Group 1: Normal control; Received water
Group 2: Diabetic Control; Received water
Group 3: Standard treatment; Received Glibenclamide (5 mg/kg
body weight)
Group 4: Treatment group; Received 25 mg/kg of Scaffold 16
Group 5: Treatment group; Received 50 mg/kg of Scaffold 16
2.3.
α
-Glucosidase assay
α
-Glucosidase inhibitory activities was determined as per reported
Fasting blood glucose levels and body weights were measured at 1st,
7th, 14th, 21st and 28th day of the study.
methods [46]. 10 L of test samples (5 mg/mL DMSO solution) were
altered in 100 L of 100 mM-phosphate buffer (pH 6.8) in 96-well
microplate and incubated with 50 L of crude intestinal -glucosidase
for 5 min before 50 L substrate (5 mM, p-nitrophenyl- -D-glucopyr-
anoside prepared in same buffer) was added. Release of p-nitrophenol
μ
μ
μ
α
μ
α
8

M. Taha et al.
Bioorganic Chemistry 110 (2021) 104808
˙
[3] I. Gulçin, P. Taslimi, A. Aygün, N. Sadeghian, E. Bastem, O.I. Kufrevioglu,
F. Turkan, F. S¸en, Antidiabetic and antiparasitic potentials: inhibition effects of
2.4.5. Oral glucose tolerance test (OGTT) in Streptozotocin–induced
diabetic rats
some natural antioxidant compounds on α-glycosidase, α-amylase and human
OGTT was carried on 28th day of the study. The animals were divided
and grouped as: Diabetic control, Standard treatment group, Scaffold 16
(25 and 50 mg/kg body weight). The diabetic control and standard
group of animals received normal saline and Glibenclamide 5 mg/kg
body weight, respectively. The group 3 and 4 received Scaffold 16 at the
dose of 25 mg and 50 mg/kg, per oral. After overnight fasting, a baseline
(t = 0 h) blood sample was taken from rats of respective groups and 2 g/
kg p.o. of Glucose was fed 0.5 h after Scaffold 16 (oral) administration.
Blood glucose levels was measured at the interval of 0, 0.5, 1, and 2 h
following treatment by tail vein method under mild sevoflurane anaes-
thesia [47–49].
glutathione S-transferase enzymes, Int. J. Biol. Macromol. 119 (2018) 741–746.
[4] J. Yang, X. Wang, C. Zhang, L. Ma, T. Wei, Y. Zhao, X. Peng, Comparative study of
inhibition mechanisms of structurally different flavonoid compounds on
α
-glucosidase and synergistic effect with acarbose, Food Chem. 347 (2021),
129056.
[5] M.Y. Kim, S.W. Choi, Can Walnut serve as a magic bullet for the management of
non-alcoholic fatty liver disease? Appl. Sci. 11 (2021) 218.
[6] F. Saleem, K.M. Khan, S. Chigurupati, M. Solangi, A.R. Nemala, M. Mushtaq, Z. Ul-
Haq, M. Taha, S. Perveen, Synthesis of azachalcones, their α-amylase, α-glucosidase
inhibitory activities, kinetics, and molecular docking studies, Bioorg. Chem. 106
(2021), 104489.
[7] V. Krishnan, R. Rani, M. Awana, D. Pitale, A. Kulshreshta, S. Sharma, H. Bollinedi,
A. Singh, B. Singh, A.K. Singh, S. Praveen, Role of nutraceutical starch and
proanthocyanidins of pigmented rice in regulating hyperglycemia: enzyme
inhibition, enhanced glucose uptake and hepatic glucose homeostasis using in vitro
model, Food Chem. 335 (2021), 127505.
2.4.6. Statistical analysis
[8] T. Iijima, K. Aoki, Y. Kondo, Y. Terauchi, Comparison of lipid-lowering effects of
anagliptin and miglitol in patients with type 2 diabetes: a randomized trial, J. Clin.
Med. Res. 12 (2020) 73.
Statistical analysis was performed using analysis of variance
(ANOVA) followed by Tukey’s post-hoc test through GraphPad Prism
v8.02 (GraphPad Software Inc.,). p < 0.05 was considered to indicate a
statistically significant difference between values.
[9] E.O. Ayua, S.G. Nkhata, S.J. Namaumbo, E.H. Kamau, T.N. Ngoma, K.O. Aduol,
Polyphenolic inhibition of enterocytic starch digestion enzymes and glucose
transporters for managing type 2 diabetes may be reduced in food systems, Heliyon
7 (2021) 6245.
[10] M. Zengin, H. Genc, P. Taslimi, A. Kestane, E. Guclu, A. Ogutlu, O. Karabay,
I. Gulcin, Novel thymol bearing oxypropanolamine derivatives as potent some
metabolic enzyme inhibitors–Their antidiabetic, anticholinergic and antibacterial
potentials, Bioorg. Chem. 81 (2018) 119–126.
3. Conclusions
New hybrid class of indole bearing sulfonamide scaffolds (1–17) as
[11] A. Biçer, P. Taslimi, G. Yakalı, I. Gülçin, M.S. Gültekin, G.T. Cin, Synthesis,
characterization, crystal structure of novel bis-thiomethylcyclohexanone
derivatives and their inhibitory properties against some metabolic enzymes,
Bioorg. Chem. 82 (2019) 393–404.
α
-glucosidase inhibitors were synthesized. All scaffolds exhibited
excellent to good potency with IC50 values ranging from 1.60 ± 0.010 to
51.20 ± 1.10 µM in comparison with standard acarbose (IC50 = 42.45 ±
1.05 µM) except scaffold 17 which was inactive. Among the synthesized
hybrid class scaffolds 1 was the most potent analogue with IC50 value
[12] C. Bayrak, P. Taslimi, H.S. Karaman, I. Gulcin, A. Menzek, The first synthesis,
carbonic anhydrase inhibition and anticholinergic activities of some bromophenol
derivatives with S including natural products, Bioorg. Chem. 85 (2019) 128–139.
¨
1.60 ± 0.010
standard acarbose. Scaffolds 1–15 showed an excellent
inhibitory potency as compared to standard. Scaffold 16 showed
excellent potency with IC50 value 1.60 M, as compared to standard
μ
M, showing ~26-fold better potency as compare to
[13] O. Talaz, I. Gülçin, S. Goksu, N. Saracoglu, Antioxidant activity of 5, 10-dihy-
droindeno [1, 2-b] indoles containing substituents on dihydroindeno part, Bioorg.
α-glucosidase
Med. Chem. 17 (2009) 6583–6589.
¨
¨
[14] U.M. Kocyigit, Y. Budak, M.B. Gürdere, S¸. Tekin, T.K. Koprülü, F. Ertürk, K. Ozcan,
˙
μ
I. Gülçin, M. Ceylan, Synthesis, characterization, anticancer, antimicrobial and
carbonic anhydrase inhibition profiles of novel (3aR, 4S, 7R, 7aS)-2-(4-((E)-3-(3-
aryl) acryloyl) phenyl)-3a, 4, 7, 7a-tetrahydro-1H-4, 7-methanoisoindole-1, 3 (2H)-
dione derivatives, Bioorg. Chem. 70 (2017) 118–125.
(42.45 ± 1.05). Antidiabetic potential of Scaffold 16 was further
confirmed in STZ induced diabetic rat model. Among the synthesized
class, scaffold 17 was found inactive. All analogues were characterized
through 1H, 13CNMR and HREI-MS analysis. Structure activity rela-
tionship of synthesized new hybrid class were established and confirmed
through molecular docking study.
[15] H. Hussain, M. Nazir, M. Saleem, A. Al-Harrasi, I.R. Green, Fruitful decade of
fungal metabolites as anti-diabetic agents from 2010 to 2019: emphasis on
α
-glucosidase inhibitors, Phytochem. Rev. 1–35 (2021) (2021).
[16] R. Rafique, K.M. Khan, S. Chigurupati, A. Wadood, A.U. Rehman, U. Salar,
V. Venugopal, S. Shamim, M. Taha, S. Perveen, Synthesis, in vitro α-amylase
inhibitory, and radicals (DPPH & ABTS) scavenging potentials of new N-
sulfonohydrazide substituted indazoles, Bioorg. Chem. 94 (2020), 103410.
[17] M. Alomari, M. Taha, F. Rahim, M. Selvaraj, N. Iqbal, S. Chigurupati, S. Hussain,
N. Uddin, N.B. Almandil, M. Nawaz, R.K. Farooq, Synthesis of indole-based-
Declaration of Competing Interest
thiadiazole derivatives as a potent inhibitor of α-glucosidase enzyme along with in
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.
silico study, Bioorg. Chem. 108 (2021), 104638.
[18] R. Tundis, M.R. Loizzo, F. Menichini, Natural products as alpha-amylase and alpha-
glucosidase inhibitors and their hypoglycaemic potential in thetreatment of
diabetes: an update, Mini Rev. Med. Chem. 10 (2010) 315–331.
[19] P. Li, M. Zhang, H. Li, R. Wang, H. Hou, X. Li, K. Liu, H. Chen, New prenylated
indole homodimeric and pteridine alkaloids from the marine-derived fungus
Aspergillus austroafricanus Y32–2, Marine Drugs 19 (2021) 98.
Acknowledgements
[20] N. Bhardwaj, A. Pathania, P. Kumar, Naturally available nitrogen-containing fused
heterocyclics as prospective lead molecules in medicinal chemistry, Curr. Trad.
Med. 7 (2021) 5–27.
Authors are thankful to Institute for Research and Medical Consul-
tations (IRMC), Imam Abdulrahman Bin Faisal University for providing
excellent research facilities. Further would like to acknowledge Malay-
sian Ministry of Higher Education (KPT) for the financial support under
FRGS Grant File No. 600-IRMI/ FRGS 5/3 (111/2019).
[21] T. Meng, Y. Hou, C. Shang, J. Zhang, B. Zhang, Recent advances in indole dimers
and hybrids with antibacterial activity against methicillin-resistant Staphylococcus
aureus, Archiv der Pharmazie 354 (2021) 2000266.
[22] Y. Chen, L. Zhang, L. Zhang, Q. Jiang, L. Zhang, Discovery of indole-3-butyric acid
derivatives as potent histone deacetylase inhibitors, J. Enzyme Inhib. Med. Chem.
36 (2021) 425–436.
Appendix A. Supplementary material
[23] S. Imran, M. Taha, N.H. Ismail, A review of bisindolylmethane as an important
scaffold for drug discovery, Cur. Med Chem. 22 (2015) 4412–4433.
[24] T. Takahashi, H. Inoue, M. Horigome, K. Momose, M. Sugita, K. Katsuyama, C.
Suzuki, S. Nagai, M. Nagase, K. Nakamaru, Nisshin Seifun Group Inc, Indole
derivatives and anti-ulcer compositions thereof. U.S. Patent No. 5, 252, 580, U.S.
Patent and Trademark Office, Washington, DC, 1993.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bioorg.2021.104808.
ˆ
[25] J.C. Delorenzi, M. Attias, C.R. Gattass, M. Andrade, C. Rezende, A. da Cunha Pinto,
References
A.T. Henriques, D.C. Bou-Habib, E.M. Saraiva, Antileishmanial activity of an indole
alkaloid Frompeschiera australis, Antimicrob. Agents Chemother. 45 (2001)
1349–1354.
˙
[1] P. Taslimi, I. Gulçin, Antidiabetic potential: in vitro inhibition effects of some
natural phenolic compounds on
Mol. Toxicol. 10 (2017) 21956.
α-glycosidase and α-amylase enzymes, J. Biochem.
[26] M.K. Park, Y.H. Rhee, H.J. Lee, E.O. Lee, K.H. Kim, M.J. Park, B.H. Jeon, B.S. Shim,
C.H. Jung, S.H. Choi, K.S. Ahn, Antiplatelet and antithrombotic activity of indole-
3-carbinol in vitro and in vivo, Phytother. Res. 22 (2008) 58–64.
˙
¨
[2] F. Erdemir, D.B. Celepci, A. Aktas¸, P. Taslimi, Y. Gok, H. Karabıyık, I. Gülçin, 2-
Hydroxyethyl substituted NHC precursors: synthesis, characterization, crystal
structure and carbonic anhydrase, α-glycosidase, butyrylcholinesterase, and
acetylcholinesterase inhibitory properties, J. Mol. Struct. 1155 (2018) 797–806.
9

M. Taha et al.
Bioorganic Chemistry 110 (2021) 104808
[27] W. Hui, Y. Dai, Therapeutic potential of aryl hydrocarbon receptor ligands derived
from natural products in rheumatoid arthritis, Basic Clin. Pharmacol. Toxicol. 126
(2020) 469–474.
I. Uddin, A. Wadood, S.A.A. Shah, R.K. Farooq, M. Nawaz, Z. Wahab, K.M. Khan,
Synthesis, molecular docking study and in vitro thymidine phosphorylase
inhibitory potential of oxadiazole derivatives, Bioorg. Chem. 78 (2018) 58–67. d)
M. Aha, M.S. Baharudin, N.H. Ismail, S. Imran, M.N. Khan, F. Rahim, M. Selvaraj,
[28] S. Süzen, Antioxidant activities of synthetic indole derivatives and possible activity
mechanisms, Bioactive Heterocycles V (2007) 145–178.
S. Chigurupati, M. Nawaz, F. Qureshi, S. Vijayabalan, Synthesis, α-amylase
[29] D. Yu, M. Suzuki, L. Xie, S.L. Morris-Natschke, K.H. Lee, Recent progress in the
development of coumarin derivatives as potent anti-HIV agents, Med. Res. Rev. 23
(2003) 322–345.
inhibitory potential and molecular docking study of indole derivatives, Bioorg.
Chem. 80 (2018) 36–42. e) T. Noreen, M. Taha, S. Imran, S. Chigurupati, F. Rahim,
M. Selvaraj, N.H. Ismail, J.I. Mohammad, H. Ullah, F. Nawaz, M. Irshad, Synthesis
of alpha amylase inhibitors based on privileged indole scaffold, Bioorg. Chem. 72
(2017) 248–255. f) M. Taha, S. Imran, N.H. Ismail, M. Selvaraj, F. Rahim, S.
Chigurupati, H. Ullah, F. Khan, U. Salar, M.T. Javid, S. Vijayabalan, Biology-
oriented drug synthesis (BIODS) of 2-(2-methyl-5-nitro-1H-imidazol-1-yl) ethyl
[30] M. Taha, E.A.J. Aldhamin, N.B. Almandil, N. Uddin, M. Alomari, F. Rahim,
B. Adalat, M. Ibrahim, F. Nawaz, N. Iqbal, B. Alghanem, Synthesis of indole based
acetohydrazide analogs: their in vitro and in silico thymidine phosphorylase
studies, Bioorg. Chem. 98 (2020), 103745.
[31] N.B. Almandil, M. Taha, M. Gollapalli, F. Rahim, M. Ibrahim, A. Mosaddik, Indole
bearing thiadiazole analogs: synthesis, β-glucuronidase inhibition and molecular
docking study, BMC Chem. 13 (2019) 1–10.
aryl ether derivatives, in vitro
α
-amylase inhibitory activity and in silico studies,
Bioorg. Chem. 74 (2017) 1–9. g) M. Taha, F. Rahim, S. Imran, N.H. Ismail, H.
Ullah, M. Selvaraj, M.T. Javid, U. Salar, M. Ali, K.M. Khan, Synthesis,
α-glucosidase
[32] H. Azevedo-Barbosa, D.F. Dias, L.L. Franco, J.A. Hawkes, D.T. Carvalho, From
antibacterial to antitumour agents: a brief review on the chemical and medicinal
aspects of sulfonamides, Mini Rev. Med. Chem. 20 (2020) 2052–2066.
[33] S.R. Wegst-Uhrich, D.A. Navarro, L. Zimmerman, D.S. Aga, Assessing antibiotic
sorption in soil: a literature review and new case studies on sulfonamides and
macrolides, Chem. Cent. J. 8 (2014) 1–12.
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. 74 (2017) 30–40. h) M. Taha, M.T. Javid, S. Imran, M. Selvaraj, S.
Chigurupati, H. Ullah, F. Rahim, F. Khan, J.I. Mohammad, K.M. Khan, Synthesis
and study of the α-amylase inhibitory potential of thiadiazole quinoline
derivatives, Bioorg. Chem. 74 (2017) 179–186. i) M. Taha, S. Imran, F. Rahim, A.
ˇ
[34] U. Kosak, B. Brus, D. Knez, S. Zakelj, J. Trontelj, A. Pislar, R. Sink, M. Jukic,
Wadood, K.M. Khan, Oxindole based oxadiazole hybrid analogs: novel
M. Zivin, A. Podkowa, F. Nachon, The magic of crystal structure-based inhibitor
optimization: development of a butyrylcholinesterase inhibitor with picomolar
affinity and in vivo activity, J. Med. Chem. 61 (2018) 119–139.
α-glucosidase inhibitors, Bioorg. Chem. 76 (2018) 273–280.
¨
˙
¨
[42] N. Oztas¸kın, R. Kaya, A. Maras¸, E. S¸ahin, I. Gülcin, S. Goksu, Synthesis and
characterization of novel bromophenols: determination of their anticholinergic,
antidiabetic and antioxidant activities, Bioorg. Chem. 87 (2019) 91–102.
[43] H.G. Bilgicli, A. Kestane, P. Taslimi, O. Karabay, A. Bytyqi-Damoni, M. Zengin,
I. Gulcin, Novel eugenol bearing oxypropanolamines: synthesis, characterization,
antibacterial, antidiabetic, and anticholinergic potentials, Bioorg. Chem. 88
(2019), 102931.
ˇ
ˇ
ˇ
ˇ
ˇ
[35] U. Kosak, B. Brus, D. Knez, R. Sink, S. Zakelj, J. Trontelj, A. Pislar, J. Slenc,
ˇ
M. Gobec, M. Zivin, L. Tratnjek, Development of an in-vivo active reversible
butyrylcholinesterase inhibitor, Sci. Rep. 6 (2016) 1–16.
[36] S. Riaz, I.U. Khan, M. Bajda, M. Ashraf, A. Shaukat, T.U. Rehman, S. Mutahir,
S. Hussain, G. Mustafa, M. Yar, Pyridine sulfonamide as a small key organic
molecule for the potential treatment of type-II diabetes mellitus and alzheimer’s
¨
[44] F. Erdemir, D.B. Celepci, A. Aktas¸, Y. Gok, R. Kaya, P. Taslimi, Y. Demir, I. Gulcin,
disease. In vitro studies against yeast
α
-glucosidase, acetylcholinesterase and
Novel 2-aminopyridine liganded Pd (II) N-heterocyclic carbene complexes:
Synthesis, characterization, crystal structure and bioactivity properties, Bioorg.
Chem. 91 (2019), 103134.
butyrylcholinesterase, Bioorg. Chem. 63 (2015) 64–71.
[37] P. Zajdel, A. Partyka, K. Marciniec, A.J. Bojarski, M. Pawlowski, A. Wesolowska,
Quinoline- and isoquinoline-sulfonamide analogs of aripiprazole: novel
antipsychotic agents, Future Med. Chem. 6 (2014) 57–75.
[45] S. Imran, M. Taha, N.H. Ismail, S.M. Kashif, F. Rahim, W. Jamil, M. Hariono,
M. Yusuf, H. Wahab, Synthesis of novel flavone hydrazones: in-vitro evaluation of
´
[38] S. Mutahir, J. Jonczyk, M. Bajda, I.U. Khan, M.A. Khan, N. Ullah, M. Ashraf,
α-glucosidase inhibition, QSAR analysis and docking studies, Eur. J. Med. Chem.
S. Riaz, S. Hussain, M. Yar, Novel biphenyl bis -sulfonamides as acetyl and
butyrylcholinesterase inhibitors: synthesis, biological evaluation, and molecular
modeling studies, Bioorg. Chem. 64 (2016) 13–20.
105 (2015) 156–170.
[46] L.R. Guerreiro, E.P. Carreiro, L. Fernandes, T.A. Cardote, R. Moreira, A.T. Caldeira,
R.C. Guedes, A.J. Burke, Five-membered iminocyclitol α-glucosidase inhibitors:
[39] M. Morris, G.M. Knudsen, S. Maeda, J.C. Trinidad, A. Ioanoviciu, A.L. Burlingame,
L. Mucke, Tau post-translational modifications in wild-type and human amyloid
precursor protein transgenic mice, Nat. Neurosci. 18 (2015) 1183–1189.
[40] H.I. Gul, C. Yamali, H. Sakagami, A. Angeli, J. Leitans, A. Kazaks, K. Tars, D.
O. Ozgun, C.T. Supuran, New anticancer drug candidates’ sulfonamides as selective
hCA IX or hCA XII inhibitors, Bioorg. Chem. 77 (2018) 411–419.
synthetic, biological screening and in silico studies, Bioorg. Med. Chem. 21 (2013)
1911–1917.
[47] M.D. Salahuddin, S.S. Jalalpure, N.B. Gadge, Antidiabetic activity of aqueous bark
extract Cassia glauca in streptozotocin-induced diabetic rats, Canadian J. Physiol.
Pharmacol. 88 (2010) 153–160.
[48] Y. Nayak, V. Hillemane, V.K. Daroji, B.S. Jayashree, M.K. Unnikrishnan,
Antidiabetic activity of benzopyrone analogues in nicotinamide-streptozotocin
induced type 2 diabetes in rats, Sci. World J. 12 (2014) 85426.
[49] D.G. Hai, L. Peng, Y. Yang, G. Fang, Sulfonamide-1,3,5-triazine–thiazoles:
discovery of a novel class of antidiabetic agents via inhibition of DPP-4, RSC Adv. 6
(2016) 83438–83447.
[41] a) M. Taha, S.A.A. Shah, M. Afifi, S. Imran, S. Sultan, F. Rahim, K.M. Khan,
Synthesis, α-glucosidase inhibition, and molecular docking study of coumarin
based derivatives, Bioorg. Chem. 77 (2018) 586–592. b) M. Taha, S.A.A. Shah, M.
Afifi, S. Imran, S. Sultan, F. Rahim, N.H. Ismail, K.M. Khan, Synthesis, molecular
docking study and thymidine phosphorylase inhibitory activity of 3-formylcou-
marin derivatives, Bioorg. Chem. 78 (2018) 17–23. c) H. Ullah, F. Rahim, M. Taha,
10