Cu/TEMPO catalyzed dehydrogenative 1,3-dipolar cycloaddition in the synthesis of spirooxindoles as potential antidiabetic agents

Article abstract of DOI:10.1039/d0ra01553a

A series of spiro-[indoline-3,3′-pyrrolizin/pyrrolidin]-2-ones, 4, 5 and 6 were synthesized in a sequential manner from Cu-TEMPO catalyzed dehydrogenation of alkylated ketones, 1 followed by 1,3-dipolar cycloaddition of azomethine ylides via decarboxylative condensation of isatin, 2 and l-proline/sarcosine, 3 in high regioselectivities and yields. The detailed mechanistic studies were performed to identify the reaction intermediates, which revealed that the reaction proceeds via dehydrogenative cycloaddition. Additionally, the regio and stereochemistry of the synthesized derivatives were affirmed by 2D NMR spectroscopic studies. The synthesized derivatives were explored further with molecular docking, in vitro antioxidant, and anti-diabetic activities.

Full text of DOI:10.1039/d0ra01553a

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Cu/TEMPO catalyzed dehydrogenative 1,3-dipolar
cycloaddition in the synthesis of spirooxindoles as
potential antidiabetic agents†
Cite this: RSC Adv., 2020, 10, 12262
Chitrala Teja,a Spoorthy N. Babu,b Ayesha Noor,b J. Arul Daniel,c S. Asha Devic
a
*
and Fazlur Rahman Nawaz Khan
A series of spiro-[indoline-3,30-pyrrolizin/pyrrolidin]-2-ones, 4, 5 and 6 were synthesized in a sequential
manner from Cu–TEMPO catalyzed dehydrogenation of alkylated ketones, 1 followed by 1,3-dipolar
cycloaddition of azomethine ylides via decarboxylative condensation of isatin, 2 and L-proline/sarcosine,
3 in high regioselectivities and yields. The detailed mechanistic studies were performed to identify the
reaction intermediates, which revealed that the reaction proceeds via dehydrogenative cycloaddition.
Additionally, the regio and stereochemistry of the synthesized derivatives were affirmed by 2D NMR
spectroscopic studies. The synthesized derivatives were explored further with molecular docking, in vitro
antioxidant, and anti-diabetic activities.
Received 18th February 2020
Accepted 15th March 2020
DOI: 10.1039/d0ra01553a
rsc.li/rsc-advances
envisioned the a,b-unsaturated carbonyl intermediate, 1d
formation from Cu–TEMPO catalyzed dehydrogenation of the
1. Introduction
saturated ketone. TEMPO is a unique free radical (oxidant); was
used as co-catalyst for several mechanistic studies.32,33 In addi-
tion, several mechanistic pathways and reports were reported
for dehydrogenation strategy. Nicolaou et al. developed a milder
method using IBX (o-iodoxybenzoic acid) as a stoichiometric
reagent,34–36 Stahl et al.,37–39 Newhouse et al.,40 and others
proposed aerobic dehydrogenation of alkyl aldehydes and
ketones, using palladium, and other catalysis.41–45 These re-
ported methods were suffering from multistep reactions,
expensive catalysts, and use of toxic volatile organic solvents
(VOCs) Me–OH, Et–OH, 1,4-dioxane, toluene, DMF46,47 and
stoichiometric reagents, the formation of unwanted by-
products and so forth.
Spirooxindoles have recently attracted signicant attention
towards versatile bioactivities, such as antimicrobial,1,2 anti-
tumor,3,4 anti-tubercular,5,6 antiviral7 and related properties.8–12
Natural products, for instance, horsline, elacomine, alstoni-
sine, mitraphylline,13 spirotryprostatin A,14,15 peteropodine,
consist of a privileged heterocyclic skeleton, where the spiro
ring is fused at the C3 position of the oxindole (Fig. 1).
The 1,3-dipolar cycloaddition16–18 of azomethine ylides is the
most efficient synthetic approach towards the spirooxindoles in
high regio and stereoselectivities. Moreover, these spiroox-
indoles were generated by the decarboxylative condensation19–21
of isatins and a-amino acids with unsaturated alkenes.22–24
A
wide variation of azomethine ylides,25 including a-amino acids,
and 1,3-dipolarophiles such as a,b-unsaturated carbonyl
compounds,26 (chalcones) arylidene-malono-dinitriles,27 nitro-
styrene,28 acrylamides29 a,b-unsaturated lactones,30 and various
electron-decient alkenes have been extensively documented.
Fokas, Lalitha and co-workers utilized a,b-unsaturated
carbonyl compounds and volatile toxic solvents, alike methanol
and dioxane (Scheme 1).23,31 Consequently, in the present study
aOrganic and Medicinal Chemistry Research Laboratory, Department of Chemistry,
School of Advanced Sciences, Vellore Institute of Technology, Vellore-632014, Tamil
Nadu, India. E-mail: nawaz_f@yahoo.co.in; Tel: +91-944-423-4609
bCentre for Bio Separation Technology, Vellore Institute of Technology, Vellore-632014,
India
cDepartment of Biomedical Sciences, School of Bioscience and Technology, Vellore
Institute of Technology, Vellore-632014, India
† Electronic supplementary information (ESI) available: Copies of NMR, HRMS
and FT-IR spectra of all compounds and 2D-NMR spectra for selected
compounds. See DOI: 10.1039/d0ra01553a
Fig. 1 Bioactive spirooxindole natural products.
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Scheme 1 1,3-Dipolar cycloaddition of a,b-unsaturated carbonyl compounds (previous work).
ꢀ
In order to overcome the above mentioned difficulties, (0.1 mmol) in DMF at 100 C. Interestingly, the Cu(OAc)2 and
herein, a Cu–TEMPO catalyzed dehydrogenative 1,3-dipolar Pd(OAc)2 provided the desired unsaturated ketone 1d within
cycloaddition of alkylated-ketones,48 1 utilizing isatin, 2, and L- 4 h, through dehydrogenation of 1ab. Further, the sequential
proline/sarcosine, 348 in TBAA is reported for the spiro-indoline- addition of isatin (0.5 mmol) and L-proline (0.6 mmol) leads to
3,30-pyrrolizin/pyrrolidines (Scheme 2). Interestingly, the TBAA the formation of spiro-oxindole 4ab in 55% and 41% of yields,
(tetrabutylammonium acetate) acted as a reaction medium respectively. The TEMPO acted as a radical initiator, while the
instead of VOCs, in several C–C bond forming reactions.46,47,49–54 2,2-bipyridyl as a bidentate transition metal chelating ligand for
Likewise, diabetes mellitus (DM) type-2, a chronic metabolic the reaction. Also, screened with Ag2O, CuSO4 CuCl2, CuBr2, and
disorder, was characterized by high blood sugar, insulin resis- Cu(OTf)2 under TEMPO/2,2-bipyridyl conditions,
a trace
tance, and secretion. The common symptoms were continual amount of 4ab was obtained (Table 1, entries 7–11). Likewise,
urination, increased hunger, and thirst, tiredness, and unex- the change of the ligand to 1,10-phenanthroline did not affect
pected weight loss, and so forth.55,56 According to the Interna- the yield of 4ab (43% in 8 h) (Table 1, entry 12). Other tested
tional Diabetes Federation (IDF) report as of 2017 ligands including, DBU, DABCO, and pyridine, respectively
approximately 425 million people were diagnosed with DM type under the same experimental conditions, provided poor yields
2.57,58 There are numerous therapeutic approaches to treat dia- of 4ab (Table 1, entries 13–15). Similarly, the change of the
betes, for instances, decreasing the postprandial hyperglycemia oxidant
to
N-hydroxyphthalimide
(NHPI),
tert-butyl-
by hydrolyzing enzyme inhibition, including a-amylase and a- hydroperoxide (TBHP) using 2,2-bipyridyl in DMF at 100 ꢀC
glucosidase.59,60 Anti-diabetic inhibitors voglibose, Acarbose, provided a trace amount of 4ab (Table 1, entries 16 and 17). In
and miglitol were utilized as drugs for years.61–63 Lately, spi- addition, screened the effect of solvent using 1,4-dioxane,
rooxindoles were reported as anti-diabetic inhibitors,64 there- DMSO, and toluene; however, there is no signicant change in
fore, the present work was envisioned to develop the yield of the desired product was observed (Table 1, entries 18–
spirooxindoles based anti-diabetic inhibitors.
20). Here all the optimizations were carried out sequentially by
in situ addition of isatin and L-proline aer the formation of
unsaturated ketone intermediate from dehydrogenation of the
saturated ketone.
2. Results and discussion
2.1 Chemistry
Interestingly, when
a sequential dehydrogenation/1,3-
dipolar cycloaddition was screened using TBA-salt as a reac-
tion medium instead of DMF by taking 3-(4-uorophenyl)-1-(p-
tolyl)propan-1-one 1ab (0.5 mmol) TBAB (tetrabutylammonium-
bromide) Cu(OAc)2 (10%), TEMPO (0.1 mmol) and 2,2-bipyridyl
(0.1 mmol) at 80 ꢀC. It provided the corresponding spiroox-
indole 4ab in good yield of 72% within 2 h (Table 1, entry 21).
The TBAB acted as an ionic medium and was advantageous over
VOCs, the TBA-salts also used in several C–C bond-forming
transformations.46,47,50,52,65–67 Encouraged by this result, further
screened with various tetrabutylammonium-salts, for instances,
TMAB (tetra-methylammonium bromide), TEAB (tetra-
ethylammonium bromide), TBAA (tetra-butylammonium
acetate), TBAI (tetra-butylammonium iodide) at 80 ꢀC carried
out, here 4ab was obtained in good to excellent yields up to 87%
(Table 1, entries 22–25). Among the tested TBA-salts, TBAA with
87% yield of desired product emerged out as the best-optimized
condition (Table 1, entry 24). Additionally, when optimizing the
loading of TBAA, for instance, 0.5 eq., 0.25 eq. (Table 1, entries
26 and 27) a less amount of product yield was observed while
comparing with 1.0 eq.
Initially, the reaction was carried out with 3-(4-uorophenyl)-1-
(p-tolyl)propan-1-one, 1ab (0.5 mmol), and optimized the reac-
tion conditions using transition metal catalysts viz. Mn(OAc)2,
Co(OAc)2, Ni(OAc)2, Cu(OAc)2, Zn(OAc)2, Pd(OAc)2 (Table 1,
entries 1–6) in the presence of TEMPO (0.1 mmol), 2,2-bipyridyl
Scheme 2 Synthesis of spirooxindoles by sequential dehydrogenative
1,3-dipolar cycloaddition of alkylated ketones (this work).
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Table 1 Optimization studies for preparation of spirooxindolopyrrolizidinesa,b,c
Entry
Cat. (mol%)
Additives
Solvent
Temp. ꢀC
Time (h)
Yield% 4abc
1
2
3
4
5
6
7
8
Mn(OAc)2
Co(OAc)2
Ni(OAc)2
Cu(OAc)2
Zn(OAc)2
Pd(OAc)2
Ag2O
CuSO4
CuCl2
CuBr2
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
NHPI
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
1,10-Phenanthroline
DBU
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
9
8
12
6
—
—
—
55
—
10
13
12
20
18
18
10
8
15
18
12
10
15
10
8
16
3
4
3
2
5
2
3
41
Trace
Trace
13
19
25
43
10
22
15
15
15
31
48
25
72
63
65
87
61
82
70
9
10
11
12
13
14
15
16
17
18
19
20
21b
22
23
24
25
26
27
DABCO
Pyridine
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
2,20-Bipyridyl
TBHP
DMF
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
1,4-Dioxane
DMSO
Toluene
TBAB (1 eq.)
TMAB
TEAB
TBAA
TBAI
TBAA (0.5 eq.)
TBAA (0.25 eq.)
80
80
80
80
80
80
a
Reaction conditions: saturated ketone, 1ab (0.5 mmol), Cu(OAc)2 (10 mol%), TEMPO (0.1 mmol) and 2,2-bipyridyl (0.1 mmol), in 2 mL of solvent at
100 ꢀC aer sequential addition of isatin, 2 (0.5 mmol), L-proline 3a or sarcosine 3b (0.6 mmol). b TBA-ionic-liquid (1 eq.) at 80 ꢀC for 1 h. c Isolated
yields.
Having streamlined optimized reaction condition in hand reports,45,68 we proposed the plausible reaction mechanism
(Table 1, entry 24), various spirooxindole derivatives were ob- Fig. 2. Also, Su et al. previously proposed the plausible mecha-
tained from different alkylated ketones by sequential dehydro- nistic pathway for dehydrogenation of saturated ketones via
genative 1,3-cycloaddition, tabulated in Tables 2–4. Also, the radical addition and elimination.45
scope of the reaction was explored using substrates with
Initially, Cu(OAc)2 gets reacted with alkylated-ketone A to
electron-donating groups (–Me, and –OMe), and with electron- provide metal-enolate complex B. Then generates Cu(I) species,
withdrawing groups (–Cl, F and Br). Favorably, all the tested a-radical intermediate C and a-TEMPO radical substituted
1
substrates transformed smoothly to provide the desired ketone D, as conrmed by H NMR studies (ESI Fig. S47†).
spirooxindoles.
Spectra-2 C reveals the a-TEMPO-adduct C–H proton at
4.6 ppm, where trans-ketone formation occurs, to form enones E
and the formation of alkene (chalcone) via dehydrogenation F.
In (ESI Fig. S47†) C and D show the formation of unsaturated
ketone (chalcone) along with saturated ketone. In the nal step,
oxidation occurs via Cu(I) species by TEMPO rather than
2.2 Proposed reaction mechanism
In addition, the control experiments and 1H NMR studies were
performed to identify the reaction mechanism (results are dis-
cussed in Fig. S46 and 47 ESI Page S54–S56†). From the above
mentioned mechanistic studies and previous literature
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Table 2 Substrate scope with alkylated saturated ketonesa,b
Table 3 Substrate scope with quinolinyl-keto alkanesa,b
a
Reaction conditions: alkylated ketone, 1a (0.5 mmol), Cu(OAc)2
(10 mol%), TEMPO (0.1 mmol) and 2,20-bipyridyl (0.1 mmol), in TBAA
(1 eq.) at 80 ꢀC for 1 h, sequential addition of isatin, 2 (0.5 mmol), L-
proline 3a or sarcosine 3b (0.6 mmol) at 80 ꢀC for another 1 h.
b
Isolated yields.
a
Reaction conditions: quinolinyl-alkylated ketone, 1b (0.5 mmol),
Cu(OAc)2 (10 mol%), TEMPO (0.1 mmol) and 2,20-bipyridyl (0.1
mmol), in TBAA (1 eq.) at 80 ꢀC for 1 h, sequential addition of isatin,
2 (0.5 mmol), L-proline 3a or sarcosine 3b (0.6 mmol) at 80 ꢀC for
TEMPO-OH G to reproduce Cu(II) H by forming 2,2,6,6-tetra-
methylpiperidine and H2O as by-products I.
b
another 1 h. Isolated yields.
The formation of Cu(II) species from the oxidation of Cu(I)
species, was observed in literature reports.69 The reactions of
Cu(OAc)2/2,2-bpy complex with TEMPO or TEMPO-OH have
been demonstrated, the both TEMPO and TEMPO-OH could
oxidize Cu(I) species to form Cu(II). Where the TBAA, as a basic
and ionic medium, alters the reaction conditions. The
sequential addition of isatin and proline to the unsaturated
ketone intermediate (chalcone) resulted in the 1,3-dipolar
cycloaddition leads to provide the 5-membered spirooxindoles.
For instance, (Fig. 2) isatin a, L-proline b leads to carboxylative
cyclic ester c, which undergoes decarboxylation d to give azo-
methine ylide e, a dipole. The azomethine ylide then undergoes
1,3-cycloaddition to provide the expected spirooxindole-1,3-
dipolar-cycloaddition product g, water, and CO2 only the by-
products. The transformation of spirooxindole from unsatu-
rated ketone has been indicated in (ESI Page S55, Fig. S47†)
NMR studies. The structural elucidation of compounds 4, 5, and
6 were identied using 1H, 13C, and 2D-NMR spectroscopic
studies (see ESI, Page S53†), as mentioned in the illustrative
example of 4aa.
synthesized compounds with alpha-amylase, alpha-glucosidase,
and GLP-1, respectively. The molecular docking study of the a-
amylase enzyme with the synthesized compounds revealed the
superior binding efficiency of the ligands when compared to the
standard reference drug Acarbose. The commercial drug Acar-
bose had binding energy of ꢁ0.74 kcal molꢁ1, and the synthe-
sized compound 6c and 6a had the best binding energy of ꢁ9.61
and ꢁ9.51 kcal molꢁ1 respectively. Furthermore, the study
revealed the interactions of the compounds with amino acid
residues like TRP59, GLN63, ASP197, GLU233, ASP300 and
HIS305 of the enzyme which is present in the active site of the
enzyme and similar to the interaction with the standard drug
Acarbose.70
Interaction of the synthesized compounds with a-glucosi-
dase enzyme revealed that 6b and 6a had the best binding
energy of ꢁ9.77 and ꢁ9.29 kcal molꢁ1, respectively. Acarbose
had binding energy of 0.32 kcal molꢁ1 and formed 3 hydrogen
bonds with PHE525 and SER626 amino acid residues of the a-
glucosidase enzyme. Most of the synthesized compounds had
interactions with the catalytic domain of the a-glucosidase
enzyme present between residues 358 to 720.71 Molecular
interactions with GLP-1 receptor revealed 6d, 5a, and 5b had the
best binding energy. Previous studies have shown that exendin-
2.3 Pharmacological studies
2.3.1 Molecular docking. The interaction study was carried
out using AutoDock, and the results obtained are shown in
Table 5. The interactions visualized using LigPlot+ are provided
in (ESI Page S62–S66, Fig. S48–S50†) for interactions of the
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Table 4 Substrate scope with quinolinyl-keto alkanesa,b
Table 5 Binding energies of the synthesized molecules
Binding energy (kcal molꢁ1
)
S. no. Compound name Alpha-amylase Alpha-glucosidase GLP-1
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
6a
6b
6c
6d
6e
ꢁ8.15
ꢁ7.3
ꢁ8.64
ꢁ8.08
ꢁ8.66
ꢁ8.27
ꢁ7.6
ꢁ9.51
ꢁ9.47
ꢁ8.31
ꢁ7.46
ꢁ8.11
ꢁ8.21
ꢁ8.15
ꢁ8.39
ꢁ8.4
ꢁ7.76
ꢁ7.78
ꢁ7.78
ꢁ8.47
ꢁ7.9
ꢁ7.23
ꢁ7.61
ꢁ7.28
ꢁ8.73
ꢁ7.91
ꢁ9.29
ꢁ9.77
ꢁ7.07
ꢁ7.44
ꢁ8.71
ꢁ7.62
ꢁ7.04
ꢁ6.85
ꢁ7.14
ꢁ6.57
0.32
ꢁ9.29
ꢁ8.57
ꢁ8.13
ꢁ9.51
ꢁ9.16
ꢁ9.61
ꢁ8.74
ꢁ9.24
ꢁ7.81
ꢁ6.95
ꢁ6.77
ꢁ7.79
ꢁ7.78
ꢁ0.74
9
10
11
12
13
14
15
16
17
18
19
20
21
ꢁ8.55
ꢁ8.85
ꢁ7.56
ꢁ8.6
ꢁ10.2
ꢁ8.95
ꢁ7.65
ꢁ7.47
ꢁ6.66
ꢁ6.87
ꢁ7.31
37.44
4aa
4ab
4ba
4bb
4bc
Std. drug
a
Reaction conditions: quinolinyl-alkylated ketone, 1c (0.5 mmol),
Cu(OAc)2 (10 mol%), TEMPO (0.1 mmol) and 2,20-bipyridyl (0.1
mmol), in TBAA (1 eq.) at 80 ꢀC for 1 hour, sequential addition of
isatin, 2 (0.5 mmol), L-proline 3a or sarcosine 3b (0.6 mmol) at 80 ꢀC
for another 1 h. b Isolated yields.
through various assays such as ABTS, DPPH, H2O2 scavenging
assay, and metal chelating assay with the respective standards.
All the compounds answered positively to these assays.
The reaction below shows the scavenging action of DPPH
due to the presence of anti-oxidants
4 binds with the GLU128 of the GLP-1 receptor having an
agonist activity (Underwood 2010).72
Current interaction studies have imparted that 5d, 5f, 5h, 6e,
4aa, 4ab, and 4bc formed a hydrogen bond with GLU128, which
implies that it could have agonist activity too as reported before.
2.3.2 In vitro antioxidant assay. All the synthesized
compounds were tested for their anti-oxidant properties
Fig. 2 Plausible mechanism for the synthesis of spirooxindoles from keto-alkanes via Cu–TEMPO catalyzed dehydrogenation and 1,3-dipolar
cycloaddition.
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All the synthesized compounds showed the potential to are considered as potential antidiabetic agents, already dis-
scavenge ABTS and DPPH radical with compound 6d having the cussed in the Introduction part.
highest activity at an IC50 value of 0.28 ꢂ 0.03 mg mLꢁ1 and 0.34
In our study, all the compounds showed positive results in
ꢂ 0.06 mg mLꢁ1 respectively while compound 6e had the least inhibiting the a-glucosidase enzyme with compounds 5h and 5i
activity with an IC50 value of 6.04 ꢂ 0.54 mg mLꢁ1 and 6.98 ꢂ having high activity. It was interesting to note that only 7
0.75 mg mLꢁ1 respectively. The principle of metal chelating compounds answered positively to the a-amylase inhibition
assay involves the chelation of ferrozine with ferrous ion. This assay with compounds 5h and 5i having higher potential.
forms a red-colored complex. The presence of antioxidants
Overall, amongst the compounds, it can be inferred that
reduces the chelation as the antioxidants compete with ferro- compounds 5h and 5i have anti-oxidant and anti-diabetic
zine to chelate with the ferrous ion. The chelation of antioxi- properties with better IC50 values (shown in Table 6).
dants with ferrous ion reduced the red color of the ferrozine
ferrous ion complex.
2.3.4 QSAR-studies
relationships)
(quantitative
structure–activity
In our study, all the compounds could chelate with ferrous
2.3.4.1 Physicochemical and pharmacokinetic properties. The
ion. The compound 6e exhibited highest potential (IC50 value: in silico physicochemical properties of synthesized spiro-
0.31 ꢂ 0.02 mg mLꢁ1) while compound 4ab showed least oxindole analogs were calculated and compared with Acarbose
potential with an IC50 value of 6.91 ꢂ 1.10 mg mLꢁ1
.
(standard antidiabetic drug). All the compound molecular
The H2O2 assay is based on the reduction of the tri- weights are calculated according to Lipinski's rule of 5, in that
phenanthroline complex formed due to the reaction between 4aa, 4ab, 4ba, 4bb, and 4bc, which molecular weights are <500,
ferrous ion and phenanthroline (red-orange). The addition of remaining all the derivatives 5a series and 6a series including
H2O2 reduced ferrous ion to ferric, and the tri-phenanthroline Acarbose are (>500) greater than its range. Polar Surface Area
complex is not formed. The presence of compounds prevents (PSA) is calculated based on TPSA methodology, TPSA is the
the action of H2O2, leading to the formation of the tri- essential factor that is showing molecular transport across the
phenanthroline complex.
membranes, all the compounds showing TPSA values within
In our study, all compounds could scavenge the H2O2 radical satisfactory range between 50–100 except 4aa series. So the
with compound 5e having the highest potential, while result is showing our synthesized compounds showing
compound 4ab had very less scavenging activity (shown in Table moderate lipophilicity across the blood-brain barrier. Other
6).
parameters, like, number of rotatable bonds (n-RotB), number
2.3.3 In vitro anti-diabetic assay. One of the factors for of O, N atoms present and NH, OH donor/acceptor, were also in
controlling diabetes is to reduce postprandial hyperglycemia. acceptable range comparing with standard drug. The results are
Inhibiting a-amylase and a-glucosidase enzymes reduced the showing excellent properties comparing with Acarbose because
postprandial hyperglycemia, and inhibitors of these enzymes electronic and steric, substitution factors of the molecules, the
positive as well as negative results also were recorded. 4aa series
Table 6 In vitro antioxidant and an anti-diabetic assay of the synthesized derivatives
S. no.
Compound
ABTS
DPPH
Metal chelating
H2O2
a-Amylase
a-Glucosidase
1
2
3
4
5
6
7
8
4aa
4ab
4ba
4bb
4bc
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
6a
1.62 ꢂ 0.21
1.54 ꢂ 0.30
2.70 ꢂ 0.60
1.42 ꢂ 0.31
1.50 ꢂ 0.45
3.25 ꢂ 0.47
0.49 ꢂ 0.32
1.57 ꢂ 0.12
1.11 ꢂ 0.36
0.79 ꢂ 0.43
0.55 ꢂ 0.20
2.72 ꢂ 0.54
0.41 ꢂ 0.06
0.86 ꢂ 0.09
3.03 ꢂ 0.65
2.75 ꢂ 0.58
0.43 ꢂ 0.05
0.34 ꢂ 0.09
0.28 ꢂ 0.03
6.04 ꢂ 0.54
0.006 ꢂ 0.002
NA
1.46 ꢂ 0.21
1.22 ꢂ 0.34
1.23 ꢂ 0.39
0.80 ꢂ 0.07
1.68 ꢂ 0.34
2.26 ꢂ 0.13
0.55 ꢂ 0.04
1.62 ꢂ 0.43
1.28 ꢂ 0.32
0.88 ꢂ 0.09
0.50 ꢂ 0.06
2.79 ꢂ 0.32
0.49 ꢂ 0.03
0.92 ꢂ 0.05
2.09 ꢂ 0.34
2.71 ꢂ 0.43
0.44 ꢂ 0.08
0.36 ꢂ 0.02
0.34 ꢂ 0.06
6.98 ꢂ 0.75
NA
0.96 ꢂ 0.23
6.91 ꢂ 1.10
3.21 ꢂ 0.76
0.46 ꢂ 0.08
0.86 ꢂ 0.09
0.93 ꢂ 0.11
0.81 ꢂ 0.06
0.92 ꢂ 0.04
1.16 ꢂ 0.31
6.00 ꢂ 0.75
1.40 ꢂ 0.62
0.69 ꢂ 0.05
1.04 ꢂ 0.08
0.77 ꢂ 0.22
0.38 ꢂ 0.07
0.43 ꢂ 0.04
0.46 ꢂ 0.08
0.99 ꢂ 0.09
0.37 ꢂ 0.03
0.31 ꢂ 0.02
0.0073 ꢂ 0.002
NA
0.63 ꢂ 0.12
6.15 ꢂ 1.12
0.88 ꢂ 0.06
0.41 ꢂ 0.04
1.16 ꢂ 0.35
0.92 ꢂ 0.09
0.79 ꢂ 0.02
0.85 ꢂ 0.07
1.50 ꢂ 0.35
0.21 ꢂ 0.03
1.52 ꢂ 0.32
1.27 ꢂ 0.32
0.78 ꢂ 0.06
0.57 ꢂ 0.09
0.35 ꢂ 0.04
1.05 ꢂ 0.27
0.68 ꢂ 0.06
0.59 ꢂ 0.03
0.33 ꢂ 0.04
0.32 ꢂ 0.07
NA
1.47 ꢂ 0.27
1.48 ꢂ 0.32
1.52 ꢂ 0.35
1.25 ꢂ 0.24
1.46 ꢂ 0.31
2.22 ꢂ 0.57
0.51 ꢂ 0.19
2.73 ꢂ 0.52
0.50 ꢂ 0.03
1.02 ꢂ 0.34
0.74 ꢂ 0.13
0.30 ꢂ 0.05
0.58 ꢂ 0.06
0.35 ꢂ 0.05
0.31 ꢂ 0.07
1.12 ꢂ 0.15
0.41 ꢂ 0.04
0.26 ꢂ 0.06
0.32 ꢂ 0.07
0.24 ꢂ 0.05
0.27 ꢂ 0.02
NA
1.11 ꢂ 0.41
0.99 ꢂ 0.06
0.98 ꢂ 0.25
1.52 ꢂ 0.40
NA
NA
NA
NA
NA
NA
NA
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
0.54 ꢂ 0.14
0.28 ꢂ 0.07
NA
NA
NA
NA
NA
NA
NA
NA
6b
6c
6d
6e
Ascorbic acid
Gallic acid
Acarbose
0.0055 ꢂ 0.001
0.0045 ꢂ 0.001
NA
NA
NA
NA
NA
0.058 ꢂ 0.012
0.046 ꢂ 0.023
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derivatives conceded 1 violation in terms of mlogPb violation, was recorded using Bruker AVANCE-III (400 MHz) using CDCl3
remaining all the compounds conceded 2 violations in terms of as a solvent system. FT-IR spectra were recorded using (Shi-
MW and mlogPb, comparing with Acarbose, which shows good madzu IR Tracer-100) spectrometer nmax are reported in cmꢁ1
.
results (Acarbose conceded 3 violations). So, according to Lip-
4.2 General procedure for synthesis of 10-(4-uorophenyl)-20-
(4-methylbenzoyl)-10,20,50,60,70,7a0-hexahydrospiro[indoline-
3,30-pyrrolizin]-2-one (spirooxindole)
inski's rule of ve, our compounds have no problems with
bioavailability. In future new drug design and discovery point of
view, a slight modication in the compounds may increase its
lipophilicity and all other parameters (ESI Page S67, Table S7†).
The pharmacokinetics of the synthesized compounds were
predicted using the pkCSM pharmacokinetic prediction tool to
nd the drug likeliness by ADMET properties (absorption,
distribution, metabolism, excretion, and toxicity).73
The results show that all the synthesized molecules show
excellent absorption properties including, water solubility,
intestinal absorption, comparing with Acarbose as a standard
drug. It shows moderate distribution properties and 4aa series
few derivatives show AMES toxicity, as well as hepatotoxicity;
remaining derivatives do not have any toxicity issues. Based on
the above results, all the synthesized molecules show excellent
ADMET properties comparing with the standard drug (ESI Page
S67, Table S8†).
(3-(4-Fluorophenyl)-1-(p-tolyl)propan-1-one) saturated ketone,
1ab (1.0 mmol), Cu(OAc)2 (10 mol%), TEMPO (0.1 mmol) and
ꢀ
2,2-bipyridyl (0.1 mmol), in TBAA (1 eq.) at 80 C for 1 h aer
formation of unsaturated enone intermediate 1d, conrmed by
TLC, sequential addition of isatin, 2 (0.5 mmol), L-proline 3a or
ꢀ
sarcosine 3b (0.6 mmol) at 80 C for another 1 h led to forma-
tion of 10-(4-uorophenyl)-20-(4-methylbenzoyl)-10,20,50,60,70,7a0-
hexahydrospiro[indoline-3,30-pyrrolizin]-2-one, as resulted spi-
rooxindole, aer conrmation of TLC, the reaction mixture was
allowed to warm at rt and extracted using water and CH2Cl2 as
solvent, and the organic extracts were dried over anhydrous
Na2SO4, and the crude reaction mixture was passed through
manual column chromatography to obtain pure product 4ab.
The same procedure as follows for the synthesis of the
remaining derivatives.
3. Conclusions
4.3 Molecular docking studies
In summary, we have developed a solvent-free protocol in the
virtue of avoiding VOCs for the synthesis of novel spiroox-
indoles from alkylated saturated ketones via Cu–TEMPO cata-
lyzed dehydrogenation and sequential 1,3-dipolar cycloaddition
pathway. Also, the detailed mechanistic studies revealed that
the reaction proceeds via dehydrogenation followed by cyclo-
addition. It is an efficient protocol in-terms of one-pot
sequential strategy, in high regio, stereo-selectivities and
yields. All the synthesized compounds were investigated further
for bio-activities, such as in silico molecular docking, in vitro
antioxidant and anti-diabetic activities, most of the synthesized
derivatives shows potential anti-oxidant and anti-diabetic
inhibition. QSAR-studies of the synthesized derivatives show
good biodegradability and bioavailability, including drug
transport and ADMET properties.
Interaction studies were carried out for the synthesized deriv-
atives with a-amylase, a-glucosidase, and glucagon-like peptide-
1 (GLP-1). The structure of the compounds was obtained using
ChemDraw, while the PDB structure of alpha-amylase, alpha-
glucosidase, and GLP-1 were obtained from protein data bank
with PDB ID 5U3A, 5NN8, and 3IOL respectively. AutoDock 4.2
was used to analyze the interactions, while LigPlot+ v1.4 was
used to visualize the interactions. Interaction studies by Auto-
Dock were carried out using different parameters for different
targets. For alpha-amylase, the interacting grid points for x, y,
ꢀ
and z-axis were set at 70, 80 and 70 of 0.9583 A spacing, 90, 90,
ꢀ
and 120 of 1.0 A spacing for alpha-glucosidase and for GLP-1 it
ꢀ
was set at 60, 90 and 80 at 0.7 A spacing.
4.4 In vitro antioxidant assay
4. Experimental procedure
4.1 General information
4.4.1 ABTS scavenging activity. ABTS assay was performed
according to Rajurkar & Hande.74 ABTS radical prepared was
incubated with different concentrations of compounds in the
dark for 15 minutes at 37 ꢀC, and the absorbance was noted at
734 nm. The blank was run parallel in the same manner.
ABTS scavenging activity was calculated as follows:
All the chemicals were purchased from Sigma-Aldrich and TCI
chemicals Ltd. used without further purication. All the reac-
tion was conducted using glass reaction vials from App-tec
Instrument Ltd., and performed by using in Apptec Lab Mate
Manual Parallel Synthesizer. Pre-coated aluminum TLC sheets
were used to check TLC (silica gel 60 F254, Merck). Aer
ABTS radical-scavenging activity (%) ¼ [(Ac ꢁ As)/Ac] ꢃ 100,
completion of the reaction, the reaction mixture was allowed to here Ac denotes the absorbance of the control reaction (con-
warm at rt and extracted using water and CH2Cl2 as a solvent, taining all reagents except the sample), and As denotes the
and the organic extracts were dried over anhydrous Na2SO4, and absorbance of the test sample.74
the crude reaction mixture was passed through manual column
4.4.2 DPPH scavenging activity. The free radical scavenging
chromatography to obtain pure product. Column chromatog- activity at various concentrations (0.1, 0.25, 0.5, 1, 2 mg mLꢁ1
)
raphy performed on silica gel (100–200 mesh, Merck Ltd.) to of compounds was evaluated by DPPH assay (Nikhat et al.,
give pure product on petroleum ether and ethyl acetate (petro- 2009).75 The different concentrations of extract were vortexed
leum ether/EtOAc 8 : 2 v/v). Characterization alike, NMR-spectra with 1.0 mL of 0.1 mM of DPPH in methanol. The mixture was
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incubated in the dark for 30 min at room temperature. The the standard reference compound. a-Glucosidase inhibition
degree of inhibition of DPPH was monitored by a decrease in was calculated as follows:
absorbance, which was measured at 517 nm against methanol
a-Glucosidase inhibition activity ¼ [(Ac ꢁ As)/Ac] ꢃ 100,
solvent blank. The DPPH solution without extract served as
control.75 Scavenging activity was calculated as
where Ac denotes the absorbance of the control reaction and As
denotes the absorbance of the test sample.69
DPPH radical-scavenging activity (%) ¼ [(Ac ꢁ As)/Ac] ꢃ 100,
here Ac denotes the absorbance of the control reaction, and As
denotes the absorbance of the test sample.
4.4.3 Hydrogen peroxide scavenging activity. H2O2 assay
was performed by adding the test solution contained ferrous
ammonium sulfate, 1,10-phenanthroline, hydrogen peroxide
along with different concentrations of compounds tested for
hydrogen peroxide scavenging activity and control solution
contained only 1 mM ferrous ammonium sulfate and 1 mM
4.7 QSAR studies
Calculation of molecular physicochemical properties from
Molinspiration online database server.
The pharmacokinetics of the synthesized compounds were
predicted using the pkCSM pharmacokinetic prediction tool to
nd the drug likeliness by ADMET properties (absorption,
distribution, metabolism, excretion, and toxicity).73
1,10-phenanthroline. Ascorbic acid used as a standard reference
compound.76 H2O2 scavenging activity was calculated as follows:
Conflicts of interest
H2O2 radical-scavenging activity (%) ¼ [(Ac ꢁ As)/Ac] ꢃ 100,
The authors declare no competing nancial interest.
where Ac denotes the absorbance of the control reaction, and As
denotes the absorbance of the test sample.
Acknowledgements
4.4.4 Metal chelating assay. Metal chelating activity was
The authors are thankful to SIF-VIT for providing NMR, GC-MS
measured by adding 0.1 mM ferrous sulfate (0.2 mL) and
and IR and other instrumentation facilities.
0.25 mM ferrozine (0.4 mL) subsequently into different
concentrations of compounds. Aer incubating at room
temperature for 10 min, absorbance was recorded at 562 nm Notes and references
with ascorbic acid as a standard reference compound.77 The
metal chelating activity was calculated as follows:
¨
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