Visible light induced nano copper catalyzed one pot synthesis of novel quinoline bejeweled thiobarbiturates as potential hypoglycemic agents

Article abstract of DOI:10.1002/jhet.4271

An efficient visible light induced one pot three component approach for the synthesis of new quinoline bejeweled thiobarbiturates via Knoevenagel condensation and N-alkylation using copper nanoparticles (CuNPs) have been reported. These copper nanoparticles due to their diverse properties, smaller size (50–100 nm), and high surface area to volume ratio exhibit promising features for the reaction response such as the shorter reaction time, simple work-up procedure, clean reaction profiles, and excellent product yields through reusability of the catalyst upto five cycles. The recovered catalyst was successfully characterized by EDAX and AFM analysis. In silico molecular docking studies were carried out to find out the effective binding affinity of the synthesized quinoline derivatives toward PPARγ protein. The results obtained showed that compounds 4d, 4e, and 4f possess good binding interaction toward PPARγ with binding energy of ?7.4, ?7.2 and, ?7.6 k.cal/mol which was greater than standard rosiglitazone (?6.4 k.cal/mol) and comparable to that of standard pioglitazone (?7.9 k.cal/mol). In vitro α-amylase and α-glucosidase assays were performed for hypoglycemic activity evaluation. The compounds 4e and 4f at a concentration of 100 μg/ml showed 82.13% and 83.26% inhibition toward α-glucosidase, 78.30% and 84.18% inhibition toward α-amylase which was higher than standard pioglitazone and on par to that of rosiglitazone and acarbose.

Full text of DOI:10.1002/jhet.4271

Received: 15 February 2021
DOI: 10.1002/jhet.4271
Revised: 23 March 2021
Accepted: 5 April 2021
A R T I C L E
Visible light induced nano copper catalyzed one pot
synthesis of novel quinoline bejeweled thiobarbiturates as
potential hypoglycemic agents
1
1
2
Gangadhara Angajala
| Valmiki Aruna | Radhakrishnan Subashini
1
Department of Chemistry, Kalasalingam
Academy of Research and Education,
Krishnankoil, Tamilnadu, India
Abstract
An efficient visible light induced one pot three component approach for the
synthesis of new quinoline bejeweled thiobarbiturates via Knoevenagel con-
densation and N-alkylation using copper nanoparticles (CuNPs) have been
reported. These copper nanoparticles due to their diverse properties, smaller
size (50–100 nm), and high surface area to volume ratio exhibit promising fea-
tures for the reaction response such as the shorter reaction time, simple work-
up procedure, clean reaction profiles, and excellent product yields through
reusability of the catalyst upto five cycles. The recovered catalyst was success-
fully characterized by EDAX and AFM analysis. In silico molecular docking
studies were carried out to find out the effective binding affinity of the synthe-
sized quinoline derivatives toward PPARγ protein. The results obtained
showed that compounds 4d, 4e, and 4f possess good binding interaction
toward PPARγ with binding energy of À7.4, À7.2 and, À7.6 k.cal/mol which
was greater than standard rosiglitazone (À6.4 k.cal/mol) and comparable to
that of standard pioglitazone (À7.9 k.cal/mol). In vitro α-amylase and
α-glucosidase assays were performed for hypoglycemic activity evaluation. The
compounds 4e and 4f at a concentration of 100 μg/ml showed 82.13% and
2
Department of Chemistry, Arignar Anna
Government Arts College for women,
Walajapet, Vellore, Tamilnadu, India
Correspondence
Gangadhara Angajala, Department of
Chemistry, Kalasalingam Academy of
Research and Education, Anand nagar,
Krishnankoil-626126, Tamilnadu, India.
Email: gangadharaangajala@gmail.com
Funding information
VIT University; Kalasalingam Academy of
Research and Education
83.26% inhibition toward α-glucosidase, 78.30% and 84.18% inhibition toward
α-amylase which was higher than standard pioglitazone and on par to that of
rosiglitazone and acarbose.
K E Y W O R D S
hypoglycemic, molecular docking, nano copper, PPARγ, quinoline, thiobarbituric acid,
visible light
1
| INTRODUCTION
become important compounds because of their variety of
applications in medicinal, synthetic organic chemistry as
Quinolines scaffold has become an important motif
among various heterocycles with interesting biological
properties. In recent years quinoline and its congeners
have attracted synthetic medicinal chemists because of
their prevalence in a variety of natural and pharmacolog-
ically active synthetic compounds [1–4]. Quinolines have
well as in the field of industrial chemistry [5–9]. Quino-
line nucleus is endowed with a variety of therapeutic
activities and new quinolone derivatives are known to be
biologically active compounds possessing several phar-
macological activities being used as antimalarial [10–12],
antiviral [13,14], anti-inflammatory [15,16], antiprotozoal
J Heterocyclic Chem. 2021;1–15.
wileyonlinelibrary.com/journal/jhet
© 2021 Wiley Periodicals LLC.
1

2
ANGAJALA ET AL.
[
17–19], antibacterial [20–22], antineoplastic [23,24],
associated with quinoline molecule we consider the
thiobarbituric acid and quinoline moieties as candidate
scaffolds for the synthesis of new therapeutic hypogly-
cemic agents for type-II diabetes (Figure 2).
antioxidant [25,26], antifungal [27,28], analgesic [29,30],
cardiovascular [31], and hypoglycemic agent [32,33].
Considering the noteworthy applications in the fields of
bioorganic, medicinal, industrial, and synthetic organic
chemistry there has been remarkable interest in develop-
ing established protocols for their construction and effec-
tive methods for the synthesis of quinolines [34–38].
Similarly, barbituric acid derivatives have shown tre-
mendous attention in the field of medicine due to their
potential pharmacological activity over the past few
decades [39]. Barbiturates one of the most interesting
derivatives of pyrimidines comprise an important valu-
able group of synthetic compounds particularly effective
on the central nervous system [40]. Thiobarbiturates are
considered as active agonists toward PPARγ protein
Discovery and application of new reagents and reac-
tions has always been the most fascinating aspect of syn-
thetic organic chemistry. Development of novel synthetic
methodologies offers a great challenge for organic chem-
ists. In recent years, nano catalysis has received signifi-
cant attention in organic chemistry because of their
greater selectivity, enhanced reaction rates, simple work-
up and recoverability of catalysts [48–51]. The application
of nano sized catalysts in heterogeneous organic synthe-
sis has numerous advantages such as safe handling, high
atom efficiency, shorter reaction time, easy recovery, and
recyclability of the catalysts [52–54]. Also, multi-
component reactions (MCRs) have emerged as a success-
ful tool that helps blending the economic aspects with
the environmental ones [55,56]. Both metal nanoparticles
and MCRs have manifested themselves as synthetic strat-
egies for the rapid introduction, expansion of molecular
diversity, and even broaden the scope of combinatorial
chemistry [57–59].
[
41,42]. In the field of molecular biology, peroxisome
proliferator activated receptors (PPARs) constitutes an
important group known as nuclear receptor proteins
which involve in regulating the expression of genes
[
43,44] cellular differentiation, metabolism of carbohy-
drates, lipid, protein as well as tumor genesis in case of
higher organisms (Figure 1) [45–47]. Thus PPARγ is con-
sidered to play a dual role as possible molecular target in
the treatment of cancer and diabetes.
Literature search reveals that only little amount of
work has been published on the condensation reaction
of quinoline and thiobarbituric acid derivatives. Keep-
ing in view of the affinity of thiobarbituric derivatives
with PPARγ receptor and various biological activities
In synthetic organic chemistry, Knoevenagel conden-
sation is considered as one of the common significant
and extensively followed methods for the construction of
carbon–carbon double bond [60–62]. As a result of their
significance, enormous number of methods have been
reported for Knoevenagel condensation employing vari-
ous bases [63,64] Lewis acids [65–67] modified inorganic
FIGURE 1 Binding of
ligand to the PPARγ and the
observed cascade

ANGAJALA ET AL.
3
solids [68–71] amino acids [72] ionic liquids [73]
palladium-nickel nanoparticles [74] and dendritic copper
powder as catalysts [75]. In addition to this, a new light
mediated Knoevenagel condensation has also been
reported in literature by using aqueous ethanol [76]. It is
important to notice that all these procedures have some
disadvantages, such as the utilization of costly catalyst,
disposal of toxic solvents and catalyst, high temperature
conditions, more reaction time frequently generates a
problem. The present work was mainly focused to
explore the feasibility of copper nano catalyst as an eco-
friendly, inexpensive- and effective catalyst for one pot
three component synthesis of new quinoline scaffold
derived thiobarbiturates through Knoevenagel condensa-
tion and N-alkyaltion.
2 | RESULTS AND DISCUSSION
The outline for the preparation of quinoline substituted
thiobarbiturates 4a-i is illustrated in Figure 3. The com-
pounds were prepared by the Knoevenagel condensation
of various 2-chloroquinoline-3-carbaldehyde, 1a-i
thiobarbituric acid, 2 and their N-alkylation with chlo-
roacetic anhydride, 3 in the presence of CuNPs as a cata-
lyst under irradiation with tungsten lamp by using
ethanol as a solvent medium. As discussed earlier the
efficiency of heterogenous catalysis can be improved by
employing metal nanoparticles which efficiently cata-
lyzes various organic transformations.
FT-IR spectrum of CuNPs shows the presence of
À1
broad band appeared at 3446.79 cm which shows the
presence of OH functional groups. Besides high surface
to volume ratio, the surface functional hydroxyl groups of
the copper nano catalyst (50–100 nm) derived from aque-
ous leaf extract of Aegle marmelos Correa expected to
play a dominant role in the synthesis of quinoline
substituted thiobarbiturates (see Figure 4).
Hence keeping these facts in mind, our work was initially
started with the optimization of the reaction conditions with
various concentrations of CuNPs as a catalytic medium by
taking (Z)-2-(3-(2-[2-chloroacetoxy]-2-oxoethyl)-5-([2-chloro
quinoline-3-yl]methylene)-4,6-dioxo-2-thioxotetrahydro
pyrimidin-1(2H)-yl)acetic 2-chloroacetic anhydride, 4a
as a model example which was synthesized by the
Knoevenagel condensation of 2-chloroquinoline-
3
-carbaldehyde, 1a with thiobarbituric acid, 2 followed
by N-alkylation in presence of chloroacetic anhydride,
as alkylating agent. The compound 4a was confirmed
3
1
from H NMR spectra which displays 5 protons in the
aromatic region and the peak centered at δ 7.27 ppm
signifies olefenic proton of the condensed product. The
four methylene protons of the N-alkylated product
FIGURE 2 Quinoline substituted thiobarbituric acid
derivatives as potential hypoglycemic agents
FIGURE 3 Synthesis of new quinoline substituted thiobaribiturates 4a-i

4
ANGAJALA ET AL.
appear assinglets at δ 3.46 and δ 3.22 ppm respectively.
absence of copper nano catalyst. After screening
the catalytic effect the reaction was further elucidated for
the role of solvents. During the progress of the reaction,
the most significant property of solvent molecules is its
ability to respond to the changes connected with charges
and their equivalent distribution. From the results it has
been found that CuNPs catalyzed Knoevenagel condensa-
tion followed by N-alkylation in high yields in the pres-
ence of ethanol as a solvent medium (see Table 2).
1
3
The C NMR spectrum of compound 4a revealed
2 carbons in which the C S of thiobarbituric acid
displayed peak at 197.45 ppm and the peaks at 172.54,
67.26, 163.71 ppm related to carbonyl groups. In addi-
2
1
tion, the compound 4a was affirmed by HRMS, which
showed the molecular ion peak at m/z 584.9530 (see,
Figure S1–S3 in supporting information).
In order to evaluate scope and limitation of the reac-
tion the catalytic effect of CuNPs under visible light in
the synthesis of compound 4a were explored. The loading
of the CuNPs was varied and optimized as 10 mol% to
afford the corresponding product 4a in 92% yield
deprived of any side products (see Table 1). However,
there is no increment in the product yield on further
increase in the concentration of the catalyst. The reaction
did not proceed even at a longer reaction time in the
Considering the optimized reaction conditions in
hand, the scope of the protocol was further monitored for
the reaction of variety of bases. The effect of bases in the
synthesis product 4a was monitored and compared with
that of CuNPs (Table 3). The results obtained gives a
clear idea that when compared to bases, CuNPs gave bet-
ter yields with shorter reaction time (60 min) toward the
formation of 4a. The three component approach through
Knoevenagel condensation reaction followed by N-
alkylation was efficiently carried out with high selectivity
by CuNPs as a catalyst under reflux condition with etha-
nol as a solvent has been chosen for further study. After
the completion of the reaction, the catalyst was filtered
off from the reaction mixture and thoroughly washed
ꢀ
with hot ethanol and water, dried, and activated at 250 C
for 3 h.
Finally, the possibility of recycling CuNPs was exam-
ined
on
the
reaction
of
2-chloroquinoline-
3-carbaldehyde, 1a with thiobarbituric acid, 2 in presence
of chloroacetic anhydride, 3 as alkylating agent to afford
Knoevenagel condensed, N-alkylated product. The cop-
per nanocatalyst was recovered successfully with recov-
ery percentage of 99%, 99%, 98%, 95%, and 92%
respectively for five cycles. Similarly, the recovered nano
catalyst reused as such for subsequent experiments up to
five cycles under similar reaction conditions. It was
observed that the isolated yields of the product were
FIGURE 4 FT-IR spectrum of biosynthesized CuNPs
(
50–100 nm)
b
TABLE 1 Effect of catalyst
S. no
Catalyst (Mol %)
Mode of reaction
Visible light
Visible light
Visible light
Visible light
Visible light
Visible light
Room temp stirring
Reflux
Time (min)
Yield (%)
a
concentration in the synthesis of 4a
1
2
3
4
5
6
7
8
9
2.5
320
250
125
60
38
54
70
92
92
92
85
78
15
5.0
7.5
10.0
12.5
15.0
15.0
15.0
No catalyst
60
60
180
220
360
Visible light
a
Reaction conditions: 2-chloroquinoline-3-carbaldehyde 1a (1 mmol), thiobarbituric acid, 2 (1 mmol),
Chloroacetic anhydride, 3 (2 mmol), CuNPs (50–100 nm), Ethanol.
b
Isolated yield.

ANGAJALA ET AL.
5
a
TABLE 2 Influence of solvent in the synthesis of 4a
similar and remained with no noticeable loss until the
fifth recycling, 92%, 92%, 92%, 90%, and 88% (see
Figure 5). In addition, the morphology of the CuNPs
remains unaffected thus showing recyclability and reus-
ability of the copper nano catalyst in the synthesis of
products 4a-4i without any considerable loss in the cata-
lytic activity (Figure 6).
b
S. no
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
Acetonitrile
Tetrahydrofuran
Ethanol
73
76
92
70
75
34
72
83
10
17
Dichloromethane
DCM
Energy dispersive X-ray (EDX) analysis was used to
probe the composition of the copper nanoparticles. The
presence of copper nano catalyst was affirmed from
the energy bands positioned at 8 and 8.8 keV [K lines]
and 0.9 keV [L lines] respectively. The concentration of
oxygen and carbon atoms in the EDX analysis of copper
nano catalyst is very low before the starting of the reac-
tion. However, increased concentration of carbon and
oxygen atoms detected in EDX analysis of the recovered
catalyst was primarily due to the interaction with solvent
during the workup process and partial oxidation of the
catalyst during handling (see Figure 7A,B). The recovered
copper nano catalyst was further characterized by using
atomic force microscopy which clearly shows the irregu-
lar copper nanoparticles and the presence of
corresponding copper nano island (Figure 8). The results
obtained from molecular docking simulations of com-
pounds 4a-i with PPARγ protein displayed the effective
binding affinities of compound 4d, 4e, and 4f with bind-
ing energies of À7.4, À7.2, and À7.6 k.cal/mol which was
better than standard rosiglitazone (À6.4 k.cal/mol) and
comparable to that of standard pioglitazone (À7.9). The
compounds 4b, 4g, and 4i possess moderate binding
affinity with PPARγ receptor having binding energies
À6.4, À6.3, and À6.7 k.cal/mol (see Table 4, Figure 9A–
F, and 10A–E).
Acetone
Toluene
DMSO
2
H O
1
0
Solventless
a
Reaction conditions: 2-chloroquinoline-3-carbaldehyde 1a (1 mmol),
thiobarbituric acid, 2 (1 mmol), Chloroacetic anhydride, 3 (2 mmol), CuNPs
50–100 nm), Visible light (200 Watt).
(
b
Isolated yield.
a
TABLE 3 Effect of base in the synthesis of 4a
b
S. no
Base
Yield (%)
1
2
3
4
5
6
7
Piperidine
Pyridine
KOH
74
78
70
71
58
75
92
3
Et N
2 3
K CO
DIPEA
CuNPs
a
Reaction conditions: 2-chloroquinoline-3-carbaldehyde 1a (1 mmol),
thiobarbituric acid, 2 (1 mmol), Chloroacetic anhydride, 3 (2 mmol),
The results obtained from enzyme inhibition assays
toward hypoglycemic activity revealed that out of the
Ethanol.
b
Isolated yield.
FIGURE 5 Reusability of the
CuNPs (50–100 nm)

6
ANGAJALA ET AL.
FIGURE 6 Quinoline substituted thiobarbituric acid derivatives (4a-i)
FIGURE 7 (A) EDX analysis of copper nano catalyst (before reaction) (B) EDX analysis of copper nano catalyst (after reaction)
synthesized quinoline derivatives 4a-i compounds 4e and
f showed 82.13 ± 0.06 and 85.26 ± 0.02 percent inhibi-
tion toward α-glucosidase, 78.30 ± 0.82 and 84.19 ± 0.05
percent inhibition toward α-amylase which was greater
than standard pioglitazone (74.06 ± 0.07, 73.62 ± 0.05)
and comparable to Rosiglitazone (89.70 ± 0.66,
88.14 ± 0.12), Acarbose (91.26 ± 0.41, 90.05 ± 0.62) (see
Table 5, 6, Figure 11, and 12). The hypoglycemic efficacy
of compounds 4e and 4f could be attributed because of
the presence of halogens which increases the lipophilicity
4

ANGAJALA ET AL.
7
FIGURE 8 The
topographical images of the
recovered copper nano catalyst
TABLE 4 Binding affinity energies
S. no
Ligand
4a
Autodock score
À4.8
À6.4
À5.5
À7.4
À7.2
À7.6
À6.3
À6.1
Lipophilicity
À1.6
À2.2
À2.0
À3.0
À2.8
À3.3
À2.5
À1.2
Hydrophobicity
À0.6
À0.8
À1.2
À1.0
À0.5
À0.3
À1.0
À0.9
(
kcal/Mol) of compounds 4a-i
1
2
3
5
6
7
8
9
with PPARγ
4b
4c
4d
4e
4f
4g
4h
10
12
13
4i
À6.7
À6.4
À7.9
À1.4
À3.9
À4.5
À0.7
À0.5
À0.2
a
Std
b
Std
a
Rosiglitazone.
b
Pioglitazone.
of the compound. Halogens generally increase the ability
of molecules to interact with lipophilic unipolar media by
allowing stronger London forces. The lower efficacy of
the fluoro substituted quinoline derivative 4e when com-
pared to chloro substituted derivative 4f was primarily
attributed to the high electronegativity and low polariz-
ability of fluorine.
3.1.1 | Biosynthesis of copper nano
catalyst
The biosynthesis of copper nano catalyst (50–100 nm)
from Aegle marmelos Correa aqueous leaf extract was
reported in our previous work [77] [Figure 13].
3
.1.2 | General procedure for the
synthesis of (Z)-2-(3-(2-[2-chloroacetoxy]-
-oxoethyl)-5-([2-chloroquinolin-3-yl]
3
3
| EXPERIMENTAL
2
.1 | Materials and method
methylene)-4,6-dioxo-2thioxo-
tetrahydropyrimidin-1(2H)-yl)acetic2
chloro acetic anhydride, 4a
Reagents and solvents were sourced commercially from
Merck and Aldrich and used without further purification.
The H NMR and C NMR for compounds 4a-i were
1
13
In a round bottom flask a mixture of 2-chloroquinoline-
3-carbaldehyde 1a (1 mmol) which was synthesized
according to the reported method by Otto-Meth-Cohn
et al. [78] (Refer supporting data S1), thiobarbituric acid,
2 (1 mmol) and chloroacetic anhydride, 3 (2 mmol) was
taken. To this mixture catalytic amount of CuNPs
obtained using a Bruker Avance-400 MHz spectrometer in
CDCl solvent with Trimethylsilane (TMS) as the internal
3
standard and JEOL GC Mate-II was used to record HRMS
spectra. The UV–Visible spectra were recorded using
Schimadzu UV spectrophotometer, model UV-1800.

8
ANGAJALA ET AL.
FIGURE 9 Molecular docking simulations of quinoline derivatives 4a-i as hypoglycemic agents (A, B) the binding interaction of 4d
with PPARγ receptor (C, D) the binding interaction of 4e with PPARγ receptor (E, F) the binding interaction of 4f with PPARγ receptor
(10 mol %) was added and the whole mixture was irradi-
3.2 | Biological evaluation
ated with tungsten lamp (200 Watt) in the presence of
ethanol (6 ml) as a solvent. Upon reaction completion
3.2.1 | In silico molecular docking
studies
(TLC, Petroleum ether: Ethyl acetate, 3:1) the catalyst
was filtered off from the reaction medium. The solution
was decanted into the beaker and the precipitate was fil-
tered, dried, and further purified using column chroma-
tography to afford compound 4a.
The binding affinity of quinoline substituted
thiobarbiturates 4a-i with peptide PPARγ were calculated
by using Autodock.v.4.2 [79]. The protein structure

ANGAJALA ET AL.
9
FIGURE 10 Binding interactions of quinoline derivatives and standards with various amino acids of the PPARγ receptor in 2D
structural view (A) binding interactions of compound 4d (B) binding interactions of compound 4e (C) binding interactions of compound 4f
(
D) binding interactions of standard rosiglitazone (E) binding interactions of standard pioglitazone
PPARγ was retrieved from RCSB PDB (PDBID - 2XKW).
From Autodock vina under protein preparation, Gas-
teiger Partial charges and further Hydrogens were added.
The docking of ligand to PPARγ was focused on the spe-
cific binding site. The number rotatable bonds of the
ligands were calculated. The atomic affinity potential and
energy of interaction of each atom in the ligand was eval-
uated. The grid maps were defined to the binding site of
PPARγ by setting the configurations along X/Y/Z coordi-
nates. The Binding energies between receptor and the
ligands are attained in terms of Kcal/mol. The various
drug receptor interactions were analyzed using Accelrys
Discovery Studio Visualizer software.
per the previous reported methods by using α-amylase
[80] and α-glucosidase assays [81] (Refer supporting
information S1).
3.3 | Spectral data of the synthesized
compounds, (4a-i)
3.3.1 | (Z)-2-(5-([2-chloroquinolin-3-yl]
methylene)-3-(2-[2-chloroacetoxy]-
2-oxoethyl)-4,6-dioxo-
2-thioxotetrahydropyrimidin-1(2H)-yl)
acetic 2-chloroacetic anhydride, (4a)
ꢀ
Creamish white solid, 92.0% yield, mp 281–283 C. IR
À1
3.2.2 | In vitro hypoglycemic studies
(KBr
pellets,
cm
)
υ:
754.18,
1080.22,
1
1
105.981278.02, 1354.07, 1710.55, 3074.16. H NMR
In vitro hypoglycemic efficacy of the synthesized quino-
(CDCl , ppm, 400 MHz) δ: 3.22 (4H, s, 2 x CH ), 3.46
3
2
line substituted thiobarbiturates 4a-i were carried out as
(4H, s, 2 x CH ), 7.17–7.19 (1H, d, J = 7.2 Hz, CH ),
2
2

10
ANGAJALA ET AL.
TABLE 5 α-Glucosidase inhibitory efficacy of compounds (4a-i)
Concentration (μg/ml)
50
S. no
Compound
100
250
1
2
3
4
5
6
7
8
9
1
1
1
.
.
.
.
.
.
.
.
4a
4b
4c
4d
4e
4f
20.13 ± 0.16
28.15 ± 0.49
22.18 ± 0.11
17.05 ± 1.01
31.02 ± 0.15
35.04 ± 0.18
19.02 ± 0.42
21.47 ± 0.78
23.96 ± 0.15
29.06 ± 0.72
37.01 ± 0.05
39.21 ± 0.12
39.31 ± 0.78
45.01 ± 0.08
41.02 ± 1.32
25.01 ± 0.08
54.22 ± 1.05
52.07 ± 1.71
27.62 ± 0.55
30.18 ± 0.62
38.33 ± 0.20
47.21 ± 0.65
56.24 ± 0.76
58.72 ± 1.02
63.12 ± 0.04
68.95 ± 1.44
66.28 ± 0.09
40.31 ± 0.64
82.13 ± 0.06
85.26 ± 0.02
44.25 ± 0.19
49.84 ± 0.11
60.59 ± 0.24
74.06 ± 0.07
89.70 ± 0.66
91.26 ± 0.41
4g
4h
4i
a
0.
1.
2
Std1
b
Std2
c
Std3
a
Pioglitazone.
b
Rosiglitazone.
c
Acarbose.
TABLE 6 α-Amylase inhibitory efficacy of compounds (4a-i)
Concentration (μg/ml)
50
S. no
Compound
100
250
1
2
3
4
5
6
7
8
9
1
1
1
.
.
.
.
.
.
.
.
4a
4b
4c
4d
4e
4f
17.98 ± 0.13
18.17 ± 0.16
21.43 ± 1.66
24.71 ± 1.50
35.29 ± 0.17
39.70 ± 0.66
20.18 ± 0.72
19.40 ± 0.32
22.16 ± 0.15
28.11 ± 0.54
34.20 ± 0.40
37.08 ± 0.55
34.05 ± 0.28
37.24 ± 1.33
40.30 ± 1.27
43.20 ± 0.38
54.21 ± 1.44
57.71 ± 0.41
39.26 ± 0.30
38.67 ± 0.54
41.62 ± 0.20
46.44 ± 0.15
53.81 ± 0.29
56.04 ± 0.05
52.12 ± 0.11
56.14 ± 0.19
60.19 ± 0.34
65.25 ± 1.47
78.30 ± 0.82
84.19 ± 0.05
57.33 ± 0.63
56.87 ± 0.82
61.36 ± 1.04
72.06 ± 0.10
85.46 ± 0.63
88.14 ± 0.18
4g
4h
4i
a
0.
1.
2
Std1
b
Std2
c
Std3
a
Pioglitazone.
b
Rosiglitazone.
c
Acarbose.
7
7
.27 (1H, s, CH), 7.42–7.45 (2H, t, J = 6.8 Hz, CH),
.63–7.65 (1H, d, J = 7.6 Hz, CH), 8.09 (1H, s, CH).
3.3.2 | (Z)-2-(5-([2-chloro-
8-methylquinolin-3-yl]methylene)-
3-(2-[2-chloroacetoxy]-2-oxoethyl)-4,6-dioxo-
2-thioxotetrahydropyrim- idin-1(2H)-yl)
acetic 2-chloroacetic anhydride, (4b)
1
3
C NMR (CDCl , ppm, 100 MHz) δ: 32.48, 37.92,
3
1
1
1
16.35, 122.56, 124.83, 125.31, 126.12, 131.14, 133.48,
34.15, 136.51, 137.67, 141.81, 145.39, 147.20, 151.74,
+
63.71, 167.26, 172.54, 197.45. HRMS [EI ] Calcd for
+
ꢀ
C H Cl N O S
5
m/z
584.9567
[M ],
found
Pale yellow solid, 90% yield, mp 241 C. IR (KBr pellets,
2
2
14
3
3
8
+
À1
84.9530 [M ].
cm ) υ: 747.29, 1074.05, 1101.561272.47, 1348.10,

ANGAJALA ET AL.
11
FIGURE 11 α-Glucosidase inhibitory efficacy of quinoline bejeweled thiobarbiturates (4a-i)
FIGURE 12 α-Amylase inhibitory efficacy of quinoline bejeweled thiobarbiturates (4a-i)
1
1
2
705.14, 3077.28. H NMR (CDCl , ppm, 400 MHz) δ:
NMR (CDCl , ppm, 100 MHz) δ: 21.79, 35.63, 41.75,
3
3
.59 (3H, s, CH ), 3.45 (4H, s, 2 x CH ), 3.62 (4H, s, 2 x
109.22, 122.89, 124.78, 125.21, 128.05, 129.56, 133.65,
139.65, 143.12, 143.55, 146.93, 151.70, 166.14, 169.25,
3
2
CH ), 7.28 (1H, s, CH), 7.36–7.42 (1H, d, J = 6.4 Hz, CH),
2
+
7
.50–7.56 (1H, q, J = 4.4 Hz, CH), 7.68–7.69 (1H, d,
175.02, 201.29. HRMS [EI ] Calcd for C H Cl N O S
23
16
3 3 8
13
+
+
J = 4.8 Hz, CH), 7.92–7.93 (1H, d, J = 7.2 Hz, CH).
C
m/z 598.9724 [M ], found 598.9730 [M ].

12
ANGAJALA ET AL.
+
for C H Cl N O S m/z 612.9880 [M ], found
24
18
+
3 3 8
612.9835 [M ].
3
5
3
2
.3.5 | (Z)-2-(5-([2-chloro-
-fluoroquinolin-3-yl]methylene)-
-(2-[2-chloroacetoxy]-2-oxoethyl)-4,6-dioxo-
-thioxotetrahydro pyrimidin À1(2H)-yl)
acetic 2-chloroacetic anhydride, (4e)
ꢀ
White solid, 94.0% yield, mp 272 C. IR (KBr pellets,
À1
cm ) υ: 742.10, 1075.26, 1098.65, 1272.80, 1348.27,
1
1
706.14, 3078.10. H NMR (CDCl , ppm, 400 MHz) δ:
3
3
.61 (4H, s, 2 x CH ), 3.91 (4H, s, 2 x CH ), 7.45–7.47 (2H,
2
2
FIGURE 13 SEM image of the CuNPs (50–100 nm)
d, J = 8.0 Hz, CH), 7.60–7.65 (2H, t, J = 6.0 Hz, CH),
13
7.84–7.86 (1H, d, J = 7.6 Hz, CH). C NMR (CDCl3,
ppm, 100 MHz) δ: 39.68, 40.78, 122.24, 125.20, 126.94,
126.97, 127.83, 131.64, 134.17, 138.13, 140.46, 144.87,
146.05, 146.93, 151.23, 164.93, 169.10, 174.17, 201.53.
3
7
3
2
.3.3 | (Z)-2-(5-([2-chloro-
,8-dimethylquinolin-3-yl]methylene)-
-(2-[2-chloroacetoxy]-2-oxoethyl)-4,6-dioxo-
-thioxotetrahydro pyrimidin-1(2H)-yl)
+
HRMS [EI ] Calcd for C H Cl FN O S m/z 602.9473
2
2
13
3
3 8
+
+
[M ], found 602.9710 [M ].
acetic 2-chloroacetic anhydride, (4c)
ꢀ
Pale brown solid, 90.0% yield, mp 274–276 C. IR (KBr
3.3.6 | (Z)-2-(5-([2,5-dichloroquinolin-
3-yl]methylene)-3-(2-[2-chloroacetoxy]-
2-oxoethyl)-4,6-dioxo-2-thioxotetrahydro
pyrimidin-1(2H)-yl)acetic 2-chloroacetic
anhydride, (4f)
À1
pellets, cm ) υ: 748.25, 1075.44, 1102.071274.82, 1350.20,
708.71, 3072.06. H NMR (CDCl , ppm, 400 MHz) δ:
.38 (3H, s, CH ), 2.54 (3H, s, CH ), 3.62 (4H, s, 2 x CH ),
.91 (4H, s, 2 x CH ), 7.18–7.21 (1H, d, J = 6.2 Hz, CH),
.37 (1H, s, CH), 7.48 (1H, s, CH), 8.19 (1H, s, CH).
NMR (CDCl , ppm, 100 MHz) δ: 17.54, 21.34, 38.40,
2.64, 117.22, 121.72, 123.45, 124.83, 125.97, 132.69,
34.06, 135.27, 137.02, 138.15, 14,033, 146.49, 147.83,
1
1
2
3
7
3
3
3
2
2
13
C
ꢀ
Pale brown, 89.0% yield, mp 265–266 C. IR (KBr pellets,
3
À1
4
1
1
cm ) υ: 745.11, 1072.05, 1103.261270.18, 1345.24,
1
1708.16, 3075.22. H NMR (CDCl , ppm, 400 MHz) δ:
3
+
52.91, 165.04, 171.22, 176.43, 202.06. HRMS [EI ] Calcd
for C H Cl N O S m/z 612.9880 [M ], found
3.31 (4H, s, 2 x CH ), 3.79 (4H, s, 2 x CH ), 7.35–7.37 (1H,
2
2
+
d, J = 8.0 Hz, CH), 7.46–7.48 (1H, s, CH), 7.63–7.64 (2H,
2
4
18
3 3 8
+
13
6
12.9827 [M ].
d, J = 6.8 Hz, CH), 7.92 (1H, s, CH), 8.05–8.06. C NMR
(
CDCl , ppm, 100 MHz) δ: 39.27, 45.78, 110.22, 121.36,
3
125.01, 125.15, 125.29, 130.72, 133.41, 133.81, 140.05,
3
6
3
2
.3.4 | (Z)-2-(5-([2-chloro-
141.12, 144.52, 146.58, 147.24, 152.23, 167.32, 172.45,
+
,8-dimethylquinolin-3-yl]methylene)-
-(2-[2-chloroacetoxy]-2-oxoethyl)-4,6-dioxo-
-thioxotetrahydro pyrimidin-1(2H)-yl)
176.28, 202.22. HRMS [EI ] Calcd for C H Cl N O S
22
13
4 3 8
+
+
m/z 618.9177 [M ], found 618.9143 [M ].
acetic 2-chloroacetic anhydride, (4d)
3
.3.7 | (Z)-2-(5-([2-chloro-
ꢀ
Off white solid, 88.0% yield, mp 257–258 C. IR (KBr pel-
6-methylquinolin-3-yl]methylene)-
À1
lets, cm ) υ: 745.38, 1072.61, 1101.77, 1275.81, 1348.15,
3-(2-[2-chloroacetoxy]-2-oxoethyl)-4,6-dioxo-
2-thioxotetrahydro pyrimidin-1(2H)-yl)
acetic 2-chloroacetic anhydride, (4g)
1
1
2
3
7
710.03, 3062.84. H NMR (CDCl , ppm, 400 MHz) δ:
3
.21 (3H, s, CH ), 2.75 (3H, s, CH ), 3.38 (4H, s, 2 x CH ),
3
3
2
.60 (4H, s, 2 x CH ), 7.13–7.15 (1H, d, J = 7.6 Hz, CH),
2
1
3
ꢀ
.30 (1H, s, CH), 7.43 (1H, s, CH), 8.02 (1H, s, CH).
C
Light yellow solid, 92% yield, mp 269 C. IR (KBr pellets,
cm ) υ: 756.18, 1078.04, 1106.10, 1276.22, 1346.02,
1710.11, 3074.19. H NMR (CDCl , ppm, 400 MHz) δ:1.72
(3H, s, CH ), 3.69 (4H, s, 2 x CH ), 4.10 (4H, s, 2 x CH ),
À1
NMR (CDCl , ppm, 100 MHz) δ: 17.92, 22.48, 37.66,
3
1
4
1
1
1.48, 116.35, 122.56, 124.83, 125.31, 126.12, 131.14,
33.48, 134.15, 136.51, 137.67, 141.81, 145.39, 147.20,
51.74, 164.65, 170.89, 175.59, 201.44. HRMS [EI ] Calcd
3
3
2
2
+
7.18 (1H, s, CH), 7.52 (1H, s, CH), 7.64 (1H, s, CH), 7.72–

ANGAJALA ET AL.
13
1
3
7
(
.73 (1H, d, J = 4.4 Hz, CH), 8.24 (1H, s, CH). C NMR
substituted thiobarbituric acid derivatives. The outstand-
ing reusability of the catalyst and operational simplicity
and high yields are among the other added advantages
that make this protocol an attractive alternative route for
the synthesis of target hypoglycemic agents. The synergis-
tic effect of both quinoline and N-alkylated thiobarbituric
acid further enhances the hypoglycemic efficacy of the
final target molecules 4a-i. The increase in lipophilicity
of the compounds 4e, 4f was mainly responsible for
showing good hypoglycemic efficacy.
CDCl , ppm, 100 MHz) δ: 20.52, 34.70, 42.91, 110.51,
21.47, 123.18, 124.10, 129.42, 130.67, 134.71, 140.11,
43.83, 144.07, 147.22, 152.19, 167.26, 170.48, 176.32,
3
1
1
2
5
+
02.18. HRMS [EI ] Calcd for C H Cl N O S m/z
23
16
3 3 8
+
+
98.9724 [M ], found 598.9745 [M ].
3
6
3
-
(
.3.8 | (Z)-2-(5-([2-chloro-
-methoxyquinolin-3-yl]methylene)-
-(2-[2-chloroacetoxy]-2-oxoethyl)
4,6-dioxo-2-thioxotetrahydro pyrimidin-1
2H)-yl)acetic 2-chloroacetic
anhydride, (4h)
ACKNOWLEDGMENTS
The authors sincerely thank the management of
Kalasalingam Academy of Research and Education and
VIT University, Tamil Nadu, India for their constant
encouragement and support and providing all the neces-
sary facilities for carrying out this research work. The
authors also thank DST-VIT-FIST, SIF-VIT for carrying
out NMR analysis.
ꢀ
Pale brown solid, 88.0% yield, mp 258 C. IR (KBr pellets,
cm ) υ: 756.18, 1078.84, 1105.42, 1276.04, 1354.22,
710.90, 3074.03. H NMR (CDCl , ppm, 400 MHz) δ: δ:
.61 (3H, s, OCH ), 4.38 (4H, s, 2 x CH ), 4.65 (4H, s, 2 x
À1
1
1
3
3
3
2
CH ), 7.44–7.50 (1H, q, J = 6.4 Hz, CH), 7.52–7.54 (2H, d,
2
J = 8.0 Hz, CH), 7.73 (1H, s, CH), 7.91–7.93 (1H, d,
CONFLICT OF INTEREST
The authors declare no conflict of interest.
13
J = 9.2 Hz, CH2). C NMR (CDCl , ppm, 100 MHz) δ:
3
3
1
1
8.22, 40.78, 55.66, 105.10, 122.92, 124.74, 125.10, 128.00,
29.52, 133.61, 139.59, 143.17, 143.50, 146.97, 158.67,
DATA AVAILABILITY STATEMENT
Data available in article supplementary material.
+
67.01, 173.62, 178.77, 200.37. HRMS [EI ] Calcd for
+
C H Cl N O S
6
m/z
614.9673
[M ],
found
2
2
16
3 3 9
+
14.2343 [M ].
ORCID
Gangadhara Angajala https://orcid.org/0000-0001-
5
065-5329
3
8
3
.3.9 | (Z)-2-(5-([2-chloro-
-methoxyquinolin-3-yl]methylene)-
-(2-[2-chloroacetoxy]-2-oxoethyl)
REFERENCES
[
1] R. D. Larsen, E. G. Corley, A. O. King, J. D. Carrol, P. Davis,
T. R. Verhoeven, P. J. Reider, M. Labelle, J. Y. Gauthier, Y. B.
Xiang, R. J. Zamboni, J. Org. Chem. 1996, 61, 3398.
-
4,6-dioxo-2-thioxotetrahydro pyrimidin-1
2H)-yl)acetic 2-chloroacetic anhydride, (4i)
(
[
2] Y. L. Chen, K. C. Fang, J. Y. Sheu, S. L. Hsu, C. C. Tzeng,
J. Med. Chem. 2001, 44, 2374.
ꢀ
White solid, 90.0% yield, mp 267–269 C. IR (KBr pellets,
À1
[
3] G. Roma, M. D. Braccio, G. Grossi, F. Mattioli, M. Ghia, G.
Roma, M. D. Braccio, G. Grossi, F. Mattioli, M. Ghia, Eur.
J. Med. Chem. 2000, 35, 1021.
cm ) υ: 752.19, 1074.62, 1108.05, 1274.92, 1352.72,
712.48, 3082.65. H NMR (CDCl , ppm, 400 MHz) δ:
.24 (3H, s, OCH ), 4.18 (4H, s, 2 x CH ), 4.37 (4H, s, 2 x
1
1
3
3
3
2
[
[
4] P. M. S. Chauhan, S. K. Srivastava, Curr. Med. Chem. 2001, 8, 1535.
5] M. I. Anderson, A. P. MacGowan, J. Antimicrob. Chemoth.
CH ), 7.52–7.58 (1H, q, J = 7.2 Hz, CH), 7.63–7.65 (2H, d,
2
J = 6.4 Hz, CH), 7.82 (1H, s, CH), 7.95–7.97 (1H, d,
2003, 51, 1.
13
J = 8.0 Hz, CH2). C NMR (CDCl , ppm, 100 MHz) δ:
3
[6] H. I. Abd-Alla, M. Shaaban, K. A. Shaaban, N. S. Abu-Gabal,
N. M. Shalaby, H. Laatsch, Nat. Pro. Res. 2009, 23, 1035.
[7] K. Goto, K. Yabe, T. Suzuki, T. Jindoa, A. Sanbuissho, Toxicol-
ogy 2010, 276, 122.
[8] P. M. Hawkey, J. Antimicrob. Chemoth. 2003, 51, 29.
[
3
1
1
7.18, 41.62, 56.72, 104.28, 121.83, 123.90, 124.09, 127.25,
30. 19, 132.48, 140.36, 142.68, 144.72, 147.10, 159.03,
+
68.15, 174.18, 176.98, 201.62. HRMS [EI ] Calcd for
+
C H Cl N O S m/z 614.9673 [M ], found 614.2362.
22
16
3 3 9
9] M. Malik, G. Hoatam, K. Chavda, R. J. Kerns, K. Drlica, Anti-
Conclusion.
microb. Agents Chemother. 2010, 54, 149.
An ecofriendly protocol has been developed for the
synthesis of quinoline substituted thiobarbiturates
through Knoevenagel condensation and N-alkylation by
using copper nano catalyst under visible light. The pre-
sent work explores a highly efficient and environmental
friendly approach for the preparation of quinoline
[
[
10] K. Raynes, M. Foley, L. Tilley, L. W. Deady, Biochem.
Pharmacol. 1996, 52, 551.
11] L. C. S. Pinheiro, L. M. Feitosa, M. O. Gandi, F. F. Silveria, N.
Boechat, Molecules 2019, 24, 4095.
[12] T. Herraiz, H. Guillen, D. Gonzalez-Pena, V. J. Aran, Sci. Rep.
019, 9, 15398.
2

14
ANGAJALA ET AL.
[
13] J. Ghosh, V. Swarup, A. Saxena, S. Das, A. Hazra, P. Paira, S.
[38] M. Matsugi, F. Tabusa, J. Minamikawa, Tetrahedron Lett.
2000, 41, 8523.
Banerjee, N. B. Mondal, A. Basu, Int. J. Antimicrob. Agents
2
008, 32, 349.
[39] H. Zheng, S. Li, L. Ma, L. Cheng, C. Deng, Z. Chen, C. Xie, M.
Xiang, W. Jiang, L. Chen, Eur. J. Pharmacol. 2011, 659, 244.
[40] J. H. Gardener, F. H. Bopp, R. F. Prindle, J. Am. Chem. Soc.
1946, 68, 585.
[41] A. Barakat, S. M. Soliman, Y. A. M. M. Elshaier, M. A.
Abdullah, M. Al-Majid, H. A. Ghabbour, J. Mol. Struct. 2017,
1134, 99.
[
[
[
[
14] C. D. L. Guardia, D. E. Stephens, H. T. Dang, M. Quijada,
O. V. Larionov, R. Lleonart, Molecules 2018, 23, 672.
15] Y. Chen, Y. Zhao, C. Lu, C. Tzeng, J. P. Wang, Bioorg. Med.
Chem. 2006, 14, 4373.
16] S. K. Gupta, A. Mishra, Antiinflamm. Antiallergy Agents Med.
Chem. 2016, 15, 31.
17] A. Fournet, A. A. Barrios, V. Munoz, R. Hocquemiller, A.
Cave, J. Bruneton, Antimicrob. Agents Chemother. 1993,
[42] V. A. Dixit, P. C. Rathi, S. Bhagat, H. Gohlke, R. K. Petersen,
K. Kristiansen, A. K. Chakraborti, P. V. Bharatam, Eur. J. Med.
Chem. 2016, 108, 423.
3
7, 859.
[
[
[
18] P. Hochegar, J. Faist, W. Seebacher, R. Saf, P. Maser, M.
[43] K. Yu, W. Bayona, C. B. Kallen, H. P. Harding, C. P. Ravera,
G. McMahon, M. Brown, M. A. Lazar, J. Biol. Chem. 1995, 270,
23975.
[44] J. Berger, D. E. Moller, Annu. Rev. Med. 2002, 53, 409.
[45] J. N. Feige, L. Gelman, L. Michalik, B. Desvergne, W. Wahli,
Prog. Lipid Res. 2006, 45, 120.
Kaiser, R. Weis, Med. Chem. 2019, 15, 409.
19] E. Garcia, J. C. Coa, E. Otero, M. Carda, I. D. Velez, S. M.
Robledo, W. I. Cardona, Med. Chem. Res. 2018, 27, 497.
20] J. P. Sanchez, J. M. Domagala, S. E. Hagen, C. L. Heifetz,
M. P. Hutt, J. B. Nichols, A. K. Trehan, J. Med. Chem. 1988,
3
1, 983.
[46] C. Janani, B. D. Ranjitha Kumari, Diabetes Metab. Syndr. Clin.
Res. Rev. 2014, 9, 46.
[
21] D. Insuasty, O. Vidal, A. Bernal, E. Marguez, J. Guzman, B.
Insuasty, J. Quiroga, L. Svetaj, S. Zacchino, G. Puerto, R.
Abonia, Antibiotics 2019, 8, 239.
22] T. D. M. Pharm, Z. M. Ziora, M. A. T. Blaskovich, Med. Chem.
Commun. 2019, 10, 1719.
23] D. A. Scott, C. L. Balliet, D. J. Cook, A. M. Davies, T. W. Gero,
C. A. Omer, S. Poondru, M. E. Theoclitou, B. Tyurin, M. J.
Zinda, Bioorg. Med. Chem. Lett. 2009, 19, 697.
24] M. R. Selim, M. A. Zahran, A. Belal, M. S. Abusaif, S. A.
Shedid, A. B. M. Mehany, G. A. M. Elhagali, Y. A. Ammar,
Anti-Cancer Agents Med. Chem. 2019, 19, 439.
[47] S. Yasmin, V. Jayaprakash, Eur. J. Med. Chem. 2017, 126, 879.
[48] A. Maleki, R. Firouji-Haji, Sci. Rep. 2018, 8, 17303.
[49] A. Corma, H. Garcia, Catal. Today 1997, 38, 257.
[50] S. K. Sikdar, S. G. J. Howell, J. Clean. Product. 1998, 6, 253.
[51] L. Liu, A. Corma, Chem. Rev. 2018, 118, 4981.
[52] G. Angajala, R. Subashini, RSC Adv. 2015, 5, 45599.
[53] G. M. Whitesides, Nat. Biotechnol. 2003, 21, 1161.
[54] R. Narayanan, M. A. El-Sayed, J. Am. Chem. Soc. 2004, 126,
7194.
[
[
[
[55] A. R. Kiasat, S. Noorizadeh, M. Ghahremani, S. F. saghanejad,
J. Mol. Struct. 2013, 1036, 216.
[
[
[
25] R. Subashini, G. Angajala, K. Aggile, F. Nawaz khan, Res.
Chem. Intermed. 2014, 41, 4899.
26] K. Douadi, S. Chafaa, T. Douadi, M. Al-Noaimi, J. Mol. Struct.
[56] A. V. Artemev, N. K. Gusarova, I. Y. Bagryanskaya, E. P.
Doronina, S. I. Verkhoturova, V. F. Sidorkin, B. A. Trofimov,
Eur. J. Inorg. Chem. 2013, 2013, 415.
[57] K. D. Bhatte, K. M. Deshmukh, Y. P. Patil, D. N. Sawant, S. I.
Fujita, M. Arai, B. M. Bhanage, Particuology 2012, 10, 140.
[58] I. Ban, J. Sterger, M. Drofenic, G. Ferk, D. Makovec, J. Magn.
Magn. Mater. 2011, 323, 2254.
[59] X. Zhao, L. Wei, S. Cheng, J. Julson, Catalysts 2017, 7, 83.
[60] E. Knoevenagel, Eur. J. Inorg. Chem. 1894, 2, 2345.
[61] E. Knoevenagel, Eur. J. Inorg. Chem. 1898, 31, 2585.
[62] G. Jones, Org. React. 1967, 15, 204.
[63] L. F. Tietze, U. Beifuss, The Knoevenagel Reaction. in Compre-
hensive Organic Synthesis (Ed: B. M. Trost), Pergamon Press,
Oxford, UK 1991, p. 341.
[64] B. F. Texier, A. Foucaud, Tetrahedron Lett. 1982, 23, 4927.
[65] G. Bartoli, M. Bosco, A. Carlone, R. Dalpozzo, P. Galzerano, P.
Melchiorre, L. Sambri, Tetrahedron Lett. 2008, 9, 2555.
[66] J. Barluenga, L. Riesgo, R. Vicente, L. A. Lopez, M. Tomas,
J. Am. Chem. Soc. 2007, 129, 7772.
[67] J. S. Yadav, B. V. Subbareddy, D. N. chary, C. Madavi, A. C.
Kunwar, Tetrahedron Lett. 2009, 50, 81.
[68] T. I. Reddy, R. S. Varma, Tetrahedron Lett. 1997, 38, 1721.
[69] S. Shanmuganathan, L. Greiner, D. M. P. Dominguez, Tetrahe-
dron Lett. 2010, 51, 6670.
2
020, 1217, 128305.
27] A. R. Gholap, K. S. Toti, F. Shirazi, R. Kumari, M. K. Bhat,
M. V. Deshpande, K. V. Srinivasan, Bioorg. Med. Chem. 2007,
1
5, 6705.
[
28] G. Z. Yang, J. K. Zhu, X. D. Yin, Y. F. Yan, Y. L. Wang, X. F.
Shang, Y. Q. Liu, Z. M. Zhao, J. W. Peng, H. Liu, J. Agric. Food
Chem. 2019, 67, 11340.
[
[
[
29] A. H. Abadi, G. H. Hegazy, A. A. E. Zaher, Bioorg. Med. Chem.
2
005, 13, 5759.
30] A. Manikandan, S. Ravichandran, K. I. Sathiyanarayanan, A.
Sivakumar, Inflammopharmacology 2017, 25, 621.
31] R. C. Bernotas, R. R. Singhaus, D. H. Kaufman, J. Ullrich, H.
Fletcher, E. Quinet, P. Nambi, R. Unwalla, A. Wilhelmsson,
A. G. Nilsson, M. Farnegardh, J. Wrobel, Bioorg. Med. Chem.
2
009, 17, 1663.
[
[
[
32] D. Edmont, R. Rocher, C. Plisson, J. Chenault, Bioorg. Med.
Chem. Lett. 2000, 10, 1831.
33] H. W. Lee, J. Y. Yang, H. S. Lee, J. Korean Soc. Appl. Biol.
Chem. 2014, 57, 441.
34] M. Z. Hoemann, G. Kumaravel, R. L. Xie, R. F. Rossi, S.
Meyer, A. Sidhu, G. D. Cuny, J. R. Hauske, Bioorg. Med. Chem.
Lett. 2000, 10, 2675.
[
35] V. V. Kouznetsov, L. Y. V. Mendez, C. M. M. Gomez, Curr.
Org. Chem. 2005, 9, 141.
[70] L. Yang, J. Zhu, F. Xie, X. Peng, B. Lin, Y. Liu, M. Cheng, Russ.
J. Org. Chem. 2019, 55, 1053.
[
[
36] F. Xiao, Y. Chen, Y. Liu, J. Wang, Tetrahedron 2008, 64, 2755.
37] P. G. Dormer, K. K. Eng, R. N. Farr, G. R. Humphrey, J. C.
McWilliams, P. J. Reider, J. W. Sager, R. P. Volante, J. Org.
Chem. 2003, 68, 467.
[71] G. Angajala, V. Aruna, R. Subashini, J. Mol. Struct. 2020, 1220,
128601.
[72] H. Ying, Z. Guan, Y. H. He, N. Louwagie, M. J. Yao, J. Chem.
Res. 2010, 34, 22.

ANGAJALA ET AL.
15
[
[
73] B. C. Ranu, R. Jana, Eur. J. Org. Chem. 2006, 16, 3767.
74] N. Lolak, E. Kuyuldar, H. Burhan, H. Goksu, S. Akocak, F.
Sen, ACS Omega 2019, 4, 6848.
75] E. M. Schneider, M. Zeltner, N. Kranzlin, R. N. Grass, W. J.
Stark, Chem. Commun. 2015, 51, 10695.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
[
[
[
[
76] S. Ghosh, J. Das, S. Chattopadhyay, Tetrahedron Lett. 2011, 52, 2869.
77] G. Angajala, P. Pavan, R. Subashini, RSC Adv. 2014, 4, 51459.
78] Otto-Meth-Cohn, B. Narine, B. Tarnowski, J. Chem. Soc.
Perkin. 1981, 1, 1520.
How to cite this article: Angajala G, Aruna V,
Subashini R. Visible light induced nano copper
catalyzed one pot synthesis of novel quinoline
bejeweled thiobarbiturates as potential
hypoglycemic agents. J Heterocyclic Chem. 2021;
1–15. https://doi.org/10.1002/jhet.4271
[
79] G. M. Morris, R. Huey, W. Lindstrom, M. F. Sanner, R. K. Belew,
D. S. Goodsell, A. J. Olson, J. Comput. Chem. 2009, 16, 2785.
80] C. P. Malik, M. B. Singh, Ludiana 1980, 39, 65.
81] S. Krishnaveni, B. Theymoli, S. Sadasivam, Food Chem. 1984,
[
[
1
5, 229.