A meglumine catalyst–based synthesis, molecular docking, and antioxidant studies of dihydropyrano[3, 2-b]chromenedione derivatives

Article abstract of DOI:10.1002/jhet.3786

A simple method was employed for the synthesis of dihydropyrano[3, 2-b]chromenedione derivatives (4a-o) in high yields by condensation of 5, 5-dimethylcyclohexane-1, 3-dione(1), different aromatic aldehydes (2a-o), and 5-hydroxy-2-(hydroxymethyl)-4H-pyran

Full text of DOI:10.1002/jhet.3786

Received: 15 July 2019
DOI: 10.1002/jhet.3786
Revised: 27 September 2019
Accepted: 7 October 2019
A R T I C L E
A meglumine catalyst–based synthesis, molecular docking,
and antioxidant studies of dihydropyrano[3, 2‐b]
chromenedione derivatives
G. Sravya1
| G. Suresh2 | Grigory V. Zyryanov1,3 | A. Balakrishna4 |
K. Madhu Kumar Reddy5 | C. Suresh Reddy5
N. Bakthavatchala Reddy1
| C. Venkataramaiah6 | W. Rajendra6 |
1 Chemical Engineering Institute, Ural
Abstract
Federal University, Yekaterinburg,
A simple method was employed for the synthesis of dihydropyrano[3, 2‐b]
chromenedione derivatives (4a‐o) in high yields by condensation of 5, 5‐
dimethylcyclohexane‐1, 3‐dione(1), different aromatic aldehydes (2a‐o), and
5‐hydroxy‐2‐(hydroxymethyl)‐4H‐pyran‐4‐one(3), using meglumine as a stable
and reusable catalyst. Meglumine, an amino sugar, was employed as an envi-
ronmentally benign catalyst, due to its splendid properties such as being inex-
pensive, recyclable, and biodegradable. The accomplished protocol employs
low catalyst loading and easy work‐up for the synthesis of 5‐hydroxy‐2‐
(hydroxymethyl)‐4H‐pyran‐4‐one derivatives. A great asset is that without
any significant loss, the catalyst could be recovered and reused for extended
synthetic steps. This offer huge advantage to overcome recyclability issues.
Russian Federation
2 Anhui Provincial Engineering
Technology Research Centre of New
silicon‐based materials, Bengbu
University, Caoshan Road, 1866 Bengbu,
Anhui, China
3 I. Ya. Postovskiy Institute of Organic
Synthesis, Ural Division of the Russian
Academy of Sciences, 22 S. Kovalevskoy
Street, Yekaterinburg, Russian Federation
4 Chemistry Department, Rajeev Gandhi
Memorial College of Engineering and
Technology (Autonomous), Nandyal
518501Andhra Pradesh, India
5 Department of Chemistry, Sri
Venkateswara University, Tirupati 517
502Andhra Pradesh, India
Our synthesized compounds were analyzed by IR, H, 13C NMR, mass spectra
1
and evaluated for their antioxidant properties by 1, 1‐diphenyl‐2‐picryl
hydrazyl radical (DPPH), hydrogen peroxide(H2O2), and nitric oxide (NO)
scavenging methods. The correlation in exhibition of antioxidant activity was
effective at all doses. The binding interactions and molecular docking studies
for entitled compounds were studied against 3MNG protein; 4k exhibited
marked binding affinity with excellent docking score of −7.6 Kcal/mol and
emerged as a lead compound.
6 Division of Molecular Biology,
Department of Zoology, Sri Venkateswara
University, Tirupati 517502Andhra
Pradesh, India
Correspondence
N. Bakthavatchala Reddy, Chemical
Engineering Institute, Ural Federal
University, Yekaterinburg 620002,
Russian Federation.
Email: drbvreddyn@gmail.com
1 | INTRODUCTION
have been recognized for its importance and are being
helpful to chemists in research and development for
The green chemistry is benign by its design and in being
constantly increasing demand because of providing for
pulling together environmental technologies and
advanced tools that are environmentally friendly.[1]
Despite in the development of wealthy advancements in
synthetic reactions, multicomponent reactions (MCRs)
enhancement of more efficient and ecofriendly methods
for synthesizing simple and readily accessible starting
materials that receive profound financial benefits. How-
ever, employing MCRs ranging from synthetic organic
to green chemistry have made much progress in adopting
a desirable ideal and green solvent, which is aided along
J Heterocyclic Chem. 2019;1–15.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
SRAVYA ET AL.
with the search for suitable efficient catalyst that should
be natural, inexpensive, and nontoxic and also must be
readily available. An efficient catalyst is concerned with
additional benefits aiding the reaction, separation from
the reaction and catalyst recycling.[2] The most challeng-
ing in chemistry is to have two or more different hetero-
cyclic moieties in a single molecule, and this approach
is fascinating and drawing much more attention because
it can notably enhance the multifaceted pharmacological
properties of the respective drug. Therefore, the develop-
ment of simple and efficient reactions for synthesizing
biologically potent molecules is an exciting goal in syn-
thetic organic chemistry and green chemistry.[3–5]
FIGURE 1 Structure of meglumine
both electrophilic and nucleophilic substitution of reac-
tants because of its ability to form hydrogen bond and
to donate lone pair of electrons. It is an FDA approved
excipient in pharmaceuticals and in medicine.
Meglumine has astonishing physical and chemical prop-
erties such as low toxicity, biocompatibility and biode-
gradability, low cost, and noncorrosive nature. As a
functional excipient, it acts as a counterion. It may help
to enhance active pharmaceutical ingredient stability
and solubility in formulation studies. Besides its availabil-
ity, meglumine can be applied in different administration
routes (eg, oral, intravenous). The main benefits of using
meglumine catalyst are high yields of products, short
reaction times, broad substrate scope, and carrying out
reactions at room temperature. On the basis of its out-
standing traits, meglumine has been proven as a notable
candidate for several organic transformations. Thus, such
selective catalysts play a prominent role for the establish-
ment of sustainable chemistry.
Inferable from the malicious impacts of volatile
organic solvents, recently, a few green solvent systems
have been projected as substituent reaction media. Water
stands out among the most stunning endowments of
nature. It has possessed an imperative noticeable quality
as a green medium in organic synthesis because of it
being sheltered, modest, ecofriendly, and nonharmful.[19]
Likewise, a result of superior qualities such as high reac-
tant proficiency, nontoxic nature, and ease and simple
reusing biodegradable material has additionally been
accepting an ever‐increasing number of considerations.
The development of MCRs in water using biodegradable
material as catalyst is progressing towards advancement
of green chemistry. Scientific reports to date disclose that
no synthetic protocols have been attempted for synthesiz-
ing dihydropyrano[3, 2‐b]chromenedione derivatives
mediated by meglumine as catalyst under ethanol:water
mixture solvent conditions. Environmentally benign
selective catalytic reactions are urgently needed in the
pharmaceutical and chemical industries; therefore, our
fundamental objective is to produce a greener technology
that is simple, cleansed, and more effective than conven-
tional reaction.[20–22] Centering our research interests on
the development of efficient ecofriendly methodology,
the versatility of meglumine as catalyst was extended for
the synthesis of 5‐hydroxy‐2‐(hydroxymethyl)‐4H‐pyran‐
4‐one derivatives successfully via a new, fast, and profit-
able process in good yields.[23–25] Our newly synthesized
Kojic acid derivatives have long fascinated the chemis-
try community since they are auxiliary scaffolds in the
structures of a number of pharmaceutical products and
also in distinguished new bioactive molecules with various
promising pharmacological activities such as antimicro-
bial,[6] anti‐inflammatory,[7] antimelanogenic,[8] tyrosi-
nase inhibitory activities,[9,10] whitening agent,[11]
antineoplastic,[12] anti‐fungal and antibacterial,[13]
depigmenting,[14] and anticonvulsant.[15] An important
interest is dedicated by organic chemists for the production
of 5‐hydroxy‐2‐(hydroxymethyl)‐4H‐pyran‐4‐one deriva-
tives in order to improve existing moieties or to create
new ones. To date, a handful of synthetic approaches have
been produced for the synthesis of 5‐hydroxy‐2‐-
(hydroxymethyl)‐4H‐pyran‐4‐one derivatives. In recent
[16]
years, several reports revealed the usage of InCl3,
FeCl3‐SiO2,[17] and alums as catalysts[18] in a safe and effec-
tive manner in the synthesis of 2‐(hydroxymethyl)‐7, 7‐
dimethyl‐10‐aryl‐7, 8‐dihydropyrano[3, 2‐b]chromene‐4,
9(6H, 10H)‐diones improved the yields enormously. Due
to the fact that, various synthetic transformations have
been indulged with some drawbacks in applications of
expensive, water‐bigoted and nonrecyclable catalysts.
Present improvement of an effective, inexpensive, reliable,
ecofriendly, cost‐effective green chemistry synthetic
approaches for synthesis of kojic acid derivatives is of
incredible interest and is highly recommended.
Owing to the harmful effects of synthetic catalysts on
the environment, many ecofriendly green catalysts have
been recently introduced as an alternative in organic syn-
thesis due to it being safe, cheap, and nontoxic in nature
and are presently receiving prominent courtesies. There-
fore, from the point of green chemistry, we have selected
meglumine as an appropriate green catalyst for present
chemical methodology. Meglumine, or D‐(‐)‐N‐
methylglucamine, is an amino sugar (derived from sorbi-
tol) consisting a molecular formula C7H17NO5 with a pKa
value of 9.6 (Figure 1).
It contains secondary amino group and four primary
and secondary hydroxyl groups and is able to facilitate

SRAVYA ET AL.
3
SCHEME 1 Meglumine catalyzed synthesis of dihydropyrano[3, 2‐b]chromenediones 4(a‐o). aIsolated yields. bCatalyst was reused five
times [Color figure can be viewed at wileyonlinelibrary.com]

4
SRAVYA ET AL.
SCHEME 1 Continued

SRAVYA ET AL.
5
compounds were evaluated for their antioxidant activi-
ties, and docking studies provided valuable information
that 3MNG protein exhibits effective binding interaction
against the active compound.
[3, 2‐b]chromenediones 4(a‐o) by reaction of dimedone
(1), various aldehydes 2(a‐o) and kojic acid (3) under
EtOH:H2O system at room temperature (Scheme 1).
2 | RESULTS AND DISCUSSION
In the panorama of meglumine catalyzed MCRs, the sim-
plification, feasibility, and practicality were thoroughly
investigated by opting few parameters such as scrutiniz-
ing the effects and performance of various catalysts. A
model reaction was employed by setting various condi-
tions such as catalyst loading, optimization of the reac-
tion conditions for conducting successful one‐pot three
component method for the synthesis of dihydropyrano
FIGURE 2 Reusability of meglumine catalyst in the synthesis of
4k [Color figure can be viewed at wileyonlinelibrary.com]
TABLE 2 The in vitro antioxidant activity of 4(a‐o) in DPPH
method.
TABLE 1 Influence of catalyst loading on the synthesis of
dihydropyrano [3, 2‐b] chromenedione derivatives 4(a‐o)a
Concentration (μg/mL)
50
75
100
IC50
Yield (%)b
Compound (μg/mL) (μg/mL) (μg/mL) (μg/mL)
Entry
Catalyst (mol%)
Time (min)
4a
4b
4c
4d
4e
4f
64.02 0.12 66.59 0.32 68.84 0.38 39.05 0.028
67.32 0.09 69.74 0.14 71.70 0.66 37.13 0.031
56.74 0.14 58.52 0.24 60.38 0.32 44.06 0.016
55.32 0.12 56.24 0.20 59.20 0.30 45.19 0.014
65.04 0.11 67.69 0.34 69.94 0.29 38.43 0.031
54.98 0.10 55.84 0.32 58.92 0.24 45.47 0.008
52.86 0.12 54.80 0.22 57.98 0.20 47.29 0.012
65.35 0.15 68.32 0.32 70.54 0.38 38.25 0.029
59.64 0.14 61.54 0.24 63.90 0.14 41.91 0.023
74.33 0.11 76.34 0.18 78.54 0.20 33.63 0.032
75.32 0.13 77.36 0.26 79.31 0.24 33.19 0.016
58.86 0.08 60.72 0.22 62.54 0.11 42.47 0.006
50.45 0.12 52.32 0.31 53.84 0.21 49.55 0.030
51.28 0.09 53.42 0.21 55.64 0.32 48.75 0.021
49.98 0.12 51.86 0.14 52.72 0.22 50.02 0.011
73.23 0.10 75.22 0.13 77.34 0.35 34.04 0.008
1
No
120
60
60
60
60
50
40
50
60
60
5
30
35
42
38
40
24
32
34
38
30
80
85
94
92
92
2
K2CO3
3
Et3N
4
DMAP
5
L‐Proline
Chitosan
6
4g
4h
4i
7
β‐CD
8
Ascorbic acid
Citric acid
CuI
9
4j
10
11
12
13
14
15
4k
4l
Meglumine (2)
Meglumine (5)
Meglumine (10)
Meglumine (15)
Meglumine (20)
5
4m
4n
4o
5
5
5
Ascorbic
acid
aReaction of 3‐nitro benzaldehyde (1 mmol), dimedone (1mmol) and kojic
acid (1 mmol).
bIsolated yields.
Values were the means of three replicates SD
SCHEME 2 A plausible reaction
mechanism

6
SRAVYA ET AL.
In order to evaluate the supremacy of meglumine, a
spectral information were in fine agreement with the
anticipated structures.
comparative study based on selecting and using different
catalysts were carried and the results are précised in
Table 1. To evaluate the prominence of catalyst in this
three‐component process, the reaction was first executed
in the absence of catalyst and only negligible yields of
30% of entitled product was perceived even after long
intervals of time (Table 1, entry 1). Moreover in the
presence of potassium carbonate, triethylamine, DMAP,
and L‐proline, the reaction gave 35%, 42%, 38%, and
40% isolated yield of product after 1 hour, respectively
(Table 1, entries 2‐5). In addition, chitosan, β‐
cyclodextrin (β‐CD), ascorbic acid, citric acid, and CuI
could also turn this conversion; however, no improve-
ment was observed (Table 1, entries 6‐10). However,
these catalysts were less effective. We then tested the
reaction in the presence of meglumine. Meglumine
was found to be the excellent catalyst for this process,
and the desired product 4k was formed in 94% yield in
just 5 minutes (Scheme 1, entry 2k). We believe that
meglumine plays a vital role for the formation of prod-
uct; this is due to the stabilization of the corresponding
intermediates and transition states by hydrogen bonding
of multiple hydroxyl groups present within the structure
of meglumine. All the synthesized compounds were
A detailed schematic representation of the reaction
mechanism showing the catalytic activity of meglumine
in the synthesis of the final products 4(a‐o) has been pro-
posed in Scheme 2. While the reaction was ongoing, we
were confident about the formation of tricyclic intermedi-
ate, which on dehydration lead to the desired product by
Knoevenagel–hetero‐Diels‐Alder reaction.[26]
The foremost benefit of solid catalysts is their recycla-
bility. The risk of recycling and reusing the meglumine
catalyst was studied in the three‐component reaction
between 3‐nitrobenzaldehyde, dimedone, and kojic acid
(Figure 2).
At the point when the reaction was finished, the cata-
lyst was recovered, and further, the filtrate was dried
under decreased weight, and recuperated catalyst was
TABLE 4 The in vitro antioxidant activity of 4(a‐o) in NO
method.
Concentration (μg/mL)
Compound
50 (μg/mL)
75 (μg/mL)
100 (μg/mL)
4a
68.20 0.14
70.72 0.26
66.62 0.18
65.96 0.16
69.62 0.22
65.84 0.14
64.86 0.12
70.33 0.20
67.42 0.18
78.92 0.36
79.04 0.38
66.86 0.16
59.92 0.14
63.20 0.12
58.98 0.18
77.11 0.31
70.92 0.24
72.80 0.35
69.10 0.20
68.89 0.22
71.86 0.18
68.76 0.22
66.90 0.24
72.62 0.16
69.86 0.24
80.66 0.12
82.40 0.15
69.22 0.22
60.76 0.24
64.34 0.22
59.86 0.32
79.86 0.43
72.40 0.32
74.80 0.16
70.12 0.34
69.90 0.30
73.92 0.24
69.60 0.28
68.97 0.26
74.75 0.16
71.24 0.20
83.70 0.28
84.36 0.32
70.34 0.34
63.67 0.26
66.54 0.32
61.78 0.36
81.36 0.34
1
characterized by H, 13C‐NMR, and LC‐MS, and all the
4b
4c
4d
TABLE 3 The in vitro antioxidant activity of 4(a‐o) in H2O2
method.
4e
4f
Concentration (μg/mL)
4g
Compound
50 (μg/mL)
75 (μg/mL)
100 (μg/mL)
4h
4a
65.42 0.18
69.92 0.24
58.34 0.22
57.98 0.16
67.22 0.32
55.86 0.18
54.92 0.16
67.62 0.19
64.74 0.30
75.85 0.45
77.65 0.32
60.24 0.16
52.98 0.18
53.42 0.14
51.94 0.12
75.28 0.19
67.54 0.22
70.53 0.34
61.20 0.30
60.84 0.22
68.25 0.18
58.90 0.24
57.86 0.22
68.64 0.30
66.82 0.62
78.32 0.64
79.40 0.28
63.68 0.20
56.84 0.22
57.65 0.24
55.68 0.22
77.29 0.09
69.62 0.40
73.84 0.43
64.58 0.37
62.96 0.34
71.34 0.42
61.24 0.36
60.96 0.32
70.52 0.34
68.96 0.42
80.24 0.37
80.72 0.26
65.90 0.38
59.96 0.40
60.26 0.36
59.86 0.32
79.20 0.12
4i
4b
4j
4c
4k
4d
4l
4e
4m
4f
4n
4g
4o
4h
Ascorbic acid
4i
Values were the means of three replicates SD
4j
4k
TABLE 5 Antioxidant activity of the compounds 4k and 4j at 10
min.
4l
4m
Compound
10 min
20 min
30 min
4n
4o
4j
74.41
75.37
74.50
75.42
74.61
75.69
Ascorbic acid
4k
Values were the means of three replicates SD
Time intervals by DPPH scavenging method.

SRAVYA ET AL.
7
washed twice with diethyl ether (2 mL) and reused in the
next run after drying. The catalyst was reused for four to
five runs, and in each and every individual reaction, the
target compounds were formed in yields (94% to 92%) in
their respective reaction times. As can be noticed, a slight
deactivation of morphology of catalyst surface and the
work up process lead to the loss of the yield, which is
negligible.
2.1 | Antioxidant activities of title
compounds 4(a‐o)
All the compounds were subjected for antioxidant activity
by DPPH (Table 2),[27,28] H2O2 (Table 3),[29] and nitric
oxide methods (Table 4).[30,31] These dihydropyrano[3,
2‐b]chromenediones 4(a‐o) compounds have one free
hydroxyl group and two carbonyl groups bonded to the
TABLE 6 Bonding characterization of synthesized compounds 4(a‐o)
S. No Compound Rank Binding energy (K calmol‐ ) Binding interaction Bond Length(AO) Bond Angle (o) Bond Type
Std
DTT
R
‐ 4.6
Gly 82 CA.…OH
Gly 17 CA…..OC
2.5
2.7
137.7
113.6
H‐ don
H‐ acc
Std
1
BHT
4a
R
6
‐ 5.2
‐ 6.5
Arg 86 CZ ….OC
2.1
113.2
H‐ acc
Gly 92 CA ….OH
Val 94 CA …. HO
Ala 90 CA …. HO
Arg 86 CZ ….OC
2.4
2.0
2.7
2.2
113.2
120.9
119.1
120.8
H‐ acc
H‐ don
H‐ don
H‐ acc
2
4b
3
‐ 6.7
Gly 92 CZ ….HO
Arg 86 CA ….OC
2.1
2.4
113.2
120.8
H‐ don
H‐ acc
3
4
5
4c
4d
4e
9
10
5
‐ 6.4
‐ 6.4
‐ 6.5
Glu 16 CB ….OC
Val 70 CZ ….HO
2.6
2.3
116.4
120.8
H‐ acc
H‐ don
Arg 86 CZ ….OC
Gly 85 CA …..OC
Val 94 CA …. HO
Gly 92 CA ….OH
2.4
2.7
1.8
2.3
120.8
113.4
120.8
113.2
H‐ acc
H‐ acc
H‐ don
H‐ acc
6
7
4f
11
12
‐ 6.4
‐ 6.4
Leu 96 CZ ….HO
Leu 96 CZ … HO
Glu 91 CB ….OC
2.4
2.0
2.5
121.0
115.3
115.7
H‐ don
H‐ acc
H‐ acc
4g
Asp 109 CB ….HO
Lys 126 CZ ….OH
Val 5 CA …. OC
22.5
2.3
2.0
121.6
92.1
115.3
H‐ don
H‐ acc
H‐ acc
8
4h
4i
4
7
2
‐ 6.5
‐ 6.5
‐6.9
Leu 96 CZ ….OH
Glu 91 CZ ….OH
2.1
2.3
115.3
115.7
H‐ acc
H‐ acc
9
Gly 17 CB ….OH
Asn 21 CZ ….ON
2.8
2.7
113.6
117.4
H‐ acc
H‐ acc
10
4j
Arg 86 CZ ….OC
Arg 86 CZ ….ON
Gly 92 CB ….OC
2.2
2.1
2.2
120.8
117.9
113.2
H‐ acc
H‐ acc
H‐ acc
11
4k
1
‐7.6
Val 94 CZ …..HO
Val 94 CB ….OH
Lys 93 CZ ….OH
Gly 92 CB ….OH
Arg 86 CB ….OC
2.4
2.7
2.7
2.2
2.4
120.9
123.2
114.8
113.2
117.9
H‐ don
H‐ acc
H‐ acc
H‐ acc
H‐ acc
12
4l
8
‐6.5
Arg 96 CZ ….OC
Gly 92 CB ….OH
2.1
2.5
120.8
113.2
H‐ acc
H‐ acc
13
14
4m
4n
14
13
‐6.3
‐6.4
Glu 16 CD ….HO
2.3
118.7
H‐ don
Leu 96 CZ ….OH
Glu 91 CA ….OH
2.2
2.3
115.3
115.7
H‐ acc
H‐ acc
15
4o
15
‐6.3
Leu 96 CZ ….OH
Glu 91 CA ….OH
2.1
2.4
115.3
115.7
H‐ acc
H‐ acc

8
SRAVYA ET AL.
aromatic ring; the antioxidant activity was magnificently
displayed by this model of substitution to scavenge the
free radicals effectively. The mean antioxidant values
are shown in Figures S1 to S3.
withdrawing substituent in 4j and 4k appears to prevent
to some extent oxidative metabolic pathways in the living
cells. Moreover, for the remaining compounds 4a, 4b, 4c,
4d, 4e, 4f, 4g, 4h, 4i, 4l, 4m, 4n, and 4o, the order is as fol-
lows: 4b > 4h > 4e > 4a > 4i > 4l > 4c > 4d > 4f> 4g > 4n
> 4m > 4o. As per the data presented in Tables 2, 3 and 4,
with the increase of the concentration, the radical scaveng-
ing activities by DPPH, hydrogen peroxide and nitric oxide
methods also displayed higher values; 4j and 4k was mea-
sured at different concentrations and monitored the
change in absorbance at 10, 20, and 30 minutes in DPPH
method (Table 5). The results indicated that the antioxi-
dant activity is independent of time even after 10‐minute
intervals of time.
The antioxidant activity was evaluated by inferring that
a stable molecule DPPH forms on accepting an electron or
a hydrogen and thus found application in the determina-
tion of radical scavenging. The dihydropyrano[3, 2‐b]
chromenediones 4(a‐o) gained the competency by donat-
ing one electron to scavenge the DPPH radical. When com-
pared with standard ascorbic acid, 4j and 4k showed good
radical scavenging activity for all the three methods; 4j and
4k displayed appreciable antioxidant activity. Both of
these showed the highest activity because –NO2 substitu-
ent, which affect the electron and hydrogen donating
capacities, appears to be useful in inducing antioxidant
activity. Since –NO2 is highly electron withdrawing moi-
ety, thereby electron density around aromatic ring moiety
decreases and increases affinity towards oxygen derived
free radicals and mobilizes ROS to be scavenged out of liv-
ing system. This points to the fact that electron
2.2 | Molecular docking analysis
In order to prove the reputation of our target molecules,
compounds 4(a‐o) with selective pharmacological target
were tested for docking analysis against 3MNG protein
TABLE 7 Physicochemical properties of compounds 4(a‐o)
Mol.
wta
≤ 500
Mol.
volb
n‐
n‐ OHNH
donord
≤ 5
n‐ON
mi Log
Pf
≤ 5
TPSA (A° 2)g
Lipinski's
violation
≤ 1
%ABSh
Compound
Rule
ROTBc
acceptore
≤ 10
4a
4b
4c
4d
4e
4f
380.2
368.6
339.8
412.6
440.4
337.8
330.6
386.1
414.2
436.3
360.1
344.2
360.8
380.3
386.1
326.6
344.0
363.4
362.4
303.9
331.0
313.3
289.6
316.6
343.3
340.0
366.6
386.1
390.9
388.8
5
6
5
5
5
5
5
4
5
5
5
6
6
5
5
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
8
7
8
7
8
7
7
6
6
7
7
8
5
7
7
3.32
3.46
3.18
3.45
3.65
3.66
4.40
4.23
4.10
3.89
3.46
2.12
3.14
2.86
3.84
82.46
84.18
86.42
80.66
86.12
92.36
88.14
88.14
86.12
90.42
82.86
92.14
84.44
92.10
91.18
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
92.5
92.5
95.3
94.5
84.7
96.5
90.5
92.3
96.4
96.2
94.6
94.6
94.4
98.2
98.6
4g
4h
4i
4j
4k
4l
4m
4n
4o
aMolecular weight
bMolecular volume
cNumber of rotatable bonds
dNumber of hydrogen bond donors
eNumber of hydrogen bond acceptors
fLogarithmic ratio of the octanol‐water partitioning coefficient
gTopological polar surface area
hPercentage of absorption. %ABS = 109 ‐ (0.345 9 TPSA)

SRAVYA ET AL.
9
TABLE 8 Prediction of pharmacokinetic properties of com-
pounds 4(a‐o)
of human being, which is a suitable target for antioxidant
activity. The 3D structure of 3MNG protein (PDB id:
3MNG) was taken from the protein data bank, and the
reference drugs such as dithiothreitol (DTT)and butylated
hydroxytoluene (BHT)were from PubChem DrugBank.
The docking results of the synthesized compounds such
as 4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j, 4k, 4l, 4m, 4n,
and 4o have significant binding modes, with dock scores
of −6.5, −6.7, −6.4, −6.4, −6.5, −6.4, −6.4, −6.5, −6.5,
−6.9, −7.6, −6.5, −6.3, −6.4 and −6.3, against 3MNG
protein when compared with the control drugs, DTT(‐
4.6) and BHT(‐5.2), respectively. The type of bonds and
energy profiles of compounds 4(a‐o) along with reference
drugs are mentioned in Table 6. Based on the dock scores,
the title compounds 4(a‐o) fitted more stably into the
binding pocket of 3MNG protein. All our newly synthe-
sized compounds will be established as promising next
generation drugs in treating several diseases associated
with oxidative stress as effective antioxidative agents.
Compounds 4c, 4d, 4m, and BHT have shown effective
hydrophobic interaction against 3MNG protein. The 3D
modeled binding modes of title compounds within the
binding domain of peroxiredoxins are shown in Figure
S4.
a
CaCO2
Compound permeability (%)
HIAb PPBc
(%)
BBBd(Cbrain/
Cblood)
4a
4b
4c
4d
4e
4f
22.36
24.18
24.12
22.86
28.24
24.86
20.14
21.14
22.82
22.60
23.16
24.64
24.46
28.12
24.00
96.14
96.26
98.66
98.12
98.36
98.69
96.16 0.102
94.28 0.113
95.36 0.108
92.38 0.116
90.46 0.142
96.88 0.186
4g
4h
4i
98.44 100.00 0.316
99.36
99.12
98.64
98.06
99.98
98.48
98.41
99.00
96.16 0.213
94.26 0.218
96.12 0.316
96.16 0.224
94.46 0.346
93.86 0.136
92.12 0.318
98.88 0.412
4j
4k
4l
4m
4n
4o
aColon adenocarcinoma
bHuman intestinal absorption
cPlasma protein binding
dBlood‐brain barrier
2.3 | Bioavailability of compounds 4(a‐o)
Bioavailability refers to the extent and rate at which the
active moiety (drug or metabolite) enters systemic circu-
lation, thereby accessing the site of action. The therapeu-
tic efficacy of a drug will be determined once the
drug/compound succeeded in ADMET liabilities. In addi-
tion, drug likeness is an important paradigm of a com-
pound that optimizes the ADMET of a compound in
mammalian body.[32] Considering the importance of drug
likeness, the title compounds were screened for their
ADMET and Lipinski Rule of Five. Fundamentals of Rule
of Five are mentioned in Table 7. The compound which
violates these rules more than one of the fundamentals
will be prone to high probability of failure to exert drug‐
likeness.[33]
Topological polar surface area (TPSA) is a prominent
considering factor in estimating the bioavailability of
compounds. Compounds that exhibit TPSA ≥140 Å come
under low bioavailability group.[34] The complete bio-
availability properties of title compounds are summarized
in Table 7. The compounds have good oral percentage of
absorption and drug likeness with the valves ranging
from 84.70% to 98.6% followed by different ADME predic-
tions such as HIA% (96.14‐99.98), CaCO2 cell permeabil-
ity (20.14‐28.24), PPB% (≥90.46), and BBB (0.120‐0.412).
From the above‐exhibited properties of compounds, it is
concluded that all the title compounds have complied
with the rules of ADME property (Table 8).
3 | CONCLUSION
In summary, we have designed an efficacious, graceful,
efficient, easy, ecofriendly, and straightforward synthesis
for substituted dihydropyrano[3, 2‐b]chromenedione
derivatives (4a‐o), which are imperative precursors for
various biologically active heterocyclic scaffolds. We have
shown the versatility use of meglumine, an ecofriendly
catalyst, for the synthesis of entitled compounds (4a‐o)
in excellent yields in shorter reaction time. Employing
meglumine as catalyst has several advantages such as
easy catalyst separation, minimal product contamination,
and the distinct possibility of reuse and easily biodegrad-
able in the environment to establish a more sustainable
society. The results of the present study showed that all
the kojic acid derivatives (4a‐o) exhibited moderate to
good antioxidant activities. Specifically, 4j and 4k com-
pounds showed high inhibitory potency when compared
with other compounds. Coincidentally, more robust
series of compounds were developed especially by a care-
ful consideration of ADMET approaches. Innovative

10
SRAVYA ET AL.
synthetic chemistry and prediction of the ADMET prop-
erties play a crucial role within the drug design method
of advanced molecular architectures that may be effec-
tively applied not only in the drug discovery setting but
also on process scale and will continue hopefully provide
inspiration to researchers worldwide within the contin-
ued discovery of the latest future medication.
163.6, 150.2, 140.2, 136.4, 129.1, 128.2, 127.7, 112.6,
112.0, 60.2, 50.4, 39.4, 38.5, 32.0, 29.2, 27.3; ESI‐MS (m/
z): 353 [M + H]+. Anal. Calcd for C21H20O5: C, 71.58;
H, 5.72. Found: C, 71.53; H, 5.68.
4.3 | 10‐(4‐Fluorophenyl)‐2‐
(hydroxymethyl)‐7, 7‐dimethyl‐7,
8‐dihydropyrano[3, 2‐b]chromene‐4, 9(6H,
10H)‐dione (4b)
4 | EXPERIMENTAL
All reagents were purchased from Sigma‐Aldrich, Hyder-
abad, India, and used without further purification. Melt-
ing points were determined on Guna Mel‐Temp
apparatus (Tempo Instruments and Equip., Mumbai,
India) and were uncorrected. The IR spectra were
recorded on Bruker Alpha ECO‐ATR FTIR (attenuated
total reflection–Fourier transform infrared) interferome-
ter with single reflection sampling module equipped with
Solid, Yield: 90%, Mp: 161‐164°C; 1H‐NMR (DMSO‐d6): δ
7.29‐7.22 (m, 2H), 6.96‐6.90 (m, 2H), 6.52 (s, 1H), 4.86 (s,
1H), 4.42‐4.35 (m, 2H), 2.70‐2.62 (m, 2H), 2.26‐2.19 (m,
2H), 1.14 (s, 3H), 1.02 (s, 3H); 13C‐NMR (DMSO‐d6): δ
195.6, 170.4, 168.2, 165.6, 161.5, 150.2, 138.0, 136.6,
129.6, 129.2, 115.5, 114.4, 112.2, 112.0, 61.4, 50.6, 40.2,
38.6, 32.2, 28.5, 27.6; ESI‐MS (m/z):371 [M + H]+. Anal.
Calcd for C21H19FO5: C, 68.10; H, 5.17. Found: C, 68.06;
H, 5.13.
1
ZnSe crystal. H, 13C‐NMR spectra were taken on Jeol
JNM ECP 400 NMR instrument (Tokyo) at room temper-
ature in DMSO‐d6 or CDCl3 using tetramethylsilane
(TMS) as internal standard. EI‐Mass spectra were
obtained on JEOL GCMATE II GC‐MS spectrometer
(Tokyo) at SAIF IIT‐Madras, Chennai.
4.4 | 10‐(4‐Chlorophenyl)‐2‐
(hydroxymethyl)‐7, 7‐dimethyl‐7,
8‐dihydropyrano[3, 2‐b]chromene‐4, 9(6H,
10H)‐dione (4c)
4.1 | General method for the preparation
of dihydropyrano[3, 2‐b]chromenedione
derivatives 4(a‐o)
Solid, Yield: 91%, Mp: 203‐206°C; 1H‐NMR (DMSO‐d6): δ
7.22‐7.14 (m, 4H), 6.52 (s, 1H), 4.82 (s, 1H), 4.42‐4.35 (m,
2H), 2.72‐2.66 (m, 2H), 2.32‐2.22 (m, 2H), 1.14 (s, 3H),
1.02 (s, 3H); 13C‐NMR (DMSO‐d6): δ 196.2, 170.6, 168.2,
164.2, 150.1, 138.6, 138.2, 132.8, 129.4, 129.6, 112.6,
111.2, 60.4, 50.2, 40.5, 38.2, 32.2, 28.4, 27.2; ESI‐MS (m/
z):387 [M + H]+. Anal. Calcd for C21H19ClO5: C, 65.20;
H, 4.95. Found: C, 65.16; H, 4.89.
In a dry 50 mL RB flask, a mixture of aldehyde
(1.0 mmol), kojic acid (1.0 mmol), dimedone (1.1 mmol),
and EtOH:H2O (1:1 mL) were taken and then stirred at
room temperature for 5 to 10 minutes along with
meglumine (10 mol%). The progress of the reaction was
monitored by TLC; after completion of the reaction, the
precipitated product was filtered and washed with aque-
ous ethanol (5 mL). The crude product was purified by
column chromatography (ethyl acetate‐hexane, 7:3) on
silica gel to get the pure substituted dihydropyrano[3,
2‐b]chromenedione derivatives 4(a‐o). The supplemen-
tary material contains complete spectral data for the
new compounds 4(a‐o) (Figures S5‐S25).
4.5 | 10‐(4‐Bromophenyl)‐2‐
(hydroxymethyl)‐7, 7‐dimethyl‐7,
8‐dihydropyrano[3, 2‐b]chromene‐4, 9(6H,
10H)‐dione (4d)
Solid, Yield: 86%, Mp: 198‐201°C; 1H‐NMR (DMSO‐d6): δ
7.24‐7.15 (m, 4H), 6.42 (s, 1H), 4.80 (s, 1H), 4.43‐4.34 (m,
2H), 2.62‐2.58 (m, 2H), 2.34‐2.22 (m, 2H), 1.12 (s, 3H),
1.02 (s, 3H); 13C‐NMR (DMSO‐d6): δ 198.4, 180.9, 176.8,
154.9, 142.0, 140.9, 131.2, 129.9, 120.4, 113.5, 112.2,
111.4, 60.2, 51.2, 39.2, 34.5, 32.6, 27.2; ESI‐MS (m/z):
431 [M + H]+. Anal. Calcd for C21H19BrO5: C, 58.48; H,
4.44. Found: C, 58.44; H, 4.41.
4.2 | 2‐(Hydroxymethyl)‐7,
7‐dimethyl‐10‐phenyl‐7, 8‐dihydropyrano[3,
2‐b]chromene‐4, 9(6H, 10H)‐dione (4a)
1
Solid, Yield: 85%, Mp: 183‐186°C; H‐NMR (DMSO‐d6): δ
7.32‐7.22 (m, 5H), 6.46 (s, 1H), 4.84 (s, 1H), 4.42‐4.35 (m,
2H), 2.84‐2.76 (m, 2H), 2.21‐2.15 (m, 2H), 1.12 (s, 3H),
1.04 (s, 3H); 13C‐NMR (DMSO‐d6): δ 196.6, 170.3, 168.2,

SRAVYA ET AL.
11
1.09 (s, 3H), 1.02 (s, 3H); 13C‐NMR (DMSO‐d6): δ198.2,
180.9, 177.2, 156.1, 150.2, 142.8, 132.0, 128.6, 114.2,
112.4, 112.8, 111.5, 60.4, 52.4, 42.2, 39.2, 34.2, 33.4, 27.2;
ESI‐MS (m/z): 396 [M
C23H25NO6: C, 69.86; H, 6.37; N, 3.54. Found: C, 69.76;
H, 6.32; N, 3.50.
4.6 | 2‐(Hydroxymethyl)‐10‐(4‐
hydroxyphenyl)‐7, 7‐dimethyl‐7,
8‐dihydropyrano[3, 2‐b]chromene‐4, 9(6H,
10H)‐dione (4e)
+
H]+. Anal. Calcd for
1
Solid, Yield: 90%, Mp: 202‐204°C; H‐NMR (DMSO‐d6): δ
7.20‐7.14 (m, 4H), 6.48 (s, 1H), 4.74 (s, 1H), 4.40‐4.32 (m,
2H), 2.79‐2.74 (m, 2H), 2.35‐2.20 (m, 2H), 1.10 (s, 3H),
1.01 (s, 3H); 13C‐NMR (DMSO‐d6): δ 198.6, 180.6, 177.2,
156.2, 155.2, 143.2, 136.2, 130.2, 115.2, 114.2, 112.2,
112.0, 60.5, 52.4, 38.4, 34.5, 32.8, 27.4; ESI‐MS (m/z):
369 [M + H]+. Anal. Calcd for C21H20O6: C, 68.47; H,
5.47. Found: C, 68.44; H, 5.41.
4.10 | 2‐(Hydroxymethyl)‐7, 7‐dimethyl‐10‐
(4‐nitrophenyl)‐7, 8‐dihydropyrano[3, 2‐b]
chromene‐4, 9(6H, 10H)‐dione (4i)
Solid, Yield: 84%, Mp: 194‐196°C; 1H‐NMR (DMSO‐d6): δ
8.12‐7.78 (m, 4H), 6.28 (s, 1H), 4.59 (s, 1H), 4.30‐4.24 (m,
2H), 2.74‐2.66 (m, 2H), 2.32‐2.21 (m, 2H), 1.11 (s, 3H),
1.04 (s, 3H); 13C‐NMR (DMSO‐d6): δ198.6, 181.4, 176.9,
155.4, 149.2, 145.2, 142.8, 127.4, 124.6, 114.5, 112.8,
112.0, 60.2, 52.2, 39.2, 33.8, 32.8, 27.4; ESI‐MS (m/z):
398 [M + H]+. Anal. Calcd for C21H19NO7: C, 63.47; H,
4.82; N, 3.52. Found: C, 63.40; H, 4.79; N, 3.49.
4.7 | 2‐(Hydroxymethyl)‐7, 7‐dimethyl‐10‐
(p‐tolyl)‐7, 8‐dihydropyrano[3, 2‐b]
chromene‐4, 9(6H, 10H)‐dione (4f)
1
Solid, Yield: 90%, Mp: 213‐216°C; H‐NMR (DMSO‐d6): δ
7.24‐7.12 (m, 2H), 6.79‐6.73 (m, 2H), 6.46 (s, 1H), 4.80 (s,
1H), 4.40‐4.34 (m, 2H), 2.76‐2.68 (m, 2H), 2.34 (s, 3H),
2.22‐2.16 (m, 2H), 1.12 (s, 3H), 1.02 (s, 3H); 13C‐NMR
(DMSO‐d6): δ 196.0, 172.2, 168.4, 162.6, 152.2, 138.4,
137.5, 137.2, 129.2, 127.6, 112.4, 111.2, 60.4, 50.2, 40.4,
37.5, 32.2, 29.6, 27.0, 21.4; ESI‐MS (m/z): 367 [M + H]+.
Anal. Calcd for C22H22O5: C, 72.12; H, 6.05. Found: C,
72.06; H, 5.99.
4.11 | 2‐(Hydroxymethyl)‐7, 7‐dimethyl‐10‐
(2‐nitrophenyl)‐7, 8‐dihydropyrano[3, 2‐b]
chromene‐4, 9(6H, 10H)‐dione (4j)
1
Solid, Yield: 89%, Mp: 190‐192°C; H‐NMR (DMSO‐d6):δ
7.05‐6.95 (m, 4H), 6.34 (s, 1H), 4.82 (s, 1H), 4.29‐4.21
(m, 2H), 2.70‐2.61 (m, 2H), 2.29‐2.19 (m, 2H), 1.12 (s,
3H), 1.04 (s, 3H); 13C‐NMR (DMSO‐d6): δ 194.6, 170.0,
168.6, 164.2, 149.8, 138.0, 137.2, 132.5, 130.6, 129.4,
128.6, 127.4, 111.6, 110.0, 58.8, 49.6, 45.0, 34.2, 31.6,
28.6, 27.2; ESI‐MS (m/z): 398 [M + H]+. Anal. Calcd for
C21H19NO7: C, 63.47; H, 4.82; N, 3.52. Found: C, 63.40;
H, 4.79; N, 3.49.
4.8 | 2‐(Hydroxymethyl)‐10‐(4‐
methoxyphenyl)‐7, 7‐dimethyl‐7,
8‐dihydropyrano[3, 2‐b]chromene‐4, 9(6H,
10H)‐dione (4g)
1
Solid, Yield: 92%, Mp: 179‐182°C, H‐NMR (DMSO‐d6): δ
7.20‐7.14 (m, 2H), 7.04‐6.98 (m, 2H), 6.44 (s, 1H), 4.84 (s,
1H), 4.38‐4.32 (m, 2H), 3.74 (s, 3H), 2.71‐2.60 (m, 2H),
2.36‐2.30 (m, 2H), 1.12 (s, 3H), 1.04 (s, 3H); 13C‐NMR
(DMSO‐d6): δ 196.4, 172.2, 168.4, 162.6, 160.0, 152.4,
136.8, 132.6, 130.0, 115.4, 112.2, 130.4, 60.2, 55.2, 51.2,
41.0, 36.4, 32.2, 29.6, 27.2; ESI‐MS (m/z): 383[M + H]+.
Anal. Calcd for C22H22O6: C, 69.10; H, 5.80. Found: C,
69.06; H, 5.76.
4.12 | 2‐(hydroxymethyl)‐7, 7‐dimethyl‐10‐
(3‐nitrophenyl)‐7, 8‐dihydropyrano[3, 2‐b]
chromene‐4, 9(6H, 10H)‐dione (4k)
Solid, Yield: 94%, Mp: 212‐214°C; 1H‐NMR (DMSO‐d6): δ
8.17‐8.02 (m, 2H), 7.62‐7.50 (m, 2H), 6.82 (s, 1H), 4.86 (s,
1H), 4.45‐4.30 (m, 2H), 2.77‐2.66 (m, 2H), 2.33‐2.21 (m,
2H), 1.16 (s, 3H), 1.04 (s, 3H); 13C‐NMR (DMSO‐d6): δ
196.6, 171.2, 168.5, 164.2, 150.4, 147.6, 143.0, 138.4,
134.2, 130.6, 124.5, 122.4, 112.6, 112.2, 60.4, 50.6, 40.4,
38.2, 32.6, 28.6, 27.4; ESI‐MS (m/z): 398 [M + H]+. Anal.
Calcd for C21H19NO7: C, 63.47; H, 4.82; N, 3.52. Found: C,
63.40; H, 4.79; N, 3.49.
4.9 | 10‐(4‐(Dimethylamino)phenyl)‐2‐
(hydroxymethyl)‐7, 7‐dimethyl‐7,
8‐dihydropyrano[3, 2‐b]chromene‐4, 9(6H,
10H)‐dione (4h)
1
Solid, Yield: 90%, Mp: 178‐180°C, H‐NMR (DMSO‐d6): δ
7.02‐6.88 (m, 4H), 6.40 (s, 1H), 4.64 (s, 1H), 4.33‐4.28 (m,
2H), 3.12 (s, 6H), 2.73‐2.60 (m, 2H), 2.32‐2.23 (m, 2H),

12
SRAVYA ET AL.
137.0, 136.5, 132.4, 129.5, 129.6, 124.2, 111.6, 111.0, 59.0,
54.2, 53.4, 49.4, 44.5, 37.0, 31.6, 28.2, 26.6; ESI‐MS (m/
z): 413 [M + H]+. Anal. Calcd for C23H24O7: C, 66.98;
H, 5.87; Found: C, 66.92; H, 5.81.
4.13 | 2‐(hydroxymethyl)‐7, 7‐dimethyl‐10‐
(pyridin‐2‐yl)‐7, 8‐dihydropyrano[3, 2‐b]
chromene‐4, 9(6H, 10H)‐dione (4l)
1
Solid, Yield: 90%, Mp: 196‐198°C; H‐NMR (DMSO‐d6): δ
8.20‐7.70 (m, 4H), 6.34 (s, 1H), 4.40‐4.32 (m, 2H), 4.26 (s,
1H), 2.73‐2.59 (m, 2H), 2.35‐2.20 (m, 2H), 1.14 (s, 3H),
1.07 (s, 3H); 13C‐NMR (DMSO‐d6): δ 198.8, 181.6, 177.9,
159.2, 155.2, 149.0, 142.8, 137.2, 124.6, 121.5, 114.4,
113.2, 112.0, 60.4, 52.6, 39.4, 34.2, 32.6, 27.2; ESI‐MS (m/
z): 354 [M + H]+. Anal. Calcd for C20H19NO5: C, 67.98;
H, 5.42; N, 3.96; Found: C, 67.88; H, 5.39; N, 3.89.
4.17 | Biology
Peroxiredoxins (Prxs) are a class of abundant thiol perox-
idases that degrade hydroperoxides to water.
Peroxiredoxins are an important antioxidant protein that
is involved in the protection of proteins from oxidative
damage caused by reactive oxygen species (ROS). The
ROS were generated as the result of the reduction of
molecular oxygen by DTT to superoxide and H2O2, which
were further reduced to hydroxyl radicals in the presence
of trace amounts of contaminating metal (iron or copper)
ions. Prxs contain an active site of cysteine that is sensi-
tive to oxidation by H2O2. Mammalian cells express six
Prx isoforms that are localized to various cellular com-
partments. The Prxs have a remarkably high catalytic effi-
ciency that makes them a dominant player in cell‐wide
peroxide reduction. The accumulation of oxidized Prxs
may indicate disruption of cellular redox homeostasis.
The biochemical properties of the Prxs make them suit-
able as endogenous biomarkers of oxidative stress in
mammals. Monitoring the oxidative state of Prxs provides
insight into disturbances of cellular redox homeostasis
and complements the use of exogenous probes of oxida-
tive stress. In the present study, title compounds 4(a‐o)
have been evaluated for their antioxidant activity against
peroxiredoxins using molecular docking approach.
4.14 | 2‐(hydroxymethyl)‐7, 7‐dimethyl‐10‐
(2‐phenoxyphenyl)‐7, 8‐dihydropyrano[3, 2‐
b]chromene‐4, 9(6H, 10H)‐dione (4m)
1
Solid, Yield: 89%, Mp: 191‐194°C; H‐NMR (DMSO‐d6): δ
7.48‐7.28 (m, 5H), 7.05‐6.87 (m, 4H), 6.50 (s, 1H), 4.83 (s,
1H), 4.44‐4.30 (m, 2H), 2.64‐2.59 (m, 2H), 2.40‐2.35 (m,
2H), 1.16 (s, 3H), 1.08 (s, 3H); 13C‐NMR (DMSO‐d6): δ
196.2, 171.2, 168.6, 164.4, 152.2, 150.6, 148.2 136.2,
135.4, 128.6, 122.4, 121.6, 113.4, 106.6, 60.6, 50.2, 40.6,
37.6, 32.6, 29.4, 27.0; ESI‐MS (m/z): 445 [M + H]+. Anal.
Calcd for C27H24O6: C, 72.96; H, 5.44. Found: C, 72.89; H,
5.41.
4.15 | 2‐(hydroxymethyl)‐7, 7‐dimethyl‐10‐
(3, 4, 5‐trimethoxyphenyl)‐7,
8‐dihydropyrano[3, 2‐b] chromene‐4, 9(6H,
10H)‐dione (4n)
1
Solid, Yield: 92%, Mp: 173‐176°C; H‐NMR (DMSO‐d6): δ
4.18 | Antioxidant activity
6.84‐6.52 (m, 3H), 6.38 (s, 1H), 4.82 (s, 1H), 4.40‐4.34 (m,
2H), 3.82 (s, 6H), 3.80 (s, 3H), 2.64‐2.60 (m, 2H), 2.30‐2.22
(m, 2H), 1.14 (s, 3H), 1.06 (s, 3H); 13C‐NMR (DMSO‐d6): δ
196.2, 170.6, 168.4, 164.2, 152.8, 150.6, 138.0, 136.3, 112.6,
106.5, 60.4, 60.1, 55.4, 50.6, 40.4, 38.6, 32.5, 29.4, 27.2;
ESI‐MS (m/z): 443 [M + H]+. Anal. Calcd for C24H26O8:
C, 65.15; H, 5.92. Found: C, 65.08; H, 5.86.
All the entitled compounds 4(a‐o) were screened for their
antioxidant property by DPPH, H2O2, and NO methods at
three different concentrations 50, 75, and 100 μg/mL.
Ascorbic acid was used as reference standard drug to
compare antioxidant activities.
4.19 | Experimental procedure for
antioxidant activity of compounds 4(a‐o)
4.16 | 10‐(3, 5‐dimethoxyphenyl)‐2‐
(hydroxymethyl)‐7, 7‐dimethyl‐7,
8‐dihydropyrano[3, 2‐b]chromene‐4, 9(6H,
10H)‐dione (4o)
4.19.1 | DPPH radical scavenging activity
This assay is based on the activity of the scavenging abil-
ity of inhibitor substances toward the stable radical. The
hydrogen atom or electron contribution capability of the
compounds was measured from the decolorizing of the
purple colored methanol solution of 1, 1‐diphenyl‐2‐
picryl hydrazyl radical (DPPH). The spectrophotometric
1
Solid, Yield: 91%, Mp: 157‐160°C; H‐NMR (DMSO‐d6): δ
7.16‐7.12 (m, 2H), 6.80‐6.74 (m, 1H), 6.30 (s, 1H), 4.72 (s,
1H), 4.26‐4.10 (m, 2H), 3.72 (s, 6H), 2.64‐2.48 (m, 2H),
2.25‐2.10 (m, 2H), 1.10 (s, 3H), 1.04 (s, 3H); 13C‐NMR
(DMSO‐d6): δ 195.2, 169.4, 168.2, 163.4, 154.2, 150.4,

SRAVYA ET AL.
13
method uses the stable radical DPPH as a reagent. To
methanol solution of DPPH (4 mL of 0.004% w/v), 1 mL
of different concentrations of the experiment compounds
(50, 75, and 100 μg/mL) in methanol were added. The
absorbance was read against blank at 517 nm after a 30‐
minute incubation period at room temperature. Ascorbic
acid was used as the standard. The percent of inhibition (I
%) of free radical production from DPPH was calculated
by the following equation:
nitrite). The quantities of which can be determined using
Griess reagent. Scavengers of nitric oxide compete with
oxygen leading to reduced production of nitrite ions. Con-
trol experiment was conducted with equal amount of sol-
vent in an identical manner. At intervals, 0.5 mL of
incubation solution was taken and diluted with 0.5 mL
of Griess reagent (1% sulfanilamide, 0.1% N‐naphthyl eth-
ylene diamine di hydrochloride and 2% o‐phosphoric acid
dissolved in distilled water). The absorbance of the chro-
mophore formed during diazotization of nitrite with sul-
fanilamide and subsequent N‐naphthyl ethylene
diamine dihydrochloride was read at 546 nm. The exper-
iment was run in triplicate. Nitric oxide scavenging activ-
ity was calculated by the following equation.
ÂÀ
Á
Ã
%of scavenging ¼
A
control − Asample =Acontrol × 100;
where Acontrol is the absorbance of the control reaction
(containing all reagents except the test compounds) and
Asample is the absorbance of the test compound (contain-
ing methanolic DPPH and test compound). Tests were
carried out in triplicate.
ÂÀ
Á
Ã
%of scavenging ¼
A
control − Asample =Acontrol × 100;
where Acontrol is the absorbance of the control reaction
(containing all reagents except the test compounds) and
Asample is the absorbance of the test compound (contain-
ing all reagents and test compound). Tests were carried
out in triplicate.
4.19.2 | Hydrogen peroxide (H2O2) scav-
enging activity
All the cellular processes are influenced by a biologically
important, nonradical ROS, which are key components in
such as hydrogen peroxide (H2O2). A solution of H2O2
(40 mm) prepared in phosphate buffer (pH 7.4) was
employed to test the compound scavenging ability by
H2O2 method. It was optimized by taking 50, 75, and
100 μg/mL concentrations of the test compounds in
3.4 mL phosphate buffer were added to H2O2 solution
(0.6 mL, 40 mm). Ascorbic acid was used as the standard.
The absorbance value of the reaction mixture was
recorded at 230 nm. The percent scavenging of H2O2
was calculated by the following equation.
4.20 | In silico studies
Molecular docking studies[35] were carried against 3MNG
protein along with the reference drugs DTT and BHT
using Pyrx 2010.12 docking module. To get the stable con-
former of the target protein, the 3D structure of protein
was protonated and subjected to energy minimization
using the MMFF94x force field. Flexible docking module
was employed, and the binding site residues of inhibitor
were softened and highlighted using “Site Finder” mod-
ule of Pymol software. Pyrx 2010.12 with default parame-
ters was used for docking analysis, and a maximum of 10
conformations of each compound were allowed for con-
sideration. After that, the docking profiles of protein‐
ligand complexes were done using Pymol viewer tool
(www.pymol.org). The 3D structure of peroxiredoxins
(PDB: 3MNG) and the reference drugs such as DTT
(PubChem ID 446094) and BHT (PubChem ID 31404)
were downloaded from the RCSB protein DataBank and
PubChem. The atomic coordinates of the protein was
estranged, and geometry optimization was done using
Argus Lab 4.0.1.[36] The chemical structure of compounds
were prepared using ChemBioDraw and converted all the
ligands into Pdbqt file format and atomic coordinates
were generated using Pyrx 2010.12.[32] The active sites
are the coordinates of the ligand in the original target
protein grids, and these active binding sites of target pro-
tein were analysed using the Drug Discovery Studio ver-
sion 3.0, and 3D Ligand Site virtual tools were used as
ÂÀ
Á
Ã
%of scavenging ¼
A
control − Asample =Acontrol × 100;
where Asample is the absorbance of the test compound
(containing all reagents and test compound). Acontrol is
the absorbance of the control reaction (containing all
reagents except the test compounds). Tests were carried
out in triplicate.
4.19.3 | Nitricoxide (NO) scavenging
activity
Sodium nitroprusside (5μM) in phosphate buffer pH 7.2
was incubated with different concentrations (50, 75, and
100 μg/mL) of test compounds dissolved in a suitable sol-
vent (methanol), and tubes were incubated at 25°C for
2 hours. The compound sodium nitroprusside is known
to decompose in aqueous solution at physiological pH
(7.2) producing NO. Under aerobic conditions, NO reacts
with oxygen to produce stable products (nitrate and

14
SRAVYA ET AL.
[9] J. M. Noh, S. Y. Kwak, D. H. Kim, Y. S. Lee, Biopolymers 2007,
88, 300.
analysing tools for the prediction of active binding sites of
target protein.[37]
[10] S. M. Ahn, H. S. Rho, H. S. Baek, Y. H. Joo, Y. D. Hong, S. S.
Shin, Y. H. Park, S. N. Park, Bioorg. Med. Chem. Lett. 2011,
21, 7466.
4.21 | In silico ADME prediction
[11] D. H. Kim, J. S. Hwang, H. S. Baek, K. J. Kim, B. G. Lee, I.
ADMET stands for Absorption, Distribution, Metabolism,
Excretion and Toxicity. The prediction of the ADME
properties plays an important role in the drug design pro-
cess because these properties account for the failure of
about 60% of all drugs in the clinical phases. Different
ADME properties such as molecular weight and volume,
H‐bond types, rotatable bonds, topological polar surface
area (TPSA), and violation of Lipinski Rule of Five were
determined to the compounds using Molinspiration
online property toolkit. In addition, the percentage of
HIA, PPB, CaCO2 permeability, and blood‐brain barrier
(BBB) were also determined by using ADMET online
server (http://preadmet.bmdrc.org/).[37]
Chang, H. H. Kang, O. S. Lee, Chem. Pharm. Bull. 2003, 51, 113.
[12] L. Novotny, P. Rauko, M. Abdel‐Hamid, A. Vachalkova,
Neoplasma 1999, 46, 89.
[13] B. V. S. Reddy, M. R. Reddy, C. Madan, K. P. Kumar, M. S. Rao,
Bioorg. Med. Chem. Lett. 2010, 20, 7507.
[14] J. C. Cho, H. S. Rho, H. S. Baek, S. M. Ahn, B. Y. Woo, Y. D.
Hong, J. W. Cheon, J. M. Heo, S. S. Shin, Y. H. Park, K. D.
Suh, Bioorg. Med. Chem. Lett. 2012, 22, 2004.
[15] M. D. Aytemir, B. Oezcelik, Eur. J. Med. Chem. 2010, 45, 4089.
[16] B. V. Subba Reddy, M. Ramana Reddy, G. Narasimhulu, J. S.
Yadav, Tetrahedron Lett. 2010, 51, 5677.
[17] W. L. Li, J. Y. Liang, T. B. Wang, Y. Q. Yang, Collect Czech
Chem Commun 2011, 76, 1791.
[18] W. L. Li, L. Q. Wu, F. L. Yan, J. Braz. Chem. Soc. 2011, 22, 2202.
[19] J. Yang, H. Q. Li, M. H. Li, J. J. Peng, Y. L. Gu, Adv Synth Catal
2012, 354, 688.
ACKNOWLEDGMENTS
[20] C. Syama Sundar, K. U. Maheswara Rao, N. Bakthavatchala
Reddy, M. V. N. Reddy, S. Siva Prasad, C. Suresh Reddy, Cat.
Sci. Technol. 2012, 2, 1382.
The authors G. Sravya and N. Bakthavatchala Reddy are
thankful to Ural Federal University, Yekaterinburg, Rus-
sia, for postdoctoral fellowship.
[21] N. Bakthavatchala Reddy, K. U. Maheswara Rao, C.
SyamaSundar, S. K. Nayak, C. SureshReddy, Heterocycl
Commun 2012, 18, 53.
ORCID
[22] G. Sravya, G. V. Zyryanov, A. Balakrishna, K. Madhu Kumar
Reddy, C. SureshReddy, G. MallikarjunaReddy, A. Camilo Jr.,
J. R. Garcia, N. BakthavatchalaReddy, Phosphorus Sulfur Sili-
con Relat Elem 2018, 193, 562.
G. Sravya https://orcid.org/0000-0002-6249-3870
C. Suresh Reddy https://orcid.org/0000-0002-9804-9683
N. Bakthavatchala Reddy
https://orcid.org/0000-0003-
2039-9277
[23] R. Y. Guo, Z. M. An, L. P. Mo, R. Z. Wang, H. X. Liu, S. X.
Wang, Z. H. Zhang, ACS Comb. Sci. 2013, 15, 557.
[24] S. Zhang, Y. C. Luo, X. Q. Hu, Z. Y. Wang, Y. M. Liang, P. F.
REFERENCES AND NOTES
Xu, J. Org. Chem. 2015, 80, 7288.
[1] (a) R. A. Sheldon, Green Chem. 2007, 9, 1273. (b) H. Ahankar,
A. Ramazani, K. Stlepokura, T. Lis, S. W. Joo, Green Chem.
2016, 18, 3582. (c) Q. Chen, E. J. Beckman, Green Chem.
2008, 10, 934. (d) D. Q. Shi, S. Zhang, Q. Y. Zhuang, X. S.
Wang, S. J. Tuand, H. W. Hu, Chin J Chem 2003, 21, 680; (e)
S. Iravani, Green Chem. 2011, 13, 2638. (f) T. H. Istvan, T. A.
Paul, Chem. Rev. 2007, 107, 2167. (g) R. B. N. Baig, R. S. Varma,
Chem. Soc. Rev. 2012, 41, 1559.
[25] X. T. Li, Y. H. Liu, X. Liu, Z. H. Zhang, RSC Adv. 2015, 5,
25625.
[26] A. Venkatesham, R. Srinivasa Rao, K. Nagaiah, J. S. Yadav, G.
Roopa Jones, S. J. Basha, B. Sridhar, A. Addlagatta, Med. Chem.
Commun. 2012, 3, 652.
[27] M. Burits, F. Bucar, Phytother. Res. 2000, 14, 323.
[28] M. Cuendet, K. Hostettmann, O. Potterat, W. Dyatmiko, Helv.
Chim. Acta 1997, 80, 1144.
[2] H. Bienayme, C. Hulme, G. Oddon, P. Schmitt, Chem. A Eur. J.
2000, 6, 3321.
[29] R. J. Ruch, S. J. Cheng, J. E. Klaunig, Carcinogenesis 1989, 10,
1003.
[3] A. Nefzi, J. M. Ostresh, R. A. Houghten, Chem. Rev. 1997, 97,
[30] L. C. Green, D. A. Wagner, J. Glogowski, P. L. Skipper, J. S.
449.
Wishnok, S. R. Tannenbaum, Anal. Biochem. 1982, 126, 131.
[4] L. A. Thompson, Curr. Opin. Chem. Biol. 2000, 4, 324.
[5] A. Domling, Curr. Opin. Chem. Biol. 2002, 6, 306.
[31] L. Marcocci, J. J. Maguire, M. T. Droy‐Lefaix, L. Packer,
Biochem Biophys ResCommun 1994, 201, 748.
[6] M. D. Aytemir, U. Calis, M. Ozalp, Arch. Pharm. 2004, 337, 281.
[32] E. F. Pettersen, T. D. Goddard, C. C. Huang, G. S. Couch, D. M.
Greenblatt, E. C. Meng, T. E. Ferrin, J. Comput. Chem. 2004, 25,
1605.
[7] H. S. Rho, S. M. Ahn, D. S. Yoo, M. K. Kim, D. H. Cho, J. Y.
Cho, Bioorg. Med. Chem. Lett. 2010, 20, 6569.
[8] H. S. Rho, H. S. Baek, S. M. Ahn, D. H. Kim, I. S. Chang, Bull
Korean Chem Soc 2008, 29, 1569.
[33] Y. H. Zhao, M. H. Abraham, J. Lee, A. Hersey, N. C. Luscombe,
G. Beek, B. Sherborne, I. Cooper, Pharm. Res. 2002, 19, 1446.

SRAVYA ET AL.
15
[34] G. Walkinshaw, C. M. Waters, Neuro Sci 1994, 63, 975.
How to cite this article: Sravya G, Suresh G,
Zyryanov GV, et al. A meglumine catalyst–based
synthesis, molecular docking, and antioxidant
studies of dihydropyrano[3, 2‐b]chromenedione
derivatives. J Heterocyclic Chem. 2019;1–15. https://
doi.org/10.1002/jhet.3786
[35] G. M. Morris, R. Huey, W. Lindstrom, M. F. Sanner, R. K.
Belew, D. S. Goodsell, A. J. Olson, J. Comput. Chem. 2009, 30,
2785.
[36] E. Ter Haar, J. T. Coll, D. A. Austen, H. M. Hsiao, L. Swenson,
J. Jain, Nat. Struct. Biol. 2001, 8, 593.
[37] G. Vistoli, A. Pedretti, B. Testa, Drug Discov. Today 2008, 13,
285.
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