An efficient multicomponent synthesis and in vitro anticancer activity of dihydropyranochromene and chromenopyrimidine-2,5-diones

Article abstract of DOI:10.1080/00397911.2018.1480042

A series of dihydropyranochromenes and chromenopyrimidine-2,5-diones having chromene scaffold were synthesized via efficient multicomponent protocol in aqueous β-cyclodextrin. The reaction is free of toxic solvents, operating under mild conditions and all

Full text of DOI:10.1080/00397911.2018.1480042

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
An efficient multicomponent synthesis and in vitro
anticancer activity of dihydropyranochromene and
chromenopyrimidine-2,5-diones
M. R. Bhosle, D. B. Wahul, G. M. Bondle, A. Sarkate & S. V. Tiwari
To cite this article: M. R. Bhosle, D. B. Wahul, G. M. Bondle, A. Sarkate & S. V.
Tiwari (2018): An efficient multicomponent synthesis and inꢀvitro anticancer activity of
dihydropyranochromene and chromenopyrimidine-2,5-diones, Synthetic Communications, DOI:
10.1080/00397911.2018.1480042
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2018.1480042
An efficient multicomponent synthesis and in vitro
anticancer activity of dihydropyranochromene and
chromenopyrimidine-2,5-diones
M. R. Bhoslea, D. B. Wahula, G. M. Bondlea, A. Sarkateb and S. V. Tiwaric
aDepartment of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, Maharashtra,
b
India; Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University,
c
Aurangabad, Maharashtra, India; Y. B. Chavan College of Pharmacy, Aurangabad, Maharashtra, India
ABSTRACT
ARTICLE HISTORY
Received 20 March 2018
A series of dihydropyranochromenes and chromenopyrimidine-2,5-
diones having chromene scaffold were synthesized via efficient mul-
ticomponent protocol in aqueous b-cyclodextrin. The reaction is free
of toxic solvents, operating under mild conditions and allows for
ease of product isolation, making it more environmentally friendly.
All the synthesized compounds biologically evaluated for their
potential inhibitory effect on both cervical cancer cell line (HeLa)
and human breast adenocarcinoma cell line (MCF-7). Of these com-
pounds, 4d was found to be the most potent inhibitors of HeLa and
MCF-7 demonstrating IC50 values of 19 mM and 7 mM. Compounds
4b, 4e and 4f also shown significantly good in vitro anticancer activ-
ity against HeLa and MCF-7 cancer cell lines.
KEYWORDS
Anticancer activity;
b-cyclodextrin; chromeno-
pyrimidine-2,5-diones;
dihydropyranochromene
GRAPHICAL ABSTRACT
O
OH
O
OH
O
H
H
R
O
O
R
O
CN
O
CN
H2N
NH2
R
R
O
O
CN
O
NH
O
N
O
O
NH2
H
(4a-o)
#Efficient synthesis,
#22 Examples
(6a-h)
# Up to 93% yield
# In vitro anticancer activity
OCH3
Cl
Br
Cl
O
O
O
O
CN
CN
NH2
CN
O
CN
O
O
O
O
NH2
O
O
NH2
O
NH2
IC50 µM:HeLa:35.88,
MCF-7:20.11
IC50 µM:HeLa:10.23,
MCF-7:23.12
IC50 µM:HeLa:19.22,
MCF-7:7.67
IC50 µM:HeLa:12.12,
MCF-7:22.11
CONTACT Manisha R. Bhosle
d.manisha11@gmail.com
Department of Chemistry, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad, Maharashtra 431004, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis

2
M. R. BHOSLE ET AL.
Introduction
Chromenes are synthetically significant structural motifs that can be easily functional-
ized to access different biologically active analogues. These privileged molecular frame-
works were often targeted because of their easily accessible chemical libraries and ability
to act as ligands for a diverse array of receptors.[1] The presence of chromene scaffold
in the framework of various pharmacologically active compounds represents an interest-
ing template for medicinal chemistry. Many of these compounds are known for their
spasmolytic,[1d] diuretic,[2] anti-HIV,[3] antitumor,[4] antimalarial,[5] anti-Alzheimer,[6]
and antileukemic[7] properties. In addition, different derivatives of chromenes are
known as valuable synthones used for potential biodegradable agrochemicals,[8] cosmet-
ics and pigments.[1] The pyranochromene possess chromene pharmacophore present in
a wide variety of natural and synthetic molecules of biological importance.[9] Among
the pyranochromenes, dihydropyrano[2,3-c]chromenes form a special sub-class exhibit-
ing diverse biological activities such as anti-microbial,[10] anti-cancer,[11] anti-dyslipi-
demic[12] anti-hyperglycemic,[13] anti-HIV,[14] antioxidant,[15] antiallergic,[16] xanthine
oxidase inhibitory,[17] butyrylcholinesterase, acetylcholinesterase,[18] and Src kinase
inhibitory activities (Fig. 1).[19]
Chromenopyrimidine-2,5-dione is fused heterocycle, can be frequently found in an
ocean of biologically active molecules as analgesic, antifungal, antibacterial antitu-
mour,[20] cardiotonic,[21] antibronchitic[22] and antifungal activity.[23] Some of them
exhibit antihypertensive activity,[24] antimalarial,[25] analgesic[26] antiviral and
CNS depressant.
Pyranochromene derivatives are accessible via the one-pot three-component reaction
of hydroxycoumarins, carbonyl compounds and active methylenes in the catalytic sys-
tems including Fe3ꢀxTixO4 nanoparticles,[27] N,N-dimethylbenzylamine (DMBA),[28] dia-
mmonium hydrogen phosphate (DAHP),[29a] tetrabutylammonium bromide
(TBAB),[29b] urea,[30] H6P2W18O62.18H2O,[31] MgO,[32] ionic liquids,[33] hexadecyltri-
methyl ammonium bromide,[34] SiO2PrSO3H,[35] Mg/La mixed metal oxides,[36] nanosil-
ica,[37] a-Fe2O3 nanoparticles,[38] and silica-grafted ionic liquid.[39]
A vigilant study dictates that most of the methodologies suffer some drawbacks such
as, require forcing conditions, reaction under high temperatures, use of expensive and
environmentally harmful catalysts, harsh reaction conditions, formation of a mixture of
H3CO
Cl
NH2
N
NH2
O
O
O
O
S
O
O
O
F
CN
Cl
O
N
O
O
NH2
O
NO2
Acetylcholine esterase
inhibitor
Anticancer
Antimicrobial
Figure 1. Representative examples of synthetically bioactive dihydropyrano[3,2-c]chromene
derivatives.

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SYNTHETIC COMMUNICATIONSV
3
products, multi-step procedure, longer reaction times and involvement of volatile
organic solvents which limits the broad use of these methodologies. Albeit there are
methods available for the synthesis of different pyranochromene and chromenopyrimi-
dine-2,5-dione derivatives, their broad utility range has accentuated the need to develop
newer synthetic routes for scaffold manipulation of chromene containing pyranochro-
mene and chromenopyrimidine-2,5-dione moiety.
The use of water in multicomponent reactions offers significant environment
advantages and has attracted a great deal of interest in recent years,[40] because water is
considered as a cheap, environmental safety, high stability, easy handling and
green solvent. Owing to the fascinating advantages of water over traditional organic
solvents, various types of in water or on water reactions are completely in conformity
with the standpoint of green chemistry and the development of green protocols for the
syntheses of highly functionalized bio-active motifs in aqueous medium is highly
desirable.[41]
Supramolecular catalysis is a discipline in chemistry which involves host–guest type
interactions where covalent bonds are not established between the interacting species
which can be molecules, ions, or radicals.[42] The most accessible b-cyclodextrin (b-CD)
is a cyclic oligosaccharide of D(þ)-glucopyranosyl units linked by a-1,4-glycosidic bonds
and consist of a hydrophilic outer surface and a hydrophobic central cavity.[43]
Cyclodextrins can include water-insoluble organic materials into the cavity in aqueous
solution because of these features. Complexation with cyclodextrin is well-known as an
effective method for enhancing dissolution properties of poorly soluble organic materi-
als and is, therefore, the molecule of choice for the water-mediated reactions.[44]
Considering the above-mentioned facts and in continuation of our previous studies
on the efficient synthesis of bioactive heterocycles[45] herein, we wish to report a
straightforward, efficient, clean, and high yielding MCR protocol for the one-pot facile
synthesis of biologically relevant diverse and densely functionalized pyranochromene
and chromenopyrimidine-2,5-dione heterocyclic scaffolds and evaluation of their
in vitro anticancer activity.
Results and discussion
Chemistry
b-Cyclodextrin is attractive as a catalyst since it is useful both from an economic and
environmental point of view, apart from being non-toxic, metabolically safe, and readily
recoverable and reusable. We chose cyclodextrin as supramolecular catalyst due to its
excellent catalytic properties in water. bCD-mediated reactions in water have been
found to be a useful tool for economical as well as environmental points of view.[46]
Initially, the three component annulation of 3-nitrobenzaldehyde (1a), malononitrile
(2a) and 4-hydroxy-2H-chromene-2-one (3) was examined in the presence of a range of
commercially available catalysts in water and conventional heating separately (Scheme
1). While the reaction proceeded in the presence of surfactant like CTAB, SDS and p-
TSA (Table 1, entries 2–4), affording the desired product 4a, the degree of conversion
varied from 48 to 64% depending on the nature of catalyst used. Improved conversion
was observed when 10 mol% of b-CD was used (Table 1). The poor conversion in the

4
M. R. BHOSLE ET AL.
O
OH
O
O
H
CN
CN
CN
H2O
60-65 0C
O
O
NH2
O
(2)
(1a)
(3)
(4a)
Scheme 1. Synthesis of 2-amino-4,5-dihydro-5-oxo-4-phenylpyrano[3,2-c]chromene-3-carbonitrile (4a)
(model reaction).
Table 1. Formation of 2-amino-4,5-dihydro-5-oxo-4-phenylpyrano[3,2-c]chromene-3-
carbonitrile (4a) using different catalyst in aqueous mediuma.
Entry
Catalyst/solvent
–/water
CTAB/water
SDS/water
p-TSA/water
a-Cyclodextrin/water
b-Cyclodextrin/water
c-Cyclodextrin/water
Time (h)
Concentration (mol%)
Yield (%)b
1
2
3
4
5
6
7
15
7
7
7
9
–
10
10
10
27
64
59
48
10
5, 10, 15, 20
20
45
71, 92, 92, 93
42
2
5
aReaction conditions: benzaldehyde (4 mmol), malanonitrile (4 mmol), 4-hydroxycou-
marin (4 mmol), water (20 mL), 60–65 ꢁC.
bIsolated yield.
absence of a catalyst (Table 1) indicated its key role in the present MCR. Thus, b-CD
was found to be the catalyst of choice and was used for our further studies.
The effect of various reaction parameters, such as the effect of solvents, catalyst con-
centration, temperature and reaction conditions was evaluated to optimize the reaction.
Firstly, the effect of catalyst concentration on the formation of the pyranochromene was
investigated (Table 1). Model reaction was performed at different concentrations of
b-CD, i.e., 5, 10, 15 and 20 mol% at 60 ꢁC and gave the product in 71, 92, 92 and 93%
yield, respectively (Table 1). Thus increasing catalyst concentration up to 20 mol%,
product yield is improved to 93% yield. Further increase in the catalyst concentration
product yield remains static. It means that the presence of 10 mol% of b-CD was suffi-
cient for catalyzing the reaction effectively in the forward direction.
Therefore, we performed the model reaction using 10 mol% b-CD in water at room
temperature the product was obtained in moderate yield (50%). The reaction was found
to be sluggish at room temperature; however, by increasing the temperature to
60–65 ꢁC, the corresponding product (4a) was obtained in 92% yield within 1 h
(Scheme 1).
The role of various solvents (polar protic and aprotic) was examined for the synthesis
of pyranochromene. The reactions conducted in polar aprotic solvents, such as aceto-
nitrile and dimethyl formamide, were found to be very slow and resulted in lower prod-
uct yield under above conditions (Table 2). Next, we tested polar protic solvents such as
methanol and ethanol and the yield of the desired products was good; however, an
excellent yield was obtained using water as the solvent (Table 2). Water was found to
be the best solvent due to high solubility of b-CD in water (Table 2). The more soluble
the cyclodextrin in the solvent, the more molecules become available for complexation.

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SYNTHETIC COMMUNICATIONSV
5
Table 2. Optimization of solvents for synthesis of 2-amino-4,5-dihydro-
5-oxo-4-phenylpyrano[3,2-c]chromene-3-carbonitrile (4a)a.
Entry
b-Cyclodextrin loading (mol%)
Solvent
Water
EtOH
MeOH
Acetonitrile
Yield (%)b
1
2
3
4
5
10
10
10
10
10
92
61
59
42
56
DMF
aReaction conditions: benzaldehyde (1a) (4 mmol), malononitrile (2)
(4 mmol), 4-hydroxycoumarin (3) (4 mmol), at 60–65 ꢁC.
bIsolated yield.
95
90
90
85
80
75
70
87
87
Yield
β-CD Recovery
80
Fresh
I Run
II Run
III Run
Figure 2. Recycling and recovery of b-CD and its effect on yield.
R
O
O
OH
O
CN
CN
β
-CD,H2O
H
60-65 0C
CN
O
NH2
O
O
R
(1a-o)
(2)
(3)
(4a-o)
Scheme 2. Synthesis of 2-amino-4,5-dihydro-5-oxo-4-(substitutedphenyl) pyrano[3,2-c]chromene-3-car-
bonitriles (4a-o).
To test the recyclability of the catalyst, the aqueous b-CD was recovered after usual
work-up with organic solvent and reused to afford 4a without changing the degree of
conversion significantly. The b-CD reused four times including the use of fresh catalyst
for the synthesis of 4a. The catalyst was almost quantitatively recovered and no signifi-
cant loss in yield was observed (Fig. 2).
Under the optimized reaction conditions, we used various aromatic aldehydes to react
with malononitrile and 4-hydroxy-2H-chromene-2-one and a series of functionalized
pyranochromene derivatives were synthesized with excellent yield (Scheme 2). The
results of the reactions are summarized in Table 3. As shown in Table 3, we found that
all the reactions were carried out smoothly, and the aromatic aldehydes, with either
electron withdrawing groups or electron-donating groups, could all be used for the syn-
thesis of functionalized pyranochromene derivatives with excellent yields.
To further explore the scope of this protocol, we decided to investigate the condensa-
tion reaction of we next turned our attention to ascertain the scope and limitations of
the reaction. We extended this process to other substrates. The scope of the reactions is

6
M. R. BHOSLE ET AL.
Table 3. Physical data of 2-amino-4,5-dihydro-5-oxo-4-(substitutedphenyl)pyrano[3,2-c]chromene-3-carbonitriles (4a-o)
and 3,4-dihydro-4-(substituted phenyl)-1H-chromeno[4,3-d]pyrimidine-2,5-diones (6a-g)a,b,c
.
aReaction conditions: substituted benzaldehyde (1a-o) (4 mmol); malononitrile (2) or urea (5) (4 mmol), 4-hydroxycou-
marin (3) (4 mmol), b-cyclodextrin (10 mol%), at 60–65 ꢁC.
bIsolated yield.
cMelting points are in good agreement with those reported in the literature.[45]

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7
R
OH
O
O
O
β-CD/H2O
60-65 0C
O
O
NH
H
H2N
NH2
O
N
H
O
R
(1a-h)
(5)
(3)
(6a-h)
Scheme 3. Synthesis of 3,4-dihydro-4-(substituted phenyl)-1H-chromeno[4,3-d]pyrimidine-2,5-diones
(6a-h).
O
OH
OH
OH
OH
H
CN
CN
O
NC
Knoevenagel
condensation
CN
H
N
NC
OH
OH
β-cyclodextrin
catalyst
OH
O
O
CN
O
O
O
NH2
Product
OH
OH
OH
OH
H
O
O
H
NH
O
C
CN
Dehydrogenation
CN
O
O
O
N
Intramolecular
Cyclization
N
O
NH2
O
O
OH
OH
Scheme 4. Plausible reaction mechanism for the synthesis of 4H,5H-pyrano[3,2 c][1]benzopyran-5-
ones (4a).
embodied with respect to urea for synthesizing chromenopyrimidine-2,5-diones (6a-g)
(Scheme 3) by employing number of aldehydes (1a-h), urea (5) and 4-hydroxycoumarin
(3). The results are tabulated in Table 3.
Plausible reaction mechanism
The mechanism proposed for the reaction using b-CD as catalyst is also outlined in
Scheme 4. The rate acceleration of this condensation can be endorsed as aqueous
b-cyclodextrin catalyst appears to play an important role in increasing the efficiency of
the reaction especially by activating the aldehyde carbonyl in addition to aiding the
water solubility of all the reactants. A subsequent nucleophilic attack by the malanoni-
trile on the activated carbonyl carbon was also facilitated by b-CD leading to the gener-
ation of intermediate benzylidinemalononitrile in situ. Once formed, the
benzylidinemalononitrile then subsequent Michael type of addition takes place by

8
M. R. BHOSLE ET AL.
Table 4. In vitro anticancer activity of 2-amino-4,5-dihydro-5-oxo-
4 (substitutedphenyl) pyrano[3,2-c]chromene-3-carbonitriles (4a-o)
and 3,4-dihydro-4-(substituted phenyl)-1H-chromeno[4,3-d]pyrimi-
dine-2,5-diones (6a-g).
IC50 mM
Compound
HeLa
MCF-7
4a
4b
4c
4d
4e
4f
4g
4h
4i
92
35
62
19
23
22
70
>100
87
76
20
50
7
10
12
60
88
69
4j
4k
4l
42
77
38
31
50
22
4m
4n
4o
6a
6b
6c
6d
6e
6f
82
63
90
>100
>100
33
38
71
>100
>100
52
>100
>100
>100
46
59
86
90
>100
73
6g
ADR
<10
<10
The IC50 values are the concentrations in micromolar needed to
inhibit cell growth by 50%.
ADR: adriamycin standard drug used; HeLa: human cervical cancer
cell line; MCF-7: human breast cancer cell line.
sequential addition of 4-hydroxy coumarine resulting into intermediate, which is also
stabilized by H-bonding with the secondary hydroxyl groups of b-CD. Then, followed
by intramolecular cyclization and hydrolysis there is formation of desired product. After
the formation of the product, the escape from the CD cavity occurs readily.
Anticancer activity
A series of 2-amino-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile (4a-o) and
3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione (6a-g) were evaluated for their in
vitro anticancer activity against MCF-7 (human breast cancer cell line) and HeLa
(human cervical cancer cell line) by MTT assay using Adriamycin standard drug. The
result obtained for in vitro anticancer activity is reported in Table 4. The IC50 (lM)
value means concentration required to inhibit 50% of cancer cells growth.
From the close examination of IC50 values, it is observed that 4d, 4e, and 4f were
active and potent anticancer agents among the synthesized derivatives 4a-o. The com-
pound 4d was found to be the most potent anticancer agents with IC50 value 19 and
7 mM against HeLa and MCF-7 respectively. The compound 4b bearing para-methoxy
group on the phenyl ring was found to be >2-folds less potent than the standard drug
Adriamycin against HeLa and MCF-7 with IC50 value 35 and 20 mM, respectively.

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SYNTHETIC COMMUNICATIONSV
9
Structure activity relationship (SAR) studies for these compounds demonstrated that
the phenyl ring substituted at para position (4b, 4c, 4d, 4f, 4g, 4k, 4l, 6b, 6c, 6d) was
more active than those substituted at ortho (4h, 6f). A series of 2-amino-5-oxo-4,5-
dihydropyrano[3,2-c]chromene-3-carbonitrile (4a-o) were found to be more active than
the 3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione (6a-g) series.
Replacing the para-methoxy group 4b by a para hydroxyl group 4g resulted in two-
fold reduction in anticancer activity, suggesting that the hydrophobic methoxy group is
preferred over the hydrophilic hydroxyl group at the para-position on the phenyl ring.
Compounds with para-position substitution on phenyl ring were more active than those
with ortho-position substitution, suggesting that there might be a sterric hindrance
effect due to ortho-position substitution on the phenyl ring. The compound 4g bearing
para-OH is more active than that of 4h with ortho-OH group on the phenyl ring.
Connecting the non-substituted phenyl ring via methyl linker to the chromone nucleus
such as in 4o resulted in decrease in anticancer activity, suggesting that the methyl
linker between the phenyl ring and chromone nucleus does not all molecule to bind
properly into the pocket. Compounds 4b, 4d, 4e and 4f have shown significantly good
in vitro anticancer activity against HeLa and MCF-7 cancer cell lines and can be devel-
oped as anticancer agents in the future.
Conclusions
This study describes the efficient, green synthesis of series of dihydropyranochromenes
and chromenopyrimidine-2,5-diones, using b-cyclodextrin as a catalyst in aqueous
medium. This multicomponent protocol is bestowed with merits like high yield, cost
effectiveness, biomimetic, neutral aqueous phase conditions and environmentally benign
nature. All the synthesized compounds screened for their in vitro anticancer activity on
human cancer cell line MCF-7 and HeLa. In the series of dihydropyranochromenes
derivatives, four compounds 4b, 4d, 4e and 4f showed very potent activity and the data
is helpful to further development of these compounds for anticancer activity mechanis-
tic studies and also supportive to design and synthesize more such derivatives to be
taken-up for further studies.
Experimental
General
All the chemicals used were of laboratory grade. Melting points of all the synthesized
1
compounds were determined in open capillary tubes and are uncorrected. H NMR
spectra were recorded with a Bruker Avance 400 spectrometer operating at 400 MHz
using CDCl3 solvent and tetramethylsilane (TMS) as the internal standard and chemical
shift in d ppm. Mass spectra were recorded on a Sciex, Model; API 3000 LCMS/MS
Instrument. The purity of each compound was checked by TLC using silica-gel, 60F254
aluminum sheets as adsorbent and visualization was accomplished by iodine/ultravio-
let light.

10
M. R. BHOSLE ET AL.
General procedure for the synthesis of 2-amino-4,5-dihydro-5-oxo-4-
(substitutedphenyl)pyrano[3,2-c]chromene-3-carbonitriles (4a-o)
A mixture of substituted benzaldehydes (1a-j) (4 mmol), malononitrile (2) (4 mmol),
4-hydroxy coumarin (4 mmol) and b-cyclodextrin (10 mol%) in water (15 ml) was sub-
jected to stir at 60–65 ꢁC. Progress of the reaction was monitored by thin layer chroma-
tography. After 60 min, reaction mixture was cooled to room temperature, filtered and
washed with hot water. Obtained solid was crystallized by ethanol:DMF. Synthesized
compounds characterized by IR, 1H NMR and are in good agreement with those
reported in the literature.[47]
General procedure for the synthesis of 3,4-dihydro-4-(substituted phenyl)-1H-
chromeno[4,3-d]pyrimidine-2,5-dione (6a-g)
A mixture of substituted benzaldehydes (1a-g) (4 mmol), urea (5) (4 mmol), 4-hydroxy
coumarin (3) (4 mmol) and b-cyclodextrin (10 mol%) in water (15 ml) was subjected to
stir at 60–65 ꢁC. Progress of the reaction was monitored by thin layer chromatography.
After 2 h, reaction mixture was cooled to room temperature, filtered and washed with
hot water. Obtained solid was crystallized by ethanol:DMF. Synthesized compounds
1
characterized by IR, H NMR and are in good agreement with those reported in the
literature.[47]
Experimental procedure for MTT assays
The stock solutions of test compounds were prepared in DMSO. After 24 h incubation,
different concentrations (2, 4, 6, 8 mM) of compounds, made by serial dilution in culture
medium, were added in 48 h incubation. The final concentration of DMSO was 0.01%
in each well. A separate well containing 0.01% DMSO only was run as DMSO control,
which was found inactive under applied conditions. The cell growth was determined
using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (Sigma)
reduction assay, which is based on ability of viable cells to reduce a soluble yellow tetra-
zolium salt to blue farmazan crystal.[48] Briefly, after 48 h of treatments, the 10 ml of
MTT dye, prepared in phosphate-buffered saline (PBS) were added to all wells. The
plates were then incubated for 4 h at 37 ꢁC. Supernatant from each well was carefully
removed, formazon crystals were dissolved in 100 mL of DMSO and absorbance at
540 nm wavelength was recorded and each concentration was tested in threefold. The
IC50 values were determined as concentration of compounds that inhibited cancer cell
growth by 50%.
Spectral analysis of representative compounds as follow[47]
2-Amino-4,5-dihydro-5-oxo-4-(4-methylphenyl)pyrano[3,2-c]chromene-
3-carbonitrile (4c)
White solid mp: 258–259 ꢁC (lit. 258–260 ꢁC)[1,2]; IR (ATR t cmꢀ1) characteristic
absorptions: 3291 (N–H stretching), 2884 (C–H stretching), 1187 (C–O–C stretching),

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SYNTHETIC COMMUNICATIONSV
11
1
1680 (C¼O stretching). H NMR (400 MHz, CDCl3, d ppm): 2.15 (s, 3H, CH3), 6.03 (s,
1H, CH), 7.09–7.37 (m, 6H, Ar-H), 7.49–7.54 (m, 2H, Ar-H), 11.21–11.49 (m, 2H,
NH2). 13C NMR (100 MHz, DMSO-d6 d ppm): 160.49, 158.37, 153.66, 152.57, 140.82,
136.74, 133.36, 129.47 (2C), 127.91 (2C), 125.08, 122.87, 119.68, 116.97, 113.36, 104.56,
58.54, 36.97, 21.04. Mass (LC-MS): m/z 331 [M þ H]þ. Anal. calcd. For C20H14N2O3: N:
8.48; C: 72.72; H: 4.27; Found: N: 8.50; C: 72.69; H: 4.25%.
3,4-Dihydro-4-phenyl-1H-chromeno[4,3-d]pyrimidine-2,5-dione (6a)
White solid mp: 238–240 ꢁC (lit. 237–239 ꢁC)[47]; IR (ATR t cmꢀ1) characteristic
absorptions: 3282 (N–H stretching), 2882 (C–H stretching), 1181 and 1208 (C–O–C
1
stretching); H NMR (400 MHz, CDCl3, d ppm): 6.04 (s, 1H, CH), 7.15–7.17 (d, 2H,
J ¼ 8 Hz, Ar-H), 7.26–7.30 (d, 2H, J ¼ 8 Hz, Ar-H), 7.41–7.43 (m, 2H, Ar-H), 7.99–8.09
(m, 3H, Ar-H) , 11.31 (s, 1H, NH) and 11.54 (s, 1H, NH); 13C NMR (100 MHz,
DMSO-d6 d ppm): 162.87, 158.00, 152.86, 149.96, 149.48, 141.56, 131.79, 129.68 (2C),
128.66 (2C), 127.34, 125.69, 119.89, 119.46, 88.43, 58.67. Mass (LC-MS): m/z 292
[M þ H]þ. Anal. calcd. For C17H12N2O3: N: 9.58; C: 69.86; H: 4.14; Found: N: 9.60; C:
70.00; H: 4.27%. Full experimental detail, IR, 1H and 13C NMR spectra, Mass and
Elemental analysis can be found via the “Supplementary Content” section.
Acknowledgments
The authors are thankful to Professor Ramrao A. Mane for his invaluable discussions and guid-
ance. The authors are also thankful to Department of Chemistry, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad and Central Drug Research Institute (CDRI), Lucknow for
providing necessary facilities and spectral analysis, respectively.
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