Synthesis, characterization, computational chemical studies and antiproliferative activity of some heterocyclic systems derived from 3-(3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl)-2H-chromen-2-one

Article abstract of DOI:10.1080/00397911.2021.1904991

The key material, 3-(3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl)-2H-chromen-2-one (3) was synthesized and its behavior toward malononitrile, hydrazine, thiourea, thiosemicarbazide, 2-aminoaniline, and 6-aminothiouracil was investigated aiming to synthesize a new series of pyrazole-based heterocycles, namely, pyranochromene, diazepine, pyrimidochromene, triazepine, benzodiazepine, pyrimidine, and pyrimidopyrimidine derivatives. Density functional theory based on quantum chemical computation outline the structure optimization of the intermediate that reacted to afford the desired product. The antiproliferative screening against HePG-2 and MCF-7 cancer cell lines disclosed that the most potent compounds against two cell lines were 9 and 17 as compared to doxorubicin which may be due to their presence in more tautomeric structures. Also, the minimized energy, dipole moment, ionization potential, transferred electrons, and charge density distribution revealed that the greater value of 0.126 and 0.8 for pyrazole derivatives 9 and 17, respectively, indicates the maximum transfer of electron and hence, greater tendency of scavenging radicals and rapidly reduce oxygen to superoxide.

Full text of DOI:10.1080/00397911.2021.1904991

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis, characterization, computational
chemical studies and antiproliferative activity of
some heterocyclic systems derived from 3-(3-(1,3-
diphenyl-1H-pyrazol-4-yl)acryloyl)-2H-chromen-2-
one
Mohamed M Kaddah, Abdelgawad A. Fahmi, Mustafa M. Kamel, Sayed K.
Ramadan & Sameh A. Rizk
To cite this article: Mohamed M Kaddah, Abdelgawad A. Fahmi, Mustafa M. Kamel, Sayed
K. Ramadan & Sameh A. Rizk (2021): Synthesis, characterization, computational chemical
studies and antiproliferative activity of some heterocyclic systems derived from 3-(3-(1,3-
diphenyl-1H-pyrazol-4-yl)acryloyl)-2H-chromen-2-one, Synthetic Communications, DOI:
10.1080/00397911.2021.1904991
To link to this article: https://doi.org/10.1080/00397911.2021.1904991
Published online: 31 Mar 2021.
Article views: 47
View supplementary material
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

R
SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2021.1904991
Synthesis, characterization, computational chemical studies
and antiproliferative activity of some heterocyclic systems
derived from 3-(3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl)-
2H-chromen-2-one
Mohamed M Kaddaha, Abdelgawad A. Fahmib, Mustafa M. Kamelc,
Sayed K. Ramadana , and Sameh A. Rizka
b
aDepartment of Chemistry, Faculty of Science, Ain Shams University, Cairo, Egypt; Department of
c
Chemistry, Faculty of Science, Cairo University, Giza, Egypt; Industrial Area, El-Nasr Company for
Intermediate Chemicals, Giza, Egypt
ABSTRACT
ARTICLE HISTORY
Received 16 January 2021
The key material, 3-(3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl)-2H-chro-
men-2-one (3) was synthesized and its behavior toward malononi-
trile, hydrazine, thiourea, thiosemicarbazide, 2-aminoaniline, and 6-
aminothiouracil was investigated aiming to synthesize a new series
of pyrazole-based heterocycles, namely, pyranochromene, diazepine,
pyrimidochromene, triazepine, benzodiazepine, pyrimidine, and pyri-
midopyrimidine derivatives. Density functional theory based on
quantum chemical computation outline the structure optimization of
the intermediate that reacted to afford the desired product. The anti-
proliferative screening against HePG-2 and MCF-7 cancer cell lines
disclosed that the most potent compounds against two cell lines
were 9 and 17 as compared to doxorubicin which may be due to
their presence in more tautomeric structures. Also, the minimized
energy, dipole moment, ionization potential, transferred electrons,
and charge density distribution revealed that the greater value of
0.126 and 0.8 for pyrazole derivatives 9 and 17, respectively, indi-
cates the maximum transfer of electron and hence, greater tendency
of scavenging radicals and rapidly reduce oxygen to superoxide.
KEYWORDS
Chromene; pyrazole;
pyrimidopyrimidine; triaze-
pine; pyrimidochromene
GRAPHICAL ABSTRACT
CONTACT Sayed K. Ramadan
sayed.karam2008@sci.asu.edu.eg
Department of Chemistry, Faculty of Science, Ain
Shams University, Cairo 11566, Egypt.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

2
M. M. KADDAH ET AL.
Introduction
Chalcones (1,3-diaryl-2-propane-1-ones) are one of the major classes of natural prod-
ucts with widespread distribution in fruits, vegetables, spices, tea, and soya-based food
stuff.[1] Also, chalcones are secondary metabolites obtained from the main precursors of
flavonoids and isoflavonoids biosynthesis occurred in terrestrial plants. Otherwise, cou-
marins and pyrazoles are of great importance due to their pharmacological effects[2–15]
(cf. Figure 1). Pyrazoles display anticancer efficacy because of their inhibition of various
targets like EGFR, B-raf, ROS1, JAK2, ALK, HDAC, among others.[8–10] Coumarins
(benzopyrones) are naturally occurring compounds serving as an important model for
design and synthesis of some potent analogues like anticancer, antioxidant, anti-
inflammatory, anticoagulation, and estrogenic activities. In many plants, naturally occur-
ring coumarins are found, especially in higher concentrations in tonka bean, woodruff,
lavender, licorice, strawberries, apricots, cherries, cinnamon, bison grass and sweet clo-
ver. The ability of synthetic coumarin-containing compounds to evoke a wide range of
pharmacological effects with a focus on their utility as anticancer therapeutic agents has
been shown as its unique skeleton has a special ability to readily interact with a diverse
enzymes and receptors in organisms via weak bond interactions and therefore a wide
potentiality as medicinal drugs.[5,6] In turn, it is well known that chalcones are highly
reactive due to a,b-unsaturated carbonyl functionality, which was a good synthon for
the synthesis of a variety of heterocyclic systems like pyrazoline, isooxazoline, pyran,
pyridine, and pyrimidine derivatives.[16,17] Thus, as an extension of our study,[18–26] we
report herein utilization of the chalcone 3 bearing both coumarin and pyrazole scaffolds
for the synthesis of some pyrazole-based heterocycles of enhanced antitumor efficacy
against two human cancer cell lines, namely, hepatocellular carcinoma (liver) HePG-2
and mammary gland breast MCF-7 cancer cell lines.
Figure 1. Anticancer, coumarin and pyrazole derivatives.

R
SYNTHETIC COMMUNICATIONSV
3
Results and discussion
Chemistry
[27]
Claisen-Schmidt condensation of 3-acetylcoumarin 1 with pyrazole aldehyde 2
achieved the chalcone derivative 3 as yellow crystals (Scheme 1). The IR spectrum dis-
1
played coumarinyl C¼O at ꢀ 1722 cmꢀ1 and ketonic C¼O at ꢀ 1655 cmꢀ1. Its H NMR
spectrum disclosed C5-H of pyrazole at d 9.29 ppm, C4-H of coumarin at d 8.65 ppm as
well as the aromatic and olefinic protons. Further support for the assigned structure 3
was acquired from its mass spectrum which showed the correct molecular ion peak at
m/z 418 (22%) and the base peak at m/z 77 (100%) corresponding to phenyl cation, in
addition to some important fragments (cf. Experimental). Treating chalcone 3 with
malononitrile in boiling ethanol and piperidine failed to produce 2-amino-3-cyanopyran
derivative 4 and afforded the arylidene malononitrile 5 as a sole product which was
identical in all respects with an authentic sample prepared from condensation of pyra-
zole aldehyde 2 with malononitrile at an ambient temperature (Scheme 1).[28] The reac-
tion pathway can be visualized via two routes as displayed in Scheme 2. Noteworthy,
the pyranochromene derivative 6 was obtained upon cyclocondensation of 5 with 4-
1
hydroxycoumarin in boiling ethanol and triethylamine. The H NMR spectrum of 6
revealed an exchangeable singlet signal for NH2 and singlet for methine proton in
Scheme 1. Synthesis of Chalcone 3 and compounds 5–7.

4
M. M. KADDAH ET AL.
Scheme 2. Plausible pathways for the reaction of chalcone 3 with malononitrile.
addition to the aromatic protons (cf. section “Experimental”). In turn, cyclocondensa-
tion reaction of 5 with thiourea in boiling ethanol including anhydrous potassium car-
bonate led to the formation of 6-aminopyrimidin-5-carbonitrile derivative 7. Its IR
spectrum disclosed bands characteristic for NH, NH2, CꢁN, and C¼N groups.
In turn, when chalcone 3 was treated with hydrazine in boiling dioxane, chromeno-
diazepine derivative 9 was obtained instead of 3-coumarinyl-5-pyrazolylpyrazole deriva-
tive 8. The IR spectrum of 9 revealed the carbonyl functionalities at ꢀ 1722 and
1676 cmꢀ1. In contrast, hydrazinolysis of chalcone 3 in glacial acetic acid afforded the
diazepinedione derivative 10 (Scheme 3). The chemical structures were substantiated
from their analytical and spectral properties (cf. section “Experimental”). The plausible
pathways of hydrazinolysis reaction can proceed via two routes as depicted in
Scheme 4.
The reaction of chalcone 3 with thiourea was not successful in boiling dioxane while
in boiling sodium ethoxide acquired the chromenopyrimidine derivative 12 instead of
pyrimidinethione derivative 11 (Scheme 5). The IR spectrum was devoid of C¼O of
coumarin moiety and displayed ꢀ C¼O of amide at 1689 cmꢀ1. The reaction pathway
can be extrapolated via Scheme 6.
Interaction of chalcone 3 with thiosemicarbazide in boiling dioxane failed to furnish
the pyrazole derivative 13 and afforded the triazepinethione derivative 14 (Scheme 7).
1
Its IR and H NMR spectra were devoid of NH2 bands. Further, the highest recorded
peak in its mass spectrum was at m/z 489 (5%) corresponding to the correct molecular
ion peak and the base peak at m/z 77 (100%) which is attributable to phenyl cation. In

R
SYNTHETIC COMMUNICATIONSV
5
Scheme 3. Reactions of chalcone 3 with hydrazine.
Scheme 4. Plausible pathways for formation of compounds 9 and 10.

6
M. M. KADDAH ET AL.
Scheme 5. Reactions of Chalcone 3 with thiourea.
Scheme 6. A suggested pathway for compound 12.
a similar manner, 2-aminoaniline reacted with chalcone 3 in boiling dioxane to provide
benzodiazepine derivative 15. In contrast, pyridopyrimidine derivative 17 was obtained
instead of pyridopyrimidine derivative 16 upon treating chalcone 3 with 6-aminothiour-
acil in boiling dioxane including piperidine (Scheme 7). The IR spectra conserved the
coumarin carbonyl functionality. The reactions can proceed via aza-Michael addition
followed by ring closure by loss of water.
Density functional theory study
It is well known that high EHOMO are likely to indicate a strong tendency of the mol-
ecule to donate electrons. The low values of the energy gap (DE ¼ ELUMO ꢀ EHOMO
)

R
SYNTHETIC COMMUNICATIONSV
7
Scheme 7. Reactions of Chalcone 3 with thiosemicarbazide, 2-aminoaniline, and 6-aminothiouracil.
will render good inhibition efficiencies because the energy needed to remove an electron
from the last occupied orbital will be low.[29] Density functional theory (DFT) based on
quantum chemical computation outline the structure optimization of the intermediate
that reacted to afford the desired product. In the presence of reaction of the coumarin
chalcone with carbon nucleophile e.g., malononitrile, the HOMO energy (ꢀ14.54 eV)
rather than HOMO of nitrogen nucleophiles e.g., hydrazine hydrate (ꢀ10.83 eV), thio-
urea (ꢀ8.96 eV) and 6-aminothiouracil (ꢀ9.05 eV) and so good matching to LUMO
energy (ꢀ6.37 eV) of the carbonyl electrophilic site of chalcone to form the correspond-
ing new heterocyclic via addition reaction followed by cyclization. In the case of using
thiosemicarbazide (HOMO ꢀ5.32 eV) is more preferred than the HOMO of o-phenyl-
enediamine (ꢀ7.72 eV) proceeding via mechanism of Scheme
7
to form

8
M. M. KADDAH ET AL.
Figure 2. Outline the EHOMO of nucleophiles toward ELUMO of the starting material.
Table 1. Global reactivity indices and energy level distribution of frontier orbitals.
Compound
EHOMO
ELUMO
DE
Ia
Ab
mc
gd
xe
DNf
Sg
Amolec (nm2)
Doxorubicin ꢀ6.69
ꢀ2.41
ꢀ6.14
ꢀ5.70
ꢀ4.40
ꢀ3.53
ꢀ2.67
ꢀ4.53
4.28 6.88 3.62
1.52 7.09 5.38
2.25 8.08 5.93
3.27 7.36 4.36
4.27 8.03 3.29
6.21 8.69 2.78
4.85 9.65 4.85
5.28 0.66
7.29 0.76
16.39 1.13
6.62 1.63
7.77 2.14
31.09
35.60
21.56
13.366 0.0748
13.88
0.56
0.028
0.046
1.98
1.34
0.88
0.61
0.46
0.39
0.398
1.67
0.349
0.719
0.645
0.64
7.69
243.621
232.246
364.594
863.013
761.829
232.246
265.246
609.594
493.013
687.625
756.888
488.744
377.146
491.093
344.641
411.210
3
ꢀ7.66
ꢀ7.95
ꢀ7.67
ꢀ7.80
ꢀ8.88
ꢀ9.38
4
5
6
7
0.0720
0.023
0.017
0.126
0.095
0.077
0.086
0.087
0.0087
6.13 3.16 102.6
8
9
7.03 2.51
4.23 0.60
5.86 2.83
4.04 1.39
62.02
5.36
48.59
12.94
11.65
11.49
ꢀ4.754 ꢀ3.604 1.15 4.96 3.82
10
11
12
13
14
15
16
17
ꢀ8.41
ꢀ7.75
ꢀ7.67
ꢀ7.46
ꢀ5.40
ꢀ7.25
ꢀ6.88
ꢀ7.51
ꢀ2.96
ꢀ4.98
ꢀ4.56
ꢀ4.35
ꢀ5.15
ꢀ4.67
ꢀ4.69
ꢀ4.62
5.45 7.36 4.36
2.77 7.66 4.66
3.11 7.63 4.24 ꢀ3.51 1.55
3.11 7.49 4.38
0.25 5.88 5.23
2.58 7.26 4.66
2.19 6.73 4.39
2.89 7.62 4.38
3.25 1.56
8.24 0.13 113.78
5.14 1.29
2.67 1.10
0.43 1.45
10.24
13.62
12.42
0.09776 0.775
0.073
0.80
0.909
0.689
aIonization potential, bElectron affinity, cChemical potential, dHardness, eElectrophilicity index, fnucleophilicity
index, gSoftness.
thermodynamically intermediate. This means in the case of malononitrile, it is a
thermodynamic stable intermediate (cf. Figure 2).
So, DFT simulation helped us to know why the reactions of chalcone 3 with malono-
nitrile, hydrazine hydrate, thiourea, thiosemicarbazide, and 6-aminothiouracil did not
afford the expected heterocyclic compounds 4, 8, 11, 13, and 16 and they yielded newly
heterocyclic compounds 5, 9, 12, 14 and 17, respectively. The structures have been sup-
ported by full spectral analysis and microanalytical data. Quantum chemical parameters
calculation is using the density functional theory (DFT) method for the calculations of
the newly synthesized compounds (Table 1). The high EHOMO is likely to indicate a
strong tendency of the molecule to donate electrons. The low values of the energy gap
(DE ¼ ELUMO ꢀ EHOMO) will render good efficiencies.[30] The dipole moment,

R
SYNTHETIC COMMUNICATIONSV
9
Figure 3. Outline the optimized structures 4–17 and the standard, doxorubicin (see more in the sup-
plemental figures).

10
M. M. KADDAH ET AL.
Figure 3. Continued.
Table 2. Outline the minimized energy and electron density of the tautomers of the more effective
anticancer compounds 9 and 17.
eCharge density
diazepine
N11, N12
eCharge density pyrimidine
Compound no
ECal/mol
DEeV
mDipole
EHOMO
ELUMO
N6 bridge head
9a
9b
17a
17b
17c
78.70
67.67
69.5
90.1
102.0
1.21
1.28
2.89
2.20
6.6
15.55
4.08
0.43
3.6
0.246, 0.256
0.807, 0.434
0.753
ꢀ2.74
ꢀ7.51
ꢀ7.0
1.746
ꢀ4.02
ꢀ4.62
ꢀ4.8
0.468
0.616
0.587
6.6
ꢀ6.70
ꢀ4.50
hardness, softness, and surface area (nm2) for newly pyrazole derivatives carrying
hydrophobic groups were agreed with an excellent explanation for the synthesized com-
pounds and their anticancer efficiency. Also, the Ionization potential (I, eV), transferred
electrons, and charge density distribution (DN) indicate the greater value pyrazole deriv-
atives 5, 9, 12, 14, and 17 have the maximum transfer of electron and hence, greater
tendency of adsorption and inhibition for the cancer cell. The optimization structures
of the synthesized pyrazole 3–17 as outlined in Figure 3 (see more in the supplemen-
tal figures).
Quantum chemical parameters calculations using density functional theory (DFT)
method used for the calculations of the synthesized compounds are in good agreement
with the anticancer efficiency (Table 1). The listed results indicate that the values of gap
energy (DE), where DE ¼ ELUMO ꢀ EHOMO, follow the order: heterocyclic derivatives
9 < 17 < doxorubicin. Compounds having small DE values are generally referred to as
soft compounds, that are more reactive toward radical surface interactions; being cap-
able of donating electrons easily to hole surface.[31] The scavenging ability toward posi-
tive hole, tumor, radical, and oxygen removable not only depended upon EHOMO values
but also, the number of heteroatoms, electron distributions, surface area, and lipophilic-
ity must be considered. The dipole moment, softness (ϭ, eVꢀ1), and surface area (nm2)

R
SYNTHETIC COMMUNICATIONSV
11
Figure 4. Structures of compounds 9 and 17.
for most potent synthesized compounds carrying hydrophobic groups were agreed to an
excellent correlation between oxidation inhibition efficiencies.
On the other hand, the minimized energy (kcal/mol), dipole moment, ionization
potential (I, eV), transferred electrons, and charge density distribution (DN) revealed
that the greater value of 0.126 and 0.8 for pyrazole 9 and 17, respectively indicates the
maximum transfer of electron and hence, greater tendency of scavenging radicals and
rapidly reduce oxygen to superoxide (O2ꢂ–)[32] (see more in Table 2).

12
M. M. KADDAH ET AL.
Table 3. Cytotoxic activity of some compounds against
human tumors.
In vitro cytotoxicity IC50 (mM)a
HePG-2
Comp.
MCF-7
doxorubicin
3
6
9
10
12
14
15
17
4.50 0.3
68.96 3.3
36.50 2.3
12.68 1.0
56.24 3.0
43.07 2.6
59.12 3.1
30.61 2.1
19.32 1.5
4.17 0.2
81.57 4.1
70.18 3.6
9.16 0.7
51.72 2.8
26.28 1.9
38.91 2.2
45.05 2.5
14.34 1.2
aIC50 (mM): 1–10 (very strong), 11–20 (strong), 21–50 (moderate), 51–100 (weak),
and above 100 (non-cytotoxic).
doxorubicin
3
6
9
10
12
14
15
17
Compounds
Figure 5. IC50 of the tested compounds.
Biological screening
It was shown that several enzymes including the cytochrome P450 reductase, NADH
dehydrogenase, and xanthine oxidoreductase could reduce doxorubicin via a one-elec-
tron reduction mechanism giving rise to the phenate radical intermediate that can rap-
idly reduce oxygen to superoxide (O2ꢂ–) via a futile redox-cycling mechanism.[33] In the
presence of a redox-active metal ion such as iron (III), hydroxyl radicals are formed via
the Fenton mechanism. Chelators such as desferrioxamine inhibit the formation of
hydroxyl radicals through inhibition of the Haber-Weiss mechanism. Based on these
ꢂ–
in vitro studies, redox activation of newly synthesized compounds 9 and 17 to O2
,
hydrogen peroxide (H2O2), and iron-catalyzed hydroxyl radical formation was suggested
to be a similar mechanism of doxorubicin toxicity.[32] Oxidative stress is thought to be
primarily responsible for phenolic diazepine 9, pyrimidinethiol 17, and doxorubicin car-
diotoxicity because the myocardial tissues lack sufficient antioxidant mechanisms.[34]

R
SYNTHETIC COMMUNICATIONSV
13
Compounds 9 and 17 are the stronger anticancer than the other synthesized com-
pounds which may be due to their presence in more tautomeric structures (Table 2;
Figure 4).
Pharmacology
Antiproliferative screening
The antiproliferative screening of the synthesized compounds was measured against two
cell lines namely, Hepatocellular carcinoma (HePG-2) and Mammary gland breast can-
cer (MCF-7) using MTT assay.[35,36] The results in Table 3 and Figure 5 disclosed that
the most potent compounds against two cell lines were 9 and 17 as compared to doxo-
rubicin. The compounds 6, 12, and 15 were moderately potent against HePG-2 cell
line. Moderate activity was shown against MCF-7 cell line by the compounds 12, 14,
and 15. The rest of the compounds were of weak activity.
Conclusion
A novel series of fused and pyrazole-based heterocyclic systems like chromenopyran,
chromenodiazepine, diazepine, chromenopyrimidine, triazepinethione, benzodiazepine,
and pyrimidopyrimidine derivatives, was prepared from the chalcone namely, 3-(3-(1,3-
diphenyl-1H-pyrazol-4-yl)acryloyl)-2H-chromen-2-one. The antiproliferative activity
screening of the synthesized compounds disclosed that the chromenodiazepine and pyri-
midopyrimidine derivatives were the most potent against the two tumor cells namely,
HePG-2 and MCF-7. DFT based on quantum chemical computation outline the struc-
ture optimization of the intermediate that reacted to afford the desired product.
Experimental
General
All melting points were measured on a GALLENKAMP electric melting point apparatus
and are uncorrected. Chemicals and solvents used were obtained from commercial sour-
ces and used as received or dried by standard procedures. IR spectra (ꢀ, cmꢀ1) were
recorded using potassium bromide disks on Fourier Transform Infrared Thermo
Electron Nicolet iS10 Spectrometer (Thermo Fisher Scientific Inc., Waltham, MA, USA)
1
at Faculty of Science, Ain Shams University. The H NMR spectra (dH, ppm) were
recorded at 300 MHz on a Varian GEMINI (GEMINI, Manufacturing & Engineering
Inc., Anaheim, CA, USA) utilizing tetramethyl silane (TMS) as an internal standard in
deuterated dimethyl sulfoxide (DMSO-d6) at Faculty of Science, Cairo University. The
mass spectra (MS) were recorded on Shimadzu GC-MS-QP-1000 EX mass spectrometer
(Shimadzu Scientific Instruments, Inc., USA) operating at 70 eV at the Regional Center
for Mycology and Biotechnology (RCMB) of Al-Azhar University, Cairo, Egypt. The
reactions were monitored by thin-layer chromatography (TLC) using Merck Kiesel gel
60 F254 analytical sheets obtained from Fluka, Switzerland. The antiproliferative activity
was carried out at the Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
The starting pyrazole-4-carbaldehyde derivative 2 was previously prepared.[27]

14
M. M. KADDAH ET AL.
3-(3-(1,3-Diphenyl-1H-pyrazol-4-yl)acryloyl)-2H-chromen-2-one (3)
A mixture of 3-acetylcoumarin 1 (0.05 mol) and pyrazole aldehyde 2 (0.05 mol) in abso-
lute ethanol (20 mL) including piperidine (0.1 mL) was refluxed for 2 h. The solid
obtained while hot was filtered off and recrystallized from n-butanol to furnish chalcone
3 as yellow crystals, mp. 260–262 ꢃC, yield 90%. IR: 1722 (C¼O coumarin), 1655 (C¼O
1
ketone). H NMR (300 MHz, DMSO-d6): 9.29 (s, 1H, C5-H pyrazole), 8.65 (s, 1H, C4-H
coumarin), 8.00–7.40 (m, 16H, Ar-H). MS, m/z (%): 418 (Mþ., 22), 341 (4), 268 (9), 245
(89), 173 (25), 115 (26), 77 (100). Anal. Calcd. for C27H18N2O3 (418.45): C, 77.50; H,
4.34; N, 6.69. found: C, 77.32; H, 4.27; N, 6.71%.
2-Amino-4-(1,3-diphenyl-1H-pyrazol-4-yl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-car-
bonitrile (6)
A mixture of arylidine malononitrile 5 (0.01 mol) and 4-hydroxycoumarin (0.01 mol) in
absolute ethanol (20 mL) including triethylamine (0.1 mL) was refluxed for 10 h (TLC),
the contents were poured onto ice-cold water and then acidified by dil. HCl (10%). The
deposited solid was filtered off and gray crystals were obtained after crystallization from
ethanol, mp. 228–230 ꢃC, yield 57%. IR: 3392, 3318 (NH2), 2193 (CꢁN), 1710 (C¼O
1
coumarin). H NMR (300 MHz, DMSO-d6): 8.58 (s, 1H, C5-H pyrazole), 7.87–7.29 (m,
14H, Ar-H), 7.26 (br.s, 2H, NH2, exchangeable), 4.70 (s, 1H, C4-H pyran). MS, m/z
(%): 458 (Mþ., 22), 419 (8), 393 (59), 392 (100), 315 (19), 270 (30), 243 (21), 120 (14),
92 (41), 77 (55). Anal. Calcd. for C28H18N4O3 (458.48): C, 73.35; H, 3.96; N, 12.22.
found: C, 73.22; H, 3.89; N, 12.25%.
Full experimental details, tables, figures, spectroscopic data can be found in supple-
mental files.
Disclosure statement
No potential conflict of interest was reported by the author(s).
ORCID
Sayed K. Ramadan
Sameh A. Rizk
http://orcid.org/0000-0003-2743-6544
http://orcid.org/0000-0002-8232-5399
References
[1] Orlikova, B.; Tasdemir, D.; Golais, F.; Dicato, M.; Diederich, M. Genes Nutr. 2011, 6,
125–147. DOI: 10.1007/s12263-011-0210-5.
[2] Kenchappa, R.; Bodke, Y. D.; Chandrashekar, A.; Sindhe, M. A.; Peethambar, S. K.
Arabian J. Chem. 2017, 10, S3895–S3906. DOI: 10.1016/j.arabjc.2014.05.029.
[3] Singh, A. D.; Kumar, A.; Saini, S.; Prabha, H. APJHS 2017, 4, 84–93. DOI: 10.21276/apjhs.
2017.4.4.21.
[4] Anees Rahman, K. N.; Haribabu, J.; Balachandran, C.; Bhuvanesh, N. S. P.; Ramasamy
Karvembu, R.; Sreekanth, A. Polyhedron. 2017, 135, 26–35. DOI: 10.1016/j.poly.2017.06.
044.

R
SYNTHETIC COMMUNICATIONSV
15
[5] (a) Abdou, M. M. Arabian J. Chem.. 2017, 10, S3664–S3675. DOI: 10.1016/j.arabjc.2014.
04.005.(b) Gomha, S. M.; Zaki, Y. H.; Abdelhamid, A. O. Molecules. 2015, 20,
21826–21839. DOI: 10.3390/molecules201219803.
[6] (a) Peng, X. M.; Damu, G. L.; Zhou, C. H. CPD. 2013, 19, 3884–3930. DOI: 10.2174/
1381612811319210013.(b) Salem, M. A. I.; Marzouk, M. I.; El-Kazak, A. M. Molecules.
2016, 21, 249 DOI: 10.3390/molecules21020249.
[7] (a) Halim, K. N. M.; Ramadan, S. K.; Rizk, S. A.; El-Hashash, M. A. Synth. Commun.
2020, 50, 1159–1175. DOI: 10.1080/00397911.2020.1720739. (b) Ramadan, S. K.; Halim,
K. N. M.; Rizk, S. A.; El-Hashash, M. A. J. Iran. Chem. Soc. 2020, 17, 1575–1589. DOI:
10.1007/s13738-020-01880-8.(c) Halim, K. N. M.; Rizk, S. A.; El-Hashash, M. A.;
Ramadan, S. K. J. Heterocyclic Chem. 2021, 58, 636–645. DOI: 10.1002/jhet.4204.
[8] (a) Ramadan, S. K.; Abou-Elmagd, W. S. I. Synth. Commun. 2018, 48, 2409–2419. DOI:
10.1080/00397911.2018.1491995. (b) El-Helw, E. A. E.; Gado, M. M.; El-Ziaty, A. K. J.
Iran. Chem. Soc. 2020, 17, 1479–1492. DOI: 10.1007/s13738-020-01873-7.(c) Ramadan, S.
K.; El-Ziaty, A. K.; Ali, R. S. J. Heterocyclic Chem. 2021, 58, 290–304. DOI: 10.1002/jhet.
4168.
[9] Tao, X. X.; Duan, Y. T.; Chen, L. W.; Tang, D. J.; Yang, M. R.; Wang, P. F.; Xu, C.; Zhu,
H. L. Bioorg. Med. Chem. Lett. 2016, 26, 677–683. DOI: 10.1016/j.bmcl.2015.11.040.
[10] Kamal, A.; Shaik, A. B.; Jain, N.; Kishor, C.; Nagabhushana, A.; Supriya, B.; Kumar, G. B.;
Chourasiya, S. S.; Suresh, Y.; Mishra, R. K.; Addlagatta, A. Eur. J. Med. Chem. 2015, 92,
501–513. DOI: 10.1016/j.ejmech.2013.10.077.
[11] Yao, Y.; Liao, C.; Li, Z.; Wang, Z.; Sun, Q.; Liu, C.; Yang, Y.; Tu, Z.; Jiang, S. Eur. J. Med.
Chem. 2014, 86, 639–652. DOI: 10.1016/j.ejmech.2014.09.024.
[12] El-Helw, E. A. E.; El-Badawy, A. A. J. Heterocycl. Chem. 2020, 57, 2354. DOI: 10.1002/
jhet.3948.
[13] Ramadan, S. K.; El-Helw, E. A. E.; Sallam, H. A. Heterocycl. Commun. 2019, 25, 107–115.
DOI: 10.1515/hc-2019-0008.
[14] Ramadan, S. K.; Sallam, H. A. J. Heterocyclic Chem. 2018, 55, 1942–1954. DOI: 10.1002/
jhet.3232.
[15] (a) Abou-Elmagd, W. S. I.; El-Ziaty, A. K.; Elzahar, M. I.; Ramadan, S. K.; Hashem, A. I.
Synth. Commun. 2016, 46, 1197–1208. DOI: 10.1080/00397911.2016.1193755. (b)
Ramadan, S. K.; Shaban, S. S.; Hashem, A. I. Synth. Commun. 2020, 50, 185–196. DOI:
10.1080/00397911.2019.1691737.
[16] Goudgaon, N. M.; Sheshikant, B. U.; Dhage, D. Heterolett. 2012, 2, 154.
[17] Powers, D. G.; Casebier, D. S.; Fokas, D.; Ryan, W. J.; Troth, J. R.; Coffen, D. L.
Tetrahedron. 1998, 54, 4085–4096. DOI: 10.1016/S0040-4020(98)00137-9.
[18] Rizk, S. A.; El-Hashash, M. A.; Mostafa, K. K. Egypt . J. Chem. 2008, 51, 116.
[19] Rizk, S. A.; Elsayed, G.; El-Hashash, M. A. J. Iran. Chem. Soc. 2018, 15, 2093–2105. DOI:
10.1007/s13738-018-1402-3.
[20] El-Hashash, M. A.; Rizk, S. A.; El-Bassiouny, F. A.; Guirguis, D. B.; Khairy S. M.,
Guirguis , Egypt J. Chem. 2017, 60, 407.
[21] El-Hashash, M. A.; Darwish, K. M.; Rizk, S. A.; El-Bassiouny, F. A. Pharmaceuticals. 2011,
4, 1032–1051. DOI: 10.1155/2011/295491.
[22] Youssef, A. M.; El-Ziaty, A. K.; Abou-Elmagd, W. S. I.; Ramadan, S. K. J. Heterocyclic
Chem. 2015, 52, 278–283. DOI: 10.1002/jhet.1943.
[23] Morsy, A. R. I.; Ramadan, S. K.; Elsafty, M. M. Med. Chem. Res. 2020, 29, 979–988. DOI:
10.1007/s00044-020-02538-z.
[24] Ramadan, S. K.; Elrazaz, E. Z.; Abouzid, K. A. M.; El-Naggar, A. M. RSC Adv. 2020, 10,
29475–29492. DOI: 10.1039/D0RA05943A.
[25] El-Naggar, A. M.; Ramadan, S. K. Synth. Commun. 2020, 50, 2188–2198. DOI: 10.1080/
00397911.2020.1769673.
[26] (a) Ramadan, S. K.; Hashem, A. I.; Abou-Elmagd, W. S. I.; El-Ziaty, A. K. J. Heterocycl.
Chem. 2017, 54, 3711.(b) Ramadan, S. K.; El-Helw, E. A. E. J. Chem. Res. 2018, 42,
332–336. DOI: 10.3184/174751918X15295796734379.

16
M. M. KADDAH ET AL.
[27] Rathelot, P.; Azas, N.; El-Kashef, H.; Delmas, F.; Giorgio, C. D.; Timon-David, P.;
Maldonado, J.; Vanelle, P. Eur. J. Med. Chem. 2002, 37, 671–679. DOI: 10.1016/s0223-
5234(02)01388-0.
[28] Li, J.-P.; Qiu, J.-K.; Li, H.-J.; Zhang, G.-S. J. Chin. Chem. Soc. 2011, 58, 268–271. DOI: 10.
1002/jccs.201190087.
[29] El-Taib Heakal, F.; Rizk, S. A.; Elkholy, A. E. J. Mol. Struct. 2018, 328, 1152.
[30] Chirlian, L. E.; Francl, M. M. J. Comput. Chem. 1987, 8, 894–905. DOI: 10.1002/jcc.
540080616.
[31] Elkholy, A. E.; Rizk, S. A.; Rashad, A. M. J. Mol. Struct. 2019, 788, 1175.
[32] Dhingra, R.; Margulets, V.; Chowdhury, S. R.; Thliveris, J.; Jassal, D.; Fernyhough, P.;
Dorn, G. W.; Kirshenbaum, L. A. Proc. Natl. Acad. Sci. USA. 2014, 111, E5537–E5544.
DOI: 10.1073/pnas.1414665111.
[33] Kalyanaraman, B. Redox Biol. 2020, 29, 101394. DOI: 10.1016/j.redox.2019.101394.
[34] Fang, X.; Wang, H.; Han, D.; Xie, E.; Yang, X.; Wei, J.; Gu, S.; Gao, F.; Zhu, N.; Yin, X.;
et al. Proc. Natl. Acad. Sci. USA. 2019, 116, 2672–2680. DOI: 10.1073/pnas.1821022116.
[35] Mosmann, T. J. Immunol. Methods. 1983, 65, 55–63. DOI: 10.1016/0022-1759(83)90303-4.
[36] Denizot, F.; Lang, R. J. Immunol. Methods. 1986, 22, 271.