An efficient synthesis and evaluation of some novel quinazolinone-pyrazole hybrids as potential antiproliferative agents

Article abstract of DOI:10.1080/00397911.2021.1939058

A series of new quinazolinones and related compounds has been conveniently synthesized via reaction of (E)-3-(1,3-diphenyl-1H-pyrazol-4-yl)-2-(6-iodo-4-oxo-4H-benzo[d] [1,3] oxazin-2-yl)acrylonitrile (2) with different nitrogen nucleophiles. The structures of the prepared compounds were fully elucidated using IR, ¹H-NMR, and ¹³C-NMR spectra. The newly synthesized compounds were tested in vitro against a panel of three human tumor cell lines, namely, hepatocellular carcinoma (liver) HepG2, mammary gland breast MCF-7, and colon cancer HCT-116. Some of the tested compounds showed satisfactory activity.

Full text of DOI:10.1080/00397911.2021.1939058

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
An efficient synthesis and evaluation of some
novel quinazolinone-pyrazole hybrids as potential
antiproliferative agents
Abdelaal A. Abdalha & Mohamed H. Hekal
To cite this article: Abdelaal A. Abdalha & Mohamed H. Hekal (2021) An efficient synthesis and
evaluation of some novel quinazolinone-pyrazole hybrids as potential antiproliferative agents,
Synthetic Communications, 51:16, 2498-2509, DOI: 10.1080/00397911.2021.1939058
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SYNTHETIC COMMUNICATIONSV
2021, VOL. 51, NO. 16, 2498–2509
https://doi.org/10.1080/00397911.2021.1939058
An efficient synthesis and evaluation of some novel
quinazolinone-pyrazole hybrids as potential
antiproliferative agents
Abdelaal A. Abdalha
and Mohamed H. Hekal
Chemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
ABSTRACT
ARTICLE HISTORY
Received 3 April 2021
A series of new quinazolinones and related compounds has been
conveniently synthesized via reaction of (E)-3-(1,3-diphenyl-1H-pyra-
zol-4-yl)-2-(6-iodo-4-oxo-4H-benzo[d] [1,3] oxazin-2-yl)acrylonitrile (2)
with different nitrogen nucleophiles. The structures of the prepared
compounds were fully elucidated using IR, 1H-NMR, and 13C-NMR
spectra. The newly synthesized compounds were tested in vitro
against a panel of three human tumor cell lines, namely, hepatocel-
lular carcinoma (liver) HepG2, mammary gland breast MCF-7, and
colon cancer HCT-116. Some of the tested compounds showed satis-
factory activity.
KEYWORDS
Benzoxazinone; quinazoli-
none; 1,3-diphenyl pyrazole;
tetrazole; antiprolifera-
tive agents
GRAPHICAL ABSTRACT
Introduction
Cancer is considered a major worldwide health problem. Currently, a wide ambit of
cytotoxic drugs is used to cure cancer, and different of these drugs are in various phases
of clinical trials. Heterocyclic compounds are vastly examined as bioactive molecules
and are considered important synthetic objectives for the expansion of novel therapeutic
agents.[1,2] Quinazolinone is one of these heterocycles for which senior research has
been done to investigate its biomedical applications.[3–5] Quinazolinone could be
CONTACT Abdelaal A. Abdalha
abdoelaal73@gmail.com
Chemistry Department, Faculty of Science, Ain Shams
University, Cairo, Egypt
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

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Figure 1. Quinazolinone and pyrazole-based drugs.
considered as one of the most representative heterocycles in medicinal chemistry pre-
sent in various compounds endowed with numerous biological efficiencies. albacona-
zole,[6] ispinesib,[7] idelalisib,[8] balaglitazone,[9] and halofuginone[10] are examples of
marketed drugs endowed with various activities (Fig. 1).
The second pharmacophore component, 1,3-diphenyl pyrazole, is an important cat-
egory of heterocyclic compounds. The pyrazole tethered heterocycles have received con-
siderable concern because of their several chemotherapeutic potentials.[11–13] Some
pyrazole-based drugs available in the market, such as apixaban, crizotinib, and ruxoliti-
nib are important pyrazole tethered anticancer drugs[14] (Fig. 1). Hence, the blending of
the pyrazole moiety is an important synthetic design in the rational drug expan-
sion process.
The biological efficiencies of these pharmacophores, quinazolinone, and pyrazole, led
us to synthesize new lead compounds containing the two pharmacophores with the tar-
get of increasing pharmacological activities. Efforts are being made on a daily basis to
make the structural changes in quinazolinone core to improve their biological activities.
For this purpose, 6-iodo-4H-benzo[d][1,3]oxazin-4-one bearing pyrazolyl group can
serve as a good substrate for inserting various moieties to quinazolinone core. As a part
of our research in the synthesis of a wide domain of heterocyclic systems with biological

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A. A. ABDALHA AND M. H. HEKAL
Scheme 1. Synthesis of 6-iodo-4H-benzo[d][1,3]oxazin-4-one derivative 2.
activities,[15–33] and considering the significant role of quinazolinone derivatives in bio-
logical applications, our current study is concerned with the utility of 6-iodo-4H-ben-
zo[d][1,3]oxazin-4-one bearing pyrazole moiety in the synthesis of new substituted
quinazolinones with anti-proliferative evaluation against three human cancer cell lines.
Results and discussion
Upon treatment of 2-amino-5-iodobenzoic acid with (E)-2-cyano-3-(1,3-diphenyl-1H-
pyrazol-4-yl)acryloyl chloride in dioxane in presence of a catalytic amount of TEA at
room temperature yielded the amide analog 1[34] followed by cyclization in freshly dis-
tilled acetic anhydride to afford the key intermediate (E)-3-(1,3-diphenyl-1H-pyrazol-4-
yl)-2-(6-iodo-4-oxo-4H-benzo[d] [1,3] oxazin-2-yl)acrylonitrile (2)[34] (Scheme 1).
Ample evidence for the suggested structure 2 was deduced from the elemental analysis
and spectral data. The IR spectrum showed absorption bands for the nitrile group at
2227 cmꢀ1 and carbonyl group of oxazinone at 1748 cmꢀ1. Another support of the pro-
1
posed structure of compound 2 was acquired from its H-NMR spectrum that revealed
signals for olefinic, and aromatic protons.
Several new quinazolinones have been obtained using the readily obtainable benzoxa-
zinone derivative 2 upon treatment with different acid hydrazides, such as semicarba-
zide hydrochloride and/or ethyl carbabazate. Thus, refluxing of compound 2 with
semicarbazide hydrochloride in dioxane in presence of a catalytic amount of fused
sodium acetate afforded the quinzolinone derivative 3 via oxazinone ring opening fol-
lowed by ring closure (Scheme 2). Strong evidence for the assigned structure of com-
pound 3 was substantiated from the correct elemental analysis and spectral data. Thus,
the IR spectrum of 3 revealed a strong absorption band for ꢀNH, NH2 at 3402, 3362,
1
3205 cmꢀ1, and carbonyl absorption bands at 1690 and 1682 cmꢀ1. The H-NMR spec-
trum of 3 is under the suggested structure as it revealed signals characteristic to olefinic,

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Scheme 2. Reaction of benzoxazinone derivative 2 with some acid hydrazides and sodium azide.
NH, NH2, and aromatic protons. When compound 2 was treated with ethyl carbazate
in boiling pyridine, the quinazolinone derivative 4 was obtained as a sole product in
fairly good yield. The structure of compound 4 was well-supported by elemental analy-
ses as well as spectral data. Its IR spectrum devoid the absorption band of the lactone
group and showed the presence of a strong absorption band at 3151 cmꢀ1 related to the
1
NH group alongside with a,b-unsaturated nitrile group at 2209 cmꢀ1. H-NMR of com-
pound 4 revealed its existence as a diastereomeric mixture (E/Z) in the ratio 61:39 (cf.
Experimental).
An attempt to construct a quinazolinone derivative through the reaction of com-
pound 2 with thiosemicarbazide in boiling pyridine was not successful because it yielded
Schiff-like base 5[29] instead of compound 6 as shown in Scheme 2. The IR spectrum of
carbothioamide derivative revealed the absorption bands for NH2 at 3329, 3257 cmꢀ1
,
NH at 3161 cmꢀ1, and C¼N at 1618 cmꢀ1. Moreover, the compelling evidence for this
structure is forthcoming from an authentic sample prepared from the reaction of thiose-
micarbazide with 1,3-diphenylpyrazole-4-carboxylaldehyde in boiling pyridine (TLC,
mp, and IR comparison).

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A. A. ABDALHA AND M. H. HEKAL
Scheme 3. Mechanistic pathway for the formation of compound 8.
Refluxing of compound 2 with p-toluenesulfonohydrazide in boiling dioxane gave the
uncyclized product 7 (Scheme 2). The moderate yield (60%) of 7 was due to the bulk
size of p-toluenesulfonohydrazide which makes the nucleophilic attack of nitrogen
nucleophile is difficult.
The spectral data and elemental analysis were in good agreement with the assigned
structure (cf. Experimental). In addition, the reaction of the oxazinone 2 with sodium
azide in refluxing acetic acid for 10 h afforded tetrazole derivative 8 rather than com-
pound 9 (Scheme 2). The moderate yield (55%) of 8 was due to the repulsion forces
between the tetrazole ring and the carboxylic group. Adequate evidence for structure 8
is forthcoming from the study of its spectral data. The IR spectrum exhibited absorption
1
bands at 3448 cmꢀ1 (br. OH), 2211 cmꢀ1 (CꢁN), and 1685 cmꢀ1 (C¼O). Also, H-
NMR and 13C-NMR spectra are in accord with the suggested structure (cf.
Experimental). A plausible mechanism for the formation of tetrazole derivative 8 is out-
lined in Scheme 3.
On the other hand, our current research was extended to examine the chemical
behavior of benzoxazinone derivative 2 toward some bidentate nucleophiles. Therefore,
ring-opening of compound 2 followed by cyclization was achieved via its reaction with
o-phenylene diamine in refluxing dioxane to yield quinazolinone derivative 10 as a sole
product (Scheme 4). IR spectrum of 10 showed absorption bands at 3376, 3208, 2217,
and 1656 cmꢀ1 corresponds to NH2, CꢁN, and C¼O groups, respectively. Moreover,
1H-NMR and 13C-NMR spectra strongly confirmed the proposed structure (cf.
Experimental).
Likewise, refluxing of compound 2 with 1,2-diaminoethane in dioxane afforded qui-
nazolinone derivative 11 (Scheme 4). It was found that 11 was formed in moderate

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Scheme 4. Reaction of benzoxazinone derivative 2 toward some bidentate nucleophiles.
yield (55%) due to the probability of formation of another opened structure that cannot
be isolated. The IR spectrum revealed the disappearance of the carbonyl absorption
band of d-lactone, whereas two absorptions bands were displayed at 1686 and
2206 cmꢀ1 for (CO, amide) and nitrile group, respectively. While, when compound 2
was allowed to react with ethanol amine in boiling dioxane gave the amide analog 12
(Scheme 4). The formation of 12 in moderate yield (50%) was due to competition
between the two nucleophilic centers (OH and NH2).
IR spectrum of compound 12 showed the carbonyl absorption band of the amide group
at 1686cmꢀ1. In addition, 1H-NMR spectrum was completely matched with the uncyclized
structure 12.
It is noteworthy that hydrazinolysis of compound 2 using hydrazine monohydrate
(1:2) in refluxing dioxane for 4 h afforded gray crystals which were identified as (Z)-2-
((hydrazineylmethylene)amino)-5-iodobenzoic acid 13 on hot in addition to the azine
derivative 14,[26] which was deposited after acidification of the mother liquor
(Scheme 5).
1
The structures of compounds 13 and 14 were approved by IR, H-NMR, and 13C-
NMR as long as elemental analyses (cf. Experimental section). While stirring the
benzoxazinone 2 with hydrazine monohydrate (1:2) in dioxane at room temperature

2504
A. A. ABDALHA AND M. H. HEKAL
Scheme 5. Treatment of benzoxazinone derivative 2 with some nitrogen nucleophiles.
for 12 h (TLC), benzoic acid derivative 15 was obtained after evaporation of the
excess solvent. The formation of compound 15 could be postulated as shown in
Scheme 6.
Moderate yields (40 and 49%) are found in reaction of start 2 with hydrazine hydrate
at room temperature and on hot, in this reaction on hot two products are formed 13
and 14 and the percentage of 13 was 40% due to high temperature and time led to
break bonds and forms another product 14 which its yield was 60%, and due to low sta-
bility of 13, its yield was low.
Also at room temperature, the product was in low yield due to the high reactivity of
hydrazine which may led to the formation of another unexpected product that cannot
be isolated, also due to the low stability of the product.
Refluxing of the benzoxazinone 2 with excess formamide in an oil bath at 170 ꢂC for
3 h gave the quinazolinone derivative, 16. The reaction presumably involved the

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Scheme 6. Mechanistic pathway for the formation of compound 15.
decomposition of formamide under the effect of the employed temperature to manufac-
ture ammonia, which reacts with compound 2 to afford the quinazolinone 16
(Scheme 5).
To extend the synthetic potential of benzoxazinone 2, it was allowed to react with
heterocyclic amines namely, 3-amino pyridine, trimethoprim, and 2-hydrazino pyridine.
The amide derivatives 17 and 18 were obtained upon the reaction of compound 2 with
3-amino pyridine and trimethoprim in refluxing dioxane (Scheme 5). The structures of
compounds 17, 18 were confirmed by studying their spectral data. Their IR spectra
showed bands corresponding to C ¼ O groups as well as bands for NH, NH2 groups.
1
Further evidence for the suggested structures was gained from their HNMR spectra,
where they were in good agreement with the assigned structures (cf.
Experimental section).
Meanwhile, the reaction of compound 2 with 2-hydrazino pyridine in refluxing
dioxane gave the Schiff-like base 19[35] rather than the quinazolinone 20. The strong
clue for structure 19 is forthcoming from an authentic sample prepared from condensa-
tion of the 2-hydrazino pyridine with 1,3-diphenylpyrazole-4-carboxaldehyde in reflux-
ing dioxane (TLC, mp, and IR comparison) (Scheme 5).
Cytotoxicity and antitumor evaluation
All the synthesized compounds were evaluated for their anti-tumor activity in vitro
against three cell lines, hepatocellular carcinoma (HePG-2), colon cancer HCT-116, and
mammary gland breast cancer (MCF-7) (Table 1). Generally, the activity detected by
these synthesized compounds extended from very strong to weak cytotoxic activity. The
novel quinazolinone derivative 3 showed promising anti-proliferative activity as strong
as doxorubicin against HepG2, HCT-116, and MCF-7 cell lines with IC50 at 4.99 3.1,
6.83 2.7, and 4.63 2.8 mM, respectively. Likewise, The novel amide analogs (7, 12, and

2506
A. A. ABDALHA AND M. H. HEKAL
Table 1. Cytotoxicity (IC50) of the tested compounds on different cell lines.
In vitro cytotoxicity IC50 (mM)
Compound no
HePG2
HCT-116
MCF-7
1
2
3
4
5
7
8
10
11
12
14
15
16
17
18
19
DOX
14.71 1.2
65.14 3.1
4.99 3.1
16.18 3.2
19.18 1.9
6.85 1.7
73.11 3.8
17.64 4.0
78.12 4.1
9.62 3.9
93.18 1.2
15.94 2.4
55.94 2.6
35.94 2.6
6.50 1.2
89.53 1.6
4.50 0.2
13.57 1.7
45.95 3.3
6.83 2.7
11.78 2.8
20.78 1.1
5.46 1.9
88.60 4.6
20.51 3.7
55.31 3.8
5.24 4.1
67.39 0.9
13.32 2.1
63.42 2.5
23.42 2.5
4.23 2.3
78.95 1.5
5.23 0.3
19.52 2.3
79.88 3.1
4.63 2.8
18.72 4.0
15.72 1.3
9.07 1.8
69.16 3.7
16.30 3.6
73.22 3.7
7.89 4.0
79.61 0.7
17.64 2.6
47.84 2.2
47.84 2.2
7.17 1.5
62.62 1.8
4.17 0.2
DOX: doxorubicin.
18) displayed strong cytotoxic activity against cancer cell lines with IC50 of 4.2–9.6 mM.
Compounds 7 and 12 showed very strong activity, owing to the presence of NH and
OH groups in addition to SO2Ph moiety in 7 which can make a hydrogen bond with
either one of the nucleobases of the DNA. Also, the presence of the SO2Ph group as a
strong electron-withdrawing group rendered the molecule positively charged forming
electrostatic attraction with the DNA nucleobases. Moreover, compound 18 showed
very strong cytotoxic activity against the three representative cell lines with IC50 ranged
from 4.23 2.3 to 7.17 1.5 mM.
In addition, compounds 1 and 4 exhibited strong activity against HCT-116 cell line
with IC50 13.57 1.7 and 11.78 2.8 mM, respectively. While compounds 5 and 10
showed strong cytotoxic activity against the MCF7 cell line with IC50 15.72 1.3 and
16.30 3.6 mM, respectively. On the other hand, compounds 2, 8, 11, 14, and 19 dis-
played moderate and weak cytotoxic activity against the three representative cell lines
with IC50 ranged from 45.95 3.3 to 89.53 1.6 mM compared to doxorubicin.
Possible structure-activity relationships (SAR)
The cytotoxic activity of the tested compounds toward different cell lines depends on
two factors:[36,37] (i) the formation of an intermolecular hydrogen bond with DNA
bases; (ii) the positive charge on the tested compounds attracted to the negative charge
on the cell wall. By comparing the experimental cytotoxicity of the compounds reported
in this study to their structures, the following SAR was postulated:
ꢃ
ꢃ
Compound 3 showed very strong anti-proliferative activity, due to the existence
of NH and NH2 groups, which may interact with any unsaturated moiety in
DNA or form hydrogen bonds with the nucleic bases of DNA.
Compounds 7 and 12 showed very strong activity owing to the presence of NH
and OH groups in addition to SO2Ph moiety in 7 which can make a hydrogen

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2507
bond with either one of the nucleobases of the DNA. Also, the presence of the
SO2Ph group as a strong electron-withdrawing group rendered the molecule
positively charged forming electrostatic attraction with the DNA nucleobases.
In addition, compound 18 with pyrimidine moiety has very strong potency due
to the incorporation of electron-donating substituents, such as NH2 and OCH3.
ꢃ
Experimental
All melting points were measured on a Griffin and George melting-point apparatus
(Griffin & Georgy Ltd., Wembley, Middlesex, UK) and are uncorrected. IR spectra were
recorded on Pye Unicam SP1200 spectrophotometer (Pye Unicam Ltd., Cambridge,
1
UK) by using the KBr wafer technique. H-NMR spectra were determined on a Varian
Gemini 300 MHz on Bruker Avance III using tetramethylsilane as an internal standard
(chemical shifts in d scale), while 13C- NMR spectra were run at 75 MHz. Elemental
analyses were carried out at the Microanalytical Unit, Faculty of Science, Ain Shams
University, using a Perkin-Elmer 2400 CHN elemental analyzer (Waltham, MA, USA),
and satisfactory analytical data ( 0.4) were obtained for all compounds. The homogen-
eity of the synthesized compounds was controlled by thin-layer chromatography (TLC),
using aluminum sheet silica gel F254 (Merck).
(E)-2-(2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acrylamido)-5-iodobenzoic acid (1)
To a solution of iodoanthranilic acid (2.6 g, 10 mmol) in dioxane (20 ml) in presence of
TEA as a catalyst, (E)-2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl chloride (3.3 g,
10 mmol) was added with stirring at room temperature for 0.5 h. The solid product that
precipitated down was filtered off, washed by cold water, dried, and then recrystallized
from ethanol to give 1 as pale yellow crystals, mp > 300 ꢂC, and yield 80% [Lit.
mp: 326–328 ꢂC].[34]
ORCID
Abdelaal A. Abdalha
Mohamed H. Hekal
http://orcid.org/0000-0002-2573-1681
http://orcid.org/0000-0001-6059-9666
References
[1] Shagufta, A. I. Sulfones: An Important Class of Organic Compounds with Diverse
Biological Activities. Int. J. Pharm. Sci. 2015, 7, 19–27.
[2] Shagufta, A. I. Recent Insight into the Biological Activities of Synthetic Xanthone
Derivatives. Eur. J. Med. Chem. 2016, 116, 267–280. DOI: 10.1016/j.ejmech.2016.03.058.
[3] Demeunynck, M.; Baussanne, I. Survey of Recent Literature Related to the Biologically
Active 4(3H)-Quinazolinones Containing Fused Heterocycles. CMC. 2013, 20, 794–814.
DOI: 10.2174/0929867311320060006.
[4] Hekal, M. H.; Abu El-Azm, F. S. M. New Potential Antitumor Quinazolinones Derived
from Dynamic 2-Undecyl Benzoxazinone: Synthesis and Cytotoxic Evaluation. Synth.
Commun. 2018, 48, 2391–2402. DOI: 10.1080/00397911.2018.1490433.
[5] Hekal, M. H.; Abu El-Azm, F. S. M.; Atta-Allah, S. R. Ecofriendly and Highly Efficient
Microwave-Induced Synthesis of Novel Quinazolinone-Undecyl Hybrids with in vitro

2508
A. A. ABDALHA AND M. H. HEKAL
Antitumor Activity. Synth. Commun. 2019, 49, 2630–2641. DOI: 10.1080/00397911.2019.
1637001.
[6] Girmenia, C.; Finolezzi, E. New-Generation Triazole Antifungal Drugs: Review of the
Phase II and III Trials. Clin. Investig. 2011, 1, 1577–1594. DOI: 10.4155/cli.11.137.
[7] Purcell, J. W.; Davis, J.; Reddy, M.; Martin, S.; Samayoa, K.; Vo, H.; Thomsen, K.; Bean,
P.; Kuo, W. L.; Ziyad, S.; et al. Activity of the Kinesin Spindle Protein Inhibitor Ispinesib
(sb-715992) in Models of Breast Cancer. Clin. Cancer Res. 2010, 16, 566–576. DOI: 10.
1158/1078-0432.CCR-09-1498.
[8] Do, B.; Mace, M.; Rexwinkle, A. Idelalisib for Treatment of B-Cell Malignancies. Am. J.
Health. Syst. Pharm. 2016, 73, 547–555. DOI: 10.2146/ajhp150281.
[9] Abida , An Updated Review: Newer Quinazoline Derivatives Under Clinical Trial. Int. J.
Pharm. Biol. Arch. 2011, 2, 1651–1657.
[10] Derbyshire, E. R.; Mazitschek, R.; Clardy, J. Characterization of Plasmodium Liver Stage
Inhibition by Halofuginone. ChemMedChem 2012, 7, 844–849. DOI: 10.1002/cmdc.
201200045.
[11] Raffa, D.; Maggio, B.; Raimondi, M. V.; Cascioferro, S.; Plescia, F.; Cancemi, G.; Daidone,
G. Recent Advanced in Bioactive Systems Containing Pyrazole Fused with a Five
Membered Heterocycle. Eur. J. Med. Chem. 2015, 97, 732–746. DOI: 10.1016/j.ejmech.
2014.12.023.
[12] Ku€c¸u€kgu€zel, S¸G.; S¸enkarde¸s, S. Recent Advances in Bioactive Pyrazoles. Eur. J. Med.
Chem. 2015, 97, 786–815. DOI: 10.1016/j.ejmech.2014.11.059.
[13] Zhang, W. M.; Xing, M.; Zhao, T. T.; Ren, Y. J.; Yang, X. H.; Yang, Y. S.; Lv, P. C.; Zhu,
H. L. Synthesis, Molecular Modeling and Biological Evaluation of Cinnamic Acid
Derivatives with Pyrazole Moieties as Novel Anticancer Agents. RSC Adv. 2014, 4,
37197–37207. DOI: 10.1039/C4RA05257A.
[14] Bronson, J.; Dhar, M.; Ewing, W.; Lonberg, N. Chapter Thirty-One-to Market, to Market-
2011. Annu. Rep. Med. Chem. 2012, 47, 499–569.
[15] Shalaby, A. A.; El-Khamry, A. M. A.; Shiba, S. A.; Ahmed, A. A. A. E. A.; Hanafi, A. A.
Synthesis and Antifungal Activity of Some New Quinazoline and Benzoxazinone
Derivatives. Arch. Pharm. Pharm. Med. Chem. 2000, 333, 365–372. DOI: 10.1002/1521-
4184(200011)333:11<365::AID-ARDP365>3.0.CO;2-2.
[16] El-Khamry, A. A.; Shiba, S. A.; Shalaby, A. A.; Abd Alaha, A. A. Synthesis of Some New
Pyrazoloquinazolinone and Quinazolinone Derivatives. J. Het. Chem. 2006, 43, 1189–1193.
DOI: 10.1002/jhet.5570430509.
[17] Abdalha, A.; Abou EL-Regal, M.; EL-Kassaby, M.; Nazeer, A. Some Reactions of 6,8-Dibromo-
2-Propenyl-4H-3,1-Benzoxazin-4-One with Nitrogen Nucleophiles under Microwave
Irradiation. Al-Azhar Bull. Sci. 2007, 18, 163–171. DOI: 10.21608/absb.2007.10873.
[18] El-Ziaty, A.; Abdalh, A.; Hamed, A.; Shiba, S.; Abdullha, A. Synthesis of Novel 2-Propenoyl
Amides, Esters, Heterocyclic Compounds and Their Screening as Antifungal and
Antibacterial Agents. Eur. J. Chem. 2012, 3, 65–70. DOI: 10.5155/eurjchem.3.1.65-70.518.
[19] Hamed, A. A.; El-Ziaty, A. K.; Abdalha, A. A.; Shiba, S. A.; Abdullha, A. H. Synthesis and
Anti-Tumor Evaluation of Some New Tranilast Analogous. World Appl. Sci. J. 2012, 19,
688–698.
[20] Abdalha, A. A.; Mekawey, A. A. I. Antimicrobial Susceptibility of Certain Fungal and
Bacterial Strains to Dodecanamide and Quinazolinone Derivatives. World Appl. Sci. J.
2013, 24, 312–319.
[21] Assy, M. G.; Abdalha, A. A.; Abdel Aziz, A. E. Synthesis and Antimicrobial Evaluation of
Some New Benzoxazinone and Quinazolinone Derivatives. JAC 2016, 8, 1491–1499. DOI:
10.24297/jac.v8i1.4030.
[22] Abou-Elmagd, W. S. I.; EL-Ziaty, A. K.; Abdalha, A. A. Ring Transformation and
Antimicrobial Activity of Indolyl-Substituted 2(3H)-Furanones. Het. Commun. 2015, 21,
179–185. DOI: 10.1515/hc-2015-0008.

R
SYNTHETIC COMMUNICATIONSV
2509
[23] Hekal, M. H.; Abu El-Azm, F. S. M. Efficient MW-Assisted Synthesis of Some New
Isoquinolinone Derivatives with in vitro Antitumor Activity. J. Het. Chem. 2017, 54,
3056–3064.
[24] Mahmoud, M. R.; Abou-Elmagd, W. S. I.; Derbala, H. A.; Hekal, M. H. Synthesis and
Spectral Characterisation of Some Phthalazinone Derivatives. J. Chem. Res. 2012, 36,
75–82. DOI: 10.3184/174751912X13274297624330.
[25] Mahmoud, M. R.; Abu El-Azm, F. S. M.; Ismail, M. F.; Hekal, M. H.; Ali, Y. M. Synthesis
and Antitumor Evaluation of Novel Tetrahydrobenzo [40,50]Thieno[30,20:5,6]Pyrimido[1,2-
b]Isoquinoline Derivatives. Synth. Commun. 2018, 48, 428–438.
[26] Mahmoud, M. R.; El-Shahawi, M. M.; Abou-Elmagd, W. S. I.; Hekal, M. H. Novel
Synthesis of Isoquinoline Derivatives Derived from (Z)-4-(1,3-Diphenylpyrazol-4-
yl)Isochromene-1,3-Dione. Synth. Commun. 2015, 45, 1632–1641. DOI: 10.1080/00397911.
2015.1030760.
[27] Hekal, M. H.; El-Naggar, A. M.; Abu El-Azm, F. S. M.; El-Sayed, W. M. Synthesis of New
Oxadiazol-Phthalazinone Derivatives with Anti-Proliferative Activity; Molecular Docking,
Pro-Apoptotic, and Enzyme Inhibition Profile. RSC Adv. 2020, 10, 3675–3688. DOI: 10.
1039/C9RA09016A.
[28] Mahmoud, M. R.; Abou-Elmagd, W. S. I.; Derbala, H. A.; Hekal, M. H. Novel Synthesis of
Some Phthalazinone Derivatives. Chin. J. Chem. 2011, 29, 1446–1450. DOI: 10.1002/cjoc.
201180264.
[29] Abdelgawad, N.; Ismail, M. F.; Hekal, M. H.; Marzouk, M. I. Design, Synthesis, and
Evaluation of Some Novel Heterocycles Bearing Pyrazole Moiety as Potential Anticancer
Agents. J. Heterocyclic Chem. 2019, 56, 1771–1779. DOI: 10.1002/jhet.3544.
[30] Ali, A. T.; Hekal, M. H. Convenient Synthesis and Anti-Proliferative Activity of Some
Benzochromenes and Chromenotriazolopyrimidines Under Classical Methods and Phase
Transfer Catalysis. Synth. Commun. 2019, 49, 3498–3509. DOI: 10.1080/00397911.2019.
1675173.
[31] Hekal, M. H.; Abu El-Azm, F. S. M.; Salla, H. A. Synthesis, Spectral Characterization, and
in vitro Biological Evaluation of Some Novel Isoquinolinone-Based Heterocycles as
Potential Antitumor Agents. J. Heterocyclic Chem. 2019, 56, 795–803. DOI: 10.1002/jhet.
3448.
[32] Abu El-Azm, F. S. M.; Ali, A. T.; Hekal, M. H. Facile Synthesis and Anticancer Activity of
Novel 4-Aminothieno[2,3-d]Pyrimidines and Triazolothienopyrimidines. Org. Prep.
Proced. Int. 2019, 51, 507–520. DOI: 10.1080/00304948.2019.1666635.
[33] Hekal, M. H.; Ali, Y. M.; Abu El-Azm, F. S. M. Utilization of Cyanoacetohydrazide and 2-
(1,3-Dioxoisoindolin-2-yl) Acetyl Chloride in the Synthesis of Some Novel anti-
Proliferative Heterocyclic Compounds. Synth. Commun. 2020, 50, 2839–2852. DOI: 10.
1080/00397911.2020.1786125.
[34] Ramadan, S. K.; El-Ziaty, A. K.; Ali, R. S. Synthesis, Antiproliferative Activity, and
Molecular Docking of Some N-Heterocycles Bearing a Pyrazole Scaffold Against Liver and
Breast Tumors. J. Heterocyclic Chem. 2021, 58, 290–304. DOI: 10.1002/jhet.4168.
[35] Prakash, O.; Khalid Hussain, K.; Aneja, D. K.; Sharma, C.; Aneja, K. R. A Facile
Iodine(III)-Mediated Synthesis of 3-(3-Aryl-1-Phenyl-1H-Pyrazol-4-yl)-[1,2,4]Triazolo[4,3-
a]Pyridines via Oxidation of 2-((3-Aryl-1-Phenyl-1Hpyrazol-4-yl)Methylene)-1-(Pyridin-2-
yl)Hydrazines and Their Antimicrobial Evaluations. Org. Med. Chem. Lett. 2011, 1, 1–9.
DOI: 10.1186/2191-2858-1-1.
[36] Bischoff, G.; Hoffmann, S. DNA-Binding of Drugs Used in Medicinal Therapies. CMC.
2002, 9, 321–348. DOI: 10.2174/0929867023371085.
[37] Martinez, R.; Chacon-Garcia, L. The Search of DNA-Intercalators as Antitumoral Drugs:
What It Worked and What Did Not Work. CMC. 2005, 12, 127–151. DOI: 10.2174/
0929867053363414.