Facile and expedient synthesis and anti-proliferative activity of diversely pyrrolones bearing 1,3-diphenylpyrazole moiety

Article abstract of DOI:10.1080/00397911.2019.1691737

A series of some pyrrolone derivatives were synthesized from the acid hydrazide, derived from a pyrazolyl-2(3H)-furanone, through treating with some carbonyl reagents such as 1-phenyl-3-(thiophen-2-yl)-1H-pyrazole-4-carbaldehyde, formic acid, lauroyl chloride, succinoyl chloride, propionic anhydride, as well as, ethoxymethylene malononitrile. All compounds were obtained in good yields and characterized by their microanalytical and spectral data. The synthesized products were evaluated for their in vitro antitumor activity against two human carcinoma cell lines (HCT-116 and MCF7) using doxorubicin as a reference drug by MTT assay. The results revealed that some compounds exhibited significant potency. Noteworthy, the N-propionyl hydrazide derivative was the most potent against both cell lines.

Full text of DOI:10.1080/00397911.2019.1691737

Synthetic Communications
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Facile and expedient synthesis and anti-
proliferative activity of diversely pyrrolones
bearing 1,3-diphenylpyrazole moiety
Sayed K. Ramadan, Safaa S. Shaban & Ahmed I. Hashem
To cite this article: Sayed K. Ramadan, Safaa S. Shaban & Ahmed I. Hashem (2019): Facile
and expedient synthesis and anti-proliferative activity of diversely pyrrolones bearing 1,3-
diphenylpyrazole moiety, Synthetic Communications, DOI: 10.1080/00397911.2019.1691737
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https://doi.org/10.1080/00397911.2019.1691737
Facile and expedient synthesis and anti-proliferative
activity of diversely pyrrolones bearing 1,3-
diphenylpyrazole moiety
Sayed K. Ramadan , Safaa S. Shaban, and Ahmed I. Hashem
Chemistry Department, Faculty of Science, Ain Shams University, Abassia, Cairo, Egypt
ABSTRACT
ARTICLE HISTORY
Received 10 October 2019
A series of some pyrrolone derivatives were synthesized from the
acid hydrazide, derived from a pyrazolyl-2(3H)-furanone, through
treating with some carbonyl reagents such as 1-phenyl-3-(thiophen-
2-yl)-1H-pyrazole-4-carbaldehyde, formic acid, lauroyl chloride, succi-
noyl chloride, propionic anhydride, as well as, ethoxymethylene
malononitrile. All compounds were obtained in good yields and
characterized by their microanalytical and spectral data. The synthe-
sized products were evaluated for their in vitro antitumor activity
against two human carcinoma cell lines (HCT-116 and MCF7) using
doxorubicin as a reference drug by MTT assay. The results revealed
that some compounds exhibited significant potency. Noteworthy,
the N-propionyl hydrazide derivative was the most potent against
both cell lines.
KEYWORDS
Cytotoxic; antitumor; acid
hydrazide; pyrro-
lones; pyrazoles
GRAPHICAL ABSTRACT
Introduction
The development of new anticancer therapeutic agents is one of the fundamental
goals in medicinal chemistry. Cytotoxicity of the anticancer drugs to the normal cells
represent major problems in cancer therapy.[1] The pyrazole scaffolds, double nitrogen-
containing heterocyclic aromatic organic compounds, have attracted significant attention
for their fascinating physiological and pharmacological applications. They have remark-
able and valuable biological properties such as anti-H5N1 activities, antiviral, antitumor,
CONTACT Sayed K. Ramadan
sayed_karam88@yahoo.com
Chemistry Department, Faculty of Science, Ain Shams
University, Abassia, Cairo, 11566, Egypt.
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 2019 Taylor & Francis Group, LLC

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S. K. RAMADAN ET AL.
antimicrobial, antihistaminic, antidepressant, antioxidant and anticonvulsant.[2–14] In
turn, 2(3H)-furanones were easily transformed into a wide variety of nitrogen hetero-
cycles of synthetic and pharmacological prominence e.g. antiviral, anti-inflammatory,
antitumor, antimalarial, antimicrobial and herbicidal activities.[15–22] The ability of these
products to contribute to cancer therapy has been evidenced by numerous in vitro as
well as in vivo studies. Therefore, extensive researches are still needed to improve and
enhance their properties and to reduce their adverse effects. Thus, in the present work,
2(3H)-furanone incorporating a pyrazole moiety was readily synthesized and efficiently
utilized for the construction of some N-heterocycles to examine them as potential anti-
tumor agents.
Results and discussion
Synthesis
The requisite acid hydrazide 2 was previously prepared from hydrazinolysis of pyra-
zolyl-2(3H)-furanone 1 with hydrazine hydrate,[18] and submitted to react with some
carbonyl reagents (Schemes 1 and 2). Indeed, condensation of the hydrazide 2 with the
pyrazole aldehyde namely, 1-phenyl-3-(thiophen-2-yl)-1H-pyrazole-4-carbaldehyde[23]
(3) afforded the corresponding hydrazone 4 as yellow crystals which was easily trans-
formed into the pyrrolone derivative 5 in a good yield by refluxing in an equimolar
mixture of HCl/CH3COOH (1:1) for 1 h (Scheme 1). The chemical structures of com-
pounds 4 and 5 were substantiated from their spectral data. The IR spectrum of hydra-
zone 4 revealed the absence of NH2 absorption band and the appearance of the
absorption bands for NH, carbonyl of ketonic and amide as well as C¼N groups at m
1
3286, 1694, 1659, and 1622 cmꢀ1, respectively. The H-NMR spectrum of compound 4
confirmed its existence as a mixture of two geometrical Syn- and Anti-isomers in an
equal ratio as it showed two singlet signals of equal integration for CH¼N proton. In
Scheme 1. Condensation of hydrazide 2 with pyrazole aldehyde 3.

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3
Scheme 2. Reaction of hydrazide 2 with formic acid and propionic anhydride.
Scheme 3. A suggested mechanistic pathway for the formation of pyridazinone 7.
1
turn, the H-NMR spectrum of compound 5 was devoid from the singlet signals of NH
and CH2 protons (cf. Experimental). Formation of pyrrolone 5 could be visualized to
occur via acid catalyzed 5-exo trig cyclization.
Refluxing the hydrazide 2 with formic acid led to the construction of pyridazinone 7
instead of the oxadiazole derivative 6 (Scheme 2). The structure of compound 7 was
supported from its spectral data and by direct comparison with an authentic sample
prepared by refluxing the hydrazide 2 in HCl/CH3COOH mixture (1:1), where they
were identical in all respects (mp, mixed mp, TLC, and IR). The driving force behind
the formation of pyridazinone 7 could be explained via protonation of the ketonic car-
bonyl oxygen by formic acid pursued by 6-exo-trig cyclization as depicted in Scheme 3.

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S. K. RAMADAN ET AL.
On the other hand, acylation of the acid hydrazide 2 using propionic anhydride under dif-
ferent reaction conditions was investigated. Indeed, stirring the hydrazide 2 with propionic
anhydride at room temperature furnished the N-propionyl hydrazide derivative 8 as pale-
yellow crystals in 82% yield. While the pyrrolone derivative 9 was obtained as canary yellow
crystals upon conveying this reaction under heating at 70ꢁC (Scheme 2). The structures of
1
compounds 8 and 9 were corroborated by spectroscopic data. The H-NMR spectrum of
compound 8 exhibited a singlet signal for CH2 protons, quartet and triplet signals for
–CH2CH3 group as well as two exchangeable broad singlet signals attributable for two NH
1
protons. Meanwhile, the H-NMR spectrum of compound 9 provided duplicate signals of
different integrations which represent good evidence for its existence as a mixture of two
geometrical E- and Z-stereoisomers in a ratio of 2:1, respectively. The higher percentage of
the E-isomer as compared with the Z-counterpart may be attributed to the steric
interference between carbonyl group of pyrrolone and the bulky substituted pyrazolyl moi-
ety in Z-isomer. The formation of pyrrolone 9 could be visualized to occur via 5-exo-trig
cyclization of the N-propionyl hydrazide derivative 8.
When the hydrazide 2 was subjected to react with dodecanoyl chloride in refluxing
benzene, the pyrrolone 11 was obtained as orange crystals in 78% yield (Scheme 4). The
IR spectrum exhibited the stretching absorption bands for C¼O of pyrrolone at
Scheme 4. Reaction of hydrazide 2 with dodecanoyl chloride and succinoyl chloride.

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5
1
m 1705 cmꢀ1 and NH at m 3310 cmꢀ1. Its H-NMR spectrum was in a good agreement
with the assigned structure as it displayed signals for protons of –(CH2)10CH3 moiety.
1
Also, the H-NMR spectrum displayed its existence as a mixture of E- and Z-isomer in
a ratio of 55:45%, respectively, as it showed two singlet signals for each of CH olefinic,
pyrazolyl and pyrrolonyl protons (cf. Experimental). Formation of pyrrolone 11 could
be interpreted to occur via nucleophilic attack of the terminal NH2 group of hydrazide
on the –COCl group of dodecanoyl chloride to give the N-dodecanoyl hydrazide deriva-
tive 10 as a non-isolable intermediate which in situ underwent 5-exo-trig cyclization to
eliminate water molecule (cf. Scheme 4).
It was fortunate that, hydrazinolysis of the pyrrolone 11 in boiling ethanol
achieved the pyridazinone 7 which was supported by direct comparison with the
product obtained from reaction of hydrazide 2 with formic acid (cf. Scheme 4). The
heterocyclic transformation of pyrrolone 11 into pyridazinone 7 could be represented
via ring opening of pyrrolone by nucleophilic attack of hydrazine which subse-
quently underwent 6-exo-trig cyclization followed by elimination of dodecanoyl
hydrazide (Scheme 5).
It was interesting that similar treatment of the hydrazide 2 with succinoyl chloride in
refluxing benzene prompted the construction of pyrrolone derivative 12 instead of pyr-
rolylpyrrolidinedione 13 (Scheme 4). The IR spectrum displayed the stretching absorp-
tion bands for NH at m 3262 cmꢀ1 and C¼O groups at m 1724 and 1690 cmꢀ1, ruling
1
out the structure 13. Likewise, its H-NMR spectrum displayed an exchangeable broad
singlet signal at d 10.62 ppm which attributed to NH proton and it was in accordance
with the proposed structure (cf. Experimental). The formation of compound 12 could
be interpreted via elimination of two HCl molecules from two hydrazide molecules with
both terminal acid chloride moieties in succinoyl chloride followed by 5-exo-trig cyc-
lization. The driving force behind the reaction pathway could be the high reactivity of
the acid chloride that will immediately form the dimer 12.
It was fortunate that, treatment of the hydrazide 2 with ethoxymethylene malononi-
trile in boiling dioxane led to the construction of pyrrolone 14 instead of the cyanoami-
nopyrazole derivative 15 (Scheme 6). The IR spectrum was devoid from the absorption
bands of CꢂN and NH2 groups, with the appearance of the stretching absorption bands
for carbonyl groups at m 1719 and 1697 cmꢀ1, which excluded the enaminonitrile struc-
1
ture 15 and confirmed the pyrrolone structure 14. Also, inspection of the H-NMR
spectrum was completely matched with the assigned structure and revealed the absence
of singlet signal for NH2 protons and showed its existence in the enol form (cf.
Experimental). Formation of pyrrolone derivative 14 could be demonstrated to occur as
depicted in Scheme 7.
In vitro antiproliferative activity
Cytotoxic effect on human cell lines (HCT-116 and MCF7)
In vitro cytotoxic activity was examined by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyl
tetrazolium bromide (MTT assay),[24–26] as this technique represent a reliable method to
determine the bioactivity of the products.[27,28] The synthesized compounds were exam-
ined against two human carcinoma cell lines namely, colon cancer HCT-116 and

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S. K. RAMADAN ET AL.
Scheme 5. A plausible pathway for hydrazinolysis of pyrrolone 11.
mammary gland breast cancer MCF7 cell lines using doxorubicin as a standard anti-
cancer drug. The anticancer activity was expressed as IC50 values (the concentration of
test compounds required to kill 50% of the cell population). The results of cytotoxic
activity of compounds are depicted in Table 1 and Figure 1. The results obtained
revealed that the tested compounds exhibited variable degrees of inhibitory activity
towards the two tested human tumor cell lines. As for activity against HCT-116, the
most potent cytotoxic activity was shown by compounds 8 and 11 which displayed the
percentage viability IC50 at 6.91 2.8 and 7.49 1.2 lM, respectively. Whereas, the
strong cytotoxic activity was displayed by compounds 9 and 12 which showed the per-
centage viability IC50 at 18.73 1.2 and 15.47 2.9 lM, respectively. While compounds 5
and 14 showed weak activity. On the other hand, the activity against MCF7 cell line
revealed that compounds 8 and 11 have the highest percentage viability IC50 at
7.68 2.5 and 8.51 2.3 lM, respectively. Both compounds 9 and 12 showed good

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7
Scheme 6. Reaction of hydrazide 2 with ethoxymethylene malononitrile.
Scheme 7. A plausible pathway for the formation of compound 14.

8
S. K. RAMADAN ET AL.
Table 1. In vitro Cytotoxic effect on human cancer cell lines (HCT-116 and MCF7).
In vitro cytotoxicity IC50 (lM)
Compound
HCT-116
MCF7
Doxorubicin
4
5
7
8
9
11
12
14
5.23 0.3
25.51 1.2
49.21 1.3
19.46 1.5
6.91 2.8
18.73 1.2
7.49 1.2
15.47 2.9
46.64 1.8
4.17 0.2
31.12 2.3
52.57 2.4
28.57 2.3
7.68 2.5
21.58 1.5
8.51 2.3
13.13 3.2
50.46 2.1
IC50 (lM): 1–10 (very strong); 11–20 (strong); 21–50 (moderate); 51–100 (weak), and >100
(non-cytotoxic).
Figure 1. In vitro Cytotoxic effect on human cancer cell lines (HCT-116 and MCF7).
activities. Whereas compound 4 showed moderate activity and compound 14 exhibited
weak activity.
Conclusion
A pyrazolyl-2(3H)-furanone was easily transformed into some pyrrolone and pyridazi-
none derivatives encompassing a pyrazole scaffold utilizing the corresponding acid
hydrazide. The synthesized compounds were screened for their in vitro antitumor activ-
ity against two human carcinoma cell lines namely, colon cancer HCT-116 and mam-
mary gland breast cancer MCF7 cell lines. The biological results revealed that some
compounds exhibited good activities. Among these compounds, the N-propionyl hydra-
zide derivative was the most potent against the two carcinoma cell lines. Thus, some of
these compounds seem to be interesting for pharmaceutical studies.

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9
Experimental
Chemistry
Melting points were measured on a GALLENKAMP electric melting point apparatus
and are uncorrected. All reagents and solvents were of analytical grade, obtained from
commercial suppliers, purified and dried by standard techniques. The infrared spectra
were recorded using potassium bromide disks on IR Thermo Electron Nicolet iS10
(USA) infrared spectrometer and expressed in wave number (m, cmꢀ1) at Chemistry
1
Department, Faculty of Science, Ain Shams University. The H-NMR spectra were run
at 300 and 400 MHz on a GEMINI/BRUKER NMR spectrometer using tetramethyl
silane (TMS) as internal standard in denudated dimethylsulfoxide (DMSO-d6) at Faculty
of Science, Cairo University, Giza; the Main Defense Chemical Laboratory, Cairo; and
Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. Chemical shifts (d) are
quoted in ppm. The abbreviations used are as follows: s, singlet; d, doublet; t, triplet; m,
multiplet. All coupling constant (J) values are given in hertz. The mass spectra were
recorded on a 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 of Al-Azhar University, Nasr City, Cairo, Egypt. The reactions were
monitored by thin layer chromatography (TLC) using Merck Kiesel gel 60 F254 alumi-
num backed plates, Fluka, Switzerland. The antitumor activity was performed at the
Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
The acid hydrazide 2 was previously prepared from hydrazinolysis of pyrazolyl-
2(3H)-furanone 1 with hydrazine hydrate.[18]
Anti/syn-2-((1,3-Diphenyl-1H-pyrazol-4-yl)methylene)-4-oxo-4-phenyl-N’-((1-phenyl-
3-(thiophen-2-yl)-1H-pyrazol-4-yl)methylene)butanehydrazide (4)
A solution of hydrazide 2 (2.11 g, 5 mmol) and 1-phenyl-3-(thiophen-2-yl)-1H-pyrazole-
4-carbaldehyde (3) (1.27 g, 5 mmol) in absolute ethanol (20 mL) was heated under reflux
for 2 h. The precipitated solid while hot was collected and recrystallized from ethanol/
dioxane mixture (1:1) to afford the corresponding hydrazone 4 as yellow crystals, mp.
300-302 ꢁC, yield 81%. IR (KBr, m, cmꢀ1): 3286 (NH), 1694 (C¼O ketone), 1659 (C¼O
1
amide), 1622 (C¼N). H-NMR (400 MHz, DMSO-d6, d, ppm): 3.45 (s, 2H, CH2), 7.01
(s, 1H, CH¼), 7.06–7.20 (m, 5H, Aryl-C¼N), 7.29–7.67 (m, 10H, two Aryl-N),
7.76–7.92 (m, 5 H, Aryl-C¼O), 7.94–8.09 (m, 3 H, Thiophene), 8.78 (s, 1H, C5–H
pyrazole–CH¼C), 8.86 (s, 1H, C5–H pyrazole–CH¼N), for Anti-isomer (50%), 9.16 (s,
1H, CH¼N), 9.56 (br.s, 1H, NH, exchangeable); for Syn-isomer (50%), 8.92 (s, 1H,
CH¼N), 9.35 (br.s, 1H, NH, exchangeable). MS (m/z, %): 658 (M.þ, 26). Anal. Calcd.
For C40H30N6O2S (658.22): C, 72.93; H, 4.59; N, 12.76. Found: C, 72.71; H, 4.32;
N, 12.71%.

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S. K. RAMADAN ET AL.
3-((1,3-Diphenyl-1H-pyrazol-4-yl)methylene)-5-phenyl-1-(((1-phenyl-3-(thiophen2-
yl)-1H-pyrazol-4-yl)methylene)amino)-1,3-dihydro-2H-pyrrol-2-one (5)
A solution of the hydrazone derivative 4 (1.31 g, 2 mmol) in HCl/CH3COOH (10 mL,
1:1) was heated under reflux for 1 h. The precipitated solid during heating was collected
by filtration and recrystallized from dioxane to furnish the pyrrolone 5 as orange crys-
1
tals, mp. 272–274 ꢁC, yield 72%. IR (KBr, m, cmꢀ1): 1688 (C¼O), 1658 (C¼N). H-
NMR (400 MHz, DMSO-d6, d, ppm): 6.99 (s, 1H, C4–H pyrrole), 7.23 (s, 1H, CH¼),
7.91–7.34 (m, 20H, Aryl), 7.93–8.07 (m, 3H, Thiophene), 8.88 (s, 1H, C5–H pyrazole),
9.26 (s, 1H, C5–H pyrazole), 9.32 (s, 1H, CH¼N). MS (m/z, %): 640 (Mþ, 13). Anal.
Calcd. For C40H28N6OS (640.20): C, 74.98; H, 4.40; N, 13.12. Found: C, 74.67; H, 4.19;
N, 13.08%.
Full tables and spectroscopic data can be found in Supplemental files.
Acknowledgments
Technical support from Chemistry Department, Faculty of Science, Ain Shams University is
gratefully acknowledged.
Disclosure statement
No potential conflict of interest was reported by the authors.
ORCID
Sayed K. Ramadan
Ahmed I. Hashem
http://orcid.org/0000-0003-2743-6544
http://orcid.org/0000-0002-7524-9279
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