Synthesis of new pyrazoles, oxadiazoles, triazoles, pyrrolotriazines, and pyrrolotriazepines as potential cytotoxic agents

Article abstract of DOI:10.1002/jhet.4216

4-Oxo-4-phenylbutanehydrazide (1) reacted with many active methylene reagents such as acetylacetone, diethylmalonate, ethylacetoacetate, ethylcyanoacetate, benzoyl-acetonitrile, and malononitrile under neat conditions to afford the corresponding pyrazoles (2–7), also, treatment of butanehydrazide (1) with electrophilic reagents as triethylorthoformate, dimethylformamide-dimethylacetal, acetic anhydride, and carbon disulfide to give 1,3,4-oxadiazoles (8,10,11) and N′-acetyl-butanehydrazide (9). Reacted of butanehydrazide (1) with potassium thiocyanate gave 1,2,4-triazoles (12). Similarly, treatment of (1) with chloroacetamide gave 1,2,4-triazinones (13). The pyrrolotriazinones (14) was obtained by cyclization of (13). Also, butanehydrazide (1) was utilized as a starting material for the synthesized of new Schiff bases as N′-(4-sub-benzylidene)-phenylbutane-hydrazide (15a-c), which are used as an initiative to prepare new compounds such as 1,2,4-triazepinones (16a-c), pyrrolotriazepinones (17a-c), 1,2,4-triazines (18a-c), and pyrrolotriazines (19a-c) by reacted of (15a-c) with each chloroacetamide or formamide. The chemical structure of the newly prepared compounds was determined through the spectrum data, including IR, NMR, and MS. The prepared compounds were tested for their in vitro antitumor activities. The compounds 17a-c, 16a-c, and 19a-c displayed activity against several types of cancer cell lines.

Full text of DOI:10.1002/jhet.4216

Received: 7 September 2020
DOI: 10.1002/jhet.4216
Revised: 12 December 2020
Accepted: 19 December 2020
A R T I C L E
Synthesis of new pyrazoles, oxadiazoles, triazoles,
pyrrolotriazines, and pyrrolotriazepines as potential
cytotoxic agents
1,2
Ameen Ali Abu-Hashem
1
Photochemistry Department
Abstract
(
Heterocyclic Unit), Organic Chemistry,
National Research Centre, Giza, Egypt
4-Oxo-4-phenylbutanehydrazide (1) reacted with many active methylene
reagents such as acetylacetone, diethylmalonate, ethylacetoacetate,
ethylcyanoacetate, benzoyl-acetonitrile, and malononitrile under neat condi-
tions to afford the corresponding pyrazoles (2–7), also, treatment of
butanehydrazide (1) with electrophilic reagents as triethylorthoformate,
dimethylformamide-dimethylacetal, acetic anhydride, and carbon disulfide to
2
Faculty of Science, Chemistry
Department, Jazan University, Jazan,
Saudi Arabia
Correspondence
Ameen Ali Abu-Hashem, Photochemistry
Department (Heterocyclic Unit), Organic
Chemistry, National Research Centre,
Dokki, Giza 12622, Egypt.
0
give 1,3,4-oxadiazoles (8,10,11) and N -acetyl-butanehydrazide (9). Reacted of
butanehydrazide (1) with potassium thiocyanate gave 1,2,4-triazoles (12). Sim-
ilarly, treatment of (1) with chloroacetamide gave 1,2,4-triazinones (13). The
pyrrolotriazinones (14) was obtained by cyclization of (13). Also,
butanehydrazide (1) was utilized as a starting material for the synthesized of
Email: aminaliabuhashem@yahoo.com
0
new Schiff bases as N -(4-sub-benzylidene)-phenylbutane-hydrazide (15a-c),
which are used as an initiative to prepare new compounds such as
1,2,4-triazepinones (16a-c), pyrrolotriazepinones (17a-c), 1,2,4-triazines (18a-
c), and pyrrolotriazines (19a-c) by reacted of (15a-c) with each
chloroacetamide or formamide. The chemical structure of the newly prepared
compounds was determined through the spectrum data, including IR, NMR,
and MS. The prepared compounds were tested for their in vitro antitumor
activities. The compounds 17a-c, 16a-c, and 19a-c displayed activity against
several types of cancer cell lines.
[
1]
1
| INTRODUCTION
and medicinal properties. Further, pyrazole derivatives
are well-known to exhibit a wide spectrum of biological
properties as follows: anticancer, antitumor, antioxidant,
antimicrobial, anti-inflammatory and analgesic, antidepres-
sant, antipyretic, antiviral, anti-HIV, anticonvulsant, anti-
Over the last 10 years, cancer is a disease with high mortal-
ity recognized via abnormal cell proliferation and spread.
Hence, synthesizing and designing new anticancer drugs
with high adequacy and selectivity have important up-to-
date significance. In this work, we highlight some of the
heterocyclic compounds that might have biological and
medicinal relation greatly such as; pyrazole nucleus is con-
sidered of among the azole family involves a (five-member
ring), pyrazole is a type found in a system of small mole-
cules which display a wide spectrum of pharmaceutical
[2–15]
fungal, and antibacterial.
pharmaceutical drugs discovered from pyrazole analogs
have been commercialized,
Fomepizole inhibits alcohol dehydrogenase and inhibits
phosphodiesterase; Rimonabant,
and act as a cannabinoid ligand; Celecoxib, exhibit anti-
inflammatory and display COX-2 effects (Figure 1).
In recent years, many
[
16]
[17]
such as Sildenafil,
[
18]
is used to treat obesity
[19]
J Heterocyclic Chem. 2021;58:805–821.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals LLC.
805

806
ABU-HASHEM
Moreover, 1,3,4-oxadiazoles containing are well known
for their different biological activities like antimicrobial,
1,2,4-triazines, pyrrolotriazines, 1,2,4-triazepinones and
pyrrolotriazepinones and these new compounds are very
important class because they afford a wide range of phar-
macological activities as, antitumor activity through pre-
sent study in the manuscript.
[
20]
[22]
[24]
[
21]
anticonvulsant,
anti-spasmolytic and hypotensive,
[23]
anti-inflammatory and analgesic,
anti-proliferative,
[25]
[26]
[27]
anticancer,
hypoglycemic,
anti-allergic,
and abil-
[28]
ity to bind to DNA. Furthermore, 1,2,4-Triazole deriva-
tives are known for their pharmacological activity as an
analgesic, anticonvulsant and anti-inflammatory,
[
29]
ant-
Also,
2 | RESULTS AND DISCUSSION
2.1 | Chemistry
[30]
[31]
[8,32–33]
iviral,
anti-tumor,
and antimicrobial.
1
,2,4-triazines are considered as 6-aza analogs of pyrimi-
dine bases, it is known that pyrimidines have great biologi-
cal importance, the 1,2,4-Triazine derivatives have been
discovered to demonstrate the diversity of biological uses
such as antimicrobial, antiprotozoal, antimalarial, anti-
parasitic, antiviral, anti-HIV, anticancer, antihypertensive,
antihistaminic, tuberculostatic, cardiotonic, nootropic,
neuroleptic, estrogen receptor modulators, cyclin-
dependent kinase inhibitors, anti-inflammatory, and anal-
[
44,45]
The reaction of 4-oxo-4-phenylbutanehydrazide (1),
with many active methylene reagents
such
as acetylacetone, diethylmalonate, ethylacetoacetate, ethyl
cyanoacetate, benzoyl-acetonitrile, and malononitrile
under neat conditions to afford the corresponding
1-(3,5-dimethyl-1H-pyrazol-1-yl)-4-phenylbutane-1,4-dione
(2), 1-(4-oxo-4-phenylbutanoyl) pyrazolidine-3,5-dione (3),
1-(5-methyl-3-oxo-2, 3-dihydro-1H-pyrazol-1-yl)-4-pheny
lbutane-1,4-dione (4), 1-(5-amino-3-oxo-2, 3-dihydro-1H-
pyrazol-1-yl)-4-phenylbutane-1,4-dione (5), 1-(5-amino-
3-phenyl-1H-pyrazol-1-yl)-4-phenylbutane-1,4-dione (6),
3-amino-5-(3-oxo-3-phenylpropyl)-4H-pyrazole-4-carbonitr
ile (7), respectively via the intermediate shown in
[34]
gesic activities.
Furthermore, triazepine derivatives are
known to possess antifungal, antibacterial, antiviral, and
[35,36]
psychotropic activities.
Triazepine derivatives have
the ability to inhibit the dipeptidyl peptidase IV (DPP-IV)
[37]
and treatment of diabetes.
In addition, 1,2,4-triazepines
have many biological activities like renal vasodilator,
salidiuretic, analgesic, antioxidant, and immunomodulat-
1
Scheme 1. The H-NMR spectrum of 2 showed one singlet
signal at δ 6.41 ppm to the one proton of the (CH-
pyrazole). The IR spectrum of 3 revealed the absorption
[35,38]
ing activities.
The fusion of triazepine to the pyrimi-
dine moiety increases the improvement of the biological
activity. Also, Benzodiazepines are psychoactive drugs
with sedative, anxiolytic, amnestic properties, and skeletal
muscle relaxant. Newly, benzodiazepines and ben-
zotriazepines have been substantiated as potent and highly
eclectic protein interaction inhibitors of bromodomain
−1
bands at ν 3250 cm due to the (NH) group and 1725,
1690, 1685, 1681 cm− to four carbonyl groups. The H-
1
1
NMR spectrum of 4 displayed one singlet signal at δ
12.12 ppm corresponding to the one proton of the
(NH) group (with D O exchangeable). Also, The H-NMR
spectrum of 5 exhibited two singlet signals at δ 6.55,
12.01 ppm corresponding to the two and one protons of
the (NH ) and (NH) groups (with D O exchangeable),
1
2
[39]
and extra-terminal (BET) proteins
. In continuation of
our past work in the synthesis of heterocyclic compounds
that have different biological and pharmaceutical
2
2
[2–11,28,32–33,40–45]
activities.
So, in this manuscript, we pre-
respectively. Furthermore, IR spectrum of 6 showed
−1
pared new heterocyclic compounds via new procedures
such as pyrazoles, 1,3,4-oxadiazoles, 1,2,4-triazoles,
absorption bands at ν 3420 cm for (NH ) group and
2
1715, 1676 cm− for two carbonyl groups. Moreover, the
1
FIGURE 1 The pyrazole derivatives drugs with bioactive molecules [Colour figure can be viewed at wileyonlinelibrary.com]

ABU-HASHEM
807
SCHEME 1 Synthesis of pyrazole derivatives from butanehydrazide [Colour figure can be viewed at wileyonlinelibrary.com]
IR spectrum of 7 displayed the absorption bands at ν
carbonyl group. Condensation of carbohydrazides (1) with
acetic anhydride for 10–15 min gave N -acetyl-4-oxo-
425 cm− due to the NH group and 2210 and 1727 cm
1
−1
0
3
2
for the one (CN) and one carbonyl group, respectively.
4-phenylbutanehydrazide (9) which underwent inter-
molecular cyclization in ethanolic sodium ethoxide solu-
tion for 6–8 h to give 3-(5-methyl-1, 3, 4-oxadiazol-2-yl)-
1-phenylpropan-1-one (10). Also, we obtained the latter
compound (10) by refluxing of carbohydrazides (1) in
acetic anhydride for a long time about 25–30 h. IR spec-
1
Besides, The H-NMR spectrum of 7 exposed one singlet
signal at δ 6.25 ppm to the two protons of the (NH2)
groups (with D O exchangeable). The MS of 2, 3, 4, 5, 6,
2
and 7 demonstrated molecular ion peaks at m/z = 256
+
+
+
+
(
3
M , 67%), 260 (M , 100%), 258 (M , 92%), 259 (M , 85%),
+
+
−1
19 (M , 84%), 240 (M , 100%), respectively. All spectral
trum of (9) showed absorption bands at ν 3250 cm for
−1
data IR, NMR, MS, and elemental analysis of new com-
pounds were elucidated in the experimental part
(2NH) and 1720, 1681 cm for two carbonyl groups. In
1
addition, the H-NMR spectrum of (9) exhibited two sin-
(Scheme 1).
glet signals at δ 10.05 and 10.47 ppm to the two protons of
Similarly, when 4-oxo-4-phenylbutanehydrazide (1)
was treated with triethylorthoformate or dimethylform
amidedimethylacetal in xylene afforded 3-(1,3,4-oxadiazol-
-yl)-1-phenylpropan- 1-one (8) via the intermediate
shown in Scheme 2. The IR spectrum of compound
the (2NH) groups (with D O exchangeable). Likewise, its
H-NMR spectrum of (10) revealed the following signals at
2
1
δ 1.86 ppm to singlet of three protons (CH ) and 2.39–-
3
2
2.43 ppm to triplet of the two protons (CH ) and 3.76–-
2
3.90 ppm to triplet of two protons (CH ) groups. In
2
8
2
1
showed the existence absorption bands at ν 3080,
addition, the 1-phenyl-3-(5-thioxo-4,5-dihydro-1,3,4-oxad
iazol-2-yl) propan-1-one (11) was synthesized by the reac-
tion of carbo-hydrazides (1) with carbondisulfide in pyri-
dine solution. The H-NMR spectrum of 11 showing one
singlet signals at δ 11.20 ppm for the one proton of one
970 cm− of one CH-aryl and CH-alkyl group's and
1
730 cm− of one carbonyl group and the C-NMR spec-
1
13
1
trum of 8 presented absorption signals at δ 26.5 and
7.1 ppm, conforming to two carbon atom of the (2CH2)
3
groups and 115.4 ppm to one carbon atom of the (CH-
oxadiazole), and 191.8 ppm to one carbon atom of the one
(NH) group (D O exchangeable). Also, the mass spectrum
of 8, 9, 10 and 11 showed the molecular ion peak at m/
2

808
ABU-HASHEM
SCHEME 2 Synthesis of substituted 1,3,4-oxadiazoles from butanehydrazide [Colour figure can be viewed at wileyonlinelibrary.com]
+
+
+
z = 202 (M , 90%), 234 (M , 100%), 216 (M , 95%), 234
(
11.60 and 12.20 ppm for the two protons of one (2NH)
+
M , 98%), respectively. The chemical structures of final
products were fully confirmed via IR, NMR, and Mass
spectra as shown in (Scheme 2).
groups (D O exchangeable). Similarly, the IR spectrum of
2
−
1
14 revealed absorption bands at ν 3255 cm for the one
(NH) and 1685 cm for the one carbonyl group and the
H-NMR spectrum of 14 demonstrated one singlet signal
−1
1
Our study was prolonged to the reaction of 4-oxo-
4
-phenylbutanehydrazide (1) with potassium thiocyanate
at δ 11.59 ppm for the one proton of (NH) group (D O
2
in the presence of aqueous hydrochloric acid for 4–7 h
gave 1-phenyl-3-(5-thioxo-4, 5-dihydro-1H-1, 2, 4-triazol-
exchangeable). Moreover, the mass spectrum of 12, 13,
and 14 displayed the molecular ion peak at m/z = 233
+
+
+
3
-yl) propan-1-one (12). Also, reacted of carbo-hydrazides
1) with chloroacetamide in dimethylformamide to give
-(3-oxo-3-phenylpropyl)-1,6-dihydro-1,2,4-triazin-5(2H)-
(M , 94%), 231 (M , 100%), 213 (M , 97%), respectively.
The chemical structures of the final products were fully
(
3
1
confirmed through IR, H-NMR, and MS as shown in
one (13) via the intermediate shown in Scheme 3. Thus,
the same acyclic compound (13) underwent intramolecu-
lar cyclization in boiling dimethylformamide in the pres-
ence of anhydrous potassium carbonate afforded
(Scheme 3).
The reaction of 4-oxo-4-phenylbutanehydrazide (1)
with appropriate aryl aldehydes namely; (benzaldehyde,
4-chlorobenzaldehyde, or 4-methoxybenzaldehyde) in
0
6
-phenyl-3,4-dihydropyrrolo [1,2-b] [1,2,4] triazin-2(8H)-
ethanol with the presence of piperidine as a base gave N -
one (14). The IR spectrum of 12 showed absorption bands
(4-substituted-benzylidene)-4-oxo-
4-phenylbutanehydrazide (15a-c). The IR spectrum of
−
1
−1
at ν 3338–3131 cm for the two (2NH) and 1673 cm
1
−1
for the one carbonyl groups. Likewise, the H-NMR spec-
15a exposed absorption bands at ν 3230 cm for the one
−1
trum of 12 showed two singlet signals at δ 10.85 and
(NH) and 1738, 1677 cm for the two carbonyl groups
1
1
2.91 ppm for the two protons of one (2NH) groups (D O
and the H-NMR spectrum of 15a proved one singlet sig-
2
exchangeable). Also, the IR spectrum of 13 indicated
nal at δ 11.50 ppm for the one proton of (NH) group
−
1
absorption bands at ν 3270–3200 cm for the two (2NH)
(D O exchangeable). Besides, the mass spectrum of 15a,
2
−
1
and 1735, 1672 cm for the two carbonyl groups and the
15b, and 15c showed the molecular ion peak at m/
1
+
+
+
H-NMR spectrum of 13 exhibited two singlet signals at δ
z = 280 (M , 100%), 314 (M , 97%), 310 (M , 88%),

ABU-HASHEM
809
SCHEME 3 Synthesis of
1
,2,4-triazoles; 1,2,4-triazinones and
pyrrolotriazinones [Colour figure can be
viewed at wileyonlinelibrary.com]
+
+
respectively. Furthermore, the reaction of arylidene car-
bohydrazones (15a-c) with chloroacetamide in
dimethylformamide to yield 7-(4-substituted-phenyl)-
cated molecular ion peaks at m/z 301 (M , 90%), 335(M ,
+
30%), and 331 (M , 84%), respectively. Also, when
arylidene carbohydrazones (15a-c) was treated with
formamide in boiling dimethylformamide afforded a
cyclic structure 3-(6-(4-substituted-phenyl)-1,2,4-triazin-
3-yl)-1-phenylpropan-1-one (18a-c) via the intermediate.
The H-NMR spectrum of 18a revealed two triplet signals
at δ 2.70 and 2.82 ppm for the four protons of (2CH ) and
one singlet signal at δ 8.10 ppm for the one proton of
(CH-triazine). Moreover, a cyclic structure (18a-c) under-
went intramolecular cyclization in refluxing dime
thylformamide in the presence of anhydrous potassium
carbonate for 15–18 h to give 3-(4-substituted-phenyl)-
6-phenyl-4, 8-dihydropyrrolo[2,1-c] [1,2,4] triazine (19a-
3
5
1
-(3-oxo-3-phenylpropyl)-4,6-dihydro-5H-1,2,4-triazepin-
-one (16a-c) via the intermediate, the IR spectrum of
6a was characterized via disappearance of carbonyl
−
1
1
group and displayed an absorption bands at 3305 cm
for the one (NH) and 1733, 1685 cm for the two car-
bonyl groups and the H-NMR spectrum of 16a
−1
2
1
evidenced one singlet signal at δ 8.52 ppm for the one
13
proton of (NH) group (D O exchangeable) and the C-
2
NMR spectrum of 16a exposed absorption signals at δ
1
5.6, 21.5, and 31.2 ppm, corresponding to three carbon
atoms of the (3CH ) groups and 168.6, 168.9 ppm, con-
2
1
forming to two carbon atoms of two carbonyl groups.
Moreover, condensation of (16a-c) in dimethylformamide
and anhydrous potassium carbonate with refluxing for
c) via the intermediate shown in Scheme 4. The H-NMR
spectrum of 19a showed one doublet signal at δ 3.11–-
3.27 ppm for the two protons of (CH -pyrrole) and one
2
1
7–20 h under control (TLC) to give 3-(4-substituted-phe-
singlet signal at δ 4.17 ppm for the two protons of (CH2-
triazine) and one triplet signal at δ 6.70 ppm for the one
proton of (CH-pyrrole) and the C-NMR spectrum of
nyl)-7-phenyl-4,9-dihydro-5H-pyrrolo[2,1-c] [1,2,4]
13
triazepin-5-one (17a-c) via the intermediate, the IR spec-
trum of 17a was described by disappearance of (NH) and
carbonyl group and exhibited an absorption bands at
19a displayed absorption signals at δ 21.6 and 58.5 ppm,
agreeing to two carbon atoms of the (2CH ) groups and
2
678 cm− for the one carbonyl groups. The H-NMR
1
1
79.7 ppm, matching to one carbon atoms of one (CH-pyr-
1
spectrum of 17a showed one doublet signal at δ 2.62 ppm
role). The MS of 19a, 19b, and 19c exhibited molecular
+
+
for the two protons of (CH ) and one singlet signal at
ion peaks at m/z 273 (M , 100%), 307 (M , 40%),
2
+
δ 3.90 ppm for the two protons of (CH ) and one triplet
and 303 (M , 90%), respectively. All spectral data of
2
signal at δ 4.90–5.10 ppm for the one proton of
new compounds are described in the experimental
section (Scheme 4).
(
CH pyrrole). The mass spectra of 17a, 17b, and 17c indi-
−

810
ABU-HASHEM
SCHEME 4 Synthesis of pyrrolo [2,1-c] [1,2,4] triazepinones and pyrrolotriazines [Colour figure can be viewed at
wileyonlinelibrary.com]
3
3
| BIOLOGICAL ACTIVITIES
.1 | Antitumor screening (in vitro
and the antitumor influence of most products on differ-
ent cancer cell lines was superior to the 5-fluorouracil
positive control. Several of the compounds exhibited
moderate and good activity on all the tested cancer cell
lines. Therefore, the compounds 17a-c, 16a-c, 19a-c, 14,
and 12 showed the highest cytotoxicity versus all carci-
noma cell lines as follows; the MGC-803 (IC : 17a-c,
cytotoxicity)
The new compounds such as pyrazoles, 1,3,4-oxadiazoles,
1
,2,4-triazoles, pyrrolotriazines, and pyrrolotriazepines
50
were tested for their in vitro cytotoxicity using the stan-
11.3, 11.1, 11.2: 16a-c, 11.7, 11.5, 11.6: 19a-c, 12.2, 11.9,
[46–48]
dard MTT method,
noma cells (MGC-803), nasopharyngeal carcinoma cells
CNE2), oral carcinoma cells (KB) and breast adenocarci-
noma cells (MCF-7).The MTT method is based on the
reduction of soluble 3-(4,5-dimethyl-2-thiazolyl)-
,5-diphenyl-2H-tetrazolium bromide. As displayed in
Table 1), the final results in products 17a-c, 16a-c, 19a-c,
4, and 12 exposed different degrees of antitumor activity,
versus the human gastric carci-
12.1: 14, 12.5 and 12, 12.8 μM), the CNE2 (IC : 17a-c,
50
12.3, 12.1, 12.2: 16a-c,12.6, 12.4, 12.5: 19a-c, 13.1, 12.8,
12.9: 14, 13.4 and 12, 13.8 μM), the KB (IC : 17a-c, 11.4,
(
50
11.2, 11.3: 16a-c, 11.7, 11.5, 11.6: 19a-c, 12.1, 11.8, 11.9:
14, 12.6 and 12, 12.9 μM), the MCF-7 (IC : 17a-c, 11.9,
50
2
(
1
11.7, 11.8: 16a-c, 12.3, 12.1, 12.2: 19a-c, 12.7, 12.5, 12.6:
14, 12.9 and 12, 14.2 μM), respectively. Furthermore,
some compounds as; 18a-c, 13, 15a-c, 11, 10, and

ABU-HASHEM
811
TABLE 1 Cytotoxic activity of the
new compounds versus diverse human
cancer cell lines
In vitro cytotoxicity IC50 (μM)
a
a
a
a
Compounds
MGC-803
>50
CNE2
KB
MCF-7
1
2
3
4
5
6
7
8
9
>50
>50
>50
34.4 ± 1.8
37.2 ± 1.6
31.1 ± 1.3
27.9 ± 1.7
25.7 ± 1.2
24.5 ± 1.4
22.3 ± 1.5
44.5 ± 2.1
19.2 ± 1.2
17.5 ± 1.8
12.8 ± 1.7
14.1 ± 2.2
12.5 ± 1.5
15.3 ± 2.2
14.6 ± 1.8
14.9 ± 2.1
11.7 ± 1.6
11.5 ± 1.2
11.6 ± 1.5
11.3 ± 1.4
11.1 ± 1.1
11.2 ± 1.3
13.7 ± 2.3
13.1 ± 1.8
13.3 ± 2.1
12.2 ± 1.3
11.9 ± 1.4
12.1 ± 1.7
11.4 ± 1.2
35.6 ± 1.7
38.4 ± 1.3
32.3 ± 1.5
29.1 ± 1.2
26.9 ± 1.4
25.7 ± 1.6
23.6 ± 1.8
45.7 ± 2.2
20.5 ± 1.7
18.7 ± 1.4
13.8 ± 1.5
15.1 ± 2.1
13.4 ± 1.3
15.9 ± 1.7
15.5 ± 1.9
15.8 ± 1.8
12.6 ± 1.4
12.4 ± 1.3
12.5 ± 1.6
12.3 ± 1.5
12.1 ± 1.3
12.2 ± 1.4
14.8 ± 1.9
14.2 ± 1.7
14.5 ± 1.4
13.1 ± 1.6
12.8 ± 1.1
12.9 ± 1.2
12.2 ± 1.5
33.9 ± 1.3
37.7 ± 1.6
30.8 ± 1.1
27.6 ± 1.4
25.4 ± 1.5
24.2 ± 1.3
22.1 ± 1.2
44.2 ± 2.4
18.9 ± 1.3
17.2 ± 1.1
12.9 ± 1.4
14.2 ± 1.5
12.6 ± 1.1
15.1 ± 1.5
14.7 ± 1.4
14.9 ± 1.6
11.7 ± 1.2
11.5 ± 1.5
11.6 ± 1.7
11.4 ± 1.3
11.2 ± 1.2
11.3 ± 1.1
13.9 ± 1.7
13.2 ± 1.5
13.6 ± 1.8
12.1 ± 1.4
11.8 ± 1.3
11.9 ± 1.6
11.1 ± 1.1
34.7 ± 1.5
37.5 ± 1.4
31.8 ± 1.6
28.7 ± 1.2
26.5 ± 1.1
25.3 ± 1.5
23.2 ± 1.4
44.8 ± 2.3
20.1 ± 1.8
18.4 ± 1.6
14.2 ± 1.5
15.3 ± 1.4
12.9 ± 1.2
16.2 ± 1.4
15.8 ± 1.7
15.9 ± 1.3
12.3 ± 1.5
12.1 ± 1.7
12.2 ± 1.8
11.9 ± 1.4
11.7 ± 1.6
11.8 ± 1.5
14.9 ± 2.1
14.5 ± 1.3
14.7 ± 2.2
12.7 ± 1.1
12.5 ± 1.4
12.6 ± 1.5
11.9 ± 1.7
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
5
0
1
2
3
4
5a
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
8c
9a
9b
9c
-Fluorouracil
a
MGC-803 cells are drug-sensitive human gastric carcinoma cells, CNE2 cells are drug-sensitive human
nasopharyngeal carcinoma cells, KB cells are drug-sensitive human oral carcinoma cells and MCF-7 cells
are drug-sensitive human breast adenocarcinoma cells.
8
exposed modest cytotoxicity versus the carcinoma cell
1,2,4-triazole; 1,2,4-triazine; 1,3,4-oxadiazole and pyrazole
moieties possibly requested for a broad spectrum of the
cytotoxicity activity. (B) The 3-(4-substituted-phenyl)-7-phe-
nyl-4,9-dihydro-5H-pyrrolo[2,1-c] [1,2,4] triazepin-5-one
lines. Also, the remainder of the compounds indicated
low cytotoxicity activities.
(17a-c), 7-(4-substituted-phenyl)-3-(3-oxo-3-phenylpropyl)-
3
.2 | Structure–activity relationships
4,6-dihydro-5H-1,2,4-triazepin-5-one (16a-c), 3-(4-substit-
uted-phenyl)-6-phenyl-4,8-dihydropyrrolo[2,1-c] [1,2,4] tri-
azine (19a-c), 6-phenyl-3,4-dihydropyrrolo[1,2-b] [1,2,4]
triazin-2(8H)-one (14) and 1-phenyl-3-(5-thioxo-4,-
5-dihydro-1H-1,2,4-triazol-3-yl) propan-1-one (12) dis-
played high in vitro anti-tumor activity and this confirms
In this study, through contrasting the monitored cytotoxic-
ity activities of the new compounds, we obtained chemical
structures, the (SAR's) were presumed. (A) The existence of
the pyrrolotriazepine; 1,2,4-triazepine; pyrrolotriazine;

812
ABU-HASHEM
previous scientific studies as follows; many heterocyclic
compounds possess biological activities such as triazepines,
oxadiazepines, oxadiazoles, pyrazolidines and ben
90%) in absolute ethanol (30 ml) was stirred under
[
45]
refluxed for 2–4 h.
The reaction mixture was then
allowed to cool to room temperature. The solid was fil-
tered, washed with methanol, dried, and crystallized
[05]
zohydrazides, revealed cytotoxic activity,
and benzofur
anquinoxalines, piperazinbenzofurans, and pyrazolobenzo-
from dioxane to give 1, as yellow crystals, in 90% yield,
[02]
ꢀ
furans showed cytotoxic activity,
and Pyrazolo-
m. p. 170–172 C. IR (KBr): ν
= 3405–3325 (brs, NH,
max
pyrimidoquinoline, triazolotetrahydropyrimidoquinoline,
triazolopyrimidoquinoline exhibited potent antitumor activ-
NH ), 3045 (CH, aryl), 2952 (CH, alkyl), 1722, 1675
2
−1
1
(2C O), 1578 (C C) cm ; H NMR (DMSO-d6):
[4,49]
ity.
Similarly, thiophenecarbohydrazide, thienopyr
δ = 2.22–2.27 (t, 2H, J = 5.48 Hz, CH ), 3.20–3.25 (t, 2H,
2
azole, and thieno-pyrimidine as potential antioxidant and
J = 5.49 Hz, CH ), 6.10 (br, 2H, NH , D O exchangeable),
2
2
2
[3]
antitumor agents. Also, 1,2,4-triazine and 1,2,3-triazine
derivatives are the most studied ones having remarkable
7.55–7.92 (m, 5H, Ar-H), 9.08 (br, 1H, NH, D O
2
13
exchangeable). C NMR (DMSO-d ) δ = 30.1, 33.8 (2C,
6
[50–53]
antitumor activity.
(C) Thus, the products 17a-c, 16a-
2CH ), 128.4, 128.9, 131.5, 134.8 (6C, Ar-C), 174.7, 182.2
2
+
c, 19a-c, 14, and 12 presented high cytotoxicity versus all
carcinoma cell lines in comparison with 5-Fluorouracil as
stander drug.
(2C, 2C O); MS (70 eV): m/z = 192 (M , 100%); Anal.
Calc. (Found) for C H N O (192.22): C, 62.49
10
12 2 2
(62.40); H, 6.29 (6.21); N, 14.57 (14.68).
4
4
| EXPERIMENTAL SECTION
.1 | Materials
4.4 | Synthesis of 1-(3,5-dimethyl-1H-
pyrazol-1-yl)-4-phenylbutane-1,4-dione (2)
A solution of compound 1 (1.92 g, 0.01 mol) and acetyl
acetone (1.03 ml, 0.01 mol) in absolute ethanol (40 ml)
with catalytic amount of (1 ml) piperidine was heated
under reflux for 10–15 h. the reaction mixture was
allowed to cool, and poured into crushed ice then acidi-
fied with hydrochloric acid. The separated solid was fil-
All materials used were obtained from Sigma Aldrich
Saint Lewis).
(
4.2 | Equipment's
tered off washed with water (H O), dried and
2
All melting points are in degree centigrade (uncorrected)
and were determined on Gallenkamp electric melting point
apparatus. TLC analysis was carried out on silica gel
recrystallized from methanol as yellowish crystals in 95%
ꢀ
yield, m. p. 274–276 C. IR (KBr): ν
= 3055 (CH, aryl),
2950 (CH, alkyl), 1730, 1680 (2C O), 1625 (C N), 1582
max
−1 1
60 F254 precoated aluminum sheets. The IR spectra were
(C C) cm ; H NMR (DMSO-d ): δ = 1.15, 1.16 (2s, 6H,
6
recorded (KBr) on a Perkin–Elmer 1430 spectrometer (λ,
2CH ), 2.01–2.22 (t, 2H, J = 4.80 Hz, CH ), 3.72–3.95 (t,
3
2
−1
1
13
cm ) in National Research Centre, Egypt. H and C-
NMR spectra were measured on JEOL-ECA 500 and JEOL
JNM-LA-400 FT NMR Spectrometers at 500, 125 MHz,
respectively, using tetramethylsilane (TMS) as an internal
2H, J = 4.75 Hz, CH ), 6.41 (s, 1H, CH-pyrazole),
2
13
7.06–7.60 (m, 5H, Ar-H); C NMR (DMSO-d ) δ = 28.6,
6
30.5 (2C, 2CH ), 39.1, 39.4 (2C, 2CH ),112.1(1C, CH-
3
2
pyrazole), 123.2, 124.2, 126.4, 126.5, 136.2, 149.4 (8C, Ar-
+
reference and DMSO-d as the solvent at the Microanalyti-
C), 160.6, 166.9 (2C, 2C O); MS (70 eV): m/z = 256 (M ,
6
cal Center in National Research Centre, Egypt. The mass
spectra (EI) were recorded on GCMS-QP 1000 EX
67%); Anal. Calc. (Found) for C H N O (256.31): C,
70.29 (70.35); H, 6.29 (6.23); N, 10.93 (10.86).
15
16 2 2
(Shimadzu) at National Research Centre, Egypt. Elemental
analyses (C, H, and N) were carried out at the Microanalyt-
ical Center in National Research Centre, Egypt. The ele-
mental analyses were found to agree favorably with the
calculated values. Biological evaluations were done by the
antitumor unit, Department of Pharmacognosy, Faculty of
pharmacy, Mansoura University, Egypt.
4.5 | Synthesis of 1-(4-oxo-
4-phenylbutanoyl) pyrazolidine-
3,5-dione (3)
A
mix of compound
1
(1.92 g, 0.01 mol) and
diethylmalonate (1.52 ml, 0.01 mol) in ethanolic sodium
ethoxide was heated under reflux for 14–17 h. The reac-
tion mixture was allowed to cool and poured into water/
ice then acidified with hydrochloric acid. The separated
solid was filtered off washed with water, dried and rec-
4
4
.3 | Synthesis of 4-oxo-
-phenylbutanehydrazide (1)
A mixture of ethyl 4-oxo-4-phenylbutanoate (2.10 ml,
.01 mol) and hydrazine monohydrate (0.01 mol; 80%–
rystallized from dioxane as white crystals in 90% yield,
ꢀ
0
m. p. 242–244 C. IR (KBr): ν
= 3250 (br, NH), 3060
max

ABU-HASHEM
813
(
(
CH, aryl), 2958 (CH, alkyl), 1725, 1690, 1685, 1681
4C O), 1580 (C C) cm ; H NMR (DMSO-d6):
(DMSO-d ) δ = 30.5, 35.1 (2C, 2CH ), 80.2 (1C, CH-
pyrazole), 128.1, 128.5, 133.6, 135.4, 156.4 (7C, Ar-C),
6
2
−
1
1
δ = 2.21–2.42 (t, 2H, J = 4.84 Hz, CH ), 3.12 (s, 2H, CH ,
165.4, 168.8, 182.7 (3C, 3C O); MS (70 eV): m/z = 259
2
2
+
pyrazole), 3.27–3.38 (t, 2H, J = 4.77 Hz, CH ), 7.41–7.81
(M , 85%); Anal. Calc. (Found) for C H N O
2
13 13
3
3
13
(
m, 5H, Ar-H); 10.47 (br, 1H, NH, D O exchangeable); C
(259.27): C, 60.23 (60.30); H, 5.05 (5.12); N, 16.21 (16.27).
2
NMR (DMSO-d ) δ = 28.5, 32.2 (2C, 2CH ), 50.2(1C,
6
2
CH -pyrazole), 128.4, 128.7, 132.8, 135.6 (6C, Ar-C),
2
1
65.3, 168.8, 170.7, 185.1 (4C, 4C O); MS (70 eV): m/
4.8 | Synthesis of 1-(5-amino-3-phenyl-
1H-pyrazol-1-yl)-4-phenylbutane-
1,4-dione (6)
+
z = 260 (M , 100%); Anal. Calc. (Found) for C H N O
12 2 4
13
(260.25): C, 60.00 (60.10); H, 4.65 (4.58); N, 10.76 (10.82).
A mixture of, 1 (1.92 g, 0.01 mol) and benzoyl acetonitrile
(1.45 g, 0.01 mol) in absolute ethanol (40 ml) was
refluxed for 6–9 h (TLC). After cooling, the solvent was
evaporated and the solid residue was recrystallized from
4
2
4
.6 | Synthesis of 1-(5-methyl-3-oxo-
,3-dihydro-1H-pyrazol-1-yl)-
-phenylbutane-1,4-dione (4)
ꢀ
dioxane as yellow crystals in 72% yield, m. p. 223–225 C.
A mix of compound 1 (1.92 g, 0.01 mol) and ethyl
IR (KBr): νmax = 3420 (br, NH ), 3075 (CH, aryl), 2962
2
acetoacetate (1.27 ml, 0.01 mol) in DMF (40 ml)/K CO3
(CH, alkyl), 1715, 1676 (2C O), 1620 (C N), 1590 (C C)
2
−1
1
was heated under reflux for 12–15 h. The reaction mix-
ture was allowed to cool and poured into water/ice. The
separated solid was filtered off washed with water, dried
cm ; H NMR (DMSO-d ): δ = 2.70–2.75 (t, 2H,
6
J = 4.90 Hz, CH ), 3.38–3.41 (t, 2H, J = 4.87 Hz, CH ),
2
2
6.40 (s, 2H, NH ), 6.80 (s, 1H, CH, pyrazole), 7.24–7.95
2
1
3
and recrystallized from methanol as yellowish crystals in
(m, 10H, Ar-H); C NMR (DMSO-d ) δ = 23.3, 32.9 (2C,
6
ꢀ
8
5% yield, m. p. 255–257 C. IR (KBr): ν
= 3260 (br,
2CH ), 88.9 (1C, CH-pyrazole), 123.9, 126.4, 129.9, 131.9,
max
2
NH), 3065 (CH, aryl), 2962 (CH, alkyl), 1727, 1682, 1675
3C O), 1578 (C C) cm ; H NMR (DMSO-d6):
132.5, 132.9, 135.3, 141.9, 148.8, 155.1 (14C, Ar-C), 165.6,
−
1
1
+
(
167.6 (2C, 2C O); MS (70 eV): m/z = 319 (M , 84%);
δ = 2.30 (s, 3H, CH ), 2.63–2.69 (t, 2H, J = 4.88 Hz, CH ),
Anal. Calc. (Found) for C H N O (319.36): C, 71.46
(71.40); H, 5.37 (5.45); N, 13.16 (13.23).
3
2
19 17 3 2
3
.30–3.33 (t, 2H, J = 4.85 Hz, CH ), 5.70 (s, 1H, CH,
2
pyrazole), 7.44–7.96 (m, 5H, Ar-H); 12.12 (br, 1H, NH,
13
D O exchangeable); C NMR (DMSO-d ) δ = 21.8 (1C,
2
6
CH ), 25.9, 35.4 (2C, 2CH ), 100.6 (1C, CH-pyrazole),
4.9 | Synthesis of 3-amino-5-(3-oxo-
3-phenylpropyl)-4H-pyrazole-
4-carbonitrile (7)
3
2
1
1
25.5, 128.4, 129.2, 135.9, 149.3 (7C, Ar-C), 164.8, 166.6,
69.2 (3C, 3C O); MS (70 eV): m/z = 258 (M , 92%);
+
Anal. Calc. (Found) for C H N O (258.28): C, 65.11
14
14 2 3
(
65.18); H, 5.46 (5.40); N, 10.85 (10.92).
A mixture of compound 1 (1.92 g, 0.01 mol) and
malononitrile (0.6 ml, 0.01 mol) in ethanol (40 ml) con-
taining (1 ml) catalytic amount of piperidine was
heated under reflux for 20–25 h.The reaction mixture
was allowed to cool and poured into crushed ice then
acidified with hydrochloric acid. The separated solid
was filtered off washed with water, dried and rec-
4
3
1
.7 | Synthesis of 1-(5-amino-3-oxo-2,
-dihydro-1H-pyrazol-1-yl)-4-phenylbutane-
,4-dione (5)
A mixture of compound 1 (1.92 g, 0.01 mol) and
ethylcyanoacetate (1.06 ml, 0.01 mol) in DMF (45 ml)/
K CO was heated under reflux for 14–17 h (TLC). The
rystallized from DMF as yellowish crystals in 70% yield,
ꢀ
m. p. 193–195 C. IR (KBr): ν
= 3425 (br, NH ), 3070
2
max
(CH, aryl), 2960 (CH, alkyl), 2210 (CN), 1727 (C O),
2
3
−
1 1
reaction mixture was allowed to cool and poured into
1625 (C N), 1586 (C C) cm ; H NMR (DMSO-d ):
6
H O / ice. The product solid was filtered off washed with
δ = 2.63–2.68 (t, 2H, J = 4.88 Hz, CH ), 3.30–3.35 (t,
2
2
water, dried and recrystallized from methanol as yellow
2H, J = 4.84 Hz, CH ), 4.45 (s, 1H, CH, pyrazole), 6.25
2
ꢀ
13
crystals in 77% yield, m. p. 208–210 C. IR (KBr):
(s, 2H, NH ), 7.50–7.97 (m, 5H, Ar-H); C NMR
(DMSO-d ) δ = 31.1, 35.3 (2C, 2CH ), 52.5 (1C, CH-
2
νmax = 3430–3405 (br, NH , NH), 3070 (CH, aryl), 2966
2
6
2
−1
(
CH, alkyl), 1720, 1684, 1670 (3C O), 1587 (C C) cm ;
pyrazole), 112.9 (1C, CN), 128.4, 128.9, 133.5, 136.3,
160.1, 163.5 (8C, Ar-C), 191.3 (1C, C O); MS (70 eV):
1
H NMR (DMSO-d ): δ = 2.24–2.31 (t, 2H, J = 4.82 Hz,
6
+
CH ), 3.03–3.39 (t, 2H, J = 4.81 Hz, CH ), 5.05 (s, 1H,
m/z = 240 (M , 100%); Anal. Calc. (Found) for
2
2
CH, pyrazole), 6.61 (s, 2H, NH ), 7.06–7.64 (m, 5H, Ar-
C H N O (240.27): C, 64.99 (64.90); H, 5.03 (5.10); N,
2
13 12
4
13
H); 10.27 (br, 1H, NH, D O exchangeable); C NMR
23.32 (23.25).
2

814
ABU-HASHEM
4
2
.10 | Synthesis of 3-(1, 3, 4-oxadiazol-
-yl)-1-phenylpropan-1-one (8)
mixture was allowed to cool and poured into crushed
ice. The separated solid was filtered off washed with
water, dried and recrystallized from methanol as yellow-
ish crystals. Method B: Refluxing of compound 9 (2.34 g,
0.01 mol) in ethanolic sodium ethoxide solution (pre-
pared via dissolving 0.23 g of sodium metal in 40 ml eth-
anol) for 6–8 h. The reaction mixture was allowed to
cool and poured into water/ice then acidified with conc.
HCl. The precipitate separated was filtered off washed
with water, dried and recrystallized from ethanol as yel-
Method A: A mix of compound 1 (1.92 g, 0.01 mol) in tri-
ethylorthoformate (10 ml) was heated under reflux for
1
5–18 h.The reaction mixture was allowed to cool. The
separated solid was filtered off washed with ether, dried
and recrystallized from toluene to give yellow crystals.
Method B: A mixture of compound 1 (1.92 g, 0.01 mol)
and (DMF-DMA), dimethyl-formamidedimethylacetal
ꢀ
(1.35 ml, 0.01 mol) in p-xylene (35 ml) was heated under
lowish crystals in 88% yield, m. p. 283–285 C. IR (KBr):
reflux for 12–16 h. after cooling, the separated solid was
filtered off, dried and recrystallized from dioxane as yel-
low crystals in 75% yield, m. p. 265–267 C. IR (KBr):
νmax = 3080 (CH, aryl), 2970 (CH, alkyl), 1730 (C O),
νmax = 3085 (CH, aryl), 2978 (CH, alkyl), 1732 (C O),
−
1
1
1624 (C N), 1592 (C C) cm ; H NMR (DMSO-d ):
6
ꢀ
δ = 1.86 (s, 3H, CH ), 2.39–2.43 (t, 2H, J = 4.97 Hz,
3
CH ), 3.76–3.90 (t, 2H, J = 4.95 Hz, CH ), 7.48–7.69 (m,
2
2
−
1
1
13
1
622 (C N), 1590 (C C) cm ; H NMR (DMSO-d ):
5H, Ar-H); C NMR (DMSO-d ) δ = 23.2 (1C, CH ),
6
6 3
δ = 2.70–2.81 (t, 2H, J = 4.90 Hz, CH ), 2.91–3.20 (t, 2H,
27.1, 38.4 (2C, 2CH ), 128.4, 128.9, 133.5, 140.8, 160.1,
2
2
J = 4.92 Hz, CH ), 6.10 (s, CH, oxadiazole), 7.30–7.55 (m,
162.3 (8C, Ar-C), 193.2 (1C, C O); MS (70 eV): m/
2
13
+
5
2
1
H, Ar-H); C NMR (DMSO-d ) δ = 26.5, 37.1 (2C,
z = 216 (M , 95%); Anal. Calc. (Found) for C H N O
6
12 12
2
2
CH ), 115.4 (1C, CH-oxadiazole),128.2, 128.7, 133.7,
(216.24): C, 66.65 (66.73); H, 5.59 (5.66); N,
12.96 (12.88).
2
40.6 (6C, Ar-C), 191.8 (1C, C O); MS (70 eV): m/
+
z = 202 (M , 90%); Anal. Calc. (Found) for C H N O
11
10
2
2
(202.21): C, 65.34 (65.40); H, 4.98 (4.91); N, 13.85 (13.92).
4
4
.13 | Synthesis of 1-phenyl-3-(5-thioxo-
,5-dihydro-1,3,4-oxadiazol-2-yl) propan-
0
4
.11 | Synthesis of N -acetyl-4-oxo-
1-one (11)
4
-phenylbutanehydrazide (9)
Method A: A mixture of compound 1 (1.92 g, 0.01 mol) in
pyridine (25 ml) and carbon disulfide (0.6 ml, 0.01 mol)
was heated under reflux for 15–19 h. The reaction mix-
ture was allowed to cool and poured into ice/water then
acidified with HCl. The separated solid was filtered off
washed with water, dried and recrystallized from dioxane
as yellowish crystals. Method B: A mixture of compound
A solution of compound 1 (1.92 g, 0.01 mol) in acetic
anhydride (15 ml) was heated under reflux for 15 min.
The reaction mixture was allowed to cool and poured
into ice/water. The separated solid was filtered off
washed with water, dried and recrystallized from meth-
ꢀ
anol as brownish crystals in 90% yield, m. p. 183–185 C.
IR (KBr): νmax = 3250 (br, 2NH), 3080 (CH, aryl), 2975
1 (1.92 g, 0.01 mol) and carbon disulfide (excess
−
1 1
(
CH, alkyl), 1720, 1681 (2C O),1586 (C C) cm ; H
10–15 ml) was heated under reflux on a water-bath
ꢀ
NMR (DMSO-d ): δ = 1.82 (s, 3H, CH ), 2.22–2.41 (t,
(75–85 C) in 35 ml pyridine for 12–15 h, under (TLC con-
6
3
ꢀ
2
H, J = 4.95 Hz, CH ), 3.10–3.38 (t, 2H, J = 4.92 Hz,
trol). The reaction mixture was allowed to cool to 0 C for
2
CH ), 7.09–7.37 (m, 5H, Ar-H), 10.05, 10.47 (br, 2H,
2
12–14 h; the final precipitate was filtered off, washed
with ethanol (50 ml), dried, and crystallized from metha-
nol as yellowish crystals. Method C: A solution of com-
pound 1 (1.92 g, 0.01 mol) in ethanol (40 ml) and
aqueous potassium hydroxide (0.56 g, 0.01 mol) was
refluxed for 30 min. After cooling to room temperature,
carbon disulfide (1 ml) was added, refluxed for 3–5 h and
poured into ice-water. The final solid obtained was fil-
tered off, dried and recrystallized from dimethyl-
2
1
2 6
3
NH, D O exchangeable); C NMR (DMSO-d ) δ = 20.8
(
1C, CH ), 31.9, 36.1 (2C, 2CH ), 128.1, 128.5, 133.4,
3 2
1
36.3, (6C, Ar-C), 165.9, 170.1, 188.5 (3C, 3C O); MS
+
(
70 eV): m/z = 234 (M , 100%); Anal. Calc. (Found) for
C H N O (234.26): C, 61.53 (61.62); H, 6.02 (6.10); N,
1
2
14
2
3
1
1.96 (11.90).
4
1
1
.12 | Synthesis of 3-(5-methyl-
,3,4-oxadiazol-2-yl)-1-phenylpropan-
-one (10)
formamide as yellowish crystals in 74% yield, m. p.
ꢀ
233–235 C. IR (KBr): ν
= 3116 (NH), 3064(CH, aryl),
2960 (CH, alkyl), 1731 (C O), 1634 (C N), 1600 (C C),
max
−
1 1
1
264 (C S) cm ; H NMR (DMSO-d ): δ = 2.66–2.71 (t,
6
Method A: Refluxing of compound 1 (1.92 g, 0.01 mol)
in acetic anhydride (20 mL) for 25–30 h. The reaction
2H, J = 5.01 Hz, CH ), 3.28–3.33 (t, 2H, J = 5.05 Hz,
2
CH ), 7.57–7.98 (m, 5H, Ar-H), 11.20 (br, 1H, NH, D O
2
2

ABU-HASHEM
815
1
3
exchangeable); C NMR (DMSO-d ) δ = 28.7, 37.1 (2C,
4.16 | Synthesis of 6-phenyl-
3,4-dihydropyrrolo [1,2-b] [1,2,4] triazin-2
(8H)-one (14)
6
2
(
CH ), 128.5, 128.7, 133.3, 137.5, 159.4 (7C, Ar-C), 181.6
2
1C, C S), 188.1 (1C, C O); MS (70 eV): m/z = 234 (M ,
8%); Anal. Calc. (Found) for C H N O S (234.27): C,
11 10 2 2
6.40 (56.49); H, 4.30 (4.22); N, 11.96 (11.90).
+
9
5
A solution of 13 (2.31 g, 0.01 mol) and anhydrous potas-
sium carbonate (2 g, 0.015 mol) in dimethylformamide
(
DMF, 45 ml) was refluxed for 13–16 h under control
4
4
1
.14 | Synthesis of 1-phenyl-3-(5-thioxo-
,5-dihydro-1H-1,2,4-triazol-3-yl) propan-
-one (12)
(TLC). The final product precipitated was filtered off and
washed with cold water (100 ml), dried, and crystallized
from ethanol as yellow crystals in 82% yield, m. p.
ꢀ
3
12–314 C. IR (KBr): ν
= 3255 (NH), 3074 (CH, aryl),
max
A mix of compound 1 (1.92 g, 0.01 mol) and potassium
thiocyanate (KSCN, 0.97 g, 0.01 mol) in 10% HCl
2950 (CH, alkyl), 1685 (C O), 1631 (C N), 1583(C C)
−1
1
cm ; H NMR (DMSO-d ): δ = 2.03–2.13 (d, 2H,
6
(
hydrochloric acid) was heated under reflux for 6–9 h.
J = 5.14 Hz, CH ), 3.38 (s, 2H, J = 5.16 Hz, CH ), 6.09 (t,
2
2
The reaction mixture was allowed to cool and poured
into ice/water. The separated solid was filtered off
washed with water, dried and recrystallized from diox-
1H, J = 5.09 Hz, CH, pyrrole), 7.07–7.51 (m, 5H, Ar-H),
13
11.59 (br, 1H, NH, D O exchangeable);
C NMR
2
(DMSO-d ) δ = 32.1, 52.5 (2C, 2CH ), 95.8 (1C, CH, pyr-
6
2
ꢀ
ane as brownish crystals in 77% yield, m. p. 292–294 C.
IR (KBr): νmax = 3338–3131 (2NH), 3012 (CH, aryl),
role), 127.8, 128.2, 128.7, 135.1,150.3, 163.8 (8C, Ar-C),
+
168.6 (1C, C O); MS (70 eV): m/z = 213 (M , 97%);
2
1
2
957 (CH, alkyl), 1673 (C O), 1633 (C N), 1605 (C C),
263(C S) cm ; H NMR (DMSO-d ): δ = 2.26–2.35 (t,
H, J = 5.07 Hz, CH ), 3.64–3.80 (t, 2H, J = 5.09 Hz,
Anal. Calc. (Found) for C H N O (213.24): C, 67.59
12
11 3
−
1 1
(67.65); H, 5.20 (5.14); N, 19.71 (19.80).
6
2
CH ), 7.20–7.88 (m, 5H, Ar-H), 10.85, 12.91 (br, 2H,
2
2
1
3
0
NH, D O exchangeable);
C
NMR (DMSO-d6)
4.17 | Synthesis of N -(4-substituted-
2
δ = 30.7, 36.8 (2C, 2CH ), 123.2, 128.7, 130.7, 151.6,
benzylidene)-4-oxo-
4-phenylbutanehydrazide (15a-c)
2
1
62.2 (7C, Ar-C), 188.2 (1C, C S), 192.5 (1C, C O); MS
+
(
70 eV): m/z = 233 (M , 94%); Anal. Calc. (Found) for
C H N OS (233.29): C, 56.63 (56.75); H, 4.75 (4.70); N,
General procedure: A mixture of compound 1 (1.92 g,
0.01 mol) and appropriate aryl aldehydes namely; benzal-
dehyde (1.06 g, 0.01 mol) or 4-chlorobenzaldehyde
1
1
11
3
1
8.01 (18.10).
(
1.40 g, 0.01 mol) or 4-methoxybenzaldehyde (1.36 g,
4
3
.15 | Synthesis of 3-(3-oxo-
-phenylpropyl)-1,6-dihydro-1,2,4-triazin-5
0.01 mol) in ethanol (40 ml) with catalytic amount of
piperidine was heated under reflux for 5–8 h. The reac-
tion mixture was allowed to cool and poured into crushed
ice then acidified with HCl. The separated solid was fil-
tered off washed with water, dried and recrystallized
from the ideal solvent to give 15a-c.
(2H)-one (13)
A mix of compound 1 (1.92 g, 0.01 mol) and chlor
oacetamide (0.93 g, 0.01 mol) in dimethyl-formamide
(30 ml) was heated under reflux for 24–28 h. The solvent
was evaporated under reduced pressure and the residue
was triturated with water. The final solid obtained was
filtered, dried and recrystallized from dioxane as yellow-
0
4.18 | Synthesis of N -benzylidene-4-oxo-
4-phenylbutanehydrazide (15a)
ꢀ
ish crystals in 69% yield, m. p. 302–304 C. IR (KBr):
νmax = 3270–3200 (2NH), 3080(CH, aryl), 2960 (CH,
The compound was obtained from the reaction of (1) and
benzaldehyde, crystallized from acetone as white crystals
alkyl), 1735, 1672 (2C O), 1636 (C N), 1588 (C C)
−
1
1
ꢀ
cm ; H NMR (DMSO-d ): δ = 2.85–2.90 (t, 2H,
in 85% yield, m. p. 320–322 C. IR (KBr): ν
= 3230 (NH),
max
6
J = 5.02 Hz, CH ), 3.37–3.42 (t, 2H, J = 5.04 Hz, CH ),
3068 (CH, aryl), 2957 (CH, alkyl), 1738, 1677 (2C O), 1629
2
2
−
1
1
3
1
.80 (s, 2H, J = 5.12 Hz, CH ), 7.54–7.95 (m, 5H, Ar-H),
(C N), 1585 (C C) cm ;
H
NMR (DMSO-d6):
2
13
1.60, 12.20 (br, 2H, 2NH, D O exchangeable); C NMR
δ = 2.72–2.77 (t, 2H, J = 5.06 Hz, CH ), 3.34–3.39 (t, 2H,
2
2
(
DMSO-d ) δ = 27.3, 31.4, 58.1 (3C, 3CH ), 128.1, 128.5,
J = 5.08 Hz, CH ), 7.25–7.97 (m, 10H, Ar-H), 8.05 (s, 1H,
6
2
2
13
1
33.4, 137.6, 157.1 (7C, Ar-C), 170.1185.5 (2C, 2C O);
CH, proton), 11.50 (br, 1H, NH, D O exchangeable);
C
2
+
MS (70 eV): m/z = 231 (M , 100%); Anal. Calc. (Found)
NMR (DMSO-d ) δ = 22.2, 35.4 (2C, 2CH ), 127.9, 128.2,
6 2
for C H N O (231.26): C, 62.33 (62.40); H, 5.67
128.4, 131.2, 132.7, 133.4, 155.7, 156.8 (12C, Ar-C), 157.9
12
13 3 2
(5.74); N, 18.17 (18.12).
(1C, CH), 170.5, 181.4 (2C, 2C O); MS (70 eV): m/z = 280

816
ABU-HASHEM
+
(
(
M , 100%); Anal. Calc. (Found) for C H N O
7 16 2 2
30–35 h, with control (TLC). The solvent was evaporated
under reduced pressure and the residue was triturated with
water. The solid precipitate obtained was filtered, dried
and recrystallized from the suitable solvent to give 16a-c.
1
280.33): C, 72.84 (72.92); H, 5.75 (5.70); N, 9.99 (9.91).
0
4
.19 | Synthesis of N -
(
4
4-chlorobenzylidene)-4-oxo-
-phenylbutanehydrazide (15b)
4.22 | Synthesis of 3-(3-oxo-
3
-phenylpropyl)-7-phenyl-4,6-dihydro-5H-
The compound was obtained from the reaction of (1) and
1,2,4-triazepin-5-one (16a)
4
-chlorobenzaldehyde, crystallized from benzene as yellow
ꢀ
crystals in 90% yield, m. p. 343–345 C. IR (KBr): ν
= 3235
The compound was obtained from the reaction of 15a
(2.80 g, 0.01 mol) and chloroacetamide, crystallized from
methanol as yellowish crystals in 78% yield, m. p.
> 350 C. IR (KBr): ν
3078 (CH, aryl), 2972 (CH, alkyl), 1733, 1685 (2C O),
1631 (C N), 1590 (C C) cm ; H NMR (DMSO-d ):
max
(NH), 3069 (CH, aryl), 2958 (CH, alkyl), 1740, 1680
−1 1
(2C O), 1635 (C N), 1587 (C C) cm ; H NMR (DMSO-
ꢀ
d ): δ = 2.65–2.70 (t, 2H, J = 5.11 Hz, CH ), 3.25–3.30 (t,
= IR (KBr): νmax = 3305 (NH),
max
6
2
2
4
2
1
H, J = 5.14 Hz, CH ), 7.20–7.26 (dd, 2H, J = 7.55 Hz,
2
−
1
1
-chlorophenyl), 7.45–7.82 (m, 5H, Ar-H), 7.88–7.95 (dd,
H, J = 7.50 Hz, 4-chlorophenyl), 8.03 (s, 1H, CH, proton),
6
δ = 2.23 (s, 2H, CH ), 2.90–3.10 (t, 2H, J = 5.16 Hz, CH ),
2
2
13
1.42 (br, 1H, NH, D O exchangeable); C NMR (DMSO-
3.70–3.86 (t, 2H, J = 5.18 Hz, CH ), 7.33–7.83 (m, 10H,
2
2
13
d ) δ = 29.5, 34.1 (2C, 2CH ), 128.1, 128.4, 128.9, 129.8,
Ar-H), 8.52 (br, 1H, NH, D O exchangeable); C NMR
6
2
2
1
31.5, 132.7, 135.9, 136.2 (12C, Ar-C), 145.3(1C, CH), 172.6,
(DMSO-d ) δ = 15.6, 21.5, 31.2 (3C, 3CH ), 121.5, 124.8,
130.2, 130.8, 130.9, 131.5, 136.1, 147.7, 158.3, 165.6 (14C,
6
2
+
185.1 (2C, 2C O); MS (70 eV): m/z = 314 (M , 97%); Anal.
Calc. (Found) for C H ClN O (314.77): C, 64.87
Ar-C), 168.6, 168.9 (2C, 2C O); MS (70 eV): m/z = 319
17
15
2 2
+
(64.95); H, 4.80 (4.88); N, 8.90 (8.84).
(M , 6%); Anal. Calc. (Found) for C H N O
19
17
3
2
(
319.36): C, 71.46 (71.52); H, 5.37 (5.31); N, 13.16 (13.24).
0
4
.20 | Synthesis of N -
(
4
4-methoxybenzylidene)-4-oxo-
-phenylbutanehydrazide (15c)
4.23 | Synthesis of 7-(4-chlorophenyl)-
3-(3-oxo-3-phenylpropyl)-4,6-dihydro-5H-
1,2,4-triazepin-5-one (16b)
The compound was obtained from the reaction of (1) and
4
-methoxyphenyl, crystallized from methanol as yellow
The compound was obtained from the reaction of 15b
ꢀ
crystals in 82% yield, m. p. 331–333 C. IR (KBr):
νmax = 3238 (NH), 3073 (CH, aryl), 2961 (CH, alkyl), 1745,
(3.14 g, 0.01 mol) and chloroacetamide, crystallized from
ꢀ
ethanol as brownish crystals in 87% yield, m. p. > 350 C.
−1 1
1
684 (2C O), 1637 (C N), 1589 (C C) cm ; H NMR
IR (KBr): νmax = IR (KBr): νmax = 3310 (NH), 3081 (CH,
(
DMSO-d ): δ = 2.61–2.67 (t, 2H, J = 5.15 Hz, CH ),
aryl), 2976 (CH, alkyl), 1735, 1689 (2C O), 1634 (C N),
6
2
−
1 1
3
7
7
7
.22–3.28 (t, 2H, J = 5.17 Hz, CH ), 3.75 (s, 3H, OCH ),
1593 (C C) cm ; H NMR (DMSO-d ): δ = 2.86 (s, 2H,
2
3
6
.10–7.15 (dd, 2H,
.55–7.60 (dd, 2H,
J
J
= 7.57 Hz, 4-methoxyphenyl),
= 7.59 Hz, 4-methoxyphenyl),
CH ), 3.01–3.07 (t, 2H, J = 5.20 Hz, CH ), 3.33–3.39 (t,
2
2
2H, J = 5.19 Hz, CH ), 7.35–7.66 (m, 5H, Ar-H),
2
.63–7.98 (m, 5H, Ar-H), 8.09 (s, 1H, CH, proton), 11.35
7.70–7.77 (dd, 2H,
J
= 7.60 Hz, 4-chlorophenyl),
13
(
br, 1H, NH, D O exchangeable); C NMR (DMSO-d6)
7.90–7.97 (dd, 2H, J = 7.57 Hz, 4-chlorophenyl), 9.25 (br,
2
13
δ = 30.2, 34.7 (2C, 2CH ), 52.8 (1C, CH ), 120.4, 127.1,
1H, NH, D O exchangeable); C NMR (DMSO-d6)
2
3
2
1
28.5, 128.7, 130.5, 133.6, 136.2, 143.9 (12C, Ar-C), 146.1
δ = 25.8, 30.9, 39.1 (3C, 3CH ), 123.4, 127.9, 128.1, 128.5,
2
(
(
(
1C, CH), 172.9, 185.8 (2C, 2C O); MS (70 eV): m/z = 310
128.7, 133.6, 135.7, 136.2, 147.5, 153.9 (14C, Ar-C), 169.1,
184.8 (2C, 2C O); MS (70 eV): m/z = 353 (M , 95%);
+
+
M , 88%); Anal. Calc. (Found) for C H N O
18
18
2
3
310.35): C, 69.66 (69.74); H, 5.85 (5.80); N, 9.03 (9.13).
Anal. Calc. (Found) for C H ClN O (353.81): C, 64.50
19
16
3 2
(
64.61); H, 4.56 (4.50); N, 11.88 (11.82).
4
.21 | Synthesis of 7-(4-substituted-
phenyl)-3-(3-oxo-3-phenylpropyl)-
4.24 | Synthesis of 7-(4-methoxyphenyl)-
4
,6-dihydro-5H-1,2,4-triazepin-5-one (16a-c)
3-(3-oxo-3-phenylpropyl)-4,6-dihydro-5H-
1,2,4-triazepin-5-one (16c)
General procedure:
A mixture of compound 15a-c
(0.01 mol) and chloroacetamide (0.93 g, 0.01 mol) in
The compound was obtained from the reaction of 15c
dimethylformamide (40 ml) was heated under reflux for
(3.10 g, 0.01 mol) and chloroacetamide, crystallized from

ABU-HASHEM
817
ꢀ
ꢀ
dioxane as brownish crystals in 80% yield, m. p. > 350 C.
IR (KBr): νmax = IR (KBr): νmax = 3315 (NH), 3085 (CH,
aryl), 2982 (CH, alkyl), 1731, 1682 (2C O), 1630 (C N),
as yellowish crystals in 79% yield, m. p. > 350 C. IR
(KBr): νmax = IR (KBr): νmax = 3075(CH, aryl), 2971
(CH, alkyl), 1680 (C O), 1641 (C N), 1583 (C C)
−1
1
−1 1
1
582 (C C) cm ; H NMR (DMSO-d ): δ = 2.90 (s, 2H,
cm ; H NMR (DMSO-d ): δ = 2.93(d, 2H, J = 5.16 Hz,
6
6
CH ), 3.05–3.11 (t, 2H, J = 5.22 Hz, CH ), 3.36–3.42 (t, 2H,
CH ), 3.07 (s, 2H, CH ), 5.28–5.33 (t, 1H, J = 5.18 Hz,
2
2
2
2
J = 5.17 Hz, CH ), 3.85 (s, 3H, OCH ), 7.10–7.16 (dd, 2H,
CH), 7.37–7.43 (dd, 2H, J = 7.68 Hz, 4-chlorophenyl),
7.50–7.75 (m, 5H, Ar-H), 7.92–7.99 (dd, 2H, J = 7.61 Hz,
2
3
J = 7.65 Hz, 4-methoxyphenyl), 7.44–7.85 (m, 5H, Ar-H),
1
3
7
.92–7.98 (dd, 2H, J = 7.62 Hz, 4-methoxyphenyl), 9.34 (br,
4-chlorophenyl); C NMR (DMSO-d ) δ = 36.3, 36.7 (2C,
6
13
1H, NH, D O exchangeable);
C NMR (DMSO-d6)
2CH ), 106.2 (1C,CH), 125.7, 126.2, 127.4, 128.7, 128.8,
2
2
δ = 26.1, 31.3, 39.7 (3C, 3CH ), 52.6 (1C, OCH ), 121.8,
129.5, 130.2, 131.2, 132.4158.5, 161.6 (15C, Ar-C), 163.6
(1C,C O); MS (70 eV): m/z = 335(M , 30%), 334 (M -
2
3
+
+
122.6, 128.2, 128.5, 128.9, 133.3, 136.4, 147.8, 154.2, 158.5
(
14C, Ar-C), 170.6, 186.2 (2C, 2C O); MS (70 eV): m/
1100%); Anal. Calc. (Found) for C H ClN O
(335.79): C, 67.96 (67.87); H, 4.20 (4.27); N,
12.51 (12.58).
1
9
14
3
+
z = 349 (M , 92%); Anal. Calc. (Found) for C H N O
0 19 3 3
2
(349.39): C, 68.75 (68.67); H, 5.48 (5.55); N, 12.03 (12.10).
4
.25 | Synthesis of 3-(4-substituted-
phenyl)-7-phenyl-4,9-dihydro-5H-pyrrolo
2,1-c] [1,2,4] triazepin-5-one (17a-c)
4.28 | Synthesis of 3-(4-methoxyphenyl)-
7-phenyl-4,9-dihydro-5H-pyrrolo [2,1-c]
[1,2,4] triazepin-5-one (17c)
[
General procedure: A mixture of 16a-c (0.01 mol) and
K CO ) anhydrous potassium carbonate (2 g, 0.015 mol)
The compound was obtained from the reaction of 16c
(
(3.49 g, 0.01 mol) and DMF, crystallized from benzene as
2
3
ꢀ
in dimethylformamide (DMF, 40 ml) was refluxed for
7–20 h under control (TLC). The product precipitated
brownish crystals in 76% yield, m. p. > 350 C. IR (KBr):
1
νmax = IR (KBr): νmax = 3079(CH, aryl), 2976 (CH, alkyl),
−1 1
was filtered off and washed with cold water (100 ml),
dried, and crystallized from the proper solvent to give
1683 (C O), 1644 (C N), 1585 (C C) cm ; H NMR
(DMSO-d ): δ = 2.97(d, 2H, J = 5.15 Hz, CH ), 3.09 (s,
6
2
1
7a-c.
2H, CH ), 3.85 (s, 3H, OCH ), 5.30–5.36 (t, 1H,
2
3
J = 5.16 Hz, CH), 7.10–7.17 (dd, 2H, J = 7.70 Hz,
-methoxyphenyl), 7.55–7.80 (m, 5H, Ar-H), 7.88–7.97
4
13
4
4
.26 | Synthesis of 3,7-diphenyl-
,9-dihydro-5H-pyrrolo [2,1-c] [1,2,4]
(dd, 2H, J = 7.72 Hz, 4-methoxyphenyl); C NMR
(DMSO-d ) δ = 34.3, 36.8 (2C, 2CH ), 55.5(1C, OCH ),
6
2
3
triazepin-5-one (17a)
106.1 (1C,CH), 127.4, 128.6, 129.1, 129.2, 129.4, 129.6,
29.7, 130.3, 157.5159.1, 161.6 (15C, Ar-C), 163.5 (1C,
C O); MS (70 eV): m/z = 331 (M , 84%); Anal. Calc.
1
+
The compound was obtained from the reaction of 16a
(
3.19 g, 0.01 mol) and DMF, crystallized from dioxane as
(Found) for C H N O (331.38): C, 72.49 (72.57); H,
5.17 (5.11); N, 12.68 (12.76).
20
17 3 2
ꢀ
yellow crystals in 74% yield, m. p. > 350 C. IR (KBr):
νmax = IR (KBr): νmax = 3072(CH, aryl), 2968 (CH, alkyl),
−
1 1
1
678 (C O), 1638 (C N), 1580 (C C) cm ; H NMR
(
2
(
2
DMSO-d ): δ = 2.62 (d, 2H, J = 5.13 Hz, CH ), 3.90 (s,
4.29 | Synthesis of 3-(6-(4-substituted-
phenyl)-1,2,4-triazin-3-yl)-1-phenylpropan-
1-one (18a-c)
6
2
H, CH ), 4.90–5.10 (t, 1H, J = 5.14 Hz, CH), 7.48–7.70
2
13
m, 10H, Ar-H); C NMR (DMSO-d ) δ = 33.5, 37.1(2C,
6
CH ), 79.1(1C,CH), 120.5, 123.2, 128.7, 130.7, 130.8,
2
1
40.7, 150.6, 151.6, 160.7, 162.2, 165.3 (15C, Ar-C), 167.6
General procedure: Method A: A mixture of 15a-c
(0.01 mol) and formamide (15 mL) was refluxed with stir-
ring in DMF (45 ml) for 9–11 h under (TLC) checking.
The reaction mixture was cooled at room temperature
and poured into (100 ml) of water was added and the
+
(
(
(
1C, C O); MS (70 eV): m/z = 301 (M , 90%); Anal. Calc.
Found) for C H N O (301.35): C, 75.73 (75.66); H, 5.02
5.10); N, 13.94 (13.88).
19
15 3
mixture was neutralized with NH OH. The solid precipi-
4
4
7
.27 | Synthesis of 3-(4-chlorophenyl)-
-phenyl-4,9-dihydro-5H-pyrrolo [2,1-c]
tate formed was filtered and washed via H O, ethanol,
2
then dried and recrystallized from a proper solvent to
yielded 18a-c. Method B: A mix of 15a-c (0.01 mol) and
formamide (10 ml) in dimethylformamide (10 ml) was
heated under reflux to 22–24 h. The solvent was evapo-
rated under reduced pressure and the residue was
[1,2,4] triazepin-5-one (17b)
The compound was obtained from the reaction of 16b
3.53 g, 0.01 mol) and DMF, crystallized from benzene
(

818
ABU-HASHEM
−
1 1
triturated with water. The solid obtained was filtered,
dried, and recrystallized from suitable solvent to afford
1578 (C C) cm ; H NMR (DMSO-d ): δ = 2.73–2.80 (t,
6
2H, J = 5.27 Hz, CH ), 2.89–2.95 (t, 2H, J = 5.24 Hz,
CH ), 3.77 (s, 3H,OCH ), 7.08–7.15 (dd, 2H, J = 7.58 Hz,
2
1
8a-c.
2
3
4
4
-methoxyphenyl), 7.46–7.52 (dd, 2H, J = 7.57 Hz,
-methoxyphenyl), 7.58–7.96 (m, 5H, Ar-H), 8.18 (s, 1H,
13
4
1
.30 | Synthesis of 1-phenyl-3-(6-phenyl-
,2,4-triazin-3-yl)propan-1-one (18a)
CH, triazine); C NMR (DMSO-d ) δ = 30.8, 39.9 (2C,
6
2CH ), 54.5 (1C, OCH ), 121.4, 123.8, 128.2, 128.4, 128.7,
33.5, 140.9, 148.2, 153.7, 159.1, 165.3 (15C, Ar-C), 190.2
(1C, C O); MS (70 eV): m/z = 319 (M , 91%); Anal. Calc.
2
3
1
+
The compound was obtained from the reaction of 15a
(
2.80 g, 0.01 mol) and formamide, crystallized from etha-
(Found) for C H N O (319.36): C, 71.46 (71.55); H,
5.37 (5.30); N, 13.16 (13.08).
19
17 3 2
ꢀ
nol as yellow crystals in 81% yield, m. p. > 350 C. IR
(
(
KBr): νmax = IR (KBr): νmax = 3093 (CH, aryl), 2933
−
1
CH, alkyl), 1713 (C O), 1632 (C N), 1607 (C C) cm ;
1
H NMR (DMSO-d ): δ = 2.67–2.73 (t, 2H, J = 5.20 Hz,
4.33 | Synthesis of 3-(4-substituted-
phenyl)-6-phenyl-4,8-dihydropyrrolo [2,1-c]
[1,2,4] triazine (19a-c)
6
CH ), 2.80–2.85 (t, 2H, J = 5.21 Hz, CH ), 7.20–7.93 (m,
1
2
2
13
0H, Ar-H), 8.10 (s, 1H, CH, triazine); C NMR (DMSO-
d ) δ = 30.2, 39.1 (2C, 2CH ), 127.1, 128.3, 128.5, 128.9,
6
2
1
1
29.1, 133.3, 133.5, 140.4, 149.4, 153.1, 165.8 (15C, Ar-C),
90.4 (1C, C O); MS (70 eV): m/z = 289 (M , 92%);
General procedure: Method A: A mixture of 18a-c
+
(0.01 mol) and anhydrous potassium carbonate (K CO ,
2
3
Anal. Calc. (Found) for C H N O (289.34): C, 74.72
2 g, 0.015 mol) in dimethylformamide (DMF, 45 ml) was
refluxed for 15–18 h under control (TLC). The solid prod-
uct of the precipitate was filtered off and washed with ice
18
15 3
(74.61); H, 5.23 (5.30); N, 14.52 (14.64).
/cold water (100 ml) and neutralized, dried, and crystal-
4
1
1
.31 | Synthesis of 3-(6-(4-chlorophenyl)-
,2,4-triazin-3-yl)-1-phenylpropan-
-one (18b)
lized from the appropriate solvent to give 19a-c. Method
B: The stirring of a mixture of 18a-c (0.01 mol) in glacial
acetic acid (40 ml), activated zinc dust (1.3 g, 0.02 mol)
was added portionwise at room temperature over a
period of 1 h, stirring was continued for an additional
4–6 h. The reaction mixture was heated on a water bath
The compound was obtained from the reaction of 15b
3.14 g, 0.01 mol) and formamide, crystallized from tetra-
(
ꢀ
hydrofuran (THF) as brownish crystals in 88% yield,
m. p. > 350 C. IR (KBr): ν
(90–95 C) for 6–8 h, with control (TLC), after allowing
ꢀ
= IR (KBr): νmax = 3075
the reaction mixture to cool at room temperature, it was
poured into cold water (100 mL). The precipitate was fil-
tered, washed with water, dried, and crystallized to pro-
duce 19a-c, respectively.
max
(CH, aryl), 2969 (CH, alkyl), 1730 (C O), 1628 (C N),
−1 1
1
2
576 (C C) cm ; H NMR (DMSO-d ): δ = 2.70–2.77 (t,
6
H, J = 5.25 Hz, CH ), 2.85–2.90 (t, 2H, J = 5.27 Hz,
2
CH ), 7.45–7.51 (dd, 2H, J = 7.62 Hz, 4-chlorophenyl),
7
4
2
.55–7.90 (m, 5H, Ar-H), 7.92–7.97 (dd, 2H, J = 7.66 Hz,
-chlorophenyl), 8.15 (s, 1H, CH, triazine); C NMR
13
4.34 | Synthesis of 3,6-diphenyl-
4,8-dihydropyrrolo [2,1-c] [1,2,4]
triazine (19a)
(DMSO-d ) δ = 30.5, 39.6 (2C, 2CH ), 128.2, 128.4, 128.7,
6 2
1
29.2, 129.5, 133.4, 134.5, 140.7, 149.6, 153.4, 165.5 (15C,
+
Ar-C), 192.1 (1C, C O); MS (70 eV): m/z = 323 (M ,
4
5%); Anal. Calc. (Found) for C H ClN O (323.78): C,
The compound was obtained from the reaction of 18a
18
14
3
6
6.77 (66.68); H, 4.36 (4.42); N, 12.98 (13.06).
(2.89 g, 0.01 mol) and DMF, crystallized from dioxane as
yellowish crystals in 80% yield, m. p. > 350 C. IR (KBr):
ꢀ
νmax = IR (KBr): νmax = 3075(CH, aryl), 2970 (CH, alkyl),
−
1
1
4
3
1
.32 | Synthesis of
-(6-(4-methoxyphenyl)-1,2,4-triazin-3-yl)-
-phenylpropan-1-one (18c)
1638 (C N), 1585 (C C) cm ; H NMR (DMSO-d ):
6
δ = 3.11–3.27 (d, 2H, J = 5.50 Hz, CH pyrrole), 4.17 (s,
2,
2H, J = 5.60 Hz, CH2, triazine), 6.58–6.82 (t, 1H,
1
3
J = 5.42 Hz, CH pyrrole), 7.15–7.85 (m, 10H, Ar-H);
C
,
The compound was obtained from the reaction of 15c
3.10 g, 0.01 mol) and formamide, crystallized from tetra-
NMR (DMSO-d ) δ = 21.6, 58.5 (2C, 2CH ), 79.7 (1C, CH
6 2 ,
(
pyrrole), 121.5, 124.8, 130.2, 130.8, 130.9131.5, 136.1147.7,
hydrofuran (THF) as yellowish crystals in 83% yield,
158.3, 165.5, 165.7 (15C, Ar-C); MS (70 eV): m/z = 273
ꢀ
+
m. p. > 350 C. IR (KBr): ν
= IR (KBr): νmax = 3078
(M , 100%); Anal. Calc. (Found) for C H N
max
18 15
3
(CH, aryl), 2971 (CH, alkyl), 1733 (C O), 1631 (C N),
(273.34): C, 79.10 (79.18); H, 5.53 (5.45); N, 15.37 (15.31).

ABU-HASHEM
819
[
46–48]
4
6
.35 | Synthesis of 3-(4-chlorophenyl)-
-phenyl-4, 8-dihydropyrrolo [2,1-c] [1,2,4]
MTT assay according to the method.
The MTT
assay is based on the reduction of the soluble
3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium
bromide (MTT) into a blue-purple formazan product,
mainly by mitochondrial reeducates activity inside living
cells. The cells used in cytotoxicity assay were cultured in
RPMI 1640 medium supplemented with 10% fetal calf
triazine (19b)
The compound was obtained from the reaction of 18b
(3.23 g, 0.01 mol) and DMF, crystallized from acetone as
ꢀ
yellow crystals in 82% yield, m. p. > 350 C. IR (KBr):
νmax = IR (KBr): νmax = 3079(CH, aryl), 2974 (CH, alkyl),
0
serum. Cells suspended in the medium (2Y 104/ml) were
plated in 96-well culture plates and incubated at 37 C in
−
1
1
ꢀ
1
640 (C N), 1590 (C C) cm ; H NMR (DMSO-d ):
6
δ = 3.05–3.10 (d, 2H, J = 5.55 Hz, CH pyrrole), 4.35 (s,
a 5% CO incubator. After 12 h, the test sample (2 ml)
2,
2
0
2
H, J = 5.65 Hz, CH2, triazine), 6.15–6.20 (t, 1H,
J = 5.48 Hz, CH pyrrole), 7.46–7.55 (dd, 2H, J = 7.65 Hz,
was added to the cells (2Y 104) in 96-well plates and cul-
ꢀ
tured at 37 C for 3 days. The cultured cells were mixed
,
4
2
-chlorophenyl),7.58–7.85 (m, 5H, Ar-H), 7.91–7.98 (dd,
with 20 ml of MTT solution and incubated for 4 h at
13
ꢀ
H, J = 7.68 Hz, 4-chlorophenyl); C NMR (DMSO-d )
37 C. The supernatant was carefully removed from each
6
δ = 31.1, 50.5 (2C, 2CH ), 95.4 (1C, CH pyrrole), 127.8,
well and 100 ml of DMSO was added to each well to dis-
solve the formazan crystals which were formed by the
cellular reduction of MTT. After mixing with a mechani-
cal plate mixer, the absorbance of each well was mea-
sured by a microplate reader using a test wavelength of
2
,
1
1
28.1, 128.5, 128.8, 129.2, 131.9, 134.1, 136.3, 149.2, 160.8,
65.3 (15C, Ar-C); MS (70 eV): m/z = 307 (M , 40%);
+
Anal. Calc. (Found) for C H ClN (307.78): C, 70.24
18
14
3
(70.32); H, 4.59 (4.67); N, 13.65 (13.57).
5
70 nm. The results were expressed as the IC , which is
50
the concentration of the drugs inducing a 50% inhibition
of cell growth of treated cells when compared to the
growth of control cells. Each experiment was performed
at least three times. There was a good reproducibility
between replicate wells with standard errors below 10%.
4
6
.36 | Synthesis of 3-(4-methoxyphenyl)-
-phenyl-4,8-dihydropyrrolo [2,1-c] [1,2,4]
triazine (19c)
The compound was obtained from the reaction of 18c
(
3.19 g, 0.01 mol) and DMF, crystallized from n-hexane as
ꢀ
brownish crystals in 77% yield, m. p. > 350 C. IR (KBr):
6 | CONCLUSION
νmax = IR (KBr): νmax = 3073(CH, aryl), 2972 (CH, alkyl),
−1
1
1635 (C N), 1583 (C C) cm ; H NMR (DMSO-d6):
The target of the recent study is to prepare and evaluate
the cytotoxicity activity of the new compounds such as;
pyrazoles, 1,3,4-oxadiazoles, 1,2,4-triazoles, 1,2,4-tria
δ = 3.08–3.13 (d, 2H, J = 5.52 Hz, CH pyrrole), 3.84(s, 3H,
2,
OCH ), 4.38 (s, 2H, J = 5.63 Hz, CH triazine), 6.19–6.23 (t,
3
2,
0
1
H, J = 5.45 Hz, CH, pyrrole), 7.11–7.17 (dd, 2H,
zines, pyrrolo [1,2-b] [1,2,4] triazinones, N -(4-sub-
J = 7.67 Hz, 4-methoxyphenyl), 7.50–7.82 (m, 5H, Ar-H),
benzylidene)-butanehydrazides, 1,2,4-triazepinones, pyrr
olo[2,1-c][1,2,4] triazepinones and pyrrolo [2,1-c] [1,2,4]
triazines with the hope of finding out new chemical
structure can be used as antitumor agents. All the results
demonstrated that pyrrolo [2,1-c] [1,2,4] triazepinones
17a-c, 1,2,4-triazepinones 16a-c, pyrrolo [2,1-c] [1,2,4] tri-
azines 19a-c, pyrrolo [1,2-b] [1,2,4] triazinones 14 and
13
7
.93–7.99 (dd, 2H, J = 7.70 Hz, 4-methoxyphenyl); C NMR
(DMSO-d ) δ = 31.6, 50.7 (2C, 2CH ), 56.7 (1C, OCH ), 95.8
6
2
3
(
1C, CH pyrrole), 122.5, 126.7, 127.8, 128.2, 128.5, 128.9,
,
1
34.6149.7, 161.1, 163.2, 165.8 (15C, Ar-C); MS (70 eV): m/
+
z = 303 (M , 90%); Anal. Calc. (Found) for C H N O
19 17 3
(303.37): C, 75.23 (75.15); H, 5.65 (5.72); N, 13.85 (13.93).
1,2,4-triazoles 12 possess promising and wonderful
in vitro antitumor activity versus carcinoma cell lines
when compared to the 5-fluorouracil drug.
5
| PHARMACOLOGICAL
SCREENING
ACKNOWLEDGMENTS
Types of human carcinoma cancer cell line [MGC-803,
CNE2, KB and MCF-7] are derived from the (National
Cancer institute, Cairo University, Cairo, Egypt).
The author wishes to express his gratitude to Prof. Farid
A. Badria (Department of Pharmacognosy, Faculty of
pharmacy, Mansoura University, Egypt) for carrying out
the biological activity tests. The anticancer data were pro-
vided by the National Cancer Institute, Cairo University
and Cairo, Egypt. This work was supported by the
Department of Photochemistry (Heterocyclic unit);
Chemical Industries research Division, National
Research Centre in Cairo, Egypt.
5.1 | Materials and methods
The in vitro cytotoxicity of the synthesized compounds
against different cancer cell lines was performed with the

820
ABU-HASHEM
DATA AVAILABILITY STATEMENT
Data available on request due to privacy/ethical restric-
tions The data that support the findings of this study are
available on request from the corresponding author. The
data are not publicly available due to privacy or ethical
restrictions.
[26] J. B. O'Neal, H. Rosen, P. B. Russell, A. C. Adams, J. Med.
Chem. 1962, 5, 617.
[
27] J. H. Musser, R. E. Brown, B. Love, K. Bailey, H. Jones, R.
Kahen, F. Huang, A. Khandwala, M. Leibowitz, P. Sonnino-
Goldman, D. Donigi-Ruzza, J. Med. Chem. 1984, 27, 121.
28] E. M. Keshk, A. A. Abu-Hashem, M. M. Girges, A. H. Abdel-
Rahman, F. A. Badria, Phosphorus Sulfur 2004, 179, 1577.
29] S. A. Said, A. E. G. E. Amr, N. M. Sabry, M. M. Abdalla, Eur.
J. Med. Chem. 2009, 44, 4787.
[
[
[
ORCID
Ameen Ali Abu-Hashem https://orcid.org/0000-0001-
30] H. Li, J. Tatlock, A. Linton, J. Gonzalez, T. Jewell, L. Patel, S.
Ludlum, M. Drowns, S. V. Rahavendran, H. Skor, R. Hunter,
J. Med. Chem. 2009, 52, 1255.
8
557-2806
REFERENCES
[31] C. F. Beyer, N. Zhang, R. Hernandez, D. Vitale, J. Lucas, T.
Nguyen, C. Discafani, S. Ayral-Kaloustian, J. Gibbons,
J. Cancer Res. 2008, 68, 2292.
[
[
1] L. Meng, Z. Bao-Xiang, Eur. J. Med. Chem. 2014, 85, 311.
2] A. A. Abu-Hashem, M. El-Shazly, Monatsh. Chem. Chem.
Mon. 2017, 148, 1853.
[32] A. A. Abu-Hashem, H. A. Hussein, K. M. Abu-zied, Med.
Chem. Res. 2016, 26, 120.
[
3] A. A. Abu-Hashem, M. F. El-Shehry, F. A. Badria, Acta.Pharm.
[33] A. A. Abu-Hashem, M. El-Shazly, Polycycl. Aromat. Comp
2
010, 60, 311.
4] A. A. Abu-Hashem, A. S. Aly, Arch. Pharmacal Res. 2012, 35
3), 437.
2019, Published online: 07 Apr 2019. https://doi.org/10.1080/
[
10406638.2019.1598448.
(
[
34] M. Arshad, T. A. Khan, M. A. Khan, Int. J. Pharm. Sci. Res.
014, 5, 149.
[
[
5] A. A. Abu-Hashem, A. S. Aly, Synth. Commun. 2017, 47, 2417.
6] A. B. A. El-Gazzar, A. M. Gaafar, M. M. Youssef, A. A. Abu-
Hashem, F. A. Badria, Phosphorus Sulfur 2007, 182, 2009.
7] A. A. Abu-Hashem, K. M. Abu-Zied, M. F. El-Shehry,
Monatsh. Chem. Chem. Mon. 2011, 142, 539.
2
[35] K. M. Elattar, M. A. Abozeid, I. A. Mousa, A. El-Mekabaty,
RSC Adv. 2015, 5, 106710.
[
[
[
[
[
36] M. Gupta, S. Paul, R. Gupta, Eur. J. Med. Chem. 2011, 46, 631.
37] W. S. Park, M. A. Jun, M. S. Shin, S. W. Kwon, S. K. Kang,
K. Y. Kim, S. D. Rhee, M. A. Bae, B. Narsaiah, D. H. Lee, H. G.
Cheon, J. H. Ahn, S. S. Kim, J. Fluorine Chem. 2009, 130, 1001.
8] A. A. Abu-Hashem, M. A. Gouda, J. Heterocyclic Chem. 2017,
5
4, 850.
9] A. A. Abu-Hashem, Acta Pol. Pharm. 2018, 75, 59.
[
38] A. Padmaja, T. Payani, G. D. Reddy, V. Padmavathi, Eur.
J. Med. Chem. 2009, 44, 4557.
39] P. Filippakopoulos, S. Picaud, O. Fedorov, M. Keller, M.
Wrobel, O. Morgenstern, F. Bracher, S. Knapp, Bioorg. Med.
Chem. 2012, 20, 1878.
[
[
10] A. A. Abu-Hashem, Molecules 2018, 23, 2793.
11] A. A. Abu-Hashem, M. A. Gouda, F. A. Badria, Eur. J. Med.
Chem. 2010, 45, 1976.
[
[
[
[
[
[
12] S. Schenone, M. Radi, F. Musumeci, C. Brullo, M. Botta,
Chem. Rev. 2014, 114, 7189.
[
[
[
40] A. A. Abu-Hashem, M. E. A. Zaki, J. Heterocyclic Chem 2019,
13] S. N. Jha, S. Mishra, S. A. Mamidi, A. Mishra, K. S. Jha, A.
Surolia, RSC Adv. 2016, 6, 7474.
14] P. Khloya, S. Kumar, P. Kaushik, P. Surain, D. Kaushik, P. K.
Sharma, Bioorg. Med. Chem. Lett. 2015, 25, 1177.
15] M. Abdel-Aziz, G. E. D. A. Abuo-Rahma, A. A. Hassan, Eur.
J. Med. Chem. 2009, 44, 3480.
16] F. M. Khan, M. M. Alam, G. Verma, W. Akhtar, M. Akhter, M.
Shaquiquzzaman, Eur. J. Med. Chem. 2016, 120, 170.
17] P. J. Dunn, S. Galvin, K. Hettenbach, Green Chem. 2004, 6, 43.
18] E. F. Chamberlain, C. Wang, H. Shi, C. D. Admas, Y. Ma,
J. Agric. Food Chem. 2010, 58, 6895.
5
6, 886.
41] A. A. Abu-Hashem, S. A. Al-Hussain, M. E. A. Zaki, Molecules
020, 25, 220.
2
42] A. A. Abu-Hashem, K. M. Abu-Zied, M. E. A. Zaki, M. F. El-
Shehry, H. M. Awad, M. A. Khedr, Lett. Drug Des. Discovery
2020, 17, 799.
[43] A. A. Abu-Hashem, H. A. R. Hussein, A. S. Aly, Med. Chem 2020,
16. https://doi.org/10.2174/1573406416666200406130047.
[44] A. A. Abu-Hashem, U. Fathy, M. A. Gouda, J. Heterocyclic
Chem 2020, 57, 3461.
[
[
[
[
[
[
[
[
19] H. A. Abadi, A. A. Eissa, S. G. Hassan, Chem. Pharm. Bull.
[45] A. A. Abu-Hashem, J. Heterocyclic Chem 2020, First published:
13 September 2020. https://doi.org/10.1002/jhet.4149.
[46] T. J. Mosmann, Immunol. Methods 1983, 65, 55.
[47] F. Denizot, R. J. Lang, Immunol. Methods 1986, 22, 271.
[48] M. I. Thabrew, R. D. Hughes, I. G. McFarlane, J. Pharm.
Pharmacol. 1997, 49, 1132.
[49] M. B. El-Ashmawy, M. A. El-Sherbeny, N. S. El-Gohary, Med.
Chem. Res. 2013, 22, 2724.
[50] R. Kumar, A. D. Singh, J. Singh, H. Singh, R. K. Roy, A.
Chaudhary, Mini Rev. Med. Chem. 2014, 14, 72.
2
003, 51, 838.
20] S. G. Kucukguzel, E. E. Oruc, S. Rollas, F. Sahin, A. Ozbek,
Eur. J. Med. Chem. 2002, 37, 197.
21] A. Zarghi, S. A. Tabatabai, M. Faizi, A. Ahadian, P. Navabi, V.
Zanganesh, A. Shafiee, Bioorg. Med. Chem. Lett. 2005, 15, 1863.
22] P. Mishra, G. K. Joshi, A. K. Shakya, R. K. Agarwal, G. K.
Patnaik, Ind. J. Physiol. Pharmacol. 1992, 36, 247.
23] S. V. Bhandari, K. G. Bothara, M. K. Raut, A. A. Patil, A. P.
Sarkate, V. J. Mokale, Bioorg. Med. Chem. 2008, 16, 1822.
24] X.-M. Zhang, M. Qiu, J. Sun, Y.-B. Zhang, Y.-S. Yang, X.-L.
Wang, J.-F. Tang, H.-L. Zhu, Bioorg. Med. Chem. 2011, 19,
[51] W. A. El-Sayed, I. F. Nassar, A. A. H. Abdel-Rahman,
J. Heterocyclic Chem. 2011, 48, 135.
6
518.
25] Y. A. Al-Soud, M. N. Al-Dweri, N. A. Al-Masoudi, IL Farmaco.
004, 59, 775.
[52] S. Cascioferro, B. Parrino, V. Spanò, A. Carbone, A.
Montalbano, P. Barraja, P. Diana, G. Cirrincione, Eur. J. Med.
Chem. 2017, 142, 328.
[
2

ABU-HASHEM
821
[
53] A. A. Abu-Hashem, M. A. Gouda, F. A. Badria, Med. Chem.
Res. 2018, 27, 2297.
How to cite this article: Abu-Hashem AA.
Synthesis of new pyrazoles, oxadiazoles, triazoles,
pyrrolotriazines, and pyrrolotriazepines as
potential cytotoxic agents. J Heterocyclic Chem.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
2021;58:805–821. https://doi.org/10.1002/jhet.4216