Synthesis and biological evaluation of some heterocyclic scaffolds based on the multifunctional N-(4-acetylphenyl)-2-chloroacetamide

Article abstract of DOI:10.1002/jhet.4012

The chloroacetamide derivative, 1, was used as a versatile precursor for the synthesis of various types of N-aryl-2-(benzothiazol-2-ylthio)acetamide derivatives. The reaction of 1 with 2-mercaptobenzothiazole followed by condensation reaction of the produced sulfide with phenylhydrazine, 2-cyanoacetohydrazide, and/or thiosemicarbazide furnished the conforming condensation products, 4, 7, and 10, respectively. Treatment of the phenylhydrazone product, 4, with Vilsmeier formylation reagent (POCl₃/DMF) yielded the corresponding 4-formylpyrazole derivative, 5. The thiosemicarbazone product, 10, was reacted with ethyl bromoacetate to furnish the thiazolin-4-one derivative, 11. The substitution reactions of chloroacetamide derivative, 1, with 2-mercapto-4,6-dimethylnicotinonitrile and 6-amino-2-mercaptopyrimidin-4-ol, were explored to identify the sulfide products, 14 and 17. Cyclization of 14 into its corresponding thieno[2,3-b]pyridine compound, 15, was performed using sodium ethoxide. The thiosemicarbazone, 10, and sulfide derivative, 14, were found to be the most potent antibacterial compounds against Escherichia coli and Staphylococcus aureus, exhibiting growth inhibitory activities of 80.8percent and 91.7percent, respectively. Moreover, the thiosemicarbazone, 10, displayed the most significant antioxidant activity with inhibitory activity of 82.6percent, which comes close to the antioxidant activity of L-ascorbic acid.

Full text of DOI:10.1002/jhet.4012

Received: 10 February 2020
DOI: 10.1002/jhet.4012
Revised: 2 April 2020
Accepted: 20 April 2020
A R T I C L E
Synthesis and biological evaluation of some heterocyclic
scaffolds based on the multifunctional N-(4-acetylphenyl)-
2-chloroacetamide
Ehab Abdel-Latif
| Mustafa M. Fahad | Amr El-Demerdash
|
Mohamed A. Ismail
Chemistry Department, Faculty of
Abstract
Science, Mansoura University, Mansoura,
Egypt
The chloroacetamide derivative, 1, was used as a versatile precursor for the synthe-
sis of various types of N-aryl-2-(benzothiazol-2-ylthio)acetamide derivatives. The
reaction of 1 with 2-mercaptobenzothiazole followed by condensation reaction
of the produced sulfide with phenylhydrazine, 2-cyanoacetohydrazide, and/or
thiosemicarbazide furnished the conforming condensation products, 4, 7, and 10,
respectively. Treatment of the phenylhydrazone product, 4, with Vilsmeier
formylation reagent (POCl3/DMF) yielded the corresponding 4-formylpyrazole
derivative, 5. The thiosemicarbazone product, 10, was reacted with ethyl
bromoacetate to furnish the thiazolin-4-one derivative, 11. The substitution reac-
tions of chloroacetamide derivative, 1, with 2-mercapto-4,6-dimethylnicotinonitrile
and 6-amino-2-mercaptopyrimidin-4-ol, were explored to identify the sulfide prod-
ucts, 14 and 17. Cyclization of 14 into its corresponding thieno[2,3-b]pyridine
compound, 15, was performed using sodium ethoxide. The thiosemicarbazone,
10, and sulfide derivative, 14, were found to be the most potent antibacterial
compounds against Escherichia coli and Staphylococcus aureus, exhibiting
growth inhibitory activities of 80.8% and 91.7%, respectively. Moreover, the
thiosemicarbazone, 10, displayed the most significant antioxidant activity with
inhibitory activity of 82.6%, which comes close to the antioxidant activity of
L-ascorbic acid.
Correspondence
Ehab Abdel-Latif, Chemistry Department,
Faculty of Science, Mansoura University,
35516 Mansoura, Egypt.
Email: ehabattia00@gmx.net
1 | INTRODUCTION
including an easy replacement of chlorine atom, a reactive
N H group, amide, ketonic carbonyls, and methylene group,
Halogenated acid derivatives gained much attention for
their promising acidity that prohibits the growth of
bacteria, fungi, parasites, and viruses.[1,2] Several N-Aryl
2-chloroacetamides displayed myriad biological potentialities
as herbicides, antifungals, and disinfectants. This might be
exemplified by the two herbicidal 2-chloroacetamides deriv-
atives, 2-chloro-N-(2,6-diethylphenyl)-N-(methoxymethyl)
acetamide (a) and 2-chloro-N-(2,6-dimethyl-phenyl)-N-[(3-
methoxy-2-thienyl)methyl]acetamide (b) (Figure 1).[3,4] The
2-chloroacetamides possess key structural features,
which make them highly attractive synthetic platforms
for synthesizing diverse heterocyclic systems, including
aziridine,[5] N-lactam,[6] piperazine,[7] imidazolidine-
containing compounds,[8] and macrocyclic ligands.[9] In
addition, various 2-chloroacetamide reagents have been
exploited in the field of solid-state chemistry[10] and
pharmacologically promising compounds.[11–14]
Moreover, compounds containing pyrazole moiety have
attracted significant attention as they showed diverse bioac-
tivities that include antimicrobial,[15,16] antimalarial,[17]
J Heterocyclic Chem. 2020;1–11.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals LLC.
1

2
ABDEL-LATIF ET AL.
FIGURE 1 Examples of
2-chloroacetamide herbicides
(a)
(b)
antioxidant,[18]anticancer,[19] and antidepressant activi-
ties.[20] In addition, several thiazole derivatives have been
recognized to have a wide spectrum of biological activity
such as antimicrobial,[21,22] antioxidant,[23] anticancer,[24,25]
and anti-inflammatory properties,[26] and potential cholin-
esterase inhibitors.[27] Besides, thienopyridine derivatives
were indicated to possess marked anticancer activities,
especially against both hepatocellular carcinoma (HepG-2)
and breast cancer (MCF-7) cell lines.[28] As a part of our
continued program dedicated to the chemistry of bioactive
N-(4-acetylphenyl)-2-(benzothiazol-2-ylthio)acetamide (3),[33]
which has been previously prepared by the direct reaction
of compound, 1, with 2-mercaptobenzothiazole in acetone
and potassium carbonate. The reaction failed to produce
our target compound, 2-(benzothiazol-2-ylthio)-N-(4-(1-(2-
phenyhydrazono)-ethyl)phenyl)-acetamide (4). The source
of water that is responsible for hydrolysis may be attributed
to the neutralization between HCl (generated in situ during
reaction progress) and K2CO3 (Figure 2). However, com-
pound 4 was realized by alternative route via the condensa-
tion of phenylhydrazine at the ketonic carbonyl group of the
acetamide derivative, 3, under refluxing in ethanol with
drops of acetic acid. This acid-catalyzed condensation of
phenylhydrazine was successfully achieved at the ketonic
carbonyl rather than nucleophilic substitution at the second
carbon of benzothiazole, which requires base catalyst to
occur.
N-aryl(heteroaryl)-2-chloroacetamides
derivatives,[29–31]
herein we report on the reactivity of N-(4-acetylphenyl)-
2-chloroacetamide toward various types of nitrogen and sul-
fur nucleophiles (phenylhydrazine, 2-cyanoacetohydrazide,
thiosemicarbazide, 4,6-dimethyl-2-mercapto-nicotinonitrile,
and 6-amino-2-mercaptopyrimidin-4-ol), and the biological
evaluations of the newly synthesized compounds.
Phenylhydrazone of the type 4 was treated with DMF
and phosphorous oxychloride under the condition of
Vilsmeier formylation reaction and successfully transformed
into the conforming 2-(benzothiazolylthio)-N-(4-(4-formyl-
1-phenylpyrazolyl)-phenyl)acetamide derivative, 5. The
suggested structure of 4-formylpyrazole derivative, 5,
finds support from its compatible spectral data. The
methylene function, flanked by amidic carbonyl and
sulfur atom, did not formylate under the reaction con-
dition. This may be attributed to the low reactivity of
such methylene as indicated from the poor literature
reviews.
The condensation of compound, 1, with 2-
cyanoacetohydrazide[34] was achieved under refluxing in eth-
anol and drops of acetic acid to furnish the condensation
product at the ketonic functionality, which was identified as
2-chloro-N-(4-(1-(2-(2-cyanoacetyl)-hydrazono)ethyl)phenyl)
acetamide (6). Similarly, the nucleophilic substitution
of the chorine atom, 6, by 2-mecrcaptobenzothiazole
affected the hydrolysis of the imine linkage to afford 3[33]
instead of having the target product, 2-(benzothiazol-
2-ylthio)-N-(4-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)phenyl)-
acetamide (7). The target compound, 7, was obtained by
an alternative route via the condensation reaction of 2-
cyanoacetohydrazide at the ketonic carbonyl group rather
2 | RESULTS AND DISCUSSION
2.1 | CHEMISTRY
The highly versatile N-(4-acetylphenyl)-2-chloroacetamide
(1) was prepared according to the previously reported litera-
ture through the chloroacetylation of 4-aminoacetophenone,
with chloroacetyl chloride, in the presence of potassium car-
bonate in acetone.[32] The multifunctional features, including
a chloroacetamide moiety, ketonic carbonyl group, and
active methyl group, featured by the key 1 encouraged us to
exploit its chemical reactivity toward a panel of nucleophilic
and electrophilic reagents. Firstly, refluxing equimolar
amounts of compound, 1, and phenylhydrazine in ethanol
with catalytic drops of acetic acid affected condensation at
the ketonic carbonyl group to produce the anticipated
phenylhydrazone, 2-chloro-N-(4-(1-(2-phenylhydrazono)ethyl)
phenyl)-acetamide (2) (Scheme 1). A nucleophilic substitu-
tion of the chorine atom in chloroacetamide derivative, 2,
by 2-mercaptobenzothiazole was proceeded successfully by
stirring in acetone and potassium carbonate. However, in a
surprise action accompanying the substitution, the imine
linkage affected hydrolysis and the product was identified as

ABDEL-LATIF ET AL.
3
SCHEME 1 Synthesis of
2-(benzothiazolylthio)-N-
(4-(4-formylpyrazolyl)phenyl)-
acetamide derivative, 5
Me
N
S
O
O
Acetone/K2CO3
SH
+
Cl
N
H
Me
1
O
N
S
O
PhNHNH2
EtOH/AcOH
N
S
H
3
Me
NHPh
PhNHNH2
EtOH/AcOH
O
N
N
S
Acetone
+
SH
Cl
K2CO3
N
H
2
Me
O
N
S
NHPh
N
N
S
H
POCl3/DMF
O
4
N
O
H
S
S
N
H
N
N
Ph
5
Me
Me
N
S
H
O
H
N
SH
N
S
N
O
N
R
N
+ HCl
R
N
Cl
S
Acetone/K2CO3
H
N
H
2: R = Ph
6: R = COCH2CN
K2CO3 + HCl
2KCl + CO2 + H2O
Me
HO
Me
O
O
H
N
N
S
O
N
S
N
R
H
N
- NH2NHR
S
N
H
H
S
3
FIGURE 2 The proposed mechanism for the cleavage of imine bond
than the amidic carbonyl of acetamide derivative, 3. The
condensation reaction was achieved in boiling ethanol
and drops of acetic acid (Scheme 2).
The cleavage of imine bond in either compounds,
2 or 6, by the action of 2-mecraptobenzothiazole, under
the reaction conditions, appears to follow the suggested
mechanism outlined in Figure (2).
Moreover, the activated nitrile functionality of
cyanoacetyl-hydrazone derivative, 7, was investigated toward
electrophilic diazo-coupling and Knoevenagel condensation
reactions. Thus, coupling reaction of compound, 7, with diaz-
otized p-anisidine (obtained by diazotization of p-anisidine
with conc. HCl and sodium nitrile at 0ꢀC-5ꢀC) proceeded in
ethanol and sodium acetate to furnish the corresponding
2-oxoacetohydrazonoyl cyanide product, 8 (Scheme 3). The
benzothiazole-S linkage was strong enough and did not
cleavage under the reaction condition, as indicated from the
correct and compatible spectral analyses for the structure of
compound, 8. The active methylene group flanked between
two withdrawing groups (cyano and carbonyl groups) in
compound 7 is acidic enough to condense with aldehyde
(Knoevenagel condensation). The condensation of com-
pound, 7, with p-anisaldehyde was achieved by stirring in
ethanol, containing a catalytic amount of piperidine, to
afford the corresponding 2-cyano-acrylohydrazone deriva-
tive, 9 (Scheme 3).

4
ABDEL-LATIF ET AL.
SCHEME 2 Synthesis of
2-(benzothiazolylthio)-N-
(4-(1-(2-(2-cyanoacetyl)
hydrazono)-ethyl)phenyl)
acetamide derivative, 7
SCHEME 3 Synthesis of
2-(benzothiazolylthio)-N-
(4-(1-(2-(2-cyanoacetyl)
hydrazono)-ethyl)phenyl)-
acetamide derivatives, 8 and 9
Although for the previously synthesized hydrazones, 2,
The formation of benzothiazole-based chalcone com-
pound, 2-(benzothiazol-2-ylthio)-N-(4-(3-(furan-2-yl)acryloyl)
phenyl)acetamide (12) was undertaken using sodium
hydroxide as a basic-catalyzed aldol condensation reaction,
for the condensation between N-(4-acetylphenyl)-2-
(benzothiazol-2-ylthio)-acetamide (3) and furan-2-
carbaldehyde in dimethylformamide (Scheme 4).
The replacement of the chlorine atom from N-
(4-acetylphenyl)-2-chloroacetamide (1) by 2-mercapton-
icotinonitrile derivative, 13,[38] was performed by boiling
in acetone in the presence of potassium carbonate as a
base to produce, N-(4-acetylphenyl)-2-((3-cyanopyridin-
2-yl)thio) acetamide sulfide derivative, 14. Heating of
sulfide derivative, 14, in ethanolic solution of sodium
hydroxide induced intramolecular hetero-cyclization
between the methylene and nitrile functionalities, yield-
ing the N-(4-acetylphenyl)-3-amino-4,6-dimethylthieno
[2,3-b]-pyridine-2-carboxamide (15). In addition, the
4, 6, 7, 8, and 9, it is possible to have E/Z isomerization
around the C N double bond. The 1H NMR spectra
of these hydrazones in DMSO-d6 showed just one set
of signals, that can be related to the geometric (E)-
configuration about the C N bond due to steric hindrance
on the imine bond as revealed from literature survey.[35–37]
Furthermore, the condensation of N-(4-acetylphenyl)-
2-(benzothiazol-2-ylthio)-acetamide (3) with thiosemi-
carbazide required heating in ethanol containing drops
of acetic acid, furnishing the anticipated condensation
product 2-(benzothiazol-2-ylthio)-N-(4-(1-(2-carbamothioyl-
hydrazineylidene)ethyl)phenyl)acetamide (10). Hetero-
cyclization of thiosemicarbazone derivative, 10, upon
treatment with ethyl bromoacetate to generate the 2-
(benzothiazol-2-ylthio)-N-(4-(1-(2-(4-oxo-4,5-dihydrothiazol-
2-yl)hydrazineylidene)-ethyl)phenyl)acetamide (11) was
achieved by heating in pyridine, under reflux, for 4 hours.

ABDEL-LATIF ET AL.
5
SCHEME 4 Synthesis of
2-(benzothiazolylthio)-N-
(4-substitutedphenyl)acetamide
derivatives, 11 and 12
SCHEME 5 Synthesis of
2-(pyridylthio)-N-
(4-acetylphenyl)-acetamide and
2-(pyrimidylthio)-N-
(4-acetylphenyl)-acetamide
derivatives, 14, 16, and 17
condensation of sulfide derivative, 14, with thiosemi-
carbazide was realized in boiling ethanol and 1 mL of
acetic acid as a catalyst to afford the thiosemicarbazone,
N-(4-(1-(2-carbamothioylhydrazono)-ethyl)phenyl)-2-((3-
cyano-4,6-dimethylpyridin-2-yl)thio)acetamide (16). Finally,
N-(4-acetylphenyl)-2-chloroacetamide (1) and 6-amino-2-
mercaptopyrimidin-4-ol were allowed to react by stirring
in acetone in the presence of potassium carbonate to yield
the sulfide derivative, N-(4-acetylphenyl)-2-((4-amino-6-
hydroxypyrimidin-2-yl)thio)acetamide (17) (Scheme 5).
As previously described in the literature,[39] the N4
unsubstituted thiosemicarbazones, of the types 10 and 16,
can adopt syn conformation and 1E configuration (Figure 3).
The proposed molecular configuration with the N4-H cis to

6
ABDEL-LATIF ET AL.
FIGURE 3
Configurations of
thiosemicarbazones, 10 and 16
TABLE 1
Activity)
Antimicrobial activity (inhibition zone, mm) of the newly synthesized N-aryl chloroacetamide-based compounds, (NA ! No
Escherichia coli (mg/mL)
Staphylococcus aureus (mg/mL)
Diameter (mm)
inhibition zone
Activity
index (%)
Diameter (mm)
inhibition zone
Activity
index (%)
Compound #
2
17
13
NA
NA
10
18
11
21
9
65.4
50.0
–
19
17
2
79.2
70.8
8.3
4
5
6
–
8
28.0
62.5
79.2
58.3
91.7
58.3
87.5
91.7
75.0
70.8
62.5
100
7
38.5
69.2
42.3
80.8
34.6
65.4
80.8
53.8
46.1
34.6
100
15
19
14
22
14
21
22
18
17
15
24
8
9
10
11
12
17
21
14
12
9
14
15
16
17
Ampicillin
26
the thiocarbonyl group, leaving the second N4-H disposed
for intramolecular hydrogen-bond formation. The proposed
configurations of these thiosemicarbazones can explain the
in DMSO and solutions of the concentration, 1 mg/mL,
were prepared separately. Paper discs of Whatman filter
paper were prepared with standard size (5 cm) and steril-
ized in an autoclave. The paper discs were soaked in the
desired concentration of the tested solution and placed
aseptically in the Petri dishes containing nutrient agar
media (agar 20g + beef extract 3g + peptone 5g) seeded
with E coli or S aureus. The Petri dishes were incubated
at 36ꢀC and the inhibition zones were recorded after
24 hours of incubation. Each treatment was replicated
three times. The antibacterial activity of a common stan-
dard antibiotic, ampicillin, was also recorded as a positive
control using the same procedures used for the investi-
gated compounds. The % activity index for the test com-
pound was calculated by the formula:
1
appearance of the NH2 in the H NMR spectra as two
separated singlet signals. They resonated in the spectrum of
compound 10 (as an example) as two singlet signals at δ
8.25 ppm, for the non-hydrogen bonded proton (Ha), and at
δ 8.64 ppm, for the hydrogen-bonded proton (Hb).
2.2 | Biological activities of the
synthesized N-aryl chloroacetamide-based
compounds
2.2.1 | Antibacterial activity
A preliminary exploration of the antibacterial activity
of the newly synthesized N-aryl chloroacetamide-based
compounds (Table 1) indicated that the thiosemicarbazone
derivative, 10, and the sulfide derivative N-(p-acetylphenyl)-
2-((3-cyano-4,6-dimethylpyridin-2-yl)thio)-acetamide (14)
are the most active compounds against E coli, with
The antibacterial properties of synthesized heterocycles,
derived from N-aryl chloroacetamides, were explored
against Gram-negative bacteria (Escherichia coli) and
Gram-positive bacteria (Staphylococcus aureus).[40] Each
compound of the investigated compounds was dissolved

ABDEL-LATIF ET AL.
7
TABLE 2
aryl chloroacetamide-based compounds
Antioxidant activity of the newly synthesized N-
10, promoted the antioxidant activity to the highest percent
of inhibition = 82.6%, which comes close to that observed
by the reference antioxidant L-ascorbic acid (88.2%).
The sulfide derivative, N-(p-acetylphenyl)-2-((3-cyano-4,6-
dimethylpyridin-2-yl)thio)-acetamide (14) showed signifi-
cant antioxidant activity with percent of inhibition = 80.2%.
The combination between benzothiazole and furan moieties
in the chalcone-containing compound, 2-(benzothiazol-2-
ylthio)-N-(4-(3-(furan-2-yl)-acryloyl)phenyl)acetamide (12),
also revealed good antioxidant activity with inhibitory
percent = 75.4%.
ABTS [Abs(control) − Abs(test)/Abs
(control)] × 100
Method
Absorbance of samples % Inhibition
Compounds
Control of ABTS 0.500
0
Ascorbic-acid
0.059
0.171
0.233
0.462
0.359
0.295
0.145
0.341
0.087
0.347
0.123
0.099
0.158
0.194
0.294
88.2%
65.8%
53.4%
7.6%
2
4
5
6
39.8%
41.0%
71.0%
31.8%
82.6%
30.6%
75.4%
80.2%
68.4%
61.2%
41.2%
3 | CONCLUSION
7
8
In summary, simple and direct synthetic strategies were
employed to exploit the reactivity of N-(4-acetylphenyl)-
2-chloroacetamide (1) toward various nucleophilic and
electrophilic reagents. A group of 14 compounds was syn-
thesized with structural diversity. All the newly synthe-
sized compounds were tested for their antibacterial and
antioxidant activities. Most of these compounds showed
significant antibacterial and antioxidant potentialities.
Particularly, compounds, 10 and 14, were the most potent
antibacterial and antioxidant agents, which highlight a
demand to extend this chemical synthesis to generate a
lead-library, which features a diversity of heterocyclic scaf-
folds to enable us to set structure-activity relationships.
9
10
11
12
14
15
16
17
inhibitory relative activity index 80.8%. Meantime, the
synthesized compounds, 2-(benzothiazol-2-ylthio)-N-(4-(1-
(2-carbamothioyl-hydrazineylidene)-ethyl)-phenyl)-acetamide
(10) and N-(p-acetylphenyl)-2-((3-cyano-4,6-dimethyl-pyridin-
2-yl)thio)-acetamide (14) displayed significant antibacterial
potentiality against S aureus (inhibition zone = 22 mm,
activity index = 91.7%). Compounds, 10 and 14, displayed
very close inhibitory activities to that displayed by the
reference antibiotic, ampicillin, which inhibits the growth
of bacteria with 24 mm inhibition zone. In addition,
the 2-(benzothiazol-2-ylthio)-N-(4-(3-(furan-2-yl)acryloyl)-
phenyl)-acetamide (12) comes second against S aureus
with activity index 87.5% (inhibition zone, 21 mm). Fur-
thermore, the phenylhydrazone derivative, 2, and 2-
oxoacetohydrazonoyl carbonitrile derivative, 8, inhibit the
growth of S aureus with activity index, 79.2% (inhibition
zone 19 mm).
4 | EXPERIMENTAL
All chemicals were obtained from Sigma-Aldrich and
used without any further purification. Progress of the
reactions was monitored by thin-layer chromatography
on Merck's silica plates. Melting points were measured in
degree centigrade on Gallenkamp apparatus and are
uncorrected. The infrared spectra were recorded (KBr) on
Thermo Scientific Nicolet iS10 FTIR spectrometer.
Nuclear magnetic resonance spectra were recorded in
CDCl3 or DMSO-d6 as a solvent at 500 MHz (1H NMR)
and 125 MHz (13C NMR) on JEOL's NMR spectrometer,
using TMS as internal standard, and chemical shifts are
expressed as δ/ppm. Perkin-Elmer 2400 analyzer has been
utilized to measure the elemental analyses (C, H, and N).
2.2.2 | Antioxidant assay
4.1 | (E)-2-Chloro-N-
The new compounds were further investigated for their
antioxidant activities (Table 2) using the ABTS radical cat-
ion decolorization assay.[41] The results indicated that the
conversion of N-(4-acetylphenyl)-2-(benzothiazol-2-ylthio)-
acetamide (3) into its corresponding thiosemicarbazone,
(4-(1-(2-phenylhydrazono)ethyl)phenyl)
acetamide (2)
Phenylhydrazine (0.005 mol, 0.55 mL) was added to a solu-
tion of chloroacetamide derivative, 1 (0.005 mol, 1.05 g) in

8
ABDEL-LATIF ET AL.
EtOH (20 mL) and 0.5 mL acetic acid. The reaction mix-
ture was boiled under reflux for 2 hours. The precipitate
obtained upon cooling was filtered off and recrystallized
from EtOH-DMF mixture (10:3) to give the phenyl-
hydrazone derivative, 2.
onto crushed ice, and neutralized with Na2CO3 solution.
The solid product was filtered off, dried, and recrystallized
from ethanol to furnish compound 5.
Brown powder, yield = 37%, m.p. = 140ꢀC to 142ꢀC. IR
(KBr): 3255 (NH), broad centered at 1678 cm−1 (C O). 1H
NMR (CDCl3): 4.09 (s, 2H, CH2), 7.36 to 7.82 (m, 12H,
Ar H), 7.99 (d, J = 9.00 Hz, 1H, Ar H), 8.50 (s, 1H,
pyrazole-H4), 10.01 (s, 1H, CHO), 10.35 ppm (s, 1H, NH).
13C NMR (DMSO-d6): 38.05, 113.28, 119.52 (2C), 120.40
(2C), 121.81, 122.17, 124.48, 125.61, 126.44, 127.25, 129.03
(2C), 129.49 (2C), 131.69, 134.48, 138.52, 140.54, 148.17,
152.54, 165.18, 166.27, 183.42. Analysis of C25H18N4O2S2
(470): Calculated: C, 63.81; H, 3.86; N, 11.91%. Found: C,
63.96; H, 3.78; N, 11.84%.
Yellowish green crystals, yield = 80%, m.p. = 178ꢀC to
1
180ꢀC. IR: 3346, 3314 (NH), 1683 cm−1 (C O). H NMR
(DMSO-d6): 2.22 (s, 3H, CH3), 4.26 (s, 2H, CH2), 6.73
(t, J = 6.50 Hz, 1H, Ar H), 7.21 (m, 4H, Ar H), 7.61
(d, J = 9.00 Hz, 2H, Ar H), 7.76 (d, J = 9.00 Hz, 2H, Ar H),
9.21 (s, 1H, NH), 10.38 (s, 1H, NH). 13C NMR (DMSO-d6):
12.68, 43.63, 112.76 (2C), 118.72, 119.05 (2C), 125.67 (2C),
128.88 (2C), 134.76, 137.88, 140.15, 146.12, 164.55. Analysis
of C16H16ClN3O (301): Calculated: C, 63.68; H, 5.34; N,
13.92%. Found: C, 63.55; H, 5.38; N, 13.98%.
4.4 | (E)-2-Chloro-N-(4-(1-(2-
(2-cyanoacetyl)hydrazineylidene)ethyl)-
phenyl)acetamide (6)
4.2 | (E)-2-(Benzothiazol-2-ylthio)-N-
(4-(1-(2-phenylhydrazineylidene)ethyl)-
phenyl)acetamide (4)
To a mixture of equimolar amounts of chloroacetamide
derivative, 1, (0.002 mol, 0.42 g) and 2-cyanoacetohydrazide
(0.002 mol, 0.2 g) in 15 mL ethanol, five drops of acetic acid
was added. The reaction components were boiled under
reflux for 90 minutes. The solid that was obtained upon
cooling was picked up by filtration to furnish the target
2-chloroacetamide derivative, 6.
Pale yellow powder, yield = 72%, m.p. = 254ꢀC to
256ꢀC. IR: 3301, 3193 (N H), 2265 (C N), 1692, 1660 cm−1
(C O). 1H NMR (DMSO-d6): 2.21 (s, 3H, CH3), 4.22 (s, 2H,
CH2), 4.26 (s, 2H, CH2), 7.61, (d, J = 9.00 Hz, 2H, Ar H),
7.78 (d, J = 9.00 Hz, 2H, Ar H), 10.44 (s, 1H, NH),
10.99 ppm (s, 1H, NH). 13C NMR (DMSO-d6): 14.05, 26.11,
43.30, 120.15 (2C), 124.35, 129.18 (2C), 134.10, 140.18,
146.15, 164.76, 170.40. Analysis of C13H13ClN4O2 (292):
Calculated: C, 53.34; H, 4.48; N, 19.14%. Found: C, 53.21; H,
4.55; N, 19.25%.
To a suspension of compound 3 (0.005 mol, 1.71 g) and
phenylhydrazine (0.005 mol, 0.55 mL) in 20 mL ethanol,
0.5 mL acetic acid was added. The reaction mixture was
boiled under reflux for 4 hours. The solid that formed
was collected by filtration to give the phenylhydrazone
derivative, 4.
Orange powder, yield = 75%, m.p. = 152ꢀC to 154ꢀC.
1
IR (KBr): 3358, 3280 (NH), 1661 cm−1 (C O). H NMR
(DMSO-d6): 2.21 (s, 3H, CH3), 4.41 (s, 2H, CH2), 6.72 (m, 1H,
Ar H), 7.18 to 7.222 (m, 4H, Ar H), 7.35 (t, J = 7.50 Hz,
1H, Ar H), 7.45 (t, J = 7.20 Hz, 1H, Ar H), 7.61 (d,
J = 8.00 Hz, 2H, Ar H), 7.75 (d, J = 8.00 Hz, 2H, Ar H),
7.83 (d, J = 7.50 Hz, 1H, Ar H), 8.02 (d, J = 7.50 Hz, 1H,
Ar H), 9.20 (s, 1H, NH), 10.53 (s, 1H, NH). 13C NMR
(DMSO-d6): 12.69, 37.75, 112.75 (2C), 118.70, 118.85 (2C),
121.08, 121.91, 124.55, 125.68 (2C), 126.44, 128.88 (2C),
134.55, 134.77, 138.19, 140.22, 146.13, 152.53, 165.13, 166.12.
Analysis of C23H20N4OS2 (432): Calculated: C, 63.86; H,
4.66; N, 12.95%. Found: C, 63.92; H, 4.61; N, 12.88%.
4.5 | (E)-2-(Benzothiazol-2-ylthio)-N-
(4-(1-(2-(2-cyanoacetyl)-hydrazineylidene)
ethyl)phenyl)acetamide (7)
4.3 | 2-(Benzothiazol-2-ylthio)-N-
(4-(4-formyl-1-phenyl-1H-pyrazol-3-yl)
phenyl)acetamide (5)
To a mixture of compound, 3 (0.002 mol, 0.68 g) and
2-cyanoacetohydrazide (0.002 mol, 0.2 g), in 20 mL etha-
nol, five drops of acetic acid were added. The reaction
components were boiled under reflux for 90 minutes. The
solid that formed upon cooling was collected by filtration
to give the acetamide derivative, 7.
Phosphorus oxychloride (0.004 mol, 0.6 mL) was gradu-
ally added to a well-cooled dimethylformamide (DMF,
10 mL) and then allowed to stir for about 30 minutes.
After addition of compound 4 (1.08 g, 0.0025 mol), the
reaction mixture was settled at room temperature for
5 minutes and then heated on water bath at 60ꢀC to 65ꢀC
for 6 hours. The reaction mixture was cooled, poured
Yellow powder, yield = 82%, m.p. = 150ꢀC to 152ꢀC. IR:
3342 (N H), 2260 (C N), broad centered at 1691 cm−1
1
(C O). H NMR (DMSO-d6):2.21 (s, 3H, CH3), 4.22 (s, 2H,
CH2), 4.41 (s, 2H, CH2), 7.35 (t, J = 7.50 Hz, 1H, Ar H),

ABDEL-LATIF ET AL.
9
7.45 (t, J = 7.50 Hz, 1H, Ar H), 7.62 (d, J = 9.00 Hz, 2H,
Ar H), 7.78 (d, J = 9.00 Hz, 2H, Ar H), 7.81 (d, J = 8.00 Hz,
1H, Ar H), 8.02 (d, J = 7.50 Hz, 1H, Ar H), 10.60 (s, 1H,
NH), 10.98 ppm (s, 1H, NH). 13C NMR (DMSO-d6): 13.67,
24.90, 37.74, 116.31, 118.63, 121.07, 121.92, 124.56, 126.44
(2C), 127.01 (2C), 129.59, 132.79, 134.76, 139.78, 148.64,
152.50, 165.40, 166.04. Analysis of C20H17N5O2S2 (423):
Calculated: C, 56.72; H, 4.05; N, 16.54%. Found: C, 56.60; H,
4.13; N, 16.64%.
4.8 | (E)-2-(Benzothiazol-2-ylthio)-N-
(4-(1-(2-carbamothioyl-hydrazineylidene]
ethyl)phenyl)acetamide (10)
A solution of compound 3 (0.002 mol, 0.68 g) and thiosemi-
carbazide (0.002 mol, 0.2 g) in 30 mL ethyl alcohol and
acetic acid (0.5 mL) was heated under reflux for 4 hours.
The reaction mixture was cooled to room temperature.
The crude solid product was filtered off, dried, and rec-
rystallized from EtOH-DMF mixture (10:7) to afford
compound 10.
4.6 | (E)-2-(2-((E)-1-(4-(2-(Benzothiazol-
2-ylthio)acetamido)phenyl)ethylidene)-
hydrazinyl)-N-(p-anisyl)-
Yellow powder, yield = 69%, m.p. = 224ꢀC to 226ꢀC. IR
(KBr): 3375, 3254, 3164 (NH2 and NH), 1684 cm−1 (C O).
1H NMR (DMSO-d6): 2.25 (s, 3H, CH3), 4.40 (s, 2H, CH2),
7.36 (t, J = 7.60 Hz, 1H, Ar H), 7.45 (t, J = 7.60 Hz, 1H,
Ar H), 7.60 (d, J = 9.00 Hz, 2H, Ar H), 7.81 (d, J = 8.00 Hz,
1H, Ar H), 7.91 (d, J = 9.00 Hz, 2H, Ar H), 8.01
(d, J = 7.50 Hz, 1H, Ar H), 8.25 (s, 1H, NHa), 8.64 (s, 1H,
NHb), 10.17 (s, 1H, NH), 10.57 ppm (s, 1H, NH). 13C NMR
(DMSO-d6): 13.69, 37.73, 118.51 (2C), 121.04, 121.89,
124.53, 126.41, 127.31 (2C), 132.68, 134.75, 139.66, 147.34,
152.48, 165.33, 166.01, 178.69. Analysis of C18H17N5OS3
(415): Calculated: C, 52.03; H, 4.12; N, 16.85%. Found: C,
52.10; H, 4.07; N, 16.91%.
2-oxoacetohydrazonoyl cyanide (8)
A solution of NaNO2 (0.14 g in 10 mL cold water) was
added to a well cold suspension (0ꢀC-5ꢀC) of p-anisidine
(0.002 mol, 0.24 g) in conc. HCl (0.6 mL) with stirring. The
diazonium chloride solution formed was added with stirring
to cold solution (0ꢀC-5ꢀC) of cyanoacetyl-hydrazone deriva-
tive, 7, (0.002 mol, 0.84 g) in 15 mL pyridine. After the addi-
tion was completed, the stirring was continued for an
additional 90 minutes. The solid obtained was filtered off,
washed with water, and recrystallized from ethyl alcohol.
Brown powder, yield = 42%, m.p. = 224ꢀC to 226ꢀC.
IR (KBr): 3368, 3280 (NH), 2208 (C N), broad centered
4.9 | 2-(Benzothiazol-2-ylthio)-N-
(4-(1-(2-(4-oxo-4,5-dihydrothiazol-2-yl)
hydrazineylidene)ethyl)phenyl)
acetamide (11)
1
at 1677 cm−1 (C O). H NMR (DMSO-d6): 2.21 (s, 3H,
CH3), 3.78 (s, 3H, OCH3), 4.41 (s, 2H, CH2), 7.01 to 8.02
(m, 12H, Ar H), 10.56 (s, 1H, NH), 11.01 (s, 1H, NH),
11.88 ppm (s, 1H, NH). Analysis of C27H23N7O3S2 (557):
Calculated: C, 58.15; H, 4.16; N, 17.58%. Found: C,
58.24; H, 4.15; N, 17.65%.
To a solution of thiosemicarbazone compound, 10,
(0.001 mol, 0.41 g) in 10 mL pyridine, ethyl 2-bromoacetate
(0.001 mol, 0.16 mL) was added and the reaction mixture
was refluxed for 2 hours. After this, the reaction mixture
was poured into 10 g crushed ice. The solid obtained after
standing 1 day (at 0ꢀC-5ꢀC in a refrigerator) was filtered
off. The product was recrystallized by heating in ethanol to
furnish the conforming thiazolin-4-one derivative, 11.
Yellow powder, yield = 35%, m.p. = 210ꢀC to 212ꢀC.
IR (KBr): 3377 (NH), 1667 cm−1 (C O). 1H NMR
(DMSO-d6): 2.33 (s, 3H, CH3), 3.84 (s, 2H, CH2), 4.41
(s, 2H, CH2), 7.35 (t, J = 7.50 Hz, 1H, Ar H), 7.45
(t, J = 7.50 Hz, 1H, Ar H), 7.65 (d, J = 9.00 Hz, 2H,
Ar H), 7.80 (d, J = 9.00 Hz, 2H, Ar H), 7.82 (d,
J = 9.00 Hz, 1H, Ar H), 7.80 to 7.82 (d, J = 9.00 Hz, 3H,
Ar H), 8.01 (d, J = 8.00 Hz, 1H, Ar H), 10.62 (s, 1H,
NH), 11.92 ppm (s, 1H, NH). 13C NMR (DMSO-d6): 14.44,
32.79, 37.77, 118.72 (2C), 121.10, 121.93, 124.57 (2C),
126.45, 127.17 (2C), 132.87 (2C), 134.78, 140.20, 152.52,
159.66, 165.45, 166.05. Analysis of C20H17N5O2S3 (455):
Calculated: C, 52.73; H, 3.76; N, 15.37%. Found: C,
52.61; H, 3.79; N, 15.45%.
4.7 | 2-(Benzothiazol-2-ylthio)-N-(4-((E)-
1-(2-((E)-2-cyano-3-(p-anisyl)acryloyl)-
hydrazineylidene)ethyl)phenyl)
acetamide (9)
To a suspension of cyanoacetyl-hydrazone derivative, 7,
(0.001 mol, 0.42 g) in 30 mL ethyl alcohol, p-anisaldehyde
(0.001 mol, 0.12 mL) and three drops of piperidine were
added. The reaction components were refluxed for 2 hours.
The precipitate obtained was picked up by filtration to fur-
nish the targeted acetamide derivative, 9.
Yellow powder, yield = 40%, m.p. = 176ꢀC to 178ꢀC. IR:
3329, 3222 (NH), 2206 (C N), broad centered at 1690 cm−1
(C O). 1H NMR (DMSO-d6): 2.23 (s, 3H, CH3), 3.85 (s, 3H,
OCH3), 4.41 (s, 2H, CH2), 7.12 to 8.02 (m, 13H, Ar H and
olefinic C CH), 10.60 (s, 1H, NH), 10.99 ppm (s, 1H, NH).
Analysis of C28H23N5O3S2 (541): Calculated: C, 62.09; H,
4.28; N, 12.93%. Found: C, 62.31; H, 4.26; N, 12.75%.

10
ABDEL-LATIF ET AL.
4.10 | 2-(Benzothiazol-2-ylthio)-N-
(4-(3-(furan-2-yl)-acryloyl)phenyl)
acetamide (12)
granules in 20 mL absolute ethanol). The reaction mixture
was cooled and diluted with 20 mL cold water. The solid
material obtained by filtration was dried and purified by
recrystallization form EtOH-DMF mixture (10:3) to give the
conforming 3-aminothieno[2,3-b]pyridine compound, 15.
Yellow powder, yield = 60%, m.p. = 226ꢀC to 228ꢀC. IR
(KBr): 3494, 3322, 3187 (NH2 and NH), 1657, 1632 cm−1
To a well-stirred suspension of compound, 3, (0.002 mol,
0.68 g) in 15 mL DMF, NaOH granules (0.16 g) was
added followed by furan-2-carbaldehyde (0.002 mol,
0.19 mL). The reaction components were stirred at 25ꢀC
to 30ꢀC for 4 hours and then poured into 15 g crushed
ice. After neutralization with dilute HCl, the solid formed
was filtered off and recrystallized from EtOH.
1
(C O). H NMR (DMSO-d6): 2.51 (s, 3H, COCH3), 2.53
(s, 3H, CH3), 2.73 (s, 3H, CH3), 7.06 (s, 1H, pyridine-H5),
7.86 (d, J = 9.00 Hz, 2H, Ar H), 7.92 (d, J = 8.00 Hz, 2H,
Ar H), 10.71 ppm (s, 1H, NH). Analysis of C18H17N3O2S
(339): Calculated: C, 63.70; H, 5.05; N, 12.38%. Found: C,
63.62; H, 5.12; N, 12.48%.
Brown powder, yield = 81%, m.p. = 230ꢀC to 232ꢀC. IR
1
(KBr): 3429 (NH), 1671 cm−1 (C O). H NMR (DMSO-d6):
4.42 (s, 2H, CH2), 6.69 (t, J = 3.75 Hz, 1H, furan-H4), 6.85
(d, J = 3.60 Hz, 1H, furan-H3), 7.33 (t, J = 7.50 Hz, 1H,
Ar H), 7.46 (t, J = 7.50 Hz, 1H, Ar H), 7.61 (d, J = 8.00 Hz,
2H, Ar H), 7.75 (d, J = 8.00 Hz, 2H, Ar H), 7.83
(d, J = 7.50 Hz, 1H, Ar H), 7.94 (d, J = 15.50 Hz, 1H, ole-
finic C CH), 8.02 (d, J = 8.00 Hz, 1H, Ar H), 8.11
(d, J = 3.60 Hz, 1H, furan-H5), 8.26 (d, J = 15.50 Hz, 1H,
olefinic C CH), 10.67 ppm (s, 1H, NH). Analysis of
C22H16N2O3S2 (420): Calculated: C, 62.84; H, 3.84; N,
6.66%. Found: C, 62.63; H, 3.75; N, 6.53%.
4.13 | (E)-N-(4-(1-(2-
Carbamothioylhydrazono)-ethyl)phenyl)-
2-((3-cyano-4,6-dimethylpyridin-2-yl)thio)
acetamide (16)
To a suspension of compound 14 (0.002 mol, 0.68 g) in
20 mL ethanol, thiosemicarbazide (0.002 mol, 0.18 g) and
0.5 mL acetic acid were added. The reaction proceeded by
boiling under reflux for 4 hours. A precipitate was picked
up upon cooling, recrystallized from a mixture of EtOH-
DMF (10:3) to furnish thiosemicarbazone compound, 16.
Yellow crystals, yield = 75%, m.p. = 238ꢀC to 240ꢀC.
IR: 3399, 3322, 3288 (NH2 and NH), 2216 (C N),
1668 cm−1 (C O). 1H NMR (DMSO-d6): 2.25 (s, 3H, CH3),
2.37 (s, 6H, 2 CH3), 4.16 (s, 2H, CH2), 7.07 (s, 1H, pyridine-
H5), 7.58 (d, J = 9.00 Hz, 2H, Ar H), 7.88 (d, J = 9.00 Hz,
3H, Ar H and NHa), 8.25 (s, 1H, NHb), 10.16 (s, 1H, NH),
10.43 ppm (s, 1H, NH). 13C NMR (DMSO-d6): 13.72, 19.65,
24.23, 34.97, 103.59, 115.04, 118.45 (2C), 120.49, 127.30
(2C), 132.44, 139.94, 147.43, 152.52, 160.27, 161.33, 166.20,
178.68. Analysis of C19H20N6OS2 (412): Calculated: C,
55.32; H, 4.89; N, 20.37%. Found: C, 55.47; H, 4.85;
N, 20.29%.
4.11 | N-(p-Acetylphenyl)-2-((3-cyano-
4,6-dimethylpyridin-2-yl)thio)-
acetamide (14)
To a stirred solution of chloroacetamide scaffold 1
(0.005 mol, 1.05 g) in 30 mL acetone, containing potas-
sium carbonate (0.005 mol 0.69 g), 2-mercapto-4,6-
dimethylnicotinonitrile (13) (0.005 mol, 0.82 g) was added
and refluxed for 4 hours. The reaction solution was poured
into 30 g crushed ice. The solid obtained was filtered and
purified by recrystallization form ethanol to give the sulfide
compound, 14.
Yellow crystals, yield = 82%, m.p. = 196ꢀC to 198ꢀC.
IR: 3373 (NH), 2214 (C N), 1713, 1666 cm−1 (C O).1H
NMR (DMSO-d6): 2.33 (s, 3H, CH3), 2.39 (s, 3H, CH3),
2.51 (s, 3H, COCH3), 4.18 (s, 2H, CH2), 7.08 (s, 1H,
pyridine-H5), 7.69 (d, J = 8.00 Hz, 2H, Ar H), 7.92
(d, J = 8.00 Hz, 2H, Ar H), 10.65 ppm (s, 1H, NH). Anal-
ysis of C18H17N3O2S (339): Calculated: C, 63.70; H,
5.05; N, 12.38%. Found: C, 63.81; H, 5.09; N, 12.41%.
4.14 | N-(p-Acetylphenyl)-2-((4-amino-
6-hydroxypyrimidin-2-yl)thio)
acetamide (17)
A mixture of chloroacetamide derivative, 1 (0.001 mol,
0.21 g) and 6-amino-2-mercaptopyrimidin-4-ol (0.001 mol,
0.14 g), in 25 mL acetone containing K2CO3 (0.002 mol
0.27 g) was stirred at room temperature for 4 hours. The
reaction mixture was poured into 15 g crushed ice. The
precipitate formed was filtered off and washed with cold
ethanol to give the conforming sulfide, 17.
4.12 | N-(p-Acetylphenyl)-3-amino-
4,6-dimethylthieno[2,3-b]pyridine-
2-carboxamide (15)
A solution of compound 14 (0.002 mol, 0.68 g) was heated
for 45 minutes in sodium ethoxide solution (0.05 g sodium
White powder, yield = 81%, m.p. = 258ꢀC to 260ꢀC. IR
(KBr): 3439, 3320, 3202 (NH2 and NH), 1696, 1661 cm−1

ABDEL-LATIF ET AL.
11
(C O). 1H NMR (DMSO-d6): 2.51 (s, 3H, CH3), 3.98 (s, 2H,
CH2), 5.01 (s, 1H, pyrimidine-H), 6.52 (s, 2H, NH2), 7.70
(d, J = 9.00 Hz, 2H, Ar H), 7.92 (d, J = 8.50 Hz, 2H,
Ar H), 10.48 ppm (s, 1H, NH). 13C NMR (DMSO-d6):
26.49, 34.69, 81.44, 118.48 (2C), 129.54 (2C), 131.89,
143.14, 160.74, 162.01, 167.16, 170.07, 196.57. Analysis
of C14H14N4O3S (318): Calculated: C, 52.82; H, 4.43; N,
17.60%. Found: C, 52.66; H, 4.51; N, 17.69%.
[23] M. K. Okla, S. A. Alamri, I. A. Alaraidh, A. A. AL-ghamdi,
W. H. Soufan, A. A. Allam, M. M. Fouda, H. E. Gaffer, Che-
mistrySelect 2019, 4, 11735.
[24] N. M. Biswas, A. Shard, S. Patel, P. Sengupta, Drug Dev. Res.
2018, 79, 391.
[25] F. M. Sroor, A. M. Abdelmoniem, I. A. Abdelhamid, Che-
mistrySelect 2019, 4, 10113.
[26] N. P. Rai, T. D. Venu, B. K. Manuprasad, S. Shashikanth,
P. N. Arunachalam, A. Firdouse, Chem. Biol. Drug Des. 2010,
75, 400.
[27] S¸. Demirayak, Z. S¸ahin, M. Ertas¸, E. F. Bülbül, C. Bender,
ORCID
ꢀ
S. N. Biltekin, B. Berk, B. N. Saglık, S. Levent, L. Yurttas¸,
Ehab Abdel-Latif https://orcid.org/0000-0003-4437-
6635
Amr El-Demerdash https://orcid.org/0000-0001-6459-
J. Heterocyclic Chem. 2019, 56, 3370.
[28] A. Y. Hassan, M. T. Sarg, S. A. El-Sebaey, J. Heterocyclic Chem.
2019, 56, 3102.
2955
[29] E. Abdel-Latif, A. S. Radwan, M. Karam, M. A. Ismail, Indian
J. Heterocyclic Chem. 2018, 28, 495.
[30] E. Abdel-Latif, E. M. Keshk, A. G. M. Khalil, A. Saeed,
H. M. Metwally, J. Heterocyclic Chem. 2018, 55, 2334.
[31] E. Abdel-Latif, M. M. Fahad, M. A. Ismail, Synth. Commun.
2020, 50, 289.
[32] A. Anthwal, B. K. Thakur, M. S. M. Rawat, J. Indian Chem.
Soc. 2014, 91, 1525.
[33] J. Maru, G. R. Patel, R. Yadav, B. Bhatt, J. Curr. Chem. Pharm.
Sci. 2014, 4, 164.
[34] N. Y. Gorolets, B. H. Yousefi, F. Belaj, C. O. Kappe, Tetrahe-
dron 2004, 60, 8633.
REFERENCES
[1] J. H. Andrew, G. Thorfinnur, Tetrahedron Lett. 2006, 47, 6321.
[2] J. A. A. Micky, N. M. Saleh, S. M. Mohamed, S. A. Mohameda,
M. M. Salem, Indian J. Chem. 2006, 45B, 1579.
[3] C. A. Duckworth, US Patent5,538,938, 1996.
[4] T. Ikeuchi, T. Ohkawa, S. Ohno, U.S. Patent 8,318,635, 2012.
[5] J. M. Concellón, H. Rodríguez-Solla, V. del Amo, P. Diaz,
J. Org. Chem. 2010, 75, 2407.
[6] D. B. Guthrie, K. Damodaran, D. P. Curran, P. Wilson,
A. J. Clark, J. Org. Chem. 2009, 74, 4262.
[35] V. Syakaev, S. Podyachev, B. Buzykin, S. Latypov,
W. Habicher, A. Konovalov, J. Mol. Struct. 2006, 788, 55.
[36] D. T. G. Gonzaga, F. C. D. Silva, V. F. Ferreira, J. L. Wardell,
S. M. S. V. Wardell, J. Braz. Chem. Soc. 2016, 27, 2322.
[37] P. Kumar, K. Kadyan, M. Duhan, J. Sindhu, V. Singh,
B. S. Saharan, Chem. Cent. J. 2017, 11, 115.
[7] E. O'Reilly, E. Lestini, D. Balducci, F. Paradisi, Tetrahedron
Lett. 2009, 50, 1748.
[8] A. Paczal, A. C. Bényei, A. Kotschy, J. Org. Chem. 2006, 71,
5969.
[9] S. Busato, D. C. Craig, Z. M. Judeh, R. W. Read, Tetrahedron
2003, 59, 461.
[38] F. A. Yassin, Chem. Heterocycl. Compd. 2009, 45, 35.
[39] R. Venkatraman, H. Ameera, L. Sitole, E. Ellis, F. R. Fronczek,
E. J. Valente, J. Chem. Crystallogr. 2009, 39, 711.
[40] S. I. Stylianakis, A. Kolocouris, N. Kolocouris, G. Fytas,
G. B. Foscolos, E. Padalko, J. Neyts, E. D. Clerq, Bioorg. Med.
Chem. Lett. 2003, 13, 1699.
[10] F. Zaragoza, H. Stephensen, J. Org. Chem. 1999, 64, 2555.
[11] G. Sirasani, R. B. Andrade, Org. Lett. 2009, 11, 2085.
[12] T. Kaoudi, L. D. Miranda, S. Z. Zard, Org. Lett. 2001, 3, 3125.
[13] M. J. Evans, B. F. Cravatt, Chem. Rev. 2006, 106, 3279.
[14] M. Shaul, G. Abourbeh, O. Jacobson, Y. Rozen, D. Laky,
A. Levitzki, E. Mishani, Bioorg. Med. Chem. 2004, 12, 3421.
[15] I. H. El Azab, O. A. Abu Ali, A. H. El-Zahrani, A. A. Gobouri,
T. A. Altalhi, J. Heterocyclic Chem. 2019, 56, 18.
[41] H. E. Gaffer, S. Abdel-Fattah, H. A. Etman, E. Abdel-Latif,
J. Heterocyclic Chem. 2017, 54, 331.
[16] A. Zhang, Y. Yang, Y. Yue, K. Tao, T. Hou, H. Jin, Chem. Bio-
divers. 2019, 16, e1900118.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
[17] A. A. Bekhit, A. Hymete, H. Asfaw, A. E. D. A. Bekhit, Arch.
Pharm. 2012, 345, 147.
[18] Dinesha, S. Viveka, B. K. Priya, K. S. R. Pai, S. Naveen,
N. K. Lokanath, G. K. Nagaraja, Eur. J. Med. Chem. 2015, 104, 25.
[19] M. M. Al-Sanea, A. Elkamhawy, A. Zakaria, B. S. Park,
Y. Kwon, S. H. Lee, S. W. Lee, I. T. Kim, Molecules 2015, 20,
1031.
[20] M. Abdel-Aziz, G. E. D. A. Abuo-Rahma, A. A. Hassan, Eur.
J. Med. Chem. 2009, 44, 3480.
[21] E. Abdel-Latif, A. S. Almatari, G. E. Abd-ElGhani,
J. Heterocyclic Chem. 2019, 56, 1978.
How to cite this article: Abdel-Latif E,
Fahad MM, El-Demerdash A, Ismail MA. Synthesis
and biological evaluation of some heterocyclic
scaffolds based on the multifunctional N-(4-
acetylphenyl)-2-chloroacetamide. J Heterocyclic
Chem. 2020;1–11. https://doi.org/10.1002/jhet.4012
[22] B. Grybaitė, R. Vaickelionienė, M. Stasevych, O. Komarovska-
Porokhnyavets, K. Kantminienė, V. Novikov, V. Mickevicˇius,
ChemistrySelect 2019, 4, 6965.