A new series of thiazolyl pyrazoline derivatives linked to benzo[1,3]dioxole moiety: Synthesis and evaluation of antimicrobial and anti-proliferative activities

Article abstract of DOI:10.1080/00397911.2019.1695839

2-(5-(Benzo[d][1,3]dioxol-5-yl)-3-(naphthalen-1-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-(4-substituted phenyl)thiazole (7) and thiazole derivatives (9) were synthesized via reaction of 4,5-dihydro-1H-pyrazoles (5a,b) with substituted phenacyl bromide and a number of α-halo-compounds respectively. Also, (E)-2-(5-(benzo[d][1,3]dioxol-5-yl)-3-(naphthalen-1-yl)-4,5 dihydro-1H-pyrazol-1-yl)-4-methyl-5-(substituted phenyldiazenyl)thiazole (11) were prepared through reactions of carbothioamide (5a,b) with hydrazonoyl halides. In addition, thioamides (5a–b) were used as starting materials for preparation of thiazoles (12a–b) and benzylidene thiazoles (13a–b). Most of synthesized compounds show interesting biological properties as antimicrobial and antiproliferative activities, the results of minimum inhibitory concentration showed that pyrazole derivative 7c (MIC: 0.23 mg/mL) showed better results when compared with 11c and 12a (MIC: 0.1–0.125 mg/mL) as obtained from their MIC values. On the other hand, 2-(5-(benzo[d][1,3]dioxol-5-yl)-3-(naphthalen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-(4-chlorophenyl) thiazole (7c) can be considered as the most promising anti-proliferative agent against HCT-116 cancer cells owing to its notable inhibitory effect on HCT-116 cells with an IC₅₀ value of 6.19 μM.

Full text of DOI:10.1080/00397911.2019.1695839

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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A new series of thiazolyl pyrazoline derivatives
linked to benzo[1,3]dioxole moiety: Synthesis and
evaluation of antimicrobial and anti-proliferative
activities
Eman Mansour, Asmaa Aboelnaga, Ekhlass M. Nassar & Safaa I. Elewa
To cite this article: Eman Mansour, Asmaa Aboelnaga, Ekhlass M. Nassar & Safaa I.
Elewa (2019): A new series of thiazolyl pyrazoline derivatives linked to benzo[1,3]dioxole
moiety: Synthesis and evaluation of antimicrobial and anti-proliferative activities, Synthetic
Communications, DOI: 10.1080/00397911.2019.1695839
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https://doi.org/10.1080/00397911.2019.1695839
A new series of thiazolyl pyrazoline derivatives linked to
benzo[1,3]dioxole moiety: Synthesis and evaluation of
antimicrobial and anti-proliferative activities
Eman Mansour, Asmaa Aboelnaga, Ekhlass M. Nassar, and Safaa I. Elewa
Organic Chemistry Department, Faculty of Women’s for Arts, Science and Education, Ain Shams
University, Cairo, Egypt
ABSTRACT
ARTICLE HISTORY
2
-(5-(Benzo[d][1,3]dioxol-5-yl)-3-(naphthalen-1-yl)-4,5-dihydro-1H-pyra-
zol-1-yl)-4-(4-substituted phenyl)thiazole (7) and thiazole derivatives
9) were synthesized via reaction of 4,5-dihydro-1H-pyrazoles (5a,b)
Received 14 September 2019
(
KEYWORDS
Acetylnaphthalene; anti-
microbial and anti-
proliferative; carbothioa-
mide; chalcone; piperonal;
thiazole; pyrazoline
with substituted phenacyl bromide and a number of a-halo-com-
pounds respectively. Also, (E)-2-(5-(benzo[d][1,3]dioxol-5-yl)-3-(naph-
thalen-1-yl)-4,5
phenyldiazenyl)thiazole (11) were prepared through reactions of car-
bothioamide (5a,b) with hydrazonoyl halides. In addition, thioamides
dihydro-1H-pyrazol-1-yl)-4-methyl-5-(substituted
(
(
5a–b) were used as starting materials for preparation of thiazoles
12a–b) and benzylidene thiazoles (13a–b). Most of synthesized
compounds show interesting biological properties as antimicrobial
and antiproliferative activities, the results of minimum inhibitory con-
centration showed that pyrazole derivative 7c (MIC: 0.23mg/mL)
showed better results when compared with 11c and 12a (MIC:
0
.1–0.125mg/mL) as obtained from their MIC values. On the other
hand, 2-(5-(benzo[d][1,3]dioxol-5-yl)-3-(naphthalen-2-yl)-4,5-dihydro-
H-pyrazol-1-yl)-4-(4-chlorophenyl) thiazole (7c) can be considered as
1
the most promising anti-proliferative agent against HCT-116 cancer
cells owing to its notable inhibitory effect on HCT-116 cells with an
IC50 value of 6.19 mM.
GRAPHICAL ABSTRACT
CONTACT Asmaa Aboelnaga
asmaa.aboelnaga@women.asu.edu.eg
Organic Chemistry Department, Faculty of
Women’s for Arts, Science and Education, Ain Shams University, Cairo 11767, Egypt.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
E. MANSOUR ET AL.
Introduction
Piperonal is a suitable compound for many products of commercial importance and it is
an organic compound which has high interesting biological and pharmacological activities
[
1]
[2–5]
[6–9]
of several heterocyclic compounds such as benzimidazoles
pyrazoles.
benzoxazoles
Furthermore, most of the compounds synthesized from piperonal have
high anti-proliferative, anti-microbial, anti-inflammatory, anti-neoplastic and fungicidal
and
[
10,11]
[
12,13]
activity.
We interested in this work to synthesis piperonal derivatives containing pyr-
azole moiety. In addition, naphthalene nucleus is present in a wide variety in the field of
[
14]
medicinal chemistry as they used in drug synthesis as nafcillin, naftifine, terbinafine
which play important role in microbial infection.
[
15]
We interested in the present work to
synthesize chalcones that can be found in natural products. Chalcones have been synthe-
[
16,17]
sized in order to develop drugs which act against cancer and malaria,
so the com-
bination of chalcone, naphthalene, and benzodioxole moiety in one entity seemed
[
18]
promising.
Chalcones and their derivatives were recognized as biologically active com-
[
19–21]
[17,22]
pounds
interest due to their pharmaceutical application,
pyrazole and thiazole moiety possess abroad spectrum as biologically active compounds as
and anticancer.
Pyrazoles also have been attracting a great deal of
[
23]
in addition, compounds containing
[
4,24–29]
[30–36]
antifungal, antibacterial and anti-inflammatory
and anticancer.
In our studies
we deal with the utility of hydrazonyl halides for the synthesis of biologically active poly-
[
33,37]
heterocylic compounds containing either pyrazole or pyrazoline thiazole heterocycles.
Furthermore, the hybridization of pyrazolyl thiazole with naphthalene revealed potent
anti-cancer. According to the aforementioned data, the principle point of this work relies
up on the synthesis of new naphthalene derivatives containing either pyrazole or pyrazo-
[
38]
line thiazole heterocycles as pharmacophoric moieties.
Results and discussion
Chemistry
In the present work, two novel chalcones were synthesized by condensing the naph-
thyl ketone with pipronal in ethanol using basic condition at room temperature. The
products obtained from the reaction mixture in a pure state and high yield to give
prop-2-en-1-ones 3a and 3b. The structures of the new chalcones 3a and 3b were
confirmed by spectroscopic data as well as elemental analysis. Infrared spectra of
ꢀ
1
chalcones revealed absorption bands in the region 1640–1690 cm corresponding to
1
the conjugated carbonyl system in chalcones. In the 400 MHz, H-NMR spectra of
3
a, 3b exhibit the presence of doublet signals at d ¼ 7.25–7.69 ppm due to the ole-
finic hydrogen in chalcones (Scheme 1), when compound 3a and 3b were treated
with thiosemicarbazide in refluxing ethanol in presence of NaOH afforded thioamide
derivatives 5a and 5b (Scheme 1). The mechanism of the reaction involved the for-
mation of hydrazones and addition of NH on the olephinic bond. The IR spectra of
ꢀ
1
the latter compounds showed absorption bands at 1598 cm corresponding to C¼N
ꢀ
1
group and at 1256–1249 cm
stretching band of C¼S group, and the absorption
ꢀ1 1
band of NH group at 3412–3255 cm . Its H-NMR spectrum showed the signals of
2
H , H , and H of pyrazole ring as multiplet in the region 3.26–3.30 ppm
a
b
c

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SYNTHETIC COMMUNICATIONS
3
Scheme 1. Synthesis of thiazolyl-pyrazolines 7a–d.
3
8
.95–4.18 ppm and 5.88–5.93 ppm respectively, in addition to the peak signals at
.2–8.22 ppm and 9.25–9.27 ppm due to NH protons.
2
The reaction of pyrazole 5a or 5b with 1-aryl-2-bromoethanone 6a or 6b in ethanol
gave thiazolyl-pyrazolines7a–d via the nucleophilic sulfur atom of thioamide group to
1
form thiohydrazonate followed by dehydration to give the final product 7a–d. The H-
NMR spectrum of the synthesized compounds, the CH protons of pyrazoline ring
2
showed as a multiplet at 3.47–3.63 (H ), 4.04–4.26 (H ). The CH (H ) proton appeared
a
b
c
as a multiplet at 5.59–5.97 ppm. The H -proton of thiazole was observed as a singlet sig-
5
nal in the region 6.90–7.45 ppm (Scheme 1).
The reaction of carbothioamide derivatives 5a or 5b with a-halo compounds 8a–c in
refluxing ethanol in the presence of Et N yielded the corresponding condensation prod-
3
ꢀ1
ucts 9a–f. IR spectra of 9a–f showed a band at 1630–1720cm due to C¼O whereas,
ꢀ
1
1
the spectra of 9c and 9f showed bands at 3235–3251cm due to NH group. H-NMR
spectra of 9a and 9d revealed singlet signals at 2.4–2.5 ppm due to methyl protons of
acetyl group, while for 9b and 9e showed a triplet-quartet pattern of ethyl protons at
1
1
.24–1.29 and 4.18–4.26ppm, while the H-NMR spectra of 9c and 9f elicited
exchangeable signals at 9.76ppm due to NH protons along with aromatic protons at
1
3
7
.05–7.66ppm. C NMR spectrum of 9e showed signals due to ethyl carbons at 14.75
and 60.66 ppm with ester carbonyl carbon at 162.29ppm (Scheme 2).
Next, thioamide 5a or 5b were reacted with the appropriate hydrazonyl chloride 10a–c
in EtOH afforded the diazenyl thiazoles 11a–f. The IR spectra of the obtained compounds
ꢀ
1
showed absorption bands at ꢀ 1576–1592cm due to N¼N groups and lack of the band
1
corresponding to NH group. The H-NMR spectrum of the synthesized compounds
2

4
E. MANSOUR ET AL.
Scheme 2. Synthesis of thiazolyl-pyrazolines 9a–f and 11a–f.
showed disappearance of the signal of NH protons and the presence of singlet peak of
2
methyl protons of the thiazole ring at 2.3–2.6 ppm, in addition to the aromatic protons
1
signals at 6.9–7.87ppm. Also, H-NMR spectra of 11b and 11e showed additional singlet
13
signals at 2.35–2.37ppm due the methyl protons of p-tolyl, C NMR spectrum of 11f
showed signals at16.61ppm for CH carbon of the thiazole ring with increase in the num-
3
ber of signals of the aromatic carbons at 101.64–159.62ppm (Scheme 2).
In addition, thioamide derivatives 5a or 5b condensed with ethyl bromo acetate in
refluxing ethanol afforded thiazoles 12a and 12b as shown in (Scheme 3). Its IR spec-
ꢀ
1
trum showed absorption bands at 2830–2925 of CH and 1693–1695 cm of carbonyl
2
1
groups. In addition, its H-NMR spectrum exhibits the presence of singlet signals at d
3
.96–3.99 ppm due to the thiazolidinone (CH ) group.
2
Finally, refluxing thioamide 5a or 5b with chloro acetic acid and benzaldehyde in acetic
acid afforded benzylidene thiazole derivatives 13a and 13b. Compounds 13a and 13b were
prepared by addition of benzaldehyde to thiazol derivatives 12a or 12b as shown in
(
scheme 3). The structure of the benzylidene thiazole 13a and 13b were confirmed from its
ꢀ
1
element and spectral data. The IR spectra showed absorption bands at 1520–1570cm
ꢀ
1
1
(
C¼N) and 1681–1694cm (C¼O). H-NMR showed the disappearance of the singlet
peak of CH group and the presence of olefinic proton peaks at 7.45ppm (Scheme 3).
2
Biological evaluation
Anti-microbial activity
The antimicrobial activity of the newly synthesized compounds was evaluated against
two gram-positive bacteria Staphylococcus aureus (S. a.) and Bacillus cereus (B. c.), and
gram-negative bacteria species Klebsiella pneumonia and pseudomonas aeruginosa by

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5
Scheme 3. Synthesis of thiazolyl-pyrazolines 13a and 13b.
[
39,40]
agar well diffusion method as reported earlier,
in addition to five different fungus
strains namly; Candida albicans, Syncephalastrum racemosum, Aspergillus fumigatus,
penicillium expansum and Aspergillus flavus.
The anti-bacterial activities of 3a, 3b, 5a, 5b, 7a–7d, 9a–9f, 11a–11f, 12a, 12b, 13a
and 13b are represented in Table 1. It is noticed that, compounds 3a, 3b, 5a, 7a, 7c, 9a,
9
d, 11a, 11c, 11e, 12a, 13a and 13b revealed a moderate antibacterial activity against
Bacillus subtilis with inhibition zones 1.6, 1.2, 0.9, 1.8, 1.0, 0.8, 0.9, 0.8, 1.8,0.8,2.0,0.8
and 0.9 mm, respectively, when compared with that of reference drug Amoxicillin (IZ ¼
3.5 mm), whereas compounds 3a, 3b, 5a, 7a, 7c, 9a, 9d, 11a, 11c, 11e, 12a, 13a and
1
3b exhibited a moderate antibacterial activity against Staphylococcus aureus with inhib-
ition zones in the range of 0.5–2.6 mm when compared with that of reference drug
Amoxicillin (IZ ¼ 2.3 mm). Additionally, compounds 3b, 5b,7a, 7c, 9a, 9d, 11a, 11c,
1
2a, 13a and 13b exhibited good antibacterial activities against gram-negative bacteria
Klebsiella pneumoniae with inhibition zones in the range of 0.9, 1.5, 1.2, 2.1, 0.5, 0.6,
.0, 1.9, 0.9, 0.8, 1.2 mm respectively, when compared with that of reference drug
1
Amoxicillin (IZ ¼ 2.4 mm), whereas compounds 3b, 5b, 7a, 7c, 9d, 11c, 12a, 13b exhib-
ited moderate antibacterial activities against Pseudomonas aeruginosa with inhibition
zones in the range of 0.5, 0.9, 1.6, 1.0, 0.5, 2.0, 0.5, 0.8 mm respectively, when compared
with that of reference drug Amoxicillin (IZ ¼ 2.2 mm). The anti-fungal activities of pyr-
azole derivatives 3a, 3b, 5a, 5b, 7a–7d, 9a–9f, 11a–11f, 12a, 12b, 13a and 13b are rep-
resented in Table 1. It is observed that compounds 5b, 7c, 11a, 11c, 11e, 12a revealed a
moderate antifungal action against C. albicans with inhibition zones in the range of 1.5,
1
.0, 0.9, 2.2, 0.5 and 2.0 mm, respectively, whereas 3a, 5a, 5b, 7c, 9d, 11a, 11c, 11e, 12a
and13b revealed a moderate antifungal action against A. fumigatus with inhibition zones
, 0.5, 1.2, 2.5, 1.0, 1.8, 2.1, 0.9, 1.5 and 0.8 mm, respectively, when compared with that
of reference drug Griseofulvin (IZ ¼ 3.3 mm), respectively. Additionally, compounds 3a,
b, 5b, 7c, 9a, 9c, 9d, 11a, 11c, 12a and 12b exhibited good antifungal activities against
1
3

6
E. MANSOUR ET AL.
Table 1. The anti-microbial activity of the newly synthesized compounds against 9 microbial species.
Inhibition ZONE (IZ, mm)
Antibacterial activityꢁ
B. K.
Antifungal activityꢁ
Comp.
S.
P.
A.
A.
S.
P.
C.
(
conc. 5 mg/mL) aureus subtilis pnumonia aeruginosa fumigatus flavus racemosum expansum albicans
3
3
5
5
7
7
7
7
9
9
9
9
9
9
1
1
1
1
1
1
1
1
1
1
a
b
a
b
a
b
c
d
a
b
c
d
e
f
1a
1b
1c
1d
1e
1f
2a
2b
3a
3b
2.0
1.0
1.8
–
2.0
–
1.4
–
1.2
–
–
1.0
–
–
0.5
–
2.6
–
1.0
–
1.9
–
1.0
1.0
1.6
1.2
0.9
–
1.8
–
1.0
–
0.8
–
–
0.9
–
–
0.8
–
1.8
–
0.8
–
2.0
0.8
–
0.9
3.5
–
0.9
–
1.5
1.2
–
2.1
–
0.5
–
–
0.6
–
–
1.0
–
1.9
–
–
–
0.9
–
0.8
1.2
2.4
–
0.5
–
0.9
1.6
–
1.0
–
–
–
–
0.5
–
–
–
–
2.0
–
–
–
0.5
–
–
0.8
2.2
1.0
–
0.5
1.2
–
–
2.5
–
–
–
–
1.0
–
–
1.8
–
2.1
–
0.9
–
1.5
–
–
0.8
3.3
1.5
0.5
–
1.0
–
–
1.8
–
0.9
–
0.5
0.8
–
–
1.5
–
0.5
–
–
1.2
–
–
1.9
–
1.0
–
–
–
–
–
1.8
–
1.9
–
0.8
–
–
0.3
0.9
–
0.9
–
–
0.5
–
–
–
0.8
0.8
–
–
2.0
–
0.8
–
–
–
2.3
1
–
–
–
–
–
1.5
–
–
1.0
–
–
–
–
–
–
–
0.9
–
2.2
–
0.5
–
2.0
–
–
2.3
–
–
–
0.5
0.9
–
–
2.4
–
0.7
0.5
2.1
–
2
.3
2.8
3
‘
–’ Indicates bacteria were resistant to the compound.
Antibacterial reference drug ¼ Amoxicilline and Antifungal reference drug ¼ Griseofulvin.
ꢁ
A. flavus with inhibition zones in the range of 1.5, 0.5, 1.0, 1.8, 0.9, 0.5, 0.8, 1.5, 2.3,
0
.5, 0.9 mm, respectively, when compared with IZ ¼ 2.4 mm of reference drug
Griseofulvin. Compounds 3a, 5b, 7c, 9a, 11a, 11c, 11e, 13a and 13b revealed a good
antibacterial activity against Syncephalastrum racemosum with inhibition zones in the
range of 0.5–1.9 mm when compared with Griseofulvinas a reference (IZ ¼ 2.1 mm)
whereas 3a, 3b, 5b, 7c, 9c, 9d, 11a, 11c, 12a, 12b and 13b revealed a moderate antifun-
gal action against Penicillium expansum in the range of 0.3–2.3 mm comparing
Griseofulvin drug as a reference (IZ ¼ 2.8 mm). From the data, it is observed that com-
pounds 7c and 11c and 12a showed good anti-microbial activity which showed the role
of chloro group on acquiring their anti-microbial activities.
Minimum inhibitory concentration (MIC). For MIC test, Figure 1 showed different min-
imum inhibition concentrations of 7c, 11c and 12a. It is already known that as the
inhibition, bactericidal or fungicidal concentrations decreases this implies the highest
efficacy, i.e., the tested compound possesses a high toxicity so that low concentration is
sufficient to cause inhibition, bactericidal or fungicidal effects.
Pyrazole derivative 7c (MIC: 0.25 mg/mL) showed better results when compared with
1
1c and 12a (MIC: 0.1–0.125 mg/mL) as obtained from their MIC values.

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SYNTHETIC COMMUNICATIONS
7
0
0
0
.25
.2
.15
.1
0
Staphylococcus aureus
Bacillus cereus
0
Klebsiella pneumonia
.05
0
pseudomonas
aeruginosa
7
c
11c
12a
Different compounds
Figure 1. MIC (mg/mL) of compounds 7c, 11c and 12a.
Table 2. The 50% inhibitory concentration (IC ) of 7c, 11c and 12a against HTC-116, BHK, HEP-G2
50
and MCF-7 cell lines.
IC50 (mM)
IC50 (mM) of
Human normal liver
HL-7702
Compounds
HCT116
BHK
HEP-G2
MCF-7
7
1
1
c
1c
2a
6.19 ± 0.02
9.82 ± 0.12
12.91 ± 0.03
7.08 ± 0.92
7.71 ± 0.31
10.76 ± 0.71
6.71 ± 0.51
7.49 ± 0.22
19 ± 1.04
6.52 ± 0.02
6.94 ± 0.21
9.1 ± 0.08
123.05 ± 1.0
279.94 ± 1.02
328.56 ± 1.04
Anti-proliferative activity
Determination of anti-proliferative activities against HCT-116, BHK, HEP G2 and MCF-7
cell lines. On the bases of the concept of broad pharmacological activity of thioimide,
pyrazole compounds we carried out the anti-proliferative activity for the newly synthe-
sized compounds 7c, 11c and 12a against four cancer cell lines HCT-116 (colon carcin-
oma) and BHK (baby hamster kidney), HEP G2 (human liver cell line) and MCF-7
(
breast cell line). As control cell, the human normal liver cell line HL-7702 was
employed to discern an unspecific cytotoxicity of newly synthesized compounds (Table
). All cell lines were gotten from the VACSERA Tissue Culture Unit. The effect of new
2
compounds on the cell was calculated and the microplate reader (SunRise, TECAN, Inc,
USA) was utilized to gauge the optical density and to determine the number of viable
cells and the percentage of viability which calculated as [1 ꢀ (ODt/ODc)] ꢂ 100% where
ODt is the mean Optical Density of wells dealed with the tested sample and ODc is the
mean Optical Density of untreated Cells.
SAR. From the results presented in Table 3, it was reported that all the tested com-
pounds have been made visible anti proliferative. Among them, compound 7c, which
had IC50 values of is the more effective one followed by 11c and 12a, this may be
attributed to the presence of pyrazole and thiazole rings in these compounds. Among
them, compound 7c, which had IC50 values of 7.90, 7.08, 6.71 and 6.52 mM against
HCT116, BHK, HepG2 and, MCF-7, respectively, displayed the most potent
anti-proliferative activity. These results suggested that compound 7c is more potent
than the other compounds overall. Presence of halogen substituent was performed to

8
E. MANSOUR ET AL.
Table 3. Anti-proliferative activities of compounds (mm/mL) against four tumor cell lines (survival %)
and IC50 of dose which reduces survival to 50%.
HCT-116
BHK
HEPG2
11c
MCF-7
11c
No.
7c
11c
12a
7c
11c
12a
7c
12a
7c
12a
Conc.
0
1
2
5
1
.0
.0
.5
.0
100
80
54
46
35
100
92
84
70
59
100
98
95
93
88
100
86
65
54
42
100
85
70
62
50
100
98
84
76
63
100
83
72
59
42
100
92
85
76
68
100
95
78
55
38
100
92
85
76
41
100
95
78
55
38
100
83
72
59
42
0.0
explore the structure-activity relationships of this compound. Also, Compound 11c
bearing one chloro group at the para-position in the phenyl ring showed strong anti-
proliferative activity (the IC50 values of 7c and 11c: 6.52 and 6.94 mM against MCF-7
cells) than compound 12a (the IC50 value: 9.1 mM against MCF-7 cells) which possess
thiazolone ring.
Conclusion
In summary, new thiazolyl pyrazoline derivatives linked to benzo[1,3]dioxole moiety
were synthesized and their structures were established by different spectral data, then
these compounds were examined for their antibacterial, antifungal activities and anti-
proliferative activity against four different cell lines. In particular, compound 7c was the
most promising antifungal derivative against A. funigatus with inhibition zone 2.5 mm.
Also, compound 11c had got high activity against S. aureus with MIC value of
0.115 mg/mL. Furthermore, compound 7c can be identified as the most promising anti-
cancer agent owing to its anti-proliferative effect on all tested cell lines and nontoxic
towards human normal liver HL-7702.
Experimental
Chemistry
General
Gallenkamp melting point device used to measure the melting points. Infrared (IR)
Spectra were recorded as KBr disks using the Perkin Elmer FT-IR Spectrum BX appar-
atus. Mass spectral data are given as m/z (Intensity %) and measured on GCQ Finnigan
MAT. Nuclear Magnetic Resonance Spectra were recorded on a Bruker NMR spectrom-
13
eter, 1H spectrum was run at 300 MHz and the C NMR spectrum was run at
25 MHz in deuterated DMSO, the chemical shift in d, ppm and the coupling constant
1
[
41]
(J) values in Hertz.
Mass spectrum was carried out on direct probe controller inlet
part to single quadro-pole mass analyzer in (thermo scientific gcms) model (isq lt) using
thermo x-calibur software at the regonal center for mycology and biotechnology (rcmb)
al-azhar university, Naser City, Cairo. Reaction courses and product mixtures were
monitored by thin layer chromatography (TLC) on silica gel plates. All the chemicals
were purchased from Sigma–Aldrich.

V
R
SYNTHETIC COMMUNICATIONS
9
Synthesis of prop-2-en-1-ones 3a and 3b. To a solution of benzo[d][1,3]dioxole-5-carbal-
dehyde (piperonal) (1) (10 mmol) and 1-acetylnaphthalene (2a) or 2-acetylnaphthalene
(2b) (1.82 g, 10 mmol), in absolute ethanol (50 mL), sodium hydroxide solution (5 mL,
20%) was added portion-wise. The mixture was stirred for 4 h. The solid product was
collected by filtration, washed with water, dried and finally recrystallized from ethanol
to give compounds 3a and 3b, respectively.
(
(
E)-3-(benzo[d][1,3]dioxol-5-yl)-1-(naphthalen-1-yl)prop-2-en-1-one (3a). Yellow crystals
ꢃ
ꢀ1
1
8.8 mmol), m.p. 176–78 C; IR (KBr, ꢀ cm ): 1640 (C ¼ C) and 1680 (C¼O); H
NMR (DMSO-d ) dppm: 6.12 (s, 2 H, CH of dioxole), 6.96–6.98 (d, 1 H, J ¼ 8 Hz, H-4
6
2
of benzodioxole), 7.25–7.27 (dd, 2 H, J ¼ 8 Hz, olefinic hydrogens), 7.55–7.57 (d, 2 H,
J ¼ 8 Hz, H-6 and H-7 of benzodioxole), 7.59–8.32 (m,7H, naphthalene Hs); MS: m/
þ
z ¼ 302.24[M] . Anal.Calcd for C H O : C, 79.46; H, 4.67. Found: C, 79.36; H, 4.50.
2
0
14 3
(
(
E)-3-(benzo[d][1,3]dioxol-5-yl)-1-(naphthalen-2-yl)prop-2-en-1-one (3b). Yellow crystals
ꢃ
ꢀ1
1
9.1 mmol), m.p. 148–150 C; IR (KBr, ꢀ cm ): 1655 (C ¼ C) and 1690 (C¼O); H
NMR (DMSO-d ) dppm: 6.13 (s, 2 H, CH of dioxole), 7.01–7.03 (d, 1 H, J ¼ 8 Hz, H-6
6
2
of benzodioxole), 7.37–7.38 (d, 1 H, J ¼ 4 Hz, H-7 of benzodioxole), 7.62–7.65 (t, 2 H,
J ¼ 12 Hz, H-6 and H-7 of naphthalene), 7.67–7.69 (dd, 2 H, J ¼ 8 Hz, olefinic hydro-
gens), 7.78 (s, 1 H, H-4 of dioxole), 8.01–8.07(m, 3 H, olefinic hydrogens, H-3 and H-4),
þ
8
7
.13–8.17 (m, 2 H, H-5 and H-8); MS: m/z ¼ 302.24[M] . Anal.Calcd for C H O : C,
20
14 3
9.46; H, 4.67. Found: C, 79.26; H, 4.52.
Synthesis of 4,5-dihydro-1H-pyrazoles 5a and 5b
To a solution of NaOH (1 g, 0.025 mol) and chalcone 3a or 3b (10 mmol) in ethanol
50 mL), thiosemicarbazide (4) (10 mmol) was added. The reaction mixture was refluxed
(
for 8 h. The resulting solid was filtered, washed with water, dried and recrystallized
from EtOH/DMF to give pyrazole derivatives 5a and 5b, respectively.
5
-(benzo[d][1,3]dioxol-5-yl)-3-(naphthalen-1-yl)-4,5-dihydro-1H-pyrazole-1-carbothioa-
ꢃ
ꢀ1
mide (5a). Off white crystals (8.3 mmol), m.p. 170–172 C; IR (KBr, ꢀ cm ):
3
1
417–3255 (NH ) 1598 (C¼N) and 1256 (C¼S); H NMR (DMSO-d ) dppm: 3.27–3.3
2
6
(m, 1 H, H of pyrazole), 4.11–4.18 (m, 1 H, H of pyrazole), 5.88–5.89 (m, 1 H, H of
a b c
pyrazole), 5.91 (d, J ¼ 3.6 Hz, 2 H, CH of dioxole), 6.64–6.68 (m, 2 H, H-6 and H-7 of
2
benzodioxole), 6.86 (d, J ¼ 8 Hz, 1 H, H-4 of benzodioxole), 7.52–7.63 (t, J ¼ 12 Hz, 2 H,
H-6 and H-7 of naphthalene), 7.68–7.23 (t, J ¼ 8 Hz,1H, H-3 of naphthalene), 7.77–7.78
(
d, J ¼ 4 Hz, 2 H, H-5 and H-8 of naphthalene), 7.99–8.04 (m, 2 H, H-2 and H-4 of
þ
naphthalene), 8.2 (s, 1 H, NH), 9.25–9.27 (d, J ¼ 8 Hz, 1 H, NH); MS: m/z ¼ 375.28[M] .
Anal.Calcd for C H N O S: C, 67.18; H, 4.56; N, 11.19. Found: C, 67.29; H, 4.58;
2
1
17 3 2
N, 11.03.
5
-(benzo[d][1,3]dioxol-5-yl)-3-(naphthalen-2-yl)-4,5-dihydro-1H-pyrazole-1-carbothioa-
ꢃ
ꢀ1
mide (5b). Pale yellow crystals(8.9 mmol), m.p. 239–240 C; IR (KBr, ꢀ cm ):
3
1
412–3234 (NH ) and 1598 (C¼N) and 1249 (C¼S); H NMR (DMSO-d ) dppm:
2
6

1
0
E. MANSOUR ET AL.
3
.26–3.3 (m, 1 H, H of pyrazole), 3.93–4.0 (m, 1 H, H of pyrazole), 5.90–5.93 (m, 1 H,
a
b
H of pyrazole), 5.93 (d, J ¼ 3.6 Hz, 2H, CH of dioxole), 6.64
̶
6.61 (m, 2 H, H-6 and H-
of benzodioxole), 6.85 (d, J ¼ 8.2 Hz,1H, H-4 of benzodioxole), 7.54–7.60 (m, 2 H, H-6
and H-7 of naphthalene), 7.94–7.99 (m, 4 H, naphthalene Hs), 8.09 (s,1H, NH), 8.21(s,
c
2
7
1
3
1
6
1
H, H-1 of naphthalene),8.22 (s, 1 H, NH). C NMR (DMSO-d ) dppm: 42.89 (CH ),
6 2
3.24 (CH), 101.40, 106.41, 108.74, 118.94, 124.08, 127.30, 127.87, 128.20, 128.48,
28.61, 128.90, 129.03, 133.13, 134.21, 137.47, 146.58, 147.78, 155.50, 176.64; MS:
þ
m/z ¼ 375.28[M] . Anal.Calcd for C H N O S: C, 67.18; H, 4.56; N, 11.19. Found: C,
2
1
17 3 2
67.19; H, 4.55; N, 11.05.
Acknowledgements
This study was supported by Faculty of Women’s for Arts, Science and Education, Ain
Shams University.
References
[
1] Gomha, S. M.; Hassaneen, H. M. Synthesis and Antimicrobial Activity of Some New
Pyrazoles, Fused Pyrazolo [3,4-d]-Pyrimidine and 1,2-Dihydroimidazo-[2,1-c][1,2,4]
Triazin-6-One Derivatives. Molecules 2011, 16, 6549–6560. DOI: 10.3390/
molecules16086549.
[
[
[
2] Gomha, S.; Khalil, K.; Abdel-Aziz, H.; Abdalla, M. Synthesis and Anti-Hypertensive
a-Blocking Activity Evaluation of Thiazole Derivatives Bearing Pyrazole Moiety.
Heterocycles 2015, 91, 1763–1773. DOI: 10.3987/COM-15-13290.
3] Abdalla, M.; Gomha, S.; Abd EL-Aziz, M.; Serag, N. Synthesis and Evaluation of Some
Novel Thiazoles and 1, 3-Thiazines as Potent Agents against the Rabies Virus. Turk. J.
Chem. 2016, 40, 441–453. DOI: 10.3906/kim-1506-13.
4] Gomha, S. M.; Riyadh, S. M.; Mahmmoud, E. A.; Elaasser, M. M. Synthesis and
Anticancer Activities of Thiazoles, 1, 3-Thiazines, and Thiazolidine Using Chitosan-
Grafted-Poly (Vinylpyridine) as Basic Catalyst. Heterocycles 2015, 91, 1227–1243.
5] Du, L.-H.; Wang, Y.-G. A Rapid and Efficient Synthesis of Benzimidazoles Using
Hypervalent Iodine as Oxidant. Synthesis 2007, 2007, 675–678. DOI: 10.1055/s-2007-965922.
6] Rida, S. M.; Ashour, F. A.; El-Hawash, S. A.; ElSemary, M. M.; Badr, M. H.; Shalaby, M. A.
Synthesis of Some Novel Benzoxazole Derivatives as Anticancer, Anti-HIV-1 and Antimicrobial
Agents. Eur. J. Med. Chem. 2005, 40, 949–959. DOI: 10.1016/j.ejmech.2005.03.023.
7] Wu, C.-C.; Wang, T.-W.; Wang, W.-Y.; Hsieh, P.-W.; Wu, Y.-C. 2-(2-Br-Phenyl)-8-
Methoxy-Benzoxazinone (HPW-RX2), a Direct Thrombin Inhibitor with a Suppressive
Effect on Thromboxane Formation in Platelets. Eur. J. Pharmacol. 2005, 527, 37–43. DOI:
[
[
[
10.1016/j.ejphar.2005.10.023.
[
8] Palmer, J. T.; Hirschbein, B. L.; Cheung, H.; McCarter, J.; Janc, J. W.; Yu, Z. W.;
Wesolowski, G. Keto-1,3,4-Oxadiazoles as Cathepsin K Inhibitors. Bioorg. Med. Chem.
Lett. 2006, 16, 2909–2914. DOI: 10.1016/j.bmcl.2006.03.001.
[
9] Mishra, V. R.; Ghanavatkar, C. W.; Mali, S. N.; Qureshi, S. I.; Chaudhari, H. K.; Sekar, N.
Design, Synthesis, Antimicrobial Activity and Computational Studies of Novel Azo Linked
Substituted Benzimidazole, Benzoxazole and Benzothiazole Derivatives. Comput. Biol.
Chem. 2019, 78, 330–337. DOI: 10.1016/j.compbiolchem.2019.01.003.
[
10] Mathew, A.; Thamban, C. Irrigation Efficiency in Coconut Gardens-A Comparative
Analysis of Different Systems of Irrigation. J. Plant. Crops (India) 2011, 39, 48–56.
[
11] Lisovenko, N. Y.; Nasibullina, E.; Dmitriev, M. Simple Synthesis of 2-[5-Substituted-4-
(
5
Trichloroacetyl)-1H-Pyrazole-3-Carbonyloxy] Benzoic Acids. Russ. Chem. Bull. 2019, 68,
78–582. DOI: 10.1007/s11172-019-2457-8.

V
R
SYNTHETIC COMMUNICATIONS
11
[
[
[
12] Bharti, R.; Kumari, P.; Parvin, T.; Choudhury, L. H. Recent Advances of
Aminopyrimidines in Multicomponent Reactions. Curr. Org. Chem. 2018, 22, 417–445.
DOI: 10.2174/1385272822666171212152406.
13] Manayi, A.; Nabavi, S. M.; Setzer, W. N.; Jafari, S. Piperine as a Potential Anti-Cancer
Agent: A Review on Preclinical Studies. Curr. Med. Chem. 2019, 25, 4918. DOI: 10.2174/
0929867324666170523120656.
14] Gouhar, R. S.; Ewies, E. F.; El-Shehry, M. F.; Shaheen, M. N.; Ibrahim, E. M. M. Synthesis
and Utility of a, b-Unsaturated Ketone Bearing Naphthalene and Benzofuran Rings in the
Synthesis of Some N-Heterocycles with Their Antiviral and Antitumor Activity
Evaluation. J. Heterocyclic Chem. 2018, 55, 2368–2380. DOI: 10.1002/jhet.3301.
[
15] Rokade, Y.; Sayyed, R. Naphthalene Derivatives: A New Range of Antimicrobials with
High Therapeutic Value. Rasayan J. Chem. 2009, 2, 972–980.
[
16] Smit, F. J.; N’Da, D. D. Synthesis, in Vitro Antimalarial Activity and Cytotoxicity of Novel
4
1
-Aminoquinolinyl-Chalcone Amides. Bioorg. Med. Chem. 2014, 22, 1128–1138. DOI: 10.
016/j.bmc.2013.12.032.
[
17] Fairhurst, R. M.; Nayyar, G. M.; Breman, J. G.; Hallett, R.; Vennerstrom, J. L.; Duong, S.;
Ringwald, P.; Wellems, T. E.; Plowe, C. V.; Dondorp, A. M. Artemisinin-Resistant
Malaria: Research Challenges, Opportunities, and Public Health Implications. Am. J. Trop.
Med. Hyg. 2012, 87, 231–241. DOI: 10.4269/ajtmh.2012.12-0025.
[
[
[
18] Nassar, E.; El-Farargy, A.; Abdelrazek, F. Synthesis of Some Novel Cyclooctane-Fused-
Heterocycles with Anticipated Biological Activities. J. Heterocyclic Chem. 2015, 52,
1395–1399. DOI: 10.1002/jhet.2246.
19] Melani, F.; Cecchi, L.; Palazzino, G.; Filacchioni, G.; Martini, C.; Pennacchi, E.; Lucacchini,
A. Pyrazolo [4, 5-c] Quinolines. Synthesis and Specific Inhibition of Benzodiazepine
Receptor Binding. J. Med. Chem. 1986, 29, 291–295. DOI: 10.1021/jm00152a019.
20] Khode, S.; Maddi, V.; Aragade, P.; Palkar, M.; Ronad, P. K.; Mamledesai, S.;
Thippeswamy, A.; Satyanarayana, D. Synthesis and Pharmacological Evaluation of a Novel
Series of 5-(Substituted) Aryl-3-(3-Coumarinyl)-1-Phenyl-2-Pyrazolines as Novel Anti-
Inflammatory and Analgesic Agents. Eur. J. Med. Chem. 2009, 44, 1682–1688. DOI: 10.
1016/j.ejmech.2008.09.020.
[
21] Kumaraswamy, M.; Chandrashekhar, C.; Shivakumar, H.; Mathias, D. P.; Mahadevan, K.;
Vaidya, V. Synthesis and Activity Evaluation of 2-(1-Naphtho [2,1-b] Furan-2-yl-
Carbonyl)-3,5-Disubstituted-2,3-Dihydro-1H-Pyrazoles. Indian J. Pharm. Sci. 2008, 70,
7
15. DOI: 10.4103/0250-474X.49090.
_
[
22] Burmaoglu, S.; Yilmaz, A. O.; Polat, M. F.; Kaya, R.; Gulcin, I.; Algul, O. Synthesis and
Biological Evaluation of Novel Tris-Chalcones as Potent Carbonic Anhydrase,
Acetylcholinesterase, Butyrylcholinesterase and a-Glycosidase Inhibitors. Bioorg. Chem.
2
019, 85, 191–197. DOI: 10.1016/j.bioorg.2018.12.035.
[
[
[
[
[
23] Abdel-Aziz, H. A.; El-Zahabi, H. S.; Dawood, K. M. Microwave-Assisted Synthesis and in-
Vitro Anti-Tumor Activity of 1,3,4-Triaryl-5-N-Arylpyrazole-Carboxamides. Eur. J. Med.
Chem. 2010, 45, 2427–2432. DOI: 10.1016/j.ejmech.2010.02.026.
24] Karegoudar, P.; Karthikeyan, M. S.; Prasad, D. J.; Mahalinga, M.; Holla, B. S.; Kumari,
N. S. Synthesis of Some Novel 2,4-Disubstituted Thiazoles as Possible Antimicrobial
Agents. Eur. J. Med. Chem. 2008, 43, 261–267. DOI: 10.1016/j.ejmech.2007.03.014.
25] Gomha, S. M.; Kheder, N. A.; Abdelaziz, M. R.; Mabkhot, Y. N.; Alhajoj, A. M. A Facile
Synthesis and Anticancer Activity of Some Novel Thiazoles Carrying 1,3,4-Thiadiazole
Moiety. Chem. Cent. J. 2017, 11, 25. DOI: 10.1186/s13065-017-0255-7.
26] Gomha, S. M.; Abdel-Aziz, H. A. Synthesis of New Heterocycles Derived from 3-(3-
Methyl-1H-Indol-2-yl)-3-Oxopropanenitrile as Potent Antifungal Agents. Bull. Korean
Chem. Soc. 2012, 33, 2985–2990. DOI: 10.5012/bkcs.2012.33.9.2985.
27] Kheder, N. A.; Riyadh, S. M.; Asiry, A. M. Azoles and Bis-Azoles: Synthesis and Biological
Evaluation as Antimicrobial and Anti-Cancer Agents. Chem. Pharm. Bull. 2013, 61,
504–510. DOI: 10.1248//cpb.c12-00939.

1
2
E. MANSOUR ET AL.
[
28] Kumar, P.; Chandak, N.; Kaushik, P.; Sharma, C.; Kaushik, D.; Aneja, K. R.; Sharma, P. K.
Synthesis and Biological Evaluation of Some Pyrazole Derivatives as Anti-
Inflammatory–Antibacterial Agents. Med. Chem. Res. 2012, 21, 3396–3405. DOI: 10.1007/
s00044-011-9853-4.
[
[
[
29] Shiradkar, M.; Kumar, G. V. S.; Dasari, V.; Tatikonda, S.; Akula, K. C.; Shah, R. Clubbed
Triazoles: A Novel Approach to Antitubercular Drugs. Eur. J. Med. Chem. 2007, 42,
807–816. DOI: 10.1016/j.ejmech.2006.12.001.
30] Gomha, S. M.; Khalil, K. D. A Convenient Ultrasound-Promoted Synthesis of Some New
Thiazole Derivatives Bearing a Coumarin Nucleus and Their Cytotoxic Activity. Molecules
2
012, 17, 9335–9347. DOI: 10.3390/molecules17089335.
31] Gomha, S. M.; Salah, T. A.; Abdelhamid, A. O. Synthesis, Characterization, and
Pharmacological Evaluation of Some Novel Thiadiazoles and Thiazoles Incorporating
Pyrazole Moiety as Anticancer Agents. Monatsh. Chem. 2015, 146, 149–158. DOI: 10.
1007/s00706-014-1303-9.
[
32] Gomha, S. M.; Riyadh, S. M.; Abbas, I. M.; Bauomi, M. A. Synthetic Utility of Ethylidene
Thiosemicarbazide: synthesis and Anti-Cancer Activity of 1,3-Thiazines and Thiazoles
with Imidazole Moiety. Heterocycles 2013, 87, e356.
[
33] Gomha, S. M.; Abdelaziz, M. R.; Kheder, N. A.; Abdel-Aziz, H. M.; Alterary, S.; Mabkhot,
Y. N. A Facile Access and Evaluation of Some Novel Thiazole and 1, 3, 4-Thiadiazole
Derivatives Incorporating Thiazole Moiety as Potent Anticancer Agents. Chem. Cent. J.
2
017, 11, 105. DOI: 10.1186/s13065-017-0335-8.
[
34] Abdel-Wahab, B. F.; Abdel-Aziz, H. A.; Ahmed, E. M. Synthesis and Antimicrobial
Evaluation of 1-(Benzofuran-2-yl)-4-Nitro-3-Arylbutan-1-Ones and 3-(Benzofuran-2-yl)-4,
5-Dihydro-5-Aryl-1-[4-(Aryl)-1, 3-Thiazol-2-yl]-1H-Pyrazoles. Eur. J. Med. Chem. 2009,
4
4, 2632–2635. DOI: 10.1016/j.ejmech.2008.09.029.
[
[
[
35] Abdelhamid, A. O.; Abdel-Riheem, N. A.; El-Idreesy, T. T.; Rashdan, H. R. M. Synthesis of
-Arylazothiazoles, Pyridines and Thieno [2, 3-b] Pyridines Derivatives Containing 1,2,3-
Triazole Moiety. Eur. J. Chem. 2012, 3, 322–331. DOI: 10.5155/eurjchem.3.3.322-331.629.
36] Ahmad, S.; Abdelriheem, N. A.; Abdelhamid, A. Cycloketones as Precursor for
Convenient Synthesis of Azolopyrimidines and 5-Arylazothiazoles. Eur. Bull. Chem. 2014,
5
3
, 1038–1045.
37] George, R. F.; Samir, E. M.; Abdelhamed, M. N.; Abdel-Aziz, H. A.; Abbas, S. E. Synthesis
and Anti-Proliferative Activity of Some New Quinoline Based 4,5-Dihydropyrazoles and
Their Thiazole Hybrids as EGFR Inhibitors. Bioorg. Chem. 2019, 83, 186–197. DOI: 10.
1016/j.bioorg.2018.10.038.
[
38] El Sayed, M. T.; El-Sharief, M. A. M. S.; Zarie, E. S.; Morsy, N. M.; Elsheakh, A. R.; Nayel,
M.; Voronkov, A.; Berishvili, V.; Sabry, N. M.; Hassan, G. S.; Abdel-Aziz, H. A. Design,
Synthesis, Anti-Inflammatory Antitumor Activities, Molecular Modeling and Molecular
V
R
Dynamics Simulations of Potential Naprosyn Analogs as COX-1 and/or COX-2
Inhibitors. Bioorg. Chem. 2018, 76, 188–201. DOI: 10.1016/j.bioorg.2017.11.002.
[
[
[
39] Nadeem, S.; Rauf, M. K.; Bolte, M.; Ahmad, S.; Tirmizi, S. A.; Asma, M.; Hameed, A.
Synthesis, Characterization and Antibacterial Activity of Palladium (II) Bromide
Complexes of Thioamides; X-Ray Structure of [Pd (Tetramethylthiourea) 4] Br 2.
Transition Met. Chem. 2010, 35, 555–561. DOI: 10.1007/s11243-010-9363-0.
40] Ahmad, S.; R u€ ffer, T.; Lang, H.; Nadeem, S.; Tirmizi, S.; Saleem, M.; Anwar, A. Synthesis,
Crystal Structure, and Antimicrobial Studies of Trans-[Pd(PPh3)2(Imidazolidine-2-
ST 1h 0i o7 0n 3e 2) 28 ]4C1 l02 0ꢄ7 30 . 05 7H9 .2 O. Russ. J. Coord. Chem. 2010, 36, 520–524. DOI: 10.1134/
41] Abdel-Aziz, H. A.; Mekawey, A. A.; Dawood, K. M. Convenient Synthesis and
Antimicrobial Evaluation of Some Novel 2-Substituted-3-Methylbenzofuran Derivatives.
Eur. J. Med. Chem. 2009, 44, 3637–3644. DOI: 10.1016/j.ejmech.2009.02.020.