Synthesis of some novel pyrazoline-thiazole hybrids and their antimicrobial activities

Article abstract of DOI:10.1002/jhet.3698

A series of novel thiazolyl pyrazolines 7a-h, 9a-f, and 11a-f have been synthesized by the reaction of thioamide derivatives 5a,b with 1-aryl-2-bromoethanones 6a-d, chloroacetones 8a-c, and hydrazonoyl chlorides 10a-c. Additionally, pyrazoles 15a-c and 20 were prepared starting from enaminone 13. These newly synthesized compounds were screened for their in vitro antibacterial activity against four bacterial species. Compound 11b showed a moderate activity against Klebsiella pneumoniae. Compounds 7c and 11c revealed a moderate activity against Pseudomonas aeruginosa. In addition, the antifungal activity of the newly synthesized compounds was determined against five fungal strains. Compounds 7e, 7g, and 11e showed a good activity against Aspergillus flavus and Penicillium expansum.

Full text of DOI:10.1002/jhet.3698

Received: 6 December 2018
DOI: 10.1002/jhet.3698
Revised: 1 August 2019
Accepted: 12 August 2019
A R T I C L E
Synthesis of some novel pyrazoline‐thiazole hybrids and
their antimicrobial activities
1
1
1
2
Doaa M. Masoud | Rasha A. Azzam
| Fatma Hamdy | Amal A.I. Mekawey |
3
Hatem A. Abdel‐Aziz
1
Chemistry Department, Faculty of
Abstract
Science, Helwan University, Cairo, Egypt
2
A series of novel thiazolyl pyrazolines 7a‐h, 9a‐f, and 11a‐f have been synthe-
sized by the reaction of thioamide derivatives 5a,b with 1‐aryl‐2‐
bromoethanones 6a‐d, chloroacetones 8a‐c, and hydrazonoyl chlorides 10a‐c.
Additionally, pyrazoles 15a‐c and 20 were prepared starting from enaminone
Regional Center of Mycology and
Biotechnology, Al‐Azhar University,
Cairo, Egypt
3
Department of Applied Organic
Chemistry, National Research Centre,
Giza, Egypt
13. These newly synthesized compounds were screened for their in vitro anti-
bacterial activity against four bacterial species. Compound 11b showed a mod-
erate activity against Klebsiella pneumoniae. Compounds 7c and 11c revealed a
moderate activity against Pseudomonas aeruginosa. In addition, the antifungal
activity of the newly synthesized compounds was determined against five fun-
gal strains. Compounds 7e, 7g, and 11e showed a good activity against Asper-
gillus flavus and Penicillium expansum.
Correspondence
Hatem A. Abdel‐Aziz, Department of
Applied Organic Chemistry, National
Research Centre, P.O. Box 12622, Dokki,
Giza, Egypt.
Email: hatem_741@yahoo.com
1
| INTRODUCTION
their biological activity; however, the presence of N─N
heterocycles is low because of the difficult construction
[
30,31]
Recently, the dramatic increase in bacterial and fungal
infections has been reported; therefore, the treatment of
these infectious diseases is considered a great challenge for
of this bond by living organism.
Moreover, thiazole derivatives showed a broad spec-
trum of biological activity, they have been reported as
anticonvulsant, antibacterial, antifungal, antiviral, and
anticancer agents. Recently, some thiazoles were discov-
[1,2]
researchers.
For that reason, there is an urgent need to
discover new effective antimicrobial agents. In addition,
the designing of these agents to treat resistant bacteria
becomes one of the most important areas in the antimicro-
bial research. Pyrazole, five‐member heterocyclic ring with
two adjacent nitrogen atoms, has gained a great attention
[32–36]
ered as new inhibitors of bacterial DNA gyrase B.
Thiazoles have been also used in the treatment of aller-
[
37]
gies.
In the light of previous data and in continuation
of our interest in the synthesis of new biologically active
[
3]
[38–43]
in pharmaceutical and chemical industries. A large num-
ber of pyrazoles showed various biological activities such as
heterocycles,
in this study, we aimed to synthesize
certain pyrazoline derivatives incorporating thiazole moi-
ety to evaluate their antimicrobial potency.
[
4,5]
[6]
[7]
[8–
anticancer,
antihistaminic, pesticidal, antifungal,
10]
[11]
[12]
anti‐rheumatoid arthritis,
anticonvulsant,
antide-
antituber-
[
13]
[14,15]
[16,17]
pressant,
antipyretic,
antibacterial,
[
18]
[19]
[20]
culosis, antiviral, and anti‐inflammatory activities.
2 | RESULTS AND DISCUSSION
2.1 | Chemistry
In addition, pyrazolines revealed numerous pharmaco-
[
21–24]
logical
antiamoebic,
activities
including
antimicrobial,
[
25]
[26]
[27]
[28]
anti‐TB,
anti‐HIV,
anticancer,
[29]
antidepressant, and anticonvulsant activities.
N─N bond in pyrazoline moiety is the main factor in
The
The key intermediates 1,3‐bis(3,4‐dimethoxyphenyl)prop‐
2‐en‐1‐one (3a) and 3‐(benzo[d][1,3]dioxol‐5‐yl)‐1‐(3,4‐
J Heterocyclic Chem. 2019;1–12.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
MASOUD ET AL.
−
1
dimethoxyphenyl)prop‐2‐en‐1‐one (3b) were prepared by
the reaction of 1‐(3,4‐dimethoxyphenyl)ethan‐1‐one (1)
with 3,4‐dimethoxybenzaldehyde (2a) or benzo[d][1,3]
dioxole‐5‐carbaldehyde (2b) according to the reported
1605 cm and the band of C═O function at 1650 to
−
1
1724 cm .
Similarly, the treatment of carbothioamides 5a,b with
hydrazonoyl chlorides 10a‐c in absolute ethanol under
reflux for 4 hours gave the corresponding pyrazoline‐
thiazoles 11a‐f. The H NMR spectra of 11a‐f showed
[44]
methods.
Prop‐2‐en‐1‐ones 3a,b were reacted with
1
thiosemicarbazide (4), in the presence of sodium hydrox-
ide, to give 4,5‐dihydro‐1H‐pyrazole‐1‐carbothioamides
the appearance of the characteristic signals because of
the proton of methyl function around δ 2.61 to
2.66 ppm and the three signals of ABX protons of
pyrazoline ring in the regions of δ 3.32 to 3.43, 3.73 to
3.85, and 5.73 to 5.97 ppm (Scheme 2). Moreover, the
infrared (IR) spectra of 11a‐f showed the band of C═N
[45]
5
a,b.
These compounds were reacted with various 1‐
aryl‐2‐bromoethanones 6a‐d in absolute ethanol to yield
the newly prepared thiazoles 7a‐h. In the latter stepwise
synthesis of 7a‐h, the reaction took place via the nucleo-
philic sulfur atom of thioamide group to form
thiohydrazonates, which underwent cyclization to give
cyclic hydroxy intermediates, followed by dehydration to
yield the final products 7a‐h through Hantzsch thiazole
synthesis type. The structures of 7a‐h have been identified
by their analytical and spectral analyses (Scheme 1). For
−
1
function at 1600 to 1605 cm .
[46]
Furthermore, the reaction of enaminone 13
as
dipolarophile, with nitrilimines, produced in situ from
hydrazonoyl chlorides 10a‐c, was realized (Scheme 3).
The reaction of enaminone 13 with 10a‐c in toluene
and TEA gave the pyrazoles 15a‐c. In the IR spectra of
15a‐c, the bands of C═N and C═O groups appeared at
example, their IR spectra were free of NH function and
2
they revealed the appearance of C═N bands in the region
−
1
1
−1
1
of 1580 to 1630 cm . The H NMR spectra of 7a‐h showed
three signals of ABX pattern around δ 3.36, 3.95, and
1590 and 1689 cm , while their H NMR exhibited the
methoxy singlet signals at δ 3.83 to 3.97 ppm and the mul-
tiplet signals of aromatic protons at δ 7.02 to 8.91. The
reaction of 13 with 10a‐c proceeds via initial 1,3‐dipolar
cycloaddition of nitrilimine, derived from 10 to the
enaminone double bond to give the cyclo adducts 14a‐c,
which undergo in situ elimination of dimethylamine to
5
.65 ppm, each is integrated for one proton, and assigned
to HA, HB, HX proton of the pyrazoline ring.
In addition, pyrazoline‐thiazoles 9a‐f were obtained by
the treatment of thioamide derivatives 5a,b with
chloroacetones 8a‐c in refluxing ethanol on the basis of
1
[43]
their spectral data (Scheme 2). The H NMR spectra of
yield pyrazoles 15a‐c as final products.
9
c and 9f exhibited the D O‐exchangeable signal of NH
On the other hand, the pyridine derivative 17 was
synthesized by treatment of enaminone 13 with ethyl
acetoacetate (16) and ammonium acetate in glacial
acetic acid (Scheme 3). A mixture of the latter ester, ethyl
6‐(3,4‐dimethoxyphenyl)‐2‐methylnicotinate (17) and
2
proton at δ 8.75 and the signals of ABX pyrazoline pro-
tons. The IR spectra of 9c and 9f appeared the NH band
at 3248 and 3284 cm . The IR spectra of 9a‐f revealed
the band of C═N function in the region 1600 to
−
1
SCHEME 1 Synthesis of 4‐arylthiazolyl
pyrazolines 7a‐h.

MASOUD ET AL.
3
SCHEME 2 Synthesis of thiazolyl pyrazolines 9a‐f and 11a‐f.
SCHEME 3 Synthesis of pyrazoles 15a‐
c and 20.

4
MASOUD ET AL.
hydrazine hydrate was refluxed to give 6‐(3,4‐
moderate antibacterial activity against P. aeruginosa with
inhibition zones in the range of 1.2, 1.5, 1.7, 1.0, and
1.8 mm, respectively, when compared with that of refer-
ence drug Amoxicilline (IZ = 2.2 mm).
[
47]
dimethoxyphenyl)‐2‐methylnicotinohydrazide
(18)
(Scheme 3). Treatment of the hydrazide 18 with
2
1
‐(ethoxymethylene)malononitrile (19) gave 5‐amino‐
‐(6‐(3,4‐dimethoxyphenyl)‐2‐methylnicotinoyl)‐1H‐pyra‐
The antifungal activities of pyrazole derivatives 7a‐h,
9a‐f, 11a‐f, 15a‐c, and 20 are represented in Table 1.
From the data, it is observed that compounds
11a (R = R = ‐OCH , Ar = ph), 11b (R = R = ‐OCH ,
zole‐4‐carbonitrile (20) (Scheme 3). The IR spectrum of
pyrazole 20 showed the bands of NH and C≡N functions
2
−
1
at 3300 and 2220 cm in addition to the band of C═O at
696 cm . The H NMR of 20 showed a broad singlet sig-
1
3
1
3
−
1
1
1
Ar = 4‐Me‐C H ), and 11f (R‐R = ‐OCH O‐, Ar = 4‐Cl‐
6
4
1
2
nal (D O‐exchangeable) at 8.17 of amino group and a
C H ) revealed a moderate antifungal action against
6 4
2
multiplet signal at δ 7.08 to 8.00 because of aromatic
C. albicans with inhibition zones in the range of 1.3,
protons.
2.1, and 1.3 mm, respectively; whereas 7c (R = R =
1
‐
OCH , Ar = 4‐F‐C H ), 11b (R = R = ‐OCH , Ar =
3
6
4
1
3
4
‐Me‐C H ), 7 h (R‐R = ‐OCH O‐, Ar = 4‐Br‐C H ),
6
4
1
2
6
4
2.2 | Antimicrobial activity
and 7e (R‐R
1
= ‐OCH O‐, Ar = Ph) revealed a moderate
2
antifungal action against A. fumigatus with inhibition
zones 1.4, 1.2, 1.2, and 1.2 mm, respectively, when
compared with that of reference drug Griseofulvin
The antimicrobial activity of the newly synthesized com-
pounds was screened against two gram‐positive bacteria
Staphylococcus aureus and Bacillus subtilis, and two
gram‐negative bacterial species Klebsiella pneumoniae
and Pseudomonas aeruginosa, in addition to five
different fungal strains, namely, Candida albicans,
Syncephalastrum racemosum, Aspergillus fumigatus, Pen-
icillium expansum, and Aspergillus flavus.The antibacte-
rial activities of 7a‐h, 9a‐f, 11a‐f, 15a‐c, and 20 are
represented in Table 1. It is noticed that compounds
(IZ = 3.3 mm). Additionally, compounds 7e (R‐R =
1
‐OCH O‐, Ar = Ph), 7 g (R‐R = ‐OCH O‐, Ar = 4‐Cl‐
2
1
2
C H ), and 11e (R‐R = ‐OCH O‐, Ar = 4‐Me‐C H )
6
4
1
2
6
4
exhibited a good antifungal activities against A. flavus
with inhibition zones in the range of 2.3, 2.2, and
2.3 mm, respectively, when compared with IZ = 2.4 mm
of reference drug Griseofulvin.
1
1c (R = R = ‐OCH , Ar = 4‐Cl‐C H ), 11e (R‐R =
1
3
6
4
1
‐
OCH O‐, Ar = 4‐Me‐C H , 7e (R‐R = ‐OCH O‐,
2
6
4
1
2
2.3 | Minimum inhibitory concentration
Ar = Ph), 9e (R‐R = ‐OCH O‐, R = ‐OCH CH ), and
1
2
2
2
3
7
g (R‐R = ‐OCH O‐, Ar = 4‐Cl‐C H ) revealed a mod-
1
2
6
4
The results of minimum inhibitory concentration (MIC)
were reported in Table 2. Pyrazoline derivatives 11b and
erate antibacterial activity against B. subtilis with inhibi-
tion zones 1.5, 1.8, 1.5, 1.4, and 1.5 mm, respectively,
when compared with that of reference drug Amoxicilline
11c (MIC: 1.25 mg/mL) showed better results when com-
pared with 7g (MIC: 2.5 mg/mL) as revealed from their
MIC values.
(IZ = 3.5 mm); whereas compounds 7e (R‐R1
=
=
‐
‐
OCH O‐, Ar = C H ), 9e (R‐R = ‐OCH O‐, R2
OCH CH ), 7 g (R‐R = ‐OCH O‐, Ar = 4‐Cl‐C H ),
2
6
5
1
2
2
3
1
2
6
4
and 11c (R = R = ‐OCH , Ar = 4‐Cl‐C H ) exhibited a
1
3
6
4
moderate antibacterial activity against S. aureus with
inhibition zones in the range of 0.9 to 1.2 mm when
compared with that of reference drug Amoxicilline
3 | EXPERIMENTAL
3.1 | Chemistry
(
IZ = 2.3 mm), which showed the role of Cl on acquiring
their antibacterial activity. Additionally, compounds 11a
R = R = OCH , Ar = C H ), 9b (R = R = OCH ,
Melting points are measured on an SMP3 apparatus and
are uncorrected. IR spectra were recorded in KBr disc
on a Perkin‐Elmer 1650 spectrophotometer at Faculty of
(
1
3
6
5
1
3
R = OCH CH ), 11b (R = R = OCH , Ar = 4‐Me‐
2
2
3
1
3
1
C H ), and 15c (Ar = 4‐Cl‐C H ) exhibited a good anti-
Science, Cairo University. H NMR (400 MHz) and
6
4
6
4
13
bacterial activities against the gram‐negative bacteria
K. pneumoniae with inhibition zones in the range of
C NMR (100 MHz) spectra were measured in DMSO
or CDCl as solvent at room temperature using Bruker
3
1
.2, 1.3, 2.0, and 1.2 mm, respectively, when compared
Avance (III)‐400 MHz. Chemical shifts (δ) were reported
in ppm to scale calibrated for tetramethylsaline (TMS),
which is used as an internal standard at the Ain Shams
University, Cairo, Egypt. TLCs were performed on silica
gel–coated aluminum sheets (Type 60 GF254, Merck)
and UV lamp at λ 254 nm.
with that of reference drug Amoxicilline (IZ = 2.4 mm);
whereas compounds 11b (R = R = OCH , Ar = 4‐Me‐
C H ), 15c (Ar = 4‐Cl‐C H ), 7c (R = R = ‐OCH ,
Ar = 4‐Cl‐C H ), 9c (R = R = ‐OCH , R = ‐OCH CH ),
1
3
6
4
6
4
1
3
6
4
1
3
2
2
3
and 11c (R‐R = ‐OCH , Ar = 4‐Cl‐C H ) exhibited a
1
3
6
4

MASOUD ET AL.
5

6
MASOUD ET AL.
TABLE 2 MIC (mg/mL) of compounds 7g, 11b, and 11c
3
.4.2 | 2‐(3,5‐Bis(3,4‐dimethoxyphenyl)‐4,5‐
dihydro‐1H‐pyrazol‐1‐yl)‐4‐(4 fluorophenyl)
thiazole (7b)
Compounds
MIC (mg/mL)
1
1
7
1b
1c
g
1.25
1.25
2.5
−
1
White powder, m.p. 183‐185°C; yield 68%; IR ν /cm :
1597 (C=N); H NMR (DMSO‐d , 400 MHz) δ ppm:
max
1
6
3
.34–3.38 (m, 1H, H of pyrazole), 3.71 (s, 3H, OCH3),
Abbreviation: MIC, mimimum inhibitory concentration.
3.76 (s, 3H, OCH ) 3.83 (s, 3H, OCH ), 3.85 (s, 3H,
3
3
3.2 | Synthesis of chalcone derivatives 3a,b
OCH ), 3.97–4.04 (m, 1H, H of pyrazole), 5.56–5.61 (m,
3
1H, H of pyrazole), 6.88–6.94 (m, 2H, ArHs), 7.05–7.07
Into a mixture of 3,4‐dimethoxyacetophenone (1) (1.8 g,
0.0 mmol) and vertaldehyde (2a) or piperonal (2b)
10 mmol) in ethanol (95%, 20 mL), sodium hydroxide
(m, 2H, ArHs), 7.18–7.22 (m, 2H, ArHs), 7.29–7.37 (m,
13
1
(
3H, ArHs), 7.78–7.82 (m, 2H, ArHs); C NMR (DMSO‐
d , 100 MHz) δ ppm: 43.7, 56.0, 56.1, 64.5 (4OCH ),
6
3
solution (10%, 1 mL) was added. The mixture was stirred
for 2 hours and the formed solid was filtered off and
recrystallized from ethanol to yield 3a,b.
104.2, 109.5, 111.6, 112.1, 112.3, 115.7, 115.9, 119.0,
120.6, 124.2, 127.9, 134.7, 148.7, 149.0, 149.3, 149.8,
151.1, 153.5 (Ar‐C), 165.1 (C=N); Anal. Calcd. For
C H FN O S (519.59): C, 64.73; H, 5.04; N, 8.09%;
[44]
28
26
3 4
Found: C, 64.98; H, 5.15; N, 8.18%.
3
5
.3 | Synthesis of 4,5‐dihydro‐1H‐pyrazoles
a,b
3.4.3 | 2‐(3,5‐Bis(3,4‐dimethoxyphenyl)‐4,5‐
dihydro‐1H‐pyrazol‐1‐yl)‐4‐(4‐chlorophenyl)
thiazole (7c)
To a solution of NaOH (1 g, 25 mmol) and 3a,b (5 mmol)
in ethanol (25 mL), thiosemicarbazide (4) (5.5 mmol)
was added under stirring. The reaction mixture was
refluxed for 1 hour. The resulting solid, after cooling
and addition of ice, was filtered and washed with water
and ether. The solid was dried and recrystallized from
−
1
Yellow powder, m.p.177‐179°C; yield 62%; IR ν /cm :
max
−
1 1
1594 (C=N) cm ; H NMR (DMSO‐d , 400 MHz) δ ppm:
6
3.34–3.38 (m, 1H, H of pyrazole), 3.72 (s, 3H, OCH ), 3.76
3
(s, 3H, OCH ) 3.83 (s, 3H, OCH ), 3.85 (s, 3H, OCH ),
3
3
3
[45]
ethanol to give 5a,b.
3.96–4.04 (m, 1H, H of pyrazole), 5.57–5.59 (m, 1H, H of
pyrazole), 6.88–6.94 (m, 2H, ArHs), 7.04–7.06 (m, 2H,
ArHs), 7.31–7.33 (m, 1H, ArHs), 7.36–7.38 (m, 2H, ArHs),
7.42 (d, J = 10 Hz, 2H, ArHs), 7.77 (d, J = 9.2 Hz, 2H, ArHs);
Anal. Calcd. For: C H ClN O S (536.04): C, 62.74; H, 4.8;
3
.4 | General method for the synthesis of
compounds 7a‐h
28
26
3 4
N, 7.84%; Found: C, 62.92; H, 4.74; N, 7.97%.
A mixture of 5a,b (1.0 mmol) and bromoethanones 6a‐d
(
4
1.0 mmol) in absolute ethanol (30 mL) was refluxed for
hours and then cooled at room temperature. The prod-
3
.4.4 | 2‐(3,5‐Bis(3,4‐dimethoxyphenyl)‐4,5‐
dihydro‐1H‐pyrazol‐1‐yl)‐4‐(4‐
bromophenyl)thiazole (7d)
uct was seperated out by filtration, dried under vacuum,
and recrystallized from ethanol to give thiazolyl
pyrazolines 7a‐h.
−
1
Yellow powder, m.p. 184‐186°C; yield 75%; IR ν /cm :
max
1
1
3
4
6
597 (C=N); H NMR (CDCl ‐d , 400 MHz) δ ppm: 3.36–
.38 (m, 1H, H of pyrazole), 3.88–4.01 (m, 13H,
OCH + 1H of pyrazole), 5.68 (m, 1H, H of pyrazole),
.83–7.18 (m, 6H, ArHs), 7.29–7.59 (m, 5H, ArHs); Anal.
3
6
3
.4.1 | 2‐(3,5‐Bis(3,4‐dimethoxyphenyl)‐4,5‐
dihydro‐1H‐pyrazol‐1‐yl)‐4‐phenylthiazole
7a)
3
(
Calcd. For: C H BrN O S (580.50): C, 57.93; H, 4.51;
28
26
3 4
N, 7.84%; Found: C, 57.80; H, 4.35; N, 7.98%.
−
1
Yellow powder, m.p. 181‐183°C; yield 63%; IR ν /cm :
max
−
1 1
1
598 (C=N) cm ; H NMR (CDCl ‐d , 400 MHz) δ ppm:
3
6
3
.35–3.38 (m, 1H, H of pyrazole), 3.89 (s, 7H, 2 OCH + H
3.4.5 | 2‐(5‐(benzo[d][1,3]dioxol‐5‐yl)‐3‐
(3,4‐dimethoxyphenyl)‐4,5‐dihydro‐1H‐
pyrazol‐1‐yl)‐4‐phenylthiazole (7e)
3
of pyrazole), 3.96 (s, 3H, OCH ), 4.01 (s, 3H, OCH ), 5.61–
3
3
5
7
.62 (m, 1H, H of pyrazole), 6.84–6.91 (m, 5H, ArHs),
.02–7.73 (m, 7H, ArHs); Anal. Calcd. For C H N O S
28
27 3 4
−
1
(
5
501.60): C, 67.05; H, 5.43; N, 8.38%; Found: C, 67.27; H,
.51; N, 8.59%.
Yellow powder, m.p. 177‐178°C; yield 66%; IR ν /cm :
max
1
1599(C=N). H NMR (CDCl ‐d , 400 MHz) δ ppm: 3.28–
3
6

MASOUD ET AL.
7
3
.34 (m, 1H, H of pyrazole), 3.85–3.92 (m, 1H, H of
3.5 | General method for synthesis of
compounds 9a‐f
pyrazole), 3.95 (s, 3H, OCH ), 4.01 (s, 3H, OCH ), 5.68–
3
3
5
.73 (m, 1H, H of pyrazole), 5.94 (d, J = 3.6 Hz, 2H,
‐
OCH O‐), 6.80–7.00 (m, 5H, ArHs), 7.14–7.50 (m, 5H,
These compounds were prepared by the same method
employed for the synthesis of 7a‐h by using
chloroacetones 8a‐c instead of bromoethanones 6a‐d.
The product that was separated out, in each case, after
cooling was filtered, dried under vacuum, and recrystal-
lized from ethanol to give 9a‐f.
2
ArHs), 7.74–7.75 (m, 2H, ArHs); Anal. Calcd. For:
C H N O S (485.56): C, 66.79; H, 4.77; N, 8.65%; Found:
C, 66.91; H, 4.63; N, 8.85%.
27
23 3 4
3
.4.6 | 2‐(5‐(benzo[d][1,3]dioxol‐5‐yl)‐3‐
3,4‐dimethoxyphenyl)‐4,5‐dihydro‐1H‐
pyrazol‐1‐yl)‐4‐(4‐fluorophenyl)thiazole (7f)
(
3.5.1 | 1‐(2‐(3,5‐Bis(3,4‐dimethoxyphenyl)‐
4
,5‐dihydro‐1H‐pyrazol‐1‐yl)‐4‐
−
1
White powder, m.p. 163‐165°C; yield 63%; IR ν /cm :
methylthiazol‐5‐yl)ethan‐1‐one (9a)
max
1
1
2
3
5
2
5
601 (C=N); H NMR (DMSO‐d , 400 MHz) δ ppm:
6
−
1
.93–2‐95 (m, 1H, H of pyrazole), 3.81 (s, 3H, OCH3),
Yellow powder, m.p. 174‐176°C; yield 72%; IR ν /cm :
max
1
.84 (s, 3H, OCH ), 3.98–4.02 (m, 1H, H of pyrazole),
1610 (C=O), 1509 (C=N); H NMR (CDCl ‐d , 400 MHz)
3
3
6
.58–5.60 (m, 1H, H of pyrazole), 5.97 (d, J = 3.6 Hz,
δ ppm: 2.46 (s, 3H, COCH ), 2.53 (s, 3H, CH ), 3.33–3.37
3
3
H, ‐OCH O‐), 6.90–7.05 (m, 4H, ArHs), 7.19–7.36 (m,
(m, 1H, H of pyrazole), 3.87–4.01 (m, 13H, 4OCH + H
2
3
H, ArHs) 7.78 (m, 2H, ArHs); Anal. Calcd. For:
of pyrazole), 5.63–5.65 (m, 1H, H of pyrazole), 6.86–6.91
(m, 3H, ArHs), 7.14–7.52 (m, 3H, ArHs); Anal. Calcd.
For: C H N O S (481.57): C, 62.35; H, 5.65; N, 8.73%;
C H FN O S (503.55): C, 64.40; H, 4.40, N, 8.34%;
Found: C, 64.55; H, 4.57; N, 8.49%.
27
22
3 4
25
27 3 5
Found: C, 62.58; H, 5.86; N, 8.64%.
3
(
.4.7 | 2‐(5‐(benzo[d][1,3]dioxol‐5‐yl)‐3‐
3,4‐dimethoxyphenyl)‐4,5‐dihydro‐1H‐
pyrazol‐1‐yl)‐4‐(4‐chlorophenyl)thiazole
7g)
3.5.2 | Ethyl‐2‐(3,5‐bis(3,4‐
dimethoxyphenyl)‐4,5‐dihydro‐1H‐pyrazol‐
1‐yl)‐4‐methylthiazole‐5‐carboxylate (9b)
(
−
1
−1
Yellow powder, m.p. 187‐189°C; yield 72%; IR ν /cm :
Yellow powder, m.p. 195‐197°C; yield 79%; IR ν /cm :
max
max
1
1
1
3
3
598 (C=N); H NMR (DMSO‐d , 400 MHz) δ ppm: 3.33–
.35 (m, 1H, H of pyrazole), 3.82 (s, 3H, OCH ), 3.84 (s,
H, OCH ), 3.95–4.02 (m, 1H, H of pyrazole), 5.58–5.62
1701 (C=O), 1601 (C=N); H NMR (DMSO‐d , 400 MHz)
δ ppm: 1.25 (t, 3H, ‐OCH CH ), 2.37 (s, 3H, CH ), 3.35–
3.39 (m, 1H, H of pyrazole), 3.71 (s, 3H, OCH ), 3.73 (s,
6
6
3
2
3
3
3
3
(
m, 1H, H of pyrazole), 5.98 (d, J = 3.6 Hz, 2H, ‐OCH O‐),
3H, OCH ), 3.81 (s, 3H, OCH ), 3.84 (s, 3H, OCH ),
2
3
3
3
6
7
.90–6.91 (m, 3H, ArHs), 7.05 (d, J = 8.4 Hz, 1H, ArHs),
.30–7.44 (m, 5H, ArHs), 7.76 (d, J = 8.8 Hz, 2H, ArHs);
3.95–4.02 (m, 1H, H of pyrazole), 4.19 (q, J = 9 Hz, 2H,
OCH CH ), 5.62–5.63 (m, 1H, H of prazole), 6.68–6.72
2
3
Anal. Calcd. For: C H ClN O S (520.00): C, 62.36; H,
(m, 1H, ArHs), 6.88–6.92 (m, 2H, ArHs), 7.02–7.05 (d,
J = 9.2 Hz, 1H, ArH), 7.31–7.36 (m, 2H, ArHs); Anal.
Calcd. For: C H N O S (511.59): C, 61.04; H, 5.71; N,
27
22
3 4
4
.26; N, 8.08%; Found: C, 62.19; H, 4.38; N, 8.20%.
26
29 3 6
8
.21%; Found: C, 61.32; H, 5.54; N, 8.37%.
3
(
.4.8 | 2‐(5‐Bbenzo[d][1,3]dioxol‐5‐yl)‐3‐
3,4‐dimethoxyphenyl)‐4,5‐dihydro‐1H‐
pyrazol‐1‐yl)‐4‐(4‐bromophenyl)thiazole
7h)
3.5.3 | 2‐(3,5‐Bis(3,4‐dimethoxyphenyl)‐4,5‐
dihydro‐1H‐pyrazol‐1‐yl)‐4‐methyl‐N‐
phenylthiazole‐5‐carboxamide (9c)
(
−
1
Yellow powder, m.p. 206‐208°C; yield 73%; IR ν /cm :
max
1
−1
1
3
3
623 (C=N). H NMR (CDCl ‐d , 400 MHz) δ ppm: 3.29–
.33 (m, 1H, H of pyrazole), 3.90 (s, 3H, OCH ), 4.01 (s,
H, OCH ), 4.65 (m, 1H, H of pyrazole), 5.65 (m, 1H, H
White powder, m.p. 136‐138°C; yield 66%; IR ν /cm :
3248 (NH), 1630 (C=O), 1599 (C=N); H NMR (DMSO‐
d , 400 MHz) δ ppm: 2.38 (s, 3H, CH ), 3.02–3.07 (m,
3
6
max
1
3
3
6
3
of pyrazole), 5.96 (d, J = 3.6 Hz, 2H, ‐OCH O‐), 6.80–
1H, H of pyrazole), 3.73 (s, 3H, OCH ), 3.75 (s, 3H,
2
3
6
7
.97 (m, 5H, ArHs), 7.15–7.16 (d, J = 5.2 Hz, 1H, ArHs),
.29–7.48 (m, 3H, ArHs), 7.60–7.61 (d, J = 7.6 Hz, 2H,
OCH ), 3.83 (s, 3H, OCH ), 3.84 (s, 3H, OCH ), 3.96–
3
3
3
4.04 (m, 1H, H of pyrazole), 5.64–5.65 (m, 1H, H of
prazole), 6.73–6.74 (m, 1H, ArHs), 6.89–6.95 (m, 2H,
ArHs), 7.04–7.08 (m, 2H, ArHs), 7.30–7.36 (m, 4H, ArHs),
ArHs); Anal. Calcd. For: C H BrN O S (564.45): C,
5
27
22
3 4
7.45; H, 3.93; N, 7.44; Found: C, 57.27; H, 4.15; N, 7.61%.

8
MASOUD ET AL.
7
.64 (d, J = 6.4 Hz, 2H, ArHs), 9.66 (s, 1H, NHPh); Anal.
1H, H of prazole), 5.97 (s, 2H, ‐OCH O‐), 6.77–6.91 (m,
2
Calcd. For: C H N O S (558.65): C, 64.50; H, 5.41; N,
4H, ArHs), 7.13–7.38 (m, 5H, ArHs), 7.50 (s, 1H, NHPh),
7.54–7.56 (m, 2H, ArHs); Anal. calcd. For: C H N O S
30
30 4 5
1
0.03%; Found: C, 64.78; H, 5.31; N, 10.27%.
29
26 4 5
(
542.61): C, 64.19; H, 4.83; N, 10.33%; Found: C, 64.00;
H, 5.94; N, 10.60%.
3
.5.4 | 1‐(2‐(5‐(benzo[d][1,3]dioxol‐5‐yl)‐3‐
(
3,4‐dimethoxyphenyl)‐4,5‐dihydro‐1H‐
3.6 | General method for synthesis of
pyrazol‐1‐yl)‐4‐methylthiazol‐5‐yl)ethan‐1‐
compounds 11a‐f
one (9d)
To an equimolar mixture of 5a,b (1.0 mmol) and
hydrazonoyl chlorides 10a‐c (1.0 mmol) in toluene
−
1
Yellow powder, m.p. 200‐202°C; yield 76%; IR νmax/cm :
1
1
615 (C=O), 1565 (C=N); H NMR (CDCl ‐d , 400 MHz)
δ ppm: 2.45 (s, 3H, COCH ), 2.51 (s, 3H, CH ), 3.26–3.31
m, 1H, H of pyrazole), 3.87–3.94 (m, 4H, OCH + H of
pyrazole), 4.00 (s, 3H, OCH ), 5.60 (m, 1H, H of pyrazole),
.95 (s, 2H, ‐OCH O‐), 6.75–6.89 (m, 4H, ArHs), 7.12–7.14
m, 1H, ArHs), 7.50 (s, 1H, ArHs); Anal. Calcd. For:
3
6
(
30 mL), triethylamine (1.0 mmol) was added. The reac-
3
3
tion mixture was refluxed for 4 hours. The formed solid
was filtered, washed with ethanol, dried under vacuum,
and recrystallized from ethanol to afford the correspond-
ing hydrazones 11a‐f.
(
3
3
5
2
(
C H N O S (465.52): C, 61.92; H, 4.98; N, 9.03%; Found:
C, 62.19; H, 5.16; N, 9.15%.
24
23 3 5
3
.6.1 | 2‐(3,5‐Bis(3,4‐dimethoxyphenyl)‐4,5‐
dihydro‐1H‐pyrazol‐1‐yl)‐4‐methyl‐5‐
phenyldiazenyl)thiazole (11a)
(
3
.5.5 | Ethyl‐2‐(5‐(benzo[d][1,3]dioxol‐5‐
yl)‐3‐(3,4‐dimethoxyphenyl)‐4,5‐dihydro‐
H‐pyrazol‐1‐yl)‐4‐methylthiazole‐5‐carbox-
ylate (9e)
−
1
Red crystals, m.p. 240‐242°C; yield 66%; IR ν /cm :
max
1
1
602(C=N); H NMR (CDCl ‐d , 400 MHz) δ ppm: 2.66
s, 3H, CH ), 3.33–3.38 (m, 1H, H of pyrazole), 3.87–3.90
3
6
1
(
3
(
m, 7H, H of pyrazole & 2OCH ), 3.95 (s, 3H, OCH ),
3
3
−
1
4
6
7
.02 (s, 3H, OCH ), 5.70–5.81 (m, 1H, H of prazole),
.83–6.92 (m, 5H, ArHs), 7.15 (d, J = 8.8 Hz, 1H, ArHs),
Yellow powder, m.p. 165–167°C; yield 68%; IR νmax/cm :
3
1
1
714 (C=O), 1604 (C=N); H NMR (DMSO‐d , 400 MHz) δ
6
.30–7.55 (m, 5H, ArHs); Anal. calcd. For: C H N O S
ppm: 1.25 (t, J = 7.6 Hz, 3H, ‐OCH CH ), 2.38 (s, 3H, CH ),
29 29 5 4
2
3
3
(
543.64): C, 64.07; H, 5.38; N, 12.88%; Found: C, 64.29;
3
.33 (m, 1H, H of pyrazole), 3.82 (s, 3H, OCH ), 3.84 (s, 3H,
3
H, 5.29; N, 12.99%.
OCH ), 4.16–4.22 (m, 1H, H of pyrazole), 4.20 (q,
3
J = 7.6 Hz, 2H, ‐OCH CH ), 5.61–5.65 (m, 1H, H of
2
3
prazole), 5.99 (s, 2H, ‐OCH O‐), 6.72 (d, J = 6.4 Hz, 1H,
ArHs), 6.79 (s, 1H, ArH), 6.87 (d, J = 7.2 Hz, 1H, ArH),
2
3
.6.2 | 2‐(3,5‐Bis(3,4‐dimethoxyphenyl)‐4,5‐
dihydro‐1H‐pyrazol‐1‐yl)‐4‐methyl‐5‐(4‐
tolyldiazenyl)thiazole (11b)
7
.04 (d, J = 8.4 Hz, 1H, ArH), 7.31 (d, J = 8.4 Hz, 1H,
13
ArH), 7.36 (s, 1H, ArH); C NMR: (DMSO‐d , 100 MHz)
6
δ ppm: 14.8, 18.0 (2CH ), 56.0, 56.1 (2OCH ), 60.6, 63.2
−1
3
3
Red crystals, m.p. 243‐245°C; yield 77%; IR ν /cm :
1604 (C=N); H NMR (CDCl ‐d , 400 MHz) δ ppm: 2.41
max
(
2CH ), 101.6, 106.7, 108.8, 109.6, 110.6, 112.0, 119.6,
1
2
3
6
1
21.2, 123.5, 135.7, 147.1, 148.0, 149.3, 151.6, 155.9, 159.7
Ar‐C), 162.3 (C=O), 165.2 (C=N); Anal. calcd. For:
C H N O S (495.55): C, 60.59; H, 5.09; N, 8.48%; Found:
(
s, 3H, CH ), 2.61 (s, 3H, CH ), 3.32–3.36 (m, 1H, H of
3
3
(
pyrazole), 3.78–3.81 (m, 1H, H of pyrazole), 3.88 (s, 6H,
2OCH ), 3.95 (s, 3H, OCH ), 4.02 (s, 3H, OCH ), 5.72–
25
25 3 6
3
3
3
C, 60.81; H, 5.21; N, 8.24%.
5
7
.75 (m, 1H, H of pyrazole), 6.83–6.90 (m, 4H, ArHs),
.14–7.28 (m, 3H, ArHs); 7.54–7.68 (m, 3H, ArHs); Anal.
calcd. For: C H N O S (557.67): C, 64.61; H, 5.60; N,
30
31 5 4
3
.5.6 | 2‐(5‐(benzo[d][1,3]dioxol‐5‐yl)‐3‐
12.56%; Found: C, 64.89; H, 5.75; N, 12.43%.
(
3,4‐dimethoxyphenyl)‐4,5‐dihydro‐1H‐
pyrazol‐1‐yl)‐4‐methyl‐N‐phenylthiazole‐5‐
carboxamide (9f)
3.6.3 | 2‐(3,5‐Bis(3,4‐dimethoxyphenyl)‐4,5‐
dihydro‐1H‐pyrazol‐1‐yl)‐5‐((4‐
chlorophenyl)diazenyl)‐4‐methylthiazole
(11c)
−
1
White solid, m.p. 200‐201°C; yield 72%; IR νmax/cm :
1
3
284 (NH), 1633 (C=O), 1507 (C=N); H NMR (CDCl ‐
3
d , 400 MHz) δ ppm: 2.57 (s, 3H, CH ), 3.27–3.31 (m,
6
3
−
1
1
3
H, H of pyrazole), 3.79–3.85 (m, 1H, H of pyrazole),
.88 (s, 3H, OCH ), 3.95 (s, 3H, OCH ), 5.59–5.61 (m,
Red crystals, m.p. 233‐235°C; yield 75%; IR ν /cm :
max
1
1601 (C=N); H NMR (CDCl ‐d , 400 MHz) δ ppm: 2.66
3
3
3
6

MASOUD ET AL.
9
(
(
s, 3H, CH ), 3.37–3.43 (m, 1H, H of pyrazole), 3.78–3.81
OCH ), 5.70–5.78 (m, 1H, H of pyrazole), 5.97 (s, 2H,
3
3
m, 1H, H of pyrazole), 3.87 (s, 3H, OCH ), 3.89 (s, 3H,
‐OCH O‐), 6.78–6.90 (m, 4H, ArHs), 7.14–7.40 (m, 3H,
3
2
OCH ), 3.96 (s, 3H, OCH ), 4.02 (s, 3H, OCH ), 5.90–
ArHs), 7.53–7.71 (m, 3H, ArHs); Anal. calcd. For:
3
3
3
4
7
.96 (m, 1H, H of pyrazole), 6.83–6.95 (m, 4H, ArHs),
.19 (d, J = 8.4 Hz, 1H, ArHs), 7.40 (d, J = 8.8 Hz, 2H,
C H ClN O S (562.04): C, 59.84; H, 4.30; N, 12.46%;
Found: C, 60.05; H, 4.51; N, 12.32%.
28
24
5 4
ArHs), 7.50–7.56 (m, 1H, ArHs), 7.71 (d, J = 8.4 Hz, 1H,
1
3
ArHs); C NMR (DMSO‐d , 100 MHz) δ ppm: 19.6
(
1
1
6
3.7 | General method for synthesis of
compounds 15a‐c
CH ), 56.0, 56.1 (4OCH ), 110.7, 112.3, 112.4, 117.9,
3 3
23.3, 129.8, 133.3, 133.4, 140.7, 148.8, 149.3, 151.5,
51.9, 157.8, 159.9, 160.0 (Ar‐C), 165.7 (C=O); Anal.
[
46]
To an equimolar mixture of enaminone 13
(0.235 g,
calcd. For: C H ClN O S (578.08): C, 60.25; H, 4.88; N,
1.0 mmol) and the appropriate hydrozonoyl chloride
29
28
5 4
1
2.12%; Found: C, 60.58; H, 4.69; N, 12.35%.
10a‐c (1.0 mmol) in toluene (50 mL), triethylamine
(
2.0 mmol) was added and the mixture was refluxed for
8
hours. The precipitated solid was filtered, washed with
3
.6.4 | 2‐(5‐(benzo[d][1,3]dioxol‐5‐yl)‐3‐
absolute ethanol, dried, and recrystallized from ethanol
to give the corresponding pyrazole derivatives 15a‐c.
(
3,4‐dimethoxyphenyl)‐4,5‐dihydro‐1H‐
pyrazol‐1‐yl)‐4‐methyl‐5‐(phenyldiazenyl)
thiazole (11d)
3
.7.1 | 1‐(4‐(3,4‐Dimethoxybenzoyl)‐1‐phe-
−
1
nyl‐1H‐pyrazol‐3‐yl)ethan‐1‐one (15a)
Red crystals, m.p. 212‐215°C; yield 74%; IR ν /cm :
max
1
1
603 (C=N); H NMR (CDCl3‐d , 400 MHz) δ ppm: 2.63
6
−1
White solid, m.p. 180‐182°C; yield 72%; IR ν /cm :
max
(s, 3H, CH ), 3.28–3.33 (m, 1H, H of pyrazole), 3.73–3.80
3
1
1689 (C=O), 1590 (C=N);
H
NMR (DMSO‐d6,
(m, 1H, H of pyrazole), 3.96 (s, 3H, OCH ), 4.03 (s, 3H,
3
400 MHz) δ ppm: 2.60 (s, 3H, COCH ), 3.83 (s, 3H,
3
OCH ), 5.71–5.77 (m, 1H, H of prazole), 5.96 (s, 2H,
3
OCH ), 3.85 (s, 3H, OCH ), 7.02–7.04 (d, J = 10 Hz, 1H,
ArHs), 7.12–7.27 (m, 1H, ArHs), 7.36–7.39 (d,
J = 9.2 Hz, 1H, ArHs), 7.46–7.62 (m, 4H, ArHs), 7.99–
3
3
‐OCH O‐), 6.77–6.91 (m, 4H, ArHs), 7.12–7.79 (m, 7H,
2
ArHs); Anal. calcd. For: C H N O S (527.60): C, 63.74;
H, 4.78; N, 13.27%; Found: C, 63.87; H, 4.99; N, 13.13%.
28
25 5 4
8
.01 (d, J = 7.2 Hz, 2H, ArHs); Anal. calcd. For:
C H N O (350.37): C, 68.56; H, 5.18; N, 8.00%; Found:
20
18 2 4
C, 68.79; H, 5.30; N, 7.88%.
3
.6.5 | 2‐(5‐(benzo[d][1,3]dioxol‐5‐yl)‐3‐
(
3,4‐dimethoxyphenyl)‐4,5‐dihydro‐1H‐
pyrazol‐1‐yl)‐4‐methyl‐5‐(4‐tolyldiazenyl)
3.7.2 | 1‐(4‐(3,4‐Dimethoxybenzoyl)‐1‐(4‐
thiazole (11e)
tolyl)‐1H‐pyrazol‐3‐yl)ethan‐1‐one (15b)
−
1
Red crystals, m.p. 205‐207°C; yield 71%; IR ν /cm :
−1
max
White solid, m.p. 191‐193°C; yield 76%; IR ν /cm :
max
1
1
605 (C=N); H NMR (CDCl ‐d , 400 MHz) δ ppm: 2.41
s, 3H, CH ), 2.62 (s, 3H, CH ), 3.26–3.32 (m, 1H, H of
pyrazole), 3.84–3.92 (m, 1H, H of pyrazole), 3.95 (s, 3H,
OCH ), 4.02 (s, 3H, OCH ), 5.70–5.71 (m, 1H, H of
pyrazole), 5.96 (s, 2H, ‐OCH O‐), 6.78–6.89 (m, 4H,
ArHs), 7.11–7.53 (m, 4H, ArHs), 7.67 (d, J = 8.4 Hz, 2H,
ArHs); Anal. calcd. For: C H N O S (541.63): C, 64.31;
H, 5.02; N, 12.93%; Found: C, 64.62; H, 4.86; N, 13.08%.
1
3
6
1685 (C=O), 1590 (C=N);
H
NMR (DMSO‐d6,
400 MHz) δ ppm: 2.39 (s, 3H, COCH ), 2.58 (s, 3H,
CH ), 3.83 (s, 3H, OCH ), 3.85 (s, 3H, OCH ), 7.03 (d,
J = 9.2 Hz, 1H, ArHs), 7.35–7.44 (m, 4H, ArHs), 7.88 (d,
J = 8.4 Hz, 2H, ArHs), 8.91 (s, 1H, ArHs); C NMR
DMSO‐d , 100 MHz) δ ppm: 21.0, 27.6 (2CH ), 56.0,
56.2 (2OCH ), 111.1, 119.8, 123.3, 125.5, 130.6, 130.7,
3
(
3
3
3
3
3
3
3
3
13
2
(
6
3
29
27
5
4
1
31.2, 136.9, 138.0, 149.2, 150.1 (Ar‐C), 153.9 (C=O),
88.3 (C=N), 193.1 (Ar‐C); Anal. calcd. For: C H N O
1
21
20 2 4
(
5
364.40): C, 69.22; H, 5.53; N, 7.69%; Found: C, 69.43; H,
.41; N, 7.85%.
3
(
.6.6 | 2‐(5‐(benzo[d][1,3]dioxol‐5‐yl)‐3‐
3,4‐dimethoxyphenyl)‐4,5‐dihydro‐1H‐
pyrazol‐1‐yl)‐5‐((4‐chlorophenyl)diazenyl)‐
‐methylthiazole (11f)
4
3.7.3 | 1‐(1‐(4‐Chlorophenyl)‐4‐(3,4‐
dimethoxybenzoyl)‐1H‐pyrazol‐3‐yl)Ethan‐
1‐one (15c)
−
1
Red crystals, m.p. 242‐244°C; yield 75%; IR ν /cm :
max
1
1
605 (C=N); H NMR (CDCl ‐d , 400 MHz) δ ppm: 2.62
3
6
−
1
(
(
s, 3H, CH ), 3.31–3.34 (m, 1H, H of pyrazole), 3.74–3.80
m, 1H, H of pyrazole), 3.95 (s, 3H, OCH ), 4.02 (s, 3H,
White solid, m.p. 213‐215°C; yield 72%; IR ν /cm :
1682 (C=O), 1588 (C=N);
3
max
1
H
NMR (CDCl3‐d6,
3

10
MASOUD ET AL.
4
00 MHz) δ ppm: 2.60 (s, 3H, COCH ), 3.90 (s, 3H,
3.11 | Antimicrobial activities
3.11.1 | Microorganisms
3
OCH ), 3.97 (s, 3H, OCH ), 6.84 (d, J = 10.8 Hz, 1H,
3
3
ArHs), 7.33 (d, J = 7.2 Hz, 1H, ArHs), 7.53 (d,
J = 8.4 Hz, 2H, ArHs), 7.61 (s, 1H, ArHs), 7.76 (d,
J = 8.4 Hz, 2H, ArHs), 8.15 (s, 1H, ArHs); Anal. calcd.
For: C H ClN O (384.82): C, 62.42; H, 4.45; N, 7.28%;
Nine clinical strains employed for this study include two
gram‐positive bacteria (S. aureus and B. subtilis), two
20
17
2 4
Found: C, 62.65; H, 4.33; N, 7.39%.
gram‐negative
bacteria
(K.
pneumoniae
and
P. aeruginosa), four filamentous fungi (A. fumigatus,
A. flavus, Syncephlastarum racemosum, and P. expansum)
and one yeast (C. albicans). All strains were provided
from culture collection of the Regional Center for Mycol-
ogy and Biotechnology (RCMB), Al‐Azhar University,
Cairo, Egypt.
3
.8 | Synthesis of ethyl 2‐methyl‐6‐(3,4‐
dimethoxyphenyl)nicotinate (17)
This compound was synthesized in 77% yield by the reac-
tion of enaminone 13 with ethyl acetoacetate and ammo-
nium acetate in refluxing glacial acetic acid according to
3.11.2 | Antimicrobial assay
[47]
the reported method.
By diffusion agar technique, the antimicrobial activities
against the tested species were expressed as the measure-
ment of diameter of their inhibition zone. Hole‐plate dif-
fusion method was used; six equidistant (1 cm diameter)
holes were made using sterile cork borer in malt extract
agar and nutrient agar sterile plates (10 cm), which had
previously been seeded with tested fungal and bacterial
species. Holes were filled with 100 uL of three concentra-
tions 5, 2.5, and 1 mg/mL of each of the tested com-
pounds in ethyl acetate. Control holes were filled with
ethyl acetate solvent.
3
2
.9 | Synthesis of 6‐(3,4‐dimethoxyphenyl)‐
‐methylnicotinohydrazide (18)
A mixture of the ester 17 (0.301 g, 1 mmol) and hydrazine
hydrate (99%, 5 mL) was refluxed for 3 hours and then
left to cool. The formed solid was filtered and recrystal-
lized from dioxan to give hydrazide 18 in 85% yield and
[47]
m.p. 204‐205°C.
o
Plates were kept in a cooled incubator at 4 (±2) C for
o
1
hour and then incubated at 37 (±2) C for bacterial spe-
o
cies and incubated at 28 (±2) C for fungal species. Inhi-
bition zones were measured after 24 to 48 hours.
Amoxicilline was used as reference antibacterial drug
while Griseofulvin was used as reference antifungal
3
.10 | Synthesis of 5‐amino‐1‐(6‐(3,4‐
dimethoxyphenyl)‐2‐methylnicotinoyl)‐1H‐
pyrazole‐4‐carbonitrile (20)
[
48]
drug.
To a stirred solution of the hydrazide 18 (0.287 g,
1
.0 mmol) in ethanol (20 mL), 2‐(ethoxymethylene)
malononitrile (0.122 g, 1.0 mmol) and catalytic amount
of glacial acetic acid were added. The reaction mixture
was heated under reflux for 6 hours. The precipitate
formed was collected by filtration while hot, washed with
hot ethanol, dried, and crystallized from ethanol to give
compound 20 as white solid, m.p. 251‐253°C; yield 64%;
3.11.3 | MIC assays
Determination of MIC was performed by a serial dilution
technique. Appling ethyl acetate solvent of the synthe-
sized compounds started with a maximum concentration
of 500 mg/mL and then reduced it by successive twofold
dilutions. MIC of the sample determination was carried
out by inoculation of their serial dilutions with test organ-
isms and measurement of inhibition zones using diffu-
sion agar technique. MIC was expressed as the lowest
concentration inhibiting test
−
1
IR νmax/cm : 3300 (NH ), 2220 (CN), 1696 (C=O), 1632
2
1
(
C=N); H NMR (DMSO‐d , 400 MHz) δ ppm: 2.51 (s,
6
3
H, CH ), 3.84 (s, 3H, OCH ), 3.87 (s, 3H, OCH ), 7.09
3 3 3
(
(
d, J = 9.2 Hz, 1H, ArHs), 7.72–7.90 (m, 4H, ArHs), 7.99
d, J = 10 Hz, 1H, ArHs), 8.17 (s, 2H, NH2); C NMR
13
6
(
DMSO‐d , 100 MHz) δ ppm: 23.6 (CH ), 56.0 (2OCH ),
Microbial cells (70 mL, 10 CFU/mL) of each tested
6
3
3
7
1
1
3.2, 110.6, 112.2 (Ar‐C), 114.1 (CN), 116.4, 120.3, 130.8,
38.6, 145.1, 149.4, 150.9, 155.9, 157.4, 158.3 (Ar‐C),
65.7 (C=O), 170.5 (C=N); Anal. calcd. For: C H N O
17 5 3
pathogen were spread onto the nutrient agar plates. The
wells (6 mm diameter) were dug on the inoculated agar
plates and 100 μL of the newly synthesized target mole-
cule was suspended in DMSO at 200 mg/mL and subse-
quently was poured in the wells. The plates were
19
(363.38): C, 62.80; H, 4.72; N, 19.27%; Found: C, 62.98;
H, 4.92; N, 19.14%.

MASOUD ET AL.
11
allowed to stand at 4°C for 2 hours before incubation for
the diffusion. The plates were incubated at 37°C for
[12] F. Lepage, B. Hublot, Chem. Abstr. 1992, 116, 128917.
[13] D. M. Bailey, P. E. Hansen, A. G. Hlavac, E. R. Baizman, J.
2
4 hours except for the yeast strains which were incu-
Pearl, A. F. DeFelice, M. E. Feigenson, J. Med. Chem. 1985,
28, 256.
bated at 28°C. Incubation step was followed by measuring
the diameter of inhibition zone (IZ) in mm and three rep-
licates were averaged.
[14] R. H. Wiley, P. Wiley, Pyrazolones, Pyrazolidones and Deriva-
tives, John Wiley and sons, New York 1964 102.
[49]
[
15] D. David do CarmoMalvar, R. T. Ferreira, R. A. De Castro, L. L.
De Castro, A. C. C. Freitas, E. A. Costa, F. A. Vanderlinde, Life
Sci. 2014, 95, 81.
4
| CONCLUSIONS
[
[
[
[
16] S. Mert, R. Kasımoğulları, T. Iça, F. Çolak, A. Altun, S. Ok, Eur.
Herein, we have reported the synthesis and characteriza-
tion of a new series of thiazole‐based pyrazolines. Com-
pounds 11b, 7c, and 11c revealed a moderate activity
against bacterial strains K. pneumoniae and P. aeruginosa.
In addition, compounds 7e, 7g, and 11e showed a good
activity against the antifungal strains A. flavus and
P. expansum. These obtained results suggest that the
new pyrazolines bearing thiazole scaffold may be consid-
ered for further investigation in the design of new antimi-
crobial agents.
J. Med. Chem. 2014, 78, 86.
17] Y. R. Li, C. Li, J. C. Liu, M. Guo, T. Y. Zhang, L. P. Sun, H. R.
Piao, Bioorg. Med. Chem. Lett. 2015, 25, 5052.
18] S. P. Satasia, P. N. Kalaria, D. K. Raval, Org. Biomol. Chem.
2014, 12, 1751.
19] S. S. Jadav, N. B. Sinha, B. Pastorino, X. de Lamballerie, R.
Hilgenfeld, V. Jayaprakash, Lett. Drug Des. Discov. 2015, 12,
292.
[
[
20] A. A. Farag, M. F. El Shehry, S. Y. Abbas, A. A. Atrees, Y. A.
Ammar, Naturforsch 2015, 70, 519.
21] S. Kini, A. M. Gandhi, Indian J. Pharm. Sci. 2008, 70, 105.
ORCID
[22] E. M. Sharshira, N. M. Hamada, Molecules 2012, 17, 4962.
[
[
[
[
[
[
23] M. Baseer, F. L. Ansari, Z. Ashraf, Pak. J. Pharm. Sci. 2013, 26,
7.
24] S. Kumar, K. S. Meenakshi, P. Kumar, Med. Chem. Res. 2013,
2, 433.
Rasha A. Azzam https://orcid.org/0000-0002-6807-2110
6
Hatem A. Abdel‐Aziz
504
https://orcid.org/0000-0002-2606-
2
2
25] M. Abid, A. R. Bhat, F. Athar, A. Azam, Eur. J. Med. Chem.
2009, 44, 417.
REFERENCES AND NOTES
26] S. Sharma, P. K. Sharma, N. Kumar, R. Dudhe, Biomed.
Pharmacother 2011, 65, 244.
[
1] K. D. Olczak, M. Daszkiewicz, K. Slawinska, D. B. Baginska, D.
Gozdowski, P. Daszkiewicz, B. Fronc, K. Semczuk, J. Oral.
Pathol. Med. 2012, 41, 568.
27] S. U. F. Rizvi, H. L. Siddiqui, M. Johns, M. Detorio, R. F.
[
[
2] N. C. Desai, N. Bhatt, H. Somani, A. Trivedi, Eur. J. Med. Chem.
Schinazi, Med. Chem. Res. 2012, 21, 3741.
2
013, 67, 54.
28] (a) R. Bashir, S. Ovais, S. Yaseen, H. Hamid, M. S. Alam, M.
Samim, S. Singh, K. Javed, Bioorg. Med. Chem. Lett. 2011, 21,
4301; (b) A. S. Hassan, T. S. Hafez, M. M. Ali, T. K. Khatab,
Res. J. Pharm. Biol. Chem. Sci. 2016, 7, 417.
3] (a) S. Fustero, M. Sanchez‐Rosello, P. Barrio, A. Simon‐
Fuentes, Chem. Rev. 2011, 111, 6984; (b) A. Ansari, A. Ali, M.
Asif, New. J. Chem. 2017, 41, 16.
[
4] A. Balbi, M. Anzaldi, C. Maccio, C. Aiello, M. Mazzei, R.
Gangemi, P. Castagnola, M. Miele, C. Rosano, M. Viale, Eur.
J. Med. Chem. 2011, 46, 5293.
[29] Z. Ozdemir, H. B. Kandilci, B. Gumusel, U. Calis, A. A. Bilgin,
Eur. J. Med. Chem. 2007, 42, 373.
[30] N. M. Abunada, H. M. Hassaneen, N. G. Kandile, O. A.
[
5] A. Kamal, A. B. Shaik, N. Jain, C. Kishor, A. Nagabhushana, B.
Supriya, S. S. Chourasiya, Y. Suresh, K. R. Mishra, A.
Addlaganatta, Eur. J. Med. Chem. 2015, 92, 501.
Miqdad, Molecules 2008, 13, 1011.
[
31] M. R. Shaaban, A. S. Mayhoub, A. M. Farag, Expert. Opin. Ther.
Pat. 2012, 22, 253.
[
[
[
[
6] P. D. Mishra, S. Wahidullah, S. Y. Kamat, Indian. J. Chem. Soc.
[
[
32] M. A. Raslan, M. A. Khalil, Heteroatom Chem. 2003, 14, 114.
1
998, 37, 199.
33] J. Banothu, K. Vaarla, R. Bavantula, P. A. Crooks, Chin. Chem.
Lett. 2014, 25, 172.
7] F. Colliot, K. A. Kukorowski, D. W. Hawkins, D. A. Roberts,
Brighton Crop. Prot. Conf. Pests. Dis. 1992, 1, 29.
[
34] K. A. Milinkevich, L. Ye, M. Kurth, J. J. Comb. Chem. 2008, 10,
8] H. S. Chen, Z. M. Li, Y. F. Han, J. Agric. Food Chem. 2000, 48,
521.
5
312.
[
35] M. A. Gouda, M. A. Berghot, G. E. Abd El‐Ghani, A. M. Khalil,
Eur. J. Med. Chem. 2010, 45, 1338.
9] M. Ramiz, I. Hafiz, S. Abdel, M. Reheim, A. M. Abdel, H. M.
Gaber, J. Chin. Chem. 2012, 59, 72.
[
10] C. B. Vicentini, C. Romagnoli, E. Andreotti, D. Mares, J. Agric.
Food Chem. 2007, 55, 10331.
[36] P. C. Lv, K. R. Wang, Y. Yang, Bioorg. Med. Chem. Lett. 2009,
19, 6750.
[
11] M. Kurowski, A. Dunky, M. Geddawi, Eur. J. Clin. Pharmacol.
[37] A. Zablotskaya, I. Segal, A. Geronikaki, Eur. J. Med. Chem.
2013, 70, 846.
1
986, 31, 307.

12
MASOUD ET AL.
[
[
[
[
[
38] M. Fares, S. R. Abd El Hadi, R. A. Eladwy, A. A. Shoun, M. M.
Abdel‐Aziz, W. M. Eldehna, H. A. Abdel‐Aziz, P. A. Keller,
Org. Biomol. Chem. 2018, 16, 3389.
[45] A. Mathew, M. T. L. Sheeja, A. T. Kumar, K. Radha, Hygeia. J.
D. Med. 2011, 3, 48.
[
[
[
[
46] B. Al‐Saleh, M. M. Abdel‐Khalik, A. M. Eltoukhy, M. H.
39] W. M. Eldehnaa, A. Nocentini, S. T. Al‐Rashood, G. S. Hassan,
H. M. Alkahtani, A. A. Almehizia, A. M. Reda, H. A. Abdel‐
Aziz, C. T. Supuranb, Bioorg. Chem. 2018, 81, 425.
Elnagdi, J. Heterocyclic Chem. 2002, 39, 1035.
47] W. M. Eldehna, M. Fares, M. M. Abdel‐Aziz, H. A. Abdel Aziz,
Molecules 2015, 20, 8800.
40] W. M. Eldehnaa, R. I. Al‐Wabli, M. S. Almutairi, A. B. Keeton,
G. A. Piazza, H. A. Abdel‐Aziz, M. I. Attia, J. Enzyme Inhib.
Med. Chem. 2018, 33, 867.
48] H. A. Abdel‐Kader, S. R. Seddkey, Assiut. Vet. Med. J. 1995, 34,
6
7.
49] J. Fagbemi, L. Ferdinand, T. Adenipekun, Afr. J. Biotechnol.
009, 8, 1176.
41] M. T. El Sayed, H. A. Hussein, N. M. Elebiary, G. S. Hassan, S.
M. Elmessery, A. R. Elsheakh, M. Nayel, H. A. Abdel‐Aziz,
Bioorg. Chem. 2018, 78, 312.
2
42] H. A. Abdel‐Aziz, W. M. Eldehna, A. B. Keeton, G. A. Piazza,
A. A. Kadi, M. W. Attwa, A. S. Abdelhameed, M. I. Attia, Drug
Des. Develop. Ther. 2017, 11, 2333.
How to cite this article: Masoud DM, Azzam
RA, Hamdy F, Mekawey AAI, Abdel‐Aziz HA.
Synthesis of some novel pyrazoline‐thiazole hybrids
and their antimicrobial activities. J Heterocyclic
Chem. 2019;1–12. https://doi.org/10.1002/jhet.3698
[
43] M. A. Bhat, A. F. Ahmed, Z.‐H. Wen, M. A. Al‐Omar, H. A.
Abdel‐Aziz, Med. Chem. Res. 2017, 26, 1557.
[
44] M. T. L. Sheeja, A. Mathew, J. Varkey, Asian J. Pharm. 2012, 2,
2
57.