Synthetic Communications

An International Journal for Rapid Communication of Synthetic Organic

Chemistry

ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20

A facile synthesis of some novel thiazoles,

arylazothiazoles, and pyrazole linked to thiazolyl
coumarin as antibacterial agents

Anhar Abdel-Aziem, Basma Saad Baaiu, Awad Wanis Elbazzar & Fakhri
Elabbar

To cite this article: Anhar Abdel-Aziem, Basma Saad Baaiu, Awad Wanis Elbazzar & Fakhri
Elabbar (2020) A facile synthesis of some novel thiazoles, arylazothiazoles, and pyrazole linked
to thiazolyl coumarin as antibacterial agents, Synthetic Communications, 50:16, 2522-2530, DOI:
10.1080/00397911.2020.1782431

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SYNTHETIC COMMUNICATIONSV
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2020, VOL. 50, NO. 16, 2522–2530

https://doi.org/10.1080/00397911.2020.1782431

A facile synthesis of some novel thiazoles, arylazothiazoles,

and pyrazole linked to thiazolyl coumarin as
antibacterial agents
Anhar Abdel-Aziema , Basma Saad Baaiub, Awad Wanis Elbazzarb, and
Fakhri Elabbarb
a
Chemistry Department, Faculty of Science (Girls), Al-Azhar University, Nasr City, Cairo, Egypt;
b
Chemistry Department, Faculty of Science, Benghazi University, Benghazi, Libya

ABSTRACT ARTICLE HISTORY

5-bromosalicylaldehyde (1) was reacted with thiosemicarbazide to Received 10 April 2020
afford thiosemicarbazone derivative 2. The latter underwent cyclocon-
densation upon reaction with a-haloester, a-haloketone as well as
KEYWORDS
hydrazonoyl halides affording 1,3-thiazoles and arylazothiazoles 3-6,
Antibacterial activity;
respectively. On the other hand, pyrazolyl thiazolyl coumarin derivatives hydrazonoyl halides;
9a–c and 11a–c was obtained via reaction of hydrazinylthiazole 8 with pyrazolyl thiazolyl
acetylacetone, trifloroacetylacetone, ethyl acetoacetate and/or arylazoa- coumarin; thiazoles
cetylacetone 10a–c, respectively. Furthermore, thiazolotriazine derivative
12 was accomplished via reaction of 8 with ethyl 2-(2-phenylhydra-
zono)-2-chloroacetate. The structures of the newly prepared com-
pounds were elucidated by spectral data. Eleven of the newly
synthesized compounds were screened for their antibacterial activity.
The results indicated that, compounds 5a, 5b, 9a, 9c, 11b and 12
were strong active toward Gram-positive bacteria Enterococcus faecalis.
Compound 5a was strong active toward Gram-positive bacteria
Staphylococcus aureus. Moreover, compounds 9b, 11b, and 12 were
strong active toward Gram-negative bacteria Pseudomonas aeruginosa.

GRAPHICAL ABSTRACT

S N
NH
H
Br N N N
N N
R HN
S O
OH

S
Br CHO Br N NH2
N H
OH R= O O

Y
S N
N
R N X

CONTACT Anhar Abdel-Aziem [email protected] Chemistry Department, Faculty of Science (Girls), Al-Azhar
University, Nasr City, Cairo, Egypt.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC
 SYNTHETIC COMMUNICATIONSV
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Introduction
Thiazoles are considered an important class of heterocyclic compounds both biologically
and chemically. Previous studies have shown that thiazole based-compounds had effective
pharmacological importance with antimicrobial,[1–8] anti-inflammatory,[9–11] anticonvul-
sant,[12,13] anti-diabetic,[14–16] anti-HIV[17,18] antitumor,[19–26] and antioxidant[27,28] activ-
ities. Moreover, a variety of natural products contain thiazole scaffold such as thiamin
(vitamin B1) and thiamin pyrophosphate (TPP). Mycothiazole is isolated from sponge
spongia mycofijiensis and shows a selective activity against lung cancer.[29] The antibiotic
cystothiazole A was isolated from the myxobacterium culture by Sakagami et al. in 1998.
In particular, thiazoles are found in many powerful biologically active synthetic drugs
(Figure 1).
On the other hand, coumarins occur in the seeds, roots, and leaves of a large number
of plants,[30] fungi, bacteria, and marine sources.[31] Coumarins exhibit diverse bio-
logical activities as antimicrobial[32] anticancer and anti-inflammatory,[33–35] antioxi-
dant,[36] antiviral,[37] and anti-tubercular. [38] Warfarin is a coumarin derivative which
possesses anticoagulant properties, used to treat or prevent blood clots in veins.[39]
Furthermore, thiazolyl coumarin moiety has antimicrobial, anticancer, and antifibrotic
activities.[40–44] Also, pyrazolyl thiazolyl coumarin is antimicrobial agents.[45] Based on
the above facts, herein, we decided to prepare new thiazoles, molecular hybrids based
on pyrazole-thiazole-coumarin (PTC), and study their antibacterial activities.

Results and discussion

Thiazoles can be synthesized by Hantzsch thiazole synthesis which involves the inter-
action between a-haloketones or a-haloesters and thioamide. Herein, synthesis of thia-
zole was accomplished by condensation of 5-bromosalicylaldehyde (1) with
thiosemicarbazide in ethanol under reflux to furnish 1-(5-bromo-2-hydroxybenzylide-
ne)thiosemicarbazide (2).[46] The latter underwent Hantzsch reaction via cyclocondensa-
tion with ethyl chloroacetate in ethanol containing triethylamine under reflux affording
thiazolinone (3). Moreover, treatment of 2 with 6-bromo-3-(2-bromoacetyl)coumarin
under the same reaction conditions yielded thiazole derivative 4 (Scheme 1). The spec-
tral data for the synthesized compounds proved their chemical structures. The infrared
spectrum lakes the absorption peaks for NH2 and C¼S groups which indicate cycliza-
tion reaction. 1H NMR spectrum of compound 4 (DMSO-d6) as an example, revealed
signals at d 6.84 (d,1H, J ¼ 8 Hz), 7.33–7.45 (m, 2H), 7.72–7.78 (m, 2H), 8.08 (s, 1H),
8.25 (s, 1H), 8.46 (s, 1H), 8.52 (s, 1H, CH¼N), 10.49 (s, 1H, NH) and 12.25 ppm (s,
1H, OH). Besides, the aryl azothiazoles were obtained by the reaction of thiosemicarba-
zone 2 with hydrazonoyl halides. Thus, compound 2 was reacted with 2-oxo-N-phenyl-
propanehydrazonoyl chloride and 2-(2-phenylhydrazono)-2-chloro-1-phenyl ethanone in
ethanol containing triehylamine to give compounds 5a and 5b, correspondingly. The IR
spectrum of compound 5a displayed absorption peaks at 3444 and 3182 cm1 for OH
and NH groups, respectively. 1H NMR spectrum of compound 5a (DMSO-d6) displayed
singlet signal at d 2.23 ppm for methyl group and aromatic protons at 6.92–7.86 ppm, in
addition to, three singlet signals at 8.64, 10.47 and 10.96 ppm attributed to CH¼N, NH
and OH, respectively. Similarly, treatment of compound 2 with ethyl 2-(2-substituted
2524 A. ABDEL-AZIEM ET AL.

H S
N H O N
N S NH2 N O
S O H
O O O
Sulfathiazole Penicillin
(antimicrobial drug) (Antibiotic)
CN
S
H N
O OH H N N
F
S
O
N N
N S
F H N O O
Ravuconazole Meloxicam
(Antifungal) (Anti-inflammatory)

OCH3OCH3
N S

OCH3 S N
H3CO O
cystothiazole A
(Antibiotic)

Figure 1. Biologically active drugs containing thiazole.

H
Br N N
N O
S
OH
Br CHO 3

OH O
1 Cl
O
O Br
H
N NH2 CH2Br H
H2N H Br N N
Br N NH2 O O N
S N R
S S
OH
OH
2 4
R O Br
X
O R=
Cl N O O
N
O N HN
H
Cl

H H
Br N N Br N N
N O
N R
S S
OH OH
5a,b N N
6a,b N NH

a, X= H, b; X=Cl a, R = CH3; b, R = Ph

Scheme 1. Synthesis of thiazoles and arylazothiazoles 3–6.

 SYNTHETIC COMMUNICATIONSV
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S
Br N N
O NH
Br Br O O O
N N
12
H
O O O
7 N N
H H
N NH2 O
H2N Cl
S
S Y
O O S N
Br N NH2 Br N
N H N
X
O O O O
8 X= CH3, CF3, OC2H5
9a-c
10a-c
(CH3CO)2C=NNHAr 9a, Y= CH3; b, Y= CF3; c, Y= OH

S N
Br N N=N Ar
N
O O
11a-c
10,11: a, Ar = C6H5; b, Ar = 4-CH3C6H4; c, Ar = 4-FC6H4

Scheme 2. Synthesis of pyrazoles 9a-c and aryalazopyrazoles 11a–c.

phenylhydrazono)-2-chloroacetate under the same reaction conditions afforded phenyla-

zothiazolinone derivatives 6a and 6 b (Scheme 1). 1H NMR specrum of 6b (DMSO-d6)
displayed signals at d 6.92-6.97 (m, 2H), 7.25-7.33 (m, 3H þ NH), 7.47-7.50 (dd, 1H,
J ¼ 8Hz), 7.87 (s, 1H), 8.65(s, 1H, CH¼N), 10.48 (s,1H, NH), 12.25 (s, 1H, OH).
In view of our aim of building bioactive pyrazole-thiazole-coumarin (PTC) based
molecular hybrids, 6-bromo-3-acetylcoumarin[42] was prepared from the reaction of 5-
bromosalicylaldehyde with ethyl acetoacetate in the presence of piperidine as a catalyst. It
was subjected to bromination using Br2/AcOH to yield 6-bromo-3-(2-bromoacetyl)cou-
marin (7).[42,47] The latter underwent Hantzsch reaction with thiosemicarbazide in
ethanol under stirring at room temperature afforded 6-bromo-3-(2-hydrazinylthiazol-4-
yl)-2H-chromen-2-one (8). The target compounds 9a–c were accomplished via cyclocon-
densation of 8 with dicarbonyl compounds such as acetylacetone, trifloroacetylacetone
and/or ethyl acetoacetate in ethanol under reflux (Scheme 2). The spectroscopic analysis
of the prepared compounds indicated the absence of signals attributed to NHNH2 moiety,
which confirm the cyclization reaction. For example, 1H NMR spectrum of compound 9a
(DMSO-d6) revealed signals at d 2.19 (s, 3H, CH3), 2.72 (s, 3H, CH3), 6.21 (s, 1H, CH-
pyrazole), 6.98 (d, 1H, J ¼ 8 Hz), 7.69 (d, 1H, J ¼ 8 Hz), 8.10 (s, 1H), 8.14 (s, 1H), 8.63 (s,
1H). Similarly, compound 8 was reacted with arylazoacetylacetone 10a-c to give pyrazoles
11a–c, respectively. Finally, thiazolotriazine derivative 12 was accomplished via the reac-
tion of 8 with ethyl 2-(2-substituted phenylhydrazono)-2-chloroacetate.
2526 A. ABDEL-AZIEM ET AL.

Table 1. Response of various microorganisms to some synthesized compounds in vitro culture.

Mean of zone diameter, nearest whole mm.
Gram-positive bacteria Gram-negative bacteria
Organism Enterococcus faecalis Staphylococcus aureus Escherichia coli Pseudomonas aeruginosa
Conc. sample 1 mg/mL 1 mg/mL 1 mg/mL 1 mg/mL
3 I I I I
4 I I I I
5a H H I I
5b H I L I
6a I L I L
6b I I L I
9a H L I I
9b I I I H
9c H I I I
11b H I L H
12 H L I H
Control # H H H H
Calculate from 3 values. L: Low activity ¼ Mean of zone diameter 1/3 of mean zone diameter of control; I:
Intermediate activity ¼ Mean of zone diameter 2/3 of mean zone diameter of control; H: High activity ¼ Mean of
zone diameter >2/3 of mean zone diameter of control; #: Chloramphenicol in the case of Gram-positive bacteria,
Cephalothin in the case of Gram-negative bacteria.

Antibacterial activity
All the tested microorganisms were chosen based on their pathogenicity. The organisms
were tested against the activity of solutions with one concentration; 100 mg/ml and then
10 ml of preparation was dropped on disk of 6 mm in diameter and the concentrations
became 1 mg/disk. In the case of insoluble compounds, the compounds were suspended
in DMF and vortexed then processed. Chloramphencol was used as standard reference
in the case of Gram-negative bacteria, Cephalothin was used as standard reference in
the case of Gram-positive bacteria. The results were depicted in Table 1. The investiga-
tion of antibacterial screening data revealed that, compounds 5a, 5b, 9a, 9c, 11b, and
12 were strong active towards Gram-positive bacteria Enterococcus faecalis, while com-
pounds 3, 4, 6a, 6b, and 9b were intermediate active. All the tested compounds showed
intermediate activity towards Staphylococcus aureus except compound 5a which was
strongly active and compounds 6a, 9a, and 12 which was low active. For Gram-negative
bacteria, all the tested compounds showed intermediate to low activity except com-
pounds 9b, 11b, and 12 were strong active towards Pseudomonas aeruginosa.

Experimental section
All reagents and solvents were of commercial grade. Melting points were determined on
the digital melting point apparatus and were uncorrected. 1H and 13C NMR spectra
were measured with a Bruker Avance spectrometer (Bruker, Germany) at 400 and
101 MHz, respectively, using TMS as the internal standard. Hydrogen coupling patterns
were described as singlet (s), doublet (d), triplet (t), quartet (q) and multiplet (m).
Chemical shifts were defined as parts per million (ppm) relative to the solvent peak.
Elemental analyses were performed on CHNS-O analyzer (Perkin-Elmer, USA).
Hydrazonoyl halides[48–50] were prepared as previously reported.
 SYNTHETIC COMMUNICATIONSV
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Synthesis of thiazoles and arylazothiazoles 3-6

A mixture of thiosemicarbazone 2 (0.01 mol), ethyl chloroacetate, 6-bromo-3-(2-bro-
moacetyl)coumarin and/or hydrazonoyl halides (0.01 mole each) in ethanol containing
triethylamine was heated under reflux for 2 h. The precipitate that separated on hot was
filtered and recrystallized from dioxane yielding the desired products 3–6, respectively.

2-f2-[(5-Bromo-2-hydroxyphenyl)methylidene]hydrazinylg-1,3-thiazol-4(5H)-one (3)
White powder (dioxane); Yield 85%; m.p: 291–92  C; IR (KBr) cm1: 3429 broad (OH,
NH), 3028, 2962 (CH), 1716 (C¼O), 1643 (C¼N), 1593 (C¼C). Anal. calcd. for
C10H8BrN3O2S (314.16): C, 38.23; H, 2.57; Br, 25.43; N, 13.38; S, 10.21. Found: C, 38.
30; H, 2.48; Br, 25.49; N, 13.43; S, 10.30%.

6-Bromo-3-(2-(2-(5-bromo-2-hydroxybenzylidene)hydrazinyl)-thiazole-4-yl)-2H-
chromen-2-one (4)
Pale yellow powder (dioxane); Yield 89%; m.p: 275–76  C; 1H NMR: (400 MHz, DMSO-
d6, d, ppm): 6.84 (d,1H, J ¼ 8 Hz), 7.33–7.45 (m, 2H), 7.72–7.78 (m, 2H), 8.08 (s, 1H),
8.25 (s, 1H), 8.46 (s, 1H), 8.52 (s, 1H, CH¼N), 10.49 (s, 1H, NH), 12.25 (s, 1H, OH).
Anal. calcd. for C19H11Br2N3O3S(521.18): C, 43.79; H, 2.13; Br, 30.66; N, 8.06; S, 6.15.
Found: C, 43.72; H, 2.19; Br, 30.60; N, 8.12; S, 6.21%.

Biological screening
Antibacterial activity of the newly synthesized compounds was determined in vitro by
standardized disk – agar diffusion method.[51] Cultures of four bacterial species, namely,
Gram-positive bacteria: Enterococcus faecalis (ATCC 29212) and Staphylococcus aureus
(ATCC 25923), Gram-negative bacteria: Escherichia coli (ATCC 25922) and pseudo-
monas aeruginosa (ATCC 27853), were used to investigate the antibacterial activity of
the newly synthesized compounds.

Conclusions
In the present study, 1-(5-bromo-2-hydroxybenzylidene)thiosemicarbazide (2) was used
as a starting material for the synthesis of thiazoles and arylazothiazoles via reaction with
a-haloketones, a-haloesters and/or hydrazonoyl halides. Also, pyrazole-thiazole-couma-
rin (PTC) hybrid was prepared via reaction of 6-bromo-3-(2-hydrazinylthiazol-4-yl)-2H-
chromen-2-one (8) with dicarbonyl compounds. Eleven of the newly synthesized
compounds were screened for their antibacterial activity. The results revealed that com-
pounds 5a, 5b, 9a, 9c, 11b, and 12 were strong active towards Gram-positive bacteria
Enterococcus faecalis. Compound 5a was strongly active towards Gram-positive bacteria
Staphylococcus aureus. Whereas, compounds 9b, 11b, and 12 were strong active towards
Gram-negative bacteria Pseudomonas aeruginosa.
2528 A. ABDEL-AZIEM ET AL.

Disclosure statement
No potential conflict of interest was reported by the author(s).

ORCID
Anhar Abdel-Aziem http://orcid.org/0000-0002-3871-3183

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